Note: Descriptions are shown in the official language in which they were submitted.
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INDAZOLES, BENZOTHIAZOLES, BENZOISOTHIAZOLES,
BENZOISOXAZOLES, PYRAZOLOPYRIDINES,
ISOTHIAZOLOPYRIDINES, AND PREPARATION AND USES
THEREOF
This application claims the benefit of U.S. Provisional Application Serial No.
60/791,881, filed April 14, 2006, and U.S. Provisional Application Serial No.
60/719,552, filed September 23, 2005, the entire disclosure of which are
hereby
incorporated by reference.
This application is also related to U.S. Patent Application Serial No.
11/089,533,
filed March 25, 2005 (which claims the benefit of U. S. Provisional
Application Serial
No. 60/555,951, filed March 25, 2004, and U. S. Provisional Application Serial
No.
60/616,033, filed October 6,2004) and U. S. Patent Application Serial No.
10/669,645,
filed September 25, 2003 (which claims the benefit of U. S. Provisional
Applicatiorn
Serial No. 60/413,151, filed September 25, 2002, and U. S. Provisional
Application
Serial No. 60/448,469, filed February 21, 2003) the entire disclosures of each
of which
are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates generally to the field of ligands for nicotinic
acetylcholine receptors (nAChIZ), activation of nAChRs, and the treatment of
disease
conditions associated with defective or malfunctioning nicotinic acetylcholine
receptors,
especially of the brain. Further, this invention relates to novel compounds,
which act as
ligands for the a7 nAChR subtype, methods of preparing such compounds,
compositions
comprising such compounds, and methods of use thereof.
BACKGROUND OF THE INVENTION
There are two types of receptors for the neurotransmitter, acetylcholine:
musearinic
receptors and nicotinic receptors, based on the selectivity of action of
muscarine and
nicotine, respectively. Muscarinic receptors are G-protein coupled receptors.
Nicotinic
SUBSTITUTE SHEET (RULE 26)
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receptors are members of the ligand-gated ion channel family. When activated,
the
conductance of ions across the nicotinic ion channels increases.
Nicotinic alpha-7 receptor protein forms a homo-pentameric channel in vitro
that is
highly permeable to a variety of cations (e.g., Ca+'). Each nicotinic alpha-7
receptor has
four transmembrane domains, named Ml, M2, M3, and M4. The M2 domain has been
suggested to form the wall lining the channel. Sequence alignment shows that
nicotinic
alpha-7 is highly conserved during evolution. The M2 domain that lines the
channel is
identical in protein sequence from chicken to human. For discussions of the
alpha-7
receptor, see, e.g., Revah et al. (1991), Nature, 353, 846-849; Galzi et al.
(1992), Nature
359, 500-505; Fucile et al. (2000), PNAS 97(7), 3643-3648; Briggs et al.
(1999), Eur. J.
Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J.
Pharmacol.
290(3), 237-246.
The nicotinic alpha-7 receptor channel is expressed in various brain regions
and is
believed to be involved in many important biological processes in the central
nervous
system (CNS), including learning and memory. Nicotinic alpha-7 receptors are
localized on
both presynaptic and postsynaptic terminals and have been suggested to be
involved in
modulating synaptic transmission. It is therefore of interest to develop novel
compounds,
which act as ligands for the a7nACh receptor subtype, for the treatment of
disease
conditions associated with defective or malfunctioning nicotinic acetylcholine
receptors.
SUMMARY OF THE INVENTION
This invention relates to novel compounds, which act as ligands for the a7
nACh
receptor subtype, methods of preparing such compounds, compositions comprising
such
compounds, and methods of use thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds of Formulas I, II, III, or IV:
2
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N N N ki
R' Rf
X / R,/N-f X N R',N-~ N
A ' ' A A
(I) (II) (III) (IV)
wherein
A is
(a) N X~s/ ~ S
3 (b) ~7~ >RZ R5
XX4 N XXB N
9 13
X~I X14/ ~
(c) \
11 N or (d) 1 1 N
X X12 g X \Xi6 - O
5 X is O or S;
XI to X4 are each, independently, N, CH, CRI, or C-, wherein C- represents the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, Xl, X2, X3 and X4 are each CH or CR', and
group
A is attached at the 3-position to the remainder of the structure of formulas
(I),
(II), (III) or (IV), XI, X2 and X3 are each CH or CRI, X4 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV), XI, X2 and X4 are each CH or CR1, X3 is N, and group A is
attached
at the 3-position to the remainder of the structure of formulas (I), (II),
(III) or
(IV), or Xl, X3 and X4 are each CH or CR', X2 is N, and group A is attached at
the
3-position to the remainder of the structure of formulas (I), (11), (III) or
(IV));
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X5 to X8 are each, independently, N, CH, CR3, or C-, wherein C- represents the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, X5, X6, and X8 are each CH or CR3 and X7 is
C-
whereby group A is attached at its 5-position to the remainder of the
structure of
formulas (I), (II), (III) or (IV), or X5, X7, and X8 are each CH or CR3 and X6
is C-
whereby group A is attached at its 6-position to the remainder of the
structure of
formulas (I), (II), (III) or (IV));
X9 to X12 are each, independently, N, CH, CR4, or C-, wherein C- represents
the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, X9, Xlo, XI1 and X12 are each CH or CR4, and
group A is attached at the 3-position to the remainder of the structure of
formulas
(I), (II), (III) or (IV), X9, X10 and Xl 1 are each CH or CR4, X12 is N, and
group A
is attached at the 3-position to the remainder of the structure of formulas
(I), (II),
(III) or (IV), or X9, X10 and XIZ are each CH or CR4, XI1 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV), or X9, X" and X12 are each CH or CR4, Xlo is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV));
X13 to X16 are each, independently, N, CH, CR, or C-, wherein C- represents
the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, XI3, X14, Xls and X16 are each CH or CR, and
group A is attached at the 3-position to the remainder of the structure of
formulas
(I), (II), (111) or (IV,J, X13, Xla and X15 are each CH or CR, X16 is N, and
group A
is attached at the 3-position to the remainder of the structure of formulas
(I), (II),
(III) or (IV), or X13, X14 and X16 are each CH or CR, X15 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV), or X13, X15 and X16 are each CH or CR, Xj4 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
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(III) or (IV));
R' is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4
carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having
4
to 7 carbon atoms;
R is H, F, CI, Br, I, OH, CN, COH, NR6R7, carboxy, CONR6R7, NRZCORB,
NRZCOORB, NRzCSRB, NRZCONRZR9, NRZCSNRZR9, NRzSO2R10,
NR2CONR6R7, NRzCSNR6R7, NR2R9, SO2R10, SOR10, -O-(C1_6-alky1-O)j_2-C1_6-
alkyl, NRZ-C1_6-alkyl-NR6R1, NRa-C1_6-alkyl-CONR61e, NR2-CO-C1_6-alkyl-Ar,
NRz-Q_6-alkyl-CO-O-RZ, NRZ-C1_6-alkyl-NRZ(CO-O-R), -C1_6-alkyl-NR2, -O-Cl_
6-alkyl-NR6R7, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having I'to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, C1-6-alkoxy, NR6R~, CO-NR6R', Cz-6-alkoxycarbonyl, or -
CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHFZ),
hydroxyalkyl
having I to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1.6-alkyl-O-, Het-CI_6-alkyl-O-
,
Het-CO-Het-, Het-CI_6-alkyl-NRz-, or Ar-CI_6-alkyl-Het-O-,
with the proviso that R is not NHZ; or
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R is of one of the following formulas
,R9
- -N
CH ~CHz)n,
n
n is2to4;
m is3to5;or
two R can together form a 5-membered fused ring structure containing at least
one N atom;
Rl is H, F, Cl, Br, I, OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7,
NRZCOR$, NRZCOOR$, NRZCSR$, NRZCONRzR9, NR2CSNRaR9, NRZSO2R10,
NRaCONRbR7, NRZCSNR6R7, NR2R9, SO2R10, SORlO, -O-(CI_6-alkyl-O)i_2-C1_6-
alkyl, NR.Z-CI_6-alkyl-NR6R7 , NRZ-CI_6-alkyl-CONR6R7 , NRZ-CO-C1_6-alkyl-Ar,
NR2-C1_6-alkyl-CO-O-R2, NRZ-C1_6-a1ky1-NRZ(CO-O-RZ), -C1_6-alkyl-NRz, -O-CI_
6-alkyl-NR6R7, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having I to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, C1_6-alkoxy, NR6R7, CO-NR6R7, C2_6-alkoxycarbonyl, or -
CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
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2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has I to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1.6-alkyl-O-, Het-C1.6-alkyl-O-
,
Het-CO-Het-, Het-C1_6-alkyl-NR2-, orAr-C1.6-alkyl-Het-O-; or
R' is of one of the following formulas
X X
J~ ~R9
-N
CH n 62), ; or
two R' can together form a 5-membered fused ring structure containing at least
one N atom;
R2 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4
to
7 carbon atoms, fluorinated C1_4-alkyl-CO-, C3.7-cycloalkyl-CO-, Ci.4-alkyl-NH-
CO-, C3_7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1_4-alkyl-CO-, Ar-Ci-4-
alkyl-SOZ-, C14-alkyl-O-CI 4-alkyl- (e.g., CHZCH2-O-CH3), Ar-Cj4-alkyl-NH-
CO-, or Het-NH-CO- (e.g., (1-azabicyclo[2.2.2]oct-3-yl)-NH-CO-);
R3 is H, F, Cl, Br, I, OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7,
NRZCORB, NR2COOR8, NRZCSRB, NRZCONRzR9, NRzCSWR9, NRzSO2R10,
NRZCONR6R7, NRZCSNR6R7, NRzR9, SO2R10, SORlO, -O-(Ci_6-alkyl-O)1_z-C1.6-
alkyl, NRZ-C1_6-alkyl-NR6R7, NRZ-C,_6-alkyl-CONR6R7, NRZ-CO-C1.6-alkyl-Ar,
NR2-C 1.6-alkyl-CO-O-Rz, NRz-C 1_6-alkyl NRz(CO-O-RZ), -C 1.6-alkyl NR2, -O-C
1.
6-alkyl-NR6R7 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1
to 4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
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atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, Cl _6-alkoxy, NR6W, CO-NR6R', Cz_6-alkoxycarbonyl, or -
CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-1-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having I to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has I to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-Q_6-alkyl-O-, Het-CI_6-alkyl-O-,
Het-CO-Het-, Het-C1_6-alkyl-NRZ-, or Ar-C1_6-alkyl-Het-O-; or
R3 is of one of the following formulas
X X
/R9
-N
- CH n 62). ~ or
two R3 can together form a 5-membered fused ring structure containing at least
one N atom;
R4 is H, F, Cl, Br, I, OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7,
NRzCORB, NRzCOORB, NRzCSRB, NRZCONRZR9, NRZCSNRZR9, NRzSO2R10,
NR2CONR6R7, NR2CSNR6R~, NR2R9, SO2R10, SORlO, -O-(C1_6-alkyl-O)1_2-CI_6-
alkyl, NR2-C1_6-alkyl-NR6R7 , NRZ-Q-6-alkyl-CONR6R~, NRZ-CO-C1_6-alkyl-Ar,
NRz-C1_6-alkyl-CO-O-R2, NR2-C1_6-alkyl-NRZ(CO-O-Rz), -C1_6-alkyl-NR2, -O-Cl_
6-alkyl-NR6R7, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
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alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, CI_6-alkoxy, NR6R7, CO-NR6R7, Cz_6-alkoxycarbonyl, or -
CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having I to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has I to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1_6-alkyl-O-, Het-C1_6-alkyl-O-
,
Het-CO-Het-, Het-Ct_6-alkyl-NRz-, or Ar-CI_6-alkyl-Het-O-; or
R4 is of one of the following formulas
R9 i
-N
CH ~CHA ; or
n
two R4 can together form a 5-membered fused ring structure containing at least
one N atom;
R5 is H, F, Cl, Br, I, OH, CN, nitro, NH2, carboxy, CONR6R7, NRzCORB,
NRzCSRB, NRZCONRzR9, NWCSNRZR9, NR2SOZR10, NR2CONR6R7,
NR2CSNRbR', NR2R9, SO2R10, SOR'O, alkyl having I to 4 carbon atoms,
fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 2 to
6
carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl,
pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups
are in
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each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene
C6H5-
C=C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8
carbon
atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl=having 6
to
9 carbon atoms, alkoxy having I to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having I to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having I to 4 carbon atoms, fluorinated hydroxyalkyl having I to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having I to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, or OHet;
R6 and R7 are each, independently, H, alkyl having I to 4 carbon atoms,
alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms,
or
cycloalkylalkyl having 4 to 7 carbon atoms, or R6 and R7 together are an
alkylene
group containing 4-6 carbon atoms which forms a ring with the N atom (e.g.,
piperidinyl, pyrrolidinyl);
R8 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3
to
6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated
alkyl,
alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar
or
Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon atoms,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to
4
carbon atoms, fluorinated hydroxyalkyl having I to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has I to 4 carbon atoms, Ar, or Het;
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R9 is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl wherein the alkyl portion
has I to 4 carbon atoms, or Het;
R10 is alkyl having I to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon
atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6
carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated alkyl,
alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar
or
Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon atoms,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to
4
carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, Nlff, NR.zRB, Ar, or Het;
Ar is an aryl group having 6 to 10 carbon atoms which is unsubstituted or
substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy
having
1 to 8 carbon atoms, halogen (F, Cl, Br, or I, preferably F or Cl),
dialkylamino
wherein the alkyl portions each have I to 8 carbon atoms, amino, cyano,
hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated
alkoxy having I to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon
atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having I to 8
carbon
atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8
carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon
atoms and is optionally substituted, aryloxy wherein the aryl portion has 6 to
10
carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted,
arylthio wherein the aryl portion has 6 to 10 carbon atoms (e.g., phenyl,
naphthyl,
biphenyl) and is optionally substituted, cycloalkyloxy wherein the cycloalkyl
group has 3 to 7 carbon atoms and is optionally substituted, sulfo,
sulfonylamino,
acylamido (e.g., acetamido), acyloxy (e.g., acetoxy) or combinations thereof;
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Het is a heterocyclic group, which is fully saturated, partially saturated or
fully
unsaturated, having 5 to 10 ring atoms in which at least I ring atom is a N, 0
or S
atom, which is unsubstituted or substituted one or more times by halogen (F,
Cl,
Br, or l, preferably F or Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl,
naphthyl, biphenyl) which is optionally substituted, alkyl having I to 8
carbon
atoms, alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon
atoms,
cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl),
halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHFz), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylaikoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethyloxy), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2),
alkyl(halogenated alkyl)amino wherein each alkyl group has I to 8 carbon atoms
(e.g., methyl(trifluoromethyl)amino), di(halogenated alkyl)amino wherein each
alkyl group has 1 to 8 carbon atoms, (halogenated alkyl)amino having I to 8
carbon atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms (e.g.,
fluorinated alkyl, such as trifluoromethyl, trifluoroethyl), nitro, oxo, OH,
alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino, monoalkylamino having
I to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon
atoms, SOZR11, -CXR' 1, piperidinylethyl or combinations thereof;
Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon
atoms,
which is unsubstituted or substituted one or more times by halogen, alkyl
having I
to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy, nitro, cyano,
oxo,
or combinations thereof (e.g., indanyl, tetrahydronaphthenyl, etc.); and
R" is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4
carbon atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3
to
6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, halogenated
alkyl,
alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar
or
Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon atoms,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to
4
carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms,
12
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monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, or Ar;
and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides
thereof, or solvates of pharmaceutically acceptable salts thereof, or
pharmaceutically
acceptable salts or solvates of N-oxides thereof.
According to a fitrther compound and/or method aspect of the invention, the
compound is selected from Formulas I, II, III, or IV:
N N N k
R' R'
X I
RliN--f A R,N~ A
A X A
(l) (II) (II1) (IV)
wherein
A is
)( 5
wZi N X~ ~ S\ 5
(a) XI\ a (b) I~ ~ --R
~ N\R2 X~X N/
9 13
X10/ ~ \ X14'/ ~
(c) X1I1I N or (d) X115 ~
\X12' S \X16' 0
X isOorS;
Xl to X4 are each, independently, N, CH; CR1, or C-, wherein C- represents the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (IlI) or (IV) (for example, XI, X2, X3 and X4 are each CH or CR1, and
group
13
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A is attached at the 3-position to the remainder of the structure of formulas
(I),
(II), (III) or (IV), Xl, X2 and X3 are each CH or CRI, X4 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV), XI, X2 and X4 are each CH or CR', X3 is N, and group A is
attached
at the 3-position to the remainder of the structure of formulas (I), (II),
(fII) or
(IV), or X', X3 and X4 are each,CH or CR1, X2 is N, and group A is attached at
the
3-position to the remainder of the structure of formulas (I), (II), (III) or
(IV));
X5 to X8 are each, independently, N, CH, CR3, or C-, wherein C- represents the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, X5, X6 , and X8 are each CH or CR3 and X7 is
C-
whereby group A is attached at its 5-position to the remainder of the
structure of
formulas (I), (II), (III) or (IV), or X5, X7 , and X$ are each CH or CR3 and
X6 is C-
whereby group A is attached at its 6-position to the remainder of the
structure of
formulas (I), (II), (III) or (IV));
X9 to X12 are each, independently, N, CH, CR4, or C-, wherein C- represents
the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, X9, X10 , X" i and X1Z are each CH or CR4,
and
group A is attached at the 3-position to the remainder of the structure of
formulas
(I), (II), (III) or (IV), X9, X10 and X" are each CH or CR4, X'z is N, and
group A
is attached at the 3-position to the remainder of the structure of formulas
(1), (II),
(III) or (IV), or X9, X10 and X12 are each CH or CR4, Xl1 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV), or X9, XI 1 and X12 are each CH or CR~, X10 is N, and group A
is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV));
X13 to X16 are each, independently, N, CH, CR, or C-, wherein C- represents
the
point of attachment of group A to the remainder of the structure of formulas
(I),
(II), (III) or (IV) (for example, X13, X14, Xls and X16 are each CH or CR, and
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group A is attached at the 3-position to the remainder of the structure of
formulas
(I), (II), (III) or (IV), X13, Xla and X15 are each CH or CR, X16 is N, and
group A
is attached at the 3-position to the remainder of the structure of formulas
(I), (II),
(III) or (IV), or X13, X14 and X16 are each CH or CR, X15 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (1),
(II),
(III) or (IV), or X13, X15 and X16 are each CH or CR, X14 is N, and group A is
attached at the 3-position to the remainder of the structure of formulas (I),
(II),
(III) or (IV));
R' is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having I to 4
carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having
4
to 7 carbon atoms;
R is H, F, Cl, Br, I, OH, CN, COH, NR6R7, carboxy, CONR6R7, NRzCORg,
NR2COOR8, NR2CSR8, NRzCONR2R9, NR2CSNRzR9, NRzSO2R10,
NRaCONR6R7, NR2CSNR6R7, NRZR9, SO2R10, SORlO, -O-(Cj_6-alkyl-O)1_a-C1_6-
alkyl, NR2-Q_6-alkyl-NR6R7 , NRZ-Q_6-alkyl-CONR6R7 , NRZ-CO-CI_&-alkyl-Ar,
NRZ-Ci_6-alkyl-CO-O-RZ, NRZ-C1_6-alkyl-NRZ(CO-O-R2), -C1_6-alkyl-NRz, -O-CI_
6-alkyl-NR6R7, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, CI.6-alkoxy, NRbR7, CO-NR6RC, C2_6-alkoxycarbonyl, or -
CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having I to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having I to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
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2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1.6-alkyl-O-, Het-C1.6-alkyl-O-
,
Het-CO-Het-, Het-C1.6-alkyl-NRZ-, or Ar-C1.6-alkyl-Het-O-,
with the proviso that R is not NH2; or
R is of one of the following formulas
x x
A,R9
- -N
CH 4CHZ)n,
n
n is 2 to 4;
m is3to5;or
two R can together form a 5-membered fused ring structure containing at least
one N atom;
R' is H, F, Cl, Br, 1, OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7,
NRZCORB, NRZCOORB, NRZCSRB, NRZCONRZR9, NRZCSNRzR9, NRZSOZRiO,
NRZCONR6R', NRZCSNR6R7, NRZR9, SO2R10, SOR10, -O-(C1.6-alkyl-O)1.2-C1.6-
alkyl, NR2-C1_6-alkyl-NR6R7, NRZ-C1.6-alkyl-CONR6R7, NRz-CO-CI _6-alkyl-Ar,
NRZ-C1_6-alkyl-CO-O-Rz, NRz-C1.6-alkyl-NRZ(CO-O-R), -CI.6-alkyl-NRZ, -O-Cl.
6-alkyl-Nlff, alkyl having I to 4 carbon atoms, fluorinated alkyl having I to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, C1.6-alkoxy, NR6R7, CO-NR6R7, C2.6-alkoxycarbonyl, or -
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CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having I to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1_6-alkyl-O-, Het-C1_6-alkyl-O-
,
Het-CO-Het-, Het-C1_6-alkyl-NRa-, or Ar-C1_6-alkyl-Het-O-; or
R' is of one of the following formulas
/R9
~
- -N I
CH ~CH2), ; or
n
two R' can together form a 5-membered fused ring structure containing at least
one N atom;
R2 is H, alkyl having I to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4
to
7 carbon atoms, fluorinated C1_4-alkyl-CO-, C3_7-cycloalkyl-CO-, CI4-alkyl-NH-
CO-, C3_7-cycloalkyl-NH-CO-, Het, Ar-Cl4-alkyl-, Ar-C1_4-alkyl-CO-, Ar-CI-4-
alkyl-SOz-, C1_4-alkyl-O-C1_4-alkyl- (e.g., CH2CH2-O-CH3), Ar-Cj.4:-alkyl-NH-
CO-, or Het-NH-CO- (e.g., (1-azabicyclo[2.2.2]oct-3-yl)-NH-CO-);
R3 is H, F, Cl, Br, I, OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7,
NRzCORB> NRzCOORB> NR2CSR$> NRZCONRzR9, NRZCSNRZR9, NRZSO2R'0, 1
NRaCONR6R7, NRaCSNR6R7, NRZR9, SOZR10, SOR'0, -O-(CI_6-a1ky1-O)1_2-CI_6-
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alkyl, NRZ-C1_6-alkyl-NR6R7, NRZ-C1.6-alkyl-CONR6R7, NR2-CO-C1_6-alkyl-Ar,
NRZ-C1_6-alkyl-CO-O-R2, NRZ-C1.6-alkyl-NRZ(CO-O-RZ), -CI_6-alkyl-NR2, -O-Ci.
6-alkyl-NR6R7, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having I to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, C1_6-alkoxy, NR6R7, CO-NR6R7, C2_6-alkoxycarbonyl, or -
CO-RlO, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having I to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has I to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-CI_6-alkyl-O-, Het-C1.6-alkyl-O-
,
Het-CO-Het-, Het-C1_6-alkyl-NRZ-, or Ar-Q.6-alkyl-Het-O-; or
R3 is of one of the following formulas
x x
'J~ ,R9
- -N
CH n 62), ~ or
two R3 can together form a 5-membered fused ring structure containing at least
one N atom;
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R4 is H, F, Cl, Br, I, OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7,
NR2COR8, NRZCOORg, NR2CSRg, NR2CONRZR9, NRZCSNRZR9, NRzSO2R10,
NRzCONR6R7, NR2CSNRW, NR2R9, SO2R10, SORjO, -O-(C1_6-alkyl-O)1_2-C1_6-
alkyl, NRx-CI_6-alkyl-NR6R7, NRZ-C1_6-a1ky1-CONR6RI, NR2-CO-CI_6-alkyl-Ar,
NRz-C1_6-alkyl-CO-O-Ra, NRZ-C1_6-alkyl-NW(CO-O-RZ), -Cl_6-alkyl-NRZ, -O-Cl_
6-alkyl-NR6R7, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to
4
carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2
to
6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,
fluorinated
alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or
substituted by
Ar or Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon
atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or
substituted by HCO-, C1_6-alkoxy, NR6R', CO-NR6R7, C2_6-alkoxycarbonyl, or -
CO-R10, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having I to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having I to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has I to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1_6-alkyl-O-, Het-CI_6-alkyl-O-
,
Het-CO-Het-, Het-C1_6-alkyl-NR2-, or Ar-C1_6-alkyl-Het-O-; or
R4 is of one of the following formulas
/Rs
-N
CH ~CHZ)m ; or
n
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two R4 can together form a 5-membered fused ring structure containing at least
one N atom;
RS is H, F, Cl, Br, I, OH, CN, nitro, NH2, carboxy, CONR6R7, NRZCORB,
NR2CSR8, NRZCONR2R9, NRZCSNRzR9, NRzSO2R10, NRZCONR6R',
NR2CSNR6R~, NRzR9, SO2R10, SOR'0, alkyl having 1 to 4 carbon atoms,
fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 2 to
6
carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl,
pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups
are in
each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene
C6H5-
C=C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8
carbon
atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6
to
9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy
having'3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having I to 4 carbon atoms (e.g., SCH3),
fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl
having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms
(e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl), hydroxyalkoxy
having
2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6
carbon atoms, Ar, Het, OAr, or OHet;
R6 and R7 are each, independently, H, alkyl having 1 to 4 carbon atoms,
alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms,
or
cycloalkylalkyl having 4 to 7 carbon atoms, or R6 and R7 together are an
alkylene
group containing 4-6 carbon atoms which forms a ring with the N atom (e.g.,
piperidinyl, pyrrolidinyl);
R8 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3
to
6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated
alkyl,
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alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar
or
Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon atoms,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to
4
carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, Ar, or Het;
R9 is alkyl having I to 4 carbon atoms, Ar, Ar-alkyl wherein the alkyl portion
has 1 to 4 carbon atoms, or Het;
R10 is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon
atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6
carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated alkyl,
alkenyl, or alkynyl groups are in each case unsubstituted'or substituted by Ar
or
Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon atoms,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to
4
carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms,
monoalkylamino having I to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, NRW, NRZRB, Ar, or Het;
Ar is an aryl group having 6 to 10 carbon atoms which is unsubstituted or
substituted one or more times by alkyl having I to 8 carbon atoms, alkoxy
having
I to 8 carbon atoms, halogen (F, Cl, Br, or I, preferably F or Cl),
dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano,
hydroxyl, nitro, halogenated alkyl having I to 8 carbon atoms, halogenated
alkoxy having I to 8 carbon atoms, hydroxyalkyl having I to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon
atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8
carbon
atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8
carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon
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atoms and is optionally substituted, aryloxy wherein the aryl portion has 6 to
10
carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted,
arylthio wherein the aryl portion has 6 to 10 carbon atoms (e.g., phenyl,
naphthyl,
biphenyl) and is optionally substituted, cycloalkyloxy wherein the cycloalkyl
group has 3 to 7 carbon atoms and is optionally substituted, sulfo,
sulfonylamino,
acylamido (e.g., acetamido), acyloxy (e.g., acetoxy) or combinations thereof;
Het is a heterocyclic group, which is fully saturated, partially saturated or
fully
unsaturated, having 5 to 10 ring atoms in which at least I ring atom is a N, 0
or S
atom, which is unsubstituted or substituted one or more times by halogen (F,
Cl,
Br, or 1, preferably F or Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl,
naphthyl, biphenyl) which is optionally substituted, alkyl having I to 8
carbon
atoms, alkoxy having I to 8 carbon atoms, cycloalkyl having 3 to 7 carbon
atoms,
cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl),
halogenated alkoxy having I to 8 carbon atoms (e.g., OCHF2), cycloalkoxy
having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethyloxy), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2),
alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms
(e.g., methyl(trifluoromethyl)amino), di(halogenated alkyl)amino wherein each
alkyl group has I to 8 carbon atoms, (halogenated alkyl)amino having I to 8
carbon atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms (e.g.,
fluorinated alkyl, such as trifluoromethyl, trifluoroethyl), nitro, oxo, OH,
alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino, monoalkylamino having
I to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon
atoms, SO2RI 1, -CXR' 1, piperidinylethyl or combinations thereof;
Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon
atoms,
which is unsubstituted or substituted one or more times by halogen, alkyl
having I
to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy, nitro, cyano,
oxo,
or combinations thereof (e.g., indanyl, tetrahydronaphthenyl, etc.); and
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R" is alkyl having 1 to 4 carbon atoms, halogenated alkyl having I to 4
carbon atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3
to
6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, halogenated
alkyl,
alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar
or
Het (e.g., phenylacetylene C6H5-C=C-), cycloalkyl having 3 to 7 carbon atoms,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to
4
carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl
group independently has 1 to 4 carbon atoms, or Ar;
and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides
thereof, or solvates of pharmaceutically acceptable salts thereof, or
pharmaceutically
acceptable salts or solvates of N-oxides thereof;
with the proviso that the 1-azabicyclo group is in the form of a quaternary
ammonium salt of the subformula:
N A-
wherein Z is alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl),
halogenated
alkyl having 1 to 4 carbon atoms (e.g., chloromethyl, chloroethyl),
cycloalkylalkyl having
4 to 7 carbon atoms (e.g., cyclopropylmethyl), or arylalkylhaving 7 to 16
carbon amtoms
(e.g., benzyl), and anion A is, for example, iodide, bromide, chloride,
triflate, tosylate, or
mesylate.
According to a further compound and/or method aspect of the invention, the
compound is selected from Formulas I-IV, wherein:
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R2 if present, is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl
having
1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl
having 4 to 7 carbon atoms, fluorinated C1_4-alkyl-CO-, C3_7-cycloalkyl-CO-,
CI_4-
alkyl-NH-CO-, C3_7-cycloalkyl-NH-CO-, Het, Ar-Cl-4-alkyl-, Ar-C1_4-alkyl-CO-,
Ar-CI-4-a1ky1-SOZ-, Cy-4-alkyl-O-CI-4-alkyl- (e.g., CH2CH2-O-CH3), or Ar-C14-
alkyl-NH-CO-; and
Het is a heterocyclic group, which is fully saturated, partially saturated or
fully
unsaturated, having 5 to 10 ring atoms in which at least I ring atom is a N, 0
or S
atom, which is unsubstituted or substituted one or more times by halogen, aryl
having 6 to 10 carbon atoms which is optionally substituted, alkyl having I to
8
carbon atoms, alkoxy having I to 8 carbon atoms, cycloalkyl having 3 to 7
carbon
atoms, halogenated alkoxy having 1 to 8 carbon atoms, cycloalkoxy having 3 to
7
carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkyl(halogenated
alkyl)amino wherein each alkyl group has 1 to 8 C atoms, di(halogenated
alkyl)amino wherein each alkyl group has 1 to 8 C atoms, (halogenated
alkyl)amino having 1 to 8 carbon atoms, cyano, halogenated alkyl having 1 to 8
carbon atoms, nitro, oxo, OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms,
amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each
alkyl group has 1 to 8 C atoms, SO2R", -CXR", piperidinylethyl or combinations
thereof.
In Formulas I-IV, the group A, for example, an indazolyl, benzothiazolyl,
benzoisothiazolyl, benzisoxazolyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[4,3-
c]pyridinyl, or
isothiazolo[5,4-b]pyridinyl group, can be attached to the remainder of the
structure via
any suitable attachment point.
In Formula I, when A is of subformula (a), e.g., an indazolyl group, it is
preferably attached to the remainder of the compound via its 3, 4 or 7
position,
particularly via the 3-position. When A is of subformula (b), e.g:, a
benzothiazolyl group,
it is preferably attached to the remainder of the compound via its 4 or 7
position. When
A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably
attached to the
24
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remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
When A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
Similarly, in Formula II, when A is of subformula (a), e.g., an indazolyl
group, it
is preferably attached to the remainder of the compound via its 3, 4 or 7
position,
particularly via the 3-position. When A is of subformula (b), e.g., a
benzothiazolyl group,
it is preferably attached to the remainder of the compound via its 4 or 7
position. When
A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
When A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
Also, in Formula III, when Ais of subformula (a), e.g., an indazolyl group, it
is
preferably attached to the remainder of the compound via its 3, 4 or 7
position,
particularly via the 3-position. When A is of subformula (b), e.g., a
benzothiazolyl group,
it is preferably attached to the remainder of the compound via its 4 or 7
position. When
A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
When A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
Further, in Formula IV, when A is of subformula (a), e.g., an indazolyl group,
it is
preferably attached to the remainder of the compound via its 3, 4 or 7
position,
particularly via the 3-position. When A is of subfornlula (b), e.g., a
benzothiazolyl group,
it is preferably attached to the remainder of the compound via its 4 or 7
position. When
A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
When A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably
attached to the
remainder of the compound via its 3, 4 or 7 position, particularly via the 3-
position.
2~
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The following subformulas illustrate some of the preferred attachments between
the A groups, e.g., indazole, benzothiazole, benzoisothiazole, benzisoxazole,
pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-c]pyridinyl,
and
isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula I.
In each of
the following subformulas, the R, R', R3, and/or R4 substituent is generally
present 1, 2,
or 3 times, preferably 1 or 2 times, more preferably once.
N
R' ~
/ X / Xi
N
N N I N
XII X~ \ XI ~ \ X N
N N '2
X~X4 N X I ~ 4 N /N R
R~ X ~Rz R~ X
(la) (Ib) (le)
N
Rw x a
N N ~ I \ N>--
.I N X6
R5 S
XXS S N
R'/ X
Of) (~~)
N
R' x R' X Xs
X111
s N N N N
X~II X~ \ X'0 1 X11 s
N N
X~ X1p S~ X1 X12 S N
R'/ X
(11) (1k) (lo)
26
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N N
~
R~ X IR X 13
N N X14iX~
13 N I I N
X111 X\ X111 ~ X15 0
15 N N
XX16 p X1 \X1fi p' N
R'~ X
(Ip) (iq) (It)
The following subfonnulas further illustrate some of the preferred attachments
between the A groups, e.g., groups, e.g., indazole, benzothiazole,
benzoisothiazole,
benzisoxazole, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-
c]pyridinyl, and isothiazolo[5,4-b]pyridinyl, and the remainder of the
structure for
Formula II. In each of the following subformulas, the R, Rl, R3, and/or R4
substituent is
generally present 1, 2, or 3 times, preferably 1 or 2 times, more preferably
once.
4x N /X N X
NR' NR' NR'
' X1
I-X~ N ~I \ N 31 ~ ~N
x
\ 4 ~ 4 " X~ 4
x N\ RZ NRZ ~ \ 2
R
(Ila) (Ilb) (IIc)
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1
CN X2i X \ I~X
~N X3 N N
X \
NR' 2 2
X R N R' R
X
(Ild) (Ile)
4x N X
NR' NR'
Xs
XII RS sl \R
X5 s
X\5 s
(Il fl (119)
a
N XI X~ N N
~ \ RN ;7,,X8 \ RNRXS S S
x NR'
(Ilh) x
(Ili)
X N /X N X
NR' NR' NR'
1 s
10/ N
X X10 I ~ ~
1 N \N
11
X XX12 S X11 ~ S X\X12 S
(Ilj) (Ilk) (Ilm)
N X1oi X~ \ X110-~
N N ~
X12 S X 11
NR'
x NR'
X
(Iln) (110)
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13 13
X14i X14IX
~N N ~ '
16 X1s O
NR'
X NR'
X
(lis) (Ilt)
X N /X N X
4 NR' NR' NR'
13 X13
14/X 14
X5I N )(1I5 r\/
N 1
5~XX18 O X\XX16 O
(Ilp) (Ilq) (Ilr)
The following subformulas further illustrate some of the preferred attachments
between the A groups, e.g., indazole, benzothiazole, benzoisothiazole,
benzisoxazole,
pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-c]pyridinyl,
and
isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula
III. In each of
the following subformulas, the R, R1, R3, and/or R4 substituent is generally
present 1, 2,
or 3 times, preferably 1 or 2 times, more preferably once.
N N N
~
R' / R'
N N N
1 X 1
XI3 X~ N XI ~~\ N 3 N
X 4 N X\ X~ X4 N
X \2 X4 ~ ~ RZ \Z
(Illa) (Illb) (Illc)
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XZ'X~ X
I 4 N N X3 N
~ N N
R' i N 11 R2 N 'R2
R'
(Illd) (Ille)
R'
N N /
/ R'
NXs
~ N
Xls N~R Xsl \R
X\X5 S XS/ S
(Illfl (flig)
~R
X' X N X N
-Rs Xs S s
S>
/ \ SJ
.-f X N
N
R'
(IIIh) (Illi)
N N N
N' R' Nt
N
s s
X'l~X \N X10 ~ \ I XN
!I
X~ Xg X~ \X1z S X~ \X12 S
(Illj) (Illk) (Illm)
s 9
Xtoi X~ loiX~
N N X I I N
X12 S X~1 S
R' N
R
~ ~ N
(Illn) (Illo)
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N N N
R' R' R'
N N N
13 X13
14/X 14
X115 ~N X1s1 \ N 1s /N
XX1B O Xx 16 0 XX1s 0
(Illp) (Illq) (Ilir)
13 13
X1a~X \ X14~X \
I N N II N
X16 O~ k15
N ~
R'~ N
R'
(I11s) (lilt)
The following subformulas further illustrate some of the preferred attachments
between the A groups, e.g., indazole, benzothiazole, benzoisothiazole,
benzisoxazole,
pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-c]pyridinyl,
and
isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula
IV. In each of
the following subformulas, the R, Rt, R3, and/or R4 substituent is generally
present 1, 2,
or 3 times, preferably I or 2 times, more preferably once.
N N N
NR' NR' NR'
1 X1
~I I ~ \ 31 ~N
xI X N
N
XX4 N X 4- N XX4 N
.RZ X R~ Z
(IVa) (lVb) (IVc)
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ti
\
N XZI ~ XII \
~ 4 NN N X3 ~ NN
NR' X RZ NR' ~Rz
(IVd) (IVe)
N N
NR' NR'
8
~Y N
X{I ~ N>Rs sl \>--RS
X6 5 XSJ~~S
X S
(IVf) (IV9)
k X~!X N ~~ N
\>--RS \R5
NRhXSJ-~S X S
NR'
(IVh) (1Vi)
N N N
NR' NR' NR'
9
~~ ~
X 10I X~ k\N Xlip
i~I ~
~h AN N
XXla S X~S~ XX1~ S
(IVj) (IVk) (IVm)
9 . 9
N X1o X ioiX
N N XII \N
X12 S X11 8
NR'
N R'
(IVn) (IVo)
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N N N
NR' NR' NRX13
13
14/X \ ~
XII \N X1114 ~N 161 N
X1 \X76 0 X1 16 X\X16 0
(IVp) (IVq) (IVr)
13 13
N X14TX> X k14-
~
N
O,
NR'
(IVs) (IVt)
In all cases, X is preferably O.
In all cases, R' is preferably H, cyclopropylmethyl, or CH3, particularly H.
Alkyl throughout means a straight-chain or branched-chain aliphatic
hydrocarbon
radical having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Suitable
alkyl groups
include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-
butyl, and tert-
butyl.
