U.S. patent application number 12/756253 was filed with the patent office on 2010-08-12 for fused heterocyclic compounds useful as kinase modulators.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Tram N. Huynh, David R. Tortolani, Wayne Vaccaro.
Application Number | 20100204212 12/756253 |
Document ID | / |
Family ID | 46062874 |
Filed Date | 2010-08-12 |
United States Patent
Application |
20100204212 |
Kind Code |
A1 |
Vaccaro; Wayne ; et
al. |
August 12, 2010 |
FUSED HETEROCYCLIC COMPOUNDS USEFUL AS KINASE MODULATORS
Abstract
Compounds having the formula (I), and enantiomers, and
diastereomers, pharmaceutically-acceptable salts, thereof,
##STR00001## are useful as kinase modulators, including MK2
modulation, wherein one of E and F is a nitrogen atom and the other
of E and F is a carbon atom, Z is N, and R.sub.1, R.sub.2, R.sub.3,
X and Y are as defined herein.
Inventors: |
Vaccaro; Wayne; (Yardley,
PA) ; Tortolani; David R.; (Skillman, NJ) ;
Huynh; Tram N.; (Pennington, NJ) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT, P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
46062874 |
Appl. No.: |
12/756253 |
Filed: |
April 8, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11689132 |
Mar 21, 2007 |
7723336 |
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12756253 |
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11524996 |
Sep 21, 2006 |
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11689132 |
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60719519 |
Sep 22, 2005 |
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Current U.S.
Class: |
514/218 ;
514/233.2; 514/248; 540/575; 544/117; 544/236 |
Current CPC
Class: |
A61P 31/12 20180101;
A61P 31/16 20180101; C07D 487/04 20130101; A61P 29/00 20180101;
A61P 31/18 20180101; A61P 3/10 20180101; A61P 25/16 20180101; A61P
31/22 20180101; A61P 1/18 20180101; A61P 19/02 20180101; A61P 21/00
20180101; A61P 35/00 20180101; A61P 25/28 20180101; A61P 11/06
20180101; A61P 9/10 20180101; A61P 1/00 20180101 |
Class at
Publication: |
514/218 ;
544/236; 514/248; 540/575; 544/117; 514/233.2 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 487/04 20060101 C07D487/04; A61K 31/5025 20060101
A61K031/5025; C07D 243/08 20060101 C07D243/08; C07D 413/14 20060101
C07D413/14; A61K 31/5377 20060101 A61K031/5377; A61P 1/18 20060101
A61P001/18; A61P 11/06 20060101 A61P011/06; A61P 3/10 20060101
A61P003/10; A61P 1/00 20060101 A61P001/00; A61P 9/10 20060101
A61P009/10; A61P 31/12 20060101 A61P031/12; A61P 29/00 20060101
A61P029/00; A61P 25/28 20060101 A61P025/28; A61P 25/16 20060101
A61P025/16; A61P 31/22 20060101 A61P031/22; A61P 31/16 20060101
A61P031/16; A61P 31/18 20060101 A61P031/18; A61P 21/00 20060101
A61P021/00; A61P 35/00 20060101 A61P035/00; A61P 19/02 20060101
A61P019/02 |
Claims
1. A compound according to formula (I), ##STR00665## or an
enantiomer, diastereomer, or a pharmaceutically-acceptable salt,
thereof, wherein: one of E or F is N, and the other of E or F is C;
X is NR.sub.4R.sub.5; Z is N; Y is selected from hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, halogen, nitro, cyano, SR.sub.8,
S(O).sub.pR.sub.8, OR.sub.8, NR.sub.6R.sub.7, CO.sub.2R.sub.8,
C(.dbd.O)R.sub.8, O--C(.dbd.O)R.sub.8, C(.dbd.O)NR.sub.8R.sub.9,
cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and
heteroaryl, provided that if Y is hydrogen then R.sub.4 is phenyl
substituted with a carboxamido group; R.sub.1 and R.sub.2 are
independently selected from (i) hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
halogen, nitro, cyano, SR.sub.10, OR.sub.10, NR.sub.10R.sub.11,
NR.sub.10C(.dbd.O)R.sub.11, CO.sub.2R.sub.10, C(.dbd.O)R.sub.10,
--O--C(.dbd.O)R.sub.10, C(.dbd.O)NR.sub.10R.sub.11, cycloalkyl,
heterocyclo, aryl, and heteroaryl; or (ii) R.sub.1 is taken
together with R.sub.2 and the ring atoms to which they are attached
to form a fused 5-, 6-, or 7-membered cycloalkyl, aryl, heteroaryl,
or cycloheteroalkyl; R.sub.3 is selected from hydrogen, halogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, cyano, SR.sub.13, OR.sub.13,
NR.sub.13R.sub.14, NR.sub.13C(.dbd.O)R.sub.14, CO.sub.2R.sub.13,
C(.dbd.O)R.sub.13, --O--C(.dbd.O)R.sub.13,
--C(.dbd.O)NR.sub.13R.sub.14, cycloalkyl, heterocyclo, aryl, and
heteroaryl; R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
independently selected from hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
OR.sub.15, SR.sub.15, C(.dbd.O)R.sub.15, CO.sub.2R.sub.15,
C(.dbd.O)NR.sub.15R.sub.16, C(W)OR.sub.16, S(O).sub.pR.sub.17,
SO.sub.2NR.sub.15R.sub.16, cycloalkyl, heterocyclo, aryl, and
heteroaryl; or (ii) R.sub.4 is taken together with R.sub.5 and the
nitrogen atom to which they are both attached and/or R.sub.6 is
taken together with R.sub.7 and the nitrogen atom to which they are
both attached to form a heteroaryl or heterocyclo; R.sub.8,
R.sub.9, R.sub.10, R.sub.11, R.sub.13, R.sub.14, R.sub.15, and
R.sub.16 at each occurrence are independently selected from (i)
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and
heterocyclo; or (ii) together with the nitrogen atom to which they
are attached, R.sub.8 is taken together with R.sub.9, and/or
R.sub.10 is taken together with R.sub.11, and/or R.sub.13 is taken
together with R.sub.14, and/or R.sub.15 is taken together with
R.sub.16 to form a heteroaryl or heterocyclo; R.sub.17 at each
occurrence is independently selected from alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl, and heterocyclo; W at each occurrence
is O, S, N, CN, or NH; and p is 1 or 2, with the following proviso:
if E is N, F is C, and Y is NR.sub.6R.sub.7; (a) then X is other
than NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
NH(C.sub.1-4alkenyl), NH(--CH.sub.2-furyl), NHNH.sub.2,
NH(methoxyalkylene), and NHAc; (b) and if X is NH(--CH.sub.2--
(substituted or unsubstituted)pyridyl) or NH(--CH.sub.2--
(substituted or unsubstituted) phenyl), then Y is other than
##STR00666## NH(substituted piperidine), or
NH(--CH.sub.2-pyridine); (c) and if X is NH(cyclopentyl), then Y is
other than NH(cyclopentyl); (d) and if X is N(CH.sub.3)(substituted
phenyl) or N(CH.sub.3)(pyridyl), ##STR00667## then Y is other than
or (e) and if X is NH(substituted phenyl), then Y is other than
##STR00668##
2. A compound according to claim 1 having formula (Ib), or (Ic),
##STR00669## or an enantiomer, diastereomer, or a
pharmaceutically-acceptable salt, thereof.
3. A compound according to claim 2, or an enantiomer, diastereomer,
or a pharmaceutically-acceptable salt, thereof in which: X is
NR.sub.4R.sub.5; R.sub.4 is -AM; R.sub.5 is hydrogen or
C.sub.1-4alkyl; or R.sub.4 and R.sub.5 together with the nitrogen
atom to which they are attached form a 5-, 6- or 7-membered
monocyclic heteroaryl or heterocyclo ring, or a 7- to 11-membered
bicyclic heteroaryl or heterocyclo ring, each ring optionally
substituted with one to three groups, T.sub.1, T.sub.2; and/or
T.sub.3; A is a bond, C.sub.1-3alkylene, C.sub.2-4alkenylene,
C.sub.2-4alkynylene, --C(O)--, or SO.sub.2--; M is (i) hydrogen,
NR.sub.15R.sub.16, alkyl, alkoxy, or alkenyl; or (ii) cycloalkyl,
heterocyclo, aryl, or heteroaryl, each group optionally substituted
by one to three groups, T.sub.1, T.sub.2, and/or T.sub.3; T.sub.1,
T.sub.2, and T.sub.3 are independently selected from (i) halogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, cyano, SO.sub.3H SR.sub.19,
S(O).sub.pR.sub.21, S(O).sub.pNR.sub.19R.sub.20,
NR.sub.19S(O).sub.pR.sup.21, OR.sub.19, NR.sub.19R.sub.20,
NR.sub.19C(.dbd.O)R.sub.20, NR.sub.19C(.dbd.O)NR.sub.19R.sub.20,
CO.sub.2R.sub.19, C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl, wherein p is one or 2; and/or (ii) two groups, T.sub.1
and T.sub.2, located on adjacent ring atoms are taken together with
the ring atoms to which they are attached to form a fused
cycloalkyl, aryl, heteroaryl, or heterocyclo; R.sub.16 and R.sub.20
at each occurrence, are selected independently from (i) hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; or (ii) R.sub.19 and R.sub.20
together with the nitrogen atom to which they are both attached
form a heteroaryl or heterocyclo; and R.sub.21 at each occurrence,
is selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl,
heteroaryl, and heterocyclo.
4. A compound according to claim 2, or an enantiomer, diastereomer,
or a pharmaceutically-acceptable salt, thereof in which: Y is
hydrogen, halogen, OR.sub.8, NR.sub.6R.sub.7,
--(CH.sub.2)heterocyclo, or aryl; R.sub.6 is selected from hydrogen
or C.sub.1-4alkyl optionally substituted by one to three groups
selected from halogen, C.sub.1-4alkyl, nitro, cyano, amino,
C.sub.1-4alkoxy, and OH; R.sub.7 and R.sub.8 are independently
selected from alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl,
each group of which is optionally substituted by one to three
groups, T.sub.4, T.sub.5, and/or T.sub.6; or R.sub.6 and R.sub.7
together with the nitrogen atom to which they are attached form a
heteroaryl or heterocyclo ring, each ring is optionally substituted
by one to three groups, T.sub.4, T.sub.5, and/or T.sub.6; T.sub.4,
T.sub.5 and T.sub.6 are independently selected from (i) halogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, cyano, SR.sub.19, OR.sub.19,
NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl; and/or (ii) two groups, T.sub.4 and T.sub.5,
substituted on adjacent ring atoms are taken together with the ring
atoms to which they are attached to form a fused cyclalkyl,
heterocyclo, aryl, or heteroaryl; and R.sub.19 and R.sub.20, at
each occurrence are selected independently from (i) hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; or (ii) R.sub.19 with R.sub.20
together with the nitrogen atom to which they are both attached
combine to form a heteroaryl or heterocyclo.
5. A compound according to formulae (Ib), or (Ic), ##STR00670## or
an enantiomer, diastereomer, or a pharmaceutically-acceptable salt,
thereof, wherein: X is NR.sub.4R.sub.5; Y is hydrogen, halogen,
OR.sub.8, NR.sub.6R.sub.7, --(CH.sub.2)heterocyclo, or aryl;
R.sub.1 and R.sub.2 are independently selected from (i) hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, halogen, nitro, cyano, SR.sub.10, OR.sub.10,
NR.sub.10R.sub.11, NR.sub.10C(.dbd.O)R.sub.11, CO.sub.2R.sub.10,
C(.dbd.O)R.sub.10, --O--C(.dbd.O)R.sub.10,
C(.dbd.O)NR.sub.10R.sub.11, cycloalkyl, heterocyclo, aryl, and
heteroaryl; or (ii) R.sub.1 is taken together with R.sub.2 and the
ring atoms to which they are attached to form a fused 5-, 6-, or
7-membered cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl;
R.sub.3 is selected from hydrogen, halogen, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
nitro, cyano, SR.sub.13, OR.sub.13, NR.sub.13R.sub.14,
NR.sub.13C(.dbd.O)R.sub.14, CO.sub.2R.sub.13, C(.dbd.O)R.sub.13,
--O--C(.dbd.O)R.sub.13, --C(.dbd.O)NR.sub.13R.sub.14, cycloalkyl,
heterocyclo, aryl, and heteroaryl; R.sub.4 is -AM; R.sub.5 is
hydrogen or C.sub.1-4alkyl; or R.sub.4 and R.sub.5 together with
the nitrogen atom to which they are attached form a 5-, 6- or
7-membered monocyclic heteroaryl or heterocyclo ring, or a 7- to
11-membered bicyclic heteroaryl or heterocyclo ring, each ring
optionally substituted with one to three groups, T.sub.1, T.sub.2;
and/or T.sub.3; A is a bond, C.sub.1-3alkylene,
C.sub.2-4alkenylene, C.sub.2-4alkynylene, --C(O)--, or
--SO.sub.2--; M is (i) hydrogen, NR.sub.15R.sub.16, alkyl, alkoxy,
or alkenyl; or (ii) cycloalkyl, heterocyclo, aryl, or heteroaryl,
each ring optionally substituted by one to three groups, T.sub.1,
T.sub.2, and/or T.sub.3; R.sub.6 is selected from hydrogen or
C.sub.1-4alkyl optionally substituted by one to three groups
selected from halogen, C.sub.1-4alkyl, nitro, cyano, amino,
C.sub.1-4alkoxy, and OH; R.sub.7 and R.sub.8 are independently
selected from alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl,
each group of which is optionally substituted by one to three
groups, T.sub.4, T.sub.5, and/or T.sub.6; or R.sub.6 and R.sub.7
together with the nitrogen atom to which they are attached form a
heteroaryl or heterocyclo ring, each ring is optionally substituted
by one to three groups, T.sub.4, T.sub.5, and/or T.sub.6; R.sub.10,
R.sub.11, R.sub.13, and R.sub.14 at each occurrence are
independently selected from (i) hydrogen, C.sub.1-4alkyl,
substituted C.sub.1-4alkyl, and an optionally substituted phenyl or
5-, 6-, or 7-membered heteroaryl or heterocyclo; or (ii) R.sub.10
and R.sub.11 and/or R.sub.13, and R.sub.14 together with the
nitrogen atom they are both attached combine to form an optionally
substituted 5-, 6-, or 7-membered heteroaryl or heterocyclo;
R.sub.15 and R.sub.16 are independently selected from (i) hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) together with the nitrogen atom to which they are attached
R.sub.15 is taken together with R.sub.16 to form a heteroaryl or
heterocyclo; T.sub.1, T.sub.2, and T.sub.3 are independently
selected from (i) halogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano,
SO.sub.3H SR.sub.19, S(O).sub.pR.sub.21,
S(O).sub.pNR.sub.19R.sub.20, NR.sub.19S(O).sub.pR.sub.21,
OR.sub.19, NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20,
NR.sub.19C(.dbd.O)NR.sub.19R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl, wherein p is one or 2; and/or (ii) two groups, T.sub.1
and T.sub.2, located on adjacent ring atoms are taken together with
the ring atoms to which they are attached to form a fused
cycloalkyl, aryl, heteroaryl, or heterocyclo; T.sub.4, T.sub.5 and
T.sub.6 are independently selected from (i) halogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, cyano, SR.sub.19, OR.sub.19,
NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl; and/or (ii) two groups, T.sub.4 and T.sub.5,
substituted on adjacent ring atoms are taken together with the ring
atoms to which they are attached to form a fused cyclalkyl,
heterocyclo, aryl, or heteroaryl; and R.sub.19 and R.sub.20 at each
occurrence are selected independently from (i) hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl,
heteroaryl, and heterocyclo; or (ii) R.sub.19 and R.sub.20 together
with the nitrogen atom to which they are both attached form a
heteroaryl or heterocyclo ring; and R.sub.21 at each occurrence, is
selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl,
heteroaryl, and heterocyclo; with the following proviso: if E is N,
F is C, and Y is NR.sub.6R.sub.7; (a) then X is other than
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NH(C.sub.2-4alkenyl),
NH(--CH.sub.2-furyl), or NHNH.sub.2, NH; (b) and if X is
NH(--CH.sub.2-- (substituted or unsubstituted)pyridyl) or
NH(--CH.sub.2-- (substituted or unsubstituted) phenyl), then Y is
other than ##STR00671## NH(substituted piperidine), or
NH(--CH.sub.2-pyridine); (c) and if X is NH(cyclopentyl), then Y is
other than NH(cyclopentyl); (d) and if X is N(CH.sub.3)(substituted
phenyl) or N(CH.sub.3)(pyridyl), then Y is other than ##STR00672##
or (e) and if X is NH(substituted phenyl), then Y is other than
##STR00673##
6. A compound according to claim 5, or an enantiomer, diastereomer,
or a pharmaceutically-acceptable salt, thereof in which: X is
NR.sub.4R.sub.5; R.sub.4 is -AM, A is a bond, --C(O)--, or
--S(O).sub.2--, or C.sub.1-3alkylene; M is (i) hydrogen,
--NH(aryl), C.sub.1-6alkyl, C.sub.2-4alkenyl, or --OC.sub.1-4alkyl
or (ii) C.sub.3-6cycloalkyl, phenyl, fluorenyl, 1-naphthyl, or
2-naphthyl, each group optionally substituted by one to three
groups, T.sub.1, T.sub.2, and/or T.sub.3; or (iii) a 5-, 6- or
7-membered monocyclic or a 7- to 11-membered bicyclic heteroaryl or
heterocyclo ring, each ring optionally substituted by one to three
groups, T.sub.1, T.sub.2, and/or T.sub.3; and T.sub.1, T.sub.2, and
T.sub.3 are independently selected from (i) C.sub.1-4alkyl,
substituted C.sub.1-4alkyl, C.sub.1-4alkyloxy, substituted
C.sub.1-4alkyloxy, C.sub.1-4alkylthio, phenoxy,
--NR.sub.19R.sub.20, halogen, hydroxy, cyano, SO.sub.3H, COOH,
--C(O)(R.sub.19), C(O)NR.sub.19R.sub.20, NR.sub.19C(O)R.sub.20,
S(O).sub.2R.sub.21, S(O).sub.2NR.sub.19R.sub.20 and
NR.sub.19(C(O)NR.sub.19R.sub.20; and/or (ii) phenyl, cyclopropyl,
cyclohexyl, tetrazolyl, imidazolyl, pyrazolyl, triazolyl,
thiazolyl, furyl, and morpholinyl, each group of which is
optionally substituted as valence allows from one to three groups,
R.sub.22, R.sub.23 and/or R.sub.24; and/or (iii) two groups,
T.sub.1 and T.sub.2, substituted on adjacent ring atoms are taken
together with the ring atoms to which they are attached to form, a
fused five- to seven-membered cycloalkyl, a fused phenyl or a fused
5- or 6-membered heterocyclo or heteroaryl, each group of which is
optionally substituted as valence allows from one to three groups,
R.sub.22, R.sub.23 and/or R.sub.24; and R.sub.19 and R.sub.20 at
each occurrence are selected independently from (i) hydrogen,
--(CH.sub.2).sub.vOH, and C.sub.1-4alkyl; or (ii)
--(CH.sub.2).sub.vcyclohexyl, --(CH.sub.2).sub.vphenyl,
--(CH.sub.2).sub.vmorpholinyl, --(CH.sub.2).sub.vpyridyl,
--(CH.sub.2).sub.vpyrazolyl, --(CH.sub.2).sub.vcyclopropyl,
--(CH.sub.2).sub.vpyrrolidinyl, --(CH.sub.2).sub.vpiperidinyl,
--(CH.sub.2).sub.vfuryl, --(CH.sub.2).sub.vimidazolyl,
--(CH.sub.2).sub.vpyrimidinyl, --(CH.sub.2).sub.vpiperazinyl, and
--(CH.sub.2).sub.vpyradizinyl, each group of which is optionally
substituted as valence allows from one to three groups, R.sub.22,
R.sub.23 and/or R.sub.24; or R.sub.19 and R.sub.20 are taken
together with the nitrogen atom to which they are both attached to
form a pyrrolindyl, morpholinyl, piperidinyl, pyradazinyl, or
piperazinyl, each group of which is optionally substituted as
valence allows from one to three groups, R.sub.22, R.sub.23 and/or
R.sub.24; R.sub.21 at each occurrence is selected from (i)
--(CH.sub.2).sub.vOH, and C.sub.1-4alkyl; or (ii)
--(CH.sub.2).sub.vcyclohexyl, --(CH.sub.2).sub.vphenyl,
--(CH.sub.2).sub.vmorpholinyl, --(CH.sub.2).sub.vpyridyl,
--(CH.sub.2).sub.vpyrazolyl, --(CH.sub.2).sub.vcyclopropyl,
--(CH.sub.2).sub.vpyrrolidinyl, --(CH.sub.2).sub.vpiperidinyl,
--(CH.sub.2).sub.vfuryl, --(CH.sub.2).sub.vimidazolyl,
--(CH.sub.2).sub.vpyrimidinyl, --(CH.sub.2).sub.vpiperazinyl, and
--(CH.sub.2).sub.vpyradizinyl, each group of which is optionally
substituted as valence allows from one to three groups, R.sub.22,
R.sub.23 and/or R.sub.24; R.sub.22, R.sub.23, and R.sub.24 at each
occurrence, are selected independently from (C.sub.1-4alkyl,
(C.sub.2-4alkenyl, halogen, hydroxy, cyano, nitro, CF.sub.3,
.dbd.O, O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2, and optionally
substituted phenyl; and v is 0, 1, 2, or 3.
7. A compound according to claim 6, or an enantiomer, diastereomer,
or a pharmaceutically-acceptable salt, thereof, wherein
NR.sub.4R.sub.5 is selected from the following: ##STR00674##
##STR00675## ##STR00676## ##STR00677## ##STR00678## ##STR00679##
##STR00680## ##STR00681## ##STR00682## ##STR00683## ##STR00684##
##STR00685##
8. A compound according to claim 5, or an enantiomer, diastereomer,
or a pharmaceutically-acceptable salt, thereof in which: Y is
NR.sub.6R.sub.7; R.sub.6 is selected from hydrogen or
C.sub.1-4alkyl; R.sub.7 is selected from C.sub.1-4alkyl,
cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, pyrrolidinyl, and
piperidinyl, each group of which is optionally substituted by one
to three groups, T.sub.4, T.sub.5, and/or T.sub.6; or R.sub.6 and
R.sub.7 together with the nitrogen atom to which they are attached
form piperazinyl, piperidinyl, pyrrolidinyl, or diazepanyl, each
group of which is optionally substituted by one to three groups,
T.sub.4, T.sub.5, and/or T.sub.6; and T.sub.4, T.sub.5, and T.sub.6
are independently selected from (i) C.sub.1-4alkyl, OH, NH.sub.2,
NH(C.sub.1-4alkyl), furyl, and N(C.sub.1-4alkyl).sub.2, and
NH(pyrimidinyl) wherein the pyrimidinyl is substituted by halogen;
or (ii) C.sub.1-4 alkyl substituted by cyclohexyl or OH, wherein
the cyclohexyl is substituted by NH.sub.2.
9. A compound according to claim 8, or an enantiomer, diastereomer,
or a pharmaceutically-acceptable salt, thereof wherein
NR.sub.6R.sub.7 is selected from the following: ##STR00686##
10. A compound according to claim 8, or an enantiomer,
diastereomer, or a pharmaceutically-acceptable salt, thereof
wherein NR.sub.6R.sub.7 is selected from: ##STR00687##
11. A compound according to claim 5, or an enantiomer,
diastereomer, or a pharmaceutically-acceptable salt, thereof
wherein R.sub.5 is hydrogen and R.sub.4 is selected from a phenyl,
pyridyl, pyrimidinyl, cyclohexyl, and piperidinyl ring, each ring
optionally substituted by one to two groups, T.sub.1, and/or
T.sub.2.
12. A compound according to claim 5, or an enantiomer,
diastereomer, or a pharmaceutically-acceptable salt, thereof, in
which: R.sub.1 and R.sub.2 are independently selected from (i)
hydrogen, halogen, OR.sub.10, cyano, CO.sub.2R.sub.10, and
C(O)NR.sub.10R.sub.11, or (ii) C.sub.1-4alkyl, C.sub.3-6cycloalkyl,
C.sub.2-C.sub.4 alkenyl, or C.sub.2-C.sub.4 alkynyl, each group of
which is optionally substituted; R.sub.3 is selected from (i)
hydrogen, halogen, nitro, cyano, OR.sub.13, NR.sub.13R.sub.14,
CO.sub.2R.sub.13, C(.dbd.O)R.sub.13, C.sub.1-4alkyl, substituted
C.sub.1-4alkyl, cycloalkyl, aryl, and heteroaryl; and R.sub.10,
R.sub.11, R.sub.13, and R.sub.14 at each occurrence are
independently selected from (i) hydrogen, C.sub.1-4alkyl,
substituted C.sub.1-4alkyl, and an optionally substituted phenyl or
5-, 6-, or 7-membered heteroaryl or heterocyclo; or (ii) R.sub.10
and R.sub.11 and/or R.sub.13, and R.sub.14 together with the
nitrogen atom they are both attached combine to form an optionally
substituted 5-, 6-, or 7-membered heteroaryl or heterocyclo.
13. A compound according to claim 12, wherein: R.sub.1 is hydrogen
or C.sub.1-4alkyl; R.sub.2 is cyano, halogen, C.sub.1-4alkyl,
C.sub.2-4alkenyl(phenyl), C.sub.2-4alkenyl(heteroaryl),
cyclopropyl, propynyl, or C(O)NR.sub.10R.sub.11; R.sub.3 is
hydrogen, halogen, C.sub.1-4alkyl, substituted C.sub.1-4alkyl, or
aryl; R.sub.10 and R.sub.11 at each occurrence are independently
selected from hydrogen, C.sub.1-4alkyl, substituted C.sub.1-4alkyl,
an optionally substituted phenyl, and an optionally substituted
heteroaryl wherein the heteroaryl is selected from pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl,
benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl,
coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,
pyrrolopyridyl, furopyridyl, dihydroisoindolyl,
tetrahydroquinolinyl, carbazolyl, benzidolyl, phenanthrollinyl,
acridinyl, phenanthridinyl, and xanthenyl.
14. A compound according to claim 1 or 5 wherein the compound has
the formula (Ib). ##STR00688## or an enantiomer, diastereomer, or a
pharmaceutically-acceptable salt, thereof.
15. A compound according to claim 1 or 5 wherein the compound has
the formula (Ic). ##STR00689## or an enantiomer, diastereomer, or a
pharmaceutically-acceptable salt, thereof.
16. A pharmaceutical composition comprising one or more compounds
according claim 1 and a pharmaceutically acceptable carrier or
diluent.
17. A method of treating pancreatitis (acute or chronic), asthma,
allergies, adult respiratory distress syndrome, chronic obstructive
pulmonary disease, glomerulonephritis, rheumatoid arthritis,
systemic lupus erythematosis, scleroderma, chronic thyroiditis,
Grave's disease, autoimmune gastritis, diabetes, autoimmune
hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic
dermatitis, chronic active hepatitis, myasthenia gravis, multiple
sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's
disease, psoriasis, graft vs. host disease, inflammatory reaction
induced by endotoxin, tuberculosis, atherosclerosis, muscle
degeneration, cachexia, psoriatic arthritis, Reiter's syndrome,
gout, traumatic arthritis, rubella arthritis, acute synovitis,
pancreatic .beta.-cell disease; diseases characterized by massive
neutrophil infiltration; rheumatoid spondylitis, gouty arthritis
and other arthritic conditions, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoisosis, bone
resorption disease, allograft rejections, fever and myalgias due to
infection, cachexia secondary to infection, meloid formation, scar
tissue formation, ulcerative colitis, pyresis, influenza,
osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic
myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma,
multiple myeloma, sepsis, septic shock, and Shigellosis;
Alzheimer's disease, Parkinson's disease, cerebral ischemias or
neurodegenerative disease caused by traumatic injury; angiogenic
disorders including solid tumors, ocular neovasculization, and
infantile haemangiomas; acute hepatitis infection (including
hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV
retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial
ischemia, ischemia in stroke heart attacks, organ hyposia, vascular
hyperplasia, cardiac and renal reperfusion injury, thrombosis,
cardiac hypertrophy, thrombin-induced platelet aggregation,
endotoxemia and/or toxic shock syndrome, conditions associated with
prostaglandin endoperoxidase synthase-2, edema, analgesia,
neuromuscular pain, headache, pain caused by cancer, dental pain,
arthritis pain, equine infectious anemia virus; feline
immunodeficiency virus, bovine immunodeficiency virus, canine
immunodeficiency virus, and pemphigus vulgaris comprising:
administering to the mammal in need of such treatment a
therapeutically-effective amount of a compound according to claim
1.
18. The method of claim 17 wherein the condition is selected from
Crohns and ulcerative colitis, allograft rejection, rheumatoid
arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis,
and pemphigus vulgaris.
19. The method of claim 17 wherein the condition is selected from
ischemia reperfusion injury, including cerebral ischemia
reperfusions injury arising from stroke and cardiac ischemia
reperfusion injury arising from myocardial infarction.
20. The method of claim 17 wherein the condition is multiple
myeloma.
Description
[0001] This is a divisional application of application Ser. No.
11/689,132, filed Mar. 21, 2007, which is a continuation-in-part of
application Ser. No. 11/524,996, filed Sep. 21, 2006, which claims
the priority benefit to U.S. Provisional Application No.
60/719,519, filed Sep. 22, 2005, all of which are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to fused heterocyclic compounds
useful as kinase modulators, including the modulation of MAPKAP
kinase-2 (MK2). The invention further pertains to pharmaceutical
compositions containing at least one compound according to the
invention that are useful for the treatment of conditions related
to kinase modulation and methods of inhibiting the activity of
kinases, including MK2, in a mammal.
BACKGROUND OF THE INVENTION
[0003] A large number of cytokines participate in the inflammatory
response, including IL-1, IL-6, IL-8 and TNF-.alpha.. The
overproduction of cytokines such as IL-1 and TNF-.alpha. is
implicated in a wide variety of diseases, including inflammatory
bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis,
endotoxin shock, osteoporosis, Alzheimer's disease, and congestive
heart failure. See e.g. Henry et al., Drugs Fut., Vol. 24 (1999),
at pp. 1345-1354; and Salituro et al., Curr. Med. Chem., Vol. 6
(1999), at pp. 807-823. Evidence in human patients indicates that
protein antagonists of cytokines are effective in treating chronic
inflammatory diseases, such as, for example, monoclonal antibody to
TNF-.alpha. (Enbrel) (see Rankin et al., Br. J. Rheumatol., Vol 34
(1995), at pp. 334-342), and soluble TNF-.alpha. receptor-Fc fusion
protein (Etanercept) (see Moreland et al., Ann. Intern. Med., Vol.
130 (1999), at pp. 478-486).
[0004] The biosynthesis of TNF-.alpha. occurs in many cell types in
response to an external stimulus, such as, for example, a mitogen,
an infectious organism, or trauma. Important mediators of
TNF-.alpha. production are the mitogen-activated protein (MAP)
kinases, including p38 kinase (p38). Activation of p38 requires
dual phosphorylation by an upstream MAP kinase (MKK3 and MKK6) on
threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of
p38 isozymes. The p38 kinase is an upstream kinase of
mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP
K2 or MK2). See Freshney et al., Cell, Vol. 78 (1994), at pp.
1039-1049.
[0005] MK2 is a protein that appears to be predominantly regulated
by p38 in cells. In fact, MK2 was the first substrate of p38.alpha.
to be identified, and in vitro phosphorylation of MK2 by p38.alpha.
is required for MK2 activation. MK2, in turn, phosphorylates
substrates including, but not limited to, heat shock protein 27
(HSP27), lymphocyte-specific protein 1 (LAP-1), leukocyte-specific
protein-1 (LSP-1), 5-lipoxygenase (5-LO), cAMP response
element-binding protein (CREB), ATF1, serum response factor (SRF),
tyrosine hydroxylase, and most importantly, adenosine and
uridine-rich element (ARE) binding proteins. ARE binding proteins
regulate the mRNA stability of inflammatory mediators such as
TNF.alpha. and COX-2.
[0006] Targeted mutations have been introduced into the mouse MK2
gene that resulted in the generation of MK2-deficient mice. See
Kotlyarov et al, Nat. Cell Biol., Vol. 1 (1999), at pp. 94-97.
These MK2-deficient mice exhibited increased stress resistance to
LPS-induced endoxic shock and had a better survival rate compared
to mice that retained the MK2 gene. See id. Isolated splenocytes
from these mice challenged with LPS had reduced levels of
TNF.alpha., IL-1.beta., IL-6 and IFN.gamma.. See id. More recently,
Lehner et al. reported that MK2-deficient mice showed increased
susceptibility to Listeria moocytogenes infection and concluded
that MK2 had an essential role in host defense against
intracellular bacteria, probably through the regulation of
TNF.alpha. and IFN.gamma., two of the cytokines required for the
activation of antibacterial effector mechanisms. See Lehner et al.,
J. Immunol., Vol. 168 (2002), at pp. 4667-4673. Moreover, since MK2
is located immediately downstream of p38 in the p38 signaling
pathway, it is recognized that MK2 could act as a focal point for
more selectively modulating the inflammatory pathway thereby
reducing the possibility of undesirable side effects.
[0007] Pyrazolo[1,5-a]pyrimidine derivatives have been disclosed in
WO2004076458(A1) and described as having kinase inhibiting
activity.
[0008] New compounds and methods of modulating the activity of
kinases, including MK2, would be desirable in the treatment of
diseases and disorders that are mediated by cytokines, such as
TNF.alpha.. It would be even more desirable to provide MK2
inhibitors that have improved potency and reduced undesirable side
effects.
SUMMARY OF THE INVENTION
[0009] The present invention provides compounds useful in treating
inflammatory or immune disease having the formula (I):
##STR00002##
or an enantiomer, diastereomer, or a pharmaceutically-acceptable
salt, thereof,
[0010] wherein:
one of E or F is N, and the other of E or F is C; [0011] X is
NR.sub.4R.sub.5; [0012] Z is N or CR.sub.3, provided that if E is N
then Z is N; [0013] Y is selected from hydrogen, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
halogen, nitro, cyano, SR.sub.8, S(O).sub.pR.sub.8, OR.sub.8,
NR.sub.6R.sub.7, CO.sub.2R.sub.8, C(.dbd.O)R.sub.8,
O--C(.dbd.O)R.sub.8, C(.dbd.O)NR.sub.8R.sub.9, cycloalkyl,
cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl,
provided that if Y is hydrogen then R.sub.4 is phenyl substituted
with a carboxamido group; [0014] R.sub.1 and R.sub.2 are
independently selected from (i) hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
halogen, nitro, cyano, SR.sub.10, OR.sub.10, NR.sub.10R.sub.11,
NR.sub.10C(.dbd.O)R.sub.11, CO.sub.2R.sub.10, C(.dbd.O)R.sub.10,
--O--C(.dbd.O)R.sub.10, C(.dbd.O)NR.sub.10R.sub.11, cycloalkyl,
heterocyclo, aryl, and heteroaryl; or (ii) R.sub.1 is taken
together with R.sub.2 and the ring atoms to which they are attached
to form a fused 5-, 6-, or 7-membered cycloalkyl, aryl, heteroaryl,
or cycloheteroalkyl; [0015] R.sub.3 is selected from hydrogen,
halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, nitro, cyano, SR.sub.13, OR.sub.13,
NR.sub.13R.sub.14, NR.sub.13C(.dbd.O)R.sub.14, CO.sub.2R.sub.13,
C(.dbd.O)R.sub.13, --O--C(.dbd.O)R.sub.13,
--C(.dbd.O)NR.sub.13R.sub.14, cycloalkyl, heterocyclo, aryl, and
heteroaryl; [0016] R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
independently selected from hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
OR.sub.15, SR.sub.15, C(.dbd.O)R.sub.15, CO.sub.2R.sub.15,
C(.dbd.O)NR.sub.15R.sub.16, C(W)OR.sub.16, S(O).sub.pR.sub.17,
SO.sub.2NR.sub.15R.sub.16, cycloalkyl, heterocyclo, aryl, and
heteroaryl; or (ii) R.sub.4 is taken together with R.sub.5 and the
nitrogen atom to which they are both attached and/or R.sub.6 is
taken together with R.sub.7 and the nitrogen atom to which they are
both attached to form a heteroaryl or heterocyclo; [0017] R.sub.8,
R.sub.9, R.sub.10, R.sub.11, R.sub.13, R.sub.14, R.sub.15, and
R.sub.16 at each occurrence are independently selected from (i)
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and
heterocyclo; or (ii) together with the nitrogen atom to which they
are attached, R.sub.8 is taken together with R.sub.9, and/or
R.sub.10 is taken together with R.sub.11, and/or R.sub.13 is taken
together with R.sub.14, and/or R.sub.15 is taken together with
R.sub.16 to form a heteroaryl or heterocyclo; [0018] R.sub.17 at
each occurrence is independently selected from alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl, and heterocyclo; [0019] W at each
occurrence is O, S, N, CN, or NH; and p is 1 or 2, with the
following provisos: [0020] (1) if E is C, F is N, Z is CR.sub.3,
and X is NH(Me), N(Me).sub.2, NH(unsubstituted phenyl), or
NHNH.sub.2, then Y is other than hydrogen or halogen; and [0021]
(2) if E is N, F is C, Z is N, and Y is NR.sub.6R.sub.7; [0022] (a)
then X is other than NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
NH(C.sub.2-4alkenyl), NH(--CH.sub.2-furyl), NHNH.sub.2,
NH(methoxyalkylene), and NHAc; [0023] (b) and if X is
NH(--CH.sub.2-- (substituted or unsubstituted)pyridyl) or
NH(--CH.sub.2-(substituted or unsubstituted) phenyl), then Y is
other than
##STR00003##
[0023] NH(substituted piperidine), or NH(--CH.sub.2-pyridine);
[0024] (c) and if X is NH(cyclopentyl), then Y is other than
NH(cyclopentyl); [0025] (d) and if X is N(CH.sub.3) (substituted
phenyl) or N(CH.sub.3)(pyridyl), then Y is other than or
##STR00004##
[0025] or [0026] (e) and if X is NH(substituted phenyl), then Y is
other than
##STR00005##
[0027] The present invention is also directed to pharmaceutical
compositions useful in treating diseases associated with kinase
modulation, including modulation (especially inhibition) of MK2,
comprising compounds of formula (I), or pharmaceutically-acceptable
salts thereof, and pharmaceutically-acceptable carriers or
diluents. The invention further relates to methods of treating
diseases associated with the kinase modulation, including the
modulation of MK2, comprising administering to a patient in need of
such treatment a therapeutically-effective amount of a compound
according to formula (I).
DETAILED DESCRIPTION OF THE INVENTION
[0028] The following are definitions of terms used in this
specification and appended claims. The initial definition provided
for a group or term herein applies to that group or term throughout
the specification and claims, individually or as part of another
group, unless otherwise indicated.
[0029] The term "alkyl" refers to straight or branched chain
hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8
carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4
carbon atoms, are most preferred. When numbers appear in a
subscript after the symbol "C", the subscript defines with more
specificity the number of carbon atoms that a particular group may
contain. For example, "C.sub.1-6alkyl" refers to straight and
branched chain alkyl groups with one to six carbon atoms, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and
so forth. The subscript "0" refers to a bond. Thus, the term
hydroxy(C.sub.0-2)alkyl or (C.sub.0-2)hydroxyalkyl includes
hydroxy, hydroxymethyl and hydroxyethyl.
[0030] The term "substituted alkyl" refers to an alkyl group as
defined above having one, two, or three substituents selected from
the group consisting of halo (e.g., trifluoromethyl), alkenyl,
substituted alkenyl, alkynyl, nitro, cyano, oxo (.dbd.O), OR.sub.a,
SR.sub.a, (.dbd.S), --NR.sub.aR.sub.b, --N(alkyl).sub.3.sup.+,
--NR.sub.aSO.sub.2, --NR.sub.aSO.sub.2R.sub.c,
--SO.sub.2R.sub.c--SO.sub.2NR.sub.aR.sub.b,
--SO.sub.2NR.sub.aC(.dbd.O)R.sub.b, SO.sub.3H, --PO(OH).sub.2,
--OC(O)R.sub.a, --C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, .dbd.N--OH,
.dbd.N--O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,
wherein R.sub.a and R.sub.b are selected from hydrogen, alkyl,
alkenyl, CO.sub.2H, CO.sub.2(alkyl), C.sub.3-7cycloalkyl, phenyl,
benzyl, phenylethyl, napthyl, a four to seven membered heterocyclo,
or a five to six membered heteroaryl, or when attached to the same
nitrogen atom may join to form a heterocyclo or heteroaryl, and
R.sub.c is selected from same groups as R.sub.a and R.sub.b but is
not hydrogen. Each group R.sub.a and R.sub.b when other than
hydrogen, and each R.sub.c group optionally has up to three further
substituents attached at any available carbon or nitrogen atom of
R.sub.a, R.sub.b, and/or R.sub.c, said substituent(s) being
selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, hydroxy, halogen, cyano, nitro, .dbd.O (as
valence allows), CF.sub.3, O(C.sub.1-6alkyl), OCF.sub.3,
C(.dbd.O)H, C(.dbd.O)(C.sub.1-6alkyl), CO.sub.2H,
CO.sub.2(C.sub.1-6alkyl), NHCO.sub.2(C.sub.1-6alkyl),
--S(C.sub.1-6alkyl), --NH.sub.2, NH(C.sub.1-6alkyl),
N(C.sub.1-6alkyl).sub.2, N(CH.sub.3).sub.3.sup.+,
SO.sub.2(C.sub.1-6alkyl), C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2,
C.sub.3-7cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy,
benzyloxy, napthyl, a four to seven membered heterocyclo or
cycloalkyl, or a five to six membered heteroaryl. When a
substituted alkyl is substituted with an aryl (including, for
example, phenyl and napthyl), heterocyclo, cycloalkyl, or
heteroaryl group, said ringed systems are as defined below and thus
may have zero, one, two, or three substituents, also as defined
below.
[0031] One skilled in the field will understand that, when the
designation "CO.sub.2" is used herein, this is intended to refer to
the group
##STR00006##
[0032] When the term "alkyl" is used together with another group,
such as in "arylalkyl", this conjunction defines with more
specificity at least one of the substituents that the substituted
alkyl will contain. For example, "arylalkyl" refers to a
substituted alkyl group as defined above where at least one of the
substituents is an aryl, such as benzyl. Thus, the term
aryl(C.sub.0-4)alkyl includes a substituted lower alkyl having at
least one aryl substituent and also includes an aryl directly
bonded to another group, i.e., aryl(C.sub.0)alkyl.
[0033] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
double bond. Alkenyl groups of 2 to 6 carbon atoms and having one
double bond are most preferred.
[0034] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one
triple bond are most preferred.
[0035] The term "alkylene" refers to bivalent straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1
to 8 carbon atoms, e.g., {--CH.sub.2--}.sub.n, wherein n is 1 to
12, preferably 1-8. Lower alkylene groups, that is, alkylene groups
of 1 to 4 carbon atoms, are most preferred. The terms "alkenylene"
and "alkynylene" refer to bivalent radicals of alkenyl and alkynyl
groups, respectively, as defined above.
[0036] When reference is made to a substituted alkenyl, alkynyl,
alkylene, alkenylene, or alkynylene group, these groups are
substituted with one to three substitutents as defined above for
substituted alkyl groups.
[0037] The term "heteroalkylene" is used herein to refer to
saturated and unsaturated bivalent straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 8
carbon atoms, wherein one or two carbon atoms in the straight chain
are replaced by heteroatom(s) selected from --O--, --S--,
--S(.dbd.O)--, --SO.sub.2--, --NH--, and --NHSO.sub.2--. Thus, the
term "heteroalkylene" includes bivalent alkoxy, thioalkyl, and
aminoalkyl groups, as defined below, as well as alkylene and
alkenylene groups having a combination of heteroatoms in the alkyl
chain. As an illustration, a "heteroalkylene" herein may comprise
groups such as --S--(CH.sub.2).sub.1-5NH--CH.sub.2--,
--O--(CH.sub.2).sub.1-5S(.dbd.O)--CH.sub.2,
--NHSO.sub.2--CH.sub.2--, --CH.sub.2--NH--, and so forth.
Preferably, a heteroalkylene does not have two adjacent atoms
simultaneously selected from --O-- and --S--. When a subscript is
used with the term heteroalkylene, e.g., as in
C.sub.2-3heteroalkylene, the subscript refers to the number of
carbon atoms in the group in addition to heteroatoms. Thus, for
example, a C.sub.1-2heteroalkylene may include groups such as
--NH--CH.sub.2--, --CH.sub.2--NH--CH.sub.2--,
--CH.sub.2--CH.sub.2--NH--, --S--CH.sub.2--,
--CH.sub.2--S--CH.sub.2--, --O--CH.sub.2--NH--CH.sub.2--,
CH.sub.2--O--CH.sub.2 and so forth.
[0038] The term "substituted heteroalkylene" refers to a
heteroalkylene group as defined above wherein at least one of the
nitrogen or carbon atoms in the heteroalkylene chain is bonded to
(or substituted with) a group other than hydrogen. Carbon atoms in
the heteroalkylene chain may be substituted with a group selected
from those recited above for substituted alkyl groups, or with a
further alkyl or substituted alkyl group. Nitrogen atoms of the
heteroalkylene chain may be substituted with a group selected from
alkyl, alkenyl, alkynyl, cyano, or A.sub.1-Q-A.sub.2-R.sub.h,
wherein A.sub.1 is a bond, C.sub.1-2alkylene, or
C.sub.2-3alkenylene; Q is a bond, --C(.dbd.O)--,
--C(.dbd.O)NR.sub.d--, --C(.dbd.S)NR.sub.1--, --SO.sub.2--,
--SO.sub.2NR.sub.d--, --CO.sub.2--, or --NR.sub.dCO.sub.2--;
A.sub.2 is a bond, C.sub.1-3alkylene, C.sub.2-3alkenylene,
--C.sub.1-4alkylene-NR.sub.d--,
--C.sub.1-4alkylene-NR.sub.dC(.dbd.O)--, --C.sub.1-4alkylene-S--,
--C.sub.1-4alkylene-SO.sub.2--, or --C.sub.1-4alkylene-O--, wherein
said A.sub.2 alkylene groups are branched or straight chain and
optionally substituted as defined herein for substituted alkylene;
R.sub.h is hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclo, or cycloalkyl; and R.sub.d
is selected from hydrogen, alkyl, and substituted alkyl, as defined
herein, provided, however, that for a substituted heteroalkylene
R.sub.h is not hydrogen when A.sub.1, Q and A.sub.2 are each bonds.
When R.sub.h is aryl, heteroaryl, cycloalkyl, or heterocyclo, these
rings are, in turn, optionally substituted with one to three groups
as defined below in the definitions for these terms.
[0039] The term "alkoxy" refers to an oxygen atom substituted by
alkyl or substituted alkyl, as defined herein. For example, the
term "alkoxy" or includes the group --O--C.sub.1-6alkyl.
[0040] The term "alkylthio" refers to a sulfur atom that is
substituted by an alkyl or substituted alkyl group as defined
herein. For example, the term "thioalkyl" includes the group
--S--C.sub.1-6alkyl, and so forth.
[0041] The term "alkylamino" refers to an amino group substituted
with an alkyl group or substituted alkyl group as defined above.
For example, the term "alkylamino" includes the group
--NR--C.sub.1-12alkyl. (where R is preferably hydrogen but may
include alkyl or substituted alkyl as defined above.)
[0042] When a subscript is used with reference to an alkoxy,
thioalkyl or aminoalkyl, the subscript refers to the number of
carbon atoms that the group may contain in addition to heteroatoms.
Thus, for example, monovalent C.sub.1-2aminoalkyl includes the
groups --CH.sub.2--N(CH.sub.3).sub.2, and
--(CH.sub.2).sub.2--NH.sub.2. A lower aminoalkyl comprises an
aminoalkyl having one to four carbon atoms. The term
(C.sub.1-4alkyl).sub.0-2amino includes the groups NH.sub.2,
--NH(C.sub.1-4alkyl), and --N(C.sub.1-4alkyl).sub.2. "Amino" refers
to the group NH.sub.2. A "substituted amino" refers to an amino
group substituted as described above for the nitrogen atom of a
heteroalkylene chain and includes, for example, the terms
alkylamino and acylamino (--NR.sub.dC(O)R.sub.e).
[0043] The alkoxy, thioalkyl, or aminoalkyl groups may be
monovalent or bivalent. By "monovalent" it is meant that the group
has a valency (i.e., ability to combine with another group), of
one, and by "bivalent" it is meant that the group has a valency of
two. Thus, for example, a monovalent alkoxy includes groups such as
--O--C.sub.1-12alkyl, whereas a bivalent alkoxy includes groups
such as --O--C.sub.1-12alkylene-.
[0044] It should be understood that the selections for all groups,
including for examples, alkoxy, thioalkyl, and aminoalkyl, will be
made by one skilled in the field to provide stable compounds. Thus,
for example, in compounds of formula (I), when G is attached to a
nitrogen atom (N*) of ring A and is selected from an alkoxy or
alkylthio group, the alkoxy and alkylthio groups will have at least
one carbon atom bonded directly to ring A (at N*), with the oxygen
or sulfur atoms being at least one atom away from said nitrogen
atom.
[0045] The term "carbonyl" refers to a bivalent carbonyl group
--C(.dbd.O)--. When the term "carbonyl" is used together with
another group, such as in "heterocyclocarbonyl", this conjunction
defines with more specificity at least one of the substituents that
the substituted carbonyl will contain. For example,
"heterocyclocarbonyl" refers to a carbonyl group as defined above
where at least one of the substituents is an heterocyclo, such as
morpholinyl.
[0046] The term "acyl" refers to a carbonyl group linked to an
organic radical, more particularly, the group C(.dbd.O)R.sub.e. The
group R.sub.e can be selected from alkyl, alkenyl, alkynyl,
aminoalkyl, substituted alkyl (i.e. substituted alkylene),
substituted alkenyl, substituted alkynyl, cycloalkyl, heterocyclo,
aryl, or heteroaryl, as defined herein. When R.sub.e is aryl,
heteroaryl, cycloalkyl, or heterocyclo, these rings are, in turn,
optionally substituted with one to three groups as defined below in
the definitions for these terms.
[0047] The term "alkoxycarbonyl" refers to a carboxy group
##STR00007##
linked to an organic radical (CO.sub.2R.sub.e), as well as the
bivalent groups --CO.sub.2--, --CO.sub.2R.sub.e-- which are linked
to organic radicals in compounds of formula (I), wherein R.sub.e is
as defined above for acyl. The organic radical to which the carboxy
group is attached may be monovalent (e.g., --CO.sub.2-alkyl or
--OC(.dbd.O)alkyl), or bivalent (e.g., --CO.sub.2-alkylene,
--OC(.dbd.O)alkylene, etc.) Accordingly, in compounds of formula
(I), when it is recited that G can be "alkoxycarbonyl," this is
intended to encompass a selection for G of --CO.sub.2-- and also
the groups --CO.sub.2R.sub.e-- or R.sub.eCO.sub.2--, wherein in
this instance, the group R.sub.e will be selected from bivalent
groups, e.g., alkylene, alkenylene, alkynylene, bivalent
aminoalkyl, substituted alkylene, substituted alkenylene, or
substituted alkynylene.
[0048] The term "carboxamide", "carboxamidyl", or "carboxamido"
refers to the group --NR.sub.dC(.dbd.O)R.sub.e, wherein the groups
R.sub.d and R.sub.e are defined as recited above in the definitions
for heteroalkyl, alkoxycarbonyl and acyl. For example, the
group
##STR00008##
is a carboxamido group where R.sub.e is a substituted heterocyclo
according to the definitions herein.
[0049] The term "amide", "amidyl", or "amido" refers to the group
--C(.dbd.O)NR.sub.aR.sub.b, wherein the groups R.sub.a and R.sub.b
are defined as recited above in the definition for substituted
alkyl groups.
[0050] The term "urea" refers to the group
--NR.sub.dC(.dbd.O)NR.sub.aR.sub.b, wherein the groups R.sub.a,
R.sub.b, and R.sub.d are defined as recited above in the definition
for substituted alkyl groups. Additionally, the urea group may be
bivalent, in which case one of the groups R.sub.a and R.sub.b will
be a bond. Thus, in compounds of formula (I), when it is stated
that G may be urea, it can mean that G is a group
--NR.sub.d(C(.dbd.O)NR.sub.a-- where appropriate.
[0051] The term "sulfonyl" refers to a sulphoxide group linked to
an organic radical in compounds of formula (I), more particularly,
the monovalent group --S(O).sub.2--R.sub.e. Additionally, the
sulfonyl group may be bivalent, in which case R.sub.e is a bond.
Accordingly, in compounds of formula (I), when it is recited that G
can be "sulfonyl," it can mean that G is a group --S(O) where
appropriate. The group R.sub.e is selected from those recited above
for acyl and alkoxycarbonyl groups, with the exception that R.sub.e
is not hydrogen.
[0052] The terms "sulfonamide", "sulfonamidyl", or "sulfonamido"
refers to the group --S(O).sub.2NR.sub.aR.sub.b, wherein R.sub.a
and R.sub.b are as defined above for substituted alkyl groups.
[0053] The term "cycloalkyl" refers to fully saturated and
partially unsaturated hydrocarbon rings (and therefore includes
hydrocarbon rings also known as "cycloalkenyl rings") of 3 to 9,
preferably 3 to 7 carbon atoms. The term "cycloalkyl" includes such
rings having zero, one, two, or three substituents selected from
the group consisting of halogen, trifluoromethyl, trifluoromethoxy,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
nitro, cyano, oxo (.dbd.O), OR.sub.a, SR.sub.a, (.dbd.S),
--NR.sub.aR.sub.b, --N(alkyl).sub.3.sup.+, --NR.sub.aSO.sub.2,
--NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.c,
--SO.sub.2NR.sub.aR.sub.b, --SO.sub.2NR.sub.aC(.dbd.O)R.sub.b,
SO.sub.3H, --PO(OH).sub.2, --C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, .dbd.N--OH,
.dbd.N--O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,
wherein R.sub.a, R.sub.b and R.sub.c are as defined above for
substituted alkyl groups, and are also in turn optionally
substituted as recited above in the definition for substituted
alkyl groups. The term "cycloalkyl" also includes such rings having
a second ring fused thereto (e.g., including benzo, heterocyclo, or
heteroaryl rings) or having a carbon-carbon bridge of 3 to 4 carbon
atoms. When a cycloalkyl is substituted with a further ring (or has
a second ring fused thereto), said ring in turn is optionally
substituted with one to two of (C.sub.1-4)alkyl,
(C.sub.2-4)alkenyl, (C.sub.2-4)alkynyl, halogen, hydroxy, cyano,
nitro, CF.sub.3, O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2 and/or phenyl
optionally substituted with any of the preceeding groups. As
valence allows, if said further ring is cycloalkyl or heterocyclo
it is additionally optionally substituted with .dbd.O (oxo).
[0054] Accordingly, in compounds of formula (I), the term
"cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the
following ring systems,
##STR00009##
and the like, which optionally may be substituted at any available
atoms of the ring(s). Preferred cycloalkyl groups include
cyclopropyl, cyclopentyl, cyclohexyl, and
##STR00010##
[0055] The term "halo" or "halogen" refers to chloro, bromo, fluoro
and iodo.
[0056] The term "haloalkyl" means a substituted alkyl having one or
more halo substituents. For example, "haloalkyl" includes mono, bi,
and trifluoromethyl.
[0057] The term "haloalkoxy" means an alkoxy group having one or
more halo substituents. For example, "haloalkoxy" includes
OCF.sub.3.
[0058] The term "aryl" refers to phenyl, biphenyl, fluorenyl,
1-naphthyl and 2-naphthyl. The term "aryl" includes such rings
having zero, one, two or three substituents selected from the group
consisting of halogen, trifluoromethyl, trifluoromethoxy, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro,
cyano, OR.sub.a, SR.sub.a, (.dbd.S), SO.sub.3H, --NR.sub.aR.sub.b,
--N(alkyl).sub.3.sup.+, --NR.sub.aSO.sub.2,
--NR.sub.aSO.sub.2R.sub.c,
--SO.sub.2R.sub.c--SO.sub.2NR.sub.aR.sub.b,
--SO.sub.2NR.sub.aC(.dbd.O)R.sub.b, SO.sub.3H, --PO(OH).sub.2,
--C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a, --C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, aryl, cycloalkyl,
heterocyclo, and/or heteroaryl, wherein R.sub.a, R.sub.b and
R.sub.c are as defined above for substituted alkyl groups, and are
also in turn optionally substituted as recited above. Additionally,
two substituents attached to an aryl, particularly a phenyl group,
may join to form a further ring such as a fused or spiro-ring,
e.g., cyclopentyl or cyclohexyl, or fused heterocyclo or
heteroaryl. When an aryl is substituted with a further ring (or has
a second ring fused thereto), said ring in turn is optionally
substituted with one to two of (C.sub.1-4)alkyl, (C.sub.2-4alkenyl,
(C.sub.2-4)alkynyl, halogen, hydroxy, cyano, nitro, CF.sub.3,
O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2 and/or phenyl
optionally substituted with any of the preceeding groups. As
valence allows, if said further ring is cycloalkyl or heterocyclo
it is additionally optionally substituted with .dbd.O (oxo).
[0059] Thus, examples of aryl groups include:
##STR00011##
(fluorenyl) and the like, which optionally may be substituted at
any available carbon or nitrogen atom. A preferred aryl group is
optionally-substituted phenyl.
[0060] The terms "heterocycloalkyl", "heterocyclo" or
"heterocyclic" may be used interchangeably and refer to substituted
and unsubstituted non-aromatic 3- to 7-membered monocyclic groups,
7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic
groups, in which at least one of the rings has at least one
heteroatom (O, S or N), said heteroatom containing ring preferably
having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring
of such a group containing a heteroatom can contain one or two
oxygen or sulfur atoms and/or from one to four nitrogen atoms
provided that the total number of heteroatoms in each ring is four
or less, and further provided that the ring contains at least one
carbon atom. The nitrogen and sulfur atoms may optionally be
oxidized and the nitrogen atoms may optionally be quaternized. The
fused rings completing the bicyclic and tricyclic groups may
contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The heterocyclo group may be attached at
any available nitrogen or carbon atom. The heterocyclo ring may
contain zero, one, two or three substituents selected from the
group consisting of halogen, trifluoromethyl, trifluoromethoxy,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
nitro, cyano, oxo (.dbd.O), OR.sub.a, SR.sub.a, (.dbd.S),
--NR.sub.aR.sub.b, --N(alkyl).sub.3.sup.+, --NR.sub.aSO.sub.2,
--NR.sub.aSO.sub.2R.sub.c,
--SO.sub.2R.sub.c--SO.sub.2NR.sub.aR.sub.b,
--SO.sub.2NR.sub.aC(.dbd.O)R.sub.b, SO.sub.3H, --PO(OH).sub.2,
--C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a, --C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, .dbd.N--OH,
.dbd.N--O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,
wherein R.sub.a, R.sub.b and R.sub.c are as defined above for
substituted alkyl groups, and are also in turn optionally
substituted as recited above. When a heterocyclo is substituted
with a further ring, said ring in turn is optionally substituted
with one to two of (C.sub.1-4alkyl, (C.sub.2-4alkenyl,
(C.sub.2-4)alkynyl, halogen, hydroxy, cyano, nitro, CF.sub.3,
O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2 and/or phenyl
optionally substituted with any of the preceeding groups. As
valence allows, if said further ring is cycloalkyl or heterocyclo
it is additionally optionally substituted with .dbd.O (oxo).
[0061] Exemplary monocyclic groups include azetidinyl,
pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic
heterocyclo groups include quinuclidinyl.
[0062] Preferred heterocyclo groups in compounds of formula (I)
include
##STR00012##
which optionally may be substituted.
[0063] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or
10-membered bicyclic groups, and 11- to 14-membered tricyclic
groups which have at least one heteroatom (O, S or N) in at least
one of the rings, said heteroatom-containing ring preferably having
1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the
heteroaryl group containing a heteroatom can contain one or two
oxygen or sulfur atoms and/or from one to four nitrogen atoms
provided that the total number of heteroatoms in each ring is four
or less and each ring has at least one carbon atom. The fused rings
completing the bicyclic and tricyclic groups may contain only
carbon atoms and may be saturated, partially saturated, or
unsaturated. The nitrogen and sulfur atoms may optionally be
oxidized and the nitrogen atoms may optionally be quaternized.
Heteroaryl groups which are bicyclic or tricyclic must include at
least one fully aromatic ring but the other fused ring or rings may
be aromatic or non-aromatic. The heteroaryl group may be attached
at any available nitrogen or carbon atom of any ring. The
heteroaryl ring system may contain zero, one, two or three
substituents selected from the group consisting of halogen,
trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, nitro, cyano, OR.sub.a,
SR.sub.a, (.dbd.S), --NR.sub.aR.sub.b, --N(alkyl).sub.3.sup.+,
--NR.sub.aSO.sub.2, --NR.sub.aSO.sub.2R.sub.c,
--SO.sub.2R.sub.c--SO.sub.2NR.sub.aR.sub.b,
--SO.sub.2NR.sub.aC(.dbd.O)R.sub.b, SO.sub.3H, --PO(OH).sub.2,
--C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a, --C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, aryl, cycloalkyl,
heterocyclo, and/or heteroaryl, wherein R.sub.a, R.sub.b and
R.sub.c are as defined above for substituted alkyl groups, and are
also in turn optionally substituted as recited above. When a
heteroaryl is substituted with a further ring, said ring in turn is
optionally substituted with one to two of (C.sub.1-4)alkyl,
(C.sub.2-4)alkenyl, (C.sub.2-4)alkynyl, halogen, hydroxy, cyano,
nitro, CF.sub.3, O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2 and/or phenyl
optionally substituted with any of the preceeding groups. As
valence allows, if said further ring is cycloalkyl or heterocyclo
it is additionally optionally substituted with .dbd.O (oxo).
[0064] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl and the like.
[0065] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the
like.
[0066] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0067] In compounds of formula (I), preferred heteroaryl groups
include
##STR00013##
and the like, which optionally may be substituted at any available
carbon or nitrogen atom. Aromatic rings may also be designated by
an unbroken circle in the ring. For example the core ring of
formula (I),
##STR00014##
represents a bicyclic heteroaryl group.
[0068] Unless otherwise indicated, when reference is made to a
specifically-named aryl (e.g., phenyl), cycloalkyl (e.g.,
cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and
morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl,
pyrazolyl, triazolyl, thiazolyl, and furyl,) unless otherwise
specifically indicated the reference is intended to include rings
having 0 to 3, preferably 0-2, substituents selected from those
recited above for the aryl, cycloalkyl, heterocyclo and/or
heteroaryl groups, as appropriate.
[0069] Generally, for a non-formula substituent listing a
combination of groups, unless specifically designated otherwise,
the last group of the combination is the point of attachment with
adjacent groups attached sequentially. Accordingly, for example,
the term "aminocyclohexylmethyl is intended" to mean
##STR00015##
and N-(n-propyl)sulfonamido is intended to mean
##STR00016##
[0070] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0071] The term "carbocyclic" means a saturated or unsaturated
monocyclic or bicyclic ring in which all atoms of all rings are
carbon. Thus, the term includes cycloalkyl and aryl rings. The
carbocyclic ring may be substituted in which case the substituents
are selected from those recited above for cycloalkyl and aryl
groups.
[0072] When the term "unsaturated" is used herein to refer to a
ring or group, the ring or group may be fully unsaturated or
partially unsaturated.
[0073] When the term "optionally substituted" is used herein to
refer to a ring or group, the ring or group may be substituted or
unsubstituted.
[0074] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds and compounds useful as
pharmaceutically-acceptable compounds and/or intermediate compounds
useful in making pharmaceutically-acceptable compounds.
[0075] According to the foregoing definitions, the instant
invention provides compounds within the scope of formula (I) having
the formulae (Ia), (Ib), or (Ic):
##STR00017##
wherein the groups R.sub.1, R.sub.2, R.sub.3, X and Y, are as
defined herein.
[0076] The compounds of formula (I) can form salts which are also
within the scope of this invention. Unless otherwise indicated,
reference to an inventive compound is understood to include
reference to salts thereof. The term "salt(s)" denotes acidic
and/or basic salts formed with inorganic and/or organic acids and
bases. In addition, the term "salt(s) may include zwitterions
(inner salts), e.g., when a compound of formula (I) contains both a
basic moiety, such as an amine or a pyridine or imidazole ring, and
an acidic moiety, such as a carboxylic acid. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, such as, for example, acceptable metal and amine salts
in which the cation does not contribute significantly to the
toxicity or biological activity of the salt. However, other salts
may be useful, e.g., in isolation or purification steps which may
be employed during preparation, and thus, are contemplated within
the scope of the invention. Salts of the compounds of the formula
(I) may be formed, for example, by reacting a compound of the
formula (I) with an amount of acid or base, such as an equivalent
amount, in a medium such as one in which the salt precipitates or
in an aqueous medium followed by lyophilization.
[0077] Exemplary acid addition salts include acetates (such as
those formed with acetic acid or trihaloacetic acid, for example,
trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides (formed with hydrochloric acid),
hydrobromides (formed with hydrogen bromide), hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates (formed with maleic
acid), methanesulfonates (formed with methanesulfonic acid),
2-naphthalenesulfonates, nicotinates, nitrates, oxalates,
pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as
those formed with sulfuric acid), sulfonates (such as those
mentioned herein), tartrates, thiocyanates, toluenesulfonates such
as tosylates, undecanoates, and the like.
[0078] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts; alkaline earth
metal salts such as calcium and magnesium salts; barium, zinc, and
aluminum salts; salts with organic bases (for example, organic
amines) such as trialkylamines such as triethylamine, procaine,
dibenzylamine, N-benzyl-.beta.-phenethylamine, 1-ephenamine,
N,N'-dibenzylethylene-diamine, dehydroabietylamine,
N-ethylpiperidine, benzylamine, dicyclohexylamine or similar
pharmaceutically acceptable amines and salts with amino acids such
as arginine, lysine and the like. Basic nitrogen-containing groups
may be quaternized with agents such as lower alkyl halides (e.g.,
methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),
dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl
sulfates), long chain halides (e.g., decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides), aralkyl halides (e.g.,
benzyl and phenethyl bromides), and others. Preferred salts include
monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or
nitrate salts.
[0079] Prodrugs and solvates of the inventive compounds are also
contemplated. The term "prodrug" denotes a compound which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of the formula
(I), and/or a salt and/or solvate thereof. Any compound that will
be converted in vivo to provide the bioactive agent (i.e., the
compound for formula I) is a prodrug within the scope and spirit of
the invention. For example, compounds containing a carboxy group
can form physiologically hydrolyzable esters which serve as
prodrugs by being hydrolyzed in the body to yield formula (I)
compounds per se. Such prodrugs are preferably administered orally
since hydrolysis in many instances occurs principally under the
influence of the digestive enzymes. Parenteral administration may
be used where the ester per se is active, or in those instances
where hydrolysis occurs in the blood. Examples of physiologically
hydrolyzable esters of compounds of formula (I) include
C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,
methoxymethyl, C.sub.1-6alkanoyloxy-C.sub.1-6alkyl, e.g.
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl,
C.sub.1-6alkoxycarbonyloxy-C.sub.1-6alkyl, e.g.
methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well known
physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
conventional techniques known in the art.
[0080] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see:
[0081] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985) and Methods in Enzymology, Vol. 112, pp. 309-396, edited by
K. Widder, et al. (Acamedic Press, 1985);
[0082] b) A Textbook of Drug Design and Development, edited by
Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and
Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991);
and
[0083] c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp.
1-38 (1992), each of which is incorporated herein by reference.
[0084] Compounds of the formula (I) and salts thereof may exist in
their tautomeric form, in which hydrogen atoms are transposed to
other parts of the molecules and the chemical bonds between the
atoms of the molecules are consequently rearranged. It should be
understood that the all tautomeric forms, insofar as they may
exist, are included within the invention. Additionally, inventive
compounds may have trans and cis isomers and may contain one or
more chiral centers, therefore existing in enantiomeric and
diastereomeric forms. The invention includes all such isomers, as
well as mixtures of cis and trans isomers, mixtures of
diastereomers and racemic mixtures of enantiomers (optical
isomers). When no specific mention is made of the configuration
(cis, trans or R or S) of a compound (or of an asymmetric carbon),
then any one of the isomers or a mixture of more than one isomer is
intended. The processes for preparation can use racemates,
enantiomers or diastereomers as starting materials. When
enantiomeric or diastereomeric products are prepared, they can be
separated by conventional methods for example, chromatographic or
fractional crystallization. The inventive compounds may be in the
free or hydrate form.
[0085] It should further be understood that solvates (e.g.,
hydrates) of the compounds of Formula (I) are also with the scope
of the present invention. Methods of solvation are generally known
in the art.
Preferred Compounds
[0086] Preferred compounds are those within the scope of formula
(I) (above) have the following formulae (Ia), (Ib) or (Ic),
##STR00018##
their enantiomers, diastereomers, a pharmaceutically-acceptable
salt, or hydrate, thereof. Compounds of each formula, (Ia), (Ib),
or (Ic), are alternatively preferred.