Alkenyl throughout means a straight-chain or branched-chain aliphatic
hydrocarbon radical having preferably 2 to 6 carbon atoms. Suitable alkenyl
groups
include but are not limited to ethenyl, propenyl, butenyl, and pentenyl.
Alkynyl throughout means a straight-chain or branched-chain aliphatic
hydrocarbon radical having preferably 2 to 6 carbon atoms. Suitable alkynyl
groups
include but are not limited to ethyne (ethynyl), propyne (propynyl), butyne
(butynyl), etc.
Alkoxy means alkyl-0- groups in which the alkyl portion has 1 to 8 carbon
atoms,
preferably 1 to 4 carbon atoms. Suitable alkoxy groups include but are not
limited to
methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.
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Alkoxyalkyl means alkyl-O-alkyl- groups in which each alkyl portion
independently has 1 to 8 carbon atoms, preferably I to 4 carbon atoms.
Suitable
alkoxyalkyl groups include, but are not limited to, methoxymethyl,
ethoxymethyl, and
methoxyethyl.
Alkylthio means alkyl-S- groups in which the alkyl portion preferably has 1 to
4
carbon atoms. Suitable alkylthio groups include but are not limited to
methylthio and
ethylthio.
Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical
having 3 to 7 carbon atoms. Suitable cycloalkyl groups include but are not
limited to
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable
cycloalkyl groups
include but are not limited to spiropentyl, bicyclo[2.1.0]pentyl, and
bicyclo[3.1.0]hexyl.
Cycloalkoxy means cycloalkyl-O- groups in which the cycloalkyl portion
preferably is a cyclic, bicyclic or tricyclic saturated hydrocarbon radical
having 3 to 7
carbon atoms. '
Cycloalkylalkyl groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkyl
groups include but are not limited to, for example, cyclopropylmethyl,
cyclopropylethyl,
cyclobutylmethyl, and cyclopentylmethyl.
Cycloalkylalkoxy groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkoxy
groups include but are not limited to, for example, cyclopropylmethyloxy,
cyclopropylethyloxy, cyclobutylmethyloxy, and cyclopentylmethyloxy.
Cycloalkyl and cycloalkylalkyl structures can be substituted by, for example,
C1_4-
alkyl, CI_4-alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon
atoms, and/or
dialklyamino in which each alkyl group has 1 to 4 carbon atoms.
Aryl, as a group or substituent per se or as part of a group or substituent
(e.g., Ar,
OAr, Ar-C1_6-alkyl-O-, or Ar-C1_6-alkyl-Het-O-), refers to an aromatic
carbocyclic radical
having 6 to 10 carbon atoms, unless indicated otherwise. Suitable aryl groups
include but
are not limited to phenyl, napthyl and biphenyl. Substituted aryl groups
include the
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WO 2007/038367 PCT/US2006/037142
above-described aryl groups which are substituted one or more times by
halogen, alkyl,
hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino,
dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl,
alkoxycarbonyl,
alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and/or acyloxy (e.g.,
acetoxy).
Heterocyclic groups (e.g., the Het portions of Het, OHet, Het-Q_6-alkyl-O-,
Het-
CO-Het-, and Het-CI_6-alkyl NRZ) refer to saturated, partially saturated and
fully
unsaturated heterocyclic groups having one, two or three rings and a total
number of 5 to
ring atoms wherein at least one of the ring atoms is an N, 0 or S atom.
Preferably, the
heterocyclic group contains I to 3 hetero-ring atoms selected from N, 0 and S.
Suitable
10 saturated and partially saturated heterocyclic groups include, but are not
limited to
dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, isoxazolinyl and the like. Suitable
heteroaryl
groups include but are not limited to furyl, thienyl, thiazolyl, oxazolyl,
pyrrolyl,
pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl,
isoquinolinyl,
naphthyridinyl and the like. Other examples of suitable heterocyclic groups
are 2-furyl,
3-furyl, 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 3-thienyl, 1,3-thiazoly-2-
yl, 1,3-oxazol-
2-yl, pyrrolidin-1-yl, 6-pyrrolidin-1-yl, piperidin-1-yl, 6-piperazin-l-yl,
morpholin-4-yl,
2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-
indoyl, 4-
pyridyl, 3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-
pyrrolyl,
tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 5-indolyl, 1,5-benzoxepin-
8-yl, 3-
pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl, 3-
carbazolyi,
hexahydropyrrolo[ 1,2-a]pyrazin-2(1 H)-yl. octahydro-6H-pyrrolo[3,4-b]pyridin-
6-yl, and
1,4-diazepan-1-yl,
Heterocyclic groups also include substituted and unsubstituted azabicyclo and
oxaazabicyclo groups, for example, 2,5-diazabicyclo[2.2.1]hept-2-y1, methyl-
2,5-
diazabicyclo[2.2.1]hept-2-yl, trifluoroethyl-2,5-diazabicyclo[2.2.1]hept-2-yl,
2-oxa-5-
azabicyclo[2.2.1]hept-5y1, 5-methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl, 1,4-
diazabicyclo[3.2.2]non-4-yl, 5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 8-
methyl-3,8-
diazabicyclo[3.2.1]oct-3-yl, 5-cyclopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl,
and 5-
(cyclopropylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl.
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Substituted heterocyclic groups refer to the heterocyclic groups described
above,
which are substituted in one or more places by, for example, halogen, aryl,
alkyl, alkoxy,
cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and/or dialkylamino.
Suitable
substituted heterocyclic groups include 2-methylpiperazin-l-y, 3-
methylpiperazin-l-yl, 4-
methylpiperazin-l-yl, 3,4-dimethylpiperazin-l-yl, 4-methyl-1,4-diazepan-l-yl,
3-
methoxypyrrolidin-l-yl, 1-methylpyrrolidin-3-yl, 1-methyl-4,5-dihydro-lH-
imidazol-2-
yl, 3-(cyclopropylmethoxy)pyrrolidin-1-yl, 6-chloroisothiazolo[5,4-
b]pyridinyl, 4-
(cyclopropylcarbonyl)piperazin-l-yl, and 1-(cyclopropylcarbonyl)octahydro-6H-
pyrrolo[3,4-b]pyridin-6-yl.
Substituted radicals are, in each case, substituted one or more times, and
preferably have 1 to 3 substituents, especially I or 2 substituents of the
exemplified
substituents. These substituents are in each case independently selected.
Thus, the
substituents can be the same or different. Halogenated radicals such as
halogenated
alkyls are preferably fluorinated and include but are not limited to perhalo
radicals such
as trifluoromethyl.
According to another compound and/or method aspect of the invention, R is not
NH2 or NHCH3. According to a further aspect of the invention, R is not NH2,
NHCH3, or
N(CH3)2. According to a further aspect of the invention, R is not NH2,
monoalkylamino,
or dialkylamino.
According to a compound and/or method aspect of the invention, R2 is Het-NH-
CO-. According to another compound and/or method aspect of the invention, when
RZ is
Het-NH-CO-, the Het group is preferably an azabicyclo group, for example, 1-
azabicyclo[2.2.2]oct-3-yl.
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According to a compound and/or method aspect of the invention, Het is
substituted by cycloalkylalkyl having 4 to 7 carbon atoms (e.g.,
cyclopropylmethyl).
According to another compound and/or method aspect of the invention, when Het
is
substituted by cycloalkylalkyl, the cycloalkyl portion preferably has 3 to 5
carbon atoms
(e.g., cyclopropyl), and the alkyl portion preferably has 1 to 2 carbon atoms.
Additionally, the Het group is preferably an azabicyclo group, for example,
2,5-
diazabicyclo[2.2.1]hept-2-yl.
According to a further compound and/or method aspect of the invention, Het is
a
heterocyclic group, which is fully saturated, partially saturated or fully
unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom,
and which is
substituted, wherein at least one of the substituents is halogenated alkoxy
having 1 to 8
carbon atoms (e.g., OCHF2), cycloalkoxy having 3 to 7 carbon atoms,
cycloalkylalkoxy
having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), cycloalkylalkyl
having 4 to 7
carbon atoms (e.g., cyclopropylmethyl), halogenated alkyl other than
trifluoromethyl
(e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as
trifluoroethyl and
trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2),
alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon
atoms,
di(halogenated alkyl)amino wherein each alkyl group has I to 8 carbon atoms,
or
(halogenated alkyl)amino having I to 8 carbon atoms.
According to a further compound and/or method aspect of the invention, the
compound is selected from Formula I-IV wherein at least one R, R', R3, R4, and
R5 group
is Het or OHet in which the Het group is selected from, in each case
substituted or
unsubstituted, azabicyclooctyl (e.g., 1-azabicyclo[2.2.2]oct-3-yl), oxa-
azabicycloheptyl
(e.g., 2-oxa-5-azabicyclo[2.2.1]heptyl), diazabicycloheptyl (e.g., 2,5-
diazabicyclo[2.2.1]hept-2-yl, 5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl,
trifluoroethyl-
2,5-diazabicyclo[2.2.1 ]hept-2-yl, and 5-(cyclopropylcarbonyl)-2,5-
diazabicyclo[2.2.1]hept-2-yl), diazabicyclononyl (e.g., 1,4-
diazabicyclo[3.2.2]non-4-yl),
diazabicyclooctyl (e.g., 5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl and 8-methyl-
3,8-
diazabicyclo[3.2.1]oct-3-yl), pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl
(e.g., 1,4-
diazepan-l-yl and 4-methyl-1,4-diazepan-l-yl), hexahydropyrrolopyrazinyl
(e.g.,
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hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl), and octahydropyrrolopyridinyl (e.g.,
1-
(cyclopropylcarbonyl)-octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl).
According to a further compound and/or method aspect of the invention, at
least
one of Xl, Xz, X3, and X4 is N; least one of X5, X6, X7, and X8 is N; at least
one of X9,
X10, X", and X'2 is N; and/or at least one of X13, X14, X'5, and X16 is N.
According to a
further embodiment of this aspect of the invention, at least one of Xl, X2,
X3, and X4 is N,
and I or 2 of the remaining Xl - X4 are CR'. According to a further embodiment
of this
aspect of the invention, at least one of X5, X6, X7, and X8 is N, and 1 or 2
of the
remaining X5- X8 are CR3. According to a further embodiment of this aspect of
the
invention, at least one of X9, X10, X", and X12 is N, and 1 or 2 of the
remaining X9- Xlz
are CR4. According to a further embodiment of this aspect of the invention, at
least one
of X13, X14, X", and X16 is N, and 1 or 2 of the remaining X13- X16 are CR.
According to a further compound and/or method aspect of the invention, X4 is N
and Xl, X2, and X3 are each CH or CR'. According to a further compound and/or
method
aspect of the invention, X3 is N and Xl, X2, and X4 are each CH or CR1.
According to a further compound and/or method aspect of the invention, X12 is
N
and X9, X10, and Xl l are each CH or CR4.
According to a further compound and/or method aspect of the invention, Het is
a
heterocyclic group, which is fully saturated, partially saturated or fully
unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom,
and which is
substituted, wherein at least one of the substituents is halogenated alkoxy
having 1 to 8
carbon atoms (e.g., OCHF2), cycloalkoxy having 3 to 7 carbon atoms,
cycloalkylalkoxy
having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl
other than
trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms
such as
trifluoromethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms
(e.g.,
CH3OCH2), alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8
carbon
atoms, di(halogenated alkyl)amino wherein each alkyl group has I to 8 C atoms,
or
(halogenated alkyl)amino having 1 to 8 carbon atoms.
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According to a further compound and/or method aspect of the invention, Het is
a
heterocyclic group, which is fully saturated and which is substituted, wherein
at least one
of the substituents is halogenated alkoxy having 1 to 8 C atoms (e.g., OCHF2),
cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon
atoms
(e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl
(e.g.,
halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl
and
trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2),
alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 C atoms,
di(halogenated alkyl)amino wherein each alkyl group has 1 to 8 C atoms, or
(halogenated
alkyl)amino having 1 to 8 carbon atoms.
According to a further compound and/or method aspect of the invention, Het is
a
heterocyclic group, which is fully saturated, partially saturated or fully
unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom,
and which is
substituted wherein at least one of the substituents is halogenated alkoxy
having 1 to 8
carbon atoms (e.g., OCHF2), cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethyloxy) halogenated alkyl other than trifluoromethyl (e.g.,
halogenated
alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and
trifluoropropyl),
alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2), or alkyl(halogenated
alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms.
According to a further compound and/or method aspect of the invention, Het is
a
fully saturated heterocyclic group, which is substituted, wherein at least one
of the
substituents is halogenated alkoxy having I to 8 carbon atoms (e.g., OCHF2),
cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy),
halogenated
alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3
to 8 carbon
atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8
carbon atoms
(e.g., CH3OCHZ), or alkyl(halogenated alkyl)amino wherein each alkyl group has
1 to 8
carbon atoms.
According to a further compound and/or method aspect of the invention, A is of
formula (a) having at least one R' substituent that is a heterocyclic group,
which is fully
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saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms
in which at
least I ring atom is a N, 0 or S atom, and which is substituted, wherein at
least one of the
substituents is halogenated alkoxy having I to 8 carbon atoms (e.g., OCHF2),
cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon
atoms
(e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl
(e.g.,
halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl
and
trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2),
alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon
atoms,
di(halogenated alkyl)amino wherein each alkyl group has I to 8 carbon atoms,
or
(halogenated alkyl)amino having I to 8 C atoms.
According to a further compound and/or method aspect of the invention, A is of
formula (a) having at least one R' substituent that is a fully saturated
heterocyclic group
which is substituted, wherein at least one of the substituents is halogenated
alkoxy having
I to 8 C atoms (e.g., OCHF2), cycloalkoxy having 3 to 7 carbon atoms,
cycloalkylalkoxy
having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl
other than
trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms
such as
trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms
(e.g.,
CH3OCH2), or alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8
carbon
atoms.
According to a further compound and/or method aspect of the invention, A is of
formula (c) having at least one R4 substituent that is a heterocyclic group,
which is fully
saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms
in which at
least 1 ring atom is a N, 0 or S atom, and which is substituted, wherein at
least one of the
substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF2),
cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon
atoms
(e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl
(e.g.,
halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl
and
trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH2),
alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8 carbon
atoms,
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di(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms,
or
(halogenated alkyl)amino having I to 8 carbon atoms.
According to a further compound and/or method aspect of the invention, A is of
formula (c) having at least one R4 substituent that is a fully saturated
heterocyclic group
which is substituted, wherein at least one of the substituents is halogenated
alkoxy having
I to 8 carbon atoms (e.g., OCHF2), cycloalkoxy having 3 to 7 carbon atoms,
cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy),
halogenated
alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3
to 8 carbon
atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8
carbon atoms
(e.g., CH3OCH2), or alky](halogenated alkyl)amino wherein each alkyl group has
I to 8
carbon atoms.
According to a further compound and/or method aspect of the invention, A is of
formula (d) having at least one R substituent that is OH, O-(C1_6-alkyl-O)i_2-
C1_6-alkyl, -
O-C1-6-alkyl-NR6R7 , alkoxy having I to 4 carbon atoms (e.g., OCH3),
cycloalkoxy having
3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,
OCF3,
OCHF2), hydroxyalkyl having I to 4 carbon atoms, fluorinated hydroxyalkyl
having 1 to
4 carbon atoms, hydroxyalkoxy having 2 to.4 carbon atoms, fluorinated
hydroxyalkoxy
having 2 to 4 carbon atoms, OAr, OHet, Carbo-O, Ar-C1_6-alkyl-0-, Het-Ci_6-
alkyl-O-, or
Ar-CI_6-alkyl-Het-O-.
According to a further compound and/or method aspect of the invention, A is of
formula (d) having at least one R substituent that is OH, O-(C1_6-alkyl-O)1_2-
C1_6-alkyl,
alkoxy having 1 to 4 carbon atoms (e.g., OCH3), cycloalkoxy having 3 to 7
carbon atoms,
cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy),
fluorinated
alkoxy having 1 to 4 carbon atoms (e.g., OCF3, OCHF2), hydroxyalkoxy having 2
to 4
carbon atoms, or fluorinated hydroxyalkoxy.
According to a further compound and/or method aspect of the invention, A is of
formula (d) having at least one R substituent that is OH, alkoxy having 1 to 4
carbon
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atoms (e.g., OCH3), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF3,
OCHFZ),
hydroxyalkoxy having 2 to 4 carbon atoms, or fluorinated hydroxyalkoxy.
According to a further compound and/or method aspect of the invention, A is of
formula (a) having at least one R' substituent that is dihydroimidazolyl.
According to a further compound and/or method aspect of the invention, A is of
formula (a) having at least one R' substituent that is Het other than
thiazolyl, and wherein
R2 is alkyl having 2 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon
atoms,
cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms,
fluorinated CI-4-alkyl-CO-, C3_7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3_7-
cycloalkyl-
NH-CO-, Het, Ar-CI-4-alkyl-, Ar-CI_4-alkyl-CO-, Ar-C1_4-alkyl-SOZ-, CI-4-alkyl-
O-C1_4-
alkyl- (e.g.; CH2CH2-O-CH3), or Ar-Q.4-alkyl-NH-CO-.
According to a further compound and/or method aspect of the invention, A is of
formula (c) having at least one R4 substituent that is imidazolyl (e.g.,
imidazol-1-yl),
pyrrolyl, pyrazolyl, C1_8alkyl-pyrazolyl (e.g., 3-methyl-lH-pyrazol-l-yl, 5-
methyl-lH-
pyrazol-l-yl), oxa-azabicycloheptyl (e.g., 2-oxa-5-azabicyclo[2.2.1]heptyl),
diazabicycloheptyl (e.g., 2,5-diazabicyclo[2.2.1]hept-2-yl), CI_$alkyl-
diazabicycloheptyl
(e.g., 5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl), halogenated C1_8alkyl-
diazabicycloheptyl (e.g. trifluoroethyl-2,5-diazabicyclo[2.2.1]hept-2-yl,
piperidinyl
substituted by amino, monoalkylamino (C1_8alkyl-NH-), or dialkylamino
((C1_8alkyl)2N-)
(e.g., (4-dimethylamino)piperidin-1-yl), or pyrrolidinyl substituted by
hydroxy,
halogenated alkoxy, cycloalkylalkoxy, amino, monoalkylamino (Cl_$alkyl-NH=),
dialkylamino ((Cl_galkyl)zN-), alkoxyalkyl, or alkyl (fluorinated alkyl)amino
(e.g., 3-
(cyclopropylmethoxy)pyrrolidin-1-yl, 3-(hydroxy)pyrrolidin-1-yl (such as 3-
(3R)-
hydroxypyrrolidin-1-yl, 3-(3S)-hydroxypyrrolidin-l-yl), 3-
(difluoromethoxy)pyrrolidin-
1-yl), 3-(dimethylamino)pyrrolidin-1-yl (such as 3-(3S)-
(dimethylamino)pyrrolidin-1-yl,
3-(3R)-(dimethylamino)pyrrolidin-l-yl), 3-methylaminopyrrolidin-lyl, 3-
(methoxymethyl)pyrrolidin-1-yl, 3-[methyl(2,2,2-
trifluoroethyl)amino]pyrrolidin-1-yl).
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According to a further aspect of the invention, the compound is of formulas I
to
IV, but the 1-azabicyclo group is in the form of a quaternary ammonium salt of
the
subformula:
N A-
wherein Z is alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl),
halogenated
alkyl having 1 to 4 carbon atoms (e.g., chloromethyl, chioroethyl),
cycloalkylalkyl having
4 to 7 carbon atoms (e.g., cyclopropylmethyl), or arylalkylhaving 7 to 16
carbon amtoms
(e.g., benzyl), and anion A is, for example, iodide, bromide, chloride,
triflate, tosylate, or
mesylate. In this embodiment, groupA is preferably of formula (a) or (c).
Also, Xl to X4
are each, preferably, CH or CR1, and X9 to X12 are each, preferably, CH or
CR4.
According to a further aspect of the invention, the compound is selected from
formula Ip according to the following subgenera:
(i) X13-X16 are independently CH or CR wherein at least one of XI3-XI6 is
other than CH;
Xis0;
R' is H, alkyl (e.g., CH3 or C2H5, particularly CH3) or cycloalkylalkyl
(e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or
cyclopropylethyl, particularly cyclopropylmethyl); and
at least one R is alkoxy (e.g., OCH3) or Het (e.g., 3-methoxy-pyrrolidin-1-
yl [such as (3R)-3-methoxypyrrolidin-1-yl, (3S)-3-methoxypyrrolidin-l-
yl.
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According to a further aspect of the invention, the compound is selected from
formula Ia or Ij according to the following subgenera:
(i) X is O;
one of Xl-X4 is N or one of X9-X1z is N and the others of XI-X4 or of X9-
X12 are CH, CR' or CR4;
R' is H, alkyl (e.g., CH3 or CzHs, particularly CH3) or cycloalkylalkyl
(e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or
cyclopropylethyl, particularly cyclopropylmethyl);
R2 is H; and
R' and R4 are independently selected from H, halogen (e.g., Cl or F), Ar
(e.g., phenyl) or Het (e.g., 3-dimethylaminopyrrolidin-l-yl.
According to a further compound and/or method aspect of the invention, the
compound is selected from the following subgenera:
(a) a compound according to formula I wherein at least one of Xl, X2 , X3, and
X4isN;
(b) a compound according to formula Ia wherein at least one of Xl, X2, X3,
and X4 is N;
(c) a compound according to formula Ij wherein at least one of Xl, X2, X3,
and X4 is N;
(d) a compound according to formula I wherein at least one of X5, X6, X7, and
X8 is N;
(e) a compound according to formula I wherein at least one of X9, X10, X1 1,
and X1Z is N;
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(f) a compound according to formula I wherein at least one of X13, X14, X15,
and X16 is N;
(g) a compound according to formula I wherein at least one of X', X2, X3, and
X4 is N, and 1 or 2 of the remaining Xl- X4 are CR1;
(h) a compound according to formula Ia wherein at least one of Xl, Xz, X3,
and X4 is N, and 1 or 2 of the remaining Xl- X4 are CR1;
(i) a compound according to formula Ij wherein at least one of X1, X2, X3,
and X4 is N, and I or 2 of the remaining X 1 - X4 are CR1;
(j) a compound according to formula I wherein at least one of X5, X6, X7, and
X8 is N, and I or 2 of the remaining XS- X8 are CR3;
(k) a compound according to formula I wherein at least one of X9, X1o, XI 1,
and X12 is N, and 1 or 2 of the remaining X9- XlZ are CR4;
(1) a compound according to formula I wherein at least one of X13, X14, X15,
and X16 is N, and I or 2 of the remaining X13- X16 are CR;
(m) a compound according to formula I wherein X4 is N and Xl, XZ, and X3
are each CH or CRI;
(n) a compound according to formula Ia wherein X4 is N and Xl, X2, and X3
are each CH or CR';
(o) a compound according to formula Ij wherein X12 is N and X9, Xl , and X"
are each CH or CR4;
(p) a compound according to formula Ia wherein X3 is N and Xi, X2, and X4
are each CH or CR';
(q) a compound according to formula Ia or Ij having at least one Ri or R4
which is substituted Het and at least one of the Het substituents is
halogenated alkoxy having I to 8 carbon atoms (e.g., OCHFz),
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cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7
carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than
trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon
atoms such as trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms
(e.g., CH2OCH3), alkyl(halogenated alkyl)amino, wherein each alkyl
group has 1 to 8 carbon atoms, di(halogenated alkyl)amino wherein each
alkyl group has 1 to 8 carbon atoms, or (halogenated alkyl)amino having I
to 8 C atoms;
(r) a compound according to formula Ia or Ij having at least one R' or R4
which is substituted Het and at least one of the Het substituents is
halogenated alkoxy having I to 8 carbon atoms (e.g., OCHF2),
cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g.,
halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as
trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH2OCH3),
or alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8
carbon atoms;
(s) a compound according to formula Ia or Ij having at least one R' or R4
which is a substituted fully saturated Het group (e.g., pyrrolidinyl or
piperidinyl) and at least one of the Het substituents is halogenated alkoxy
having 1 to 8 carbon atoms (e.g., OCHF2), cycloalkoxy having 3 to 7
carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g.,
halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as
trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH2OCH3),
alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8 carbon
atoms, di(halogenated alkyl)amino wherein each alkyl group has 1 to 8
carbon atoms, or (halogenated alkyl)amino having I to 8 carbon atoms;
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(t) a compound according to formula Ia or Ij having at least one R' or W
which is substituted fully saturated Het group (e.g., pyrrolidinyl) and at
least one of the Het substituents is halogenated alkoxy having 1 to 8
carbon atoms (e.g., OCHF2), cycloalkylalkoxy having 4 to 7 carbon atoms
(e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl
(e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as
trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH2OCH3),
or alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8
carbon atoms;
(u) a compound according to formula Ip having at least one R substituent that
is OH, O-(CI_6-alkyl-O)1_2-CI_6-alkyl, -0-C,1_6-alkyl-NR6R7, alkoxy having
I to 4 carbon atoms (e.g., OCH3), cycloalkoxy having 3 to 7 carbon atoms,
cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy),
fluorinated alkoxy having I to 4 carbon atoms (e.g., OCF3, OCHF2),
hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having
1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms,
fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, OAr, OHet,
Carbo-O, Ar-C1_6-alkyl-O-, Het-C1_6-alkyl-O-, or Ar-C1_6-alkyl-Het-O-;
(v) a compound according to formula Ip having at least one R substituent that
is OH, 0-(C1_6-alkyl-O)1_2-CI_6-alkyl, alkoxy having I to 4 carbon atoms
(e.g., OCH3), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy
having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy), fluorinated alkoxy
having 1 to 4 carbon atoms (e.g., OCF3, OCHF2), hydroxyalkoxy having 2
to 4 carbon atoms, or fluorinated hydroxyalkoxy;
(w) a compound according to formula Ip having at least one R substituent that
is OH, alkoxy having I to 4 carbon atoms (e.g., OCH3), fluorinated alkoxy
having I to 4 carbon atoms (e.g., OCF3, OCHF2), hydroxyalkoxy having 2
to 4 carbon atoms, or fluorinated hydroxyalkoxy;
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(x) a compound according to formula Ia having at least one R substituent that
is dihydroimidazolyl;
(y) a compound according to formula Ia having at least one Rl substituent that
is Het other than thiazolyl, and wherein RZ is alkyl having 2 to 4 carbori
atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3
to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated
C14-alkyl-CO-, C3_7-cycloalkyl-CO-, CI_4-alkyl-NH-CO-, C3_7-cycloalkyl-
NH-CO-, Het, Ar-Cl-4-alkyl-, Ar-C1_4-alkyl-CO-, Ar-C1_4-alkyl-SOz-, C14-
alkyl-O-C1_4-alkyl- (e.g., CHZCH2-O-CH3), or Ar-C1-4-alkyl-NH-CO-;
(z) a compound according to formula Ij having at least one R4 substituent that
is imidazolyl (e.g., imidazol-l-yl), pyrrolyl, pyrazolyl, Cl_$alkyl-pyrazolyl
(e.g., 3-methyl-lFl-pyrazol-l-yl, 5-methyl-lH-pyrazol-l-yl), oxo-
azabicycloheptyl (e.g., 2-oxo-5-azabicyclo[2.2.1]heptyl), 2,5-
diazabicyclo[2.2.1]hept-2-yl, C1_8alkyl-diazabicycioheptyl (e.g., 5-methyl-
2,5-diazabicyclo [2.2. 1 ]hept-2-yl), halogenated C1_8alkyl-
diazabicycloheptyl (e.g. trifluoroethyl-2,5-diazabicyclo [2.2. 1 ]hept-2-yl),
piperidinyl substituted by amino, monoalkylamino (Cl_$alkyl-NH-), or
dialkylamino ((Cj_$alkyl)zN-) (e.g., (4-dimethylamino)piperidin-1-yl), or
pyrrolidinyl substituted by hydroxy, halogenated alkoxy,
cycloalkylalkoxy, amino, monoalkylamino(Cl_$alkyl-NH-), dialkylamino
((CI_$alkyl)2N-), alkoxyalkyl, or alkyl (fluorinated alkyl)amino (e.g., 3-
(cyclopropylmethoxy)pyrrolidin-1-yl, 3-(hydroxy)pyrrolidin-l-yl (such as
3-(3R)-hydroxypyrrolidin-1-yl, 3-(3S)-hydroxypyrrolidin-l-yl), 3-
(difluoromethoxy)pyrrolidin-1-yl), 3=(dimethylamino)pyrrolidin-1-yl
(such as 3-(3S)-(dimethylamino)pyrrolidin-l-yl, 3-(3R)-
(dimethylamino)pyrrolidin-l-yl), 3-methylaminopyrrolidin-1y1, 3-
(methoxymethyl)pyrrolidin-1-yl, 3-[methyl(2,2,2-
trifluoroethyl)amino]pyrrolidin-1-yl)
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(aa) a subgenus according to any of subgenus (a)-(z) above wherein X is 0;
and
(ab) a subgenus according to any of subgenus (a)-(aa) above wherein R' is H or
alkyl, especially H.
According to a compound and/or method aspect of the invention, the compound
of formulas I-IV is selected from:
1) (3S)-3-({ [6-(Cyclopropylmethoxy)-1,2-benzisothiazol-3-yl]carbonyl}amino)-1-
(cyclopropylmethyl)-1-azoniabicyclo[2.2.2]octane bromide or formate,
2) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide,
3) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,6-dimethoxy-lH-indazole-3-
carboxamide
hydroformate,
4) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-propyl-6-(1,3-thiazol-2-yl)-1H-
indazole-
3-carboxamide,
5) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-isopropyl-6-(1,3-thiazol-2-yl)-1H-
indazole-3-carboxamide,
6) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yloxy)-1H-
indazole-3-
carboxamide hydroformate,
7) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yloxy)-1H-
indazole-3-carboxamide hydroformate,
8) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(l-methylpyrrolidin-3-yl)oxy]-1H-
indazole-3-carboxamide hydroformate,
9) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-hydroxy-1Hindazole-3-carboxamide
hydroformate,
10) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-hydroxy-lH-indazole-3-
carboxamide hydroformate,
11) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-dibromo-4-hydroxy-IH-indazole-3-
carboxamide hydroformate,
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12) N-[(3S)-1-Azabicyclo [2.2.2] oct-3-yl]-5-hydroxy-1,2-benzisothiazole-3-
carboxamide hydroformate,
13) (3S')-3-{ [(5-Hydroxy-1,2-benzisothiazol-3-yl)carbonyl]amino}-1-methyl-l-
azoniabicyclo[2.2.2]octane iodide or formate,
14) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-furylmethoxy)-1,2-
benzisothiazole-3-
carboxamide hydroformate,
15) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(2-oxopyrrolidin-1-yl)-1H-
indazole-3-carboxamide hydroformate,
16) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-hydroxy-lH-indazole-3-carboxamide
hydroformate,
17) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-m~-.thoxy-N-methyl-lH-indazole-3-
carboxamide hydroformate,
18) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-1-methyl-6-{[(propylamino)carbonyl]
amino}-1H-indazole-3-carboxamide hydroformate,
19) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-methoxy-lH-indazole-3-
carboxamide,
20) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-methoxy-lH-indazole-3-
carboxamide,
21) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-methoxy-lH-
indazole-
3-carboxamide,
22) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-(1,3-thiazol-2-
yl)-1H-
indazole-3-carboxamide,
23) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-
methyl-
1 FI-indazole-3-carboxamide hydroformate,
24) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-
(difluoromethyl)-1H-indazole-3-carboxamide hydroformate,
25) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-
{ [(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide hydroformate,
26) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-(1,3-thiazol-2-yl)-
1H-
indazole-3-carboxamide,
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27) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(3-thienyl)-1H-
indazole-3-carboxamide,
28) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-oxazol-2-yl)-1H-
indazole-
3-carboxamide,
29) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-thiazol-2-yl)-1H-
indazole-
3-carboxamide,
30) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-1H-
indazole-3-
carboxamide,
31) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-oxazol-2-
yl)-
1 H-indazole-3-carboxamide,
32) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1-propyl-lH-
indazole-
3-carboxamide,
33) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-N-methyl-6-(1,3-oxazol-2-yl)-
1H-
indazole-3-carboxamide,
34) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(tetrahydro-2H-pyran-4-yl)-
1H-
indazole-3-carboxamide,
35) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-5-(tetrahydro-2H-pyran-4-
yl)-1FI-
indazole-3-carboxamide,
36) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide,
37) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide,
38) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-
[(cyclopropylcarbonyl)
amino] -1 H-indazole-3-carboxamide,
39) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-{
[(propylamino)carbonyl]
amino}-1 H-indazole-3-carboxamide,
40) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-N-methyl-lH-indazole-3-
carboxamide,
41) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(4S)-4-hydroxy-2-oxopyrrolidin-l-
yl]-
1H-indazole-3-carboxamide hydroformate,
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42) N-[(3R)-1-Azabicyclo[2.2.2]oct -Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-N-
methyl- IH-
hydroformate,
43) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide hydroformate,
44) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-N-methyl-1 H-
indazole-3-carboxamide hydroformate,
45) N-[(3R)-1-Azabicyclo [2.2.2]oct-3-yl]-N-methyl-6-(tetrahydro-2H pyran-4-
y1)-
1Hindazole-3-carboxamide hydroformate,
46) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl] N methyl-5-(tetrahydro-2H-pyran-4-yl)-
IH-indazole-3-carboxamide hydroformate,
47) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyi-6-(1,3-thiazoI-2-yl)-IH-
indazole-
3-carboxamide hydroformate,
48) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1,2-
benzisothiazo]e-
3-carboxamide hydroformate,
49) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide hydrochloride,
50) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1,2-benzisothiazole-3-
carboxamide,
51) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisothiazole-3-
carboxamide hydrochloride,
52) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1]-6-methoxy-1,2-benzisothiazole-3-
carboxamide hydrochloride,
53) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1]-7-methoxy-1,2-benzisothiazole-3-
carboxamide hydrochloride,
54) N-[(3S)-l-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-l-yl)-
1,2-
benzisothiazole-3-carboxamide hydrochloride,
55) N-[(3S)-1-Oxido-l-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-
indazole-
3-carboxamide, and
56) 6-Methoxy-N-[(3S)-I-oxido-I-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-
3-
carboxamide,
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wherein salts listed above can also be in free base form or in the form of
another
pharmaceutically acceptable salt, and free base forms listed above can also be
in the form
of a pharmaceutically acceptable salt,
wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of a solvate (such
as a hydrate),
wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of an N-oxide,
wherein a compound listed above (in a free base form or solvate or N-oxide
thereof, or in the form of a pharmaceutically acceptable salt or solvate
thereof) can also
be in the form of a polymorph, and
wherein if the compound exhibits chirality it can be in the form of a mixture
of
enantiomers such as a racemate or a mixture of diastereomers, or can be in the
form of a
single enantiomer or a single diastereomer.
According to a further compound and/or method aspect of the invention, the
compound of formulas I-IV is selected from:
1) (3S)-3-({[6-(Cyclopropylmethoxy)-1,2-benzisothiazol-3-yl]carbonyl}amino)-1-
(cyclopropylmethyl)-1-azoniabicyclo[2.2.2]octane bromide or formate,
2) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazol e-3 -carboxamide,
3) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,6-dimethoxy-lH-indazole-3-
carboxamide
hydroformate,
4) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-propyl-6-(1,3-thiazol-2-yl)-1H-
indazole-
3-carboxamide,
5) 1V-[(38)-1-Azabicyclo[2.2.2]oct-3-yl]-1-isopropyl-6-(1,3-thiazol-2-yl)-IH-
indazole-3-carboxamide,
6) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yloxy)-1H-
indazole-3-
carboxamide hydroformate,
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7) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yloxy)-1H-
indazole-3-carboxamide hydroformate,
8) . N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1H-
indazole-3-carboxamide hydroformate,
9) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-hydroxy-lH-indazole-3-carboxamide
hydroformate,
10) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-hydroxy-lH-indazole-3-
carboxamide hydroformate,
11) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-dibromo-4-hydroxy-lH-indazole-3-
carboxamide hydroformate,
12) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1,2-benzisothiazole-3-
carboxamide hydroformate,
13) (3S)-3-{[(5-Hydroxy-1,2-benzisothiazol-3-yl)carbonyl]amino}-1-methyl-l-
azoniabicyclo[2.2.2]octane iodide or formate,
14) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-furylmethoxy)-1,2-
benzisothiazole-3-
carboxamide hydroformate,
15) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(2-oxopyrrolidin-l-yl)-1H-
indazole-3-carboxamide hydroformate,
16) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-hydroxy-lH-indazole-3-carboxamide
hydroformate,
17) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-lH-indazole-3-
carboxamide hydroformate,
18) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-methyl-6-{[(propylamino)carbonyl]
amino}-1H-indazole-3-carboxamide hydroformate,
19) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-methoxy-lH-indazole-3-
carboxamide,
20) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-methoxy-lH-indazole-3-
carboxamide,
21) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-methoxy-lH-
indazole-
3-carboxamide,
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22) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-(1,3-thiazol-2-
yl)-1H-
indazole-3-carboxamide,
23) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-
methyl-
1H-indazole-3-carboxamide hydroformate,
24) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-
(difluoromethyl)-1H-indazole-3-carboxamide hydroformate,
25) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-
{ [(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide hydroformate,
26) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-(1,3-thiazol-2-yl)-1H-
indazole-3-carboxamide,
27) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(3-thienyl)-1H
indazole-3-carboxamide,
28) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-oxazol-2-yl)-1H-
indazole-
3-carboxamide,
29) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-thiazol-2-yl)-1H-
indazole-
3-carboxamide,
30) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-1H-
indazole-3-
carboxamide,
31) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-oxazol-2-
yl)-
1 H-indazol e-3-carboxamide,
32) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1-propyl-lH-
indazole-
3-carboxamide,
33) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-N-methyl-6-(1,3-oxazol-2-yl)-
1H-
indazole-3-carboxamide,
34) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(tetrahydro-2H-pyran-4-
yl)-1H
indazole-3-carboxamide,
35) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-5-(tetrahydro-2H-pyran-4-yl)-
1H-
indazole-3-carboxamide,
36) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide,
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37) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide,
38) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-
[(cyclopropylcarbonyl)
amino] -1 FI-indazole-3-carboxamide,
39) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-{
[(propylamino)carbonyl]
amino}-1 H-indazole-3-carboxamide,
40) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-N-methyl-lH-indazole-3-
carboxamide,
41) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(4S')-4-hydroxy-2-oxopyrrolidin-l-
yl]-
1H-indazole-3-carboxamide hydroformate,
42) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-N-methyl-lFl-indazole-3-
carboxamide hydroformate,
43) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide hydroformate,
44) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-N-methyl-lFl-
indazole-3-carboxamide hydroformate,
45) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(tetrahydro-2H-pyran-4-yl)-
1H-indazole-3-carboxamide hydroformate,
46) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl] -N-methyl-5-(tetrahydro-2H-pyran-4-
yl)-
11Y-indazole-3-carboxamide hydroformate,
47) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-thiazol-2-yl)-1Fl-
indazole-
3-carboxamide hydroformate,
48) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1,2-
benzisothiazole-
3-carboxamide hydroformate,
49) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide hydrochloride, and
50) N-[(35)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-l,2-benzisothiazole-3-
carboxamide,
wherein salts listed above can also be in free base form or in the form of
another
pharmaceutically acceptable salt, and free base forms listed above can also be
in the form
of a pharmaceutically acceptable salt,
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wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of a solvate (such
as a hydrate),
wherein a compound listed above (in a free base form or solvate thereof, or in
the
form of a pharmaceutically acceptable salt or solvate thereof ) can also be in
the form of a
polymorph, and
wherein if the compound exhibits chirality it can be in the form of a mixture
of
enantiomers such as a racemate or a mixture of diastereomers, or can be in the
form of a
single enantiomer or a single diastereomer.