[0087] Other preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, within the scope of each of formulae (Ia), (Ib) or (Ic)
are those in which: [0088] X is NR.sub.4R.sub.5; [0089] R.sub.4 is
-AM; [0090] R.sub.5 is hydrogen or C.sub.1-4alkyl (more preferably
R.sub.5 is hydrogen or methyl); [0091] or R.sub.4 and R.sub.5
together with the nitrogen atom to which they are attached form a
5-, 6- or 7-membered monocyclic heteroaryl or heterocyclo ring, or
a 7- to 11-membered bicyclic heteroaryl or heterocyclo ring, each
ring optionally substituted with one to three groups, T.sub.1,
T.sub.2; and/or T.sub.3; [0092] A is a bond, C.sub.1-3alkylene,
C.sub.2-4alkenylene, C.sub.2-4alkynylene, --C(O)--, or SO.sub.2--;
[0093] M is (i) hydrogen, NR.sub.15R.sub.16, alkyl, alkoxy, or
alkenyl; or (ii) cycloalkyl, heterocyclo, aryl, or heteroaryl, each
group optionally substituted by one to three groups, T.sub.1,
T.sub.2, and/or T.sub.3; [0094] T.sub.1, T.sub.2, and T.sub.3 are
independently selected from (i) halogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro,
cyano, SO.sub.3H SR.sub.19, S(O).sub.pR.sub.21,
S(O).sub.pNR.sub.19R.sub.20, NR.sub.19S(O).sub.pR.sub.21,
OR.sub.19, NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20,
NR.sub.19C(.dbd.O)NR.sub.19R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl, wherein p is one or 2; and/or (ii) two groups, T.sub.1
and T.sub.2, located on adjacent ring atoms are taken together with
the ring atoms to which they are attached to form a fused
cycloalkyl, aryl, heteroaryl, or heterocyclo; [0095] R.sub.19,
R.sub.20, and R.sub.21 at each occurrence, are selected
independently from (i) hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) R.sub.19 and R.sub.20 together with the nitrogen atom to
which they are both attached form a heteroaryl or heterocyclo; and
[0096] R.sub.21 at each occurrence, is selected from alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and
heterocyclo.
[0097] More preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, within the scope of formula (I) are those in which [0098]
X is NR.sub.4R.sub.5; [0099] R.sub.4 is -AM, [0100] A is a bond,
--C(O)--, or S(O).sub.2--, or C.sub.1-3alkylene (A is more
preferably a bond; methylene, or ethylene, especially a bond);
[0101] M is (i) hydrogen, --NH(aryl), C.sub.1-6alkyl,
C.sub.2-4alkenyl, or --OC.sub.1-4alkyl or (ii) C.sub.3-6cycloalkyl,
phenyl, fluorenyl, 1-naphthyl, or 2-naphthyl, each group optionally
substituted by one to three groups, T.sub.1, T.sub.2, and/or
T.sub.3; or (iii) a 5-, 6- or 7-membered monocyclic or a 7- to
11-membered bicyclic heteroaryl or heterocyclo ring, each ring
optionally substituted by one to three groups, T.sub.1, T.sub.2,
and/or T.sub.3 (is more preferably a C.sub.3-6cycloalkyl, or a 5-,
6-, or 7-membered aryl, heteroaryl, or heteroaryl ring, each ring
optionally substituted by 1 to 3 groups, T.sub.1, T.sub.2, and/or
T.sub.3, especially a 5-, 6-, or 7-membered aryl, heteroaryl, or
heteroaryl ring, each ring optionally substituted by 1 to 2 groups,
T.sub.1 and/or T.sub.2); and [0102] T.sub.1, T.sub.2, and T.sub.3
are independently selected from (i) C.sub.1-4alkyl, substituted
C.sub.1-4alkyl, C.sub.1-4alkyloxy, substituted C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, phenoxy, --NR.sub.19R.sub.20, halogen, hydroxy,
cyano, SO.sub.3H, COOH, --C(O)(R.sub.19), C(O)NR.sub.19R.sub.20,
NR.sub.19C(O)R.sub.20, S(O).sub.2R.sub.21,
S(O).sub.2NR.sub.19R.sub.20 and NR.sub.19(C(O)NR.sub.19R.sub.20;
and/or (ii) phenyl, cyclopropyl, cyclohexyl, tetrazolyl,
imidazolyl, pyrazolyl, triazolyl, thiazolyl, furyl, and
morpholinyl, each group of which is optionally substituted as
valence allows from one to three groups, R.sub.22, R.sub.23 and/or
R.sub.24; and/or (iii) two groups, T.sub.1 and T.sub.2, substituted
on adjacent ring atoms are taken together with the ring atoms to
which they are attached to form, a fused five- to seven-membered
cycloalkyl, a fused phenyl or a fused 5- or 6-membered heterocyclo
or heteroaryl, each group of which is optionally substituted as
valence allows from one to three groups, R.sub.22, R.sub.23 and/or
R.sub.24; and [0103] R.sub.19 and R.sub.20 at each occurrence are
selected independently from (i) hydrogen, --(CH.sub.2).sub.vOH, and
C.sub.1-4alkyl; or (ii) --(CH.sub.2).sub.vcyclohexyl,
--(CH.sub.2).sub.vphenyl, --(CH.sub.2).sub.vmorpholinyl,
--(CH.sub.2).sub.vpyridyl, --(CH.sub.2).sub.vpyrazolyl,
--(CH.sub.2).sub.vcyclopropyl, --(CH.sub.2).sub.vpyrrolidinyl,
--(CH.sub.2).sub.vpiperidinyl, --(CH.sub.2).sub.vfuryl,
--(CH.sub.2).sub.vimidazolyl, --(CH.sub.2).sub.vpyrimidinyl,
--(CH.sub.2).sub.vpiperazinyl, and --(CH.sub.2).sub.vpyradizinyl,
each group of which is optionally substituted as valence allows
from one to three groups, R.sub.22, R.sub.23 and/or R.sub.24; or
R.sub.19 and R.sub.20 are taken together with the nitrogen atom to
which they are both attached to form a pyrrolindyl, morpholinyl,
piperidinyl, pyradazinyl, or piperazinyl, each group of which is
optionally substituted as valence allows from one to three groups,
R.sub.22, R.sub.23 and/or R.sub.24; [0104] R.sub.21 at each
occurrence is selected from (i) --(CH.sub.2).sub.vOH, and
C.sub.1-4alkyl; or (ii) --(CH.sub.2).sub.vcyclohexyl,
--(CH.sub.2).sub.vphenyl, --(CH.sub.2).sub.vmorpholinyl,
--(CH.sub.2).sub.vpyridyl, --(CH.sub.2).sub.vpyrazolyl,
--(CH.sub.2).sub.vcyclopropyl, --(CH.sub.2).sub.vpyrrolidinyl,
--(CH.sub.2).sub.vpiperidinyl, --(CH.sub.2).sub.vfuryl,
--(CH.sub.2).sub.vimidazolyl, --(CH.sub.2).sub.vpyrimidinyl,
--(CH.sub.2).sub.vpiperazinyl, and --(CH.sub.2).sub.vpyradizinyl,
each group of which is optionally substituted as valence allows
from one to three groups, R.sub.22, R.sub.23 and/or R.sub.24;
R.sub.22, R.sub.23, and R.sub.24 at each occurrence, are selected
independently from (C.sub.1-4)alkyl, (C.sub.2-4)alkenyl, halogen,
hydroxy, cyano, nitro, CF.sub.3, .dbd.O, O(C.sub.1-4alkyl),
OCF.sub.3, C(.dbd.O)H, C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), NHCO.sub.2(C.sub.1-4alkyl),
--S(C.sub.1-4alkyl), --NH.sub.2, NH(C.sub.1-4alkyl),
N(C.sub.1-4alkyl).sub.2, N(C.sub.1-4alkyl).sub.3.sup.+,
SO.sub.2(C.sub.1-4alkyl), C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2, and optionally
substituted phenyl; and v is 0, 1, 2, or 3.
[0105] Other more preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, within the scope of formula (I) are those in which: [0106]
X is NR.sub.4R.sub.5; [0107] R.sub.4 is -AM; [0108] A is a bond,
methylene, or ethylene; [0109] M is hydrogen, methoxy, phenyl,
fluorenyl, pyridyl, cyclopropyl, cyclohexyl, isopropyl, ethyl,
n-propenyl, isopentyl, n-propyl, n-butyl, pyrazolyl, or
pyrimidinyl, each group optionally substituted by one to two groups
selected from T.sub.1 and T.sub.2; and [0110] T.sub.1 and T.sub.2
are independently selected from ethoxy, methoxy, methyl, n-butoxy,
phenyl, benzyloxy, dimethylamino, chloro, iodo, trifluoromethyl,
fluoro, hydroxyl, cyano, carboxylic acid,
N-methyl-N-(pyridinylethyl)amido, ethyltetrazole, phenoxy,
chlorophenyl, methylphenyl, benzyl, morpholinyl, isopropyl,
n-propyl, n-butyl, ethyl, isopropoxy, n-propoxy, methylthio,
cyclohexyl, t-butyl, trifluoromethoxy, amino, triazolyl,
dichloroimidazolyl, dimethylpyrazolyl, methyltriazolyl,
methylimidazolyl, methylthiazolyl, methylfuryl, N,N-dimethylamido,
phenylsulfonyl, morpholinylsulfonyl, pyrrolidinylsulfonyl,
N,N-diethylamido, N-methylamido, N-methylsulfonamido,
N-methylsulfonamido, methanesulfonamido, N,N-dimethylsulfonamido,
N,N-diethylsulfonamido, N-propylsulfonamido, N-ethylsulfonamido,
N-methylsulfonamido, sulfonamido, aminomethyl, amido,
N-(furylmethyl)amido, N-(imidazolylmethyl)amido;
N-(pyridylmethyl)amido, (phenylpiperidinyl)carbonyl,
piperidinylcarbonyl, N-benzylamido, N-methoxyphenylamido,
N-phenylamido, N-(hydroxyethyl)amido, 1-morpholinylcarbonyl,
N-(pyridinyl)amido, N-(pyridinylmethyl)amido,
N-(pyridinylethyl)amido, N,N-diethylamido, N-cyclopropylamido,
N-(cyclohexylmethyl)amido, N-(cyclohexyl)amido
N-(methylpyrazolyl)amido, N-((oxopyrrolidinyl)propyl)amido,
3-phenylurea, and
1-(fluorophenyl)-N-methyl-oxo-dihydropyridine-3-carboxamido; [0111]
or T.sub.1 and T.sub.2 substituted on adjacent atoms of M combine
with the atoms to which they are attached to form a fused ring
thereby forming a ring system selected from indolyl,
methylbenzothiazolyl, napthyl, methylindolyl, tetrahydroquinolinyl,
fluorenyl, quinolinyl, and dihydroindazol-one-yl.
[0112] Other preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, within the scope of formula (I) are those in which [0113]
Y is hydrogen, halogen, OR.sub.8, NR.sub.6R.sub.7,
--(CH.sub.2)heterocyclo, or aryl; (more preferably Y is hydrogen,
halogen, OR.sub.8, NR.sub.6R.sub.7,
[0113] ##STR00019## even more preferably Y is NR.sub.6R.sub.7);
[0114] R.sub.6 is selected from hydrogen or C.sub.1-4alkyl
optionally substituted by one to three groups selected from
halogen, C.sub.1-4alkyl, nitro, cyano, amino, C.sub.1-4alkoxy, and
OH(R.sub.6 is more preferably hydrogen or C.sub.1-4alkyl); [0115]
R.sub.7 and R.sub.8 are independently selected from alkyl,
cycloalkyl, heterocyclo, aryl, and heteroaryl, each group of which
is optionally substituted by one to three groups, T.sub.4, T.sub.5,
and/or T.sub.6 (R.sub.7 is more preferably C.sub.1-4alkyl,
C.sub.3-6cycloalkyl, or a 5-, 6-, or 7-membered heterocyclo, each
group optionally substituted by one to three groups T.sub.4,
T.sub.5, and/or T.sub.6; R.sub.8 is more preferably
C.sub.3-6cycloalkyl, especially cyclohexyl substituted by
C.sub.1-4alkyl, amino, amino substituted with C.sub.1-4alkyl,
substituted C.sub.1-4alkyl, furyl, or piperidinyl); [0116] or
R.sub.6 and R.sub.7 together with the nitrogen atom to which they
are attached form a heteroaryl or heterocyclo ring (more preferably
5-, 6-, or 7-membered rings), each ring is optionally substituted
by one to three groups, T.sub.4, T.sub.5, and/or T.sub.6; [0117]
T.sub.4, T.sub.5 and T.sub.6 are independently selected from (i)
halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, nitro, cyano, SR.sub.19, OR.sub.19,
NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19;
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl; and/or (ii) two groups, T.sub.4 and T.sub.5,
substituted on adjacent ring atoms are taken together with the ring
atoms to which they are attached to form a fused cyclalkyl,
heterocyclo, aryl, or heteroaryl (T.sub.4, T.sub.5 and T.sub.6 are
more preferably C.sub.1-4alkyl, and --NR.sub.19R.sub.20); and
[0118] R.sub.19 and R.sub.20, at each occurrence are selected
independently from (i) hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) R.sub.19 with R.sub.20 together with the nitrogen atom to
which they are both attached combine to form a heteroaryl or
heterocyclo.
[0119] Other more preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, within the scope of formula (I) are those in which [0120]
Y is NR.sub.6R.sub.7; [0121] R.sub.6 is selected from hydrogen or
C.sub.1-4alkyl (R.sub.6 is more preferably hydrogen); [0122]
R.sub.7 is selected from C.sub.1-4alkyl, cyclopentyl, cyclohexyl,
bicyclo[2.2.2]octyl, pyrrolidinyl, and piperidinyl, each group of
which is optionally substituted by one to three groups, T.sub.4,
T.sub.5, and/or T.sub.6 (R.sub.7 is more preferably cyclohexyl and
bicycle {222]octyl, each group substituted by one group, T.sub.4);
[0123] or R.sub.6 and R.sub.7 together with the nitrogen atom to
which they are attached form piperazinyl, piperidinyl,
pyrrolidinyl, or diazepanyl, each group of which is optionally
substituted by one to three groups, T.sub.4, T.sub.5, and/or
T.sub.6 (more preferably R.sub.6 and R.sub.7 are taken together
with the nitrogen atom to which they are both attached form an
unsubstituted piperidinyl ring); and [0124] T.sub.4, T.sub.5, and
T.sub.6 are independently selected from (i) C.sub.1-4alkyl, OH,
NH.sub.2, NH(C.sub.1-4alkyl), furyl, and N(C.sub.1-4alkyl).sub.2,
and NH(pyrimidinyl) wherein the pyrimidinyl is substituted by
halogen; or (ii) C.sub.1-4alkyl substituted by cyclohexyl or OH,
wherein the cyclohexyl is substituted by NH.sub.2. (More preferably
T.sub.4, T.sub.5, and T.sub.6 are selected from NH.sub.2,
NH(C.sub.1-4alkyl), and (4-NH.sub.2-cyclohexyl)methyl).
[0125] Yet other preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, within the scope of formula (I) are those in which [0126]
R.sub.6 is hydrogen; [0127] R.sub.7 is methyl, ethyl, n-propyl,
n-butyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octane,
pyrrolidinyl, or piperidinyl, each group of which is optionally
substituted by T.sub.4 selected from amino, methyl,
aminocyclohexylmethyl, dimethylamino, furyl, ethylamino,
methylamino, piperidinyl, and (chloropyrimidinyl)amino; or [0128]
R.sub.6 and R.sub.7 together with the nitrogen atom to which they
are attached form a piperazinyl, piperidinyl, pyrrolidinyl, and
diazepanyl ring, each ring optionally substituted by T.sub.4
selected from amino, hydroxyethyl, aminopyrrolidinyl, and
methyl.
[0129] Other preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, are those within the scope of formula (I) (above) having
the formula (Ia), (Ib) or (Ic), in which:
##STR00020## [0130] or an enantiomer, diastereomer, or a
pharmaceutically-acceptable salt, thereof, wherein: [0131] X is
NR.sub.4R.sub.5; [0132] Y is hydrogen, halogen, OR.sub.8, or
NR.sub.6R.sub.7 (Y is more preferably NR.sub.6R.sub.7); [0133]
R.sub.1 and R.sub.2 are independently selected from hydrogen,
halogen, OR.sub.10, cyano, C.sub.1-4alkyl, CO.sub.2R.sub.10, and
C(O)NR.sub.10R.sub.11; [0134] R.sub.3 is selected from (i)
hydrogen, halogen, nitro, cyano, OR.sub.10, NR.sub.10R.sub.11,
CO.sub.2R.sub.10, and C(.dbd.O)R.sub.10, (ii) C.sub.1-4alkyl,
substituted C.sub.1-4alkyl, cycloalkyl, aryl, and heteroaryl;
[0135] R.sub.4 is -AM; [0136] R.sub.5 is hydrogen or
C.sub.1-4alkyl; [0137] or R.sub.4 and R.sub.5 together with the
nitrogen atom to which they are attached form a 5-, 6- or
7-membered monocyclic heteroaryl or heterocyclo ring, or a 7- to
11-membered bicyclic heteroaryl or heterocyclo ring, each ring
optionally substituted with one to three groups, T.sub.1, T.sub.2;
and/or T.sub.3; [0138] A is a bond, C.sub.1-3alkylene,
C.sub.2-4alkenylene, C.sub.2-4alkynylene, --C(O)--, or SO.sub.2--;
[0139] M is (i) hydrogen, NR.sub.15R.sub.16, alkyl, alkoxy, or
alkenyl; or (ii) cycloalkyl, heterocyclo, aryl, or heteroaryl, each
ring optionally substituted by one to three groups, T.sub.1,
T.sub.2, and/or T.sub.3; [0140] R.sub.6 is selected from hydrogen
or C.sub.1-4alkyl optionally substituted by one to three groups
selected from halogen, C.sub.1-4alkyl, nitro, cyano, amino,
C.sub.1-4alkoxy, and OH; [0141] R.sub.7 and R.sub.8 are
independently selected from alkyl, cycloalkyl, heterocyclo, aryl,
and heteroaryl, each group of which is optionally substituted by
one to three groups, T.sub.4, T.sub.5, and/or T.sub.6 (R.sub.8 is
preferably C.sub.3-6cycloalkyl, especially cyclohexyl optionally
substituted by NH.sub.2, NH(C.sub.1-4alkyl), and
(4-NH.sub.2-cyclohexyl)methyl); [0142] or R.sub.6 and R.sub.2
together with the nitrogen atom to which they are attached form a
heteroaryl or heterocyclo ring, each ring is optionally substituted
by one to three groups, T.sub.4, T.sub.5, and/or T.sub.6; [0143]
R.sub.10 and R.sub.11 at each occurrence are independently selected
from (i) hydrogen, C.sub.1-4alkyl, and substituted C.sub.1-4alkyl;
or (ii) R.sub.10 and R.sub.11 together with the nitrogen atom they
are both attached combine to form an optionally substituted 5-, 6-,
or 7-membered heteroaryl or heterocyclo; [0144] R.sub.15 and
R.sub.16 are independently selected from (i) hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) together with the nitrogen atom to which they are attached
R.sub.15 is taken together with R.sub.16 to form a heteroaryl or
heterocyclo; [0145] T.sub.1, T.sub.2, and T.sub.3 are independently
selected from (i) halogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano,
SO.sub.3H SR.sub.19, S(O).sub.pR.sub.21,
S(O).sub.pNR.sub.19R.sub.20, NR.sub.19S(O).sub.pR.sub.21,
OR.sub.19, NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20,
NR.sub.19C(.dbd.O)NR.sub.19R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl, wherein p is one or 2; and/or (ii) two groups, T.sub.1
and T.sub.2, located on adjacent ring atoms are taken together with
the ring atoms to which they are attached to form a fused
cycloalkyl, aryl, heteroaryl, or heterocyclo; [0146] T.sub.4,
T.sub.5 and T.sub.6 are independently selected from (i) halogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, cyano, SR.sub.19, OR.sub.19,
NR.sub.19R.sub.20, NR.sub.19C(.dbd.O)R.sub.20, CO.sub.2R.sub.19,
C(.dbd.O)R.sub.19, --O--C(.dbd.O)R.sub.19,
--C(.dbd.O)NR.sub.19R.sub.20, cycloalkyl, heterocyclo, aryl, and
heteroaryl; and/or (ii) two groups, T.sub.4 and T.sub.5,
substituted on adjacent ring atoms are taken together with the ring
atoms to which they are attached to form a fused cyclalkyl,
heterocyclo, aryl, or heteroaryl; and [0147] R.sub.19 and R.sub.20
at each occurrence are selected independently from (i) hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; or (ii) R.sub.19 and R.sub.20
together with the nitrogen atom to which they are both attached
form a heteroaryl or heterocyclo ring; and [0148] R.sub.21 at each
occurrence, is selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; with the following provisos:
[0149] (1) if E is C, F is N, Z is CR.sub.3, and X is NH(Me),
NH(Me).sub.2, NH(unsubstituted phenyl), or NHNH.sub.2, then Y is
other than hydrogen or halogen; and [0150] (2) if E is N, F is C, Z
is N, and Y is NR.sub.6R.sub.7, [0151] (a) then X is other than
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NH(C.sub.1-4alkenyl),
NH(--CH.sub.2-furyl), NHNH2, NH(Cmethoxyalkylene), and NHAc; [0152]
(b) and if X is NH(--CH.sub.2-(substituted or
unsubstituted)pyridyl) or NH(--CH.sub.2-(substituted or
unsubstituted) phenyl), then Y is other than
##STR00021##
[0152] NH(substituted piperidine), or NH(--CH.sub.2-pyridine);
[0153] (c) and if X is NH(cyclopentyl), then Y is other than
NH(cyclopentyl); [0154] (d) and if X is N(CH.sub.3)(substituted
phenyl) or N(CH.sub.3)(pyridyl), then Y is other than
##STR00022##
[0154] or [0155] (e) and if X is NH(substituted phenyl), then Y is
other than
##STR00023##
[0156] Particularly preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, are those within the scope of formula (I) (above) having
the formula (Ia), (Ib) or (Ic), in which: [0157] R.sub.1 and
R.sub.2 are independently selected from (i) hydrogen, halogen,
OR.sub.10, cyano, CO.sub.2R.sub.10, and C(O)NR.sub.10R.sub.11, or
(ii) C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.2-C.sub.4 alkenyl,
or C.sub.2-C.sub.4 alkynyl, each group of which is optionally
substituted; [0158] R.sub.3 is selected from (i) hydrogen, halogen,
nitro, cyano, OR.sub.13, NR.sub.13R.sub.14, CO.sub.2R.sub.13,
C(.dbd.O)R.sub.13, C.sub.1-4alkyl, substituted C.sub.1-4alkyl,
cycloalkyl, aryl, and heteroaryl; and [0159] R.sub.10, R.sub.11,
R.sub.13, and R.sub.14 at each occurrence are independently
selected from (i) hydrogen, C.sub.1-4alkyl, substituted
C.sub.1-4alkyl, and an optionally substituted phenyl or 5-, 6-, or
7-membered heteroaryl or heterocyclo; or (ii) R.sub.10 and R.sub.11
and/or R.sub.13, and R.sub.14 together with the nitrogen atom they
are both attached combine to form an optionally substituted 5-, 6-,
or 7-membered heteroaryl or heterocyclo.
[0160] Even more preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, are those within the scope of formula (I) (above) having
the formula (Ia), (Ib) or (Ic), in which: [0161] R.sub.1 is
hydrogen, fluoro, or C.sub.1-4alkyl (more preferably R.sub.1 is
hydrogen, fluoro, or methyl); [0162] R.sub.2 is cyano, halogen,
C.sub.1-4alkyl, C.sub.2-4alkenyl(phenyl),
C.sub.2-4alkenyl(heteroaryl), cyclopropyl, propynyl, or
C(O)NR.sub.10R.sub.11 (more preferably R.sub.2 is hydrogen, cyano,
halogen, C(O)NH.sub.2, C(O)NH(4-pyridinyl), cyclopropyl,
--CH.dbd.CH(4-pyridinyl), or C(O)NH(4-pyridinyl); [0163] R.sub.3 is
hydrogen, halogen, C.sub.1-4alkyl, substituted C.sub.1-4alkyl, or
aryl (more preferably R.sub.3 is hydrogen, halogen, C.sub.1-4alkyl,
substituted methylene, or optionally substituted phenyl, even more
preferably R.sub.3 is hydrogen, methyl, ethyl, isopropyl, benzyl,
unsubstituted phenyl, 3-chlorophenyl, or 4-chlorophenyl), [0164]
R.sub.10 and R.sub.11 at each occurrence are independently selected
from hydrogen, C.sub.1-4alkyl, substituted C.sub.1-4alkyl, an
optionally substituted phenyl, and an optionally substituted
heteroaryl wherein the heteroaryl is selected from pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl,
benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl,
coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,
pyrrolopyridyl, furopyridyl, dihydroisoindolyl,
tetrahydroquinolinyl, carbazolyl, benzidolyl, phenanthrollinyl,
acridinyl, phenanthridinyl, and xanthenyl.
[0165] Even more particularly preferred compounds, including
enantiomers, diastereomers, a pharmaceutically-acceptable salt, or
hydrate, thereof, are those within the scope of formula (I) (above)
having the formula (Ia), (Ib) or (Ic), in which NR.sub.4R.sub.5 is
selected from:
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035##
[0166] Alternative even more particularly preferred compounds,
including enantiomers, diastereomers, a pharmaceutically-acceptable
salt, or hydrate, thereof, are those within the scope of formula
(I) in which NR.sub.6R.sub.7 is selected from:
##STR00036##
[0167] Other preferred compounds within the scope of formula (I),
or an enantiomer, diastereomer, or a pharmaceutically-acceptable
salt, thereof wherein: [0168] R.sub.4 is selected from a
C.sub.3-6cycloalkyl, a 5-, 6-, or 7-membered aryl, heteroaryl, or a
heteroaryl ring optionally substituted by 1 to 3 groups selected
from T.sub.1, T.sub.2, and T.sub.3 (More preferably, R.sub.4 is
selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, and
piperidinyl, each group optionally substituted by 1 to 2 groups,
T.sub.1 and/or T.sub.2. T.sub.1 and/or T.sub.2 are preferably
selected from ethoxy, methoxy, methyl, ethyl, n-butoxy, phenyl,
benzyloxy, dimethylamino, chloro, iodo, trifluoromethyl, fluoro,
hydroxyl, cyano, carboxylic acid, N-methyl-N-(pyridinylethyl)amido,
ethyltetrazole, phenoxy, chlorophenyl, methylphenyl, benzyl,
morpholinyl, isopropyl, n-propyl, n-butyl, ethyl, isopropoxy,
n-propoxy, methylthio, cyclohexyl, t-butyl, chloro,
trifluoromethoxy, amino, triazolyl, dichloroimidazolyl,
dimethylpyrazolyl, methyltriazolyl, methylimidazolyl,
methylthiazolyl, methylfuryl, N,N-dimethylamido,
morpholinylsulfonyl, pyrrolidinylsulfonyl, N,N-diethylamido,
N-methylamido, N-methylsulfonamido, N-methylsulfonamido,
methanesulfonamido, N,N-dimethylsulfonamido,
N,N-diethylsulfonamido, N-propylsulfonamido, N-ethylsulfonamido,
N-methylsulfonamido, sulfonamido, aminomethyl, amido,
N-(furylmethyl)amido, N-(imidazolylmethyl)amido;
N-(pyridylmethyl)amido, (phenylpiperidinyl)carbonyl,
piperidinylcarbonyl, N-benzylamido, N-methoxyphenylamido,
N-phenylamido, N-(hydroxyethyl)amido, 1-morpholinylcarbonyl,
N-(pyridinyl)amido, N-(pyridinylmethyl)amido,
N-(pyridinylethyl)amido, N,N-diethylamido, N-cyclopropylamido,
N-(cyclohexylmethyl)amido, N-(cyclohexyl)amido
N-(methylpyrazolyl)amido, N-((oxopyrrolidinyl)propyl)amido,
phenylurea, and
1-(fluorophenyl)-N-methyl-oxo-dihydropyridine-3-carboxamido);
[0169] or T.sub.1 and T.sub.2 located on adjacent atoms of M
together with the atoms to which they are attached combine to form
a fused ring thereby forming a fused ring system selected from
indolyl, methylbenzothiazolyl, napthyl, methylindolyl,
tetrahydroquinolinyl, fluorenyl, quinolinyl, and
dihydroindazol-one-yl.
[0170] Yet other preferred compounds, including enantiomers,
diastereomers, a pharmaceutically-acceptable salt, or hydrate,
thereof, are those within the scope of formula (I) in which
NR.sub.6R.sub.7 is selected from:
##STR00037##
[0171] All aspects of the preferred compounds, including individual
variable definitions, may be combined with other aspects to form
other preferred compounds.
Methods of Preparation
[0172] Compounds of the present invention may be prepared by the
exemplary processes described in the following reaction schemes, A
to E. Exemplary reagents and procedures for these reactions appear
hereinafter. Starting materials are commercially available or can
be readily prepared by one of ordinary skill in the art.
Modifications can be made to the methods of schemes by one skilled
in the art using known methods. For all of the schemes, the groups
R.sub.1, R.sub.2, are as described herein for a compound of formula
(I), unless otherwise indicated. Groups designated generally as R',
R'', Z, P' and P'' as well as appropriate solvents, temperatures,
pressures, starting materials (having the desired substituents),
and other reaction conditions, may be readily selected by one of
ordinary skill in the art. It is anticipated that, where possible,
the products of the reaction schemes described below may be further
elaborated by one of ordinary skill in the art
##STR00038##
[0173] Compounds of general formula (I) where E=C and F.dbd.N, and
Z.dbd.CR3 (i.e. formula (Ia)) may be prepared as described below in
Schemes A, B and C.
##STR00039##
[0174] Readily prepared 3-amino-4,6-dihalopyridazines 1 are
condensed with commercially available or readily prepared
2-haloaldehydes or 2-haloketones 2 or their equivalents to provide
6,8-dihaloimidazo[1,2-b]pyridazines 3 in an alcoholic solvent (such
as ethanol). The reaction of 3 with an amine in a suitable solvent
(such as N-methylpryrrolidinone or alcohols) in the presence of a
suitable base (such as triethylamine or cesium carbonate) provides
6-haloimidazo[1,2-b]pyridazines 4. Alternatively, the reaction of 3
with non-reactive nucleophiles (such as electron deficient
anilines) in a suitable solvent (such as dimethylformamide or
tetrahydrofuran) with a suitable base (such as sodium hydride) may
provide compounds having the formula 4. Reaction of
6-haloimidazo[1,2-b]pyridazines 4 with nucleophiles (such as
amines) provides imidazo[1,2-b]pyridazines (Ia) under either neat
conditions or in a solvent (such as N-methylpryrrolidinone) in the
presence of a suitable base (such as cesium carbonate).
##STR00040##
[0175] Compounds having the formula (Ia) can also be obtained via
treatment of 6,8-dihaloimidazo[1,2-b]pyridazines 3 prepared as
described in Scheme A with halogenating agents (such as NBS, NCS,
NIS, selectfluor) in a suitable solvent (such as chloroform or
acetonitrile) to provide the corresponding
3,6,8-trihaloimidazo[1,2-b]pyridazines 5. The reaction of 5 with an
amine in a suitable solvent (such as N-methylpryrrolidinone or
alcohols) in the presence of a suitable base (such as triethylamine
or cesium carbonate) provides 3,6-dihaloimidazo[1,2-b]pyridazines
6. Alternatively, the reaction of 5 with non-reactive nucleophiles
(such as electron deficient anilines) in a suitable solvent (such
as dimethylformamide or tetrahydrofuran) with a suitable base (such
as sodium hydride) may provide compounds having the formula 6. The
reaction of 6-haloimidazo[1,2-b]pyridazines such as 6 with amines
provides imidazo[1,2-b]pyridazines (Ia) under either neat
conditions or in a solvent (such as N-methylpryrrolidinone,
dioxane) in the presence of a suitable base (such as cesium
carbonate) with or without a catalyst (such as palladium acetate).
Alternately, the 3-position of 3,6-dihaloimidazo[1,2-b]pyridazines
6 may be readily converted by one skilled in the art employing one
of the many procedures of converting aryl halides into other
functional groups to provide of 6-haloimidazo[1,2-b]pyridazines
such as 7 where R.sub.2 is other than halogen. The newly introduced
functionality at R.sub.2 can be further elaborated by known methods
to prepare additional analogs. The reaction of
6-haloimidazo[1,2-b]pyridazines such as 7 with nucleophiles (such
as amines or alcohols) provides imidazo[1,2-b]pyridazines (Ia)
under either neat conditions or in a solvent (such as
N-methylpryrrolidinone, dioxane) in the presence of a suitable base
(such as cesium carbonate) with or without a catalyst (such as
palladium acetate).
##STR00041##
[0176] Compounds having the formula (Ia) can also be obtained via
treatment of imidazo[1,2-b]pyridazine 8 with nucleophiles (such as
amines) in a suitable solvent (such as ethanol) with a suitable
base (such as triethylamine) to provide imidazo[1,2-b]pyridazines
9. See e.g. Synthesis Vol. 8 (1971) at pp 424. Reaction of
imidazo[1,2-b]pyridazines 9 with nucleophiles (such as amines)
provides imidazo[1,2-b]pyridazines 10. Treatment of
imidazo[1,2-b]pyridazines 10 with a suitable catalyst (such as
platinum oxide) in a suitable solvent (such as ethanol) under
hydrogen pressure (such as 55 psi) provides
imidazo[1,2-b]pyridazines (Ia) where R.sub.1, R.sub.2, and R.sub.3
are independently selected from H and Cl.
[0177] Compounds of general formula (I) where E=N, F.dbd.C, Z.dbd.N
(i.e. formula (Ib)) may be prepared by as described in Scheme
D.
##STR00042##
[0178] Treatment of pyrazolotriazines 11 with nucleophiles (such as
amines) in a suitable solvent (such as dioxane) provides
pyrazolotriazines 12. See e.g. Journal of Heterocyclic
Chemistry_Vol. 11(2) (1974) at pp. 199. Treatment of
pyrazolotriazine 12 with a suitable oxidizing agent (such as MCPBA)
in a suitable solvent (such as DMF) provides pyrazolotriazine 13
Treatment of pyrazolotriazine 13 with a nucleophile (such as an
amine) under neat conditions provides pyrazolotriazines (Ib).
[0179] Compounds of general formula (I) where E=C, F.dbd.N, Z.dbd.N
(i.e. formula (Ic)) may be prepared by as described in Scheme E
##STR00043##
[0180] Treatment of imidazotriazine 14 with nucleophiles (such as
amines) under neat conditions provides imidazotriazine 15. See e.g.
Journal of The Chemical Society, Perkins Transactions I, Vol. 20
(1999) at pp. 2929. Treatment of imidazotriazine 15 with a suitable
oxidizing agent (such as MCPBA) in a suitable solvent (such as DMF)
provides imidazotriazine 16. Treatment of imidazotriazine 16 with a
nucleophile (such as an amine) under neat conditions provides
imidazotriazine (Ic).
Utility
[0181] The compounds of the invention modulate kinase activity,
including the modulation of MAPKAP kinase-2 (MK2). Other types of
kinase activity may be modulated by the compounds of the invention
including, but not limited to AKT1, AKT2, AKT3, DMPK1, MRCKA,
GPRK4, GPRK5, GPRK6, NDR2, PKACA, PKACB, PRKX, PKACA, PDK1, PKCA,
PKCD, PKCT, PKCH, PKCI, PKCZ, PKG1, PKG2, PKN2, MSK1, MSK2, RSK1,
RSK2, RSK4, YANK2, YANK3, ADCK3, ADCK4, CAMK1A, CAMK1D, CAMK1G,
CAMK2A, CAMK2B, CAMK2D, CAMK2G, AMPKA1, AMPKA2, BRSK2, LKB1, MARK1,
MARK2, MARK4, QIK, STK33, DAPK2, DAPK3, DRAK1, DRAK2, DCAMKL3,
MNK2, SKMLCK, PHKG1, PHKG2, PIM1, PIM2, CK1A2, CK1D, CK1E, CK1G1,
CK1G2, CDK2, CDK2, CDK5, CDK5, PCTAIRE1, CLK1, CLK2, CLK3, CLK4,
GSK3A, GSK3B, GSK3B, ERK1, ERK2, JNK1, JNK2, JNK3, NLK, P38A, P38B,
P38G, SRPK1, AURA, AURB, AURC, CAMKK1, CAMKK2, CK2A1, CK2A2, IKKB,
AAK1, BIKE, GAK, MPSK1, NEK2, NEK6, NEK7, NEK9, GCN2, PLK1, PLK3,
PLK4, TLK1, TLK2, TTK, FUSED, ULK3, MYT1, MAP3K4, MAP3K5, HPK1,
KHS1, KHS2, ZC1/HGK, ZC2/TNIK, MST1, MST2, PAK1, PAK2, PAK3, PAK4,
PAK5, PAK6, LOK, SLK, MST3, MST4, YSK1, ABL, ARG, ACK, TNK1, ALK,
LTK, AXL, MER, TYRO3, CSK, DDR2, EGFR, HER2/ERBB2, HER4/ERBB 4,
EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB 1,
EPHB2, EPHB3, EPHB4, FAK, PYK2, FER, FES, FGFR1, FGFR2, FGFR3,
FGFR4, IGF1R, INSR, IRR, IGF1R, INSR, JAK1, JAK2, TYK2, JAK2, MET,
MUSK, FLT3, FMS, KIT, PDGFRA, PDGFRB, FLT3, RET, ROS, BLK, BRK,
FGR, FRK, FYN, HCK, LCK, LYN, SRC, YES, LCK, SYK, ZAP70, BMX, BTK,
ITK, TXK, TIE2, TRKA, TRKB, TRKC, TRKA, TRKB, FLT1, FLT4, KDR,
LIMK1, LIMK2, TESK1, HH498, MLK3, BRAF, BRAF, RAF1, RIPK2, ALK1,
ALK2, ALK4, BMPR1A, TGFBR1, ACTR2, ACTR2B, and mutants thereof.
[0182] Accordingly, compounds of formula (I) have utility in
treating conditions associated with the modulation of kinase
activity, and particularly the selective inhibition of MK2
activity. Such conditions include diseases in which cytokine levels
are modulated as a consequence of intracellular signaling via the
p38 pathway, with MK2 as the downstream kinase substrate, and in
particular, diseases that are associated with an overproduction of
cytokines IL-1, IL-6, IL-8, IFN.gamma. and TNF-.alpha.. As used
herein, the terms "treating" or "treatment" encompass either or
both responsive and prophylaxis measures, e.g., measures designed
to inhibit or delay the onset of the disease or disorder, achieve a
full or partial reduction of the symptoms or disease state, and/or
to alleviate, ameliorate, lessen, or cure the disease or disorder
and/or its symptoms.
[0183] In view of their activity as selective inhibitors of MK2,
compounds of Formula (I) are useful in treating cytokine-associated
conditions including, but not limited to, inflammatory diseases
such as Crohn's and ulcerative colitis, asthma, graft versus host
disease, chronic obstructive pulmonary disease; autoimmune diseases
such as Grave's disease, rheumatoid arthritis, systemic lupus
erythematosis, psoriasis; destructive bone disorders such as bone
resorption disease, osteoarthritis, osteoporosis, multiple
myeloma-related bone disorder; proliferative disorders such as
acute myelogenous leukemia, chronic myelogenous leukemia;
angiogenic disorders such as angiogenic disorders including solid
tumors, ocular neovasculization, and infantile haemangiomas;
infectious diseases such as sepsis, septic shock, and Shigellosis;
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease, cerebral ischemias or neurodegenerative disease caused by
traumatic injury, oncologic and viral diseases such as metastatic
melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and
CMV retinitis, AIDS, respectively.
[0184] More particularly, the specific conditions or diseases that
may be treated with the inventive compounds include, without
limitation, pancreatitis (acute or chronic), asthma, allergies,
adult respiratory distress syndrome, chronic obstructive pulmonary
disease, glomerulonephritis, rheumatoid arthritis, systemic lupus
erythematosis, scleroderma, chronic thyroiditis, Grave's disease,
autoimmune gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, atopic dermatitis,
chronic active hepatitis, myasthenia gravis, multiple sclerosis,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
psoriasis, graft vs. host disease, inflammatory reaction induced by
endotoxin, tuberculosis, atherosclerosis, muscle degeneration,
cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic
arthritis, rubella arthritis, acute synovitis, pancreatic
.beta.-cell disease; diseases characterized by massive neutrophil
infiltration; rheumatoid spondylitis, gouty arthritis and other
arthritic conditions, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoisosis, bone
resorption disease, allograft rejections, fever and myalgias due to
infection, cachexia secondary to infection, meloid formation, scar
tissue formation, ulcerative colitis, pyresis, influenza,
osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic
myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma,
multiple myeloma, sepsis, septic shock, and Shigellosis;
Alzheimer's disease, Parkinson's disease, cerebral ischemias or
neurodegenerative disease caused by traumatic injury; angiogenic
disorders including solid tumors, ocular neovasculization, and
infantile haemangiomas; viral diseases including acute hepatitis
infection (including hepatitis A, hepatitis B and hepatitis C), HIV
infection and CMV retinitis, AIDS, ARC or malignancy, and herpes;
stroke, myocardial ischemia, ischemia in stroke heart attacks,
organ hyposia, vascular hyperplasia, cardiac and renal reperfusion
injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet
aggregation, endotoxemia and/or toxic shock syndrome, conditions
associated with prostaglandin endoperoxidase syndase-2, and
pemphigus vulgaris. Preferred methods of treatment are those
wherein the condition is selected from Crohns and ulcerative
colitis, allograft rejection, rheumatoid arthritis, psoriasis,
ankylosing spondylitis, psoriatic arthritis, and pemphigus
vulgaris. Alternatively preferred methods of treatment are those
wherein the condition is selected from ischemia reperfusion injury,
including cerebral ischemia reperfusions injury arising from stroke
and cardiac ischemia reperfusion injury arising from myocardial
infarction. Another preferred method of treatment is one in which
the condition is multiple myeloma.
[0185] In addition, the MK2 inhibitors of the present invention
inhibit the expression of inducible pro-inflammatory proteins such
as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to
as cyclooxygenase-2 (COX-2). Accordingly, additional MK2-associated
conditions include edema, analgesia, fever and pain, such as
neuromuscular pain, headache, pain caused by cancer, dental pain
and arthritis pain. The inventive compounds also may be used to
treat veterinary viral infections, such as lentivirus infections,
including, but not limited to equine infectious anemia virus; or
retro virus infections, including feline immunodeficiency virus,
bovine immunodeficiency virus, and canine immunodeficiency
virus.
[0186] When the terms "MK2-associated condition" or "MK2-associated
disease or disorder" are used herein, each is intended to encompass
all of the conditions identified above as if repeated at length, as
well as any other condition that is affected by MK2 kinase
activity.
[0187] The present invention thus provides methods for treating
such conditions, comprising administering to a subject in need
thereof a therapeutically-effective amount of at least one compound
of Formula (I) or a salt thereof. Therapeutically effective amount"
is intended to include an amount of a compound of the present
invention that is effective when administered alone or in
combination to inhibit MK2.
[0188] The methods of treating MK2 kinase-associated conditions may
comprise administering compounds of Formula (I) alone or in
combination with each other and/or other suitable therapeutic
agents useful in treating such conditions. Accordingly,
"therapeutically effective amount" is also intended to include an
amount of the combination of compounds claimed that is effective to
inhibit MK2. The combination of compounds is preferably a
synergistic combination. Synergy, as described, for example, by
Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when
the effect (in this case, inhibition of P2Y.sub.1) of the compounds
when administered in combination is greater than the additive
effect of the compounds when administered alone as a single agent.
In general, a synergistic effect is most clearly demonstrated at
sub-optimal concentrations of the compounds. Synergy can be in
terms of lower cytotoxicity, increased antithrombotic effect, or
some other beneficial effect of the combination compared with the
individual components.
[0189] Exemplary of such other therapeutic agents include
corticosteroids, rolipram, calphostin, cytokine-suppressive
anti-inflammatory drugs (CSAIDs), 4-substituted
imidazo[1,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750;
Interleukin-10, glucocorticoids, salicylates, nitric oxide, and
other immunosuppressants; nuclear translocation inhibitors, such as
deoxyspergualin (DSG); non-steroidal antiinflammatory drugs
(NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such
as prednisone or dexamethasone; antiviral agents such as abacavir;
antiproliferative agents such as methotrexate, leflunomide, FK506
(tacrolimus, Prograf); cytotoxic drugs such as azathiprine and
cyclophosphamide; TNF-.alpha. inhibitors such as tenidap, anti-TNF
antibodies or soluble TNF receptor, and rapamycin (sirolimus or
Rapamune) or derivatives thereof.
[0190] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art. In the methods of the present invention, such
other therapeutic agent(s) may be administered prior to,
simultaneously with, or following the administration of the
inventive compounds. The present invention also provides
pharmaceutical compositions capable of treating MK2
kinase-associated conditions, including IL-1, IL-6, IL-8,
IFN.gamma. and TNF-.alpha.-mediated conditions, as described
above.
[0191] The inventive compositions may contain other therapeutic
agents as described above and may be formulated, for example, by
employing conventional solid or liquid vehicles or diluents, as
well as pharmaceutical additives of a type appropriate to the mode
of desired administration (e.g., excipients, binders,
preservatives, stabilizers, flavors, etc.) according to techniques
such as those well known in the art of pharmaceutical
formulation.
[0192] Accordingly, the present invention further includes
compositions comprising one or more compounds of Formula I and a
pharmaceutically acceptable carrier.
[0193] A "pharmaceutically acceptable carrier" refers to media
generally accepted in the art for the delivery of biologically
active agents to animals, in particular, mammals. Pharmaceutically
acceptable carriers are formulated according to a number of factors
well within the purview of those of ordinary skill in the art.
These include, without limitation: the type and nature of the
active agent being formulated; the subject to which the
agent-containing composition is to be administered; the intended
route of administration of the composition; and, the therapeutic
indication being targeted. Pharmaceutically acceptable carriers
include both aqueous and non-aqueous liquid media, as well as a
variety of solid and semi-solid dosage forms. Such carriers can
include a number of different ingredients and additives in addition
to the active agent, such additional ingredients being included in
the formulation for a variety of reasons, e.g., stabilization of
the active agent, binders, etc., well known to those of ordinary
skill in the art. Descriptions of suitable pharmaceutically
acceptable carriers, and factors involved in their selection, are
found in a variety of readily available sources such as, for
example, Remington's Pharmaceutical Sciences, 17th ed., 1985, which
is incorporated herein by reference in its entirety.
[0194] The compounds of Formula (I) may be administered by any
means suitable for the condition to be treated, which may depend on
the need for site-specific treatment or quantity of drug to be
delivered. Topical administration is generally preferred for
skin-related diseases, and systematic treatment preferred for
cancerous or pre-cancerous conditions, although other modes of
delivery are contemplated. For example, the compounds may be
delivered orally, such as in the form of tablets, capsules,
granules, powders, or liquid formulations including syrups;
topically, such as in the form of solutions, suspensions, gels or
ointments; sublingually; bucally; parenterally, such as by
subcutaneous, intravenous, intramuscular or intrasternal injection
or infusion techniques (e.g., as sterile injectable aq. or non-aq.
solutions or suspensions); nasally such as by inhalation spray;
topically, such as in the form of a cream or ointment; rectally
such as in the form of suppositories; or liposomally. Dosage unit
formulations containing non-toxic, pharmaceutically acceptable
vehicles or diluents may be administered. The compounds may be
administered in a form suitable for immediate release or extended
release. Immediate release or extended release may be achieved with
suitable pharmaceutical compositions or, particularly in the case
of extended release, with devices such as subcutaneous implants or
osmotic pumps.
[0195] Exemplary compositions for topical administration include a
topical carrier such as PLASTIBASE.RTM. (mineral oil gelled with
polyethylene).
[0196] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may also be orally
delivered by sublingual and/or buccal administration, e.g., with
molded, compressed, or freeze-dried tablets. Exemplary compositions
may include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
GANTREZ.RTM.); and agents to control release such as polyacrylic
copolymer (e.g., CARBOPOL 934.RTM.). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0197] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0198] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0199] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0200] The therapeutically-effective amount of a compound of the
present invention may be determined by one of ordinary skill in the
art, and includes exemplary dosage amounts for a mammal of from
about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg;
250-1000 mg/kg of body weight of active compound per day, which may
be administered in a single dose or in the form of individual
divided doses, such as from 1 to 4 times per day. It will be
understood that the specific dose level and frequency of dosage for
any particular subject may be varied and will depend upon a variety
of factors, including the activity of the specific compound
employed, the metabolic stability and length of action of that
compound, the species, age, body weight, general health, sex and
diet of the subject, the mode and time of administration, rate of
excretion, drug combination, and severity of the particular
condition. Preferred subjects for treatment include animals, most
preferably mammalian species such as humans, and domestic animals
such as dogs, cats, horses, and the like. Thus, when the term
"patient" is used herein, this term is intended to include all
subjects, most preferably mammalian species, that are affected by
mediation of MK2 enzyme levels.
[0201] Examples of formula (I) as specified in the "Examples"
section below, have been tested in one or more of the assays
described below and have activity as inhibitors of MK2 enzymes at
an IC.sub.50 of less than 30 .mu.M and preferably less than 10
.mu.M; and inhibit TNF-.alpha. at an IC.sub.50 of less than 100
.mu.M and preferably less than 30 .mu.M.
Biological Assays
Generation of Activated MK2 Kinase
[0202] DNA oligonucleotide PCR primers were synthesized and used to
amplify from template DNA the MK2 DNA sequence (NCBI Refseq
NM.sub.--032960.2) encoding native amino acid residues 47-400. The
PCR primers were designed such that the amplified DNA also encoded
an N-terminal (His)-.sub.6-affinity purification tag followed by a
thrombin-cleavable linker. This amplified product was inserted into
the pET28N vector. E. coli strain BL21(DE3) was transformed with
the MK2(47-400)-pET28N plasmid and cultured at 37.degree. C. in a
defined medium. IPTG (0.5 mM) was added to the medium to induce
recombinant protein expression at 20.degree. C. for 18 hours. The
cell paste was harvested by sedimentation and frozen at -80.degree.
C.
[0203] Frozen cell paste was thawed and lysed in buffer at
4.degree. C. using a microfluidizer. The MK2 protein was purified
by sequential chromatography on columns of SP-Sepharose Fast Flow
and Ni-NTA Superflow. The N-terminal (His).sub.6-tag was removed
from the purified MK2 protein by digestion with thrombin followed
by sequential benzamidine-Sepharose and Superdex 200 size exclusion
chromatography.
[0204] MK2(47-400) was dialyzed and diluted into a final reaction
buffer of 0.5 mg/ml MK2(47-400) in 20 mM HEPES pH 7.5, 5% glycerol,
2 mM DTT, 20 mM MgCl.sub.2, 1 mM ATP, and 8 .mu.g/ml activated
(His).sub.5-p38alpha. The reaction was incubated at 25.degree. C.
for 1 hour, after which an additional 1 mM fresh ATP was added.
After an additional 30 minute incubation at 25.degree. C. the
reaction was stopped by placing it on ice and adding NaCl and EDTA
to 200 mM and 30 mM, respectively.
[0205] The protein in the activation reaction was concentrated,
filtered, and buffer exchanged into 25 mM HEPES pH 7.2, 400 mM
NaCl, 20 mM imidazole, 5% glycerol, 10 mM 2-mercaptoethanol, 0.5 mM
TCEP. The void volume peak from this column was concentrated and
loaded onto a Ni-NTA column to capture the (His).sub.5-p38 protein.
The activated MK2(47-400) protein was not retained and eluted in
the flow-through fractions. Fractions containing activated
MK2(47-400) were pooled, supplemented with 10 mM EDTA,
concentrated, and loaded onto a Superdex 200 column equilibrated
with 20 mM HEPES pH 7.5, 100 mM NaCl, 10% (v/v) glycerol, 0.1 mM
EDTA, 2 mM DTT). The activated MK2(47-400) protein eluted as a
single, large peak, and fractions from the center of this peak were
pooled, divided into aliquots, and frozen at -80.degree. C.
MK2 Assay
[0206] The MK2 radioactive assay was performed in a 96 well round
bottom non-binding polystyrene plates (Corning 3605). The final
assay volume was 30 .mu.l prepared from three 10 .mu.l additions of
enzyme, substrates (HSP-27 and ATP) and test compounds in assay
buffer (20 mM HEPES pH 7.5, 25 mM .beta.-glycerolphosphate, 15 mM
MgCl.sub.2, 1 mM DTT). The reaction was incubated at RT for 30 min.
and terminated by adding 20 .mu.l of 0.5 M EDTA to each sample.
Then 40 .mu.l of the reaction mixture was transferred onto a
pre-wet (2% phosphoric acid) Millipore Multiscreen phosphocellulose
filter plate (MAPHNOB 50). This reaction mixture was filtered
through a Millipore multiscreen resist vacuum manifold. The
filterplate was washed 3.times. with 2% phosphoric acid and air
dried. The filterplate is put into a Packard multiscreen adapter
plate. 50 .mu.l of Microscint 20 was added to each well and sealed
with a plate sealer and counted on the Packard Top Count NXT
Inhibition data were analyzed in ABASE using excel fit. The final
concentration of reagents in the assay are 5 .mu.M ATP; 10
.mu.Ci/.mu.l [.gamma.-.sup.33P]ATP, 5 ng MK2 enzyme, 30 .mu.M
HSP-27 and DMSO, 0.3% for screening.
[0207] The Molecular Devices IMAP MAPKAP K2 Assay Kit is performed
in a HE black microplate (Molecular Devices 75-000-005). The final
assay volume is 10 .mu.l prepared from 2.5 .mu.l compound, 5 .mu.l
ATP/Peptide and 2.5 .mu.l MK2 enzyme. The final concentration of
reagents in the assay are 1 .mu.M ATP, 200 n Peptide and 0.070 nM
MK2 enzyme (note: The MK2 enzyme concentration should produce
approximately 70% of the maximal signal of 380 mP=/-40 mP). Prepare
a 1.times. complete reaction buffer (CRB) using distilled water
from a 5.times. stock and add DTT to a 1 mM final concentration.
The CRB is used for the initial reaction preparation. Incubate the
reaction covered in foil at room temperature for 30 minutes.
Prepare 1.times. Buffer A using distilled water from the 5.times.
Buffer A stock. Add IMAP reagent by diluting 400 times into Buffer
A. Add 30 uL of IMAP reagent in buffer to each well. Incubate for
30 minutes at RT covered in foil. Read on LJL analyst using 485
excitation 530 emission.
[0208] Caliper LabChip 3000 Assay is performed in U-bottom 384-well
plates. The final assay volume is 30 .mu.l prepared from 15 .mu.l
additions of enzyme and substrates (MK2 peptide and ATP) and test
compounds in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCl.sub.2,
0.015% Brij35 and 4 mM DTT). The reaction is initiated by the
combination of MapKapK2 with substrates and test compounds. The
reaction is incubated at room temperature for 60 min. and
terminated by adding 30 .mu.l of 35 mM EDTA to each sample. The
reaction mixture is analyzed on the Caliper LabChip 3000 by
electrophoretic separation of the fluorescent substrate and
phosphorylated product Inhibition data were calculated by
comparison to no enzyme control reactions for 100% inhibition and
vehicle-only reactions for 0% inhibition. The final concentration
of reagents in the assays are ATP, 1 .mu.M; MK2 peptide, 1.5 uM;
MapKapK2, 0.08 nM; Brij35, 0.015% and DMSO, 1.6%. Dose response
curves are generated to determine the concentration required
inhibiting 50% of kinase activity (IC.sub.50). Compounds are
dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at
eleven concentrations, each in duplicate. IC.sub.50 values are
derived by non-linear regression analysis.
TNF-.alpha. Production by LPS-Stimulated PBMCs
[0209] EDTA-treated human whole blood was obtained from healthy
volunteers. Peripheral blood mononuclear cells (PBMCs) were
purified from human whole blood by Ficoll-Hypaque density gradient
centrifugation (Lympho Separation Media Cellgro #25-072-CV) and
resuspended at a concentration of 2.5.times.10.sup.6/ml in assay
medium (RPMI medium containing 10% fetal bovine serum). 100 ul of
cell suspension was incubated with 50 ul of test compound (4.times.
concentration in assay medium containing 0.3% DMSO) in 96-well
tissue culture plates for 1 hour at 37.degree. C. 50 ul of LPS (400
ng/ml stock) was then added to the cell suspension yielding a 100
ng/ml final concentration of LPS and the plate was incubated for 5
hours at 37.degree. C. Following incubation, the culture medium was
collected and assayed. TNF-.alpha. concentration in the medium was
quantified using a standard ELISA kit (R&D Systems Cat#DY210).
Concentrations of TNF-.alpha. and IC.sub.50 values for test
compounds (concentration of compound that inhibited LPS-stimulated
TNF-.alpha. production by 50%) were calculated using softmax
software using a 4-parameter curve fit.
EXAMPLES
[0210] The following Examples illustrate embodiments of the
inventive compounds and starting materials, and are not intended to
limit the scope of the claims. For ease of reference, the following
abbreviations are used herein:
ABBREVIATIONS
[0211] BOC=tert-butoxycarbonyl bp=boiling point Bu=butyl
DMAP=4-dimethylaminopyridine
DIPEA or DIEA=N,N-diisopropylethylamine
[0212] DME=1,2-dimethoxyethane DMF=dimethyl formamide
EDCI=1-3-dimethylaminopropyl)-3-ethylcarbodiimide Et=ethyl
Et.sub.2O=diethyl ether HOBT=1-hydroxybenzotriazole EtOAc=ethyl
acetate EtOH=ethanol g=gram(s) H=hydrogen l=liter mCPBA--meta
chloro perbenzoic acid Me=methyl MeCN=acetonitrile MeOH=methanol
NMP=1-methyl-2-pyrrolidinone Ph=phenyl Pr=propyl PS=polystyrene
TEA=triethylamine TFA=trifluoroacetic acid mg=milligram(s) ml or
mL=milliliter .mu.l=microliter mmol=millimole .mu.mol=micromole
mol=mole mp=melting point RT=room temperature HPLC=high pressure
liquid chromatography LC/MS=liquid chromatography/mass
spectrometry
Example I(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-[4-(ethyloxy)phenyl]imidazo[1,2--
b]pyridazine-6,8-diamine
##STR00044##
[0214] (1a) Bromine (9.71 g, 3.15 mL, 60.75 mmol) was added
dropwise to a mixture of 3-amino-6-chloropyridazine (7.87 g, 60.75
mmol) in methanol (115 mL) and sodium bicarbonate (10.22 g, 121.67
mmol). The resultant mixture was stirred at room temperature for 16
hours and then filtered. Water (500 mL) was added to the filtrate
and the solution was extracted with ethyl acetate (3.times.500 mL).
The organic layers were combined and concentrated in vacuo. The
resulting residue was purified by flash chromatography eluting with
1/1 hexane/ethyl acetate to give 5.40 g (43%)
3-amino-4-bromo-6-chloropyridazine.
[0215] (1b) Chloroacetaldehyde solution (50% in water, 13.2 mL,
16.32 g, 104.6 mmol) was added to
3-amino-4-bromo-6-chloropyridazine (4.2 g, 20.2 mmol) from 1a in
ethanol (28 mL). The solution was heated to 50.degree. C. for 16
hours and then concentrated in vacuo. Acetone (22 mL) was added to
the residue and the solid was collected by vacuum filtration and
washed with cold acetone. Upon air drying 4.3 g (79%) of
8-bromo-6-chloroimidazo[1,2-b]pyridazine was obtained as a
hydrochloride salt.
[0216] (1c variation 1) To a mixture of
8-bromo-6-chloroimidazo[1,2-b]pyridazine (257 mg, 0.956 mmol) from
1b in THF (2.0 ml) was added p-phenetidine (131 mg, 0.956 mmol) and
a 1.0 M solution of KOt-Bu in THF (2.5 eq, 2.4 ml, 2.39 mmol). The
mixture was allowed to heat at 50.degree. C. for 1 hour. The
solution was then concentrated in vacuo to provide crude
6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine as a
solid. The solid was then used as is in the following step.
[0217] (1c variation 2) p-Phenetidine (1.0 eq, 0.149 mmol) and
triethyamine (33 mg, 0.327 mmol) were added to a mixture of
8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride (40 mg,
0.149 mmol) from 1b in EtOH (1.5 mL). The mixture was heated to
90.degree. C. and stirred for 24-48 hours. The solution was then
concentrated in vacuo to give crude
6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
[0218] (1d) trans-1,4-Diaminocyclohexane (1000 mg, 8.77 mmol) was
added to the crude
6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (0.149
mmol) from 1c. The mixture was heated to 160.degree. C. and allowed
to melt. After stirring at 160.degree. C. for 24-48 hrs, the liquid
mixture was cooled to room temperature. Water was added, followed
by extraction with dichloromethane. The organic layer was
concentrated in vacuo. The resulting residue was purified by
reverse phase preparative HPLC to provide the above titled compound
as a TFA salt in approximately 35% yield. .sup.1H NMR (400 MHz,
MeOH) .delta. ppm 7.59 (1H, s), 7.29 (1H, s), 7.23 (2H, d, J=8.8
Hz), 6.95 (2H, d, J=8.8 Hz), 5.85 (1H, s), 4.04 (2H, q, J=7 Hz),
3.51-3.61 (1H, m), 2.65-2.73 (1H, m), 2.10 (2H, d, J=12.30 Hz),
1.92 (2H, d, J=12.30 Hz), 1.38 (3H, t, J=7 Hz), 1.20-1.33 (4H, m).
LC/MS, m/e 367 (M+1). HPLC Rt, 2.11 min. YMC ODSC18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
[0219] Examples prepared in a similar manner are indicated in Table
1.
[0220] Alternatively, Example I(1) may also be prepared by the
following method.
[0221] (1e) To perchloroimidazo[1,2-b]pyridazine (Synthesis 1971,
8, 424) (213 mg, 0.731 mmol) in EtOH (5 mL) was added p-phenetidine
(100 mg, 0.731 mmol) and triethyamine (86 mg, 0.804 mmol). The
mixture was allowed to heat at 90.degree. C. for 5 hours. The
solution was then cooled to 0.degree. C. The resulting solid was
collected by vacuum filtration and washed with cold EtOH. Upon air
drying 191 mg (67%) of crude
2,3,6,7-tetrachloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
was isolated.
[0222] (1f) To
2,3,6,7-tetrachloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
(184 mg, 0.47 mmol) from 1e was added trans-1,4-diaminocyclohexane
(360 mg, 3.16 mmol). The mixture was allowed to melt at 120.degree.
C. for 11/2 hours. The melt was then cooled, diluted with water and
extracted with ethyl acetate. The organic layer was then
concentrated in vacuo to give 200 mg (91%) of crude product. 20 mg
of this product was then purified by preparative HPLC. This gave
8.0 mg of
N.sup.6-(4-aminocyclohexyl)-2,3,7-trichloro-N.sup.8-(4-ethoxyphenyl)imida-
zo[1,2-b]pyridazine-6,8-diamine as a TFA salt.
[0223] (1g) To a mixture of crude
N.sup.6-(4-aminocyclohexyl)-2,3,7-trichloro-N.sup.8-(4-ethoxyphenyl)imida-
zo[1,2-b]pyridazine-6,8-diamine from 1f as a free base (140 mg,
0.300 mmol) in EtOH (10 ml) in a 500 ml PARR bottle was added 10%
Palladium on carbon (175 mg). The PARR bottle was then charged with
H.sub.2 at 55 psi and allow to shake at room temperature for 24
hours. The catalyst was then filtered and the filtrate was
concentrated in vacuo to give a crude mixture of 3 compounds. This
mixture was purified by preparative HPLC to give 4.7 mg of Example
I(1),
N.sup.6-(4-aminocyclohexyl)-N.sup.8-(4-ethoxyphenyl)imidazo[1,2-b]pyridaz-
ine-6,8-diamine as a TFA salt, LC/MS, m/e 367 (M+1). 9.0 mg of
N.sup.6-(4-aminocyclohexyl)-3-chloro-N.sup.8-(4-ethoxyphenyl)imidazo[1,2--
b]pyridazine-6,8-diamine, LC/MS, m/e 401 (M+1) and 18.5 mg of
N.sup.6-(4-aminocyclohexyl)-2,3-dichloro-N.sup.8-(4-ethoxyphenyl)imidazo[-
1,2-b]pyridazine-6,8-diamine, LC/MS, m/e 435 (M+1).