According to a further compound and/or method aspect of the invention, the
compound of formulas I-IV is selected from:
57) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-lH-pyrazolo[3,4-b]pyridine-3-
carboxamide hydroforrnate,
58) N-[(35)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(cyclopropylmethoxy)pyrrolidin-l-
yl]-
1H-indazole-3-carboxamide hydroformate,
59) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1H-pyrazolo[4,3-c]pyridine-3-
carboxamide,
60) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1J-1H-pyrazolo[3,4-c]pyridine-3-
carboxamide hydroformate,
61) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(cyclopropylmethoxy)pyrrolidin-l-
yl]-
IH-indazole-3-carboxamide hydroformate,
62) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1H-
indazole-
3-carboxamide hydroformate,
63) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-1-yl)-
1H-
indazole-3-carboxamide hydroformate,
64) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-l-yl-l,2-benzisothiazole-
3-
carboxamide,
65) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxopyrrolidin-l-yl)-1,2-
benzisothiazole-3 -carboxamide,
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66) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-(IH-pyrrol-l-yl)-1,2-
benzisothiazole-3-
carboxamide,
67) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethyl-2-oxoimidazolidin-l-yl)-
1,2-
benzisothiazole-3 -carboxamide,
68) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(cyclopropylmethoxy)pyrrolidin-l-
yl]-
1,2-benzisothiazole-3-carboxamide,
69) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisoxazole-3-carboxamide,
70) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide,
71) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisoxazole-3-
carboxamide hydrochloride
72) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2- -
benzisothiazole-3-carboxamide,
73) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-
IHindazole=3-
carboxamide hydroformate,
74) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-1H-
indazole-3-
carboxamide hydrochloride,
75) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide,
76) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-methoxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide,
77) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-1-yl)-
IH-
indazole-3-carboxamide,
78) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-hydroxypyrrolidin-1-yl)-1,2-
benzisothiazole-3-carboxamide,
79) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(difluoromethoxy)pyrrolidin-l-
yl]-1,2-
benzisothiazole-3 -carboxamide,
80) N-[(3S)-1-Azabicyclo[2.2.2]oct-3=y1]-6-(1H-imidazol-1-yl)-1,2-
benzisothiazole-
3-carboxamide,
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81) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-pyrazol-l-yl)-1,2-
benzisothiazole-3-
carboxamide,
82) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-lH-pyrazol-l-yl)-1,2-
benzisothiazole-3-carboxamide,
83) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-lH-pyrazol-l-yl)-1,2-
benzisothiazole-3-carboxamide,
84) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]-1,2-
benzisothiazole-3 -carboxamide,
85) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-methoxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide,
86) 1V-[(3R)-I-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisoxazole-3-
carboxamide,
87) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1]-6-(3-ethoxypyrrolidin-l-yl)-7-fluoro-
1,2-
benzisothiazole-3-carboxamide,
88) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-phenyl-lFl-pyrazolo[3,4-b]pyridine-
3-
carboxamide,
89) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4,5-dihydro-lH-imidazol-2-yl)-1H-
indazole-3-carboxamide,
90) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(dimethylamino)pyrrolidin-l-yl]-
1H-
pyrazolo[3,4-b]pyridine-3-carboxamide,
91) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(dimethylamino)pyrrolidin-l-yl]-
1H-
pyrazolo [3,4-b]pyridine-3-carboxamide,
92) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-(3-methoxypyrrolidin-l-yl)-
1,2-
benzisothiazole-3-carboxamide,
93) N-[(3S")-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-(3-methoxypyrrolidin-l-
yl)-1,2-
benzisothiazole-3-carboxamide,
94) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide,
95) N=[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide,
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96) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazo le-3-carboxamide,
97) lJ-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]hept-
5-yl]-1,2-benzisothiazole-3-carboxamide,
98) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide,
99) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide,
100) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazole-3-carboxamide,
101) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3R)-3-hydroxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide,
102) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-hydroxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide,
103) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazo le-3-carboxamide,
104) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]hept-
5-yl]-1,2-benzisothiazole-3-carboxamide,
105) 1V [(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazole-3-carboxamide,
106) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]isothiazolo[5,4-b]pyridine-3-
carboxamide
hydroformate,
107) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]isothiazolo[5,4-b]pyridine-3-
carboxamide
hydroformate,
108) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisoxazole-3-carboxamide,
109) N-[(3S)-I -Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzi soxazole-3-carboxamide,
110) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide hydroformate,
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111) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide,
112) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide hydroformate,
113) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-methoxypyrrolidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide hydroformate,
114) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-l,2-
benzisothiazole-3-
carboxamide,
115) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-l,2-
benzisothiazole-3-
carboxamide,
116) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-methyl-2,5-
diazabicyclo[2.2.1 ]hept-2-yl]-1,2-benzisothiazole-3-carboxamide,
117) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yi]-6-[(1S,4S)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide,
118) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-y1]-6-[(1S,4S)-2,5-
diazabicyclo[2.2.1]hept-2-
yl]-1,2-benzisothiazole-3-carboxamide,
119) N=[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-2,5-
diazabicyclo[2.2.1]hept-2-
yl]-1,2-benzisothiazole-3-carboxamide,
120) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methylamino)pyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide,
121) N [(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methylamino)pyrrolidin-l-yl]-
1,2-
benzisothiazole-3 -carboxamide,
122) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-(2,2,2-trifluoroethyl)-
2,5-
diazabicyclo[2.2.1 ]hept-2-yl]-1,2-benzisothiazole-3-carboxamide,
123) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{3-[methyl(2,2,2-
trifluoroethyl)amino]pyrrolidin-l-yl}-1,2-benzisothiazole-3-carboxamide,
124) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{3-[methyl(2,2,2-
trifluoroethyl)amino]pyrrolidin-1-yl}-1,2-benzisothiazole-3-carboxamide,
125) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methoxymethyl)pyrrolidin-l-yl]-
1,2-benzisothiazole-3-carboxamide,
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126) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methoxymethyl)pyrrolidin-l-yl]-
1,2-benzisothiazole-3 -carboxamide,
127) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-(dimethylamino)pyrrolidin-
l-
yl]-1,2-benzisothiazole-3-carboxamide,
128) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-(dimethylamino)pyrrolidin-
l-
yl]-1,2-benzisothiazole-3-carboxamide,
129) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(dimethylamino)piperidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, and
130) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(dimethylamino)piperidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide,
wherein salts listed above can also be in free base form or in the form of
another pharmaceutically acceptable salt, and free base forms listed above can
also be in
the form of a pharmaceutically acceptable salt,
wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of a solvate (such
as a hydrate),
wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of an N-oxide,
wherein a compound listed above (in a free base form or solvate or N-oxide
thereof, or in the form of a pharmaceutically acceptable salt or solvate
thereof) can also
be in the form of a polymorph, and
wherein if the compound exhibits chirality it can be in the form of a mixture
of
enantiomers such as a racemate or a mixture of diastereomers, or can be in the
form of a
single enantiomer or a single diastereomer.
According to a further compound and/or method aspect of the invention, the
compound of formulas I-IV is:
131) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-l-yl)-
1,2-
benzisothiazole-3-carboxamide
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or pharmaceutically acceptable salt thereof,
wherein the compound listed above (in either a free base form or in the form
of a
pharmaceutically acceptable salt) can also be in the form of a solvate (such
as a hydrate),
wherein the compound listed above (in either a free base form or in the form
of a
pharmaceutically acceptable salt) can also be in the form of an N-oxide,
wherein the compound listed above (in a free base form or solvate or N-oxide
thereof, or in the form of a pharmaceutically acceptable salt or solvate
thereof) can also
be in the form of a polymorph.
According to a further compound'and/or method aspect of the invention, the
compound of formulas I-IV is selected from:
132) NN [(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-[(1S,4S)-5-methyl-2,5-
diazabicyclo [2.2.1 ]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
dihydroformate
133) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-[(1S,4S)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide dihydroformate
134) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1R,4R)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
135) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1R,4R)-5-methyl-2,5-
diazabicyclo [2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
136) N [(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazabicyclo[3.2.2]non-4-yl)-
1,2-
benzisothiazole-3-carboxamide dihydroformate
137) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazabicyclo[3.2.2]non-4-yl)-
1,2-
benzisothiazole-3-carboxamide dihydroformate
138) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-l-yl-1,2-
benzisothiazole-3-
carboxamide
139) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide
140) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methylpiperazin-1-yl)-1,2-
benzisothiazole-3-carboxamide
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141) N-[(3R)-1-Azabicyclo[2.2:2]oct-3-yl]-6-(4-methyl-1,4-diazepan-l-yl)-1,2-
benzisothiazole-3-carboxamide
142) 1V [(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,4-diazepan-l-yl)-1,2-
benzisothiazole-3-carboxamide
143) 1V [(3R)-I-Azabicyclo[2.2.2]oct-3-yl]-6-(hexahydropyrrolo[1,2-a]pyrazin-
2(1H)-
yl)-1,2-benzisothiazole-3-carboxamide
144) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hexahydropyrrolo[1,2-a]pyrazin-
2(IH)-
yl)-1,2-benzisothiazole-3-carboxamide
145) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-2,5-
diazabicyclo[2.2.2]oct-2-
yl)-1,2-benzisothiazole-3-carboxamide
146) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-2,5-
diazabicyclo[2.2.2]oct-2-
yl )-1,2-benzisothiazole-3-carboxamide
147) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(8-methyl-3,8-
diazabicyclo[3.2.1]oct-3-
yl)-1,2-benzisothiazole-3-carboxamide
148) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-(8-methyl-3,8-
diazabicyclo[3.2.1]oct-3-
yl)-1,2-benzisothiazole-3-carboxamide
149) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-cyclopropyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
150) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-cyclopropyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
151) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(IS,4S)-5-(cyclopropylmethyl)-2,5-
diazabicyclo [2.2.1 ]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
152) N-[(3S)-1-Azabicyclo [2.2.2]oct-3-yl]-6-[(1S,4S)-5-(cyclopropylmethyl)-
2,5-
diazabicyclo [2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
153) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,4-diazepan-l-yl)-1,2-
benzisothiazole-3-carboxamide
154) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3 -carboxamide
155) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3R)-3-methoxypyrrolidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide
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156) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3S)-3-methoxypyrrolidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide
157) N-[(3R)-1-Azabicyclo[2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1,2-
benzisothiazole-3-carboxamide
158) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1,2-
benzisothiazole-3 -carboxamide
159) .N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-azabicyclo[2.2.2]oct-3-yloxy)-
1,2-
benzisothiazole-3-carboxamide
160) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-azabicyclo[2.2.2]oct-3-yloxy)-
1,2-
benzisothiazole-3-carboxamide
161) N,N'-di-(3S)-1-Azabicyclo[2.2.2]oct-3-yl-IH-indazole-1,3-dicarboxamide
162) N-[(3R)-I-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-4,5-dihydro-IH-imidazol-
2-
yl)-1 H-indazole-3-carboxamide
163) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-4,5-dihydro-lH-imidazol-
2-
yl)- I H-indazole-3-carboxamide
164) N-[(3.S)-1-Azabicyclo [2.2.2]oct-3-yl]-5-[(3S)-3-
(cyclopropylmethoxy)pyrrolidin-
1-yl]-1H-indazole-3-carboxamide
165) (3S')-1-(Chloromethyl)-3-[(1H-indazol-3-ylcarbonyl)amino]-1-
azoniabicyclo[2.2.2]octane chloride
166) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3S)-3-methoxypyrrolidin-1-yl]-IH-
indazole-3-carboxamide dihydroformate
167) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-chloroisothiazolo[5,4-b]pyridine-3-
carboxamide
168) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-y1]-6-(3-methylpiperazin-1-yl)-1,2-
benzisothiazole-3-carboxamide
169) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(octahydro-6H-pyrrolo[3,4-
b]pyridin-6-
yl)-1,2-benzisothiazole-3-carboxamide
170) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(octahydro-6H-pyrrolo[3,4-
b]pyridin-6-
yl)-1,2-benzisothiazole-3-carboxamide
171) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperazin-1-yl-1,2-benzisothiazole-
3-
carboxamide
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172) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperazin-l-yl-l,2-benzisothiazole-
3-
carboxamide
173) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazepan-l-yl)-1,2-
benzisothiazole-
3-carboxamide
174) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazepan-l-yl)-1,2-
benzisothiazole-
3-carboxamide
175) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-methylpiperazin-l-y1)-1,2-
benzisothiazole-3-carboxamide
176) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-methylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide
177) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(cyclopropylcarbonyl)piperazin-
l-yl]-
1,2-benzisothiazole-3 -carboxamide
178) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(cyclopropylcarbonyl)piperazin-
l-yl]-
1,2-benzisothiazole-3 -carboxamide
179) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(cyclopropylcarbonyl)octahydro-
6H-
pyrro lo [3,4-b] pyridin-6-yl]-1,2-benzisothiazol e-3 -carboxamide
180) N [(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(cyclopropylcarbonyl)octahydro-
6H-
pyrrolo[3,4-b]pyridin-6-y1]-1,2-benzisothiazole-3-carboxamide '
181) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-(cyclopropylcarbonyl)-
2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
182) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(IS,4S)-5-(cyclopropylcarbonyl)-
2,5-
diazabicyclo [2.2.1 ]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
183) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,4-dimethylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide
184) NN [(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-IH-indazole-3-carboxamide,
185) 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl-IH-indazole-6-
carboxylic
acid hydrochloride,
186) N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1]N(6),N(6)-dimethyl-IH-indazole-3,6-
dicarboxamide,
187) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(4-methylpiperazin-1-yl)carbonyl]-
IH-
indazole-3-carboxamide,
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188) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-1-
yl]carbonyl-
1 H-indazole-3-carboxamide,
189) NV [(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxyisothiazolo[5,4-
b]pyridine-3-
carboxamide,
190) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-
indazole-3-carboxamide,
wherein salts listed above can also be in free base form or in the form of
another
pharmaceutically acceptable salt, and free base forms listed above can also be
in the form
of a pharmaceutically acceptable salt,
wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of a solvate (such
as a hydrate),
wherein a compound listed above (in either a free base form or in the form of
a
pharmaceutically acceptable salt) can also be in the form of an N-oxide,
wherein a compound listed above (in a free base form or solvate or N-oxide
thereof, or in the form of a pharmaceutically acceptable salt or solvate
thereof) can also
be in the form of a polymorph, and
wherein if the compound exhibits chirality it can be in the form of a mixture
of
enantiomers such as a racemate or a mixture of diastereomers, or can be in the
form of a
single enantiomer or a single diastereomer.
The following table presents the structures for selected compounds of Formulas
I-
IV in accordance with the present invention:
Compound Structure Compound Structure
0
N
) C ) "
o S N N er' "' Q H
o
2
'N
67
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O,'Z~OH .Nj
N Hy(/~'V1
CH' p H 0 NH H
3) 0 4)
p O N
H.iC N/N N_
g C
H,
H N
oH
- H~1VVI///~~~VJJ .J
0 NH H o-
5) 6) O NH H
P N .N_ ~CH3 H3C
~s
oH ., =,~
H f~llvl
p~ N
7) o NH H ~) H
o m
oN
o~
H H
9) 0 NH H 0 10) O NN N p
Hp HO
H OH N pH
H N
H~' N
HV~~ O
1 1) HO 0 NH k 12) HO
0
H OH ~ / \N
er v\ r 5~ HO O
H
er
H'
H O~/OH O
13) HO H H 14) 0~0 H
0
/ \N
\N
,
H
x~
4
O NH H
15) " 16) NN
o N\ / ~ d
b H~COH
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D H N
17) ~ ~ 18) D N N
D oH
HN~/~ N ~ D I ~N DJ
N H Ok H~D N~N \ H~
H P~N
N
H ..N~
~j-_l~V O N ~'~r']\t1
19) H H 20) H
N
H,C.O N N
~ N !
HC-O ~
H,O~ H~C
y 4 H
y O NH H
21) O NH 22)
\N ~ \ N
H3C-0 _F F
~
DH H OH H
; p , = N
D~ D NH H .. ' O NH
23) 24)
o N\ p N'
N cH, \~ T-F
N
pH N( 1 y H
D- o ~iJH"lH~ 0 NH H
25) 26)
N
N F
N-.
~S
HN~ OH
0
27) 28) cH,
p N N
N_
~5 S ~O
o H N~
o H N
N
29) Zt H' 30)
"
N_ N_ ~ HS c
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H y
O NH 0 NH
31) 32)
"
v } N
N +
~p ' ~0 CHa
34) ,C~
33 N'cH O
)
.
Nf
~O1 H'C O
N
H H
35) 0 N.cN 36) F cH,
a F
~
0 N 0 v , N
H H
N
H H~
N'cH, 38) O NH H
37)
N
F ~, v N
H
F
N N
H H
H
39) o NH 40) o N'cH
a
~
~ HaC
N O N
_ H
N
H
O NH H
O
41) 0 1 H 42)
p H HN,~N H H H~OH
o
OH
F FI
F
43) 44)
.. " NN' v HN~ d : H H OH
N N N
o O
CA 02622677 2008-03-14
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Q 0 0 a
HlkOH
45) H 46)
,~~
HN / H N OH
~N H HN, /
N
O 0
S /N CH,
0
47) H N
~ H 48) II
H H" ' H
HN\ / H
N H N H
O 0
N 0
H
49) ,l H 50) ~ ' H N
HO j/
N
~
~ ' CiH S
N N
,
p , CH3
O
51) 52)
N ~N.S ~j ~N,s
N~ p CIH AN CIH
/
p N N
~ I 01
53) MJ'4N,e H, 54) ~ p N
~,,, Q N1 5/N
CIH
O.N Q
55) 0 NH 56)
H H ,V
'~\ .N H H
CF30 / N
~ /
~ H H3C S
H N
O q
ON
57) a H 58)
H .zt,,OH ~ !-ry
N N
H H
59) 0 NH H 60) 0 NH H
N C ~ N Ho~
H N_\ ~J o
71
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o q o q
H H
61) 62) ~ ~ p 0 ~ H
FC'
0 C
( f}
-~'1"'~~- ,{'
0 1 H 0 NH
63) S 1= H oH 64)
r o~ .
N ~ 3
H, H _ 4N
O NH H NH
65) 66)
$ N
p
N N
/
NC~
H H
H O H
N H
67) 0 NH 68)
~ N ~ N
H'G~..-N~
4
H H
O NH H
O NH H
69) 70) S
\N
O
/''- N
H3pp ~"
Hp--o
j p
~
71) 72) H H
s
O
HaC1
N3r'
72
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N
4N H
O H
H O NH
73) ~ \ H 0 74) \{J
H OH ~ / ciH
O N
J 1
\N H,C N
H~O
\ O
H 4
N
H
~
O NH H 0 NH H
75) 76)
S
H3C, H ~/ ,C 0~~, N
O
H ~N H a
O NH H 0 NH H
77) 78)
~ ~ N
0 ~ H
N N
H3C~-N HO V
H ~N H4
0 NH H 0 NH H
79) 80)
-N
F
NN
F_jO-0
H a
a H
_
O NHH 0 NHH
81) 82)
~ \ \N \ s
-
N-N N-N
ul H3C /~
73
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H N
N
Z-S,N NH H p C~/lH
83) 84) . N N
/ s
,~( /- N~
N-N H3C,p" v
/
~ CH,
N
0 N
85) ~ H H 86) p HN H
_~ S i H
N H3C'p \N
H3C-p G p
N
a H H '
H
O NH H o N
87) 88)
~ N
3N
~ \ rJ/
HC--\p 1 N F N
0 4N. 0 N
89) _
~ N N H 90)
NN
~ ~
N
0 N
, 0 N
91) 0\ H 92)
N N
\N~ ~0 r 1 F
1 ~I,VJ
74
CA 02622677 2008-03-14
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N
N
H H
H
O N H
N
93) 94)
N
HO'
\/ F N
H H
O N O N
95) ' 96)
N S
HO, ,..C S ~ ,.==~
H
; H N
0 N
97) ~ \J 98) ~ \, H H
H \ S \ s
', I N
\I/~/(\F\L-_-NJ, HO~
O H
N N
N O N
99) ! H 100) H
I/~- N1 ~N1
Ho,,,..' , % .,..=~ ,
N N
H
N
- H
0 N H
O N
101) N 102) N
' s s ~ s
HO HO
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H N
N
H H
N
=
O N
103) N 104)
0
,~..N\ F{
~ H
N
O N
N
= H H
~ H
N
105) 106) O N H
0
N H
H
O N o N
107) 108)
H
f 1 N
\ S p~ o
H O N
~ N
o N H
109) 110) o
=/
~o.....~ ~
O N~C~~ H
N w\~~
H O N
Ff
112)
~ .._
~..-o
76
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H
.~
H
0 N
4
/\ H
113) ~ 114) ~ "
9
~ \ 1
N
0
i~
N
o N N 0 N
H "
115) \ H " 116) c N
~ i s
~ s H N
'.0 H3C'NJ "H
N
H H 0 a
0 NH , H
117) 118) N H
N S
N S H N
H
HN "'H
HC-N 7H
H
- H Y ,v
0 NH H 0 H
NH
119) 120)
S
s 0 \ N
H N HaC ~
HN H
N
N
O N 0
"
121) H H 122) N
_~ S \ s
H3C H
H' F' O ~N 'H
77
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WO 2007/038367 PCT/US2006/037142
O N H
4
= H O NH H
H
123) 6~-
H3C. S 124) N
N H,C N
F3CJ F3CJ
H a
N
O N
O NH H H
125) 126) H
N ~\ S
H'C-0
HaC_O N
~ _( \
N
O N~ H _
H O NH H
127) -N H 128) _s N
s
H3C N I-~i H3C ~
H3C-~~ HC
N
H _ H~
0 N
0 NH H H H
129) ~ \ 'nt 130) s
N
HsC'-N
H3C-N CHa
CH,
N
H N ON "
O N o, = H
N~
H CH.
131) -N H 132) OH O
N
S s
H ~-N N3C~~N J
H,C-N H
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N
0 H' N ,
= H H
133) N 134) 'SN H
~ S OH
H N
N
H -/ OH N
OJ HJC- =
H'O~N H
H 4 - v
~
NHH o - H
135) 136) H
Z-S,N
/ oH H N ~ 71~7 oH
o
HaC-N H v
H N
~
OH O NH H O N
= H
137) OH 138) H
S
~O
N
N H
0 N '
= H
H 0 NH
H
139) N 140)
S ~N
N S
~N
H3C N~
H3C
/N~ HN
0 N~~ =
H
H 0 NH
141) 0 ' N H 142)
N
H3C-N
H3C'N~ ~ J
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NN H
,
' H
H o NH
143) 'SN H 144)
~
N ~_ S
> N
N_f '~
N
N
N H
0
H
H O NH
145) N H 146)
&N' S s N
r
H3C N
H3C
O N~ N :w 1
E N
H N
147) -N H 148) a
S
~N
~N
H3C-N
N
O H4 N H _
H NH H
149) N H 150) H~N CZ-SN
N H
V 7\-/}~ HN
V N H
O N ;~ HN
H 0 NH H
151) -N H 152)
S \N
H
N H N
H
CA 02622677 2008-03-14
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a N
H CH3 N
153) 0 NH H 154) 0 H
H
H C, N
~ N
N / S
'-/ S
H a IC H3 /N~
tJ~
155) IC H3 O NH H 156) O, H
0
CN N H
S S
N H
4
O
N H
157) H 158) 0 NH
H,C e ~ N -SN
S H3c=
O '
N }{
-'
O
H H
159) H H 160) 0 NH
C~ N
~N
N S
~ S ~ ~ \ r
0
N
HN
H O H
161) o NH 162)
N H,('N~ N \NN
;L_h(~O ~
H H N
0
N N
N
N
163) ~ H H 164) N H
\ N ~0=,.
N1I ~ N N
N N
N~ ~ J
81
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CI
H 4 H N
CI
165) 0 NH H 166) o H, a NH H
'o I'
H'OH
e ~ \N
ON
4N
H 0 N
H H
167) 0 NH 168) N H
s
S
HJ
~CN
CI
N
H N H
N 0 NH H
H H
169) 170) .
/ ~ s
N
H N
H
N
H H ~N~
'\v11~1+
'
0 NH H O N
- H
171) ~ \ \N 172) S H
S
CN p
N~ H
N
0 N~ H -
H
= H 0 NH
173) N H 174)
s s
N
N
HN~ H
N
Nav-" H
H 0 NH H
175) H 176)
H3 S
N H3C
J 'f\ N
H NJ
H
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_N-L H
_
'(V/lHV\ 0 NH H
177) 178) _ N
~N S
O N
zzzl~
~
N
Ozz:/
N H
_~
O
H 0 NH H
H
179) c~ s 180)
N N
NN "4
0 p NH"
~ H
181) 182)
HN "N N H
H
0 N 6
~
H H
183) ~~, N H 184) 0 NH
s
N
HO g N
N H
H,0 N /~
H _~ H _
H H
0 NH 0 NH
185) 186)
N N
N N
CIH
H H
HO N
0 0
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H~~ \ a
H H
0 NH O NH
187) 188)
H -O / \ H
N \__,,N ~N
O O
N
H o
p
189) 0 N H 190) N~j~=H~
0 H
N N I
~O N S
Additional aspects include pharmaceutical compositions comprising a compound
of this invention and a pharmaceutically acceptable carrier and, optionally,
another active
agent as discussed below; a method of stimulating or activating inhibiting
alpha-7
nicotinic receptors, e.g., as determined by a conventional assay or one
described herein,
either in vitro or in vivo (in an animal, e.g., in an animal model, or in a
mammal or in a
human); a method of treating a neurological syndrome, e.g., loss of memory,
especially
long-term memory, cognitive impairment or decline, memory impairment, etc.
method of
treating a disease state modulated by nicotinic alpha-7 activity, in a mammal,
e.g., a
human, e.g., those mentioned herein.
The compounds of the present invention may be prepared conventionally. Some
of the known processes that can be used are described below. All starting
materials are
known or can be conventionally prepared from known starting materials by one
of
ordinary skill.
Acids that were used in the preparation of the bicyclobase amides were
commercially available or were prepared by known procedures described in the
literature
or as described below. For= example, indazole-3-carboxylic acid was
commercially
available. A variety of the simple substituted indazole-3-acids, such as the
84
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WO 2007/038367 PCT/US2006/037142
bromoindazole acids, were prepared from the corresponding isatins by basic
hydrolysis,
diazotization, and reduction (Snyder, H.R. et al., J. Am. Chem. Soc. 1952, 74,
2009).
Several substituted indazole-3-acids were prepared by modifying existing
indazole acids or esters. For example, N(1)- and N(2)-protected indazole acids
were
prepared from the ester through reaction with methoxyethoxymethyl chloride
(MEM-Cl)
or trimethylsilylethoxymethyl chloride (SEM-Cl) and either sodium hydride or
di-
isopropylethylamine. N(1)-Alkylated indazole-3-carboxylic acids were prepared
from
the corresponding indazole esters by standard alkylation or Mitsunobu
procedures. N(1)-
Arylated indazole-3-carboxylic acids were prepared from the corresponding
indazole
esters by copper mediated cross couplings with boronic acids. Non-aromatic
heterocyclic
derivatives were prepared from the corresponding bromides by metal-halogen
exchange,
trapping of indazole aryllithiums with ketones, followed by reduction or acid
mediated
elimination. Aromatic substituted indazole-3-acids were prepared from the
corresponding bromides via palladium mediated cross-coupling with boronic
acids or aryl
zinc reagents (Reeder, M.R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696).
Amino
indazole acids were prepared using a palladium mediated cross-coupling
reaction with
secondary amines. Phenol derivatives were prepared from the corresponding
methoxy
acids using boron tribromide. 6-Amino- and 6-phenyl-7-azaindazole-3-carboxylic
acids
were prepared from the commercially available 6-fluoro material by reaction
with a
secondary amine or by nickel mediated cross-coupling with aryl Grignard
reagents.
Several substituted indazole-3-acids were prepared from benzene derivatives.
For
example, 5-difluoromethoxyindazole-3-acid was prepared from 3-bromo-4-
nitrophenol
by reaction with ethyl difluoroacetate, reaction with diethyl malonate,
decarboxylative
saponification, esterification, reduction of the nitro group, and
diazotization. 6-
Difluoromethoxyindazole-3-acid was prepared in a similar manner from 2-bromo-5-
difluoromethoxynitrobenzene. The 2-bromo-5-difluoromethoxynitrobenzene was
prepared from 4-nitrophenol by ether formation, nitro reduction with
concomitant
protection as the amide, nitration, amide hydrolysis, and a Sandmeyer reaction
with
copper (I) bromide. 6-Benzyloxyindazole-3-carboxylic acid and ester were
prepared
from 4-methoxynitrobenzene by nitro reduction with concomitant protection as
the
CA 02622677 2008-03-14
WO 2007/038367 PCT/US2006/037142
amide, nitration, amide hydrolysis, Sandmeyer reaction with copper (I)
bromide, and
demethylation. The phenol was alkylated with benzyl bromide and the
arylbromide was
subjected to reaction with diethyl malonate, decarboxylative saponification,
esterification, reduction of the nitro group, and diazotization. The 5-
benzyloxy analog
was prepared in a similar manner from 4-benzyloxy-2-bromonitrobenzene (Parker,
K.A.;
Mindt, T.L. Org. Lett. 2002, 4, 4265.) The benzyl group was removed by
hydrogenolysis
and the resulting phenol was transformed to ether derivatives via either
alkylation or
Mitsunobu reaction conditions. 4-Methoxyindazole acid was prepared from 4-
methoxyaniline by amide formation, nitration, amide hydrolysis, Sandmeyer
reaction
with copper (I) bromide, nitro reduction, isatin formation and rearrangement
to the
indazole, followed by hydrogenolytic removal of the bromine. 5-Azaindazole-3 -
acid was
prepared from 4-chloropyridine by metallation and trapping with
diethyloxalate,
cyclization with hydrazine, and saponification. 6-Azaindazole-3-acid was
prepared from
4-chloro-3-nitropyridine by reaction with a malonate anion, decarboxylation,
nitro
reduction, diazotization, and saponification.
The benziosoxazole esters were prepared from simple benzene derivatives using
similar techniques. For example, ethyl 6-bromobenzisoxazole-3-carboxylate was
prepared from 2-nitro-1,4-dibromobenzene by reaction with dimethylmalonate, a
saponification/decarboxylation sequence, esterification, and reaction with
isoamyl nitrite
under basic conditions. The 6-methoxybenzisoxazole ester compound was
prepared,
analogously, from 2,4-dinitrochlorobenzene. Reduction of the resultant 6-nitro
group
followed by diazotization and oxidation provided the 6-hydroxy compound. The
ether
was obtained by simple alkylation.
The benzisothiazole carboxylic acids were also prepared using similar
strategies
outlined for the indazole acids. For example, 6-methoxybenzisothiazole-3-
carboxylic
acid was prepared from 3-methoxythiophenol by reaction with oxalyl chloride
and
aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide,
and
sodium hydroxide. Amino substituted benzisothiazole acids were prepared from
the
requisite bromide by a palladium mediated cross-coupling reaction with
secondary
amines or benzophenone imine. The primary and secondary amines generated this
way
86
CA 02622677 2008-03-14
WO 2007/038367 PCT/US2006/037142
serve as intermediates for other ligands. For example, the amines were
transformed into
tertiary amines and amides using standard reductive amination and acylation
reactions
practiced by those of ordinary skill in the art. 7-Azabenzisothiazole-3-
carboxylic acid
was prepared from 2-chloronicotinoyl chloride by reaction with the
diethylmalonate
anion and decarboxylation followed by reaction of the ketone with sulfer,
ammonium
hydroxide, and ammonia to generate the 7-aza-3-methylbenzisothiazole core. The
acid
was installed using a benzylic oxidation with N-bromosuccinamide and
hydrolysis,
followed by basic permanganate oxidation of the alcohol. 7-Aza-6-
chlorobenzisothiazole-3-acid was synthesized from the 7-aza-3-
methylbenzisothiazole
core by oxidation of the pyridine ring nitrogen followed by a rearrangement
reaction
mediated by triphosgene to install a chlorine atom at the 6-position. The
synthesis was
completed by a benzylic oxidation in a similar manner to the unsubstituted
azabenzisothiazole acid.
The bicycloamines, 3-aminoquinuclidine and the R- and S enantiomers thereof,
used in the preparation of the bicyclobase amides were commercially available.
The N-
alkylated quinuclidines were prepared by acylation of 3-aminoquinuclidine
followed by
reduction of the amide.
The bicyclobase amides were prepared from the acids and the bicycloamines
using standard peptide coupling agents, such as O-(benzotriazol-1-yl)-N,N,N,N'-
tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-l-yl)-
N,N,N;N'-tetramethyluronium tetrafluoroborate (TBTU), hydroxybenztriazole
(HOBt)
and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), carbonyl
diimidazole
(CDI), and 2-chloro-1,3,-dimethylimidazolinium hexafluorophosphate (CIP), or
by
converting the acids to the corresponding acid chloride followed by reaction
with the
bicycloamine (Macor, J.E.; Gurley, D.; Lanthorn, T.; Loch, J.; Mack, R.A.;
Mullen, G.;
Tran, 0.; Wright, N.; and J. E. Macor et al., "The 5-HT3-Antagonist
Tropisetron (ICS
205-930) was a Potent and Selective a-7 Nicotinic Receptor Partial Agonist,"
Bioorg.
Med. Chem. Lett. 2001, 9, 319-321). The couplings were generally performed at
room
temperature for 18-24 hours. The resultant adducts were isolated and purified
by
87
CA 02622677 2008-03-14
WO 2007/038367 PCT/US2006/037142
standard techniques practiced by those of ordinary skill in the art, such as
chromatography or recrystallization.
The nicotinic ligands can, alternatively, be prepared by modification of other
nicotinic ligands. For example, the cyclic urea ligand was prepared from the
corresponding bromide ligand by a palladium-catalyzed cross-coupling reaction.
Amino-
substituted ligands were prepared by similar palladium mediated coupling
reactions with
secondary amines or benzophenone imine. The primary and secondary amines
generated
this way serve as intermediates for other ligands, as understood by those of
ordinary skill
in the art. 5-Alkoxybenzisothiazole ligands were prepared by palladium
mediated cross
coupling with pinacolborane dimer followed by oxidation and alkylation. In
some cases,
the indazole quinuclidine carboxamides were derivatized at the indazole
nitrogen under
Mitsunobu conditions or through the copper mediated coupling with boronic
acids.
Quaternary quinuclidine salts were prepared by the reaction of the final
product with
alkylating agents. N-Oxides were prepared by the reaction of the final product
with
oxidants.
One of ordinary skill in the art will recognize that compounds of Formulas I-
IV
can exist in different tautomeric and geometrical isomeric forms. All of these
compounds, including cis isomers, trans isomers, diastereomic mixtures,
racemates,
nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers,
are within
the scope of the present invention. Substantially pure enantiomers contain no
more than
5% w/w of the corresponding opposite enantiomer, preferably no more than 2%,
most
preferably no more than 1%.
The optical isomers can be obtained by resolution of the racemic mixtures
according to conventional processes, for example, by the formation of
diastereoisomeric
salts using an optically active acid or base or formation of covalent
diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric,
ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can
be
separated into their individual diastereomers on the basis of their physical
and/or
chemical differences by methods known to those skilled in the art, for
example, by
88
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WO 2007/038367 PCT/US2006/037142
chromatography or fractional crystallization. The optically active bases or
acids are then
liberated from the separated diastereomeric salts. A different process for
separation of
optical isomers involves the use of chiral chromatography (e.g., chiral HPLC
columns),
with or without conventional derivation, optimally chosen to maximize the
separation of
the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel,
e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely selectable.
Enzymatic
separations, with or without derivitization, are also useful. The optically
active
compounds of Formulas I-IV can likewise be obtained by utilizing optically
active
starting materials in chiral synthesis processes under reaction conditions
which do not
cause racemization.
In addition, one of ordinary skill in the art will recognize that the
compounds can
be used in different enriched isotopic forms, e.g., enriched in the content of
2H, 3H, "C,
13 C and/or 14C. In one particular embodiment, the compounds are deuterated.
Such
deuterated forms can be made by the procedures described in U.S. Patent Nos.
5,846,514
and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997,
deuteration
can improve the efficacy and increase the duration of action of drugs.
Deuterium substituted compounds can be synthesized using various methods such
as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and
Applications of Radiolabeled Compounds for Drug Discovery and Development.
[In:
Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538
CAPLUS; Kabalka, George W.; Vanna, Rajender S. The synthesis of mdiolabeled
compounds via organometallic intermediates. Tetrahedron (1989), 45(21), 6601-
21,
CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and
Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem.
(1981),
64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229
CAPLUS.
Where applicable, the present invention also relates to useful forms of the
compounds as disclosed herein, including free base forms and pharmaceutically
acceptable salts or prodrugs of all the compounds of the present invention for
which salts
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or prodrugs can be prepared. Pharmaceutically acceptable salts include those
obtained by
reacting the main compound, functioning as a base, with an inorganic or
organic acid to
form a salt, for example, salts of hydrochloric acid, sulfuric acid,
phosphoric acid,
methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,
succinic acid,
citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid,
fumaric acid,
salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable
salts also
include those in which the main compound functions as an acid and is reacted
with an
appropriate base to form, e.g., sodium, potassium, calcium, magnesium,
ammonium, and
choline salts. Those skilled in the art will further recognize that acid
addition salts of the
claimed compounds may be prepared by reaction of the compounds with the
appropriate
inorganic or organic acid via any of a number of known methods. Alternatively,
alkali
and alkaline earth metal salts can be prepared by reacting the compounds of
the invention
with the appropriate base via a variety of known methods.
The following are further examples of acid salts that can be obtained by
reaction
with inorganic or organic acids: acetates, adipates, alginates, citrates,
aspartates,
benzoates, benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates,
cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates,
glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates,
hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates,
nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates,
persulfates, 3-
phenylpropionates, picrates, pivalates, propionates, succinates, tartrates,
thiocyanates,
tosylates, mesylates and undecanoates.
For example, the pharmaceutically acceptable salt can be a hydrochloride, a
hydrobromide, a hydroformate, or a maleate.
The salts of the present invention also include quaternary ammonium salts
obtained by reacting the main compound, functioning as a nucleophile, with
agents
bearing nucleofugal groups. Examples of those agents include, but are not
limited to,
methyl iodide, methyl bromide, methyl chloride, methyl triflate, methyl
tosylate, methyl
mesylate, ethyl iodide, ethyl bromide, ethyl chloride, ethyl triflate, ethyl
tosylate, ethyl
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mesylate, propyl iodide, propyl bromide, propyl chloride, cyclopropylmethyl
bromide,
benzyl bromide, methylene chloride, and dichloroethane. One skilled in the art
will
recognize that the list of example agents presented is non-exhaustive and can
be
expanded within reason.
For example, the quaternary ammonium salt can be formed at the N atom of the
azabicyclo structute as shown in the following formula:
~
-N A-
-r
wherein Z is, for example, methyl, chloromethyi, ethyl, chloroethyl, propyl,
cyclopropylmethyl, or benzyl, and the corresponding anion A is, for example,
iodide,
bromide, chloride, triflate, tosylate, or mesylate. See, for example,
compounds 1, 13, and
165.
Preferably, the salts formed are pharmaceutically acceptable for
administration to
mammals. However, pharmaceutically unacceptable salts of the compounds are
suitable
as intermediates, for example, for isolating the compound as a salt and then
converting
the salt back to the free base compound by treatment with an alkaline reagent.
For
example, alkyl halide addition salts (e.g., salts formed by reaction with
methyl iodide)
may be envisaged. The free base can then, if desired, be converted to a
pharmaceutically
acceptable acid addition salt.
One of ordinary skill in the art will also recognize that some of the
compounds of
Formulas I, II, III, and IV can exist in different polymorphic forms. As known
in the art,
polymorphism is an ability of a compound to crystallize as more than one
distinct
crystalline or "polymorphic" species. A polymorph is a solid crystalline phase
of a
compound with at least two different arrangements or polymorphic forms of that
compound molecule in the solid state. Polymorphic forms of any given compound
are
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defined by the same chemical formula or composition and are as distinct in
chemical
structure as crystalline structures of two different chemical compounds.
One of ordinary skill in the art will further recognize that compounds of
Formulas
I, II, III, and IV can exist in different solvate forms. Solvates of the
compounds of the
invention may also form when solvent molecules are incorporated into the
crystalline
lattice structure of the compound molecule during the crystallization process.
The compounds of the invention can be administered alone or as an active
ingredient of a formulation. Thus, the present invention also includes
pharmaceutical
compositions of compounds of Formulas I-IV, containing, for example, one or
more
pharmaceutically acceptable carriers.
Numerous standard references are available that describe procedures for
preparing
various formulations suitable for administering the compounds according to the
invention. Examples of potential formulations and preparations are contained,
for
example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association (current edition); Pharmaceutical Dosage Forms: Tablets
(Lieberman,
Lachman and Schwartz, editors) current edition, published by Marcel Dekker,
Inc., as
well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593
(current
edition).
In view of their alpha-7 stimulating activity and, preferably their high
degree of
selectivity, the compounds of the present invention can be administered to
anyone
needing stimulation of alpha-7 receptors. Administration may be accomplished
according to patient needs, for example, orally, nasally, parenterally
(subcutaneously,
intraveneously, intramuscularly, intrasternally and by infusion) by
inhalation, rectally,
vaginally, topically and by ocular administration.
Various solid oral dosage forms can be used for administering compounds of the
invention including such solid forms as tablets, gelcaps, capsules, caplets,
granules,
lozenges and bulk powders. The compounds of the present inveption can be
administered
alone or combined with various pharmaceutically acceptable carriers, diluents
(such as
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sucrose, mannitol, lactose, starches) and excipients known in the art,
including but not
limited to suspending agents, solubilizers, buffering agents, binders,
disintegrants,
preservatives, colorants, flavorants, lubricants and the like. Time release
capsules, tablets
and gels are also advantageous in administering the compounds of the present
invention.
Various liquid oral dosage forms can also be used for administering compounds
of the inventions, including aqueous and non-aqueous solutions, emulsions,
suspensions,
syrups, and elixirs. Such dosage forms can also contain suitable inert
diluents known in
the art such as water and suitable excipients known in the art such as
preservatives,
wetting agents, sweeteners, flavorants, as well as agents for emulsifying
and/or
suspending the compounds of the invention. The compounds of the present
invention
may be injected, for example, intravenously, in the form of an isotonic
sterile solution.
Other preparations are also possible.
Suppositories for rectal administration of the compounds of the present
invention
can be prepared by mixing the compound with a suitable excipient such as cocoa
butter,
salicylates and polyethylene glycols. Formulations for vaginal administration
can be in
the form of a pessary, tampon, cream, gel, paste, foam, or spray formula
containing, in
addition to the active ingredient, such suitable carriers as are known in the
art.
For topical administration the pharmaceutical composition can be in the form
of
creams, ointments, liniments, lotions, emulsions, suspensions, gels,
solutions, pastes,
powders, sprays, and drops suitable for administration to the skin, eye, ear
or nose.
Topical administration may also involve transdermal administration via means
such as
transdermal patches.
Aerosol formulations suitable for administering via inhalation also can be
made.
For example, for treatment of disorders of the respiratory tract, the
compounds according
to the invention can be administered by inhalation in the form of a powder
(e.g.,
micronized) or in the form of atomized solutions or suspensions. The aerosol
formulation
can be placed into a pressurized acceptable propellant.
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The compounds can be administered as the sole active agent or in combination
with other pharmaceutical agents such as other agents used in the treatment of
cognitive
impairment and/or memory loss, e.g., other a-7 agonists, PDE4 inhibitors,
calcium
channel blockers, muscarinic ml and m2 modulators, adenosine receptor
modulators,
ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin
modulators, canabinoid modulators, and cholinesterase inhibitors (e.g.,
donepezil,
rivastigimine, and glanthanamine). In such combinations, each active
ingredient can be
administered either in accordance with their usual dosage range or a dose
below their
usual dosage range.
The compounds of the invention can be used in conjunction with "positive
modulators" which enhance the efficacy of nicotinic receptor agonists. See,
e.g., the
positive modulators disclosed in WO 99/56745, WO 01/32619, and WO 01/32622.
Such
combinational therapy can be used in treating conditions/diseases associated
with reduced
nicotinic transmission.
Further the compounds may be used in conjunction with compounds that bind to
A(3 peptides and thereby inhibit the binding of the peptides to a7nACh
receptor subtypes.
See, e.g., WO 99/62505.
The present invention further includes methods of treatment that involve
activation of a-7 nicotinic receptors. Thus, the present invention includes
methods of
selectively activating/stimulating a-7 nicotinic receptors in a patient (e.g.,
a mammal
such as a human) wherein such activation/stimulation has a therapeutic effect,
such as
where such activation may relieve conditions involving neurological syndromes,
such as
the loss of memory, especially long-term memory. Such methods comprise
administering to a patient (e.g., a mammal such as a human), an effective
amount of a
compound of Formulas I-IV, alone or as part of a formulation, as disclosed
herein.
In accordance with a method aspect of the invention, there is provided a
method
of treating a patient (e.g., a mammal such as a human) suffering from a
disease state (e.g.,
memory impairment) comprising administering to the patient a compound
according to
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Formulas I-IV. Preferably, the disease state involves decreased nicotinic
acetylcholine
receptor activity.
In accordance with a method aspect of the invention there is provided a method
for the treatment or prophylaxis of a disease or condition resulting from
dysfunction of
nicotinic acetylcholine receptor transmission in a patient (e.g., a mammal
such as a
human) comprising administering an effective amount of a compound according to
Formulas I-IV.
In accordance with a method aspect of the invention there is provided a method
for the 'treatment or prophylaxis of a disease or condition resulting from
defective or
malfunctioning nicotinic acetylcholine receptors, particularly a7nACh
receptors, in a
patient (e.g., a mammal such as a human) comprising administering an effective
amount
of a compound according to Formulas I-IV.
In accordance with a method aspect of the invention there is provided a method
for the treatment or prophylaxis of a disease or condition resulting from
suppressed
nicotinic acetyicholine receptor transmission in a patient (e.g., a mammal
such as a
human) comprising administering an amount of a compound according to Formulas
I-IV
effective to activate a7nACh receptors.
In accordance with another method aspect of the invention there is provided a
method for the treatment or prophylaxis of a psychotic disorder, a cognition
impairment
(e.g., memory impairment), or neurodegenerative disease in a patient (e.g., a
mammal
such as a human) comprising administering an effective amount of a compound
according to Formulas I-IV.
In accordance with another method aspect of the invention there is provided a
method for the treatment or prophylaxis of a disease or condition resulting
from loss of
cholinergic synapses in a patient (e.g., a mammal such as a human) comprising
administering an effective amount of a compound according to Formulas I-IV.
In accordance with another method aspect of the invention there is provided a
method for the treatment or prophylaxis of a neurodegenerative disorder by
activation of
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a7nACh receptors in a patient (e.g., a mammal such as a human) comprising
administering an effective amount of a compound according to Formulas I-IV.
In accordance with another method aspect of the invention there is provided a
method for protecting neurons in a patient (e.g., a mammal such as a human)
from
neurotoxicity induced by activation of a7nACh receptors comprising
administering an
effective amount of a compound according to Formulas I-IV.
In accordance with another method aspect of the invention there is provided a
method for the treatment or prophylaxis of a neurodegenerative disorder by
inhibiting the
binding of A(3 peptides to a7nACh receptors in a patient (e.g., a mammal such
as a
human) comprising administering an effective amount of a compound according to
Formulas I-IV.
In accordance with another method aspect of the invention there is provided a
method for protecting neurons in a patient (e.g., a mammal such as a human)
from
neurotoxicity induced by A(3 peptides comprising administering an effective
amount of a
compound according to Formulas I-IV.
In accordance with another method aspect of the invention there is provided a
method for alleviating inhibition of cholinergic function induced by AP
peptides in a
patient (e.g., a mammal such as a human) comprising administering an effective
amount
of a compound according to Formulas I-IV.
A subject or patient in whom administration of the therapeutic compound is an
effective therapeutic regimen for a disease or disorder is preferably a human,
but can be
any animal, including a laboratory animal in the context of a clinical trial
or screening or
activity experiment. Thus, as can be readily appreciated by one of ordinary
skill in the
art, the methods, compounds and compositions of the present invention are
particularly
suited to administration to any animal, particularly a mammal, and including,
but by no
means limited to, humans, domestic animals, such as feline or canine subjects,
farm
animals, such as but not limited to bovine, equine, caprine, ovine, and
porcine subjects,
wild animals (whether in the wild or in a zoological garden), research
animals, such as
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mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such
as chickens,
turkeys, songbirds, etc., i.e., for veterinary medical use.
The compounds of the present invention are nicotinic alpha-7 ligands,
preferably
agonists, especially partial agonists, for the alpha-7 nicotinic acetylcholine
receptor.
Assays for determining nicotinic acetylcholine activity are known within the
art. See,
e.g., Davies, A.R., et al., Characterisation of the binding of
[3H]methyllycaconitine= a
new radioligand for labelling alpha 7-type neuronal nicotinic acetylcholine
receptors.
Neuropharmacology, 1999. 38(5): p. 679-90. As agonists for a7nACh receptors,
the
compounds are useful in the prophylaxis and treatment of a variety of diseases
and
conditions associated with the central nervous system. Nicotinic acetylcholine
receptors
are ligand-gastrol ion-channel receptors that are composed of five subunit
proteins which
form a central ion-conducting pore. Presently, there are eleven known neuronal
nACh
receptor subunits (a2 - 0 and (32 -(34). There are also five further subunits
expressed in
the peripheral nervous system (al, (31, ,y, S, s).
The nACh receptor subtypes can be homopentameric or heteropentameric. The
subtype which has received considerable attention is the homopentameric a7
receptor
subtype formed from five 0 subunits. The a7nACh receptors exhibit a high
affinity for
nicotine (agonist) and for a-bungarotoxin (antagonist). Studies have shown the
a7nACh
receptor agonists can be useful in the treatment of psychotic diseases,
neurodegenerative
diseases, and cognitive impairments, among other things. While nicotine is a
known
agonist, there is a need for the development of other a7nACh receptor
agonists,
especially selective agonists, which are less toxic or exhibit fewer side
effects than
nicotine.
The compound anabaseine, i.e., 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine is a
naturally occurring toxin in certain marine worms (nemertine worms) and ants.
See, e.g.,
Kem et al., Toxicon, 9:23, 1971. Anabaseine is a potent activator of mammalian
nicotinic receptors. See, e.g., Kem, Amer. Zoologist, 25, 99, 1985. Certain
anabaseine
analogs such as anabasine and DMAB (3-[4-(dimethylamino)benzylidene]-3,4,5,6-
tetrahydro-2',3'-bipyridine) are also known nicotinic receptor agonists. See,
e.g., US
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5,602,257 and WO 92/15306. One particular anabaseine analog, (E-3-[2,4-
dimethoxy-
benzylidene]-anabaseine, also known as GTS-21 and DMXB (see, e.g., US
5,741,802),
is a selective partial a7nACh receptor agonist that has been studied
extensively. For
example, abnormal sensory inhibition is a sensory processing deficit in
schizophrenics
and GTS-21 has been found to increase sensory inhibition through interaction
with
a7nACh receptors. See, e.g., Stevens et al., Psychopharmacology, 136: 320-27
(1998).
Another compound which is known to be a selective a7nACh receptor agonist is
Tropisetron, i.e., laH, 5aH-tropan-3a-yl indole-3-carboxylate. See J. E. Macor
et al.,
The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7
Nicotinic
Receptor Partial A og nist. Bioorg. Med. Chem. Lett. 2001, 319-321).
Agents that bind to nicotinic acetylcholine receptors have been indicated as
useful
in the treatment and/or prophylaxis of various diseases and conditions,
particulariy
psychotic diseases, neurodegenerative diseases involving a dysfunction of the
cholinergic
system, and conditions of memory and/or cognition impairment, including, for
example,
schizophrenia, anxiety, mania, depression, manic depression [examples of
psychotic
disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease
[examples of
neurodegenerative diseases], cognitive disorders (such as Alzheimer's disease,
Lewy
Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss,
cognition deficit, attention deficit, Attention Deficit Hyperactivity
Disorder), and other
uses such as treatment of nicotine addiction, inducing smoking cessation,
treating pain
(i.e., analgesic use), providing neuroprotection, and treatingjetlag. See,
e.g., WO
97/30998; WO 99/03850; WO 00/42044; WO 01/36417; Holladay et al., J. Med.
Chem.,
40:26, 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem., Chapter 5,
41-51
(2000); Stevens et al., Psychopharmatology, (1998) 136: 320-27; and Shytle et
al.,
Molecular Psychiatry, (2002), 7, pp. 525-535.
Thus, in accordance with the invention, there is provided a method of treating
a
patient, especially a human, suffering from psychotic diseases,
neurodegenerative
diseases involving a dysfunction of the cholinergic system, and conditions of
memory
and/or cognition impairment, including, for example, schizophrenia, anxiety,
mania,
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depression, manic depression [examples of psychotic disorders], Tourette's
syndrome,
Parkinson's disease, Huntington's disease [examples of neurodegenerative
diseases],
and/or cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia,
Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition
deficit,
attention deficit, Attention Deficit Hyperactivity Disorder) comprising
administering to
the patient an effective amount of a compound according to Formulas I-IV.
Neurodegenerative disorders included within the methods of the present
invention
include, but are not limited to, treatment and/or prophylaxis of Alzheimer's
diseases,
Pick's disease, diffuse Lewy Body disease, progressive supranuclear palsy
(Steel-
Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor
neuron
diseases including amyotrophic lateral sclerosis, degenerative ataxias,
cortical basal
degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing
panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies,
primary
progressive aphasia, striatonigral degeneration, Machado-Joseph
disease/spinocerebellar
ataxia type 3, olivopontocerebellar degenerations, Gilles De La Tourette's
disease, bulbar,
pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy
(Kennedy's
disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-
Hoffmann
disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,
familial
spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis,
progressive
multifocal leukoencephalopathy, prion diseases (such as Creutzfeldt-Jakob,
Gerstmann-
Straussler-Scheinker disease, Kuru and fatal familial insomnia), and
neurodegenerative
disorders resulting from cerebral ischemia or infarction including embolic
occlusion and
thrombotic occlusion as well as intracranial hemorrhage of any type
(including, but not
limited to, epidural, subdural, subarachnoid and intracerebral), and
intracranial and
intravertebral lesions (including, but not limited to, contusion, penetration,
shear,
compression and laceration).
In addition, a7nACh receptor agonists, such as the compounds of the present
invention can be used to treat age-related dementia and other dementias and
conditions
with memory loss including age-related memory loss, senility, vascular
dementia, diffuse
white matter disease (Binswanger's disease), dementia of endocrine or
metabolic origin,
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dementia of head trauma and diffuse brain damage, dementia pugilistica and
frontal lobe
dementia. See, e.g., WO 99/62505. Thus, in accordance with the invention,
there is
provided a method of treating a patient, especially a human, suffering from
age-related
dementia and other dementias and conditions with memory loss comprising
administering
to the patient an effective amount of a compound according to Formulas I-IV.
Thus, in accordance with a further embodiment, the present invention includes
methods of treating patients suffering from memory impairment due to, for
example,
Alzheimer's disease, mild cognitive impairment due to aging, schizophrenia,
Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease,
depression,
aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct
dementia and
other neurological conditions, as well as HIV and cardiovascular diseases,
comprising
administering an effective amount of a compound according to Formulas I-IV.
Amyloid precursor protein (APP) and A(3 peptides derived therefrom, e.g.,
API_40,
A(3142 , and other fragments, are known to be involved in the pathology of
Alzheimer's
disease. The A(31_42peptides are not only implicated in neurotoxicity but also
are known
to inhibit cholinergic transmitter function. Further, it has been determined
that A(3
peptides bind to a7nACh receptors. Thus, agents which block the binding of the
A(3
peptides to a-7 nAChRs are useful for treating neurodegenerative diseases.
See, e.g.,
WO 99/62505. In addition, stimulation a7nACh receptors can protect neurons
against
cytotoxicity associated with Appeptides. See, e.g., Kihara, T. et al., Ann.
Neuro1.,1997,
42, 159.
Thus, in accordance with an embodiment of the invention there is provided a
method of treating and/or preventing dementia in an Alzheimer's patient which
comprises
administering to the subject a therapeutically effective amount of a compound
according
to Formulas I-IV to inhibit the binding of an amyloid beta peptide
(preferably, A(3I-42)
with riACh receptors, preferable a7nACh receptors, most preferably, human
a7nACh
receptors (as well as a method for treating and/or preventing other clinical
manifestations
of Alzheimer's disease that include, but are not limited to, cognitive and
language
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deficits, apraxias, depression, delusions and other neuropsychiatric symptoms
and signs,
and movement and gait abnormalities).
The present invention also provides methods for treating other amyloidosis
diseases, for example, hereditary cerebral angiopathy, nonneuropathic
hereditary
amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean
fever,
Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related
amyloidosis,
chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
In addition, nicotinic receptors have been implicated as playing a role in the
body's response to alcohol ingestion. Thus, agonists for a7nACh receptors can
be used in
the treatment of alcohol withdrawal and in anti-intoxication therapy. Thus, in
accordance
with an embodiment of the invention there is provided a method of treating a
patient for
alcohol withdrawal or treating a patient witll anti-intoxication therapy
comprising
administering to the patient an effective amount of a compound according to
Formulas I-
IV.
Agonists for the a7nACh receptor subtypes can also be used for neuroprotection
against damage associated with strokes and ischemia and glutamate-induced
excitotoxicity. Thus, in accordance with an embodiment of the invention there
is
provided a method of treating a patient to provide for neuroprotection against
damage
associated with strokes and ischemia and glutamate-induced excitotoxicity
comprising
administering to the patient an effective amount of a compound according to
Formulas I-
IV.
As noted above, agonists for the a7nACh receptor subtypes can also be used in
the treatment of nicotine addiction, inducing smoking cessation, treating
pain, and
treating jetlag, obesity, diabetes, and inflammation. Thus, in accordance with
an
embodiment of the invention there is provided a method of treating a patient
suffering
from nicotine addiction, pain, jetlag, obesity, diabetes, and/or inflammation,
or a method
of inducing smoking cessation in a patient comprising administering to the
patient an
effective amount of a compound according to Formulas I-IV.
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The inflammatory reflex is an autonomic nervous system response to an
inflammatory signal. Upon sensing an inflammatory stimulus, the autonomic
nervous
system responds through the vagus nerve by releasing acetylcholine and
activating
nicotinic 0 receptors on macrophages. These macrophages in turn release
cytokines.
Dysfunctions in this pathway have been linked to human inflammatory diseases
including
rheumatoid arthritis, diabetes and sepsis. Macrophages express the nicotinic 0
receptor
and it is likely this receptor that mediates the cholinergic anti-inflammatory
response.
Therefore, compounds with affinity for the a7nACh receptor on macrophages may
be
useful for human inflammatory diseases including rheumatoid arthritis,
diabetes and
sepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005, 257(2), 156-66.
Thus, in accordance with an embodiment of the invention there is provided a
method of treating a patient (e.g., a mammal, such as a human) suffering from
an
inflammatory disease or disorder, such as, but not limited to, rheumatoid
arthritis,
diabetes or sepsis, comprising administering to the patient an effective
amount of a
compound according to Formulas I-IV.
In addition, due to their affinity to a7nACh receptors, labeled derivatives of
the
compounds of Formulas I-IV (e.g., C' I or F18labeled derivatives), can be used
in
neuroimaging of the receptors within, e.g., the brain. Thus, using such
labeled agents in
vivo imaging of the receptors can be performed using, e.g., PET imaging.
The condition of memory impairment is manifested by impairment of the ability
to learn new information and/or the inability to recall previously learned
information.
Memory impairment is a primary symptom of dementia and can also be a symptom
associated with such diseases as Alzheimer's disease, schizophrenia,
Parkinson's disease,
Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV,
cardiovascular
disease, and head trauma as well as age-related cognitive decline.
Thus, in accordance with an embodiment of the invention there is provided a
method of treating a patient suffering from, for example, mild cognitive
impairment
(MCI), vascular dementia (VaD), age-associated cognitive decline (AACD),
amnesia
associated w/open-heart-surgery, cardiac arrest, and/or general anesthesia,
memory
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deficits from early exposure of anesthetic agents, sleep deprivation induced
cognitive
impairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia,
epilepsy-
related cognitive impairment, Down's syndrome, Alcoholism related dementia,
drug/substance induced memory impairments, Dementia Puglistica (Boxer
Syndrome),
and animal dementia (e.g., dogs, cats, horses, etc.) comprising administering
to the
patient an effective amount of a compound according to Formulas I-IV.
The dosages of the compounds of the present invention depend upon a variety of
factors including the particular syndrome to be treated, the severity of the
symptoms, the
route of administration, the frequency of the dosage interval, the particular
compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile of the
compound, and
the presence of any deleterious side-effects, among other considerations.
The compounds of the invention can be administered to patients, e.g., mammals,
particularly humans, at typical dosage levels customary for a-7 nicotinic
receptor
agonists such as the known a-7 nicotinic receptor agonist compounds mentioned
above.
For example, the compounds can be administered, in single or multiple doses,
by oral
administration at a dosage level of, for example, 0.0001-10 mg/kg/day, e.g.,
0.01-10
mg/kg/day. Unit dosage forms can contain, for example, 1-200 mg of active
compound.
For intravenous administration, the compounds can be administered in single or
multiple
dosages.
In carrying out the procedures of the present invention it is of course to be
understood that reference to particular buffers, media, reagents, cells,
culture conditions
and the like are not intended to be limiting, but are to be read so as to
include all related
materials that one of ordinary skill in the art would recognize as being of
interest or value
in the particular context in which that discussion is presented. For example,
it is often
possible to substitute one buffer system or culture medium for another and
still achieve
similar, if not identical, results. Those of skill in the art will have
sufficient knowledge of
such systems and methodologies so as to be able, without undue
experimentation, to
make such substitutions as will optimally serve their purposes in using the
methods and
procedures disclosed herein.
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The present invention will now be further described by way of the following
non-
limiting examples. In applying the disclosure of these examples, it should be
kept clearly
in mind that other and different embodiments of the methods disclosed
according to the
present invention will no doubt suggest themselves to those of skill in the
relevant art.
In the foregoing and in the following examples, all temperatures are set forth
uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and
percentages
are by weight.
The entire disclosures of all applications, patents and publications, cited
above
and below; are hereby incorporated by reference.
Using the following procedures and further procedures described below, the
following compounds were prepared. The syntheses of related compounds are also
described in U.S. Patent Application Serial Nos. 11/089,533 and 10/669,645,
which are
hereby incorporated by reference in their entireties.
EXAMPLES
All spectra were recorded at 300 MHz on a Bruker Instruments NMR unless
otherwise stated. Coupling constants (J) are in Hertz (Hz) and peaks are
listed relative to
TMS (S 0.00 ppm). Microwave reactions were performed using a Personal
Chemistry
OptimizerTM microwave reactor in 2.5 mL or 5 mL Personal Chemistry microwave
reactor vials. All reactions were performed at 200 C for 600 s with the fixed
hold time
ON unless otherwise stated. Sulfonic acid ion exchange resins (SCX) were
purchased
from Varian Technologies. Analytical HPLC was performed on 4.6 mm x 100 mm
Xterra RP18 3.5 columns using a gradient of 20/80 to 80/20 acetonitrile
(0.1% formic
acid)/water (0.1 % formic acid) over 6 min. For compound 57, a gradient of
5/95 to 60/40
acetonitrile (0.1% formic acid)/water (0.1 1o formic acid) was used. For
compounds 116-
130, a gradient of 10/90 to 80/20 acetonitrile (0.1% formic acid)/water (0.1%
formic
acid) over 8 min was used.
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Preparative HPLC was performed on 30 mm x 100 mm Xterra Prep RP18 5
columns using (i) an 8 min gradient of 20/80 to 80/20 acetonitrile (0.1%
formic
acid)/water (0.1% formic acid) (compounds 1-50, 54-57, 59, 60, 63-77, 79-13 1,
and 149-
185), (ii) a 30 min gradient of 5/95 to 95/5 acetonitrile (0.05%
trifluoroacetic acid)/water
(0.05% trifluoroacetic acid) (compounds 51-53), (iii) an 8 min gradient of
10/90 to 60/40
acetonitrile (0.1% formic acid)/water (0.1% formic acid) (compounds 58, 61,
62, 78, and
132-137), (iv) an 8 min gradient of 5/95 to 60/40 acetonitrile (0.1% formic
acid)/water
(0.1% formic acid) (compounds 186-190), or (v) an 8 min gradient of 10/90 to
80/20
acetonitrile (0.1 % formic acid)/water (0.1 Jo formic acid) (compounds 138-
148).
Acid Preparations.
The following procedures (1 - 29) detail the preparation of the indazole,
benzisoxazole, and benzisothiazole acids and esters that were not commercially
available.
Procedure 1
Procedure 1 provides a preparation of substituted benzisothiazole-3-carboxylic
acids fr6m the corresponding thiophenols.
To a solution of 3-methoxythiophenol (26.7 mmol) in ether (20 mL) was added
oxalyl chloride (43 mmol) dropwise. The mixture was heated at reflux for 1.5
h, cooled
to rt (room temperature), and concentrated in vacuo. The resulting yellow oil
was
dissolved in dichloromethane (50 mL), cooled to 0 C, and was treated with
aluminum
chloride (32.0 mmol) in portions. The mixture was heated at reflux for 30 min,
cooled to
rt, and poured onto ice water with stirring. The organic layer was separated
and
successively washed with saturated, aqueous sodium bicarbonate, water, and
brine. The
organic layer was dried over magnesium sulfate, filtered and concentrated in
vacuo. The
residue was purified by chromatography (4/1 ethyl acetate/hexane), thus
providing 6-
methoxy-l-benzothiophene-2,3-dione in 47% yield as an orange solid.
To a mixture of the dione (0.44 mmol) in 30% aqueous solution of ammonium
hydroxide (2.0 mL) was added 35% aqueous solution hydrogen peroxide (0.2 mL)
and
the reaction mixture was maintained for 12 h. The precipitated pink solids
were isolated
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by filtration, washed with water, and dried under high vacuum, thus providing
the amide
in 42% yield.
To a solution of the amide (5.46 mmol) in methanol (100 mL) was added 10 N
sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h, cooled to
rt, and
was acidified to pH < 2 by the slow addition of conc. hydrochloric acid. The
organic
layer was extracted with dichloromethane (2x) and was dried over sodium
sulfate. The
crude product was purified by chromatography (300/50/1
dichloromethane/methanol/formic acid), thus providing the acid in 89% as a
pink solid.
The following acids were prepared using this method:
6-Bromobenzisothiazole-3-carboxylic acid.
5-Bromobenzisothiazole-3-carboxylic acid.
6-Methoxybenzisothiazole-3-carboxylic acid.
7-Bromobenzisothiazole-3-carboxylic acid.
The following esters were prepared from the acid using ethanol and sulfuric
acid:
Ethy16-bromobenzisothiazole-3-carboxylate.
Ethyl 6-methoxybenzisothiazole-3-carboxylate.
tert-Butyl 5-bromo-1,2-benzisothiazole-3-carboxylate.
The following procedure was used to prepare benzisothiazole tert-butyl esters:
Di-tert-butyldicarbonate (128 mmol) was added to a suspension of 6-bromo-1,2-
benzisothiazole-3-carboxylic acid (46.5 mmol) and 4-dimethylaminopyridine
(4.26
mmol) in tert-butyl alcohol (40.0 mL) and tetrahydrofuran (40.0 mL) and the
reaction
mixture was heated at 65 C for 16 hours. There was vigorous carbon dioxide
evolution
which gradually subsided as the mixture become homogeneous. The reaction
mixture
was concentrated and the residue was dissolved in dichloromethane. The
dichloromethane solution was filtered through silica gel (ca. 50g) and the
eluent was
concentrated to provide the ester product in 99% yield.
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The following ester was prepared using this method:
tert-Butyl6-bromo-1,2-benzisothiazole-3-carboxylate.
Procedure 2
Procedure 2 provides a method for the preparation of isatins from anilines and
the
conversion of the isatins to the corresponding indazole-3-carboxylic acids.
A solution of the substituted aniline (565 mL) in 6N hydrochloric acid (106
mL)
was added to a suspension of 2,2,2-trichloro-l-ethoxyethanol (678 mL) and
sodium
sulfate (3.15 mol) in water (1.4 L) and the reaction mixture was stirred
vigorously for 1 h.
A solution of hydroxylamine hydrochloride (2.08 mol) in water (650 mL) was
added in
one portion and the reaction mixture was heated at 80 C for 1.5 h. The
reaction mixture
was cooled to 10 C and the precipitated solids were collected by filtration,
washed with
water, and dried to provide the amide in 91 % yield.
The amide was added to sulfuric acid (1.9L) and the reaction mixture was
heated
at 60 C for 6h. The reaction mixture was allowed to cool to room temperature
and was
cautiously poured onto ice (7 kg). The precipitated solids were collected by
filtration,
washed with water, and dried to provide the isatin in 61 % yield.
The conversion of the substituted isatins to the corresponding indazole-3-
carboxylic acids is essentially the same method as described for indazole-3-
carboxylic
acid: Snyder, II.R., et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted
isatin (22.1
mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 C
for 30
min. The burgundy solution was allowed to cool to rt and was maintained for
lh. The
reaction mixture was cooled to 0 C and was treated with a 0 C solution of
sodium nitrite
(22.0 mmol) in water (5.5 mL). This solution was added through a pipet
submerged
below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL)
in water (45
mL) at 0 C. The addition took 15 min and the reaction was maintained for an
additional
min. A cold (0 C) solution of tin (II) chloride dihydrate (52.7 mmol) in
concentrated
hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and
the
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reaction mixture was maintained for 60 min. The precipitated solids were
isolated by
filtration, washed with water, and dried to give a quantitative mass balance.
This
material was of sufficient purity (1H NMR and LC/MS) to use in the next step
without
further purification. Alternatively, the acid was recrystallized from acetic
acid to provide
pure material.
The following acids were prepared using this method:
6-Bromo-l.H-indazole-3 -acid.
5-Methoxy-1 H-indazole-3-acid.
6-Methoxy-1 H-indazole-3-aci d.
Procedure 3
Procedure 3 provides a method for the trapping of indazole aryllithiums with
ketones and the coupling with 3-aminoquinuclidine to form heterocyclic
derivatives.
tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by
reaction
with a 2-fold excess of di-tert-butyldicarbonate followed by treatment with
sodium
hydroxide. To a suspension of sodium hydride (60% mineral oil dispersion) (4.8
mmol)
in tetrahydrofuran (40 mL) at 0 C was slowly added a solution of tert-butyl 6-
bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL). After
stirring for
0.5 h at 0 C, the mixture was cooled to -78 C and a 1.7 M solution of tert-
butyllithium
in pentane (5.1 mmol) was added. After 0.5 h at -78 C, a solution of
tetrahydropyran-4-
one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was
stirred at
-78 C for 1 h and warmed to 0 C. The reaction mixture was quenched with
saturated
aqueous ammonium chloride and the mixture was partitioned between ethyl
acetate (100
mL) and water (100 mL). The organic layer was separated, washed with brine (50
mL),
dried (magnesium sulfate), and concentrated. The residue was purified by
chromatography (70/30 ethyl acetate/hexanes) to yield 6-(4-
hydroxytetrahydropyran-4-
yl)-1H-indazole-3-carboxylic acid tert-butyl ester (68%) as a colorless solid.
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6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl
ester
(0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was
maintained
at room temperature for 16 h. The solvent was removed in vacuo and the residue
was
triturated with ethyl acetate to provide 6-(3,6-dihydro-2H-pyran-4-yl)-1H-
indazole-3-
carboxylic acid (76%). The acids were coupled with quinuclidine amine
according to
procedure A.
6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl
ester
(1.0 mmol) was taken up in trifluoroacetic acid (5 mL), triethylsilane (2 mL),
and
dichloromethane (3 mL) and the mixture was refluxed for 16 h. The solvent was
removed in vacuo and the residue was triturated with ethyl acetate to provide
6-
(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tan solid.
The following acids and esters were prepared using this method:
5-(Tetrahydro-2H-pyran-4-yl)-1Fl-indazole-3-carboxylic acid.
6-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.
tert-Butyl6-formyl-1 H-indazole-3 -carboxylic acid.
tert-Butyl6-formyl-1 H-indazole-3 -carboxyl ate.
Procedure 4
Procedure 4 provides a method for the preparation of1V-l-alkylated indazole-3-
carboxylic acids from the corresponding indazole ester.
To a solution of ethyl 5-methoxyindazole-3-carboxylate (1.50 mmol) in
acetonitrile (15 mL) was added potassium carbonate (5.99 mmol) and methyl
iodide (3.00
mol). The reaction was heated at 60 C for 4 hours, allowed to cool to ambient
temperature, and was partitioned between water (50 mL) and ethyl acetate (50
mL). The
layers were separated and the organic later was washed with brine (25 mL),
dried
(magnesium sulfate), and concentrated. The residue was purified by
chromatography
using a gradient of 95/5 to 80/20 hexanes/ethyl acetate to provide the 2-
substituted
indazole (17%) and the 1-substituted indazole (44%). The 1-substituted
indazole (61 mg,
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0.26 mmol) was suspended in ethanol (5.0 mL) and was warmed to facilitate
dissolution.
An aliquot of a 5.0 M solution of sodium hydroxide in water (2.00 mL) was
added and
the reaction mixture was maintained at ambient temperature for.16 h. The
reaction
mixture was diluted with water (50 mL) and was acidified with 6.0 N
hydrochloric acid.
The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and the
combined
organic layers were washed with brine (25 mL), dried (magnesium sulfate), and
concentrated, thus providing the acid in 95% yield.
The following acids were prepared using this method:
6-Bromo-l-methyl-lH-indazole-3-carboxylic acid.
6-Bromo-l-ethyl-lH-indazole-3-carboxylic acid.
1-Ethyl-6-methoxy-lH-indazole-3-carboxylic acid.
Procedure 5
Procedure 5 provides a method for the preparation of 5-difluoromethoxyindazole-
3-acid from 3-bromo-4-nitrophenol.
3-Bromo-4-nitrophenol (10.0 mmol) was added to a suspension of sodium
hydroxide (29.0 mmol) in N,N-dimethylformamide (15 mL) and the suspension was
maintained for 15 min at rt. The reaction mixture was cooled to 0 C and was
treated
with ethyl chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated
at 70 C
for 16 h and was concentrated. The residue was diluted with ice water (200 mL)
and was
extracted with ethyl acetate (3x100 mL). The combined organic layers were
dried
(magnesium sulfate) and concentrated to provide the difluoromethyl ether in
75% yield as
a yellow oil.
Diethyl malonate (328 mmol) was added dropwise to a suspension of sodium
hydride (328 mmol) in dimethylsulfoxide (40 mL) at 0 C. The reaction mixture
was
warmed to 60 C and maintained for 0.5 h A solution of the difluoromethyl
ether (149
mmol) in dimethylsulfoxide (80 mL) was added dropwise and the reaction mixture
was
heated at 100 C for 5 h. The cooled solution was poured onto ice water; and
the aqueous
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layer was extracted with dichloromethane (3x100 mL). The combined organic
layers
were dried (magnesium sulfate) and concentrated to give the crude diester in
112% yield
as an oil. The diester (167 mmol), sodium hydroxide (500 mmol), and water (335
mL)
were combined and heated at 60 C for 1 h. The reaction mixture was allowed to
cool to
rt and the aqueous layer was washed with dichloromethane (3x100 mL). The pH of
the
aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid
and the
reaction mixture was heated at 60 C for 1 h. The suspension was cooled to 5 C
and the
solids were collected by filtration and dried to provide the acid in 61%
yield.
Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0 C.
After 0.5 h, the acid (101 mmol) was added and the reaction mixture was heated
at reflux
for 15 h. The reaction mixture was concentrated and the residue was
partitioned between
dichloromethane (200 mL) and saturated sodium bicarbonate (100 mL). The
aqueous
layer was further extracted with dichloromethane (2x200 mL) and the combined
organic
layers were dried (magnesium sulfate) and concentrated to provide the ester in
60% yield
as a brown oil.
The ester (60.4 nunol) was dissolved in ethanol (103 mL), diluted with water
(71
mL), and was treated with ammonium chloride (243 mmol) and iron powder (301
mmol).