##STR00045##
[0224] Compounds having the formula (Ia) were prepared according to
procedures similar to Example I(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 1, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00001 TABLE 1 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) I(2) N.sup.6-(2-aminoethyl)-N.sup.8-(4-
(ethyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00046## NH--(CH.sub.2).sub.2--NH.sub.2 313 I(3)
N.sup.6-(4-aminobutyl)-N.sup.8-(4- (ethyloxy)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00047##
NH--(CH.sub.2).sub.4--NH.sub.2 341 I(4) 7-chloro-N-(4-
(ethyloxy)phenyl)-6-(1- piperazinyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H Cl ##STR00048## ##STR00049## 373 I(5)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
(methyloxy)phenyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00050## ##STR00051## 353 I(6)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
(ethyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00052## ##STR00053## 367 I(7)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-phenylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00054## ##STR00055## 323 I(8)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
(methyloxy)phenyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00056## ##STR00057## 353 I(9)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3,4-
dimethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00058## ##STR00059## 351 I(10)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
(phenyloxy)phenyl(imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00060## ##STR00061## 415 I(11)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
(butyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00062## ##STR00063## 395 I(12)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-4-biphenylylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00064## ##STR00065## 399 I(13)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00066## ##STR00067## 339 I(14)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3,4-
bis(methyloxy)phenyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00068## ##STR00069## 383 I(15)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
((phenylmethyl)oxy)phenyl) imidazo[1,2-b]pyridazine-6,8- diamine H
H H ##STR00070## ##STR00071## 429 I(16)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
(propyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00072## ##STR00073## 387 I(17)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-pyridin-3-ylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00074## ##STR00075## 324 I(18)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-methyl-1H-indol-5-
yl)imidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00076##
##STR00077## 376 I(19) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-methyl-N.sup.8- phenylimidazo]1,2- b]pyridazine-6,8-diamine
H H H ##STR00078## ##STR00079## 337 I(20)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-[2-
(methyloxy)phenyl]imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00080## ##STR00081## 353 I(21)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2,3-
dimethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00082## ##STR00083## 351 I(22)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2,4-
dimethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00084## ##STR00085## 351 I(23)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2,5-
dimethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00086## ##STR00087## 351 I(24)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00088## ##STR00089## 337 I(25)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3,5-
dimethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00090## ##STR00091## 351 I(26)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-[3-
(dimethylamino)phenyl]imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00092## ##STR00093## 366 I(27)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(2-methyl-1,3-benzothiazol- 6-yl)imidazo[1,2-b]pyridazine-
6,8-diamine H H H ##STR00094## ##STR00095## 394 I(28)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(2-methyl-1,3-benzothiazol- 5-yl)imidazo[1,2-b]pyridazine-
6,8-diamine H H H ##STR00096## ##STR00097## 394 I(29)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-cyclopropylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00098## ##STR00099## 287 I(30)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-cyclohexylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00100## ##STR00101## 329 I(31)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(cyclohexylmethyl)imidazo[1,2- b]pyridazine-6,8-diamine H H
H ##STR00102## ##STR00103## 393 I(32)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(1-methylethyl)imidazo[1,2- b]pyridazine H H H ##STR00104##
##STR00105## 289 I(33) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(phenylmethyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00106## ##STR00107## 337 I(34)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-[(2-
chlorophenyl)methyl]imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00108## ##STR00109## 371 I(35)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-((4-
chlorophenyl)methyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00110## ##STR00111## 371 I(36)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-((4-
(methyloxy)phenyl)methyl) imidazao[1,2-b]pyridazine-6,8- diamine H
H H ##STR00112## ##STR00113## 367 I(37)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-ethylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00114## ##STR00115## 275 I(38)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-
(methyloxy)ethyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00116## ##STR00117## 305 I(39)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-(4-
(methyloxy)phenyl)ethyl) imidazao[1,2-b]pyridazine-6,8- diamine H H
H ##STR00118## ##STR00119## 381 I(40)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-2-propen-1-ylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00120## ##STR00121## 287 I(41)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
methylbutyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00122## ##STR00123## 317 I(42)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-propylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00124## ##STR00125## 289 I(43)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-
(cyclopropylmethyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00126## ##STR00127## 301 I(44)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-((3-
chlorophenyl)methyl)imidazo [1,2-b]pyridazin-6,8-diamine H H H
##STR00128## ##STR00129## 371 I(46)
N.sup.6-(3-aminopropyl)-N.sup.8-(4- (ethyloxy)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00130## ##STR00131## 327 I(48)
N.sup.6-(4-((4- aminocyclohexyl)methyl)cyclo- hexyl)-N.sup.8-(4-
(ethyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00132## ##STR00133## 463 I(49) 2-(1-(8-((4-
(ethyloxy)phenyl)amino)imidazo [1,2-b]pyridazin-6-yl)-4-
piperidinyl)ethanol H H H ##STR00134## ##STR00135## 382 I(50)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-1H-indol-5-ylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00136## ##STR00137## 363 I(51)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-
(ethyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00138## ##STR00139## 368 I(52) 6-(3-amino-1-pyrrolidinyl)-N-
(4- (ethyloxy)phenyl)imidazo[1,2- b]pyridazine-8-amine H H H
##STR00140## ##STR00141## 339 I(53)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(2-phenylethyl)aimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00142## ##STR00143## 351 I(54) N-(4-(ethyloxy)phenyl)-6-(1-
piperazinyl)imidazo[1,2- b]pyridazine-8-amine H H H ##STR00144##
##STR00145## 339 I(55) N.sup.6-(2-(dimethylamino)ethyl)-
N.sup.8-(4- (ethyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine
H H H ##STR00146## ##STR00147## 341 I(56)
N.sup.8-(4-(ethyloxy)phenyl)-N.sup.6-(2- furanylmethyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00148## ##STR00149## 350 I(57)
N-(4-(ethyloxy)phenyl)-6-(4- methyl-1,4-diazepan-1-
yl)imidazo[1,2-b]pyridazin-8- amine H H H ##STR00150## ##STR00151##
368 I(58) 2-((6-((trans-4- aminocyclohexyl)amino)imidazo
[1,2-b]pyridazin-8- yl)amino)phenol H H H ##STR00152## ##STR00153##
339 I(59) N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
((phenylmethyl)oxy)phenyl) imidazo[1,2-b]pyridazine-6,8- diamine H
H H ##STR00154## ##STR00155## 430 I(60) 3-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)phenol H
H H ##STR00156## ##STR00157## 339 I(61) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)phenol H
H H ##STR00158## ##STR00159## 339 I(62) N.sup.6-(trans-4-
aminocyclohexyl)aimidazo[1,2- b]pyridazine-6,8-diamine H H H NH2
##STR00160## 247 I(63) 3-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzonitrile H H H ##STR00161## ##STR00162## 348 I(64)
4-((6-((trans-4- aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzonitrile H H H ##STR00163## ##STR00164## 348 I(65)
3-((6-((trans-4- aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzoic acid H H H ##STR00165## ##STR00166## 367 I(66)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-1H-pyrazol-3-
ylimidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00167##
##STR00168## 313 I(67) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)benzoic
acid H H H ##STR00169## ##STR00170## 367 I(68) 4-((6-trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino-N,N-
dimethylbenzenesulfonamide H H H ##STR00171## ##STR00172## 431
I(69) N.sup.6-(trans-4-aminocyclohexyl)- M.sup.8-(4-(1H-tetrazol-5-
yl)phenyl)imidazo[1,2- b]pyridazin-6,8-diamine H H H ##STR00173##
##STR00174## 391 I(70) N.sup.6-(trans-4-
(ethylamino)cyclohexyl)-N.sup.8-
phenylimidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00175##
##STR00176## 351 I(71) N.sup.6-(trans-4-
(methylamino)cyclohexyl)-N.sup.8- phenylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00177## ##STR00178## 337 I(72)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-
(phenyloxy)phenyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00179## ##STR00180## 416 I(73)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4'-chloro-4-
biphenylyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00181##
##STR00182## 434 I(74) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(2'-methyl-4- biphenylyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00183## ##STR00184## 414 I(75)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3'-chloro-4-
biphenylyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00185##
##STR00186## 434 I(76) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4- (phenylmethyl)phenyl)imidazo
[1,2-b]pyridazine-6,8-diamine H H H ##STR00187## ##STR00188## 414
I(77) N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(4-
morpholinyl)phenyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00189## ##STR00190## 409 I(78)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3'-chloro-3-
biphenylyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00191##
##STR00192## 434 I(79) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-(1- methylethyl)phenyl)imidazo[1,
2-b]pyridazine-6,8-diamine H H H ##STR00193## ##STR00194## 366
I(80) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-butylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00195## ##STR00196## 380 I(81)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(5,6,7,8-tetrahydro-1-
naphthalenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00197## ##STR00198## 378 I(82)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-1-naphthalenylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00199## ##STR00200## 374 I(83)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
(phenylethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00201## ##STR00202## 414 I(84)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
propylaphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00203## ##STR00204## 366 I(85)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4'-methyl-4-
biphenylyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00205##
##STR00206## 414 I(86) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(3-(1- methylethyl)phenyl)imidazo[1,
2-b]pyridazine-6,8-diamine H H H ##STR00207## ##STR00208## 366
I(87) N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-((1-
methylethyl)oxy)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00209## ##STR00210## 382 I(88)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3,5-
bis(methyloxy)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00211## ##STR00212## 384 I(89) trans-N-(8-(6-methyl-3,4-
dihydro-1(2H)- quinolinyl)imidazo[1,2- b]pyridazin-6-yl)-1,4-
cyclohexanediamine H H H ##STR00213## ##STR00214## 378 I(90)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-2-naphthalenylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00215## ##STR00216## 374 I(91)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
(methylsulfanyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00217## ##STR00218## 370 I(92)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(3-ethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00219## ##STR00220## 352 I(93)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-ethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00221## ##STR00222## 352 I(94)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
(methylsulfanyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00223## ##STR00224## 370 I(95)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-9H-fluoren-2-
ylimidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00225##
##STR00226## 412 I(96) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(2-ethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00227## ##STR00228## 352 I(97)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
dimethylethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00229## ##STR00230## 406 I(98)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(1,1-
dimethylethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00231## ##STR00232## 380 I(99)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
(phenyloxy)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00233## ##STR00234## 416 I(100)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-3-biphenylylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00235## ##STR00236## 400 I(101)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-((1-
methylethyl)oxy)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00237## ##STR00238## 382 I(102)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-
chlorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00239## ##STR00240## 358 I(103)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
chlorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00241## ##STR00242## 358 I(104)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
chlorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00243## ##STR00244## 358 I(105)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-chloro-1-
naphthalenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00245## ##STR00246## 408 I(106)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-3-quinolinylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00247## ##STR00248## 375 I(107)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3,5-
dichlorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00249## ##STR00250## 392 I(108)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
(trifluoromethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00251## ##STR00252## 391 I(109)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-chloro-2-
fluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00253## ##STR00254## 376 I(110)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-fluoro-5-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00255## ##STR00256## 355 I(111)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-chloro-3-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00257## ##STR00258## 372 I(112)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(5-phenyl-2-
pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00259##
##STR00260## 401 I(113) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(3-fluoro-4- methylphenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00261## ##STR00262## 355 I(114)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-methyl-4-
pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00263##
##STR00264## 338 I(115) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-fluoro-3- methylphenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00265## ##STR00266## 355 I(116)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2-fluoro-4-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00267## ##STR00268## 355 I(117)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-
((trifluoromethuyl)oxy)phenyl) imidazo[1,2-b]pyridazine-6,8-
diamine H H H ##STR00269## ##STR00270## 407 I(118)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-methyl-3-
(trifluoromethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00271## ##STR00272## 405 I(119)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-ethyl-2-
pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00273##
##STR00274## 353 I(120) N.sup.6-(trans-4-methylcyclohexyl)-
N.sup.8-(4-(1H-1,2,4-triazol-1- yl)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00275## ##STR00276## 390 I(121)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(1H-pyrrol-1-
yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00277##
##STR00278## 389 I(122) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-(4,5-dichloro-1H- imidazol-1- yl)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00279## ##STR00280## 458 I(123)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(1H-pyrazol-1-
yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00281##
##STR00282## 390 I(124) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-(3,5-dimethyl-1H- pyrazol-1- yl)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00283## ##STR00284## 418 I(125)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(4-methyl-4H-1,2,4-
triazol-3- yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00285## ##STR00286## 405 I(126)
N.sup.6-(trans-4-aminocyclohexyl)- M.sup.8-(4-(1H-imidazol-1-
yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00287##
##STR00288## 390 I(127) N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-(1-methyl-1H-imidazol- 2-yl)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00289## ##STR00290## 404 I(128)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-(2-methyl-1,3-thiazol-4- yl)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00291## ##STR00292## 421 I(129)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(5-methyl-2-
furanyl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00293## ##STR00294## 404 I(130)
N.sup.6-(trans-4-aminocyclohexyl)-
N.sup.8-(4-(2-ethyl-2H-tetrazol-5- yl)phenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00295## ##STR00296## 420 I(131)
4-((6-trans-4- aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)-3-hydroxy-N,N- dimethylbenzenesulfonamide H H H
##STR00297## ##STR00298## 447 I(132)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(2,3-dihydro-1H-inden-5-
yl)imidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00299##
##STR00300## 364 I(133) 3-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)-N,N-
dimethylbenzenesulfonamide H H H ##STR00301##
##STR00302## 431 I(134) 4-((6-trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)-N,N-
dimethylbenzamide H H H ##STR00303## ##STR00304## 395 I(135)
N.sup.6-(trans-4-((2-chloro-4- pyrimidinyl)amino)cyclohexyl)-
N.sup.8-phenylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00305## ##STR00306## 436 I(136)
N.sup.6-(3-aminocyclopentyl)-N.sup.8- phenylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00307## ##STR00308## 309 I(137)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(3-(4-
morpholinylsulfonyl)phenyl) imidazo[1,2-b]pyridazine-6,8- diamine H
H H ##STR00309## ##STR00310## 473 I(138) 3-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)-N,N-
diethylbenzamide H H H ##STR00311## ##STR00312## 423 I(139)
3-((6-((trans-4- aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)-N-methyl-N- phenylbenzenesulfonamide H H H ##STR00313##
##STR00314## 493 I(140) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)-2-hydroxy-N,N- dimethylbenznesulfonamide H H H
##STR00315## ##STR00316## 447 I(141)
N.sup.6-(4-aminobicyclo[2.2.2]oct- 1-yl)-N.sup.8-phenylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00317## ##STR00318## 349 I(42)
N-(4-((6-((trans-4- aminocyclohexyl)amino)imidazo
[1,2-b]pyridazin-8- yl)amino)phenyl)methanesul- fonamide H H H
##STR00319## ##STR00320## 417 I(143)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(3-(dimethylamino)-1-
pyrrolidinyl)phenyl)imidazo[1, 2-b]pyridazine-6,8-diamine H H H
##STR00321## ##STR00322## 436 I(144)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-(1-
pyrrolidinylsulfonyl)phenyl) imidazo[1,2-b]pyridazine-6,8- diamine
H H H ##STR00323## ##STR00324## 457 I(145) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzenesulfonic acid H H H ##STR00325## ##STR00326## 403
I(146) 4-((6-((trans-4- aminocyclohexyl)amino)imidazo
[1,2-b]pyridazin-8- yl)amino)-N,N- diethylbenzenesulfonamide H H H
##STR00327## ##STR00328## 459 I(147) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)-N-
propylbenzenesulfonamide H H H ##STR00329## ##STR00330## 445 I(148)
4-((6-((trans-4- aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)-N- ethylbenzenesulfonamide H H H ##STR00331##
##STR00332## 431 I(149) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8- yl)amino)-N-
methylbenzenesulfonamide H H H ##STR00333## ##STR00334## 417 I(150)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
aminophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00335## ##STR00336## 338 I(151) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzenesulfonamide H H H ##STR00337## ##STR00338## 402
I(152) 3-((6-((trans-4- aminocyclohexyl)amino)imidazo
[1,2-b]pyridazin-8- yl)amino)benzenesulfonamide H H H ##STR00339##
##STR00340## 402 I(153) 3-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzamide H H H ##STR00341## ##STR00342## 366 I(154)
4-((6-((trans-4- aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)benzamide H H H ##STR00343## ##STR00344## 366 I(155)
N.sup.6-(trans-4-aminocyclohexyl)- N.sup.8-(4-
(aminomethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00345## ##STR00346## 352 I(156) 6-((6-((trans-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-
yl)amino)-1,2-dihydro-3H- indazol-3-one H H H ##STR00347##
##STR00348## 379 I(157) N.sup.8-(trans-4-aminocyclohexyl)-
N.sup.8-(3- (aminomethyl)phenyl)imidazo
[1,2-b]pyridazine-6,8-diamine H H H ##STR00349## ##STR00350## 352
I(158) N.sup.6-(4-Aminocyclohexyl)-N.sup.8- phenylimidazo[1,2-
b]pyridazine-6,8-diamine (3:1 cis:trans mixture) H H H ##STR00351##
##STR00352## 323 I(159) N.sup.6-(trans-4-Aminocyclohexyl)-
N.sup.8-2-quinolinylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00353## ##STR00354## 374 I(160)
N.sup.6-(trans-4-Aminocyclohexyl)-
N.sup.8-1-isoquinolinylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00355## ##STR00356## 374 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example II(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(2,6-difluorophenyl)imidazo[1,2--
b]pyridazine-6,8-diamine
##STR00357##
[0226] (1a) To 60% NaH (22.5 mg, 0.563 mmol) in DMF (400 n1) was
added 2,6-difluoroaniline (24 mg, 0.186 mmol). After stirring at RT
for 5 minutes THF (1000 .mu.l) was added followed by
8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.186 mmol,
prepared as described in Example 1, step (1b). The reaction was
heated at 50.degree. C. for 3 hours. The reaction was quenched with
a few drops of water and methanol. The solution was then
concentrated in vacuo to give crude
6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine.
[0227] (1b) To crude
6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine
(0.186 mmol) from 1a was added trans-1,4-diaminocyclohexane (1000
mg, 8.77 mmol). The mixture was allowed to melt at 160.degree. C.
for 24 hrs. The melt was then cooled, water was added, followed by
extraction with dichloromethane. The organic layer was then
concentrated in vacuo and the resulting residue purified by reverse
phase preparative HPLC to provide 50.6 mg (46%) of the titled
compound as a TFA salt. LC/MS, m/e 359 (M+1). HPLC Rt, 1.7 min. YMC
ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH,
10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1%
TFA). Gradient, start % B=0, final % B=100, gradient time 4 min,
hold at 100% B 1 min, flow rate 4 mL/min. Examples prepared in a
similar manner are indicated in Table 2.
[0228] Compounds having the formula (Ia) were prepared according to
procedures similar to Example II(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 2, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00002 TABLE 2 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) II(2) N.sup.6-(trans-4-aminocyclohexyl)-7-
chloro-N.sup.8-[4- (ethyloxy)phenyl]imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00358## ##STR00359## 375 II(3)
N.sup.6-(3-aminopropyl)-N.sup.8-[4- (ethyloxy)phenyl]imidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00360## ##STR00361## 385 II(4)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(2-
fluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00362## ##STR00363## 341 II(6)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-
(2,4-difluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00364## ##STR00365## 359 II(7)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(3-
fluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00366## ##STR00367## 341 II(8)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-
fluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00368## ##STR00369## 341 II(9)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-
(3,4-difluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00370## ##STR00371## 359 II(10)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-
(2,5-difluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00372## ##STR00373## 359 II(11)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-
(2,3-difluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00374## ##STR00375## 359 II(12)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-
(3,5-difluorophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00376## ##STR00377## 359 II(13)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(3-
iodophenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00378##
##STR00379## 449 II(14)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-[4-
(trifluoromethyl)phenyl]imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00380## ##STR00381## 391 II(15)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8- pyridin-2-ylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00382## ##STR00383## 324 II(16)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-
methylpyridin-2-yl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00384## ##STR00385## 338 II(17)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(5-
methylpyridin-2-yl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00386## ##STR00387## 338 II(18)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8- (4,6-dimethylpyridin-2-
yl)imidazo[1,2-b]pyridazine-6,8- diamine H H H ##STR00388##
##STR00389## 352 II(19) N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-
pyrimidin-2-ylimidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00390## ##STR00391## 325 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example III(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-[4-(ethyloxy)phenyl]-7-methylimi-
dazo[1,2-b]pyridazine-6,8-diamine
##STR00392##
[0230] (1a) 3,6-Dichloro-4-methyl pyridizine (4.2 g, 26 mmol, Alfa)
was suspended in aqueous 28% NH.sub.4OH (14 mL) in a sealed
microwave tube and heated at 155.degree. C. for 1.5 h. The
microwave tube was uncapped and allowed to stir at room temperature
for 30 min and in an ice bath for 30 min. The solid that crashed
out was filtered, washed with ice water, and dried to give a
mixture of 6-chloro-5-methylpyridazin-3-amine and
3-chloro-5-methylpyridazin-6-amine (3.4 g, 91%).
[0231] (1b) The mixture of 6-chloro-5-methylpyridazin-3-amine and
3-chloro-5-methylpyridazin-6-amine (1.45 g, 10 mmol) from 1a and
NaHCO.sub.3 (2.1 g, 25 mmol) were suspended in MeOH (20 mL) and
treated with Br.sub.2 (0.57 mL, 11 mmol). The mixture was stirred
at room temperature for 4 h, then filtered. The filtrate was
condensed in vacuo. The resulting residue was resuspended in EtOAc
(100 mL) and washed sequentially with sat. aqueous NaHCO.sub.3
solution (2.times.20 mL) and aqueous NaCl solution (1.times.20 mL).
The solution was dried over MgSO.sub.4. The solvent was removed in
vacuo to give crude 4-bromo-6-chloro-5-methylpyridazin-3-amine
(1g).
[0232] (1c) Chloroacetaldehyde (1.6 ml, 10 mmol, 50% in H.sub.2O)
was added to a solution of crude
4-bromo-6-chloro-5-methylpyridazin-3-amine (0.5 g, 2 mmol) from 1b
in EtOH (5 mL). The mixture was heated in a sealed vial at
110.degree. C. for 2 h. Solvent was removed in vacuo and the
resulting solid was suspended in acetone/Et.sub.2O (1/1, 5 mL),
filtered, and then washed with Et.sub.2O to give
8-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (0.5 g,
>90% pure).
[0233] (1d variation 1) A mixture of
8-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (30 mg,
0.1 mmol) from 1c, p-methoxyaniline (20 .mu.L, 0.15 mmol) and
K.sub.2CO.sub.3 (75 mg) were suspended in NMP (600 .mu.L) and
heated in a microwave at 225.degree. C. for 15 min. The mixture was
cooled to room temperature and then treated with H.sub.2O (5 mL).
The solid that precipitated out was filtered, washed with water and
dried to provide
6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine
(21 mg, >90% pure by HPLC).
[0234] (1d variation 2) To a mixture of
bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (102 mg,
0.36 mmol) from 1c, in THF (1.5 ml) was added p-Phenetidine (49 mg,
0.36 mmol) and a 1.0 M solution of KOt-Bu in THF (3.0 eq, 1.08 ml,
1.08 mmol). The mixture was allowed to heat at 50 C for 1 hour. The
solution was then concentrated in vacuo to dryness to provide
6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine
as a solid. m/e 303 (MH+).
[0235] (1e)
6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine
(20 mg, 0.067 mmol) from 1d and trans-1,4-diaminocyclohexane (150
mg) were combined and heated at 165.degree. C. for 70 h. The
mixture was cooled to room temperature, then diluted with water (10
mL) and extracted with EtOAc (4.times.5 mL). The organic layers
were combined and concentrated in vacuo. The resulting residue was
purified using preparative HPLC to give the above titled compound
as a TFA salt (4.5 mg, 11%). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.97 (d, J=2.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 6.90 (m,
4H), 4.05 (q, 2H, J=7.2 Hz), 4.00 (m, 1H), 3.20 (m, 1H), 2.30 (m,
2H), 2.20 (m, 2H), 2.15 (s, 3H), 1.60 (m, 4H), 1.40 (t, J=7.2H,
3H). LC/MS, m/e 381 (M+1). HPLC Rt, 2.1 min. YMC ODSC18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
[0236] Compounds having the formula (Ia) were prepared according to
procedures similar to Example III(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 3, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00003 TABLE 3 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) III(2) N.sup.6-(trans-4- aminocyclohexyl)-7-ethyl-
N.sup.8-[4- (ethyloxy)phenyl]imidazo [1,2-b]pyridazine-6,8-diamine
H H Et ##STR00393## ##STR00394## 395 III(3) N.sup.6-(trans-4-
aminocyclohexyl)-7-methyl- N.sup.8-phenylimidazo
[1,2-b]pyridazine-6,8-diamine H H Me ##STR00395## ##STR00396## 337
III(4) N.sup.6-(trans-4- aminocyclohexyl)-N.sup.8-(3,4-
dimethylphenyl)-7- methylimidazo[1,2- b]pyridazine-6,8-diamine H H
Me ##STR00397## ##STR00398## 365 III(5) N.sup.6-(trans-4-
aminocyclohexyl)-7-methyl- N.sup.8-(4- methylphenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H Me ##STR00399## ##STR00400## 351
III(6) N.sup.6-(trans-4- aminocyclohexyl)-7-methyl- N.sup.8-[3-
(methyloxy)phenyl]imidazo [1,2-b]pyridazine-6,8-diamine H H Me
##STR00401## ##STR00402## 367 III(7) N.sup.6-(trans-4-
aminocyclohexyl)-N.sup.8- biphenyl-4-yl-7- methylimidazo[1,2-
b]pyridazine-6,8-diamine H H Me ##STR00403## ##STR00404## 413
III(8) N.sup.6-(trans-4- aminocyclohexyl)-7-methyl- N.sup.8-[4-
(propyloxy)phenyl]imidazo [1,2-b]pyridazine-6,8-diamine H H Me
##STR00405## ##STR00406## 395 III(9) 4-((6-((trans-4-
aminocyclohexyl)amino)-7- methylimidazo[1,2- b]pyridazin-8-
yl)amino)benzoic acid H H Me ##STR00407## ##STR00408## 381 III(10)
4-((6-((4- aminocyclohexyl)amino)-7- methylimidazo[1,2-
b]pyridazin-8-yl)amino)- N,N- dimethylbenzenesulfonamide H H Me
##STR00409## ##STR00410## 444 III(11) 1 N-(4-((6-((trans-4-
aminocyclohexyl)amino)-7- methylimidazo[1,2- b]pyridazin-8-
yl)amino)phenyl)-N- methylacetamide H H Me ##STR00411##
##STR00412## 408 III(12) N.sup.6-(trans-4-
aminocyclohexyl)-7-ethyl- N.sup.8-phenylimidazo[1,2-
b]pyridazine-6,8-diamine.sup.6 H H Et ##STR00413## ##STR00414## 351
III(13) N.sup.6-(4-Aminocyclohexyl)-7- methyl-N.sup.8-
phenylimidazo[1,2- b]pyridazine-6,8-diamine (3:1 cis:trans mixture)
H H Me ##STR00415## ##STR00416## 337 III(14) N.sup.6-(trans-4-
Aminocyclohexyl)-7- methyl-N.sup.8-(4- phenoxyphenyl)imidazo
[1,2-b]pyridazine-6,8-diamine H H Me ##STR00417## ##STR00418## 429
III(15) N.sup.6-(trans-4- Aminocyclohexyl)-7- methyl-N.sup.8-(4-(1-
piperidinylcarbonyl)phenyl) imidazo[1,2-b]pyridazine- 6,8-diamine H
H Me ##STR00419## ##STR00420## 448 III(16) 4-((6-((trans-4-
Aminocyclohexyl)amino)- 7-methylimidazo[1,2-
b]pyridazin-8-yl)amino)- 2-hydroxy-N,N- dimethylbenzenesulfonamide
H H Me ##STR00421## ##STR00422## 460 III(17) N.sup.6-(trans-4-
Aminocyclohexyl)-7- methyl-N.sup.8-(4-(5-phenyl- 1,3,4-oxadiazol-2-
yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H Me ##STR00423##
##STR00424## 481 III(18) N.sup.6-(trans-4- Aminocyclohexyl)-7-
methyl-N.sup.8-(4-(4- morpholinylcarbonyl)phenyl)
imidazo[1,2-b]pyridazine- 6,8-diamine H H Me ##STR00425##
##STR00426## 450 III(19) 4-((6-((trans-4- Aminocyclohexyl)amino)-
7-methylimidazo[1,2- b]pyridazin-8-yl)amino)-N- phenylbenzamide H H
Me ##STR00427## ##STR00428## 456 III(20) N.sup.6-(trans-4-
Aminocyclohexyl)-7- methyl-N.sup.8-(2-methyl-1,3- benzothiazol-6-
yl)imidazo[1,2- b]pyridazine-6,8-diamine H H Me ##STR00429##
##STR00430## 408 III(21) N.sup.6-(trans-4- Aminocyclohexyl)-7-
methyl-N.sup.8-(2-methyl-1H- indol-5-yl)imidazo[1,2-
b]pyridazine-6,8-diamine H H Me ##STR00431## ##STR00432## 390
III(22) 4-((6-((trans-4- Aminocyclohexyl)amino)-
7-methylimidazo[1,2- b]pyridazin-8-yl)amino)-N-
methylbenzenesulfonamide H H Me ##STR00433## ##STR00434## 430
III(23) 4-((6-((trans-4- Aminocyclohexyl)amino)-
7-methylimidazo[1,2- b]pyridazin-8-yl)amino)-N- cyclohexylbenzamide
H H Me ##STR00435## ##STR00436## 462 III(24) N.sup.6-(trans-4-
aminocyclohexyl)-7-methyl- N.sup.8-(2- methylphenyl)imidazo[1,2-
b]pyridazine-6,8-diamine H H Me ##STR00437## ##STR00438## 351
III(25) N.sup.6-(trans-4- aminocyclohexyl)-N.sup.8-(2-
fluorophenyl)-7- methylimidazo[1,2- b]pyridazine-6,8-diamine H H Me
##STR00439## ##STR00440## 355 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example IV(1)
N.sup.6-(trans-4-aminocyclohexyl)-7-chloro-N.sup.8-[4-(ethyloxy)phenyl]imi-
dazo[1,2-b]pyridazine-6,8-diamine
##STR00441##
[0238] (1a) 3-Hydroxy-4,5-dichloropyridizine (5.34 g, 32.5 mmol)
was added to a stirred solution of fuming H.sub.2SO.sub.4 (14.0 mL,
273 mmol) and conc. H.sub.2SO.sub.4 (7.3 mL, 137 mmol). KNO.sub.3
(9.0 g, 88 mmol) was subsequently added slowly at room temperature.
The reaction mixture was heated to 90.degree. C. and the
temperature was maintained at 90.degree. C. for 18 hrs. The
solution was cooled and poured over ice water. After stirring for
one hour, the solid suspension was filtered to give
3-hydroxy-4,5-dichloro-6-nitropyridizine as a white solid (4.2 g,
62%).
[0239] (1b) Na.sub.2S.sub.2O.sub.4 (0.65 g, 3.6 mmol) was added to
a stirred solution of 3-hydroxy-4,5-dichloro-6-nitropyridizine
(0.26 g, 1.2 mmol) from 1a in THF (4.0 mL, 0.3 M) and H.sub.2O (4.0
mL, 0.3 M). The reaction mixture was warmed to reflux, after 1 hr
ethyl acetate was added. The layers were allowed to separate and
the organic layer was washed with H.sub.2O (10 mL), followed by
brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4
and then concentrated in vacuo. The resulting residue was
triterated with diethyl ether and filtered to give
3-hydroxy-4,5-dichloro-6-aminopyridizine as a white solid (0.165 g,
67%).
[0240] (1c) Chloroacetaldehyde (0.57 ml, 4.6 mmol, 50% in H.sub.2O)
was added to a solution of 3-hydroxy-4,5-dichloro-6-aminopyridizine
(0.165 g, 0.92 mmol) from 1b in EtOH (1.3 mL, 0.7 M). The reaction
was heated in a sealed vial at 150.degree. C. for 15 minutes in the
microwave. The solvent was removed in vacuo and the solid was
re-suspended in diethyl ether (10 mL), filtered and rinsed with
diethyl ether to give
6-hydroxy-7,8-dichloroimidazo[1,2-b]pyridazine as an HCl salt (0.3
g, 60%).
[0241] (1d) 6-Hydroxy-7,8-dichloroimidazo[1,2-b]pyridazine (0.1 g,
0.5 mmol) from 1c was added to POCl.sub.3 (0.4 mL, 1.4 M) in a 1
dram vial. The mixture was heated to 120.degree. C. for 2 days.
Upon cooling CH.sub.2Cl.sub.2 was added and the mixture was poured
onto ice water. The layers were separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 (15 mL). The organic layers were
combined and washed with H.sub.2O (5 mL), followed by brine (5 mL).
The solution was dried over Na.sub.2SO.sub.4 and concentrated in
vacuo to give 6,7,8-trichloroimidazo[1,2-b]pyridazine as a tan
solid (0.04 g, 37%).
[0242] (1e) A mixture of 6,7,8-trichloroimidazo[1,2-b]pyridazine
(0.04 g, 0.18 mmol) from 1d, p-ethoxyaniline (0.025 g, 0.18 mmol)
and triethylamine (0.055 mL, 0.4 mmol) were suspended in EtOH (1.0
mL) and heated to 90.degree. C. for 2.5 hours. The reaction mixture
was then cooled to room temperature and concentrated in vacuo to
provide crude
6,7-dichloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
(0.05 g, 86%).
[0243] (1f) Crude
6,7-dichloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
(0.03 g, 0.09 mmol) from 1e was mixed with
trans-1,4-diaminocyclohexane (0.07 g, 0.6 mmol). The resulting
mixture was heated to 120.degree. C. for 1.5 days. Upon cooling,
CH.sub.2Cl.sub.2 (10 mL) and H.sub.2O (10 mL) were added and the
layers separated. The organic layer was washed with brine (5 mL),
dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The
resulting oil was purified by preparative HPLC to give the above
titled compound as a TFA salt (0.010 g, 29%); .sup.1H NMR (MeOH)
.delta. 8.00 (s, 1H), 7.70 (s, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.98
(d, J=8.8 Hz, 2H), 4.09 (q, J=7.0 Hz, 2H), 4.00-3.90 (m, 1H),
3.24-3.15 (m, 1H), 2.30-2.23 (m, 2H), 2.20-2.10 (m, 2H), 1.65 1.57
(m, 4H), 1.50 (t, 3H). LC/MS, m/e 402 (M+1). HPLC Rt, 1.95 min. YMC
ODSC18 column (4.6.times.100 mm) 20%-100% B. Solvent B: (90% MeOH,
10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1%
TFA). Gradient, start % B=20, final % B=100, gradient time 10 min,
hold at 100% B, 2 min, flow rate 4 mL/min.
Example V(1)
N.sup.8-[4-(ethyloxy)phenyl]-N.sup.6-piperidin-3-ylimidazo[1,2-b]pyridazin-
e-6,8-diamine
##STR00442##
[0245] To a mixture of a
N.sup.6-(1-benzylpiperidin-3-yl)-N.sup.8-(4-ethoxyphenyl)imidazo[1,2-b]py-
ridazine-6,8-diamine TFA salt (14 mg, 0.021 mmol), prepared by the
method of example I(1) using 1-benzylpiperidin-3-amine in place of
trans-1,4-diaminocyclohexane in step (1d), and MeOH (5 mL) in a 500
ml PARR bottle was added 10% Pd/C (20 mg) and 3 drops of glacial
acetic acid. The PARR bottle was then charged with H.sub.2 at 55
psi and allow to shake at room temperature for 5 hours. The
reaction mixture was then filtered and the filtrate concentrated in
vacuo. The residue was purified by preparative HPLC followed by
neutralization with ion exchange resin to furnish 0.5 mg (7%) of
the title compound .sup.1H NMR (500 MHz, MeOH) .delta. ppm 7.57
(1H, s), 7.31 (1H, s), 7.24 (2H, d, J=8.7 Hz), 6.97 (2H, d, J=8.7
Hz), 5.89 (1H, s), 4.05 (2H, q, J=6.9 Hz), 3.85 (1H, m), 3.45 (1H,
m), 3.10 (1H, m), 2.85 (1H, m), 2.75 (1H, m), 2.05 (1H, m), 1.90
(1H, m), 1.70 (1H, m), 1.55 (1H, m), 1.39 (3H, t, J=6.9 Hz), LC/MS,
m/e 353 (M+1). HPLC Rt, 2.04 min. YMC ODSC18 column (4.6.times.50
mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA).
Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start %
B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow
rate 4 mL/min.
[0246] Compounds having the formula (Ia) were prepared according to
procedures similar to Example V(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 4, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00004 TABLE 4 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) V(2) N.sup.8-[4-(ethyloxy)phenyl]-N.sup.6-pyrrolidin-3-
ylimidazo[1,2-b]pyridazine-6,8-diamine H H H ##STR00443##
##STR00444## 339 V(3)
N.sup.8-[4-(ethyloxy)phenyl]-N.sup.6-piperidin-4-
ylimidazo[1,2-b]pyridazine-6,8-diamine H H H ##STR00445##
##STR00446## 353 V(4) 6-(3-amino-1-piperidinyl)-N-(4-
(ethyloxy)phenyl)imidazo[1,2-b]pyridazin-8- amine H H H
##STR00447## ##STR00448## 323 V(5)
N.sup.8-(4-(ethyloxy)phenyl)-7-methyl-N.sup.6-3-
piperidinylimidazo[1,2-b]pyridazine-6,8- diamine H H Me
##STR00449## ##STR00450## 367 V(6)
N.sup.8-phenyl-N.sup.6-3-piperidinylimidazo[1,2-
b]pyridazine-6,8-diamine H H H ##STR00451## ##STR00452## 309 V(7)
N.sup.8-Phenyl-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H H
##STR00453## ##STR00454## 309 V(8)
N.sup.8-(4-Phenoxyphenyl)-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H H
##STR00455## ##STR00456## 401 V(9)
7-Methyl-N.sup.8-phenyl-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H Me
##STR00457## ##STR00458## 323 V(10)
N.sup.8-(4-(4-Morpholinylcarbonyl)phenyl)-N.sup.6-
((3S)-3-piperidinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00459## ##STR00460## 422 V(11)
3-((6-((3S)-3-Piperidinylamino)imidazo[1,2-
b]pyridazin-8-yl)amino)phenol H H H ##STR00461## ##STR00462## 325
V(12) N-Cyclohexyl-4-((6-((3S)-3- piperidinylamino)imidazo[1,2-
b]pyridazin-8-yl)amino)benzamide H H H ##STR00463## ##STR00464##
434 V(13) N.sup.8-1-Naphthyl-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00465## ##STR00466## 359 V(14)
N.sup.8-(5-Methyl-2-pyridinyl)-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H H
##STR00467## ##STR00468## 324 V(15)
N.sup.6-((3S)-3-Piperidinyl)-N.sup.8-(4-(1-
pyrrolidinylcarbonyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H
H H ##STR00469## ##STR00470## 406 V(16) N-Methyl-4-((6-((3S)-3-
piperidinylamino)imidazo[1,2-b]pyridazin-
8-yl)amino)benzenesulfonamide H H H ##STR00471## ##STR00472## 402
V(17) N.sup.6-((3S)-3-Piperidinyl)-N.sup.8-(4-
(trifluoromethyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H H H
##STR00473## ##STR00474## 377 V(18) N,N-Diethyl-4-((6-((3S)-3-
piperidinylamino)imidazo[1,2-b]pyridazin- 8-yl)amino)benzamide H H
H ##STR00475## ##STR00476## 408 V(19)
N.sup.8-(4-Ethoxyphenyl)-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H H
##STR00477## ##STR00478## 353 V(20)
N.sup.8-(2-Methyl-1,3-benzothiazol-6-yl)-N.sup.6-
((3S)-3-piperidinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00479## ##STR00480## 380 V(21)
4-((6-((3S)-3-Piperidinylamino)imidazo[1,2-
b]pyridazin-8-yl)amino)-N- propylbenzenesulfonamide H H H
##STR00481## ##STR00482## 430 V(22)
N.sup.8-(4-Ethoxyphenyl)-7-methyl-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H Me
##STR00483## ##STR00484## 367 V(23)
7-Ethyl-N.sup.8-phenyl-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H Et
##STR00485## ##STR00486## 337 V(24)
7-Isopropyl-N.sup.8-phenyl-N.sup.6-((3S)-3-
piperidinyl)imidazo[1,2-b]pyridazine-6,8- diamine H H i-Pr
##STR00487## ##STR00488## 351 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example VI(1)
6-[(3S)-3-aminopyrrolidin-1-yl]-N-[4-(ethyloxy)phenyl]imidazo[1,2-b]pyrida-
zin-8-amine
##STR00489##
[0248] To
6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (26 mg,
0.090 mmol), prepared as described in example 1, step (1c) was
added (S)-3-amino-1-N-boc-pyrrolidine (180 mg, 0.96 mmol). The
mixture was microwaved at 225.degree. C. for one hour. The melt was
then cooled, water was added followed by extraction with
dichloromethane. The organic layer was then concentrated in vacuo
and purified by preparative HPLC to give 0.9 mg (2%) of the title
compound as a TFA salt, (Note that during the reaction the Boc
cleaves and the 1-nitrogen of the pyrrolidine adds). .sup.1H NMR
(500 MHz, MeOH) .delta. ppm 7.99 (1H, s), 7.88 (1H, s), 7.31 (2H,
d, J=7.7 Hz), 7.03 (2H, d, J=7.7 Hz), 6.18 (1H, s), 4.07 (2H, q,
J=6.9 Hz), 4.0 (1H, m), 3.80 (1H, m), 3.55 (3H, m), 2.50 (1H, m),
2.15 (1H, m), 1.40 (3H, t, J=6.9 Hz). LC/MS, m/e 339 (M+1). HPLC
Rt, 1.83 min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example VII(1)
[0249]
N.sup.2-(trans-4-aminocyclohexyl)-N.sup.4-[4-(ethyloxy)phenyl]pyraz-
olo[1,5-a][1,3,5]triazine-2,4-diamine
##STR00490##
[0250] (1a) Ethoxycarbonyl isothiocyanate (3.16 g, 24.07 mmol) was
added to 3-aminopyrazole (Aldrich) (2.0 g, 24.07 mmol) in acetone
(20 mL). The reaction mixture was stirred at room temperature for 1
hour. Then cold water (100 mL) was added to the reaction mixture.