The reaction mixture was heated at reflux for 10 minutes and the suspension
was filtrated
through Celite and the filter cake was washed with ethanol three times. The
filtrate was
concentrated, the residue was suspended in 2 N hydrochloric acid and was
stirred
vigorously for 0.5 h. The aqueous layer was washed with ethyl acetate (3x5OmL)
and the
pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted
with
chloroform (3xlOOmL) and the combined organic layers were dried (magnesium
sulfate).
Acetic anhydride (392 mmol), isoamyl nitrite (291 mmol), and potassium acetate
(51.0
mmol) were added to the organic layer and the suspension was heated at reflux
for 16 h.
The solution was evaporated and the residue was partitioned between saturated
sodium
bicarbonate (50 mL) and dichloromethane (100 mL). The aqueous layer was
further
extracted with dichloromethane (2x100 mL) and the combined organic layers were
dried
(magnesium sulfate) and concentrated to provide the N-acetylindazole ester in
79% yield
as a brown oil.
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The ester (63.8 mmol), sodium hydroxide (193 mmol), and water (65 mL) were
combined and the reaction was maintained for 24 h at 60 C. After cooling to
rt, the
aqueous layer was washed with dichloromethane (3x5OmL). The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid. The precipitated solids
were
collected by filtration, washed with water and dichloromethane, and dried to
provide the
acid in 27% yield.
The following acid was prepared according to this method:
5-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
Procedure 6
Procedure 6 provides a method for the preparation of 6-difluoromethoxyindazole-
3-acid from 4-nitrophenol.
4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485
mmol) in N,1V-dimethylformamide (150 mL) and the suspension was maintained for
15
min at rt. The reaction mixture was cooled to 0 C and was treated with ethyl
chlorodifluoroacetate (329 mmol). The reaction mixture was heated at 70 C for
16 h and
was concentrated. The residue was diluted with ice water (200 mL) and was
extracted
with ethyl acetate (3x100 mL). The combined organic layers were dried
(magnesium
sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as
a yellow
oil.
The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with
water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron
powder
(105 mmol). The reaction mixture was heated at reflux for 30 minutes and the
suspension was filtered through Celite. The filter cake was washed with
ethanol three
times and the combined filtrates were concentrated. The residue was dissolved
in water
and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was
extracted with ethyl acetate (3x100mL) and the combined organic layers were
dried
(magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in
acetic
anhydride (23.5 mrnol) and the reaction mixture was maintained at rt for 16 h.
The
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reaction mixture was diluted with water (50 mL) and was neutralized with solid
sodium
bicarbonate. The precipitated solids were isolated by filtration, washed with
water, and
dried to provide the acetamide in 62% yield as a light yellow solid.
Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2
mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux.
Fuming
nitric acid (16.0 mmol) was added dropwise and the reaction mixture was
maintained at
reflux for 30 min. The cooled solution was diluted with water (20 mL) and the
aqueous
layer was extracted with dichloromethane (3x 10mL). The combined organic
layers were
dried (magnesium sulfate) and concentrated to provide the nitro- amide in 83%
yield.
The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were
combined and the reaction mixture was maintained for 1.5 hour at 60 C. the
reaction
was allowed to cool to rt and the precipitated solids were isolated by
filtration, and
washed with water, and dried to provide the aniline in 98% yield as a light
yellow solid.
The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and
water (10 mL) and the reaction mixture was warmed to 80-90 C in order to
completely
dissolve the aniline. The reaction mixture was cooled to 0 C and a solution of
sodium
nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The
solution
was maintained for 40 minutes at 0-5 C and filtered. Copper (1) bromide (18.8
mmol)
was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0 C. The
solution of
the diazo salt was added slowly to the copper solution and the mixture was
maintained
for 30 min at 0-10 C. The reaction mixture was heated at 60 C for 30 min and
then at
100 C for 10 min to ensure completion. The reaction mixture was allowed to
cool to rt
and was extracted with dichloromethane (3x40mL). The combined organic layers
were
washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. The
organic layer was dried (magnesium sulfate) and concentrated to provide the
nitro
bromide in 76% yield as a light yellow solid.
Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium
hydride (25.8 mmol) in dimethylsulfoxide (5 mL) at 0 C. The reaction mixture
was
warmed to 60 C and maintained for 30 min. A solution of the nitro bromide
(11.7
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mmol) in dimethylsulfoxide (7 mL) was added dropwise and the reaction mixture
was
heated at 100 C for 5 h. The cooled solution was poured onto ice water and
the aqueous
layer was extracted with dichloromethane (3x 100 mL). The combined organic
layers
were dried (magnesium sulfate) and concentrated to give the crude diester as
an oil. The
diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were
combined
and heated at 60 C for I h. The reaction mixture was allowed to cool to rt
and the
aqueous layer was washed with dichloromethane (3x100 mL). The pH of the
aqueous
layer was cautiously adjusted to I with concentrated hydrochloric acid and the
reaction
mixture was heated at 60 C for 1 h. The suspension was cooled to 0 C and the
solids
were collected by filtration and dried to provide the acid in 64% yield.
Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 C.
After 30 min, the acid (7.69 mmol) was added and the reaction mixture was
heated at
reflux for 15 h. The reaction mixture was concentrated and the residue was
partitioned
between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The
aqueous layer was further extracted with dichloromethane (2x20 mL) and the
combined
organic layers were dried (magnesium sulfate) and concentrated to provide the
ester in
94% yield as a brown oil.
Acetic anhydride (6.0 mL) was added to a suspension of the ester (3.64 mmol),
and acetic acid (7.0 mL) at 0 C. Zinc dust (14.6 mmol) was added in portions
over 15
min and the reaction mixture was maintained for 30 min at 0 C and then for 1.5
h at rt.
Additional zinc powder (6.15 mmol) was added and the reaction maintained for 3
h. The
suspension was filtered through Celite and the filtrate was concentrated. The
residue was
partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20
mL).
The aqueous layer was further extracted with ethyl acetate (3x2OmL) and the
combined
organic layers were dried (magnesium sulfate) and concentrated to provide the
acetamide
in 92% yield as a brown oil.
Acetic anhydride (13.7 mmol),'isoamyl nitrite (13.7 mmol), and potassium
acetate
(2.04 mmol) were added to a solution of the acetamide (3.92 mmol) in
chloroform (20
mL) and the suspension was heated at reflux for 16 h. The solution was
evaporated and
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the residue was partitioned between saturated sodium bicarbonate (10 mL) and
dichloromethane (20 mL). The aqueous layer was further extracted with
dichloromethane (2x20 mL) and the combined organic layers were dried
(magnesium
sulfate) and concentrated to provide the crude N-acetylindazole ester as a
brown oil.
The ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were
combined and the reaction was maintained for 24 h at 60 C. After cooling to
rt, the
aqueous layer was washed with dichloromethane (3x3OmL). The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid and the precipitated
solids were
collected by filtration, washed with water and dichloromethane, and dried to
provide the
acid in 26% yield.
The following acid was prepared according to this method:
6-(Difluoromethoxy)-1 H-indazole-3 -carboxylic acid.
Procedure 7
Procedure 7 provides a method for the coupling between brominated
benzisothiazole-3-carboxylic esters and brominated indazole-3-carboxylic
esters and
Grignard reagents to form heteroaromatic-substituted acids.
A 0.5 M solution of Grignard reagent (75.0 mmol) in tetrahydrofuran was
diluted
with tetrahydrofuran (150 mL), cooled to 5 C, and treated with solid zinc
chloride (165
mmol). The reaction mixture was allowed to warm to rt and the brominated ester
(28.2
mmol) and tetrakis(triphenylphosphine)palladium (0) (1.64 mmol) were added.
The
suspension was heated at 65 C for 16 h and was concentrated. The reaction was
partitioned between ethyl acetate (250 mL) and 7 M ammonium chloride (500 mL).
The
aqueous layer was extracted with ethyl acetate (3 x 250 mL) and the combined
extracts
were dried over sodium sulfate and concentrated to dryness. The residue was
purified by
chromatography using a gradient of 100/0 to 97/3 chloroform/methanol to
provide the
ester in 80% yield. The ester was suspended in methanol (100 mL) and was
treated with
8 M sodium hydroxide (30 mL). The mixture was heated at 60 C for 3 h, cooled
to rt,
filtered, and was acidified to pH < 2 by the slow addition of conc.
hydrochloric acid. The
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aqueous layer was concentrated and the residue was triturated with water. The
resultant
solid was recrystallized from water to give the acid in 81% yield.
The Grignard reagent of thiazole is commercially available. Alternatively, the
aryllithium and the corresponding arylzinc reagent can be generated according
to the
procedure outlined by Reeder, M.R.; et. al., Org. Proc. Res. Devel. 2003, 7,
696. The
zinc reagent of oxazole was prepared according to this procedure.
The following acids were prepared using this method:
6-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid.
6-(1,3-Oxazol-2-yl)-1 H-indazole-3-carboxylic acid.
1-Ethyl-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxylic acid.
Procedure 8
Procedure 8 provides a method for the preparation of N-methoxyethoxymethyl
and N-trimethylsilylethoxymethyl protected indazole acids and esters from the
corresponding indazole esters using alkylation conditions.
Representative Procedure for N(1)-alkylation: A solution of ethyl5-(benzyloxy)-
1H-indazole-3-carboxylate (2.70 mmol) in tetrahydrofuran (10 mL) was added
dropwise
to a 0 C suspension of sodium hydride (60% mineral oil dispersion, 8.1 mmol)
in
tetrahydrofitran (54.0 mL). The reaction was maintained at 0 C for 1 h. [(3-
(Trimethylsilyl)ethoxy]methyl chloride (3.2 mmol) was added and the reaction
mixture
was maintained for I h. The reaction was partitioned between water (50 mL) and
ethyl
acetate (50 mL) and the organic layer was washed with brine (25 mL), dried
(magnesium
sulfate), and concentrated. The residue was purified by chromatography (95/5
to 85/15
hexanes/ethyl acetate to provide the protected indazole in 89% yield.
Representative Procedure for N(2)-alkylation: 2-Methoxyethoxy methyl chloride
(48.0 mmol) was added slowly to a suspension of ethyl 6-bromo-lH-indazole-3-
carboxylate (40.0 mmol) and NN-diisopropylethylamine (80.0 mmol) in methylene
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chloride (80.0 mL). The reaction became homogeneous and was maintained for 4 h
at rt.
The reaction mixture was concentrated and the residue was partitioned between
water (50
mL) and ethyl acetate (100 mL). The layers were separated and the organic
layer was
washed with brine (25 mL), dried (magnesium sulfate), and concentrated to give
sufficiently pure product (89%) as a 2/1 mixture of N(2)- and N(1)-
regioisomers as a
yellow oil.
5.0 M of Sodium hydroxide (52 mL) was added to a solution of ethyl 6-bromo-l-
[(2-methoxyethoxy)methyl]-1H-indazole-3-carboxylate (18.2 mmol) and the
reaction
mixture were maintained for 16 h. The solution was diluted with 50 mL water
(50 mL)
and acidified with 6.0 N hydrochloric acid. The slurry was extracted with
ethyl acetate
(50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium
sulfate), and concentrated. The residue was recrystallized from toluene to
give a
colorless solid (82%) as a mixture of regioisomers.
The following esters and acids were prepared using this method:
6-Bromo-l-[(2-methoxyethoxy)methyl]-1H-indazole-3-carboxylic acid.
Ethyl 6-bromo-l-[(2-methoxyethoxy)methyl]-1 H-indazole-3-carboxylate.
Ethyl 6-benzyloxy-l-[(2-methoxyethoxy)methyl]-1 H-indazole-3-carboxylate.
6-Bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic acid.
Ethy16-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic
acid.
5-Bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic acid.
6-Bromo-2-{ [2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic acid.
5-Bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic acid.
Ethyl 6-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic
acid.
Ethyl 5-bromo-2-{ [2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic
acid.
Ethyl 5-bromo-l-{ [2-(trimethylsilyl)ethoxy]methyl}-1Fl-indazole-3-carboxylic
acid
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Procedure 9
Procedure 9 provides a method for the preparation of alkoxy indazole acids
from
the corresponding benzyloxy indazole esters using Mitsunobu conditions.
S Ethyl 6-benzyloxy-l-[(2-methoxyethoxy)methyl]-1 H-indazole-3-carboxylate
(9.38 mmol) was added to a suspension of 10% palladium on carbon (249 mg) in
ethanol
(66.7 mL). The reaction was shaken under an atmosphere of hydrogen (50 psi)
for 4.0 h.
The reaction was filtered through Celite and concentrated to give the phenol
in 87% yield
as a white solid.
Diisopropyl azodicarboxylate (0,841 mmol) was added dropwise to a solution of
ethyl6-hydroxy-l-[(2-methoxyethoxy)methyl]-1H-indazole-3-carboxylate (0.765
mmol),
1-methyl-3-pyrrolidinol (0.917 mmol), and triphenylphosphine (1.15 mmol) in
tetrahydrofuran (4.6 mL). The reaction was maintained for 16 h and was
concentrated.
The residue was purified by chromatography (100/0 to 90/10 ethyl
acetate/[70/30/2 ethyl
acetate/methanol/dimethylethylamine] to provide the ether product in 28%
yield. The
ester was saponified to provide the acid which was coupled to the bicyclobase
using
Procedure C.
The following acids were prepared using this method:
Ethy) 6-hydroxy-l-[(2-methoxyethoxy)methyl]-1 H-indazole-3 -c arboxylate.
1-[(2-Methoxyethoxy)methyl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1 H=indazole-3-
carboxylic acid.
1-[(2-Methoxyethoxy)methyl]-6-(tetrahydrofuran-3-yloxy)-1 H-indazole-3-
carboxylic
acid.
1-[(2-Methoxyethoxy)methyl]-6-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole-3-
carboxylic acid.
6-[(1-Methylpyrrolidin-3-yl)oxy]-1,2-benzisothiazole-3-carboxylic acid.
6-(1-Azabicyclo [2.2.2]oct-3-yloxy)-1,2-benzisothiazole-3-carboxylic acid
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Procedure 10
Procedure 10 provides a method for the preparation of 4-methoxyindazole acid
from 4-methoxyaniline.
A solution of 4-methoxyaniline (1.63 mol) in acetic acid (244 mL) was treated
with acetic anhydride (244 mL) and zinc powder (30.8 mmol) and the reaction
mixture
was heated at reflux for 30 min. The suspension was allowed to cool to rt and
was
filtered and concentrated. The residue was diluted with water (200 mL) and the
pH of the
solution was adjusted to 8 with 10% sodium hydroxide. The precipitated solids
were
collected by filtration, washed with water (1L), and dried to give the
acetarnide in 94%
yield as a purple solid.
Concentrated nitric acid (210 mL) was added dropwise to a solution of the
acetamide (1.52 mol) in dichloromethane (1.5 L) at rt. The reaction mixture
was heated
at reflux for 1 h and was allowed to cool to rt. The reaction mixture was
washed with
water (1.0 L), saturated sodium carbonate (1.0 L), and water (1.0 L). The
organic layer
was dried over anhydrous sodium sulfate and concentrated to provide the
nitroacetamide
in 83% yield as an orange solid.
A solution of the nitroacetamide (1.27 mol) in water (1.27 L) was treated with
sodium hydroxide (5.07 mol) and the reaction mixture was heated at 60 C for 2
h.. The
precipitated solids were collected by filtration, washed with water, and dried
to provide
the nitroaniline in 85% yield as an orange solid.
A solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold
(0-
5 C) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol)
(prepared by
heating the reaction mixture at 90 C for 2 h). The reaction mixture was
maintained for
40 min and was filtered. The filtrate was added dropwise to a cold (0-5 C)
solution of
copper (1) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction
mixture
was maintained for 30 min. The reaction mixture was warmed to 60 C and was
maintained for 30 min. The reaction mixture was warmed to reflux and was
maintained
for I h. The reaction mixture was diluted with water (2 L) and was extracted
with
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dichloromethane (3 x 1 L). The combined organic layers were washed with 10%
sodium
hydroxide (1.0 L), water (2.0 L), 10% hydrochloric acid (1.6 L) and water (2.0
L), dried
(magnesium sulfate) and concentrated. The residue was recrystallized from
ethanol to
provide the bromide in 50% yield as a yellow solid.
Iron powder (1.08 mol) and ammonium chloride (862 mmol) were added to a
solution of the bromide (216 mmol) in ethanol (200 mL) and water (140 mL) and
the
reaction mixture was heated at reflux for 1 h. The suspension was filtered and
concentrated and the residue was extracted with ethyl acetate (3 x 200 mL).
The
combined organic layers were dried (sodium sulfate) and concentrated to give
the
bromoaniline in 96% yield as a yellow liquid.
A solution of the bromoaniline (208 mmol) in 50% hydrochloric acid (40 mL)
was added to a solution of trichloroacetaldehyde hydrate (312 mmol) and sodium
sulfate
(967 mmol) in water (450 mL) and the reaction mixture was maintained for 1 h.
A
solution of hydroxylamine hydrochloride (793 mmol) in water (240 mL) was added
and
the reaction mixture was heated at 60 C for 2 h. The aqueous layer was
decanted and the
residual red oil, which solidifies upon standing, was purified by
chromatography (6/6/1
petroleum ether/dichloromethane/ethyl acetate) to provide the a-oxime amide in
29%
yield as a light yellow solid.
The a-oxime amide (58.6 mmol) was added in one portion to warm (40 C) 90%
sulfuric acid (16 mL) and the reaction mixture was heated at 60 C for 30 min.
The
reaction mixture was allowed to cool to rt and was poured into ice water. The
precipitated orange solids were collected by filtration and dried. The crude
product was
purified by chromatography (15/1 petroleum ether/ethyl acetate) to provide the
isatin in
57% yield as a yellow solid.
The isatin (20.7 mmol) was mixed with 1 M sodium hydroxide (23 mL) and the
reaction mixture was heated to 30-40 C for 30 min. The reaction mixture was
cooled to
0 C and treated with a solution of sodium nitrite (20.7 mmol) in water (5.1
mL) and was
maintained for 20 min. That solution was added dropwise to a cold (0-5 C)
solution of
concentrated sulfuric acid (2.24 mL) in water (43.3 mL) and the reaction
mixture was
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maintained for 0.5 h. A solution of tin (II) chloride (50.5 mmol) in
concentrated
hydrochloric acid (19.6 mL) was added dropwise and the reaction mixture was
maintained at 0-5 C for I h. The precipitated solids were isolated by
filtration and dried
to provide the indazole acid as a yellow solid (100% by mass).
Acetylchloride (18 mL) was added to methanol (180 mL) at 0 C and the reaction
mixture maintained for 1 h. The indazole acid (21.8 mmol) was added and the
reaction
mixture was heated at reflux for 3 h. The solution was concentrated to dryness
and the
residue was suspended in water and the pH adjusted to 7 with saturated sodium
hydrogen
carbonate. The mixture was extracted with ethyl acetate (3 x 100 mL), and the
combined
organic layers were dried (magnesium sulfate) and concentrated. The crude
product was
purified by chromatography (2/1 petroleum ether/ethyl acetate) to provide the
indazole
ester in 5% yield (two steps) as a yellow solid.
The indazole ester (1.02 mmol) was combined with 10% palladium on carbon
(30mg) and methanol (20 mL) under an atmosphere of hydrogen gas for 30 min at
rt.
The catalyst was removed by filtration and the eluent was concentrated to
afford the de-
brominated indazole ester in 24%yield as an orange solid.
1 M Sodium hydroxide (1.5mL) was added to a solution of the de-brominated
indazole ester (0.243 mmol) in methanol (3.OmL) and the reaction mixture was
heated at
60 C for 3 h. The solution was concentrated, the pH adjusted to 1-2, and the
solids
collected by filtration to provide the indazole acid in 100% yield as a yellow
solid.
The following acid was prepared using this procedure:
4-Methoxy-IH-indazole-3-carboxylic acid.
Procedure 11
Procedure 11 provides a method for the preparation of benzyloxy-substituted
indazole-3-carboxylic acids and esters from the corresponding bromo
nitrobenzenes.
Acetic anhydride (34 mL) and zinc dust (4.59 mmol) were added to a solution of
4-methoxynitrobenzene (230 mmol) in glacial acetic acid (34 mL) and the
reaction
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mixture was heated at reflux for 0.5 h.. The reaction mixture was poured into
water (340
mL) and the pH of the solution was adjusted to 8 with 10% sodium hydroxide.
The
precipitated solids were isolated by filtration, washed with water (100 mL),
and dried to
provide the acetamide in 88% yield.
65% Nitric acid (22 mL) was added dropwise over 0.5 h to a solution of the
acetamide (200 mmol) in dichloromethane (200 mL). The reaction mixture was
maintained for 1 h at rt and was heated at reflux for 1 h. The reaction
mixture was
washed with water (200 mL), saturated sodium carbonate solution (100 mL), and
water
(200 mL). The combined organic layers were dried (magnesium sulfate) and
concentrated to provide the nitro acetamide in 90% as a yellow solid.
The nitroacetamide (180 mmol) was added to 4 M sodium hydroxide (180 mL)
and the reaction mixture was maintained for 2 h at 60 C. The precipitated
solids were
isolated by filtration, washed with water, and dried to provide the
nitroaniline in 70%
yield as a red solid.
A solution of sodium nitrite (11.8g) in water (28 mL) was added dropwise over
0.5 h to a solution of the nitroaniline (125 mmol) in 40%. hydrobromic acid
(110g) at 10
C. The reaction mixture was maintained for 40 min at 0-10 C and was filtered.
The
filtrate was added dropwise over 1 h to a 0 C, purple solution of copper (1)
bromide (209
mmol) in hydrobromic acid (74 mL). The reaction mixture was allowed to warm to
and
maintained at rt for 30 min, was maintained at 60 C for 0.5 h, and was heated
at reflux
for 1 h. The reaction mixture was partitioned between water (2.0 L) and
dichloromethane
(600 mL) and the aqueous layer was further extracted with dichloromethane (300
mL).
The combined organic layers were washed with 10% sodium hydroxide (200 mL),
water
(600 mL), 10% hydrochloric acid (300 mL), and water (600 mL), dried (magnesium
sulfate) and concentrated to provide the nitrobromide in 83% yield as a yellow
oil.
A solution of boron tribromide (250 mmol) in dichloromethane (200 mL) was
added drop wise over I h to a solution of the nitrobromide (100 mmol) in
dichloromethane (250 mL) at -78 C. The reaction mixture was allowed to warm
to rt
and was maintained for 30 h. The reaction mixture was cooled to 0 C, quenched
with
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water (300 mL) and the aqueous layer was extracted with ethyl acetate (2 x 300
mL).
The combined organic layers were washed with saturated sodium bicarbonate (2 x
300
mL), dried (magnesium sulfate), and concentrated to provide the nitrophenol in
87%
yield as a brown crystalline solid.
Benzyl bromide (131 mmol) and potassium carbonate (130 mmol) were added to
a solution of the nitrophenol (87.0 mmol) in 2/1 acetonitrile/acetone (840
mL). The
reaction mixture was heated at reflux for 17 h and was concentrated to
dryness. The
residue was suspended in ethyl acetate (756 mL), filtered, and the organic
layer was
washed with water (567 mL), I M hydrochloric acid (2 x 567 mL), and brine (567
mL).
The organic layer was dried (magnesium sulfate) and concentrated to the benzyl
ether in
78% yield.
Diethyl malonate (890 mmol) was added drop wise over I h to a suspension of
sodium hydride (520 mmol) in dimethylsulfoxide (100 mL) at 0 C. The benzyl
ether
(44.0 mmol) was added and the reaction mixture was heated at 100 C for 5 h.
The
reaction mixture was poured into ice water and was extracted with ethyl
acetate (3 x 70
mL). The combined organic layers were dried (magnesium sulfate) and
concentrated to
provide the diethylmalonate addition product. The diethylmalonate addition
product was
diluted with a 4 M solution of sodium hydroxide (100 mL) and the reaction
mixture was
heated at 60 C for 6 h. The solution was extracted with dichloromethane (3 x
50 mL)
and the aqueous layer was adjusted to pH 1 with concentrated hydrochloric
acid. The
reaction mixture was heated at 60 C for 1 h, allowed to cool to rt, and was
extracted with
ethyl acetate (3 x 50 mL). The combined organic layers were dried (magnesium
sulfate)
and concentrated to provide the phenylacetic acid in 78% yield as a solid.
The phenylacetic acid (350 mmol) was added to a freshly prepared solution of
ethanolic hydrochloric acid [acetyl chloride (5 mL) was added to ethanol (100
mL)] and
the reaction mixture was heated at reflux for 20 h. The reaction mixture was
concentrated to dryness and the residue was partitioned between saturated
sodium
bicarbonate (200 mL) and ethyl acetate (150 mL). The aqueous layer was
extracted with
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ethyl acetate (2 x 50 mL) and the combined organic layers were dried
(magnesium
sulfate), filtered and concentrated to provide the ester in 77% yield.
The nitro ester (27.0 mmol) was dissolved in acetic acid (60 mL) and acetic
anhydride (44 mL) and was cooled to 0 C. Zinc dust (153 mmol) was added and
the
reaction mixture was allowed to warm to rt and was maintained for 2 h.
Additional
quantities of zinc dust (2 x 45.9 mmol) were added during a 3 h course of
time. After I
h, the reaction mixture was filtered and the filter cake was washed with
ethanol (100
mL). The combined filtrates were concentrated and the residue was partitioned
between
saturated sodium bicarbonate and ethyl acetate (50 mL). The solution was
extracted with
ethyl acetate (2 x 50 mL) and the combined organic layers were dried
(magnesium
sulfate), filtered and concentrated to provide the acetamide in 82% yield.
Isoamyl nitrite (47.2g) was added dropwise over 30 min to a solution of the
acetamide (21.0 mmol) in chloroform (80 mL) and acetic anhydride (45 mL).
Solid
potassium acetate (7.13 mmol) was added in several portions and the reaction
mixture
was heated at reflux for 1.5 h. The reaction mixture was washed with water (2
x 80 mL)
and brine (80 mL), dried (magnesium sulfate), and concentrated to provide the
acetylated
indazole ester in 68% yield.
The acetylated indazole ester (15.0 mmol) was suspended in 2 M sodium
hydroxide (35 mL) and the reaction mixture was heated at 60 C for 24 h. The
pH of the
solution was adjusted to 1-2 with concentrated hydrochloric acid and the
solids were
collected by filtration and dried to provide 6-benzyloxy-IH-indazole-3-
carboxylic acid in
28% yield as a yellow solid.
6-Benzyloxy-lH-indazole-3-carboxylic acid (1.85 mmol) was added to a freshly
prepared solution of ethanolic hydrochloric acid jprepared from ethanol (20
mL) and
acetyl chloride (5 mL)] and the reaction mixture was heated at reflux for 25 h
and was
concentrated. The residue was partitioned between saturated sodium bicarbonate
(20
mL) and ethyl acetate (20 mL) and the layers were separated. The aqueous layer
was
extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were
dried
(magnesium sulfate) and concentrated. The residue was purified by
chromatography
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(300/1 dichloromethane/methanol) to provide the product in 36.4% yield.
Alternatively,
the ester can be obtained from the acetylated indazole ester by maintaining
the acetylated
material in 2 M ammonia in methanol for 30 min.
The following acids were prepared using this method:
6-Benzyloxy-lH-indazole-3-carboxylic acid.
5-Benzyloxy-lH-indazole-3-carboxylic acid (from 4-benzyloxy-2-
bromonitrobenzene:
see Parker, K.A.; Mindt, T.L. Org. Lett., 2002, 4, 4265).
Ethy16-benzyloxy-1 H-indazole-3 -carboxylate.
Ethyl 5-benzyloxy-1 H-indazole-3 -carboxyl ate.
Procedure 12
Procedure 12 provides a method for the preparation of N(1)-
difluoromethylindazole acids from the corresponding indazole-3-carboxylic
acids.
Acetyl chloride (141 mmol) was added dropwise to a solution of 6-methoxy-3-
indazole-carboxylic acid (26.0 mmol) in ethanol (200 mL) and the reaction
mixture was
heated at reflux for 16 h. The reaction mixture was allowed to cool to rt and
was
concentrated. The residue was dissolved in ethyl acetate (300 mL) and was
washed with
aqueous sodium bicarbonate (2 x 50 mL). The combined aqueous layers were back-
extracted with ethyl acetate (2 x 200 mL). The combined organic layers were
washed
with brine (5,0 mL), dried (sodium sulfate), concentrated, and dried under
vacuum to
afford 4.91 g (86%) of the ester as a solid.
A solution of ethyl 6-methoxy-lH-indazole-3-carboxylate (4.54 mmol) in N,N-
dimethylformamide (6.11 mL) was added dropwise to a suspension of sodium
hydride
(5.45 mmol) and N,1V-dimethylformamide (12.2 mL) and the reaction mixture was
maintained at room temperature for 30 min. Chlorodifluoromethane (17.0 mol)
was
bubbled into the reaction and the mixture was warmed to 80 C and maintained
for 2 h.
The mixture was diluted with water (200 mL) and the precipitates were
collected to give
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a white solid. The solid was dissolved in ethanol (20.0 mL) and a 5.0 M
solution of
sodium hydroxide (3.6 mL) was added. The reaction mixture was maintained at rt
for 2
h, diluted with water (50 mL) and acidified with 6.0 N hydrochloric acid. The
precipitate
was collected and dried to provide the acid in 65% yield.
The following acids were prepared using this method:
1-(Difluoromethyl)-6-methoxy-lH-indazole-3-carboxylic acid.
6-Bromo-l-(difluoromethyl)-1Fl-indazole-3-carboxylic acid.
Procedure 13
Procedure 13 provides a preparation of 5-azaindazole-3-carboxlic acid from 4-
chloropyridine.
A saturated aqueous sodium bicarbonate solution was carefully added to a
solution of 4-chloropyridine hydrochloride (56.7 mmol) in water (20 mL) until
the
solution was basic. The mixture was extracted with hexanes (3 x 25 mL). The
combined
organic layers were dried over magnesium sulfate and concentrated to a volume
of ca. 25
mL to give a solution of the free base.
n-Butyllithium (2.0 M in Pentane, 68mmol) was added dropwise to a solution of
N,N-
diisopropylamine (62.3 mmol) in tetrahydrofuran (61.6 mmol) at 0 C and the
reaction
mixture was maintained for 30 min. The reaction mixture was cooled to -78 C
and the
hexanes solution of 4-chloropyridine was added dropwise and the mixture was
maintained for 1 h. Diethyl oxalate (56.7 mmol) was added to the orange
homogeneous
solution and the mixture was allowed to warm to rt. Analysis by LClMS revealed
that
the main product was not the ethyl oxalate, but the 1V;1VVdiisopropylamide.
The reaction
was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers
were
separated and the organic washed with brine (25 mL), dried (magnesium
sulfate), and
concentrated. The residue was dissolved in ethanol (50.0 mL), treated with
hydrazine
(160 mmol) and the mixture was heated at reflux for I h. The reaction mixture
was
concentrated and the residue was titrated with dichloromethane to give 1.20 g
(8.6%) of
hydrazone product.
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A mixture of N,N-diisopropyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (0.800
g, 0.00325 mol) and aqueous hydrogen chloride (10 M, 3.00 mL) in a microwave
reaction
vessel was heated at 120 C for 10 min, The mixture had to be heated on the
high
absorbance setting to avoid pressure build-up. The reaction was diluted with
water and
neutralized with 3 N sodium hydroxide. The resultant white precipitate was
collected and
found to be a mixture of the acid (47%) and the mono-isopropyl amide (25%).
The
mixture was used without further purification.
The following acid was prepared using this method:
1H-Pyrazolo[4,3-c]pyridine-3-carboxylic acid.
Procedure 14
Procedure 14 provides a preparation of 6-azaindazole-3-carboxlic acid from 4-
chloro-3-nitropyridine.
tert-Butyl ethyl propane-1,3-dioate (26.6 mmol) was added to a suspension of
sodium hydride (1.11 g) in tetrahydrofuran (50.0 mL) at 0 C. The reaction
mixture was
allowed to warm to rt and was maintained for 30 min. The reaction mixture was
then
cooled to 0 C and a solution of 4-chloro-3-nitropyridine (12.6 mmol) in
tetrahydrofuran/N,N-dimethylformamide (9/1, 10 mL) was added dropwise. The
mixture
was allowed to warm to rt and was maintained for I h. The reaction was
quenched with
water (50 mL) and was neutralized with acetic acid to a pH of 5 (the color
went from
dark brown to yellow on neutralization). The mixture was extracted with ethyl
acetate
(50 mL) and the combined organic layers were washed with brine (25 mL), dried
(magnesium sulfate), and concentrated to provide the product in 94% yield.
The crude tert-butyl ethyl (3-nitropyridin-4-yl)malonate (12.6 mmol) was
dissolved in 4/1 dichloromethane/trifluoroacetic acid (25.0 mL) and the
mixture was
heated at reflux for 2 h. The reaction mixture was concentrated and the
residue was
partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl
acetate (50
mL). The layers were separated and the ethyl acetate layer was washed with
brine (25
mL), dried (magnesium sulfate), and concentrated. The residue was purified by
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chromatography (95/5 dichloromethane/ethyl acetate) to provide the product in
77%
yield.
Ethyl (3-nitropyridin-4-yl)acetate (9.66 mmol) and 10% palladium on carbon
(2.10 g) were diluted with ethanol (25.0 mL) in a Parr pressure reactor. The
reaction
mixture was shaken under an atmosphere of hydrogen (30 psi) for 3 h. The
reaction
mixture was filtered (Celite) and concentrated to provide the product in 97%
yield.
Amyl Nitrite (18.9 mmol) was added to a solution of ethyl (3-aminopyridin-4-
yl)acetate (9.43 mmol), potassium acetate (11.3 mmol), and acetic anhydride
(28.3 mmol)
in chloroform (10.0 mL) and the reaction was heated at 60 C for 16 h. The
cooled
reaction mixture was carefully diluted with aqueous sodium bicarbonate and was
extracted with dichloromethane (2 x 50 mL). The combined organic layers were
washed
with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue
was pre-
purified by chromatography (50/50 to 0/100 hexanes/ethyl acetate) to yield a
complex
mixture of products. The mixture was dissolved in ethanol (10.0 mL), diluted
with 5.0 M
sodium hydroxide (5.00 mL), and the reaction mixture was maintained for 16 h.
The
reaction mixture was concentrated to -5 mL, diluted with water (20 mL), and
was
neutralized with acetic acid. The yellow solid was collected by filtration to
provide the
desired product in 18% yield.
The following acid was prepared using this method:
1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid.
Procedure 15
Procedure 15 provides a preparation of aminobenzisothiazole-3-carboxlic acids
from the ester.
Cesium carbonate (3.18 mmol), palladium(II) acetate (0.24 mmol), and 2-
dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl (0.24 mmol) were
combined in a
microwave vessel and the vessel was flushed with nitrogen. A solution of (R)-
(+)-3-
pyrrolidinol (3.18 mol) and tert-butyl 6-bromo-l,2-benzisothiazole-3-
carboxylate (1.59
mol) in tetrahydrofuran (20.0 mL) was added. The vessel was sealed and was
heated at
135 C for 30 minutes. The reaction mixture was filtered through Celite (ethyl
acetate)
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and the filtrate was concentrated. The residue was purified by chromatography
(70/30 to
50/50 hexanes/ethyl acetate) to provide the purified ester. The ester was
dissolved in
dichloromethane/trifluoroacetic acid (4:1, 2.00 mL) and was maintained for 16
h. The
reaction mixture was concentrated to provide the product in 23% yield. The
product was
used without further purification.
Alternatively, when ethyl 6-bromo-1,2-benzisothiazole-3-carboxylate was used,
a
solution of the ester in ethanol was saponified using 5N sodium hydroxide. The
acid was
collected by filtration after diluting with water and neutralizing with acetic
acid.
The following acids and esters were prepared using this method:
6-[(3R)-3-Ilydroxypyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylic acid.
6-[(3S)-3-Hydroxypyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylic acid.
6-[(3R)-3-Methoxypyrrolidin-l-yl]-1,2-benzisothiazole-3-carboxylic acid.
6-[(3S)-3-Methoxypyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylic acid.
6-(3-Methoxypyrrolidin-l-yl)-1,2-benzisothiazole-3-carboxylic acid.
6-[(3S)-3-Dimethylaminopyrrolidin-l-yl]-1,2-benzisothiazole-3-carboxylic acid.
6-[(3R)-3-Dimethylaminopyrrolidin-l-yl]-1,2-benzisothiazole-3-carboxylic acid.
6-(3-Ethoxypyrrolidin-l-yl)-1,2-benzisothiazole-3-carboxylic acid.
6-[(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,2-benzisothiazole-3-
carboxylic acid.
tert-Butyl7-bromo-1,2-benzisothiazole-3-carboxylate.
7-[(3R)-3-Hydroxypyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylic acid.
7-[(3S)-3-Hydroxypyrrolidin-l-yl]-1,2-benzisothiazole-3-carboxylic acid.
6- [(1 S,4S)-5 -(tert-B utoxycarbonyl)-2, 5-diazabicyclo [2.2.1 ]hept-2-yl]-
1,2-
benzisothiazole-3-carboxylic acid
6-[(1 S,4S)-5-Methyl-2,5-diazabicyclo [2.2.1 ]hept-2-yl]-1,2-benzisothiazole-3-
carboxylic
acid
6-[3-[(tert-Butoxycarbonyl)(methyl)amino]pyrrolidin-l-yl]-1,2-benzisothiazole-
3-
carboxylic acid
6-[3-(Methoxymethyl)pyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylicacid
6-[4-(Dimethylamino)piperidine-1-yl]-1,2-benzisothiazole-3-carboxylicacid
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6-(1,4-Diazabicyclo[3.2.2]non-4-y1)-1,2-benzisothiazole-3-carboxylic acid.
6-[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-
carboxylic
acid.
6-[(1R,4R)-5-Methyl-2,5-diazabicyclo[2.2.1]hept 2-yl]-1,2-benzisothiazole-3-
carboxylic
acid.
6-(Pyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxylic acid.
6-(4-Methylpiperazin-l-yl)-1,2-benzisothiazole-3-carboxylic acid.
6-(4-Methyl-1,4-diazepan-l-yl)-1,2-benzisothiazole-3-carboxylic acid.
6-(Hexahydropyrrolo[1,2-a]pyrazin-2(lB)-yl)-1,2-benzisothiazole-3-carboxylic
acid,
6-(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)-1,2-benzisothiazole-3-carboxylic
acid.
6-(8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-1,2-benzisothiazole-3-carboxylic
acid.
5-(4-Methyl-1,4-diazepan-1-y1)-1,2-benzisothiazole-3-carboxylic acid.
5-[(3R)-3-Methoxypyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylic acid.
5-[(3S)-3-Methoxypyrrolidin-1-yl]-1,2-benzisothiazole-3-carboxylic acid.
5-j(3S)-3-(Cyclopropylmethoxy)pyrrolidin-1-y1]-2-{ [2-
(trimethylsilyl)ethoxy]methyl}-
IH-indazole-3-carboxylic acid.
5-[(3S)-3-(Methoxy)pyrrolidin-1-yi]-2-{ [2-(trimethylsilyl)ethoxy]methyl}-1H-
indazole-
3-carboxylic acid.
5-((3R)-3-{ [2-(Trimethylsilyl)ethoxy]methoxy}pyrrolidin-l-yl)-1,2-
benzisothiazole-3-
carboxylic acid.
5-((3S)-3-{ [2-(Trimethylsilyl)ethoxy]methoxy} pyrrolidin-1-yl)-1,2-
benzisothiazole-3-
carboxylie acid.
6-[4-(tert-Butoxycarbonyl)-3-methylpiperazin-1-y1]-1,2-benzisothiazole-3-
carboxylic
acid.
6-[ 1-(tert-Butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1,2-
benzisothiazole-3-carboxylic acid.
5-[(3S)-3-methoxypyrrolidin-1-yl]-1-{ [2-(trimethylsilyl)ethoxy]methyl}-,1H-
indazole-3-
carboxylic acid.
6-[4-(tert-Butoxycarbonyl)-3-methylpiperazin-l-y1]-1,2-benzisothiazole-3-
earboxylic
acid.
6-[1-(tert-Butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1,2-
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benzisothiazole-3-carboxylic acid.
6-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-1,2-benzisothiazole-3-carboxylic
acid.
Ethy16-[4-(tert-butoxycarbonyl)-1,4-diazepan-l-yl]-1,2-benzisothiazole-3-
carboxylate.
6- [4-(tert-Butoxycarbonyl)-2-methylpiperazin-l-yl]-1,2-benzisothiazole-3-
carboxylic
.5 acid.
6-(3,4-Dimethylpiperazin-1-yl)-1,2-benzisothiazole-3-carboxylic acid.
Ethyl 6-[3-[(tert-butoxycarbonyl)(methyl)amino]pyrrolidin-l-yl]-1,2-
benzisothiazole-3-
carboxylate
The following esters were prepared from the 1V-Boc intermediates using
trifluoroacetic acid:
Ethyl 6-[(1S,4S)-2,5-diazabicycIo[2.2.1]hept 2-yl]-1,2-benzisothiazole-3-
carboxylate
Ethyl 6-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1,2-benzisothiazole-3-
carboxylate.
Ethy16-piperazin-l-yl-l,2-benzisothiazole-3-carboxylate.
Procedure 16
Procedure 16 provides a preparation of 6-amino-7-azaindazole-3-carboxlic acids
from tert-butyl6-fluoro-lFl-pyrazolo[3,4-b]pyridine-3-carboxylate.
3-Pyrrolidinol (24.7 mmol) was added to a solution of tert-butyl 6-fluoro-lH-
pyrazolo[3,4-b]pyridine-3-carboxylate (4.22 mmol) in toluene (4.00 mL) in a
microwave
reaction vessel. The reaction mixture was subjected to microwave irradiation
at 120 C
for 300 s. The reaction mixture was partitioned between water (100 mL) and
ethyl
acetate (200 mL) and the layers were separated. The organic layer was washed
with
water (2 x 50 mL) and brine (25 mL) and was filtered through silica gel (50
g). The silica
was washed with 100 mL EtOAc and the combined EtOAc solutions were
concentrated
to provide the product in 63% yield.
Methanesulfonyl chloride (5.52 mmol) was added dropwise to a cold (0 C)
solution of tert-butyl 6-(3-hydroxypyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-
3-
carboxylate (2.63 mmol) and triethylamine (6.57 mmol) in dichloromethane (2.7
mL).
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The reaction mixture was maintained at rt for 16 h and was diluted with water
(25 mL).
The dichloromethane layer was separated and was transferred to a silica gel
column. The
column was eluted using a gradient of 90/10 to 0/100 hexanes/ethyl acetate to
provide the
bis-mesylate in 60% yield and the monomesylate in 28% yield.
tert-Butyl 1-(methylsulfonyl)-6-3-[(methylsulfonyl)oxy]pyrrolidin-l-yl-1H-
pyrazolo[3,4-b]pyridine-3-carboxylate (0.380 mmol) was diluted with a 2.0 M
solution of
dimethylamine in tetrahydrofuran (5.0 mL) in a microwave vessel. The reaction
mixture
was subjected to microwave irradiation at 135 C for 80 min. The reaction
mixture was
concentrated and the residue was purified by chromatography {100/0 to 90/10
ethyl
acetate/[(50/50/2) ethyl acetate/methanol/dimethylethylamine]} to provide the
purified
ester. The ester was dissolved in 4/1 dichloromethane/trifluoroacetic acid
(5.00 mL) and
the mixture was maintained at rt for 16 h. The volatiles were removed and the
residue
was dissolved in water. The mixture was neutralized with half saturated sodium
bicarbonate and the solid precipitate was collected by filtration to provide
the product in
79% yield.
The following acid was prepared using this method:
6-[3-(Dimethylamino)pyrrolidin-l-yl]-1H-pyrazolo[3,4-b]pyridine-3-carboxylic
acid.
Procedure 17
Procedure 17 provides a preparation of fluorinated benzisothiazole-3-carboxlic
acids from the ester of the corresponding benzisothiazole-3-carboxlic acid.
1-Fliuoro-2,6-dichloropyridinium triflate (2.25 mmol) was added to a solution
of
ethyl 6-(3-methoxypyrrolidin-l-yl)-1,2-benzisothiazole-3-carboxylate (1.87
mmol) in
dichloromethane (20.0 mL) and the reaction mixture was maintained at rt for 6
h. The
reaction mixture was filtered through silica gel (10 g, dichloromethane wash)
and the
eluent was concentrated. The residue was purified by chromatography 90/10 to
70/30
hexanes/ethyl acetate to provide the product in 22% yield.
A solution of ethyl 7-fluoro-6-(3-methoxypyrrolidin-l-yl)-1,2-benzisothiazole-
3-
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carboxylate (0.177 mmol) in ethanol (1.5 mL) was treated with a 5.0 M solution
of
sodium hydroxide (3.0 mmol). Within minutes, a gelatinous solid precipitated.
The
reaction mixture was diluted with water (50 mL) and was acidified with 6.0 N
hydrochloric acid. The precipitate was collected by filtration to provide the
product in
80% yield. The acid was used without further purification.
The following acid was prepared using this method:
7-Fluoro-6-(3-methoxypyrrolidin-l-yl)-1,2-benzisothiazole-3-carboxylic acid.
7-Fluoro-6-(3-ethoxypyn:olidin-l-yl)-1,2-benzisothiazole-3-carboxylic acid.
7-Fluoro-6-methoxy-1,2-benzisothiazole-3-carboxylic acid.
Procedure 18
Procedure 18 provides a preparation of 6-phenyl-IH-pyrazolo[3,4-b]pyridine-3-
carboxylic acid from tert-butyl6-phenyl-lH-pyrazolo[3,4-b]pyridine-3-
carboxylate.
[1,3-Bis(diphenylphosphino)propane]nickel(II) chloride (0.0999 mmol) and tert-
butyl 6-fluoro-lH-pyrazolo[3,4-b]pyridine-3-carboxylate (0.999 mmol) were
dissolved in
tetrahydrofuran (20.0 mL) and the reaction mixture was cooled to 0 C. A 1.00 M
solution of phenylmagnesium bromide in tetrahydrofuran (2.40 mL) was added and
the
reaction mixture was allowed to warm to rt and was maintained for 4 h. The
reaction was
partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were
separated
and the organic washed with brine (25 mL), dried (magnesium sulfate), and
concentrated.
The residue was purified by chromatography (95/5 to 85/15 hexanes/ethyl
acetate) to
provide the product in 56% yield.
tert-Butyl 6-phenyl-lH-pyrazolo[3,4-b]pyridine-3-carboxylate (0.555 mmol) was
dissolved in a 4/1 dichloromethane/trifluoroacetic acid solution (2.00 mL) and
the
reaction was maintained for 16 h at rt. The reaction mixture was concentrated
and the
residue was diluted with water (5 mL). The reaction mixture was neutralized to
pH 5-7,
stirred vigorously for 1 h, and the precipitated solids were collected by
filtration to
provide the acid in 92% yield.
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The following acid was prepared using this method:
6-Phenyl-lH-pyrazolo[3,4-b]pyridine-3-carboxylic acid.
Procedure 19
Procedure 19 details the preparation of ethyl 6-bromobenzisoxazole-3-
carboxylate
from 2,5-dibromonitrobenzene.
Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride
(3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature
of the
reaction rose to 60 C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene
(10 g, 36.0
mmol) was added and the solution was maintained for 2 h at 100 C. The
reaction
mixture was allowed to cool to rt and was poured into ice (300g-400g). The
precipitated
solids were isolated by filtration and dried to provide 11.0 g of the product
(89%).
The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium
hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room
temperature for 16 h. The aqueous layer was extracted with dichloromethane (20
mL)
and was acidified. The precipitated solids were isolated by filtration and
dried to provide
7.00 g of the acid (89%).
Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol)
in
ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2
h, and was
concentrated under reduce pressure. The residue was partitioned between ethyl
acetate
(250 mL) and saturated sodium carbonate (50 mL) and the organic layer was
washed with
saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was
dried
(sodium sulfate) and concentrated to provide 8.00 g (98%) of the ester as a
liquid.
Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol)
in
ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was
warmed to
60 C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46
mmol)
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in ethanol (1 L) was added dropwise and the reaction mixture was maintained
for 2 h.
The reaction mixture was allowed to cool to rt and was neutralized with 2 N
hydrochloric
acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the
combined
organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried
(sodium
sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl
acetate) to
provide 110 g of the product (28%).
See, for example, International Publication Number WO 2004/010995.
The following ester was prepared using this method:
Ethyl 6-bromo-1,2-benzisoxazole-3-carboxyl ate.
Procedure 20
Procedure 20 details the preparation of ethyl 6-methoxybenzisoxazole-3-
carboxylate from 1-chloro-2,4-dinitrobenzene.
Sodium hydride (417 mmol) was added to a solution of ethyl 3-oxobutanoate (129
mmol) in tetrahydrofuran (350 mL). 1-Chloro-2,4-dinitrobenzene (123 mmol) was
added
and the resulting suspension was maintained for 24 h at rt. The pH was
adjusted to 5 by
the addition of 3 M hydrochloric acid and the resulting solution was extracted
with
diethyl ether (300 mL). The organic layer was washed with water (3 x 300 mL),
dried
(magnesium sulfate), and concentrated to provide ethyl 2-(2,4-dinitrophenyl)-3-
oxobutanoate in 98% yield as a brown solid.
Propan-l-amine (136 mmol) was added to a solution of ethyl 2-(2,4-
dinitrophenyl)-
3-oxobutanoate (135 mmol) in chloroform (500 mL). The reaction mixture was
maintained for 12 h at rt and was concentrated. The residue was purified by
chromatography 20/1 hexane/ethyl acetate to provide ethyl 2-(2,4-
dinitrophenyl)acetate
in 99% yield as a brown oil.
A solution of ethyl 2-(2,4-dinitrophenyl)acetate (18.1 mmol) and 3-
methylbutanyl
nitrite (73.5 mmol) in ethanol (70 mL) was warmed to 60 C. A solution of
sodium
ethoxide, prepared from sodium (21.7 mmol) and ethanol (70 mL), was added and
the
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reaction mixture was maintained for 1 h. The reaction mixture was cooled to 0
C and
the pH adjusted to 7 by the addition of 5% hydrochloric acid. The resulting
solution was
diluted with water (500 mL) and was extracted with ethyl acetate (200 mL). The
organic
layer was washed with brine (4 x 200 mL), dried (magnesium sulfate), and
concentrated.
The residue was purified by chromatography (30/1 petroleum ether/ethyl
acetate) to
provide 6-nitrobenzo[d]isoxazole-3-carboxylate in 70% yield as a orange solid.
Ethyl 6-nitrobenzo[d]isoxazole-3-carboxylate (12.7 mmol), iron (53.6 mmol),
and
ammonium chloride (56.1 mmol) were combined and diluted with ethanol (150 mL)
and
water (20 mL). The resulting suspension was heated at reflux, with vigorous
stirring, for
2 h. The reaction mixture was filtered through Celite, diluted with brine (200
mL), and
the resulting solution was extracted with ethyl acetate (200 mL). The organic
layer was
washed with of brine (3 x 200 mL), dried (magnesium sulfate), and
concentrated. The
residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to
provide
ethyl 6-aminobenzo[d]isoxazole-3-carboxylate 49.6% yield as a orange solid
Ethyl 6-aminobenzo[d]isoxazole-3-carboxylate (2.43 mmol) was diluted with a
solution of sulfuric acid (2.5 mL) in water (2.5 mL) and the resulting mixture
was
maintained at rt for 30 min. A solution of sodium nitrite (2.67 mmol) in water
(2.5 ml)
was added dropwise at 0 C and the resulting mixture was maintained for 30 min
at 0 C.
This aqueous solution was added to a cold (0 C) solution of copper (II)
nitrate (149
mmol) in water (80 mL) and the reaction mixture was allowed to warm to rt.
After' 5
min., copper (1) oxide (2.78 mmol) was added to the mixture and the reaction
mixture
was maintained for 1 h at rt. The reaction mixture was extracted with ethyl
acetate (3 x
100 mL) and the combined organic layers were dried (magnesium sulfate) and
concentrated to provide crude ethyl 6-hydroxybenzo[d]isoxazole-3-carboxylate
in 99%
yield as a brown oil.
Potassium carbonate (9.42 mmol) and iodomethane (8.45 mmol) were added to a
solution of crude ethyl 6-hydroxybenzo[d]isoxazole-3-carboxylate (2.42 mmol)
in N,1V-
dimethylformamide (30 mL) and the reaction mixture was maintained for 48 h at
rt in the
dark. The reaction mixture was diluted with water (100 mL) and was extracted
with ethyl
acetate (2 x 100 mL). The combined organic layers were washed with brine (3 x
100
mL), dried (magnesium sulfate), and concentrated. The residue was purified by
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chromatography (30/1 petroleum ether/ethyl acetate) to provide ethyl 6-
methoxybenzo[d]isoxazole-3-carboxylate in 19% yield as a yellow solid.
The following ester was prepared using this method:
Ethy16-methoxybenzo[d]isoxazole-3-carboxylate.
Procedure 21
Procedure 21 provides a preparation of 7-azabenzisothiazole-3-carboxlic acid
from 2-chloronicotinic acid.
2-Chloronicotinic acid (317 mmol) was diluted with oxalyl chloride (130 mL)
and
the resulting solution was heated at reflux for 18 h. The volatiles were
removed by
evaporation to provide 2-chloronicotinoyl chloride in 98% yield as a white
solid.
Magnesium.chloride (221 mmol) and triethylamine (752 mmol) were added to a
solution of diethyl malonate (375 mmol) in toluene (250 ml) and the reaction
mixture was
maintained for I h at 25 C. A solution of 2-chloronicotinoyl chloride (313
mmol) in
toluene (80 mL) was added dropwise over the course of 2 h. The reaction
mixture was
maintained at rt for 3.5 h and was quenched with cold (0 C) water (500 mL).
The
resulting solution was extracted with ethyl acetate (500 mL) and the organic
layers
combined. The organic layer was washed with brine (3 x 300 mL), dried (sodium
sulfate), and was concentrated to provide diethyl 2-(2-
chloronicotinoyl)malonate in 85%
yield as a brown oil.
A solution of diethyl 2-(2-chloronicotinoyl)malonate (267 mmol) in
dimethylsulfoxide (100 ml) was added dropwise over 1.5 h to a 130 C solution
of water
(10 mL) in dimethylsulfoxide (260 mL). The reaction mixture was maintained at
130 C
for an additional 2 h and was allowed to cool to rt. The reaction mixture was
diluted with
cold (0 C) water (500 mL) and was extracted with ethyl acetate (3 x 200 mL).
The
combined organic layers were washed with brine (5 x 200 mL), dried (sodium
sulfate),
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and concentrated. The residue was purified by chromatography (10/1 petroleum
ether/ethyl acetate) to provide 1-(2-chloropyridin-3-yl)ethanone 52% yield as
yellow oil.
A solution of 1-(2-chloropyridin-3-yl)ethanone (129 mmol) in ammonium
hydroxide (130 mL) and ethanol (500 mL) was added to a 1 L high pressure steel
vessel
under an atmosphere of ammonia. Sulfur (129 mmol) was added to the reaction
mixture,
the vessel was sealed, and the reaction mixture was heated at 130 C for 16 h.
The
reaction mixture was filtered through Celite and the eluent was extracted with
ethyl
acetate (300 mL). The organic layer was washed with brine (100 mL), dried
(sodium
sulfate) and concentrated. The residue was purified by chromatography (20/1
petroleum
ether/ethyl acetate) to provide 3-methylisothiazolo[5,4-b]pyridine in 22%
yield as a white
solid.
N-Bromosuccinamide (10.7 mmol) was added to a solution of 3-
methylisothiazolo[5,4-b]pyridine (10.0 mmol) in carbontetrachloride (20 mL).
Benzoyl
peroxide (0.82 mmol) was added and the reaction mixture was heated at reflux
for 48 h.
The reaction mixture was filtered through Celite (ethyl acetate) and the
eluent was
concentrated to provide crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine as a
yellow
solid.
A solution of the crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine (3.49 mmol)
in dimethylsulfoxide (20 mL) was treated with water (4 mL) and the reaction
mixture was
heated at 80 C for 1.5 h. The reaction mixture was diluted with water (100
mL), filtered
through Celite, and was extracted with ethyl acetate (3 x 30 mL). The combined
organic
layers were washed with water, dried (magnesium sulfate), and concentrated to
provide
isothiazolo[5,4-b]pyridin-3-ylmethanol in 31 % yield as yellow oil.
Potassium permanganate (2.25 mmol) and potassium hydroxide (1.79 mmol) were
added to a solution of isothiazolo[5,4-b]pyridin-3-ylmethanol (1.08 mmol) in
water (4
mL) and the resulting solution was allowed to react for 3 h at rt. The
reaction mixture
was filtered through Celite and was extracted with ethyl acetate (3 x 10 mL).
The pH of
the combined aqueous layers was adjusted to 2 by the addition of 0.6 M
hydrochloric
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acid. The slurry was stirred for 5 min and the solids were collected by
filtration to
provide isothiazolo[5,4-b]pyridine-3-carboxylic acid in 42% yield as a light
yellow solid.
The following acid was prepared using this method:
Isothiazolo[5,4-b]pyridine-3-carboxylic acid.
Procedure 22
The following procedure provides a method for the preparation of 2,2,2-
trifluoroethyl substituted acids.
A mixture of ethyl6-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxylate (1.16 mmol) in
4/1
methylene chloride/trifluoroacetic acid (10.00 mL) was maintained at room
temperature
for 16 h. The reaction mixture was concentrated and the residue was loaded
onto a SCX
column (10g) and flushed with 5 volumes of methanol. The partially purified
product
was then eluted using 2.0 M ammonia in methanol to provide the amine in 68%
yield.
2,2,2-Trifluoroethylmethanesulfonate (0.330 mmol) was added to a solution of
ethyl 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-
carboxylate
(0.165 mmol) in N,N-diisopropylethylamine (0.20 mL) and acetonitrile (15 mL)
and the
resulting mixture was maintained for 16 h at room temperature. The reaction
mixture
was concentrated and the residue was purified by chromatography (90/10 to
70/30
hexanes/ethyl acetate) to yield the purified ester. The ester was dissolved in
ethanol (5.0
mL) and an aqueous solution of sodium hydroxide (5.0 M, 2.0 mL) was added. The
reaction was maintained at room temperature for 4 h, then diluted with water
(50 mL) and
neutralized with acetic acid. The precipitate was collected by filtration to
provide 6-
[(1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-
benzisothiazole-3-
carboxylic acid in 29 % yield.
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The following acid was prepared using a similar procedure:
6-{ 3-[Methyl(2,2,2-trifluoroethyl)amino]pyrrolidin-l-yl}=1,2-benzisothiazole-
3-
carboxylic acid
Procedure 23
Procedure 23 provides a preparation of amidine substituted indazole-3-
carboxylic
acids from the corresponding aldehydes.
N-Methyl-1,2-ethanediamine (4.7 mmol) was added to ;a soluton of tert-butyl 6-
formyl-IH-indazole-3-carboxylate (4.2 mmol) in tert-butanol (40 mL) and the
reaction
mixture was maintained for 30 min. Potassium carbonate (10 mmol) and iodine
(5.3
mmol) were added and the slurry was heated at 70 C for 3 h. The reaction
mixture was
allowed to cool to rt and was quenched with aqueous sodium thiosulfate (40
mL). The
aqueous layer was extracted with 9/1 dichloromethane/methanol and the combined
organic layers were dried (magnesium sulfate) and concentrated. The residue
was
purified by chromatography [100/0 to 60/40 dichloromethane/(8/1/1
dichloromethane/methanolJ7 M ammonia in methanol) to provide the amidine in
51%
yield.
tert-Butyl 6-(1-methyl-4,5-dihydro-1 H-imidazol-2-yl)-1 FI-indazole-3-
carboxylate
(2.2 mmol) was 'diluted with trifluoroacetic acid (3.7 mL) and the reaction
mixture was
maintained for 16 h at rt. The precipitated product was isolated by filtration
to provide
the acid in 93% yield.
The following acid was prepared using this method:
6-(1-Methyl-4,5-dihydro-lH-imidazol-2-yl)-1H-indazole-3-carboxylic acid.
Procedure 24
Procedure 24 provides a preparation of N-alkyl aminobenzisothiazole-3-
carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic
esters.
Sodium cyanoborohydride (8.57 mmol) was added to a solution of ethyl 6-
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[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxylate
(0.260 g,
0.857 mmol) and 1-ethoxy-l-(trimethylsilyloxy)cyclopropane (8.57 mmol) in
ethanol
(11.2 mL) and the reaction mixture was heated at 60 C for 6 h. The reaction
mixture
was diluted with water (50 mL) and was extracted with ethyl acetate (2 x50
mL). The
combined organic layers were washed with brine (25 mL), dried (magnesium
sulfate),
and were concentrated. The residue was purified by chromatography (ethyl
acetate) to
yield the ester. A 5.0 M solution of sodium hydroxide in water (4.00 mL) was
added to a
solution of the ester in ethanol (10.0 mL) and the reaction mixture was
maintained for 16
h. The reaction was neutralized with acetic acid and was loaded onto a SCX
column.
The column was flushed with water (200 mL) and methanol (100 mL) and the
product
was eluted with 2.0 M ammonia in methanol (60 mL) to provide the acid in 56%
yield.
The acid was used without further purification.
The following acid was prepared using this method:
6-[(1S,4S)-5-Cyclopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-
3-
carboxylic acid.
Procedure 25
Procedure 25 provides a preparation of N-alkyl aminobenzisothiazole-3-
carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic
esters.
Cyclopropylmethyl bromide (1.71 mmol) was added to a suspension of ethyl 6-
[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxylate
(0.857
mmol) and sodium bicarbonate (3.43 mmol) in acetonitrile (10.0 mL) and the
reaction
mixture was heated at 60 C for 6 h. The acetonitrile was decanted from the
solids and
the solids were washed with acetonitrile (2 x 5 mL). The acetonitrile solution
was
transferred to a silica gel column and the mixture was purified by
chromatography {9/1 to
7/3 ethyl acetate/ [(50/50/2) ethyl acetate/methanol/dimethylethylamine]} to
yield the
purified ester. A 5.0 M solution of sodium hydroxide in water (2.00 mL) was
added to a
solution of the ester in ethanol (5.0 mL) and the reaction mixture was
maintained for 16
h. The reaction was neutralized with acetic acid and the reaction mixture was
transferred
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to a SCX column (lOg). The column was flushed with water (200 mL) and methanol
(100 mL) and the product was eluted with 2.0 M ammonia in methanol to provide
the
product in 50% yield. The acid was used without further purification.
The following acid was prepared using this method:
6-[(1 S,4S)-5-(Cyclopropylmethyl)-2,5-diazabicyclo [2.2.1 ]hept-2-yl]-1,2-
benzisothiazole-
3-carboxylic acid.
Procedure 26
Procedure 26 provides a preparation of 6-hydroxybenzisothiazole-3-carboxylic
acid and the ester from the corresponding anisole.
A 1.0 M solution of boron tribromide in methylene chloride (20.00 mL) was
added dropwise to a 0 C solution of ethyl 6-methoxy-1,2-benzisothiazole-3-
carboxylate
(12.6 mmol) in methylene chloride (30.0 mL). The reaction mixture was allowed
to
warm to rt and was maintained for 16 h. The reaction mixture was poured into
100 mL
of ice cold 2 N sodium hydroxide and the mixture was stirred vigorously for 20
min. The
precipitated solids were removed by filtration and the eluent was washed with
ethyl
acetate (2 x 50 mL). The aqueous layer was neutralized with 6 N hydrochloric
acid and
the precipitated tan solid was collected by filtration to give a mixture of
the methoxy
(-48% yield) and hydroxy acids (-37% yield).
Thionyl chloride (27.0 nnnol) was added dropwise to a round bottom flask
containing ethanol (50.0 mL) at 0 C. The reaction mixture was allowed to wann
to rt
and the mixture of hydroxy and methoxy acids was added after 30 min. The
reaction
mixture was heated at 95 C for 4 h and was concentrated to ca. 25 mL. The
reaction
mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous
sodium
bicarbonate (100 mL) and the organic layer was washed with brine and
concentrated.
The residue was purified by chromatography using a gradient of 80/20 to 60/40
hexanes/ethyl acetate to provide the product in 82% yield.
The following acids and esters were prepared using this method:
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6-Hydroxy-1,2-benzisothiazole-3-carboxylic acid.
6-Methoxybenzo[d]isothiazole-3-carboxylic acid.
Ethyl 6-hydroxy-1,2-benzisothiazole-3-carboxyl ate.
Procedure 27
Procedure 27 provides a preparation of 7-aza-6-chlorobenzisothiazole-3-
carboxylic acid from 2-chloronicotinoyl chloride.
Magnesium metal (1.25 mol) was diluted with ethanol (250 mL) and carbon
tetrachloride (5 mL) and the suspension was heated at 70-80 C for 1 h. A
solution of
diethylmalonate (1.21 mol) in toluene (200 mL) was added dropwise and the
reaction
mixture was maintained for 2 h. The reaction mixture was cooled to 0 C and a
solution
of 2-chloronicotinoyl chloride (313 mmol) in toluene (200 mL) was added
dropwise,
while maintaining the temperature between 0 and 5 C. The resulting solution
was
allowed to warm to rt and was maintained for 2 h. The reaction mixture was
diluted with
50 mL of water and the precipitated solids were collected by filtration to
provide 104 g of
crude diethyl 2-(2-chloronicotinoyl) malonate as a pink solid.
Water (1.3 mL) was added to a solution of diethyl 2-(2-
chloronicotinoyl)malonate
(31.7 mmol) in dimethylsulfoxide (50 mL). The pH of the reaction mixture was
added
adjusted to 5-6 by the addition of hydrochloric acid and the reaction mixture
was heated
at 130 C for 2 h. The reaction mixture was then quenched with ice water (300
mL) and
the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined
organic
layers were washed with brine, dried (sodium sulfate), and concentrated. The
residue
was purified by chromatography (1/20 ethyl acetate/petroleum ether to provide
1-(2-
chloropyridin-3-yl)ethanone in 56% yield as light yellow oil.
Ammonium hydroxide (368 mL) was added to a mixture of sulfur (386 mmol)
and 1-(2-chloropyridin-3-yl)ethanone (350 mmol) and the slurry was diluted
with
methanol (960 mL). Ammonia gas was bubbled through the reaction mixture for 10
min
and the reaction mixture was heated at 110 C for 24 h. The reaction mixture
was
concentrated to dryness and the residue was extracted with water (3 x 500 mL).
The
aqueous layer was extracted with ethyl acetate (5 x 500 mL) and the combined
organic
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layers were dried (magnesium sulfate) and concentrated. The residue was
purified by
chromatography (1/25 ethyl acetate/petroleum ether to provide 3-
methylisothiazolo[5,4-
b]pyridine in 67% yield as a light yellow solid.
A solution of m-chloroperbenzoic acid (160 mmol) in acetic acid (200 mL) was
added dropwise to a solution of 3-methylisothiazolo[5,4-b]pyridine (107 mmol)
in
dichloromethane (200 mL). The reaction mixture was maintained for 6 h at 25
C. The
reaction mixture was diluted with water (100 mL), the pH was adjusted to 8
with 10%
sodium hydroxide, and the layers were separated. The aqueous layer was
extracted with
ethyl acetate (10 x 100 mL) and the combined organic layers were dried
(magnesium
sulfate) and concentrated to provide 3-methylisothiazolo[5,4-b]pyridine-N-
oxide in 62%
yield as a yellow solid.
A solution of triphosgene (190 mmol) in dichloromethane (200 mL) was added
dropwise over 20 min to a solution of 3-methylisothiazolo [5,4- b] pyridine-N-
oxide (47.4
mmol) in dichloromethane (150 mL)at -20 C. A solution of diisopropylamine
(190
mmol) in dichloromethane (200 mL) was added dropwise over 1 h. The reaction
mixture
was allowed to warm to rt and was maintained for 16 h. The reaction mixture
was
quenched with water (40 mL) of water and the pH ws adjusted to 7 by the
addition of
10% sodium hydroxide. The organic layer was washed with water (100 mL). The
combined aqueous layers were extracted with dichloromethane (10 x 100 mL) and
the
combined organic layers were dried (magnesium sulfate) and concentrated. The
residue
was purified by chromatography (1/80 ethyl acetate/petroleum ether) to provide
6-chloro-
3-methylisothiazolo[5,4-b]pyridine in 46% yield as a colorless solid.
AIBN (1.35 mmol) was added to a solution of 6-chloro-3-methylisothiazolo[5,4-
b]pyridine (13.5 mmol) and N-bromosuccinamide (27.1 mmol) in carbon
tetrachloride
(25 mL). The reaction mixture was heated at 80 C for 6 h, allowed to cool to
rt, and the
precipitated solids were removed by filtration. The filtrate was concentrated
to provide
crude 3-(bromomethyl)-6-chloroisothiazolo[5,4-b]pyridine as yellow oil.
Water (8 mL) was added to a solution of 3-(bromomethyl)-6-
chloroisothiazolo[5,4-b]pyridine (19.0 mmol) in dimethylsulfoxide (40 mL) and
the
reaction mixture was heated at 80 C for 1.5 h. The reaction mixture was then
quenched
with water (50 mL) and the resulting solution was extracted with ethyl acetate
(3 x 40
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mL). The combined organic layers were dried (magnesium sulfate) and
concentrated to
provide the crude (6-chloroisothiazolo[5,4-b]pyridin-3-yl) methanol as a
yellow solid.
Potassium permanganate (1.69 mmol) was added in several batches a solution of
(6-chlorobenzo[d]isothiazol-3-yl)methanol (2.50 mmol) in water (3 mL).
Potassium
carbonate (2.90 mmol) was added and the reaction mixture was maintained for 30
min at
25 C. The insoluble materials were removed by filtration and the aqueous
layer was
extracted with ethyl acetate (3 x 10 mL). The pH of the aqueous layer was
adjusted to 3-
4 by the addition of I N hydrochloric acid and the reaction mixture was
maintained for 10
min. The solids were collected by filtration to provide 6-
chlorobenzo[d]isothiazole-3-
carboxylic acid in 15% yield as a white solid.
The following acid was made using this method:
6-Chloroisothiazolo[5,4-b]pyridine-3-carboxylic acid.
Procedure 28
Procedure 28 provides a preparation of N-acylated aminobenzisothiazole-3-
carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic
esters.
Cyclopropanecarbonyl chloride (0.37 mmol) and N,N-diisopropylethylamine
(0.49 mmol) were added to a solution of ethyl 6-piperazin-1-yl-1,2-
benzisothiazole-3-
carboxylate (0.12 mmol) in methylene chloride (3.0 mL) and the reaction
mixture was
maintained for 1 h at rt. The reaction mixture was quenched with methanol (10
mL) and
the mixture was maintained for an additional 30 min. The reaction mixture was
poured
onto a 5 g SCX column and the product was eluted with methanol (20 mL). A 5.0
M
solution of sodium hydroxide in water (1.2 mL) was added to the methanol
solution and
the mixture was maintained for 2 h. The reaction mixture was diluted with
water (50
mL) and neutralized with a 6N solution of hydrochloric acid (1.5 mL). The pH
was
further adjusted to between 5 and 7 with acetic acid. The precipitated solids
were
collected by filtration to provide the acid in 88% yield.
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The following acids were prepared using this method:
6-[4-(Cyclopropylcarbonyl)piperazin-l-yl]-1,2-benzisothiazole-3-carboxylic
acid.
6-[ 1-(Cyclopropylcarbonyl)octahydro-6H-pyrrolo [3,4-b]pyridin-6-yl]-1,2-
benzisothiazole-3-carboxylic acid.
6-[(1S,4S)-5-(Cyclopropylcarbonyl)-2,5-diazabicyclo [2.2.1 ]hept=2-yl]-1,2-
benzisothiazole-3-carboxylic acid.
Procedure 29
Procedure 29 provides a preparation of nitrile substituted indazole-3-
carboxylic
acids from the corresponding bromoindazole-3-carboxylic esters.
Zinc Cyanide (1.00 mmol) was added to a solution of ethyl6-bromo-lH-indazole-
3-carboxylate (0.502 mmol) and tetrakis(triphenylphosphine)palladium(0)
(0.0502 mmol)
in N,N-dimethylformamide (5.00 mL) and the reaction mixture was heated at 100
C for
16 h. The reaction mixture was diluted with ethyl acetate and water and the
layers were
separated. The aqueous layer was extracted with ethyl acetate (2 x) and the
combined
organic layers were washed with brine and dried (sodium sulfate). The residue
was
purified by chromatography 70/30 to 50/50 hexane/ethyl acetate to provide the
nitrile in
65% yield. The ester was hydrolyzed with sodium hydroxide in ethanol to
provide the
acid.
The following acid and ester were prepared using this procedure:
Ethy16-cyano-1 H=indazole-3-carboxylate.
6-Cyano-lH-indazole-3-carboxylic acid.
Base Preparations.
The following procedures (30-35) detail the preparation of the bicyclobases
and
amines that were not commercially available.
Procedure 30
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Procedure 30 provides a method for the preparation of N-alkylated 3-
aminoquinuclidines from 3-aminoquinuclidine.
Acetyl chloride (12 mmol) was added dropwise to a solution of (R)-3-
aminoquinuclidine (10 mmol) andN,N-diisopropylethylamine (30 mmol) in
dichloromethane (100 mL). The resulting solution was maintained at rt for 4 h
and was
evaporated to dryness. The crude amide was dissolved in tetrahydrofuran (150
mL) and
was treated with lithium aluminum hydride (66 mmol) in small portions. The
reaction
mixture was quenched with sodium sulfate decahydrate and the resulting slurry
was
diluted with tetrahydrofuran and filtered through Celite. The filtrate was
concentrated
and the residue was then diluted with freshly prepared methanolic hydrogen
chloride
(generated by the dropwise addition of 3 mL of acetyl chloride into 30 mL of
methanol)
and maintained at rt for 15 min. The residue obtained by the removal of the
volatiles was
recrystallized (2-propanol/methanol) to provide the secondary amine in 41 %
yield as a
colorless solid.
The following bases were prepared using this method:
(3R)-N-(Methyl)quinuclidin-3-amine dihydrochloride.
(3S)-N-(Methyl)quinuclidin-3-amine dihydrochloride.
Procedure 31
Procedure 31 provides a method for the preparation of cyclic ureas from
diamines.
Carbonic acid, dimethyl ester (10.0 mmol) was added dropwise to a mixture of N-
propyl-l,2-ethanediamine(10.0 mmol) and cesium carbonate (2.00 mmol) and the
reaction mixture was heated at 70 C for 1 h. The reaction mixture was
concentrated and
the residue was heated at 130 C for 3 h. The reaction mixture was
concentrated and the
residue was purified by chromatography [(50/50 to 0/100) hexane/ethyl acetate]
to
provide the product (60%) as an oil.
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The following cyclic urea was prepared using this method:
1-Propylimidazolidin-2-one.
1-Ethylimidazolidin-2-one.
Procedure 32
Procedure 32 provides a method for the preparation of 3-alkoxypyrrolidines
from
N-Boc-3-hydroxypyrrolidine.
1-Boc-3-hydroxypyrrolidine (16.1 mmol) was added in portions to a suspension
of
sodium hydride (22.0 mmol) in tetrahydrofuran (40 mL) at 0 C. The reaction
mixture
was diluted with tetrahydrofuran (60 mL) and allowed to warm to rt. Methyl
iodide (21.0
mmol) was added to the cloudy suspension after I h and the reaction mixture
was
maintained at rt for 6 h. The reaction mixture was concentrated and
redissolved in ethyl
acetate (100 mL). The extract was washed with saturated ammonium chloride (20
mL),
water (20 mL), and brine (20 mL) and was dried (sodium sulfate). The residue
was
purified by chromatography (1/4 ethyl acetate/hexane) to give the ether. The N-
Boc
product was dissolved in tetrahydrofuran (30 mL) and 6 N hydrochloric acid (20
mL) was
added. The resultant mixture was stirred for I h and was concentrated to give
an oil.
Toluene (10 mL) and ethanol (10 mL) were added and the mixture was
concentrated to
give 1.79 g of brownish, very hygroscopic solid. The solid was suspended in
ethyl
acetate and stirred vigorously for 12 h. The solids were quickly collected by
filtration
and dried under high vacuum to give the product (81 %) as a colorless solid.
An alternative procedure used for the removal of the N-Boc groups entails
exposure to trifluoroacetic acid for 4 h. followed by concentration of the
reaction
mixture. This procedure may be useful for the production of the amine as a
free base.
The following amine was prepared using this procedure:
3-Methoxypyrrolidine hydrochloride.
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The free base was obtained by neutralization of the salt residue with
saturated
sodium carbonate (5 mL), extraction with 9/1 dichloromethane/methanol (3 x 20
mL),
drying (potassium carbonate), and concentration, followed by capturing the
amine on a
SCX column and eulting with 2M ammonia in methanol:
3-Methoxypyrrolidine.
3-Ethoxypyrrolidine.
(3R)-3-Methoxypyrrolidine.
(3S)-3-Methoxypyrrolidine.
3-(Methoxymethyl)pyrrolidine
Procedure 33
Procedure 33 provides a preparation of SEM protected hydroxypyrrolidines from
hydroxypyrrolidine.
A solution of 1-Boc-3-hydroxy-pyrrolidine (26.7 mmol) in tetrahydrofuran (20
mL) was
added slowly to a suspension of sodium hydride (30.8 mmol) in tetrahydrofuran
(78 mL)
and the reaction mixture was maintained for 30 min. A solution of [(3-
(trimethylsilyl)ethoxy]methyl chloride (30.7 mmol) in tetrahydrofuran (4.4 mL)
was
added and the reaction mixture was maintained for 18 h. The reaction was
partitioned
between water (50 mL) and ethyl acetate (50 mL) and the layers were separated.