The solid precipitate was collected through filtration, washed with
water (50 mL), and then air dried to give 4.64 g (90%) of ethyl
1H-pyrazol-5-ylcarbamothioylcarbamate.
[0251] (1b) Ethyl 1H-pyrazol-5-ylcarbamothioylcarbamate (4.64 g,
21.68 mmol) from 1a was added to 2N NaOH solution (51 mL). The
reaction mixture was stirred at room temperature for 21/2 hours and
then acidified with 2N H.sub.2SO.sub.4. The resulting precipitate
was collected by vacuum filtration, washed with water followed by
diethyl ether, and then air dried to give 3.32 g (82%) of
2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one as a
pale yellow solid.
[0252] (1c) A 1.75N NaOH solution (39.52 mmol, 22.58 ml) was added
to a suspension of
2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one (3.32
g, 19.76 mmol) from 1b in absolute EtOH (80 mL). Methyl iodide
(2.80 g, 19.76 mmol) was then added and the reaction mixture was
allowed to stir for 2 hours at room temperature. The resulting
precipitate was collected by vacuum filtration, suspended in water
(110 mL) and acidified with 2NH.sub.2SO.sub.4. The solution was
stirred at 0.degree. C. for 5 minutes and the new precipitate was
collected by vacuum filtration, washed with cold water, and then
air dried to give 1.88 g (52%) of
2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one.
[0253] (1d) N,N-Dimethylaniline (601 mg, 4.96 mmol) was added to a
suspension of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one
(1.88 g, 10.33 mmol) from 1c in POCl.sub.3 (29 mL). The reaction
mixture was heated to reflux for 7 hours, and then cooled to room
temperature, concentrated in vacuo, and diluted with cold water
(110 mL). The resulting solid was collected by vacuum filtration,
washed with cold water and hexane, and then air dried to give 1.68
g (81%) of
4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine.
[0254] (1e) p-Phenetidine (3.09 g, 22.51 mmol) was added to a
mixture of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine
(300 mg, 1.5 mmol) from 1d in 1,4-dioxane (6 mL). The mixture was
heated to 100.degree. C. for 1/2 hour. Water (15 mL) was then added
to the reaction mixture and the resulting precipitate was collected
by vacuum filtration, washed with cold water and hexane, and then
air dried to give 360 mg (80%) of
N-(4-ethoxyphenyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine.
[0255] (1f) mCPBA (702 mg, 4.06 mmol) was added to
N-(4-ethoxyphenyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine
(360 mg, 1.19 mmol) from 1e in DMF (10 mL) at room temperature.
After 1 hour the reaction mixture was concentrated in vacuo,
followed by the addition of saturated sodium bicarbonate. The
aqueous solution was then extracted with ethyl acetate and the
organic layer was dried to give 250 mg (63%) of
N-(4-ethoxyphenyl)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-amin-
e.
[0256] (1g) trans-1,4-Diaminocyclohexane (200 mg, 1.75 mmol) was
added to
N-(4-ethoxyphenyl)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-amin-
e (50 mg, 0.15 mmol) from 1f The reaction mixture was melted at
100.degree. C. for 1 hour. The melt was then cooled to room
temperature. Water was added, followed by extraction with ethyl
acetate. The organic layer was then concentrated in vacuo and the
residue was purified by preparative HPLC to gave 35.3 mg (20%) of
above titled compound as a TFA salt. .sup.1H NMR (500 MHz, DMSO)
.delta. ppm 7.90 (3H, m), 7.63 (2H, m), 6.88 (2H, m), 3.98 (2H, m),
3.60 (1H, m), 2.95 (1H, m), 1.92 (4H, m), 1.30 (7H, m). LC/MS, m/e
368 (M+1). HPLC Rt, 2.05 min. YMC ODSC18 column (4.6.times.50 mm)
0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent
A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final
% B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example XIII(1)
Imidazo[2,1-f][1,2,4]triazine-2,4-diamine,
N.sup.2-(trans-4-aminocyclohexyl)-N.sup.4-(4-ethoxyphenyl)-
##STR00491##
[0258] (1a) 2,4-bis(Methylthio)imidazo[1,2-f][1,2,4]triazine (0.077
g, 0.36 mmol), prepared as described in Journal of The Chemical
Society, Perkins Transactions 11999, 20, 2929, and p-phenetidine
(0.75 g, 5.46 mmol) were melted together in a vial at 90.degree. C.
for 6 hrs. The mixture was cooled and diluted with HCl (1N). The
brown precipitate that formed was filtered and dried under vacuum
to provide 0.103 g, (95%) of
N-(4-ethoxyphenyl)-2-(methylthio)imidazo[1,2-f][1,2,4]triazin-4-amine.
[0259] (1b) A vial was charged with
N-(4-ethoxyphenyl)-2-(methylthio)imidazo[1,2-f][1,2,4]triazin-4-amine
(0.103 g, 0.34 mmol) from 1a, meta-chloroperbenzoic acid. (0.286 g,
1.16 mmol) and dimethylformamide (5 mL) and stirred at room
temperature for 2 hrs. The mixture was quenched with aqueous
saturated sodium bicarbonate, extracted with ethyl acetate,
concentrated and dried under vacuum to provide 0.105 g, of crude
N-(4-ethoxyphenyl)-2-(methylsulfonyl)imidazo[1,2-f][1,2,4]triazin-4-amine-
.
[0260] (1c) A vial was charged with
N-(4-ethoxyphenyl)-2-(methylsulfonyl)imidazo[1,2-f][1,2,4]triazin-4-amine
(0.105 g, 0.32 mmol) from 1b, trans-1,4-cyclohexyldiamine (0.54 g,
4.7 mmol) and melted at 100.degree. C. for 6 hrs. The mixture was
cooled to room temperature, diluted with methanol, and purified by
preparative HPLC to provide 0.006 g (11%) of the titled compound as
a TFA salt. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm 7.75 (4H,
m), 6.95 (2H, m), 4.03 (2H, m), 3.68 (1H, m), 3.11 (1H, m), 2.22
(2H, m), 2.10 (2H, m), 1.4 (7H, m). LC/MS, m/e 368 (M+1). HPLC Rt,
2.18 min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example IX(1)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-[4-(ethyloxy)phenyl]-7-methylimida-
zo[1,2-b]pyridazine-6,8-diamine
##STR00492##
[0262] To
6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-am-
ine (40 mg, 0.14 mmol) from Example III(1), step 1d was added
cis-1,4-diaminocyclohexane (250 mg, 2.19 mmol). The mixture was
allowed to heat at 165.degree. C. for 48 hrs. The reaction mixture
then cooled, diluted with methanol and purified by preparative
HPLC. The eluent was then concentrated in vacuo, diluted with
methanol (2 mL), purified and neutralized by passing through a 500
mg SCX (Cation exchange column). The eluent was concentrated to
give 6.0 mg (11.3%) of the titled compound. .sup.1H NMR (500 MHz,
MeOH) .delta. ppm 7.65 (1H, s), 7.25 (1H, s), 6.85 (4H, m), 3.95
(2H, d, J=7.2 Hz), 3.95 (1H, m), 3.05 (1H, m), 1.95 (2H, m), 1.85
(3H, s), 1.80 (4H, m), 1.65 (2H, m), 1.35 (3H, t, J=7.2 Hz). LC/MS
m/e 381 (M+1). HPLC, 1.91 min. Waters Sunfire C18
4.6.times.50.0%-100% B. B: 90% MeOH, 10% H.sub.2O, 0.1% TFA. A: 10%
MeOH, 90% H.sub.2O, 0.1% TFA, gradient time 4 min, hold at 100% B1
min, flow rate 4 mL/min.
[0263] Compounds having the formula (Ia) were prepared according to
procedures similar to Example IX(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 5 using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00005 TABLE 5 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) IX(2) N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(5-
methyl-2-pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00493## ##STR00494## 338 IX(3)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-
phenylimidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00495##
##STR00496## 323 IX(4) N.sup.6-(cis-4-aminocyclohexyl)-7-
methyl-N.sup.8-phenylimidazo[1,2- b]pyridazine-6,8-diamine H H Me
##STR00497## ##STR00498## 337 IX(5)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(4-
(ethyloxy)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00499## ##STR00500## 367 IX(6)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-
(3,4-dimethylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00501## ##STR00502## 351 IX(7)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(5-
phenyl-2-pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00503## ##STR00504## 400 IX(8) 4-((6-((cis-4-
aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-yl)amino)-N,N-
dimethylbenzenesulfonamide H H H ##STR00505## ##STR00506## 430
IX(9) N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(4-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00507## ##STR00508## 336 IX(10)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8- (4,6-dimethyl-2-
pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00509##
##STR00510## 352 IX(11) N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(4-
(1H-pyrazol-1- yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H
H ##STR00511## ##STR00512## 389 IX(12)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(4- (4-
morpholinocarbonyl)phenyl) imidazo[1,2-b]pyridazine-6,8- diamine H
H H ##STR00513## ##STR00514## 436 IX(13)
N.sup.6-(cis-4-aminocyclohexyl)-7- methyl-N.sup.8-(2-
methylphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H Me
##STR00515## ##STR00516## 351 IX(14)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(2- fluorophenyl)-7-
methylimidazo[1,2-b]pyridazine- 6,8-diamine H H Me ##STR00517##
##STR00518## 355 IX(15) N.sup.6-(cis-4-Aminocyclohexyl)-N.sup.8-
(4-phenoxyphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H
##STR00519## ##STR00520## 415 IX(15a) 4-((6-((cis-4-
Aminocyclohexyl)amino)imidazo [1,2-b]pyridazin-8-yl)amino)-2-
hydroxy-N,N- dimethylbenzenesulfonamide H H H ##STR00521##
##STR00522## 446 IX(16) N.sup.6-(cis-4-Aminocyclohexyl)-N.sup.8-4-
biphenylylimidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00523##
##STR00524## 399 IX(17) N.sup.6-(cis-4-Aminocyclohexyl)-N.sup.8-2-
pyridinylimidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00525##
##STR00526## 324 IX(18) N.sup.6-(cis-4-Aminocyclohexyl)-N.sup.8-
(4-(1H-pyrrol-1- yl)phenyl)imidazo[1,2- b]pyridazine-6,8-diamine H
H H ##STR00527## ##STR00528## 388 IX(19)
N.sup.6-(cis-4-Aminocyclohexyl)-N.sup.8- (4-methyl-2-
pyridinyl)imidazo[1,2- b]pyridazine-6,8-diamine H H H ##STR00529##
##STR00530## 338 IX(20) N.sup.6-(cis-4-Aminocyclohexyl)-N.sup.8-
(4-(1- piperidinylcarbonyl)phenyl)imidazo
[1,2-b]pyridazine-6,8-diamine H H H ##STR00531## ##STR00532## 434
IX(21) N.sup.6-(cis-4-Aminocyclohexyl)-7- methyl-N.sup.8-(4-
phenoxyphenyl)imidazo[1,2- b]pyridazine-6,8-diamine H H Me
##STR00533## ##STR00534## 429 IX(22)
N.sup.6-(cis-4-Aminocyclohexyl)-7- methyl-N.sup.8-(4-(1-
piperidinylcarbonyl)phenyl)imidazo [1,2-b]pyridazine-6,8-diamine H
H Me ##STR00535## ##STR00536## 448 IX(23) 4-((6-((cis-4-
Aminocyclohexyl)amino)-7- methylimidazo[1,2-b]pyridazin-8-
yl)amino)-2-hydroxy-N,N- dimethylbenzenesulfonamide H H Me
##STR00537## ##STR00538## 460 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example X(1)
##STR00539##
[0265] (1a) p-Methoxybenzyl amine (1.0 eq, 1.49 mmol) and
triethylamine (330 mg, 3.27 mmol) were added to a mixture of
8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride (40 mg, 1.49
mmol) from Example 1, step 1b in EtOH (15 mL). The mixture was
heated to 90.degree. C. and stirred for 24 hours. The solution was
then concentrated in vacuo. The resulting residue was purified by
reverse phase preparative HPLC to provide
6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine as a
TFA salt. LC/MS, m/e 288.97 (M+1). HPLC Rt, 2.84 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0266] (1b) trans-1,4-Diaminocyclohexane (1000 mg, 8.77 mmol) was
added to
6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine (426
mg, 1.475 mmol) from 1a. The mixture was heated to 160.degree. C.
and allowed to melt. After stirring at 160.degree. C. for 7 days,
the liquid mixture was cooled to room temperature. Water was added,
followed by extraction with dichloromethane. The organic layer was
concentrated in vacuo. The resulting residue was purified by
reverse phase preparative HPLC to provide the
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-methoxybenzyl)imidazo[1,2-b]-
pyridazine-6,8-diamine as a TFA salt in approximately 44% yield
(0.315 g). LC/MS, m/e 367.27 (M+1). HPLC Rt, 1.81 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0267] (1c) To
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-methoxybenzyl)imidazo[1,2-b]-
pyridazine-6,8-diamine from 1b in dichloromethane (5 mL) was added
TFA (2 mL). After stirring at RT for 2 hours, the reaction solution
was concentrated in vacuo To provide crude
N.sup.6-(trans-4-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine
that was used without further purification. LC/MS, m/e 247.16
(M+1). HPLC Rt, 0.73 min. Waters Sunfire C18 column (4.6.times.50
mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA).
Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start %
B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow
rate 4 mL/min.
[0268] (1d) To
N.sup.6-(trans-4-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine
(70 mg, 0.284 mml, 1.0 eq.) from 1c in THF (3 mL) was added
triethylamine (31.6 mg, 0.313 mmol, 1.1 eq.) and boc anhydride
(68.2 mg, 0.313 mmol, 1.1 eq). The reaction solution was stirred at
RT for 2 hours. The solution was then concentrated in vacuo to give
crude tert-butyl
(trans)-4-(8-aminoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate
which was used as is in the next reaction. LC/MS, m/e 347.23 (M+1).
HPLC Rt, 2.50 min. Waters Sunfire C18 column (4.6.times.50 mm)
0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent
A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final
% B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
[0269] (1e) To 60% NaH (2.9 mg, 0.072 mmol) in THF (2 ml) was added
tert-butyl
(trans)-4-(8-aminoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate
(25 mg, 0.072 mmol) from 1d. After stirring at RT for 1 hour,
benzoyl chloride (20.3 mg, 0.144 mg, 2.0 eq.) was added and the
reaction solution was heated at 60.degree. C. for 3 days. The
reaction was quenched with a few drops of water and methanol. The
solution was then concentrated in vacuo. The resulting residue was
purified by reverse phase preparative HPLC to provide tert-butyl
(trans)-4-(8-benzamidoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbama-
te as a TFA salt in approximately 10% yield (9.1 mg). LC/MS, m/e
451.26 (M+1). HPLC Rt, 2.99 min. Waters Sunfire C18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
[0270] (1f) To tert-butyl
(trans)-4-(8-benzamidoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbama-
te from 1e in dichloromethane (2 mL) was added TFA (1 mL). After
stirring at RT for 2 hours, the reaction solution was concentrated
in vacuo. The residue was purified by SCX column (300 mg, eluting
with 2M ammonia in methanol) to give the titled compound as a TFA
salt in approximately 50% yield. .sup.1H NMR (500 MHz, MeOH)
.delta. ppm 8.07 (2H, d, J=7.7 Hz), 7.69 (2H, s), 7.65 (1H, t),
7.55 (2H, t), 7.36 (1H, s), 3.65 (1H, m), 2.72 (1H, m), 2.17 (2H,
m), 1.95 (2H, m), 1.31 (4H, t). LC/MS, m/e 351.21 (M+1). HPLC Rt,
1.70 min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example XI(1)
1-(6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)-3-pheny-
lurea
##STR00540##
[0272] (1a) To 60% NaH (2.9 mg, 0.072 mmol) in THF (2 ml) was added
tert-butyl
(trans)-4-(8-benzamidoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbama-
te (25 mg, 0.072 mmol, prepared in Example X step 1d). After
stirring at RT for 1 hour, phenyl isocyanate (17 mg, 0.144 mmol,
2.0 eq.) was added and the reaction solution was heated at
60.degree. C. for 3 days. The reaction was quenched with a few
drops of water and methanol. The solution was then concentrated in
vacuo. The resulting residue was purified by reverse phase
preparative HPLC to provide tert-butyl
(trans)-4-(8-(3-phenylureido)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexyl-
carbamate as a TFA salt (6.5 mg). LC/MS, m/e 466.29 (M+1). HPLC Rt,
3.39 min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
[0273] (1b) To tert-butyl
(trans)-4-(8-(3-phenylureido)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexyl-
carbamate (6.3 mg, 0.135 mmol) from 1a in dichloromethane (2 mL)
was added TFA (1 mL). After stirring at RT for 2 hours, the
reaction solution was concentrated in vacuo. The residue was
purified by SCX column (300 mg, eluting with 2M ammonia in
methanol) to give the title compound as a TFA salt 3.2 mgs (64%).
.sup.1H NMR (500 MHz, MeOH) .delta. ppm 7.64 (1H, s), 7.47 (2H, m),
7.31 (2 H, m), 7.06 (2H, m), 6.71 (2H, m), 3.63 (1H, m), 2.71 (1H,
m), 2.15 (2H, m), 1.91 (2H, m), 1.28-1.33 (4H, t). LC/MS, m/e
366.27 (M+1). HPLC Rt, 2.18 min. Waters Sunfire C18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
Example XII(1)
N,N'-bis(4-trans-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine
##STR00541##
[0275] To 8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.19
mmol) from Example 1, step 1b was added
trans-1,4-diaminocyclohexane (430 mg, 3.8 mmol). The mixture heated
at 180.degree. C. for 48 h. The reaction vessel was cooled to rt.
and diluted with water (10 mL) and extracted with DCM (3.times.10
mL). The organic extracts were combined, concentrated in vacuo and
purified using preparative HPLC to provide the title compound (40
mg, 30%) as a TFA salt. .sup.1H NMR (400 MHz, MeOH) .delta. ppm
7.90 (1H, d, J=2 Hz), 7.81 (1H, d, J=2 Hz), 6.06 (1H, s), 3.75 (1H,
m), 3.50 (1H, m), 3.20 (2H, m), 2.28 (4H, M), 2.16 (4H, m),
1.70-1.48 (6H. m), 1.42 (2H, m).). LC/MS, m/e 344 (M+1). HPLC Rt,
1.01 min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example XIII(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-ethyloxyphenyl)-7-phenylimida-
zo[1,2-b]pyridazine-6,8-diamine
##STR00542##
[0277] (1a) 3,6-dichloro-4-phenylpyridazine (J. Med. Chem. 2005,
48, 7089; 5.93 g, 26.3 mmol) was divided into 6 microwave tubes,
and concentrated NH.sub.4OH (7 mL) was added to each. After
sealing, each was heated at 140.degree. C. for 1 h. The microwave
tubes were uncapped, the precipitates were filtered and washed with
cold water. The precipitates from all reactions were combined, and
Et.sub.2O (150 mL) was added. After stirring overnight, the
remaining solid was filtered, rinsed with Et.sub.2O and dried to
give 6-chloro-5-phenylpyridazin-3-amine (3.06 g, 56%)
[0278] (1b) To a suspension of 6-chloro-5-phenylpyridazin-3-amine
(1.01 g, 4.9 mmol) from 1a in methanol (25 mL) under nitrogen was
added NaHCO.sub.3 (1.09 g, 13.0 mmol). At 0.degree. C., bromine
(0.55 M in methanol, 10 mL, 5.5 mmol) was added over 5 min. After 1
h, the cold bath was removed, and the reaction mixture was stirred
at room temperature for 6 h. After concentrating in vacuo, the
residue was taken up in CH.sub.2Cl.sub.2 and saturated aqueous
Na.sub.2S.sub.2O.sub.5, and the layers were separated. The organic
layer was washed with saturated aqueous NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
give crude 4-bromo-6-chloro-5-phenylpyridazin-3-amine (1.28 g).
[0279] (1c) Chloroacetaldehyde (2.0 mL, 31.5 mmol) was added to a
solution of crude 4-bromo-6-chloro-5-phenylpyridazin-3-amine (0.193
g, 0.676 mmol) from 1b in EtOH (5.0 mL). The mixture was heated in
a sealed tube at 118.degree. C. for 5 h. After cooling to room
temperature, the reaction mixture was concentrated in vacuo, and
suspended in acetone/Et.sub.2O (1:1, 3 mL), filtered, and washed
with Et.sub.2O to give
8-bromo-6-chloro-7-phenylimidazo[1,2-b]pyridazine HCl salt (0.147
g, >94% purity).
[0280] (1d) To a solution of
8-bromo-6-chloro-7-phenylimidazo[1,2-b]pyridazine HCl salt (0.0431
g, 0.125 mmol) from 1c and 4-ethoxyaniline (0.31 M in THF, 0.40 mL)
under nitrogen at 0.degree. C. was added KOtBu (1 N in THF, 0.32
mL, 0.32 mmol). After 1 min, the cold bath was removed, and the
reaction mixture was stirred to room temperature for 1 h. After
concentrating in vacuo, the residue was taken up in
CH.sub.2Cl.sub.2 and water, and the layers were separated. The
aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.). The
organic layers were combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. Trituration with hexanes
provided
6-chloro-N-(4-ethoxyphenyl)-7-phenylimidazo[1,2-b]pyridazin-8-amine
(0.0334 g).
[0281] (1e)
6-chloro-N-(4-ethoxyphenyl)-7-phenylimidazo[1,2-b]pyridazin-8-amine
(0.0201 g, 0.058 mmol) from 1d and (trans)-cyclohexane-1,4-diamine
(0.1702 g, 1.49 mmol) were heated at 165.degree. C. for 6 d. After
cooling to room temperature, the mixture was taken up in
CH.sub.2Cl.sub.2 and water, and the layers were separated. The
aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.). The
organic layers were combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The residue was purified using
preparative HPLC. The appropriate fraction was collected, and
NaHCO.sub.3 (solid) was added to it. It was concentrated in vacuo
not to dryness, and extracted with CH.sub.2Cl.sub.2 (2.times.). The
organic layers were combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to give the above titled
compound (1.5 mg, 4.0% yield). LC/MS, m/e 443.40 (M+1). HPLC RT,
2.29 min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B:
(90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
[0282] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XIII(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 6 using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00006 TABLE 6 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) XIII(2)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(phenyl)-7-
phenylimidazo[1,2-b]pyridazine-6,8-diamine H H Ph ##STR00543##
##STR00544## 399 XIII(3)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(phenyl)-7-
phenylimidazo[1,2-b]pyridazine-6,8-diamine H H Ph ##STR00545##
##STR00546## 399 XIII(4)
N.sup.6-(cis-4-aminocyclohexyl)-N.sup.8-(4-
ethoxyphenyl)-7-phenylimidazo[1,2- b]pyridazine-6,8-diamine H H Ph
##STR00547## ##STR00548## 443 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example XIV(1)
4-((6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amino)--
N-(2-(4-pyridinyl)ethyl)benzamide
##STR00549##
[0284] (1a) In a 250 ml round bottom flask, under a nitrogen
atmosphere, was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (5.0
g, 18.6 mmol) from Example I(1), step 1b, tert-butyl
4-aminobenzoate (3.95 g, 20.5 mmol), and DMF (30 ml). The solution
was cooled to 0.degree. C. and 1.0 M potassium tert-butoxide in THF
(46 ml) was added dropwise via syringe over 30 minutes. The
reaction was allowed to stir at room temperature for 30 minutes and
then warmed to 50.degree. C. for 2 hrs and then concentrated in
vacuo to remove THF. The resulting solution was taken up in ethyl
acetate, washed with H.sub.2O (3.times.300 ml) and then brine
(1.times.50 ml). The organic layers were combined, dried over
Na.sub.2SO.sub.4 and filtered. Following solvent evaporation, 6.0 g
of crude product was obtained. Further purification was done via
triteration with 3:1 diethyl ether/heptane to give 2.2 g of
tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate as
a brown solid after filtration.
[0285] (1b) In a 50 ml round bottom flask was added tert-butyl
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate (1.07 g, 3.1
mmol) from 1a and 4M HCl in 1,4 Dioxane (8.0 ml, 31.0 mmol). The
reaction was stirred at room temperature for 18 hrs and then
concentrated in vacuo. The resulting
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoic acid HCl salt
(1.05 g) was used crude.
[0286] (1c) In a 50 ml round bottom flask was added
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoic acid HCl salt
(0.53 g, 1.6 mmol) from 1b, dichloromethane (10 ml) and DMF (20
ul). To this solution, neat oxalyl chloride (0.71 ml 8.2 mmol) was
added dropwise. The solution was allowed to stir for 1 hr then
concentrated in vacuo. This gave 0.5 g of
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoyl chloride as a
yellowish solid.
[0287] (1d) To a one dram concave vial was added
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoyl chloride
(0.024 g, 0.070 mmol) from 1c, dichloromethane (0.7 ml, 0.1M),
2-(pyridine-4-yl)ethanamine (0.017 ml, 0.13 mmol) and
diisopropylethylamine (0.012 ml, 0.18 mmol) The reaction was capped
and allowed to stir at room temperature for 2 hours. The solvent
was removed in vacuo and trans-1,4-cyclohexyldiamine was added. The
reaction was sealed and allowed to stir at 165.degree. C. for 18
hrs. Upon cooling, the sample was dissolved in a methanol
(25%)/water (75%) mixture with 4 drops of trifluoroacetic acid. The
solution was purified by HPLC (5-60% methanol gradient), which
provided the TFA salt of the title compound as a brown solid 0.128
g (21%). .sup.1H NMR (400 MHz, MeOH) .delta. ppm 8.75 (2H, d, 6.6
Hz), 8.04-8.06 (2H, dd, 6.5 Hz), 8.01 (1H, d, 2 Hz), 7.88-7.90 (3H,
m), 7.43 (2H, d, J=8.6 Hz), 6.74 (1H, s), 3.81-3.83 (3H, m),
3.30-3.34 (2H, m), 3.10-3.20 (1H, m), 2.30 (2H, m), 2.10 (2H, m),
1.55-1.58 (2H, m), 1.35-1.45 (2H, m,). LC/MS, m/e 471 (M+1). HPLC
Rt, 1.39 min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
[0288] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XIV(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 7 using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00007 TABLE 7 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) XIV(2) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N-(2- furanylmethyl)benzamide
H H H ##STR00550## ##STR00551## 446 XIV(3) 4-((6-((trans-4-
aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8-
yl)amino)-N-(1H-imidazol- 4-ylmethyl)benzamide H H H ##STR00552##
##STR00553## 446 XIV(4) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N-(3-
pyridinylmethyl)benzamide H H H ##STR00554## ##STR00555## 457
XIV(5) N.sup.6-(trans-4- aminocyclohexyl)-N.sup.8-(4- ((4-phenyl-1-
piperidinyl)carbonyl)phenyl) imidazo[1,2-b]pyridazine- 6,8-diamine
H H H ##STR00556## ##STR00557## 510 XIV(6) N.sup.6-(trans-4-
aminocyclohexyl)-N.sup.8-(4-(1- pyrrolidinylcarbonyl)phenyl)
imidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00558##
##STR00559## 420 XIV(7) N.sup.6-(trans-4-
aminocyclohexyl)-N.sup.8-(4-(1- piperidinylcarbonyl)phenyl)
imidazo[1,2-b]pyridazine- 6,8-diamine H H H ##STR00560##
##STR00561## 434 XIV(8) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N- (phenylmethyl)benzamide H H
H ##STR00562## ##STR00563## 456 XIV(9) 4-((6-((trans-4-
aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8- yl)amino)-N-(3-
(methyloxy)phenyl)benzamide H H H ##STR00564## ##STR00565## 472
XIV(10) N.sup.6-(trans-4- aminocyclohexyl)-N.sup.8-(4-
((3-phenyl-1- pyrrolidinyl)carbonyl)phenyl) imidazo[1,2-b]
pyridazine-6,8-diamine H H H ##STR00566## ##STR00567## 496 XIV(11)
3-((6-((trans-4- aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8-
yl)amino)-N- phenylbenzamide H H H ##STR00568## ##STR00569## 442
XIV(12) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N-(2- hydroxyethyl)benzamide H
H H ##STR00570## ##STR00571## 410 XIV(13) 4-((6-((trans-4-
aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8-
yl)amino)-N-(3-(2-oxo-1- pyrrolidinyl)propyl)benzamide H H H
##STR00572## ##STR00573## 491 XIV(14) N.sup.6-(trans-4-
aminocyclohexyl)-N.sup.8-(4-(4- morpholinylcarbonyl)phenyl)
imidazo[1,2-b]pyridazine-6,8- diamine H H H ##STR00574##
##STR00575## 436 XIV(15) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N-methyl-N-(2-
(2-pyridinyl)ethyl) benzamide H H H ##STR00576## ##STR00577## 485
XIV(16) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N,N- diethylbenzamide H H H
##STR00578## ##STR00579## 423 XIV(17) 4-((6-((trans-4-
aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8- yl)amino)-N-
cyclopropylbenzamide H H H ##STR00580## ##STR00581## 406 XIV(18)
4-((6-((trans-4- aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8-
yl)amino)-N- (cyclohexylmethyl)benzamide H H H ##STR00582##
##STR00583## 462 XIV(19) 4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-N-3- pyridinylbenzamide H H H
##STR00584## ##STR00585## 443 XIV(20) 4-((6-((trans-4-
aminocyclohexyl)amino) imidazo[1,2-b]pyridazin-8-
yl)amino)-N-(1-methyl-1H- pyrazol-5-yl)benzamide H H H ##STR00586##
##STR00587## 446 *For substituents X and Y, substitution on the
core (formula Ia) occurs at the available nitrogen atom
Example XV(1)
4-((6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amino)--
N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinyl)benzamide
##STR00588##
[0290] (1a) To a 2 dram vial was added
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoic acid (0.050 g,
0.17 mmol, prepared as described in Example XIV, step 1b),
3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (0.053 g, 0.26) from
1a-1 and 1a-2 described below, EDCI (0.050 g, 0.26 mmol), HOBt
(0.035 g, 0.26 mmol), TEA (0.07 ml, 0.51 mmol), DMF (0.8 ml) and
CH.sub.3CN (0.8 ml). the reaction was allowed to stir at 50.degree.
C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and
diluted with methanol (2 ml). The solution was purified by HPLC
(20-100% methanol gradient), which yielded 0.0.12 g of
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-
-1,2-dihydropyridin-3-yl)benzamide.
[0291] (1a-1) To a solution of 2-hydroxy-3-nitropyridine (Aldrich,
3.0 mmol, 420 mg) in 1,4-dioxane (20 mL), were added 4-fluorophenyl
boronic acid (Combi-block, 6.0 mmol, 840 mg), copper(II) acetate
(Aldrich, 4.5 mmol, 815 mg) and pyridine (2 mL). The reaction was
heated at 80.degree. C. for 20 h. After cooling to room
temperature, 30 mL of cold water was added. The solid formed was
collected by filtration, washed with ammonium hydroxide and water,
and dried under vacuum to give
1-(4-fluorophenyl)-3-nitropyridin-2(1H)-one (610 mg, 87% yield) as
a solid.
[0292] (1a-2) To a solution of
1-(4-fluorophenyl)-3-nitropyridin-2(1H)-one (610 mg, 2.6 mmol) from
1a-1 in THF (50 mL) and MeOH (50 mL), were added ammonium chloride
(695 mg, 13.0 mmol, EMD) and Zn dust (850 mg, 13.0 mmol, Aldrich).
The reaction mixture was stirred at room temperature for 3 h,
diluted with 200 mL of EtOAc and filtered through a pad of
Celite.RTM.. The filtrate was concentrated in vacuo to give
3-Amino-1-(4-fluorophenyl)pyridin-2(1H)-one (530 mg, 100% yield) as
a brown solid.
[0293] (1b) To
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-
-1,2-dihydropyridin-3-yl)benzamide (0.011 g, 0.023 mmol) from 1a
was added trans-1,4-diaminocyclohexane (0.5 g, 57.0 mmol). The
mixture was allowed to melt at 160.degree. C. for 12 hours. The
melt was then cooled, diluted with water and extracted with
dichloromethane. The organic layer was then concentrated in vacuo
to give 0.020 g of crude product. Purification was done via
preparative HPLC providing 0.006 g of the title compound as aTFA
salt. 1H NMR (400 MHz, MeOD) .delta. ppm 8.56 (1H, dd, J=7.38, 1.78
Hz), 7.92-8.10 (3H, m), 7.88 (1H, d, J=2.03 Hz), 7.42-7.61 (3H, m),
7.39 (1H, dd, J=7.12, 1.53 Hz), 7.30 (2H, t, J=8.65 Hz), 6.77 (1H,
s), 6.54 (1H, t, J=7.12 Hz), 3.97 (1H, s), 3.66-3.84 (1H, m),
3.03-3.24 (1H, m), 2.26 (2H, m), 2.00-2.20 (2H, m), 1.44-1.68 (2H,
m), 1.22-1.46 (2H, m). LC/MS, m/e 533 (M+1). HPLC Rt, 2.14 min. YMC
ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH,
10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1%
TFA). Gradient, start % B=0, final % B=100, gradient time 4 min,
hold at 100% B 1 min, flow rate 4 mL/min.
[0294] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XV(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 8 using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00008 TABLE 8 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) XV(2) 4-((6-((trans-4- aminocyclohexyl)amino)imidazo[1,2-
b]pyridazin-8-yl)amino)-N- phenylbenzamide H H H ##STR00589##
##STR00590## 442 XV(3) 4-((6-((trans-4-
aminocyclohexyl)amino)imidazo[1,2- b]pyridazin-8-yl)amino)-N-
cyclohexylbenzamide H H H ##STR00591## ##STR00592## 448 XV(4)
4-((6-((trans-4- aminocyclohexyl)amino)imidazo[1,2-
b]pyridazin-8-yl)amino)-N-(4- pyridinylmethyl)benzamide H H H
##STR00593## ##STR00594## 457 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example XVI(1)
1-(446-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amino)-
phenyl)-3-phenylurea
##STR00595##
[0296] (1a) p-Aminoaniline (0.48 g, 4.4 mmol) and triethylamine
(1.3 ml, 9.2 mmol) were added to
8-bromo-6-chloroimidazo[1,2-b]pyridazine HCl (1.0 g, 4.2 mmol) from
Example I(1), step 1b in EtOH (20 mL). The mixture was heated to
90.degree. C. and stirred for 1 hr. The solution was then
concentrated in vacuo to give crude
3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
Cold ethanol was then added and the crude solid rinsed 3.times..
Following filtration, collected 0.45 g of the desired material.
[0297] (1b) To
3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
(0.2 g, 0.77 mmol) from 1a was added trans-1,4-diaminocyclohexane
(1.7 g, 15.0 mmol). The mixture was allowed to melt at 160.degree.
C. for 3 days. The melt was then cooled, diluted with water and
extracted with dichloromethane. The organic layer was then
concentrated in vacuo to give 0.4 g of crude
N6-(trans-4-aminocyclohexyl)-N8-(4-aminophenyl)imidazo[1,2-b]pyridazine-6-
,8-diamine
[0298] (1c) In a 200 ml round bottom flask charged with
N.sup.6-(trans)-4-aminocyclohexyl)-N.sup.8-(4-aminophenyl)imidazo[1,2-b]p-
yridazine-6,8-diamine (0.39 g, 1.1 mmol) from 1b and
dichloromethane (10 ml) was added di-tert-butyl dicarbonate (0.25
g, 1.1 mmol) in dichloromethane (2 ml). The reaction was stirred at
room temperature for 30 min, then concentrated and purified on
silica gel (ethyl acetate/heptane, 20 min gradient: 15-100% ethyl
acetate). tert-butyl
(trans)-4-(8-(4-aminophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cycloh-
exylcarbamate (0.050 g) was obtained as a white solid.
[0299] (1d) In a 2 dram vial was added tert-butyl
(trans)-4-(8-(4-aminophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cycloh-
exylcarbamate (0.04 g, 0.09 mmol) from 1c, dichloroethane (1.0 ml)
and phenylisocyanate (0.05 ml, 0.5 mmol). The reaction was allowed
to stir for 2 hrs and then concentrated to dryness. Diethyl ether
was added and the resulting suspension was stirred for 30 min. Upon
filtration, tert-butyl
(trans)-4-(8-(4-(3-phenylureido)phenylamino)imidazo[1,2-b]pyridazin-6-yla-
mino)cyclohexylcarbamate (0.035 g) was collected and used with no
further purification.
[0300] (1e) In a 2 dram vial was added tert-butyl
(trans)-4-(8-(4-(3-phenylureido)phenylamino)imidazo[1,2-b]pyridazin-6-yla-
mino)cyclohexylcarbamate (0.035 g, 0.06 mmol) from 1d and 4.0M HCl
in 1,4 Dioxane (2.0 ml). The reaction was stirred for 1 hr at
25.degree. C., concentrated and then triterated with diethyl ether.
The titled compound was filtered off as an HCl salt (0.018 g). 1H
NMR (400 MHz, DMSO-D6) .delta. ppm 9.36 (1H, s), 9.00 (1H, s), 8.88
(1H, s), 8.67 (1H, s), 8.60 (1H, s), 8.10 (1H, s), 7.87 (2H, d,
J=5.09 Hz), 7.54 (1H, d, J=9.16 Hz), 7.44 (2H, t, J=7.63 Hz), 7.34
(1H, s), 7.20-7.31 (2H, m), 6.85-7.04 (2H, m), 6.27 (1H, s), 3.38
(1H, s), 3.02 (1H, s), 2.04 (2H, m), 1.95 (2H, m), 1.31-1.53 (2H,
m), 1.11-1.29 (2H, m). LC/MS, m/e 457 (M+1). HPLC Rt, 1.93 min. YMC
ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH,
10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1%
TFA). Gradient, start % B=0, final % B=100, gradient time 4 min,
hold at 100% B 1 min, flow rate 4 mL/min.
[0301] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XVI(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 9, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00009 TABLE 9 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3 X
Y (M + 1) XVI(2) 1-(4-((6-((cis-4- aminocyclohexyl)amino)-7-
methylimidazo[1,2- b]pyridazin-8- yl)amino)phenyl)-3- phenylurea H
H Me ##STR00596## ##STR00597## 471 XVI(3) 1-(4-((6-((trans-4-
aminocyclohexyl)amino)-7- methylimidazo[1,2- b]pyridazin-8-
yl)amino)phenyl)-3- phenylurea H H Me ##STR00598## ##STR00599## 471
*For substituents X and Y, substitution on the core (formula Ia)
occurs at the available nitrogen atom
Example XVII(1)
N-(4-((6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amin-
o)-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide
##STR00600##
[0303] (1a) In a 2 dram reaction vial was added
8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloric acid salt
(0.5 g, 1.9 mmol) from Example I(1), step 1b, 4-nitroaniline (0.27
g, 1.9 mmol), 1.0 M potassium tert-butoxide in THF (7.6 ml, 7.6
mmol) and DMF (1.4 ml). Under N.sub.2, the reaction was stirred for
16 hr at 50.degree. C. and the concentrated in vacuo. The resulting
material was taken up in ethyl acetate and washed with H.sub.2O
(2.times.50 ml) and then brine (1.times.20 ml). the organic layers
were combined and dried over Na.sub.2SO.sub.4 and filtered.
Following solvent evaporation, 0.42 g of crude
6-chloro-N-(4-nitrophenyl)imidazo[1,2-b]pyridazin-8-amine was
obtained.
[0304] (1b) In a 2 dram reaction vial was added crude
6-chloro-N-(4-nitrophenyl)imidazo[1,2-b]pyridazin-8-amine (0.42 g,
1.4 mmol) from 1a and trans-1,4-diaminocyclohexane (1.0 g, 8.0
mmol). The mixture was allowed to melt at 160.degree. C. for 8 hrs.
The melt was then cooled, diluted with water and extracted with
dichloromethane. The organic layer was concentrated to provide
crude
N6-((trans)-4-aminocyclohexyl)-N-8-(4-nitrophenyl)imidazo[1,2-b]pyridazin-
e-6,8-diamine which was used without further purification.
[0305] (1c) In a 100 ml round bottom flask charged with
N6-((trans)-4-aminocyclohexyl)-N8-(4-nitrophenyl)imidazo[1,2-b]pyridazine-
-6,8-diamine (0.31 g, 0.85 mmol) from from 1b, triethylamine (0.13
ml, 0.93 mmol) add dichloromethane (10 ml) was added di-tert-butyl
dicarbonate (0.3 ml, 1.3 mmol). The reaction was stirred at
25.degree. C. for 0.5 hrs, then concentrated and purified on silica
gel (ethyl acetate/heptane, 20 min gradient: 25-100% ethyl acetate)
to give tert-butyl
(trans)-4-(8-(4-nitrophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cycloh-
exylcarbamate (0.090 g) as a white solid.
[0306] (1d) In a 50 ml round bottom flask was added tert-butyl
(trans)-4-(8-(4-nitrophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cycloh-
exylcarbamate (0.090 g, 0.19 mmol) from 1c, chloroform (2.0 ml),
methanol (2.0 ml), ammonium chloride (0.12 g, 0.19 mmol) and zinc
dust (0.13 g, 0.19 mmol). The reaction was allowed to stir for 30
min at room temperature. The reaction was then filtered through a
plug of celite and rinsed with dichloromethane to afford 0.1 g of
crude tert-butyl
(trans)-4-(8-(4-aminophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cycloh-
exylcarbamate.
[0307] (1e) To a 2 dram vial was added crude tert-butyl
(trans)-4-(8-(4-aminophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cycloh-
exylcarbamate (0.064 g, 0.15 mmol) from 1d,
1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
(0.051 g, 0.22 mmol) prepared as described in steps 1e-1, 1e-2
below, EDCI (0.043 g, 0.22 mmol), HOBt (0.030 g, 0.22 mmol), TEA
(0.06 ml, 0.45 mmol), and CH.sub.3CN (1 ml). The reaction was
allowed to stir around 25.degree. C. for 16 hrs. The solvent was
then removed in vacuo and the sample was diluted with MeOH (4 ml).
The solution was purified by HPLC (20-100% methanol gradient),
which yielded 0.025 g of tert-butyl
(trans)-4-(8-(4-(5-(4-fluorophenyl)-6-oxocyclohexa-1,3-dienecarboxamido)p-
henylamino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate as
a TFA salt.
[0308] (1e-1) In a 200 ml round bottom flask added methyl
2-oxo-2H-pyran-3-carboxylate (5.45 g, 35.0 mmol), 4-floroaniline
(3.35 ml, 35.0 mmol) and DMF (63 ml). The reaction was stirred for
3 hrs at room temperature. EDCI (9.4 g, 50.0 mmol) and DMAP (0.3 g,
2.0 mmol) were then added and the reaction was allowed to stir at
room temperature overnight. The reaction was quenched with 50 ml of
1N HCl and ethyl acetate was added. The layers were separated and
the resulting aqueous phase was extracted 2.times. with ethyl
acetate. The combined organics were washed 2.times. with 10%
lithium chloride solution and dried over Na.sub.2SO.sub.4.
Following filtration of the solids and concentration in vacuo, the
product was obtained as a yellow solid. (1e-2) In a 200 ml round
bottom flask added methyl
5-(4-fluorophenyl)-6-oxocyclohexa-1,3-dienecarboxylate (1.1 g, 4.3
mmol), THF (8 ml), MeOH (8 ml) and 1N NaOH solution (13 ml). The
reaction was allowed to stir overnight at room temperature. Upon
concentration of the volatiles, the basic solution was extracted
2.times. with diethyl ether. The aqueous phase was then acidified
to pH 3 with 1N HCl and subsequently extracted 2.times. with
dichloromethane. The organics were collected and washed with
saturated NaCl and the layers separated. The organic solution was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
This resulted in 0.7 g of product,
5-(4-fluorophenyl)-6-oxocyclohexa-1,3-dienecarboxylic acid.
[0309] (1f) In a 50 ml round bottom flask added tert-butyl
(trans)-4-(8-(4-(5-(4-fluorophenyl)-6-oxocyclohexa-1,3-dienecarboxamido)p-
henylamino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate
(0.025 g, 0.04 mmol) from 1e and 20% trifloroacetic acid in
methylene chloride (4 ml). The reaction was allowed to stir at room
temperature for 5 min. The reaction was then concentrated in vacuo
and diluted with methanol and purified via HPLC (20-100% methanol
gradient), which provided the titled compound as a TFA salt (0.007
g). 1H NMR (400 MHz, MeOD) .delta. ppm 12.11 (1H, s), 8.68 (1H, dd,
J=7.38, 2.29 Hz), 7.87-8.13 (2H, m), 7.71-7.88 (3H, m), 7.41-7.63
(2H, m), 7.33 (4H, t, J=8.65 Hz), 6.65-6.82 (1H, m), 6.43 (1H, s),
3.54-3.88 (1H, m), 2.96-3.17 (1H, m), 2.23 (2H, m), 2.08 (2H, m),
1.44-1.68 (2 H, m), 1.17-1.43 (2H, m). LC/MS, m/e 553 (M+1). HPLC
Rt, 2.14 min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
[0310] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XVII(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 10, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00010 TABLE 10 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3
X Y (M + 1) XVII(2) N-(4-((6-((trans-4- aminocyclohexyl)amino)
imidazo[1,2-b]pyridazin-8- yl)amino)-2-ethylphenyl)-
1-(4-fluorophenyl)-2-oxo- 1,2-dihydro-3- pyridinecarboxamide H H H
##STR00601## ##STR00602## 581 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example XVIII(1)
N-(4-((6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amin-
o)phenyl)benzamide
##STR00603##
[0312] In a 2 dram reaction vial was added
N-1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine
(0.050 g, 0.19 mmol, prepared in Example XVI, step 1a),
dichloromethane (1.0 ml) and triethylamine (0.040 ml, 0.29 mmol).
To this solution benzoyl chloride (0.025 ml, 0.21 mmol) was added
dropwise. The reaction was stirred for 30 min at 25.degree. C. and
then concentrated in vacuo. To this was added
trans-1,4-diaminocyclohexane (0.5 g, 23.0 mmol). The mixture was
allowed to melt at 160.degree. C. for 24 hrs. The melt was then
cooled, diluted with water and extracted with dichloromethane. The
organic layer was then concentrated in vacuo to give 0.036 g of
crude product. The crude material was then purified by preparative
HPLC to provide 0.018 g of the title compound as a TFA salt. 1H NMR
(400 MHz, MeOD) .delta. ppm 7.94 (3H, m), 7.76-7.88 (3H, m),
7.45-7.67 (3H, m), 7.36 (2H, d, 8.8 Hz), 6.45 (1H, s), 3.59-3.87
(1H, m), 3.01-3.21 (1H, m), 2.24 (2H, m), 2.09 (2H, m), 1.46-1.65
(2H, m), 1.24-1.42 (2H, m). LC/MS, m/e 442 (M+1). HPLC Rt, 1.80
min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XIX(1)
N-(4-((6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amin-
o)phenyl)acetamide
##STR00604##
[0314] In a 2 dram reaction vial was added
N-1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine
(0.050 g, 0.19 mmol, prepared as described in Example XVI, step
1a), dichloromethane (1.0 ml) and triethylamine (0.040 ml, 0.29
mmol). To this solution acetic anhydride (0.022 ml, 0.23 mmol) was
added dropwise. The reaction was stirred for 30 min at 25.degree.
C. and then concentrated in vacuo. To this was added
trans-1,4-diaminocyclohexane (0.5 g, 4.3 mmol). The mixture was
allowed to melt at 160.degree. C. for 24 hrs. The melt was then
cooled, diluted with water and extracted with dichloromethane. The
organic layer was then concentrated in vacuo to give 0.030 g of
crude product. The crude material was then purified by preparative
HPLC. This gave 0.008 g of the title compound as aTFA salt. 1H NMR
(400 MHz, MeOD) .delta. ppm 7.95 (1H, d, J=2.03 Hz), 7.86 (1H, d,
J=2.03 Hz), 7.65 (2H, d, J=8.65 Hz), 7.29 (2H, d, J=9.16 Hz), 6.40
(1H, s), 3.60-3.81 (1 H, m), 3.02-3.24 (1H, m), 2.17-2.30 (2H, m),
2.13 (3H, s), 2.04-2.12 (2H, m), 1.43-1.64 (2H, m), 1.24-1.42 (2H,
m). LC/MS, m/e 380 (M+1). HPLC Rt, 1.62 min. YMC ODSC18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
Example XX(1)
3-((6-((trans-4-aminocyclohexyl)amino)-7-methylimidazo[1,2-b]pyridazin-8-y-
l)amino)phenol
##STR00605##
[0316] (1a) In a microwave vial was added
8-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine (0.070 g, 0.24
mmol, prepared as described in Example III, step 1c), NMP (1.4 ml),
K.sub.2CO.sub.3 (0.17 g, 1.2 mmol) and 3-(benzyloxy)aniline (0.050
g, 0.24 mmol). The reaction was heated via microwave at 225.degree.
C. for 15 min. Upon cooling, the solution was diluted with MeOH (2
ml) and purified by preparative HPLC. This gave 0.011 g of
3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)phenol.
m/z=275. (Note: the benzyl ether was cleaved during the
reaction)
[0317] (1b) In a 2 dram reaction vial was added
3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)phenol (0.011
g, 0.028 mmol) from 1a and trans-1,4-diaminocyclohexane (1.0 g, 8.0
mmol). The mixture was allowed to melt at 160.degree. C. for 24
hrs. The melt was then cooled, diluted with water and MeOH, and
then purified by preparative HPLC to give 0.005 g of the title
compound as aTFA salt. 1H NMR (400 MHz, MeOD) .delta. ppm 8.01 (1H,
s), 7.73 (1H, s), 7.11 (1H, t, J=8.14 Hz), 6.48 (1H, d, J=7.63 Hz),
6.28 (1H, s), 3.88-4.10 (1H, m), 3.05-3.27 (1H, m), 2.24-2.37 (2H,
m, J=8.65 Hz), 2.11-2.23 (5H, m), 1.45-1.70 (4H, m). LC/MS, m/e 353
(M+1). HPLC Rt, 1.20 min. YMC ODSC18 column (4.6.times.50 mm)
0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent
A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final
% B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example XXI(1)
N-(4-((6-chloroimidazo[1,2-b]pyridazin-8-yl)amino)phenyl)-1-(4-fluoropheny-
l)-2-oxo-1,2-dihydro-3-pyridinecarboxamide
##STR00606##
[0319] To a 2 dram vial was added
N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.078
g, 0.3 mmol, prepared as described in Example XV1, step 1a),
1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
(0.10 g, 0.45 mmol, prepared as described in Example XVII, step
1e2), EDCI (0.086 g, 0.45 mmol), HOBt (0.061 g, 0.45 mmol), TEA
(0.12 ml, 0.9 mmol), DMF (0.8 ml) and CH.sub.3CN (1.5 ml). The
reaction was allowed to stir around 50.degree. C. for 12 hrs. Upon
cooling, the solvent was removed in vacuo and diluted with methanol
(2 ml). The solution was purified by HPLC (20-100% methanol
gradient), which yielded 0.014 g of the title compound as a TFA
salt. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 11.88 (1H, s),
8.70 (1H, dd, J=7.12, 2.03 Hz), 7.71-7.91 (3H, m), 7.67 (1H, s),
7.50-7.63 (1H, m), 7.10-7.43 (5H, m), 6.64 (1H, s), 6.56 (1H, t,
J=7.12 Hz). LC/MS, m/e 475 (M+1). HPLC Rt, 2.82 min. YMC ODSC18
column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10%
H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
Example XXII(1)
1-(4-fluorophenyl)-N-(4-(imidazo[1,2-b]pyridazin-8-ylamino)phenyl)-2-oxo-3-
-piperidinecarboxamide
##STR00607##
[0321] To a suspension of
N-(4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)phenyl)-5-(4-fluorophenyl-
)-6-oxocyclohexa-1,3-dienecarboxamide TFA salt (0.013 g, 0.027
mmol) From Example XXI and EtOH (4 mL) in a 500 ml PARR bottle was
added 10% Pd/C (20 mg) and 2 drops of triethylamine. The PARR
bottle was then charged with Hydrogen gas at 55 psi and allow to
shake at room temperature for 12 hours. The reaction mixture was
then filtered and the filtrate concentrated in vacuo. The residue
was purified by preparative HPLC to furnish 0.008 g of the title
compound as a TFA salt. LC/MS, m/e 445 (M+1). HPLC Rt, 1.81 min.
YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XXIII(1)
1-(4-fluorophenyl)-N-(4-(imidazo[1,2-b]pyridazin-8-ylamino)phenyl)-2-oxo-1-
,2-dihydro-3-pyridinecarboxamide
##STR00608##
[0323] (1a) In a 100 ml round bottom flask charged with
N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.5
g, 1.9 mmol, prepared as described in Example XVI, step 1a) and
tetrahydrofuran (10 ml) was added di-tert-butyl dicarbonate (0.44
g, 1.9 mmol). The reaction was stirred at 50.degree. C. for 5 hrs,
then concentrated and purified on silica gel (ethyl
acetate/heptane, 20 min gradient: 5-50% ethyl acetate) to give
tert-butyl
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate (0.050
g) as a white solid.
[0324] (1b) To a mixture of tert-butyl
4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate (0.1
g, 0.28 mmol) from 1a and EtOH (4 mL) in a 500 ml PARR bottle was
added 10% Pd/C (0.02 g) and 2 drops of triethyl amine The PARR
bottle was then charged with H.sub.2 at 55 psi and allow to shake
at room temperature for 12 hours. The reaction mixture was then
filtered and the filtrate concentrated in vacuo to give 0.085 g of
crude tert-butyl
4-(imidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate.
[0325] (1c) In a 2 dram vial was added tert-butyl
4-(imidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate. (0.085 g,
0.26 mmol) from 1b and 4.0M HCl in 1,4 dioxane (5.0 ml). The
reaction was stirred for 2 hr at 25.degree. C., concentrated.
N.sup.1-(imidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine resulted
as a di-HCl salt (0.085 g). The product was used with no further
purification.
[0326] (1d) To a 2 dram vial was added
N.sup.1-(imidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine di-HCl
salt (0.080 g, 0.3 mmol) from 1c,
1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
(0.13 g, 0.57 mmol), EDCI (0.11 g, 0.57 mmol), HOBt (0.077 g, 0.57
mmol), TEA (0.16 ml, 1.1 mmol), and CH.sub.3CN (4 ml). The reaction
was allowed to stir around 25.degree. C. for 12 hrs. The solvent
was then removed in vacuo and the sample was diluted with MeOH (4
ml). The solution was purified by HPLC (20-100% methanol gradient),
which yielded 0.015 g of the title compound as a TFA salt. 1H NMR
(400 MHz, DMSO-D6) .delta. ppm 11.96 (1H, s), 9.47 (1H, s), 8.59
(1H, dd, J=7.38, 2.29 Hz), 7.99-8.27 (3H, m), 7.67-7.85 (3H, m),
7.55-7.67 (2H, m, J=9.16, 5.09 Hz), 7.33-7.49 (3H, m), 6.66-6.82
(1H, m), 6.55 (1H, d, J=6.10 Hz) LC/MS, m/e 441 (M+1). HPLC Rt,
2.64 min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B:
(90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XXIV(1)
6-((trans-4-aminocyclohexyl)amino)-8-((4-(ethyloxy)phenyl)amino)imidazo[1,-
2-b]pyridazine-3-carbonitrile
##STR00609##
[0328] (1a) In a 200 ml round bottom flask was added
8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride (3.0 g, 11.2
mmol) from Example I(1), step 1b, chloroform (55 ml) and NBS (3.0
g, 16.8 mmol). The reaction was heated at 80.degree. C. for 1 hr,
cooled to room temperature and the volatiles removed under reduced
pressure. Ethyl acetate was added and the mixture was washed with
Na.sub.2CO.sub.3 (2.times.100 ml), H.sub.2O (2.times.100 ml) and
then brine (1.times.25 ml). The organic layers were combined and
dried over Na.sub.2SO.sub.4 and then concentrated. This gave 1.8 g
of crude 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine.
[0329] (1b) p-Phenetidine (0.38 ml, 2.9 mmol) and triethylamine
(0.8 ml, 5.8 mmol) were added to a mixture of
3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.83 g, 2.67 mmol)
from 1a in EtOH (10 mL). The mixture was heated to 80.degree. C.
and stirred for 16 hrs. The solution was then concentrated in vacuo
to give crude
3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
[0330] (1c) In a 5 ml microwave vial was added
3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine
(0.3 g, 0.8 mmol) from 1b, Pd(PPh.sub.3).sub.4 (0.18 g, 0.16 mmol),
Zn(CN).sub.2 (0.47 g, 4.0 mmol) and DMF (3 ml). The reaction was
heated via microwave for 25 min at 200.degree. C. Upon cooling, the
reaction mixture was diluted with ethyl acetate and filtered
through a plug of celite. The solvent was removed in vacuo and the
resulting material was purified by silica gel chromatography (ethyl
acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to give 0.11
g of
6-chloro-8-(4-ethoxyphenylamino)imidazo[1,2-b]pyridazine-3-carbonitrile.
[0331] (1d) In a 2 dram reaction vial was added
6-chloro-8-(4-ethoxyphenylamino)imidazo[1,2-b]pyridazine-3-carbonitrile
(0.055 g, 0.017 mmol) from 1c and trans-1,4-diaminocyclohexane (1.0
g, 8.0 mmol). The mixture was allowed to melt at 160.degree. C. for
1.5 hrs. The melt was then cooled, diluted with water and extracted
with dichloromethane. The organic layer was concentrated and then
diluted with MeOH, and then purified by preparative HPLC to give
0.039 g of the title compound as a TFA salt. 1H NMR (500 MHz,
Solvent) .delta. ppm 7.91 (1H, s), 7.23 (2H, d, J=8.80 Hz), 6.96
(2H, d, J=8.80 Hz), 5.96 (1H, s), 4.04 (4H, q, J=6.78 Hz),
3.61-3.80 (1H, m), 2.99-3.19 (1H, m), 2.16-2.35 (2H, m, J=11.55
Hz), 2.01-2.16 (2H, m, J=12.65 Hz), 1.47-1.65 (2H, m), 1.39 (3H, t,
J=7.15 Hz), 1.24-1.36 (2H, m). LC/MS, m/e 392 (M+1). HPLC Rt, 2.69
min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0332] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XXIV(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 11, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00011 TABLE 11 LC/MS m/z Exp) Name R.sub.1 R.sub.2 R.sub.3
X Y (M + 1) XXIV(2) 6-((trans-4-aminocyclohexyl)amino)-8-
(phenylamino)imidazo[1,2-b]pyridazine-3- carbonitrile H CN H
##STR00610## ##STR00611## 348 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example XXV(1)
6-((4-trans-aminocyclohexyl)amino)-7-m
ethyl-8-(phenylamino)imidazo[1,2-b]pyridazine-3-carbonitrile
##STR00612##
[0334] (1a) In a 200 ml round bottom flask was added
8-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine hydrochloride
(0.52 g, 1.8 mmol) from Example III, step 1c, chloroform (10 ml)
and NBS (0.5 g, 2.7 mmol). The reaction was heated at 80.degree. C.
for 1 hr, cooled to room temperature and the volatiles removed
under reduced pressure. Ethyl acetate was added and the mixture was
washed with Na.sub.2CO.sub.3 (2.times.100 ml), H.sub.2O
(2.times.100 ml) and then brine (1.times.25 ml). The organic layers
were combined and dried over Na.sub.2SO.sub.4 and then
concentrated. This gave 1.8 g of crude product that was then dry
loaded onto silica gel and purified via column chromatography using
30% ethyl acetate as the mobile phase. This resulted in 0.14 g of
pure 3,8-dibromo-6-chloro-7-methylimidazo[1,2-b]pyridazine.
[0335] (1b) In a 2 dram reaction vial was added
3,8-dibromo-6-chloro-7-methylimidazo[1,2-b]pyridazine (0.14 g, 0.43
mmol) from 1a, 1.0M potassium tert-butoxide in THF (1.0 ml) and THF
(1.4 ml). Under N.sub.2, the reaction was stirred for 1 hr at room
temperature and then concentrated in vacuo. The resulting material
was taken up in ethyl acetate, washed with H.sub.2O (2.times.50 ml)
and then brine (1.times.20 ml). the organic layers were combined
and dried over Na.sub.2SO.sub.4 and filtered. Following solvent
evaporation, 0.14 g of crude product was obtained. Further
purification was done via silica gel chromatography (ethyl
acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to give
0.053 g of
3-bromo-6-chloro-7-methyl-N-phenylimidazo[1,2-b]pyridazin-8-amine
[0336] (1c) In a 5 ml microwave vial was added
3-bromo-6-chloro-7-methyl-N-phenylimidazo[1,2-b]pyridazin-8-amine
(0.053 g, 0.16 mmol) from 1a, Pd(PPh.sub.3).sub.4 (0.036 g, 0.032
mmol), Zn(CN).sub.2 (0.088 g, 0.78 mmol) and DMF (3 ml). The
reaction was heated via microwave for 30 min at 180.degree. C. Upon
cooling, the reaction mixture was diluted with ethyl acetate and
filtered through a plug of celite. The solvent was removed in vacuo
and the resulting material was purified by preparative HPLC to give
0.013 g of
3-bromo-6-chloro-7-methyl-N-phenylimidazo[1,2-b]pyridazin-8-amine
[0337] (1d) In a 2 dram reaction vial was added
3-bromo-6-chloro-7-methyl-N-phenylimidazo[1,2-b]pyridazin-8-amine
(0.013 g, 0.045 mmol) from 1b and trans-1,4-diaminocyclohexane (1.0
g, 8.0 mmol). The mixture was allowed to melt at 160.degree. C. for
45 min. The melt was then cooled, diluted with water and extracted
with dichloromethane. The organic layer was concentrated and then
diluted with MeOH and then purified by preparative HPLC to give the
title compound as a TFA salt. 1H NMR (400 MHz, MeOD) .delta. ppm
7.99 (1H, s), 7.19-7.33 (2H, m), 6.97 (1H, t, J=7.38 Hz), 6.87 (2H,
d, J=7.63 Hz), 3.88-4.02 (1H, m), 3.07-3.25 (1H, m), 2.25-2.40 (2H,
m, J=12.21 Hz), 2.07-2.22 (2H, m, J=12.21 Hz), 1.94 (3H, s),
1.41-1.72 (4H, m). LC/MS, m/e 362 (M+1). HPLC Rt, 2.58 min. YMC
ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH,
10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1%
TFA). Gradient, start % B=0, final % B=100, gradient time 4 min,
hold at 100% B 1 min, flow rate 4 mL/min.
[0338] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XXV(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 12 using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00012 TABLE 12 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3
X Y (M + 1) XXV(2) 6-((trans)-4- aminocyclohexylamino)-7- ethyl-8-
(phenylamino)imidazo[1,2-b] pyridazine-3-carbonitrile H CN Et
##STR00613## ##STR00614## 376 XXV(3) 6-((trans-4-
aminocyclohexyl)amino)-8- anilino-7-isopropylimidazo[1,2-b]
pyridazine-3-carbonitrile H CN i-Pr ##STR00615## ##STR00616## 390
XXV(4) 6-((trans-4- Aminocyclohexyl)amino)-8-
anilino-7-benzylimidazo[1,2-b] pyridazine-3-carbonitrile H CN
CH.sub.2Ph ##STR00617## ##STR00618## 438 XXV(5) 6-((trans-4-
Aminocyclohexyl)amino)-8- anilino-7-(4- chlorophenyl)imidazo[1,2-b]
pyridazine-3-carbonitrile H CN Ph(4-Cl) ##STR00619## ##STR00620##
459 XXV(6) 6-((trans-4- Aminocyclohexyl)amino)-8-
((4-ethoxyphenyl)amino)-7- phenylimidazo[1,2-b]
pyridazine-3-carbonitrile H CN Ph ##STR00621## ##STR00622## 468
*For substituents X and Y, substitution on the core (formula Ia)
occurs at the available nitrogen atom
Example XXVI(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-(ethyloxy)phenyl)-3-fluoroimi-
dazo[1,2-b]pyridazine-6,8-diamine
##STR00623##
[0340] (1a) In a 20 ml reaction vial was added
8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride salt (0.33
g, 1.4 mmol) from Example I(1), step 1b, CH.sub.3CN (7.0 ml) and
selectflor (0.5 g, 1.4 mmol). The reaction was stirred at 50 C for
6 hrs, then concentrated to dryness. Purification was done by
silica gel chromatography (ethyl acetate/heptane, 25 min gradient:
5-50% ethyl acetate) to give 0.085 g of
8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine.
[0341] (1b) p-Phenetidine (0.044 ml, 0.34 mmol) and triethylamine
(0.1 ml, 0.75 mmol) were added to a mixture of
8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine (0.085 g, 0.34
mmol) from 1a in EtOH (1.7 mL). The mixture was heated to
80.degree. C. and stirred for 16 hors. The solution was then
concentrated in vacuo to give crude
6-chloro-N-(4-ethoxyphenyl)-3-fluoroimidazo[1,2-b]pyridazin-8-amine-
.
[0342] (1c) In a 2 dram reaction vial was added
6-chloro-N-(4-ethoxyphenyl)-3-fluoroimidazo[1,2-b]pyridazin-8-amine
(0.080 g, 0.26 mmol) from 1b and trans-1,4-diaminocyclohexane (1.0
g, 8.0 mmol). The mixture was allowed to melt at 160.degree. C. for
5 hrs. The melt was then cooled, diluted with water and extracted
with dichloromethane. The organic layer was concentrated and then
diluted with MeOH, and then purified by preparative HPLC to give
the titled compound as a TFA salt. 1H NMR (500 MHz, Solvent)
.delta. ppm 7.32 (1H, d, J=6.05 Hz), 7.24 (2H, d, J=8.80 Hz), 6.98
(2H, d, J=8.80 Hz), 5.99 (1H, s), 4.05 (2H, q, J=7.15 Hz),
3.66-3.79 (1H, m), 3.04-3.18 (1H, m), 2.16-2.28 (2H, m, J=11.55
Hz), 1.99-2.12 (2H, m, J=12.10 Hz), 1.46-1.62 (2H, m), 1.39 (3H, t,
J=6.87 Hz), 1.25-1.36 (2H, m). LC/MS, m/e 385 (M+1). HPLC Rt, 2.25
min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XXVII(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-(ethyloxy)phenyl)-3-methylimi-
dazo[1,2-b]pyridazine-6,8-diamine
##STR00624##
[0344] (1a) To a mixture of crude
4-bromo-6-chloro-2,3-dihydropyridazin-3-amine (0.5 g, 2.3 mmol)
from Example I(1), step 1b, 2-chloro-1,1-dimethoxypropane (1.6 ml),
EtOH (5 ml) and H.sub.2O (2 ml) was added 4 drops of 35% HBr in
acetic acid. The reaction was stirred at 100.degree. C. for 16 hrs.
The reaction was then concentrated to dryness and triterated from
diethyl ether. Upon filtration a mixture of
8-bromo-6-chloro-3-methylimidazo[1,2-b]pyridazine and
6,8-dichloro-3-methylimidazo[1,2-b]pyridazine were obtained as HCl
salts.