The
organic layer was washed with brine (25 mL), dried (magnesium sulfate), and
concentrated. The residue was purified by chromatography 95/5 to 80/20
hexanes/ethyl
acetate to provide the Boc-protected product. The residue was heated neat at
350 C for
3 h. The resulting brown oil was purified by chromatography [100/0 to 80/20
ethyl
acetate/(50/50/2 ethyl acetate/methanol/dimethylethylamine)] to give a brown
oil after
concentration. The oil was dissolved in ethanol and the solution was treated
with
activated carbon, filtered, and concentrated to provide the product in 52%
yield.
The following amine was prepared using this method:
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3-{ [2-(Trimethylsilyl)ethoxy]methoxy}pyrrolidine.
Procedure 34
Procedure 34 provides a preparation of 3-trifluoromethoxypyrrolidine from
hydroxypyrrolidine.
A solution of 1-Boc-3-hydroxypyrrolidine (26.7 mmol) in tetrahydrofuran (20
mL) was added slowly to a suspension of sodium hydride (30.8 mmol) in
tetrahydrofuran
(78 mL) at 0 C. Chlorodifluoromethane (30.7 mmol) was added to the reaction
and the
reaction mixture was allowed to warm to rt where it was maintained for 18 h.
The
reaction was partitioned between water (50 mL) and ethyl acetate (50 niL) and
the layers
were separated. The organic layer was washed with brine (25 mL), dried
(magnesium
sulfate), and concentrated. The residue was purified by chromatography 95/5 to
80/20
hexanes/ethyl acetate to provide the Boc-protected product. The purified
product (ca. 2g)
was dissolved in a 4/1 mixture of dichloromethane/trifluoroacetic acid (20.0
mL) and was
maintained for 4 h. The solvent was removed and the residue was purified by
chromatography [100/0 to 90/10 ethyl acetate/(50/50/2 ethyl
acetate/methanol/dimethylethylamine)]. The product was unexpectedly volatile
and
much of it was lost on concentration. The final yield for the product was 2%.
The following amine was prepared using this method:
3-(Difluoromethoxy)pyrrolidine.
Procedure 35
Procedure 35 provides a preparation of 3-cyclopropylmethoxypyrrolidine from
hydroxypyrrolidine.
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A solution of 3-hydroxy-pyrrolidine-hydrochloride (162 mmol) in
tetrahydrofuran
(100 mL) was treated with potassium carbonate (210 mmol) and a solution of
benzyl
chloroformate (210 mmol) in tetrahydrofuran (50 mL). The resulting solution
was
maintained for 16 h at rt. The reaction mixture was concentrated and the
residue was
dissolved in ethyl acetate (200 mL). The solution was washed with brine (3 x
100 mL),
dried (magnesium sulfate), and concentrated to provide the protected amine in
90% yield
as a yellow liquid.
Sodium hydride (280 mmol) was added in portions to a cold (0 C) solution of
benzyl 3-hydroxypyrrolidine-l-carboxylate (76.9 mmol) in N,N-dimethylformamide
(100
mL). The mixture was maintained for 60 min and was then treated with a
solution of
(bromomethyl)cyclopropane (231 mmol) in N,N-dimethylformamide (100 mL) and
potassium iodide (0.66 mmol). The reaction mixture was allowed to warm to rt
where it
was maintained for 30 min. The reaction mixture was subjected to microwave
irradiation
for 2 h at 90 C. The reaction mixture was concentrated and the residue was
diluted with
ethyl acetate (200 mL) and water (200 mL) and the layers were separated. The
aqueous
layer was extracted with ethyl acetate (3 x 200 mL) and the combined organic
layers
were washed with brine (2 x 200 mL) and dried (magnesium sulfate). The residue
was
purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide the
product in
81 % yield.
A suspension of benzyl 3-(cyclopropylmethoxy) pyrrolidine-l-carboxylate (17.4
mmol) and 10% palladium on carbon (600 mg) in ethyl acetate (20mL) and
methanol (20
mL) was placed under an atmosphere of hydrogen gas. The reaction mixture was
maintained for 16 h and was filtered through Celite. The filtrate was
concentrated to
provide the product in 86% yield as a yellow liquid.
The following amine was prepared using this method:
3-(Cyclopropylmethoxy)pyrrolidine.
Representative Procedures.
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The following procedures (A-AA) detail the preparation of the bicyclobase
analogs.
Procedure A
Procedure A provides a method for the coupling between 3-aminoquinuclidine
and benzisoxazole carboxylic esters to form carboxamide derivatives.
The suspension of (S)-3-aminoquinuclidine hydrochloride (3.50 mmol) in ethanol
(5 mL) was treated with N,.N-diisopropylethylamine (4.00 mmol). Ethyl 6-bromo-
l,2-
benzisoxazole-3-carboxylate (1.86 mmol) was added and the suspension was
heated at 85
C for 3 d. The reaction mixture was allowed to cool to rt, was diluted with
dichloromethane (30 mL), and was washed with 10 mL of saturated sodium
bicarbonate.
The aqueous layer was back-extracted with dichloromethane (30 mL) and the
combined
organic layers were washed with brine and dried (sodium sulfate). The organic
layer was
loaded on a 10 g SCX column. The column was washed with methanol (50 mL), 2 M
ammonia in methanol (60 mL) and the ammonia wash was concentrated. The residue
was purified by chromatography [40/60 to 0/100 ethyl acetate/(70/30/1 ethyl
acetate/methanol/ammonium hydroxide)] to provide the product in 63% yield as a
colorless oil.
The following compound was prepared using this method:
86) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisoxazole-3-
carboxamide, 'H NMR (CD3OD) S 7.94 (d, IH, J= 8.8), 7.24 (d, IH, J= 2), 7.06
(dd, 1H, J=2.1, 8.7), 4.51 (m, 1H), 3.91 (s,1H), 3.84 (m, IH), 3.38 (m, 1H),
2.38
(m, 1 H), 2.22 (m, 1 H), 2.09 (m, 2H), 1.94 (m, 1 H); LC/MS (El) tR 3.37, m/z
302.1
(M++1);
1V-[(35)-1-Azabicyclo [2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-
carboxamide.
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Procedure B
Procedure B provides a method for the coupling between 3-aminoquinuclidine
and benzisothiazole carboxylic acids to form carboxamide derivatives.
To a solution of the benzisothiazole-3-carboxylic acid (0.30 mmol) in a 5/1
mixture of tetrahydrofuran/N,N-dimethylformamide (12 mL) was added
diisopropylethylamine (1.1 mmol) and (R)-3-aminoquinuclidine dihydrochloride
(0.6
mmol). The mixture was cooled to 0 C, and HATU (0.3 mmol) was added in one
portion. The reaction mixture was allowed to warm to rt and was maintained for
16 h.
The mixture was partitioned between saturated aqueous potassium carbonate
solution and
a 95/5 mixture of dichloromethane/methanol. The aqueous layer was extracted
with 95/5
dichloromethane/methanol (2X), and the combined organic layers were washed
with
brine and dried over sodium sulfate. Alternatively, the reaction mixture was
loaded on a
10 g SCX column and the column was washed with methanol (50 mL), 2 M ammonia
in
methanol (60 mL) and the ammonia wash was concentrated. The crude product was
purified by chromatography 100/0 to 30/70 ethyl acetate/[(50/50/2) ethyl
acetate/methanol/dimethylethylamine] or by preparative HPLC, thus providing
the amide
in 75% yield as a colorless solid.
The following compounds were prepared using this method:
84) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-1-yl]-1,2-
benzisothiazole-3-carboxamide,'H NMR (CD30D) S 8.47 (d, J= 9.1, 1H); 6.98
(d, J= 1.9, 1H); 6.88 (dd, J= 2.0/9.2, 1H); 4.30 (m,1H); 4.16 (m, 1H); 3.60-
3.35
(m, 5H); 3.38 (s, 3H); 3.3-2.95 (m, 5H); 2.30-2.00 (m, 4H); 1.92 (m, 2H); 1.61
(m, 1 H); LC/MS (EI) tR 3.84, m/z 387.2 (M"+ 1);
85) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-methoxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.91, m/z 387.2 (M++1);
87) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-l-yl)-7-fluoro-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.82, m/z 419.1 (M++1);
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92) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-(3-methoxypyrrolidin-l-yl)-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 5.11, m/z 405.2 (M}+1);
93) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-(3-methoxypyrrolidin-l-yl)-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 5.08, m/z 405.2 (M}+1);
94) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.25, m/z 373.1 (M'+1);
95) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.23, m/z 373.1 (M++1);
96) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.92, m/z 400.2 (M'+1);
97) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]hept-
5-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.26, m/z 385.1 (M++1);
98) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.27, m/z 373.1 (M++1);
99) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-hydroxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.23, m/z 373.1 (M++1);
100) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.89, m/z 400.2 (M'+l);
101) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3R)-3-hydroxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.27, m/z 373.1 (lVI'+1);
102) 1V-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-hydroxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.26, m/z 373.1 (MF+1);
103) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.92, m/z 400.2 (M++1);
104) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(IS,4S)-2-oxa-5-
azabicyclo[2.2.1]hept-5-
yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.36, m/z 385.1 (M++1);
105) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-(dimethylamino)pyrrolidin-
l-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.81, m/z 400.2 (M"+1);
106) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]isothiazolo[5,4-b]pyridine-3-
carboxamide
hydroformate, LC/MS (EI) tR 2.71, m/z 289.1 (M"+1);
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107) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]isothiazolo[5,4-b]pyridine-3-
carboxamide
hydroformate, LC/MS (EI) tR 2.48, m/z x289.1 (M++l);
114) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1,2-
benzisothiazole-3-
carboxamide, LC/MS (EI) tR 3.8, m/z 336.1 (M++1);
115) IV-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1,2-
benzisothiazole-3-
carboxamide, LC/MS (EI) tR 3.81, m/z 336.1 (M}+1;.
116) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1 S,4S)-5-methyl-2,5-
diazabicyclo
[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (El) tR 1.84, m/z
398.2 (M++1);
117) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1J-6-[(1S,4S)-5-methyl-2,5-diazabicyclo
[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.87, m/z
398.2 (W+1);
122) I+l-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1 S,4S)-5-(2,2,2-
trifluoroethyl)-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI)
tR 4.69, m/z 466.1 (M'+1);
123) N-[(3R)-l-Azabicyclo[2.2.2]oct-3-yl]-6-{3-[methyl(2,2,2-
trifluoroethyl)amino]pyrrolidin-l-yl } -1,2-benzisothiazol e-3-carboxamide,
LC/MS (EI) tR 4.77, m/z 468.1 (M++1);
124) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{3-[methyl(2,2,2-
trifluoroethyl)amino]pyrrolidin-l-yl}-1,2-benzisothiazole-3-carboxamide,
LC/MS (EI) tR 4.75, m/z 468.1 (M++1);
125) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methoxymethyl)pyrrolidin-l-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (BI) tR 4.98, m/z 401.1 (M++1);
126) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methoxymethyl)pyrrolidin-1-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.94, m/z 401.1 (NI'+1);
127) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-ylJ-6-[(3R)-3-(dimethylamino)pyrrolidin-
l-
yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.55, m/z 400.2 (Ne+1);
128) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-(dimethylamino)pyrrolidin-
l-
y1J-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.55, m/z 400.1 (M++1);
129) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(dimethylamino)piperidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide LC/MS (EI) tR 1.59, m/z 414.1 (1Vf}+1).;
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130) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(dimethylamino)piperidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.61, m/z 414.2 (M++1);
177) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(cyclopropylcarbonyl)piperazin-
1-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.30, m/z 440 (M++1);
178) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(cyclopropylcarbonyl)piperazin-
l-yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.30, m/z 440 (MF+1);
179) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(cyclopropylcarbonyl)octahydro-
6H-
pyrrolo[3,4-b]pyridin-6-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.81, m/z 480 (M"+1);
180) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(cyclopropylcarbonyl)octahydro-
6H-
pyrrolo[3,4-b]pyridin-6-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.85, m/z 480 (M}+1);
181) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1 S,4S)-5-(cyclopropylcarbonyl)-
2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.97, m/z 452 (M'+1);
182) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-(cyclopropylcarbonyl)-
2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/1VIS (EI)
tR
3.04, m/z 452 (M++l);
183) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,4-dimethylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/1VIS (EI) tR 1.30, m/z 400 (M++1);
132) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-[(1 S,4S)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
dihydroformate,
LC/MS (EI) tR 3.27, m/z 412.2 (M++l);
133) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-[(I. S,4S)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide
dihydroformate,
LC/MS (EI) tR 3.19, m/z 412.2 (M}+1);
134) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1R,4R)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.26, m/z 398.2 (M'+1);
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135) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-y1]-6-[(1R,4R)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.2, m/z 398.2 (M'+1);
136) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazabicyclo[3.2.2]non-4-yl)-
1,2-
benzisothiazole-3-carboxamide dihydroformate, LC/MS (EI) tR 1.61, m/z 412.2
(M++1);
137) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazabicyclo[3.2.2]non-4-yl)-
1,2-
benzisothiazole-3-carboxamide dihydroformate, LC/MS (EI) tR 3.51, m/z 412.1
(Ivl}+1);
138) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-l-yl-l,2-
benzisothiazole-3-
carboxamide, LC/MS (EI) tR 4.66, m/z 357.2 (M+1);
139) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.67, m/z 386.2 (M}+l);
140) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.63, m/z 386.2 (M'-+1);
141) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,4-diazepan-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.8, m/z 400.2(M41);
142) IV-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,4-diazepan-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.84, m/z 400.2 (M'+1);
143) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hexahydropyrrolo[1,2-a]pyrazin-
2(1H)-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.79, m/z 412.1 (W+1);
144) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hexahydropyrrolo[1,2-a]pyrazin-
2(IH)-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.81, m/z 412.2 (M}+1);
145) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-2,5-
diazabicyclo[2.2.2]oct-2-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.88, m/z 412.2 (M++1);
146) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-2,5-
diazabicyclo[2.2.2]oct-2-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.88, m/z 412.2 (M++1);
147) N-[(3R)-I-Azabicyclo[2.2.2]oct-3-yl]-6-(8-methyl-3,8-
diazabicyclo[3.2.1]oct-3-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.95, m/z 412.2 (MF+1);
148) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(8-methyl-3,8-
diazabicyclo[3.2.1]oct-3-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.93, m/z 412.2 (M++1);
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149) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-cyclopropyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.08, m/z 424.1 (M}+1);
150) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-cyclopropyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
3.24, m/z 424.1 (M'+1);
151) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-(cyclopropylmethyl)-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
1.31, m/z 438.2 (M++1);
152) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-5-(cyclopropylmethyl)-2,5-
diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR
1.31, m/z 438.2 (M++l);
153) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-l,4-diazepan-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 2.14, m/z 400.2 (M'+1);
154) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3R)-3-methoxypyrrolidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.57, m/z 387.2 (M'+1);
155) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.57, m/z 387.2 (W+1);
156) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.56, m/z 387.2 (MF+1);
157) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.25, m/z 387.2 (W+1) ;
158) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.25, m/z 387.2 (MF+1);
159) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-azabicyclo[2.2.2]oct-3-yloxy)-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.33, m/z 413.2 (Me+1);
160) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-azabicyclo[2.2.2]oct-3-yloxy)-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.32, m/z 413.2 (M'+1);
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(bromo)-1,2-benzisothiazole-3-
carboxamide;
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1V-[(3S)-1-Azabicyclo [2.2.2]oct-3-yl]-6-(bromo)-1,2-benzisothiazole-3-
carboxamide;
N-[(3R)-1-Azabicyclo [2.2.2] oct-3 -yl]-6-(bromo)-1,2-benzisothiazole-3 -
carboxamide;
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(methoxy)-1,2-benzisothiazole-3-
carboxamide.
The following compounds were prepared using this procedure, followed by
treatment with trifluoroacetic acid, isolation by ion exchange, and
purification by
chromatography or preparative HPLC as described above:
118) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1S,4S)-2,5-
diazabicyclo[2.2.1]hept-2-
yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.87, m/z 384.1 (M++1);
119) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1 S,4S)-2,5-
diazabicyclo[2.2.1]hept-2-
yl]-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.87, m/z 384.1 (M++1);
120) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methylamino)pyrrolidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.96, m/z 386.1 (MF+1);
121) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(methylamino)pyrrolidin-1-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.94, m/z 386.2 (1Vf +l);
168) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methylpiperazin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.28, m/z 386.2 (M'+1);
169) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(octahydro-6H-pyrrolo[3,4-
b]pyridin-6-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.33, m/z 412.2 (M'+1);
170) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(octahydro-6H-pyrrolo[3,4-
b]pyridin-6-
yl)-1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.35, m/z 412.2 (M++1);
171) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperazin-l-yl-l,2-benzisothiazole-
3-
carboxamide, LC/MS (EI) tR 1.29, m/z 372 (M'+1);
172) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperazin-l-yl-l,2-benzisothiazole-
3-
carboxamide, LC/MS (EI) tR 1.47, m/z 372 (M'+l);
173) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazepan-1-yl)-1,2-
benzisothiazole-
3-carboxamide, LC/MS (EI) tR 1.74, m/z 386 (M'-+1);
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174) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,4-diazepan-1-yl)-1,2-
benzisothiazole-
3-carboxamide, LC/MS (EI) tR 1.70, m/z 386 (M'-+1);
175) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-methylpiperazin-1-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.57, m/z 386 (M'+1);
176) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-methylpiperazin-1-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 1.55, m/z 386 (M++1).
Procedure C
Procedure C provides a method for the coupling between 3-aminoquinuclidine
and carboxylic acids to form carboxamide derivatives.
To a solution of the carboxylic acid (16.1 mmol) in N,N-dimethylformamide (65
mL) was added HBTU (16.1 mmol), catalytic amount of dimethylaminopyridine, N,N-
diisopropylethylamine (96.6 mmol) and 4 A activated molecular sieves (2.6 g).
The
reaction mixture was maintained at room temperature for 2 h under nitrogen and
then 3-
aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h, the
solvent was
removed under reduced pressure. The oily residue was partitioned between
saturated,
aqueous sodium bicarbonate (25 mL) and dichloromethane (100 mL). The aqueous
layer
was further extracted with 9/1 dichloromethane/methanol (5 x 100 mL) and the
combined
organic layers were concentrated. The residue was purified by chromatography
[90/10/1
dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl
acetate/(70/30/1
ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus
providing
the product in 30%-70% yield.
The following compounds were prepared using this method:
42) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-N-methyl-lH-indazole-3-
carboxamide hydroformate. 'H NMR (CD3OD) S 8.42 (br s, 1H), 7.49 (d, J= 9.1,
1H), 7.38 (d, J= 2.1, 1H), 7.09 (dd, J= 9.1, 2.4, 1H), 4.89 (m, 1H), 3.85 (s,
3H),
3.83 (m, 2H), 3.60-3.46 (m, IH), 3.38-3.30 (m, 2H), 2.57 (m, 2H), 2.36-2.30
(m,
114), 2.10-1.97 (m, 3H); LC/MS (EI) tR 2.56, m/z 315 (M'+l);
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43) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide hydroformate. LC/MS (EI) tR 2.82, m/z 351 (M++1);
44) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide hydroformate. LC/MS (EI) tR 2.9, m/z 351 (M'+1);
45) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(tetrahydro-2H-pyran-4-yl)-
1FI-indazole-3-carboxamide hydroformate. LC/MS (EI) tR 2.55, m/z 369 (M++1);
46) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-5-(tetrahydro-2H-pyran-4-yl)-
1FI-indazole-3-carboxamide hydroformate. LC/MS (EI) tR 2.89, m/z 369 (M++1);
47) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-thiazol-2-yl)-1H-
indazole-
3-carboxamide hydroformate. LC/MS (EI) tR 3.33, m/z 368 (M++1);
48) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1,2-
benzisothiazole-
3-carboxamide hydroformate. LC/MS (EI) tR 3.21, m/z 348 (M++l);
N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-lH-indazole-3-carboxamide.
Procedure D
Procedure D provides a method for the coupling between 3-aminoquinuclidine
and carboxylic acids to form carboxamide derivatives.
To a solution of the carboxylic acid (4.77 mmol) in N,N-dimethylformamide (14
mL) was added N,N-diisopropylethylamine (19 mmol) and 3-aminoquinuclidine
dihydrochloride (4.29 mmol). The reaction mixture was maintained at room
temperature
for 30 min under nitrogen and then HATU (4.76 mol) was added. After 18 h, the
reaction
mixture was filtered through Celite (methanol rinse) and was divided equally
amongst 3
SCX columns. The columns were washed with methanol (100 mL each) and the basic
components were eluted with 2 M ammonia in methanol (100 mL each) and
concentrated. The residue was purified by chromatography [1/1 to 0/1 ethyl
acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparative
HPLC,
thus providing the product in 15%-50% yield.
The following compounds were prepared using this method:
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3) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,6-dimethoxy-IH-indazole-3-
carboxamide
hydroformate. 'H NIV1R (CD3OD) 6 8.33 (bs, 2H), 7.55 (s, 1H), 7.05 (s, IH),
4.52
(m, IH), 3.87 (s, 3H), 3.86 (s, 3H), 3.79 (m, 1H), 3.37 (m, 6H), 2.38 (m, 4H),
2.11
(m, 5H); LC/MS (EI) tR 2.48, m/z 331 (1VI'-+1);
17) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-lH-indazole-3-
carboxamide hydroformate. LC/MS (EI) tR 2.53, m/z 315 (M'+1);
19) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-methoxy-IH-indazole-3-
carboxamide. LC/MS (EI) tR 3.55, m/z 329 (M"+1);
20) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-methoxy-IH-indazole-3-
carboxamide. LC/MS (EI) tR 3.54, m/z 329 (M'+1);
21) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-methoxy-IH-
indazole-
3-carboxamide. LC/MS (EI) tR 3.75, m/z 351 (M'+1);
28) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-oxazol-2-yl)-IH-
indazole-
3-carboxamide. LC/MS (EI) tR 3.09, m/z 352 (M"+1);
29) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(1,3-thiazol-2-yl)-IH-
indazole-
3-carboxamide. LC/MS (EI) tR 3.33, m/z 368 (M'+1);
34) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-6-(tetrahydro-2H-pyran-4-yl)-
1H
indazole-3-carboxamide. LC/MS (EI) tR 2.52, m/z 369 (M}+1);
35) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-methyl-5-(tetrahydro-2H-pyran-4-yl)-
1H-
indazole-3-carboxamide. LC/MS (EI) tR 2.85, m/z 369 (M'+1);
36) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-N-methyl-lH-
indazole-3-carboxamide. LC/MS (EI) tR 3.4, m/z 351 (M'+1);
37) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy) N methyl-IH
indazole-3-carboxamide. LC/MS (EI) tR 3.48, m/z 351 (1Vf+1);
40) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-N-methyl-1Hindazole-3-
carboxamide. LC/MS (EI) tR 2.51, m/z 315 (1VI}+1);
57) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-IH-pyrazolo[3,4-b]pyridine-3-
carboxamide hydroformate, LC/MS (EI) tR 2.47, m/z 290 (M++1);
59) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-IH-pyrazolo[4,3-c]pyridine-3-
carboxamide,
LC/MS (EI) tR 1.29, m/z 272.2 (1Vf++1);
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60) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1H-pyrazolo[3,4-c]pyridine-3-
carboxamide
hydroformate, LC/MS (EI) tR 1.59, m/z 272.2 (M++1);
73) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-1H-
indazole-3-
carboxamide hydroformate, LC/MS (EI) tR 3.13, m/z 366 (1Vl++1);
88) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-phenyl-IH-pyrazolo[3,4-b]pyridine-3-
carboxamide, LC/MS (EI) tR 4.18, m/z 348.1 (M~+I);
90) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(dimethylamino)pyrrolidin-l-yl]-
IH-
pyrazolo[3,4-b]pyridine-3-carboxamide, LC/MS (EI) tR 2.64, m/z 384.2 (M++1);
91) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(dimethylamino)pyrrolidin-l-yl]-
1H-
pyrazolo[3,4-b]pyridine-3-carboxamide, LC/MS (EI) tR 2.62, m/z 384.2 (M'+1);
N- [(3S)-1-Azabicyclo [2.2.2] oct-3 -yl]-6-(bromo)- I H-indazole-3 -
carboxamide;
N-[(3S)-1-Azabicyclo [2.2.2] oct-3-yl] -4-methoxy-1 H-indazole-3-carboxamide.
N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-l-ethyl-IH-indazole-3-
carboxamide;
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-l-methyl-lH-indazole-3-
carboxamide;
N-[(3.S')-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-l-difluoromethyl-1 H-indazole-3-
carboxamide;
N-[(3S)-1-Azabicyclo [2.2.2] oct-3 -yl]-6-(1,3-thiazol-2-yl)- I H-indazole-3 -
carboxamide;
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-
carboxamide;
N- [(3S)-1-Azabicyclo [2.2.2] oct-3 -yl] -6-bromo-l- [(2-methoxyethoxy)methyl]
- I H-
indazole-3-carboxamide;
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-l-{[2-(trimethylsilyl)
ethoxy] methyl }- I Hindazo le-3 -carboxamide;
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-l-{ [2-(trimethylsilyl)
ethoxy]methyl}-1H-indazole-3-carboxamide;
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-2-{ [2-(trimethylsilyl)
ethoxy]methyl}-IH-indazole-3-carboxamide;
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N- [(3R)-1-Azabicyclo [2.2.2] oct-3 -yl] -6-bromo-2- { [2-(trimethylsilyl)
ethoxy]methyl } -1 H-indazole-3-carboxamide.
The following compounds were prepared using this procedure, followed by
removal of the protecting group using 6 N hydrochloric acid, isolation by ion
exchange,
and purification by preparative HPLC:
6) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yloxy)-1H-
indazole-3-
carboxamide hydroformate. LC/MS (EI) tR 2.68, m/z 357 (Nr+l);
7) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yloxy)-1H-
indazole-3-carboxamide hydroformate. LC/MS (EI) tR 2.73, m/z 371 (M'+1);
8) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-1H-
indazole-3-carboxamide hydroformate. LC/MS (EI) tR 1.4, m/z 370 (M++1).
The following compound was prepared using this procedure, followed by
treatment with tetrabutylammonium fluoride:
164) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(35)-3-
(cyclopropylmethoxy)pyrrolidin-
1-yl]-1H-indazole-3-carboxamide, LC/MS (EI) tR 3.67, m/z 410 (Ivt++1);
166) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(3S)-3-methoxypyrrolidin-1-yl]-1H-
indazole-3-carboxamide dihydroformate, LC/MS (EI) tR 2.44, m/z 369 (M'+1).
Procedure E
Procedure E provides a method for the coupling between 3-aminoquinuclidine
and carboxylic acids, amines, and indazoles to form amide and urea
derivatives.
A mixture of 6-(1-methyl-4,5-dihydro-lH-imidazol-2-yl)-1H-indazole-3-
carboxylic acid (0.500 mmol) , TBTU (0.624 mmol), and (3R)-quinuclidin-3-amine
dihydrochloride (0.706 mmol) was diluted with N,N-dimethylformamide (4 mL) and
N,N-diisopropylethylamine (2.34 mmol) was added. The reaction mixture was
maintained for 16 h at rt. The reaction mixture was loaded onto a SCX column
(10 g)
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and was washed with methanol (100 mL). The partially purified product was then
eluted
using 2.OM ammonia in methanol (60 mL). The solvent was removed and the
residue
was purified by preparative HPLC, thus providing the product in 20% yield.
The following compounds were prepared using this method:
162) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-4,5-dihydro-lH-imidazol-
2-
yl)-1H indazole-3-carboxamide, 'H NMR (CD3OD) 6 8.53 (s, 2H), 8,46 (d, J=
8.5, 1 H, rotamer), 8.40 (d, J= 8.4, 1 H, rotamer), 8.06 (s, 1 H, rotamer),
7.90 (s,
1 H, rotamer), 7.50 (d, J= 8.3, 1 H, rotamer), 7.35 (d, J= 8.4, 1 H, rotamer),
4.91
(s, 1H), 4.20 (m, 3H), 4.03 (m, 3H), 3.82 (m, 1H), 3.33 (m, 6H), 3.19 (s, 3H),
2.39
(m, 1H), 2.38 (m, 1H), 2.11 (m, 214), 1.22 (m, 114); LC/MS (ET) tR 1.43, m/z
352
(M'+1);
163) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-4,5-dihydro-lH-imidazol-
2-
yl)-1H-indazole-3-carboxamide, LC/MS (EI) tR 1.26, m/z 352 (M'+1);
167) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-chloroisothiazolo[5,4-b]pyridine-3-
carboxamide, LC/MS (EI) tR 2.46, m/z 322 (IVI++1);
184) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-lH-indazole-3-carboxamide,
LC/MS (EI) tR 2.50, m/z 2.96 (M'+1).
Procedure F
Procedure F provides a method for the coupling between 3-aminoquinuclidine and
carboxylic acids, amines, and indazoles to form amide and urea derivatives.
N,N-Carbonyldiimidazole (0.62 mmol) was added to a solution of (S) 3-
aminoquinuclidine hydrochloride (0.500 mmol) in N,N-dimethylformamide (3.0
mL).
N,N-Diisopropylethylamine (1.48 mmol) was added dropwise and the reaction
mixture
was maintained for 2 h at rt. N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1H-indazole-
3-
carboxamide (0.370 mmol) was added and the reaction mixture was maintained for
16 h.
The reaction mixture was transferred to a SCX column (lOg) and the column was
flushed
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with 5 volumes of methanol. The partially purified product was then eluted
using 5%
dimethylethylamine in methanol. The residue was purified by chromatography
using
50/50 to 30/70 ethyl acetate/[(50/50/2) ethyl
acetate/methanol/dimethylethylamine] to
provide the urea in 61% yield.
The following compound was prepared using this method:
161) NN-di-(3S)-1-Azabicyclo[2.2.2]oct-3-yl-lH-indazole-l,3-dicarboxamide, 'H
NMR (CD3OD) S 8.34 (d, J= 8.5, 1H); 8.27 (d, J= 8.2, 1H); 7.57 (t, J= 7.3,
1H);
7.40 (t, J= 7.3,1 H); 4.21 (m, l H); 4.11 (m, 1 H); 3.39 (m, 2H); 3.1-2.7 (m,
l OH);
2.12 (m, 2H); 1.97 (m, 2H); 1.81 (m, 4H); 1.59 (m,2H); LC/MS (EI) tR 1.38, m/z
423.2 (M}+1);
N-[(3S)-1-Azabicyclo [2.2.2] oct-3 -yl]-6-(bromo)-1,2-benzisothiazole-3-
carboxamide.
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1-[2-
(trimethylsilyl)ethoxy]methyl-1 H-indazole-3-carboxamide
The following compound was prepared using this procedure, followed by
treatment with tetrabutylammonium fluoride:
190) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-
indazole-3-carboxamide, ); LC/MS (EI) tR 4.46, m/z 370.4 (M++1);
Procedure G
Procedure G provides a method for the coupling between 3-aminoquinuclidine
and carboxylic acids to form carboxamide derivatives.
The coupling reaction and purification was performed according to procedure A
(benzisoxazoles), procedures B, E, or F (benzisothiazoles), or procedures C,
D, E, or F
(indazoles). The free base was dissolved in methanol (3.5 mL/mmol starting
acid) and
treated with 1N hydrochloric acid in ether (3.5 mL/mmol starting acid). The
resulting
suspension was diluted with ether (7 mL/mmol starting acid) and was maintained
at room
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temperature for 2 h. The solids were collected by filtration, rinsed with
ether, and dried,
thus providing the hydrochloride salt in 40-60% yield.
The following compounds were prepared using this method:
71) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisoxazole-3-
carboxamide hydrochloride, 'H NMR (CD30D) S 7.93 (d, J= 8.7, IH), 7.23 (s,
1H), 7.05 (d, J= 8.7, IH), 4.47 (m, IH), 3.91 (s, 3H), 3.82-3.69 (m, 1H), 3.35-
3.25 (m, 5H), 2.32 (m, 1H), 2.16 (m, 1 H), 2.04 (m, 2H), 1.86 (m, 2H); LC/MS
(EI) tR 2.75, m/z 302 (M'+1);
74) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-1H-
indazole-3-
carboxamide hydrochloride, LC/MS (EI) tR 3.07, m/z 366 (M++1);
51) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisothiazole-3-
carboxamide hydrochloride. LC/MS (EI) tR 14.4, m/z 318 (M++1);
52) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1,2-benzisothiazole-3-
carboxamide hydrochloride. LC/MS (EI) tR 14.35, m/z 318 (M++1);
53) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1,2-benzisothiazole-3-
carboxamide hydrochloride. LC/MS (EI) tR 15.36, m/z 318 (M++1),
Procedure H
Procedure H provides a method for the coupling between brominated 3-
aminoquinuclidinecarboxamides and Grignard reagents to form alkyl-substituted
derivatives.
A 5 mL microwave reaction vessel was charged with
bis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq) and the
bromide
(0.30 mmol). The vessel was evacuated and back-filled with argon gas. In a
separate
reaction vessel, solution of the Grignard (1.2 mmol, 4 eq) was added to a 0.5
M solution
of zinc chloride (1.2 mmol, 4 eq) in tetrahydrofuran at rt. The suspension was
maintained
for 30 min and the entire contents were transferred to the reaction vessel via
cannula.
The vessel was sealed and subjected to microwave irradiation at 100 C for 600
sec with
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a pre-stir time of 60 s. The reaction was quenched with acetic acid (0.5 mL),
diluted with
methanol, and was transferred to a SCX column. The column was washed with
methanol
(50 mL) and the product was eluted with 2 M ammonia in methanol (50 mL) and
concentrated. The residue was purified by chromatography [90/10/1
dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl
acetate/(70/30/1
ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus
providing
the product in 20-50% yield.
The following compound was prepared using this method:
22) N-[(3S')-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-(1,3-thiazol-2-
y1)-1H-
indazole-3-carboxamide. 'H NMR (CD3OD) 6 8.46 (s, 1H); 8.40 (d, J= 8.6, 1H);
8.05 (d, J= 8.6, 1H); 7.98 (t, J= 58.3, 1H); 7.97 (d, J= 3.3, 1H); 7.73 (d, J=
3.3,
1H); 4.57 (m, 1 H); 3.86 (m, 1 H); 3.60-3.20 (m, 5H); 2.43 (m, 1 H); 2.26 (m,
1 H);
2.16 (m, 2H); 1.95 (m, 1H); LC/MS (EI) tR 4.04, mlz 404 (M++1).
Procedure I
Procedure I provides a method for the coupling between aniline or phenol
bearing
aminoquinuclidinecarboxamides and alkylating agents to form secondary aniline-
or
ether-substituted derivatives.
To a solution ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-y1]-6-hydroxy-I,2-
benzisothiazole-3-carboxamide (0.400 mol) in N,N-dimethylformamide (6 mL) was
added potassium carbonate (2.00 mol) and cyclopropylmethyl bromide (0.47
mmol). The
reaction was maintained for 16 h and the solvent was removed in vacuo. The
residue was
extracted with 10/1 dichloromethane/methanol (3 x) and the combined extracts
were
concentrated. The residue was purified by preparative HPLC using an 8 min
gradient of
95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1 % formic acid), thus
providing
the product in 32% yield.
The following compounds were prepared using this method:
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N-[(3S)-1-Azabicyclo [2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-
benzisothiazole-3-carboxamide hydroformate;
13) (3S)-3-{[(5-Hydroxy-1,2-benzisothiazol-3-yl)carbonyl]amino}-1-methyl-I-
azoniabicyclo[2.2.2]octane iodide or formate. LC/MS (EI) tR 2.55, m/z 318
(M'+1);
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1,2-benzisothiazole-3-
carboxamide hydroformate.
The following compound may be prepared using this method:
1) (3S')-3-({ [6-(Cyclopropylmethoxy)-1,2-benzisothiazol-3-yl]carbonyl}amino)-
1-
(cyclopropylmethyl)-1-azoniabicyclo[2.2.2]octane bromide or formate. LC/MS
(EI) tR 5.76, m/z 412 (M}+1).
Procedure J
Procedure J provides a method for the coupling between brominated 3-
aminoquinuclidine benzisothiazoles and cyclic amines to form aniline
derivatives.
Pyrrolidine (0.361 mmol), N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-
benzisothiazole-3-carboxamide (0.259 mmol), palladium acetate (0.021 mmol), 2-
dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl (0.049 mmol), and
cesium
carbonate (0.586 mmol) were combined in a microwave vessel. The vessel was
evacuated and back-filled under an atmosphere of argon. Tetrahydrofuran (3.7
mL) was
added and the vessel was sealed. The reaction was subjected to microwave
irradiation at
135 C for 30 min. The reaction mixture was filtered through Celite and the
residue was
purified by chromatography [100/0 to 80/20 ethyl acetate/(50/50/2 ethyl
acetate/methanol%dimethylethylamine)] or prparative HPLC to provide the
product in
34% yield.
The following compounds were prepared using this method:
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2) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide, 'H NMR (CD3OD) 8 7.91 (d, J= 8.9, 1H); 7.77
(s, 1H); 7.09 (d, J= 8.9, 1H); 4.3-4.1 (m, 2H); 3.7-3.3 (m, 8H); 3.1-2.8 (m,
5H);
2.20 (m, 2H); 2.09 (m, l H); 1.98 (m, 1 H); 1.83 (m, 2H); 1.60 (m, 1 H); LC/MS
(EI) tR 3.7, m/z 387 (M++1);
64) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-y1-1,2-benzisothiazole-
3-
carboxamide, LC/MS (EI) tR 4.13, m/z 357.2 (M++1);
66) N-[(35)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-pyrrol-l-yl)-1,2-
benzisothiazole-3-
carboxamide, LC/MS (EI) tR 4.04, m/z 353.1 (M++1);
68) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(cyclopropylmethoxy)pyrrolidin-l-
yl]-
1,2-benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.31, m/z 427.2 (M++1);
69) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisoxazole-3-carboxamide, LC/MS (EI) tR 3.57, m/z 371.2 (M++1);
70) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.83, m/z 387.2 (M++1);
72) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.8, m/z 387.2 (M++l);
75) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.74, m/z 387.2 (M++1);
76) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3,S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.77, m/z 387.2 (M++1);
79) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(difluoromethoxy)pyrrolidin-l-
yl]-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.22, m/z 423.2 (M++1);
108) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]-
l,2-
benzisoxazole-3-carboxamide, LCMIS (EI) tR 4.5, m/z 371.1 (M++1);
109) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisoxazole-3-carboxamide, LC/MS (EI) tR 4.5, m/z 371.1 (M++1);
110) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide hydroformate, LC/MS (EI) tR 3.92, m/z 387.1
(M++1);
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111) 1V-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.91, m/z 387.1 (M++l);
112) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3R)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide hydroformate, LC/MS (EI) tR 3.91, m/z 387.1
(M++1);
113) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[(3S)-3-methoxypyrrolidin-l-yl]-
1,2-
benzisothiazole-3-carboxamide hydroformate, LC/MS (EI) tR 3.94, m/z 387.1
(M++1).
The following compound was prepared from 3-[(2-trimethylsilylethoxy)
methoxy]pyrrolidine using this method followed by treatment with 6 N
hydrochloric acid,
preparative HPLC purification, and isolation using SCX ion exchange:
78) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-hydroxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 4.44, m/z 373.1 (M'+1).
Procedure K
Procedure K provides a method for the coupling between brominated 3-
aminoquinuclidine indazoles and cyclic amines to form aniline derivatives.
2-Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (0.0450 mmol),
palladium(II) acetate (0.0150 mmol), cesium carbonate (2.25 mmol) and 3-
(cyclopropylmethoxy)pyrrolidine (2.25 mmol) were combined in a vial. A
solution of N-
[(3,5)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-2-[2-
(trimethylsilyl)ethoxy]methyl-1H-
indazole-3-carboxamide (0.751 mmol) in toluene (6.36 mL) was added and the
mixture
was heated at 80 C for 3 d. The reaction mixture was filtered through Celite,
loaded
onto a RediSep column (silica gel), and eluted using a gradient of 100/0 to
80/20 ethyl
acetate/(50/50/2 ethyl acetate/methanol/dimethylethylamine). The residue was
transferred to a SCX column (10 g) and the column was washed with methanol (5
volumes), 2.0 M ammonia in methanol (most of the SEM was removed by this
process),
and the ammonia eluent was concentrated. The residue was purified by
preparative
HPLC [90/10 to 50/50 water (0.1% formic acid)/acetonitrile (0.1% formic acid)
over 10
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min.] to give the desired product in 7% yield.
The following acid was prepared using this method:
58) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(cyclopropylmethoxy)pyrrolidin-1-
yl]-
1H-indazole-3-carboxamide hydroformate, 'H NMR (CD3OD) 8 8.44 (br s, 1H);
7.95 (d, J= 9.0, 1 H); 6.75 (d, J= 9.0, 1 H); 6.46 (s, 1 H); 4.50 (m, 1 H);
4.3 0(m,
1 H); 3.81 (m, 1 H); 3.60-3.20 (m, 9H); 3.36 (d, J= 6.9, 2H); 2.37 (m, 1 H);
2.26
(m, 1 H); 2.17 (m, 2H); 2.09 (m, 2H); 1.92 (m, 1 H); 1.05 (m, 1 H); 0.52 (m,
2H);
0.22 (m, 2H); LC/MS (EI) tR 4.48, m/z 410.2 (Me+1);
61) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(cyclopropylmethoxy)pyrrolidin-l-
yl]-
1H-indazole-3-carboxamide hydroformate, LC/MS (EI) tR 4.49, m/z 410.2
(M++1);
62) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1Fl-
indazole-
3-carboxamide hydroformate, LC/MS (EI) tR 4.1, m/z 370.3 (M++1).
Procedure L
Procedure L provides a method for the coupling between brominated
aminoquinuclidinecarboxamides and cyclic amines to form aniline derivatives.
A mixture of 3-methoxypyrrolidine hydrochloride (6.27 mmol),1V-[(3S)-1-
azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide (4.42
mmol), 2-
dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl(0.845 mmol),
palladium acetate
(0.363 mmol), and cesium carbonate (9.97 mmol) was evacuated and back-filled
with an
atmosphere of argon. Tetrahydrofuran (60 mL) was added and the reaction was
heated at
reflux for 67 h. The reaction mixture was allowed to cool to rt and was
filtered through
Celite (MeOH) and concentrated. The residue was partitioned between 9/1
dichloromethane/methanol (100 mL) and sat sodium bicarbonate (40 mL) and the
layers
were separated. The aq layer was extracted with 9/1 dichloromethane/methanol
(3 x 50
mL) and the combined organic layers were washed with brine and dried (sodium
sulfate).
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The residue was purified by chromatography (70/30/1 ethyl
acetate/methanol/ammonium
hydroxide) to give the free base (84%) as a yellow foam. The mono-
hydrochloride salt
was prepared from methanolic hydrogen chloride [acetyl chloride (0.95 eq) in
methanol
(5 mL)] and was recrystallized from methanol/ethyl acetate.
The following compound was prepared using this procedure:
49) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide hydrochloride. 'H NMR (CD3OD) S 8.48 (d, J=
9.1, 1H), 7.02 (d, J= 1.9, 1H), 6.91 (dd, J= 9.2, 2.1, 1H), 4.52-4.48 (m, 1H),
4.20-4.17 (m, 1H), 3.87-3.78 (m, 1H), 3.58 (dd, J= 11.0, 4.7, 1H), 3.50-3.42
(m,
3H), 3.38 (s, 3H), 3.36-3.34 (m, 3H), 2.40-2.37 (m, 1H), 2.26-2.08 (m, 3H),
1.95-
1.87 (m, 1H); LC/MS (EI) tR 3.47, m/z 387 (MF+1).
Procedure M
Procedure M provides a method for the coupling between brominated
aminoquinuclidinecarboxamides and benzophenone imine to form aniline
derivatives.
The mixture of bromide (6.30 mmol), palladium acetate (1.00 mmol), and 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (0.700 mmol) was
evacuated
and back-filled with argon. The solids were diluted with tetrahydrofuran (150
mL) and
treated with cesium carbonate (7.00 mmol) and benzophenone imine (6.80 mmol).
The
reaction mixture was heated at reflux for 16 h. The reaction mixture was
concentrated
and redissolved in a mixture of tetrahydrofuran (90 mL) and 3 N hydrochloric
acid (30
mL). The reaction mixture was maintained for 2 h and was concentrated. The
residue
was purified by chromatography using a mixture of 70/30/1 ethyl
acetate/methanol/
/ammonium hydroxide, thus providing the aniline in 79% yield. The aniline was
used
directly in subseqitent reactions.
The following compounds were prepared using this method:
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6-Amino-N-[(3,S')-1-azabicyclo[2.2.2]oct 3-yl]-1-(methyl)-1Fl-indazole-3-
carboxamide;
6-Amino-N-[(3S)-1-azabicyclo [2.2.2]oct-3-yl]-1-(difluoromethyl)-1 H-indazole-
3-
carboxamide;
6-Amino-N-[(3S')-1-azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-lH-indazole-3-
carboxamide;
Procedure N
Procedure N provides a method for the coupling between amino
aminoquinuclidinecarboxamides and acylating agents to form carboxamide
derivatives.
To a solution of the aniline (0.42 mmol) in pyridine (2 mL) and N,N-
dimethylformamide (2 mL) was added the acid chloride (0.55 mmol). The mixture
was
maintained at ambient temperature for 16 h and was concentrated in vacuo. The
residue
was purified by preparative HPLC, thus providing the product in 30-80% yield.
The following compounds were prepared using this method:
23) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-
methyl-
1FI-indazole-3-carboxamide hydroformate, 'H NMR (CD3OD) 5 8.40 (br s, 1H);
8.18 (s, 1 H); 8.07 (d, J= 8.7, 1 H); 7.20 (d, J= 8.7, 1 H); 4.50 (m, 1H);
4.09 (s,
3H); 3.81 (m, 1H); 3.60-3.20 (m, 5H); 2.37 (m, 1H); 2.26 (m, 1H); 2.11 (m,
2H);
1.92 (m, 1H); 1.81 (m, 1H); 0.99 (m, 2H); 0.91 (m, 2H); LC/MS (EI) tR 3.15,
m/z
368 (M++1);
24) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-
(difluoromethyl)-1H-indazole-3-carboxamide hydroformate. LC/MS (EI) tR 3.79,
m/z 404 (M++1);
38) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-
[(cyclopropylcarbonyl)
amino]-1H-indazole-3-carboxamide. LC/MS (EI) tR 3.65, m/z 394 (M++1).
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Procedure 0
Procedure 0 provides a method for the coupling between amino
aminoquinuclidinecarboxamides and isocyanates to form urea derivatives.
To the aniline (0.40 mmol) in a mixture of pyridine (2 mL) and N,N-
dimethylformamide (1 mL) was added the isocyanate (0.53 mmol). The reaction
mixture
was maintained at ambient temperature for 16 h and was concentrated in vacuo.
The
residue was purified by preparative HPLC, thus providing the product in 50-80%
yield.
The following compounds were prepared using this method:
18) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-methyl-6-{ [(propylamino)carbonyl]
amino}-1H-indazole-3-carboxamide hydroformate, 'H NMR (CD3OD) S 8.50 (br
s, 1 H); 8.00 (d, J= 8.7, 1 H); 7.92 (s, 1 H); 7.01 (d, J= 8.7, 1 H); 4.50 (m,
1 H);
4.06 (s, 3H); 3.81 (m, 1H); 3.60-3.30 (m, 5H); 3.20 (t, J= 7.1, 2H); 2.37 (m,
1H);
2.26 (m, 1H); 2.11 (m, 2H); 1.92 (m, 1H); 1.58 (m, J= 7.1, 2H); 0.98 (t, J=
7.3,
2H); LC/MS (EI) tR 3.36, m/z 385 (M++1);
25) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(difluoromethyl)-6-{[(propylamino)
carbonyl]amino}-1Fl indazole-3-carboxamide hydroformate. LC/MS (EI) tR 3.81,
m/z 421 (M'+1);
39) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-
{[(propylamino)carbonyl]
amino}-1H-indazole-3-carboxamide. LC/MS (EI) tR 3.71, m/z 411 (M++1).
Procedure P
Procedure P provides a method for the demethylation of methoxy-substituted
quinuclidinecarboxamides to form phenol derivatives.
Boron tribromide (20.0 mmol) to a solution of N-[(3S)-1-azabicyclo[2.2.2]oct-3-
yl]-6-methoxy-1,2-benzisothiazole-3-carboxamide (3.80 mmol) in dichloromethane
(100
mL) at 0 C. The reaction mixture was allowed to warm to rt and was maintained
for 3 d.
The reaction mixture was quenched with a saturated potassium carbonate
solution (50
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mL) and the layers were separated. The aqueous layer was further extracted
with (10/1)
dichloromethane/methanol (50 mL) and the organic layers were combined and
concentrated. The residue was purified by chromatography [(70/30/1) ethyl
acetate/methanol/ammonium hydroxide] to provide the product in 70% yield.
The following compounds were prepared using this procedure:
9) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-hydroxy-lH-indazole-3-carboxamide
hydroformate. 'H NMR (CD3OD) S 8.39 (s, 1H), 7.28 (t, J= 8.3, 1H), 7.00 (d, J=
8.4, 1 H), 6.54 (d, J= 7.6, 1 H), 4.57 (m, 1 H), 3.83 (t, J= 11.4, 1 H), 3.52-
3.31 (m,
5H), 2.42-2.39 (m, IH), 2.27 (m, IH), 2.12=2.07 (m, 2H), 1.98-1.90 (m, 1H);
LC/MS (EI) tR 3.18, m/z 287 (M'+1);
10) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-hydroxy-lH-indazole-3-
carboxamide hydroformate. LC/MS (EI) tR 3.9, m/z 365/367 (M'+1);
11) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-dibromo-4-hydroxy-lH-indazole-3-
carboxamide hydroformate. LC/MS (EI) tR 4.26, m/z 443/445/447 (1VI'-+1);
16) N-[(3S)-1-Azabicyclo [2.2.2] oct-3-yl]-7-hydroxy-1 H-indazole-3-
carboxamide
hydroformate. LC/MS (EI) tR 2.48, m/z 287 (M'+1);
50) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1,2-benzisothiazole-3-
carboxamide. LC/MS (EI) tR 2.58, m/z 304 (M'+1).
Procedure 0
Procedure Q provides a method for the preparation of cyclic amide derivatives
from the corresponding brominated quinuclidine derivatives.
Palladium (II) acetate (0.09 mmol) was added to a solution of 2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl (0.14 mmol) in toluene (10 mL) and the
reaction
mixture was maintained until the contents completely dissolved. The resultant
yellow
solution was transferred to a mixture of the bromide (0.33 mmol), cesium
carbonate (0.60
mmol) and the amide (1.00 mmol) under an atmosphere of nitrogen gas and the
reaction
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mixture was heated at 100 C for 16 h. The reaction mixture was filtered
through Celite
and concentrated. The residue was purified by HPLC, thus providing the product
in 72%
yield.
The following compounds were prepared using this method:
15) NV [(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(2-oxopyrrolidin-l-yl)-1H-
indazole-3-carboxamide hydroformate, 'H NMR (CD3OD) S 8.40 (br s, 1H); 8.15
(d, J= 8.9, 1H); 7.88 (s, 1H); 7.54 (d, J= 8.9, 1H); 4.55 (m, 1H); 4.49 (q, J=
7.2,
2H); 3.99 (t, J= 7.0, 2H); 3.81 (m, 11-1); 3.60-3.30 (m, 5H); 2.63 (t, J= 8.1,
2H);
2.38 (m, 1H); 2.26 (m, 1H); 2.19 (m, 2H); 2.10 (m, 2H); 1.92 (m, 1H); 1.51 (t,
J
= 7.2, 3H); LC/MS (EI) tR 2.59, m/z 382 (M++1);
65) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxopyrrolidin-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 2.93, m/z 385.2 (M'+1).
The following compound was prepared using this procedure, followed by removal
of the protecting groups using 6 N hydrochloric acid:
41) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(4S)-4-hydroxy-2-oxopyrrolidin-l-
yl]-
1H-indazole-3-carboxamide hydroformate. LC/MS (EI) tR 1.39, m/z 370 (M++1);
Procedure R
Procedure R provides a method for the coupling between
aminoquinuclidinecarboxamides and alcohols via Mitsunobu conditions to form
N(1)-
alkylated derivatives.
Diisopropyl azodicarboxylate (0.212 mmol) was added dropwise to a solution of
N-[(35)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-
carboxamide
(0.141 mmol), cyclopropyl carbinol (0.283 mmol), triphenylphosphine (0.283
mmol), and
N,N-dimethylformamide (1.00 mL). The reaction mixture was maintained for 16 h
at rt'
and was loaded onto a column of silica gel. The mixture was purified by
chromatography
{95/5 to 85/15 ethyl acetate/[(50/50/2) ethyl acetate/methanol/
dimethylethylamine]} to
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provide the product (20%) as a solid. The product contained about 7% of the 2-
cyclopropylmethyl isomer.
The following compounds were prepared using this procedure:
4) N-[(3S)-l-Azabicyclo[2.2.2]oct-3-yl]-1-propyl-6-(1,3-thiazol-2-yl)-1H-
indazole-
3-carboxamide, 'H NMR (CD3OD) 8 8.44 (br s,1H); 8.27 (d, J= 8.6, 1H); 8.25 (s,
1H); 7.94 (d, J= 3.3, 1H); 7.85 (d, J= 8.5, 1H); 7.68 (d, J= 3.3, 1H); 4.55
(m,
1 H); 4.53 (t, J= 7.0, 2H); 3.83 (m, 1 H); 3.60-3.25 (m, 5H); 2.40 (m, 1 H);
2.25
(m, 1H); 2.12 (m, 2H); 2.08 (m, 2H); 2.00 (m, IH); LC/MS (EI) tR 4.02, m/z 396
(M++1);
5) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-isopropyl-6-(1,3-thiazol-2-yl)-1H
indazole-3-carboxamide. LC/MS (EI) tR 3.9, m/z 396 (M++1);
30) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-oxazol-2-yl)-1H-
indazole-3-
carboxamide. LC/MS (EI) tR 3.61, m/z 366 (M-+-1);
31)* N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-oxazol-
2-yl)-
1Hindazole-3-carboxamide. LC/MS (EI) tR 3.88, m/z 392 (M++1);
32) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1-propyl-lH-
indazole-
3-carboxamide. LC/MS (EI) tR 3.79, m/z 380 (M++1);
33) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-N-methyl-6-(1,3-oxazol-2-yl)-
1H-
indazole-3-carboxamide. LC/MS (EI) tR 3.79, m/z 380 (M}+1).
Procedure S
Procedure S provides a method for the formation of ether derivatives from the
corresponding phenols using Mitsunobu conditions.
Diisopropyl azodicarboxylate (0.618 mmol) was added dropwise to a solution of
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1,2-benzisothiazole-3-
carboxamide
(0.594 mmol), 3-furanmethanol (0.594 mmol), and triphenylphosphine (0.594
mmol) in
N,N-dimethylformamide (3.40 mL). The reaction mixture was maintained for 16 h
and
was concentrated. The residue was purified by chromatography { 100/0 to 90/10
ethyl
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acetate/[(70/30/2) ethyl acetate/methanoUdimethylethylamine]} to provide the
product in
26% yield.
The following compound was prepared using this procedure:
14) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-furylmethoxy)-1,2-
benzisothiazole-3-
carboxamide hydroformate. 'H NMR (CD3OD) S 8.50-8.41 (m, 1H), 7.86-7.80
(m, 1H), 7.70-7.69 (m, 1H), 7.27-7.22 (m, 1H), 7.01-6.93 (m, 1H), 6.64-6.59
(m,
IH), 4.52 (m, 1H), 4.30 (m, 2H), 3.98-3.89 (m, 1H), 3.56-3.38 (m, 5H), 2.41-
2.39
(m, 1H), 2.29 (m, 2H), 2.15-2.13 (m, 1H), 2.00 (m, IH); LC/MS (EI) tR 3.58,
m/z
384 (M++1).
Procedure T
Procedure T provides a method for the preparation of phenol-substituted
quinuclidinecarboxamides from bromide derivatives.
Potassium acetate (0.600 mmol), palladium acetate (0.060 mmol),
bis(pinacolato)diboron (0.800 mmol), and 2-dicyclohexylphosphino-2',4',6'-tri-
i-propyl-
1,1'-biphenyl (0.200 mmol) were added to a suspension ofN-[(3S)-1-
azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisothiazole-3-carboxamide (0.500
mmol) in
toluene (8 mL). The reaction mixture was subjected to microwave irradiation
(150 C)
for 5 min. The reaction mixture was allowed cool to rt, was filtered through
Celite
(methanol), and the filtrate was concentrated. The residue was purified by
preparative
HPLC to provide the product in 60% yield.
Hydrogen peroxide (0.500 mmol) was added to a solution ofN-[(3S)-l-
azabicyclo[2.2.2]oct-3-yl]-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-
1,2-
benzisothiazole-3-carboxamide (0.200 mmol) in acetone (3 mL). The reaction
mixture
was maintained for 2 h at rt and was diluted with water (2 mL). The product
was
extracted with (9/1) dichloromethane/methanol and the extract was concentrated
to
provide the product in 70% yield. The phenol was used directly in subsequent
reactions.
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The following compounds were prepared using this procedure:
12) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1,2-benzisothiazole-3-
carboxamide hydroformate. 'H NMR (CD3OD) 6 8.55 (d, IH, J= 9), 7.36 (d, 1H,
J= 2), 7.05 (dd, 1H, J= 2,9), 4.51 (m, 1H), 3.83 (m, 1H), 3.38 (m, 5H), 2.40
(m,
IH), 2.38 (m,1H), 2.12 (m, 2H), 1.94 (m, IH); LC/MS (EI) tR 2.58, m/z 304
(M'+1);
(3-[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl-1,2-benzisothiazol-5-
yl)boronic acid;
(3-[(3,S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl-1,2-benzisothiazol-6-
yl)boronic acid.
Procedure U
Procedure U provides a method for the coupling between 3-aminoquinuclidine
benzisothiazole boronic acids to form aromatic aniline derivatives.
(3-[(3S')-1-Azabicyclo[2.2.2] oct-3-ylamino]carbonyl-1,2-benzisothiazol-6-
yl)boronic acid (0.604 mmol), 1H-imidazole (1.8 mmol), cupric acetate (1.21
mmol),
triethylamine (3.0 mmol), pyridine (4.8 mmol) and tetrahydrofuran (8.5 mL)
were
combined in a microwave vessel. The reaction mixture was subjected to
microwave
irradiation at 140 C for 600s. The reaction mixture was concentrated and
residue was
purified by chromatography [95/5 to 85/15 ethyl acetate/(1/1/0.1 ethyl
acetate/methanol/dimethylethylamine)] to provide the pre-purified product as a
yellow
oil. The residue was further purified by preparative HPLC and the fractions
containing
the desired product were pooled and loaded onto a 5 g SCX column. The column
was
washed with methanol (120 mL), 2.0 M ammonia in methanol, and the ammonia
eluent
was concentrated to provide the product in 14% yield a white solid.
The following compounds were prepared using this method:
80) N-[(3,S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1F1-imidazol-l-yl)-1,2-
benzisothiazole-
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3-carboxamide, 'H NMR (CD3OD) S 8.87 (d, J= 8.9, 1H); 8.35 (m, 2H); 7.81 (d,
J= 8.9, 1 H); 7.75 (s, 1 H); 7.22 (s, 1 H); 4.20 (m, 1 H); 3.35 (m, 1 H); 3.20-
2.75 (m,
5H); 2.09 (m, 1H); 1.95 (m, 1H); 1.82 (m, 2H); 1.56 (m, 1H); LC/MS (EI) tR
1.7,
m/z 354.1 (M++1);
81) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-pyrazol-l-yl)-1,2-
benzisothiazole-3-
carboxamide, LC/MS (EI) tR 3.27, m/z 354.1 (M41);
82) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-lH-pyrazol-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.85, m/z 368.1 (M}+1);
83) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-lH-pyrazol-l-yl)-1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.47, m/z 368.1 (M++l).
Procedure V
Procedure V provides a method for the coupling between indazole
quinuclidinecarboxamides and boronic acids to form N(1)-alkylated and arylated
carboxamide derivatives.
A mixture ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-
indazole-3-carboxamide (0.280 mmol), cyclopropylboronic acid (0.840 mmol), and
copper (II) acetate (5.60 mmol), was diluted with triethylamine (1.40 mmol),
pyridine
(2.2 mmol), and tetrahydrofuran (3.00 mL). The reaction mixture was subjected
to
microwave irradiation at 140 C for 600 s. The reaction mixture was filtered
and
transferred to a SCX column. The column was washed with methanol (5 volumes)
and
the product was then eluted using 2.0 M ammonia in methanol, thus providing a
light
yellow solid. The residue was purified by chromatography {90/10 to 80/20 ethyl
acetate/[(50/50/2) ethyl acetate/methanol/dimethylethylamine]} to provide the
product in
22% yield. The final product contained about 3% of the regioisomer.
The following compounds were prepared using this method:
26) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropyl-6-(1,3-thiazol-2-yl)-1H-
indazole-3-carboxamide, 'H NMR (CD3OD) S 8.28 (s, 1H); 8.21 (d, J= 8.6, IH);
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7.91 (d, J= 3.3, 1 H); 7.80 (d, J= 8.6, 1 H); 7.65 (d, J= 3.3, 1 H); 4.20 (m,
1 H);
3.82 (m, 1H); 3.35 (m,1 H); 3.20-2.80 (m, 5H); 2.07 (m, 1 H); 1.95 (m, 1 H);
1.81
(m, 2H); 1.57 (m, 1H); 1.25 (m, 4H); LC/MS (EI) tR 3.9, m/z 394 (M++1);
27) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(3-thienyl)-1H-
indazole-3-carboxamide LC/MS (EI) tR 4.28, m/z 436 (M++1);
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-l-cyclopropyl-lH-indazole-3-
carboxamide.
Procedure W
Procedure W provides a method for the coupling between bromo
aminoquinuclidine benzisothiazoles and cyclic ureas to form urea derivatives.
A mixture of 1-propylimidazolidin-2-one (19.0 mmol),1V-[(3,S)-1-
azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide (10.0
mmol),
palladium(II) acetate (1.00 mmol), and di-tert-butyl(2',4',6'-
triisopropylbiphenyl-2-
yl)phosphine (2.00 mmol) was diluted with toluene (100 mL) and tetrahydrofuran
(50
mL). The reaction mixture was heated at 100 C for 16 h and the reaction
mixture was
filtered through Celite (methanol) and concentrated. The residue was
transferred to a
SCX column and was washed with methanol (100 mL). The crude product was eluted
with 7 M ammonia in methanol (100 mL) and the combined product fractions were
concentrated. The residue was purified by chromatography [(70/35/1) ethyl
acetate/methanol/ammonium hydroxide] to provide the product in 90% yield. The
mono-
hydrochloride salt was prepared from methanolic hydrogen chloride [acetyl
chloride
(0.95.eq) in methanol (5 mL)] and was recrystallized from methanol/ethyl
acetate.
Alternative method: A mixture of 1-ethylimidazolidin-2-one (41.2 mg, 0.000361
mol), N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-
carboxamide
(95.0 mg, 0.000259 mol), palladium(II) acetate (4.8 mg, 0.000021 mol), 2-
dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl (23.2 mg, 0.0000488
mol), and
cesium carbonate (191 mg, 0.000586 mol) in a microwave tube was evacuated and
back-
filled under an atmosphere of argon. Tetrahydrofuran (3.7 mL, 0.045 mol) was
added,
the vessel was sealed, and the reaction mixture was subjected to microwave
irradiation at
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135 C for 30 min. The reaction mixture was filtered through Celite and was
concentrated. The residue was purified by chromatography [100/0 to 80/20 ethyl
acetate/(50/50/2 ethyl acetate/methanol/dimethylethylamine)] to provide the
product in
24% yield.
The following compounds were prepared using this method:
67) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethyl-2-oxoimidazolidin-1-yl)-
1,2-
benzisothiazole-3-carboxamide, 'H NMR (CD3OD) S 8.64 (d, J = 9.1, 1H); 8.16
(d, J= 1.8, 1 H); 7.93 (dd, J= 1.9/9.1, 1 H); 4.20 (m, 1 H); 3.98 (m, 2H);
3.61 (m,
2H); 3.60-3.35 (m, 1H); 3.37 (q, J= 7.3, 2H); 3.1-2.75 (m, 5H); 2.08 (m, 1H);
1.92 (m, IH); 1.81 (m, 2H); 1.55 (m, 1H); 1.20 (t, J= 7.3, 3H); LC/MS (EI) tR
3.25, m/z 400.2 (M'+l);
131) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-1-yl)-
1,2-
benzisothiazole-3-carboxamide, LC/MS (EI) tR 3.76, m/z 414.2 (M'+1);
54) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-1-yl)-
1,2-
benzisothiazole-3-carboxamide hydrochloride. LC/MS (EI) tR 3.68, m/z 414
(M +1).
Procedure X
Procedure X provides a method for the coupling between bromo
aminoquinuclidine indazoles and cyclic ureas to form urea derivatives.
A mixture of 1-propylimidazolidin-2-one (0.5684 mmol), N-[(3S)-1-
azabi cyclo [2.2.2] oct-3 -yl]-6-bromo-2-[2-(trimethylsi lyl)ethoxy]methyl-1 H-
indazole-3-
carboxamide (0.409 mmol), palladium acetate (0.034 mmol), 2-
dicyclohexylphosphino-
2',4',6'-tri-i-propyl-1,1'-biphenyl (0.0768 mmol), and cesium carbonate (0.924
mmol) in a
microwave tube was evacuated and back-filled under an atmosphere of argon.
Tetrahydrofuran (5.8 mL) was added and the vessel was sealed. The reaction
mixture
was subjected to microwave irradiation at 135 C for 30 min. The reaction
mixture was
filtered through Celite and concentrated. The residue was purified by
chromatography
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[100/0 to 80/20 ethyl acetate/(50/50/2 ethyl
acetate/methanol/dimethylethylamine)] to
yield the purified SEM protected product. The residue was dissolved in
tetrahydrofuran
(5 mL) and 6 N hydrochloric acid (5 mL) and the reaction mixture was subjected
to
microwave irradiation at 140 C for 600 s. The reaction mixture was
transferred to a
SCX column (lOg) and the column was flushed with methanol (120 mL) and 2.0 M
ammonia in methanol (60 mL) and the ammonia eluent was concentrated. The
residue
was purified by preparative HPLC and the fractions containing the desired
product were
pooled and transferred to a SCX column (10 g). The column was flushed with
methanol
(120 mL) and 2.0 M ammonia in methanol (60 mL) and the ammonia eluent was
concentrated to provide the product in 28% yield.
The following compounds were prepared using this method:
77) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-l-yl)-
1H-
indazole-3-carboxamide, 'H NMR (CD3OD) S 8.09 (d, J= 9.0, 1H); 7.72 (s, 1H);
7.51 (d, J 9.0, 1H); 4.18 (m, 1H); 3.90 (m, 2H); 3.51 (m, 2H); 3.35 (m, 1H);
3.23 (t, J 7.2, 2H); 3.15-2.75 (m, 5H); 2.05 (m, 1H); 1.95 (m,1H); 1.79 (m,
2H); 1.60 (m, 1H); 1.59 (m, J= 7.3, 2H); 0.95 (t, J= 7.3, 3H); LC/MS (EI) tR
3.03, m/z 397.2 (M++l);
63) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-3-propylimidazolidin-1-yl)-
1H-
indazole-3-carboxamide, LC/MS (EI) tR 4.14, m/z 397.3 (M++1).
Procedure Y
Procedure Y provides a method for the oxidation of quinuclidinecarboxamides to
form N-oxide derivatives.
nz-Chloroperbenzoic acid (0.266 mmol) was added in portions to a -78 C
suspension of the quinuclidine amide (0.21 mmol) in dichloromethane (3 mL) and
the
reaction mixture was allowed to warm to rt and was maintained for 16 h. The
reaction
mixture was diluted with methanol and loaded onto an SCX column. The column
was
washed with methanol (50 mL), 2 M ammonia in methanol (60 mL) and the ammonia
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wash was concentrated. The crude product was purified by preparative HPLC thus
providing 26.5 mg (38%) of the product.
The following compounds were prepared using this method:
55) 1V-[(3S)-1-Oxido-l-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-
indazole-
3-carboxamide, 'H NMR (CD3OD) S 8.31 (br m, 1H), 8.08 (s,1H), 7.69 (d, J=
9.1, 1 H), 7.36 (dd, J= 9.0, 1.3, 1 H), 4.72-4.69 (m, 1H), 4.13-4.04 (m, 1 H),
3.80-
3.63 (m, 5H), 2.45-2.35 (m, 3H), 2.28-2.25 (m, 1H), 2.15-2.11 (m, 1H); LC/MS
(EI) tR 3.99, m/z 371 (M"+1);
56) 6-Methoxy-N-[(3S)-1-oxido-l-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-
3-
carboxamide, LC/MS (EI) tR 3.65, m/z 334 (W+1).
Procedure Z
Procedure Z provides a method for the conversion of
aminoquinuclidinecarboxamide nitriles to dihydroimidazole derivatives using
diamines.
Hydrogen sulfide was bubbled through a solution of 6-cyano-N-(quinuclidin-3-
yl)-1H-indazole-3-carboxamide (90 mg, 0.31 mmol) in ethanol (6 mL) in a
pressure tube
at 0 C for 30 min. The vessel was sealed and the reaction mixture was heated
at 80 C
for 16 h and was concentrated. The residue was diluted with ethylenediamine (4
mL) and
was heated at 100 C for 16 h. The reaction mixture was concentrated to
provide 110 mg
(94%) of the dihydroimidazole as a brown solid.
The following compound was prepared using this method:
89) N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4,5-dihydro-1H-imidazol-2-yl)-1H-
indazole-3-carboxamide, 'H NMR (CD3OD) 6 8.27 (d, J=8.5, 1H), 8.08 (s, 1H),
7.66 (d, J= 8.5, 1H), 4.22 (m, 1H), 3.87 (s, 3H), 3.69 (s, 1H), 3.37 (m, 6H),
2.91
(m, 8H), 2.08 (m, 211), 1.82 (m, 2H), 1.55 (m, 1H); LC/MS (EI) tR 1.63, m/z
339.2
(M++1).
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Procedure AA
Procedure AA provides a method for the reaction of 3-aminoquinuclidine
carboxamides with electrophiles to form quaternary ammonium salt derivatives.
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide (3.26 mmol)
was dissolved in dichloromethane (50.0 mL) and the reaction mixture was
maintained at
rt for 3 d. After a few minutes the mixture became cloudy and after 1 h a
white
precipitate was evident. The precipitated solid was collected by filtration,
washed with
dichloromethane and ethyl acetate, and was dried to provide the product in 92%
yield as a
colorless solid. Analysis by analytical LC/MS showed the product was
contaminated
with a small amount of starting material (ca. 5%).
To a solution of (35)-1-(chloromethyl)-3-[(1H-indazol-3-ylcarbonyl)amino]-1-
azoniabicyclo[2.2.2]octane chloride (0.999 mmol) in methanol (10.0 mL) was
added MP-
diisopropylethylamine (415 mmol/g loading; 41.5 mol) and MP-carbonate (3.5
mmol/g
loading; 0.050 mmol). The reaction mixture was shaken for 24 h and the solid
support
reagents were removed by filtration. The solvent was evaporated to ca. 3 mL
and ethyl
acetate (15 mL) was added. The precipitated solid was collected to provide the
product
in 94% yield.
The following compound was prepared using this method:
165) (35)-1-(Chloromethyl)-3-[(1H-indazol-3-ylcarbonyl)amino]-1-azoniabicyclo
[2.2.2]octane chloride, 'H NMR (CD3OD) 6 8.19 (d, J= 8.2, 1H); 7.60 (d, J=
8.5,
1 H); 7.43 (t, J= 8.5, 1 H); 7.26 (t, J= 8.2, 1H); 5.23 (s, 2H); 4.63 (m, 1
H); 4.10
(m, 1H); 3.55-3.85 (m, 5H); 2.48 (m, 1H); 2.41 (m, 1H); 2.23 (m, 2H); 2.09 (m,
1H); LC/MS (EI) tR 2.38, m/z 321/319 (MF+1).
Procedure AB
Procedure AB provides a method for the hydrolysis of 3-aminoquinuclidine
nitriles to the carboxylic acids and subsequent coupling with amines to form
amide
derivatives.
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Potassium hydroxide (7.0 mmol) was added to a solution of N-[(3S)-1-
azabicyclo[2.2.2]oct-3-yl]-6-cyano-lH-indazole-3-carboxamide (2.3 mmol) in 1,2-
ethanediol (6 mL) and the reaction mixture was heated at140 C for 7 h. The
reaction
was allowed to cool to rt and was treated with 6 mL of 1 M hydrochloric acid.
The
precipitate formed was isolated by filtration and dried under vacuum to
provide the
product in 45% yield as the HCI salt.
Into a vial was added 3-[(3S')-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl-lH-
indazole-6-carboxylic acid hydrochloride (0.3 mmol), TBTU (0.4 mmol) and
dimethylamine (0.432 mmol). N,N-Dimethylformamide (2 mL) and NN-
diisopropylethylamine (0.249 mL, 1.43 mmol) were added and the reaction
mixture was
maintained for 16 h at rt. The reaction mixture was loaded onto a SCX column
(lOg) and
flushed with methanol (200 mL). The partially purified product was then eluted
using 7.0
M ammonia in methanol (60 mL). The residue was purified by preparative HPLC
and
the product fractions were pooled and loaded onto a SCX column (lOg). The
column was
flushed with methanol (200 mL) followed by 7.0 M ammonia in methanol (60 mL).
The
ammonia layer was evaporated to provide the amide in 30% yield.
The following compounds were prepared using this method:
185) 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl-lH-indazole-6-
carboxylic
acid hydrochloride, LC/MS (EI) tR 1.50, m/z 315 (M++1);
186) N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]N(6),N(6)-dimethyl-lH-indazole-3,6-
dicarboxamide, 'H NMR (CD3OD) S 8.22 (s, 1H), 7.74 (s, IH), 7.25 (s, 1H), 4.78
(s, 6H), 4.58 (m, 1H), 3.67 (m, 1H), 3.33 (m, 6H), 2.39 (m, 1H), 2.38 (m, 1H),
2.11 (m, 2H), 1.22 (m, 1H); LC/MS (EI) tR 2.50, m/z 342 (\e+1);
187) N-[(3S")-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(4-methylpiperazin-1-
yl)carbonyl]-IH-
indazole-3-carboxamide, LC/MS (EI) tR 2.40, m/z 397 (M'+l);
188) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(3R)-3-methoxypyrrolidin-1-
yl]carbonyl-
1H-indazole-3-carboxamide, LC/MS (EI) tR 2.50, m/z 398 (M'+l).
Procedure AC
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Procedure AC provides a method for the production of ether derivatives of 7-
azabenzisothiazoles from the corresponding chloride.
Sodium methoxide (30.0 mmol) was added to a solution of 1V-[(3S)-1-
azabicyclo[2.2.2]oct-3-yl]-6-chloroisothiazolo[5,4-b]pyridine-3-carboxamide
(0.3 mmol)
in methanol (2 mL) and the reaction mixture was heated at reflux for 16 h. The
reaction
mixture was allowed to cool to rt, quenched with methanol, and concentrated.
The
residue was purified by preparative HPLC and the product fractions were pooled
and
loaded onto a SCX column (lOg). The column was flushed with methanol (200 mL)
followed by 7.0 M ammonia in methanol (60 mL). The ammonia layer was
evaporated to
provide the product in 30% yield.
The following compound was prepared using this method:
189) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxyisothiazolo[5,4-b]pyridine-
3-
carboxamide, LC/MS (EI) tR 3.25, m/z 319 (MF+1).
Binding Example: [3H] MLA binding
Materials:
Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2
Protease inhibitor cocktail tablet: Roche, CAT No. 1697498
Membrane preparation
Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose with protease inhibitors
(one
tablet per 50 ml,) were homogenized with a polytron for 10 sec at setting 11,
then
centrifuged 10 min at 1000 g, 4 C. The supernatant was centrifuged again for
20 min at
20,000 g, 4 C. The pellets were resuspended in binding buffer (200 mM TRIS-
HCI, 20
mM HEPES, pH 7.5, 144 mM NaCI, 1.5 mM KC1, 1 mM MgSO4, 2 mM CaClz, 0.1%
(w/v) BSA) and stored membrane prep at -80 C.
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For saturation assay, the 200 l assay, mixture in binding buffer contains 200
g
of membrane protein, 0.2 to 44 nM of [3H] MLA. The nonspecific binding was
defined
using 1 M MLA. Competition assay was carried out with 2 nM [3H] MLA and a
desirable range of compounds. The assay mixture was incubated at 22 C for 2
hours,
then harvested with GF/B filter presoaked with 0.3% PEI in binding buffer
using Tomtec
harvester. The filter was washed three times with binding buffer and the
radioactivity was
counted with Trilux.
Binding affinities for the preferred compounds of the invention are 2 nM to 25
M, especially 2 nM to 2.5 M.
The preceding examples can be repeated with similar success by substituting
the
generically or specifically described reactants and/or operating conditions of
this
invention for those used in the preceding examples.
While the invention has been illustrated with respect to the production and of
particular compounds, it is apparent that variations and modifications of the
invention can
be made without departing from the spirit or scope of the invention.
189