[0345] (1b) p-Phenetidine (0.068 g, 0.5 mmol) and triethylamine
(0.15 ml, 1.1 mmol) were added to a mixture of
8-bromo-6-chloro-3-methylimidazo[1,2-b]pyridazine and
6,8-dichloro-3-methylimidazo[1,2-b]pyridazine (0.011 g, 0.5 mmol)
both from 1a in EtOH (10 mL). The mixture was heated to 90.degree.
C. and stirred for 30 hrs. The solution was then concentrated in
vacuo to give crude
6-chloro-N-(4-ethoxyphenyl)-3-methylimidazo[1,2-b]pyridazin-8-amine
[0346] (1c) In a 2 dram reaction vial was added crude
6-chloro-N-(4-ethoxyphenyl)-3-methylimidazo[1,2-b]pyridazin-8-amine
(0.15 g, 0.5 mmol) from 1b and trans-1,4-diaminocyclohexane (1.0 g,
8.0 mmol). The mixture was allowed to melt at 160.degree. C. for 48
hrs. The melt was then cooled, diluted with water and extracted
with dichloromethane. The organic layer was concentrated and then
diluted with MeOH and then purified by preparative HPLC to give the
title compound as a TFA salt. 1H NMR (400 MHz, MeOD) .delta. ppm
7.62 (1H, s), 7.25 (2H, d, J=9.16 Hz), 6.99 (2H, d, J=9.16 Hz),
6.21 (1H, s), 4.05 (2H, q, J=7.12 Hz), 3.64-3.89 (1H, m), 3.00-3.22
(1H, m), 2.48 (3H, s), 2.17-2.38 (2H, m, J=11.19 Hz), 1.99-2.18
(2H, m, J=12.21 Hz), 1.45-1.71 (2H, m), 1.22-1.46 (5H, m). LC/MS,
m/e 381 (M+1). HPLC Rt, 1.91 min. YMC ODSC18 column (4.6.times.50
mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA).
Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start %
B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow
rate 4 mL/min
Example XXVIII(1)
N.sup.6-(trans-4-aminocyclohexyl)-N.sup.8-(4-(ethyloxy)phenyl)-2,3-dimethy-
limidazo[1,2-b]pyridazine-6,8-diamine
##STR00625##
[0348] (1a) A mixture of
4-bromo-6-chloro-2,3-dihydropyridazin-3-amine (0.1 g, 0.48 mmol)
from Example I(1), step 1a, 3-chlorobutan-2-one (0.42 g, 3.3 mmol)
and EtOH (1 ml) was stirred at 90.degree. C. for 48 hrs. The
reaction was then concentrated to dryness and triterated from
diethyl ether. Upon filtration, an oily material resulted. The frit
containing the oily solid was rinsed with methanol and the material
collected as a mixture of
8-bromo-6-chloro-2,3-dimethylimidazo[1,2-b]pyridazine and
6,8-dichloro-2,3-dimethylimidazo[1,2-b]pyridazine (HCl salt).
[0349] (1b) p-Phenetidine (0.04 g, 0.29 mmol) and potassium
carbonate (0.12 g, 0.87 mmol) were added to a mixture of
8-bromo-6-chloro-2,3-dimethylimidazo[1,2-b]pyridazine and
6,8-dichloro-2,3-dimethylimidazo[1,2-b]pyridazine (HCl salt) (0.063
g, 0.29 mmol) both from 1a, in EtOH (1.0 mL). The mixture was
heated to 90.degree. C. and stirred for 48 hrs. The solution was
then concentrated in vacuo and purified by preparative HPLC
(20-100% Methanol/Water gradient). This gave 0.013 g of
6-chloro-N-(4-ethoxyphenyl)-3-methylimidazo[1,2-b]pyridazin-8-amine
[0350] (1c) In a 2 dram reaction vial was added crude
6-chloro-N-(4-ethoxyphenyl)-2,3-dimethylimidazo[1,2-b]pyridazin-8-amine
(0.013 g, 0.04 mmol) from 1b and trans-1,4-diaminocyclohexane (1.0
g, 8.0 mmol). The mixture was allowed to melt at 160.degree. C. for
4 days. The melt was then cooled, diluted with water and extracted
with dichloromethane. The organic layer was concentrated and then
diluted with MeOH and then purified by preparative HPLC. This gave
0.005 g of the titled compound as a TFA salt. 1H NMR (500 MHz,
MeOD) .delta. ppm 7.24 (2H, d, J=8.25 Hz), 7.00 (2H, d, J=8.80 Hz),
6.17 (1H, s), 4.05 (2H, q, J=6.96 Hz), 3.62-3.83 (1H, m), 3.02-3.21
(1H, m), 2.47 (3H, s), 2.42 (3H, s), 2.18-2.29 (2H, m, J=11.55 Hz),
2.03-2.14 (2H, m, J=12.65 Hz), 1.45-1.62 (2H, m), 1.39 (3H, t,
J=6.87 Hz), 1.26-1.36 (2H, m). LC/MS, m/e 395 (M+1). HPLC Rt, 2.49
min. YMC ODSC18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XXIX(1)
N-(6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)benzenes-
ulfonamide
##STR00626##
[0352] (1a) To a 16.times.100 mm tube was added benzenesulfonamide
(58 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (2
mg, 0.0022 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(4 mg 0.0077 mmol) and cesium carbonate (240 mg, 1.25 mmol). The
tube was evacuated and back filled with nitrogen.
8-Bromo-6-chloroimidazo[1,2-b]pyridazine (120 mg, 0.447 mmol) from
Example I(1), step 1b and 1,4-dioxane (1.0 ml) was then added. The
mixture was allowed to heat at 100.degree. C. for 16 hours. The
solution was then diluted with dichloromethane, filtered and
concentrated in vacuo to afford crude
N-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide 100 mg
(73%).
[0353] (1b) To
N-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide (100 mg,
0.325 mmol) from 1a was added trans-1,4-diaminocyclohexane (1000
mg, 8.77 mmol). The mixture was allowed to melt at 165.degree. C.
for 3 days. The melt was then cooled, water was added followed by
extraction with dichloromethane. The organic layer was then
concentrated in vacuo and purified by preparative HPLC. This gave
4.5 mg (2%) of the title compound as a TFA salt. .sup.1H NMR (500
MHz, MeOH-D.sub.3) .delta. ppm 7.97 (2H, d, J=5 Hz), 7.85 (1H, s),
7.71 (1H, s), 7.63 (1H, m), 7.56 (2H, m), 6.63 (1H, s), 3.64 (1H,
m), 3.12 (1H, m), 2.23-2.04 (4H, m), 1.51 (2H, m), 1.34 (2 H, m).
LC/MS m/e 387 (MH+). HPLC, 1.60 min. Waters Sunfire C18
4.6.times.50. 0%-100% B. B: 90% MeOH, 10% H.sub.2O, 0.1% TFA. A:
10% MeOH, 90% H.sub.2O, 0.1% TFA.
Example XXXI(1)
6-((trans-4-aminocyclohexyl)oxy)-8-anilinoimidazo[1,2-b]pyridazine-3-carbo-
nitrile
##STR00627##
[0355] (1a) N-(4-Methoxybenzyl)aniline (215 mg, 1 mmol) was
dissolved in dry DMF (4 mL), placed under a nitrogen atmosphere,
and cooled to 0.degree. C. in an ice bath. Potassium t-butoxide (1
mL, 1 mmol, 1M THF solution) was added and the mixture was allowed
to stir for 10 min at 0.degree. C. and room temperature for 30 min.
The resulting mixture was cool to 0.degree. C. Solid
3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (310 mg, 1 mmol) from
Example XXIV, step 1a was added. The mixture was allowed to stir
for 30 min at 0.degree. C. and overnight at room temperature. The
mixture was diluted with ethyl acetate (100 mL), washed
sequentially with 10% LiCl, water and brine, and dried over
anhydrous magnesium sulfate. The solvent was removed in vacuo and
the resulting material was purified by silica gel chromatography
(ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to
provide 0.27 g of
3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-
-amine
[0356] (1b) A microwave vial was charged with
3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine (220 mg, 0.49 mmol) from step 1a, zinc cyanide (34.8 mg, 0.3
mmol), Tris(dibenzylidenaceton)dipalladium(0) (22.7 mg, 0.025
mmol), 1,1'-Bis(diphenylphosphino)ferrocene (19.8 mg, 0.036 mmol)
and DMF (2 mL). The resulting mixture was heated in a microwave for
15 min at 150.degree. C. The solution was cooled, diluted with
ethyl acetate, washed with saturated LiCl solution, dried over
anhydrous magnesium sulfate and concentrated in vacuo. The
resulting residue was purified silica gel chromatography (5% ethyl
acetate/heptane) to provide 91 mg of
6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine
[0357] (1c) A mixture of
6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine (20 mg, 0.05 mmol) from 1b, tert-butyl
(trans)-4-hydroxycyclohexylcarbamate (22 mg, 0.1 mmol),
palladium(II) acetate (1.1 mg, 0.005 mmol),
1,2,3,4,5-Pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (7.5,
0.01 mmol) and cesium carbonate (100 mg) was suspended in anhydrous
dioxane (1 mL) in a Teflon lined septum capped vial. The vessel was
purged with argon and heated at 105.degree. C. for 48 h. LCMS shows
that product (m/z, M+1, 569.4) is present (.about.25% conversion)
along with starting materials. The reaction is cooled and filtered
thru a plug of celite and the celite pad rinsed with .about.5 ml of
ethyl acetate. The solvents are removed in vacuo and the resulting
oil suspended in 1 mL of TFA and heated at 50.degree. C. of 2 h.
The reaction showed complete removal of the p-methoxybenzyl
protecting group. TFA is removed under a stream of air and the
resulting mixture taken up in MeOH (2 mL) and purified by
preparative HPLC to yield 2.2 mg of the titled compound as a TFA
salt. MS m/e 349 (M+1); 1H NMR (MeOH, .delta.) 8.1 (1H, s), 7.48
(2H, t, J=8 Hz), 7.39 (2H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz), 6.21
(1H, s), 5.00 1H, m), 3.21 (1H, m), 2.38 (2H, m), 2.15, 2H, m),
1.62 (4H, m).
Example XXXII(1)
6-((trans-4-aminocyclohexyl)amino)-8-anilinoimidazo[1,2-b]pyridazine-3-car-
boxamide
##STR00628##
[0359] (1a) A mixture of
6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine (25 mgs) from Example XXXI(1) step 1b, 6N NaOH (0.1 mL), MeOH
(0.1 mL) and dioxane (1 mL) in a vial was heated to 100.degree. C.
for 16 h. The mixture was cooled to room temperature and
concentrated in vacuo. Upon addition of 1M HCl a precipitate forms.
The precipitate was collected by filtration and dried to provide 35
mgs of crude
6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-car-
boxamide.
[0360] (1b) To a vial containing crude
6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-car-
boxamide 35 mgs from 1a was added trans-1,4-cyclohexyldiamine (250
mgs, mmol). The resulting mixture was heated to 160.degree. C. for
4 h. The mixture was cooled to room temperature and diluted with
water causing a precipitate to form. The precipitate was collected,
washed with water and dried to give crude
6-((trans)-4-aminocyclohexylamino)-8-((4-methoxybenzyl)(phenyl)amino)imid-
azo[1,2-b]pyridazine-3-carboxamide.
[0361] (1c) Crude
6-((trans)-4-aminocyclohexylamino)-8-((4-methoxybenzyl)(phenyl)amino)imid-
azo[1,2-b]pyridazine-3-carboxamide from 1b was suspended in
trifluoracetic acid (1 mL) and heated to 50.degree. C. for 2 h. The
mixture was cooled to room temperature and the trifluoractic acid
was evaporated under a stream of nitrogen. The residue was
suspended in methanol, filtered to remove solids and purified by
prep HPLC to provide 2.1 mg of the titled compound as a TFA salt.
MS m/e 366 (M+1); 1H NMR (MeOH, .delta.) 8.1 (1H, s), 7.46 (2H, t,
J=8 Hz), 7.39 (2H, d, J=8 Hz), 7.23 (1H, t, J=8 Hz), 6.31 (1H, s),
3.62 (1H, m), 3.17 (1H, m), 2.30 (2H, m), 2.13, (2H, m), 1.55 (2H,
m), 1.42 (2H, m).
Example XXXIII(1)
N.sup.6-(trans-4-aminocyclohexyl)-7-ethyl-N.sup.8-phenylimidazo[1,2-b]pyri-
dazine-6,8-diamine
##STR00629##
[0363] (1a) To a suspension of 3,6-dichloropyridazine (11.25 g,
0.076 mol, 1.0 eq), silver nitrate (6.41 g, 0.038 mol, 0.5 eq),
propionic acid (8.39 g, 0.113 mol, 1.5 eq) in water (125 mL) at
50.degree. C. was added a solution of sulfuric acid (11.54 mL,
0.227 ml. 3.0 eq) in water (125 mL). The solution was heated to
60.degree. C. and then a solution of ammonium persulfate (51.7 g,
0.227 mol, 3.0 eq) was added in slowly in 20 minutes. The solution
was then heated to 75.degree. C. for 30 minutes. The reaction
solution was poured into ice water and adjusted to pH 7 with 30%
ammonium hydroxide solution. The mixture was extracted with
dichloromethane (3.times.), and the extracts washed with water,
brine, dried with sodium sulfate and concentrated in vacuo. The
resulting residue was purified using an ISCO chromatography system
(120 g silica cartridge, 5% ethyl acetate in heptane) to provide
the compound 3,6-dichloro-4-ethylpyridazine (7.3 g, 54% yield).
LC/MS, m/e 177.15 (M+1). HPLC Rt, 2.03 min. Waters Sunfire C18
column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10%
H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
[0364] (1b) 3,6-Dichloro-4-ethylpyridazine (3.5 g, 0.020 mol) from
1a was suspended in aqueous 28% NH.sub.4OH (12 mL) in a sealed
microwave tube and heated at 145.degree. C. for 1 h. The reaction
solution was cooled and then heated once more at 145.degree. C. for
1 h. The microwave tube was uncapped and allowed to stir at room
temperature for 30 min and in an ice bath for 30 min. The solid
that crashed out was filtered and then washed with ice water and
dried to give 3.5 g of a mixture of the desired
6-chloro-5-ethylpyridazin-3-amine and the
6-chloro-4-ethylpyridazin-3-amine regioisomer LC/MS, m/e 158.19
(M+1). HPLC Rt, 0.78 min. Waters Sunfire C18 column (4.6.times.50
mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA).
Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start %
B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow
rate 4 mL/min.
[0365] (1c) The mixture of 6-Chloro-5-ethylpyridazin-3-amine and
chloro-4-ethylpyridazin-3-amine (3.50 g, 0.022 mol) from 1b and
NaHCO.sub.3 (3.73 g, 0.044 mol, 2 eq) were suspended in MeOH (20
mL) and treated with Br.sub.2 (1.25 mL, 0.024 mol). The mixture was
stirred at room temperature for 24 h, then filtered. The filtrate
was condensed in vacuo. The resulting residue was resuspended in
EtOAc (100 mL) and washed sequentially with sat. aqueous
NaHCO.sub.3 solution (2.times.20 mL) and aqueous NaCl solution
(1.times.20 mL). The solution was dried over sodium sulfate. The
solvent was removed in vacuo to give crude
4-bromo-6-chloro-5-ethylpyridazin-3-amine. LC/MS, m/e 236 (M+1).
HPLC Rt, 2.15 min. Waters Sunfire C18 column (4.6.times.50 mm)
0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent
A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final
% B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
[0366] (1d) Chloroacetaldehyde (17.26 ml, 0.111 mol, 50% in
H.sub.2O) was added to a solution of crude
4-bromo-6-chloro-5-ethylpyridazin-3-amine (5.23 g, 0.022 mol) from
1c in EtOH (30 mL). The mixture was heated in a sealed vial at
50.degree. C. for 24 h. Solvent was removed in vacuo and the solid
was resuspended in acetone/Et.sub.2O (1/1, 5 mL), filtered, and
then washed with Et.sub.2O to give
8-bromo-6-chloro-7-ethylimidazo[1,2-b]pyridazine as an HCl salt
(3.02 g, >80% pure). LC/MS, m/e 260 (M+1). HPLC Rt, 2.68 min.
Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B:
(90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
[0367] (1e) A mixture of
8-bromo-6-chloro-7-ethylimidazo[1,2-b]pyridazine (60 mg, 0.2 mmol,
1 eq) from 1d, aniline (20.3 .mu.L, 0.22 mmol, 1.1 eq) and
potassium tert-butoxide (0.51 mL, 0.51 mmol, 2.5 eq) were suspended
in DMF (3 mL) and stirred at RT for 1 h. The mixture was quenched
with ethyl acetate and washed with lithium chloride saturated
solution, dried with sodium sulfate and concentrated in vacuo. The
residue was purified using an ISCO chromatography system (4 g
silica cartridge, 5% ethyl acetate in heptane) to provide
6-chloro-N-phenyl-7-ethylimidazo[1,2-b]pyridazin-8-amine (22 mg).
LC/MS, m/e 273.14 (M+1). HPLC Rt, 2.24 min. Waters Sunfire C18
column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10%
H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
[0368] (1f)
6-Chloro-N-phenyl-7-ethylimidazo[1,2-b]pyridazin-8-amine (22 mg,
0.08 mmol) from 1e and trans-1,4-diaminohexane (230 mg) were
combined and heated at 165.degree. C. for 4 days. The mixture was
cooled to room temperature, then diluted with methanol. The
resulting residue was purified using preparative HPLC to give the
titled compound as a TFA salt (18.9 mg, 66%). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.95 (d, 1H), 7.62 (d, 1H), 7.27 (t, J=7.4 Hz,
2H), 7.0 (t, J=7.4 Hz, 1H), 6.85 (d, J=8.2 Hz, 2H), 4.0 (m, 1H),
3.20 (m, 1H), 2.79 (m, 2H), 2.25 (m, 2H), 2.14 (m, 2H), 1.58 (m,
4H), 1.13 (t, J=7.2 Hz, 3H). LC/MS, m/e 351 (M+1). HPLC Rt, 1.67
min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent
B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
[0369] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XXXIII(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 13, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00013 TABLE 13 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3
X Y (M + 1) XXXIII(2) N.sup.6-(trans-4- aminocyclohexyl)-7-ethyl-
N.sup.8-[4-(ethyloxy) phenyl]imidazo[1,2-b] pyridazine-6,8-diamine
H H i-Pr ##STR00630## ##STR00631## 365 XXXIII(3) N.sup.6-(trans-4-
Aminocyclohexyl)-7-benzyl- N.sup.8-phenylimidazo[1,2-
b]pyridazine-6,8-diamine H H CH.sub.2Ph ##STR00632## ##STR00633##
365 XXXIII(4) 3-((6-((trans-4- Aminocyclohexyl)amino)-7-
isopropylimidazo[1,2- b]pyridazin-8-yl)amino)-N-
ethylbenzenesulfonamide H H i-Pr ##STR00634## ##STR00635## 472
XXXIII(5) 4-((6-((trans-4- Aminocyclohexyl)amino)-7-
isopropylimidazo[1,2- b]pyridazin-8-yl)amino)-N-
ethylbenzenesulfonamide H H i-Pr ##STR00636## ##STR00637## 472
XXXIII(6) 4-((6-((trans-4- Aminocyclohexyl)amino)-7-
isopropylimidazo[1,2- b]pyridazin-8-yl)amino)-N- phenylbenzamide H
H i-Pr ##STR00638## ##STR00639## 484 XXXIII(7) N.sup.6-(trans-4-
Aminocyclohexyl)-7- isopropyl-N.sup.8-3- pyridinylimidazo[1,2-
b]pyridazine-6,8-diamine H H i-Pr ##STR00640## ##STR00641## 366
XXXIII(8) N.sup.6-(trans-4- Aminocyclohexyl)-N.sup.8-(3-
ethoxyphenyl)-7- isopropylimidazo[1,2- b]pyridazine-6,8-diamine H H
i-Pr ##STR00642## ##STR00643## 409 XXXIII(9) N.sup.6-(trans-4-
Aminocyclohexyl)-N.sup.8-(4- ethoxyphenyl)-7- isopropylimidazo[1,2-
b]pyridazine-6,8-diamine H H i-Pr ##STR00644## ##STR00645## 409
XXXIII(10) 4-((6-((trans-4- Aminocyclohexyl)amino)-7-
isopropylimidazo[1,2- b]pyridazin-8- yl)amino)phenol H H i-Pr
##STR00646## ##STR00647## 381 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example XXXV(1)
N.sup.6-(trans-4-Aminocyclohexyl)-N.sup.8-(4-(aminomethyl)phenyl)-7-methyl-
imidazo[1,2-b]pyridazine-6,8-diamine
##STR00648##
[0370] (1a) To a mixture of free based
8-bromo-6-chloroimidazo[1,2-b]pyridazine from Example 1, step 1b
(100 mg, 0.35 mmol) in THF (1.0 ml) was added p-cyanoaniline (42
mg, 0.35 mmol) and a 1.0 M solution of KOt-Bu in THF (3.0 eq, 1.05
ml, 1.05 mmol). The mixture was allowed to heat at 50.degree. C.
for 1 hour. The solution was then concentrated in vacuo to dryness
to provide
4-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)benzonitrile
as a solid m/e 284 (MH+) (1b) To
4-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)benzonitrile
from step (1a) was added trans-1,4-diaminocyclohexane (500 mg, 4.38
mmol). The mixture was allowed to melt at 165.degree. C. for 24
hours. The melt was then cooled, water added, followed by
extraction with dichloromethane. The organic layer was concentrated
in vacuo and purified by preparative HPLC to provide
4-(6-(4-trans-aminocyclohexylamino)-7-methylimidazo[1,2-b]pyridazin-8-yla-
mino)benzonitrile 42 mg (20%) as a TFA salt. m/e 362 (MH+). (1c) To
4-(6-(4-trans-aminocyclohexylamino)-7-methylimidazo[1,2-b]pyridazin-8-yla-
mino)benzonitrile (42 mg, 0.071 mmol) from step (1b) in 2N ammonia
in MeOH (10 ml) was added palladium on carbon (50 mg). The reaction
mixture was allowed to shake in a PARR apparatus for 16 hours at 55
psi of hydrogen. The catalyst was filtered and the filtrate was
concentrated in vacuo. The resulting residue was purified by
preparative HPLC to give 5.3 mg (10%) of the titled compound as a
TFA salt. NMR (500 MHz, MeOH) .delta. ppm 8.01 (1H, d, J=2.0 Hz),
7.73 (1H, d, J=2.0 Hz), 7.36 (2H, d, J=8.5 Hz), 6.86 (2H, d, J=8.5
Hz), 4.04 (2H, s), 3.97 (1H, m), 3.17 (1H, m), 2.27 (2H, m), 2.15
(2H, m), 2.12 (3H, s), 1.57 (4H, m). LC/MS, m/e 366 (M+1). HPLC Rt,
0.91 min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
Example XXXVI(1)
6-(3-Amino-1,2-benzisoxazol-5-yl)-N-phenylimidazo[1,2-b]pyridazin-8-amine
##STR00649##
[0372] (1a) A solution of potassium t-butoxide in THF (4.73 mL,
4.73 mmol) was added dropwise to a solution of
N-(4-methoxybenzyl)aniline (0.92 g, 4.3 mmol) in THF (10 mL) at
0.degree. C. The solution was warmed to RT for 15 minutes, recooled
to 0.degree. C. and a solution of
8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 4.30 mmol) from
Example 1, step 1b, in THF (10 mL) was added in rapidly. The
solution was stirred at 0.degree. C. for 30 minutes and then at RT
for 30 minutes. The reaction solution was concentrated in vacuo.
The resulting residue was purified by flash chromatography eluting
with 10% ethyl acetate/heptane to provide 0.75 g (48%) of
6-chloro-N-(4-methoxybenzyl)-N-phenyl
imidazo[1,2-b]pyridazin-8-amine.
[0373] (1b) To a vial was added
6-chloro-N-(4-methoxybenzyl)-N-phenyl
imidazo[1,2-b]pyridazin-8-amine (150 mg, 0.411 mmol) from (1a),
3-cyano-4-fluorophenylboronic acid (74.6 mg, 0.452 mmol), potassium
phosphate (174 mg, 0.822 mmol),
tris(dibenzylideneacetone)dipalladium (2.0 mg, 0.002 mmol) and
1,2,3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene
(CTC-Q-Phos) (5.8 mg, 0.008 mmol) in toluene (2 mL) under nitrogen.
The solution was heated to 100.degree. C. for 10 hours. After
checking the reaction solution which showed no reaction, more
palladium reagent (2.0 mg), ligand (5.8 mg) and boronic acid (74.6
mg) were added. After heating at 100.degree. C. for another 24
hours, the reaction went to completion with no SM left. The crude
product mixture was filtered through celite, concentrated in vacuo
to provide
2-fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-y-
l)benzonitrile which was used as is in the next reaction. LC/MS,
m/e 450 (M+1). HPLC Rt, 3.60 min. Waters Sunfire C18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
[0374] (1c) To a solution of acetohydroxamic acid (42 mg, 0.556
mmol) in DMF (1 mL) was added a solution of potassium t-butoxide in
THF (0.56 mL, 0.56 mmol). The reaction solution was stirred at RT
for 15 minutes and then a solution of
2-fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-y-
l)benzonitrile (25 mg, 0.056 mmol) from (1b) in DMF (1 mL) was
added. The reaction solution was stirred at RT for 24 hours. The
solution was diluted with methanol and purified by preparative HPLC
to give
5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d-
]isoxazol-3-amine LC/MS, m/e 463 (M+1). HPLC Rt, 3.13 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0375] (1d) To a solution of
5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d-
]isoxazol-3-amine from (1c) was added TFA (1 mL) and the solution
stirred at RT for 1 hour. The reaction solution was concentrated in
vacuo, diluted with methanol and purified by preparative HPLC to
provide the titled compound (13.20 mg, 70%). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. ppm 8.3 (1H, s), 8.21 (1H, d=2.2 Hz), 8.11 (1H,
m), 7.97 (1H, m), 7.52 (4H, m), 7.3 (1H, m), 7.1 (1H, m), 7.07 (1H,
d, J=8.8 Hz). LC/MS, m/e 343 (M+1). HPLC Rt, 2.63 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XXXVII(1)
6-(3-Amino-1,2-benzisoxazol-6-yl)-N-phenylimidazo[1,2-b]pyridazin-8-amine
##STR00650##
[0377] (1a) To a vial was added
6-chloro-N-(4-methoxybenzyl)-N-phenyl
imidazo[1,2-b]pyridazin-8-amine (100 mg, 0.274 mmol) from Example
XXXVI(1) step (1a), 4-cyano-3-fluorophenylboronic acid (49.7 mg,
0.302 mmol), tetrakis(triphenylphosphine) palladium (17.4 mg, 0.015
mmol) and cesium carbonate (295 mg, 0.905 mmol in water (0.2 mL))
and DMF (2 mL). The solution was heated to 100.degree. C. for 10
hours. The crude product mixture was filtered through celite,
concentrated in vacuo and purified by preparative HPLC to give
2-fluoro-4-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-y-
l)benzonitrile (30 mg, 24%). LC/MS, m/e 463 (M+1). HPLC Rt, 3.80
min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent
B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
[0378] (1b) To a solution of acetohydroxamic acid (50 mg, 0.667
mmol) in DMF (1 mL) was added a solution of potassium t-butoxide in
THF (0.667 mL, 0.667 mmol). The reaction solution was stirred at RT
for 15 minutes and then a solution of
2-fluoro-4-(844-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)-
benzonitrile (30 mg, 0.067 mmol) from (1a) in DMF (1 mL) was added.
The reaction solution was stirred at RT for 24 hours. The solution
was diluted with methanol and purified by preparative HPLC to give
6-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d-
]isoxazol-3-amine LC/MS, m/e 463 (M+1). HPLC Rt, 3.08 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0379] (1c) To a solution of
6-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d-
]isoxazol-3-amine from (1b) was added TFA (1 mL) and the solution
stirred at RT for 1 hour. The reaction solution was concentrated in
vacuo and then diluted with methanol and purified by preparative
HPLC to provide the titled compound (3.90 mg, 17%). .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. ppm 8.26 (1H, s), 7.92 (1H, s), 7.86
(1H, d, J=8.6 Hz), 7.80 (1H, d, J=8.25 Hz), 7.52 (4H, m), 7.35 (1H,
t, J=7.15 Hz), 7.27 (1H, s). LC/MS, m/e 343 (M+1). HPLC Rt, 2.52
min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent
B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Example XXXVIII(1)
N.sup.6-(trans-4-Aminocyclohexyl)-7-(3-chlorophenyl)-N.sup.8-phenylimidazo-
[1,2-b]pyridazine-6,8-diamine
##STR00651##
[0381] (1a) To a flask was added ethyl
2-(3-chlorophenyl)-2-oxoacetate (1.8 g, 8.47 mmol) and acetic
anhydride (1.60 ml, 16.93 mmol) in DCE (5 ml) at RT. To the
resulting solution was added titanium(IV) chloride (16.93 ml, 16.93
mmol) and tributylamine (2.42 ml, 10.16 mmol). The solution was
heated to reflux for 12 hours. The solution was then cooled in ice,
and a solution of ammonium chloride was added. The mixture was
stirred for 30 min. LC/MS indicated all starting material was gone.
The solution was washed with 1.times.NH.sub.4Cl, 1N HCl, water,
dried and concentrated in vacuo to provide
3-(3-chlorophenyl)furan-2,5-dione which was used as is in the next
reaction. LC/MS, m/e 209 (M+1). HPLC Rt, 2.89 min. Waters Sunfire
C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10%
H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
[0382] (1b) To a 25 mL flask was added
3-(3-chlorophenyl)furan-2,5-dione (1.7 g, 8.15 mmol) from (1a) and
hydrazine hydrate (0.476 mL, 9.78 mmol) in water (6 mL) and acetic
acid (4 mL). The resulting mixture was refluxed for 18 hours. The
solution was cooled and placed in the refrigerator for 1 hour. The
resulting precipitate was filtered and dried, then purified by
flash chromatography eluting with 5% methanol/dichloromethane to
give 4-(3-chlorophenyl)pyridazine-3,6-diol.
[0383] (1c) To a vial was added
4-(3-chlorophenyl)pyridazine-3,6-diol (0.2 g, 0.898 mmol) from (1b)
and phosphorus oxychloride (0.837 mL, 8.98 mmol). The reaction was
stirred for 24 h at 100.degree. C. The excess reagent was removed
in vacuo and the residue was dissolved in dichloromethane, washed
2.times. with sodium bicarbonate solution, dried and concentrated
to give 3,6-dichloro-4-(3-chlorophenyl)pyridazine (0.43 g). LC/MS,
m/e 258 (M+1). HPLC Rt, 3.22 min. Waters Sunfire C18 column
(4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O,
0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA). Gradient,
start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1
min, flow rate 4 mL/min.
[0384] (1d) 3,6-dichloro-4-(3-chlorophenyl)pyridazine from (1c) was
processed as described in Example XIII (1) steps (1a-e) to provide
the titled compound (4.9 mgs, 27%). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. ppm 8.04 (1H, s), 7.75 (1H, s), 7.46 (2H, d,
J=8.80 Hz), 7.29 (2H, d, J=8.25 Hz), 7.19 (2H, t, J=7.97 Hz), 7.02
(1H, t, J=7.42 Hz), LC/MS, m/e 433 (M+1). HPLC Rt, 2.28 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0385] Compounds having the formula (Ia) were prepared according to
procedures similar to Example XXXVIII(1), where in R.sub.1,
R.sub.2, R.sub.3, X and Y have the values listed in Table 14 using
the appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00014 TABLE 14 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3
X Y (M + 1) N.sup.6-(trans-4- Aminocyclohexyl)-7-(4-
chlorophenyl)-N.sup.8- phenylimidazo[1,2-b] pyridazine-6,8-diamine
H H 4-PhCl ##STR00652## ##STR00653## 434 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example XXXIX(1)
8-Anilino-6-((3S)-3-piperidinylamino)imidazo[1,2-b]pyridazine-3-carbonitri-
le
##STR00654##
[0386] (1a)
6-Chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-car-
bonitrile (100 mg, 0.257 mmol) from example XXXI, step (1b) and
(S)-3-amino-1-benzylpiperidine (195 mg, 1.026 mmol) were combined
in a 1-dram vial and heated at 160.degree. C. for 6 h. The reaction
was cooled to room temperature, dissolved in DCM (2 mL) and loaded
onto to a 12 g silica gel column and eluted with 5%-100%
EtOAc/heptane to give
(S)-6-(1-benzylpiperidin-3-ylamino)-8-((4-methoxybenzyl)(phenyl)amino)imi-
dazo[1,2-b]pyridazine-3-carbonitrile (55 mg, 40%). LCMS m/z (544,
M+1). (1b)
6-(1-Benzylpiperidin-3-ylamino)-8-((4-methoxybenzyl)(phenyl)amino)im-
idazo[1,2-b]pyridazine-3-carbonitrile from step (1a) (50 mg, 0.092
mmol) was dissolved in DCE (2 ml) and treated with 1-chloroethyl
chloroformate (0.030 ml, 0.276 mmol). The mixture was heated at
85.degree. C. overnight. The solvent was removed in vacuo to give a
slurry that was suspended in MeOH (2 mL). The mixture was heated at
85.degree. C. for 5 h. The mixture was cooled to room temperature.
and purified on a reverse-phase HPLC to give the titled compound
(17 mg, 0.039 mmol, 42.9%) as a TFA salt. LCMS, m/z (334, M+1).
HPLC Rt, 2.47 min. Sunfire C18 column (4.6.times.50 mm) 0%-100% B.
Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min. 1H NMR (400 MHz, MeOD) .delta. ppm 7.96 (s, 1H), 7.39-7.48
(m, 2H), 7.33-7.38 (m, 2H), 7.18-7.24 (m, 1H), 6.27 (s, 1H), 4.11
(m, 1H), 3.64 (m, 1H), 3.25 (m, 1H), 3.01 (m, 2H), 2.02-2.14 (m,
2H), 1.78-1.90 (m, 1H), 1.62-1.72 (m, 1H).
Example XL(1)
3-((6-((trans-4-Aminocyclohexyl)amino)-7-isopropylimidazo[1,2-b]pyridazin--
8-yl)amino)phenol
##STR00655##
[0388] (1a) To a vial was added
N6-(4-trans-aminocyclohexyl)-N-8-(3-(benzyloxy)phenyl)-7-(isopropyl)imida-
zo[1,2-b]pyridazine-6,8-diamine (20.2 mg, 0.043 mmol) prepared by
the method described in Example XXXIII(1) in dichloromethane (2
mL). To the reaction solution at RT was added a solution of boron
tribromide (0.1 mL, 1M). The reaction was stirred for 1 h at RT.
The solution was quenched with methanol, concentrated in vacuo and
purified by preparative HPLC to provide the titled compound (10.50
mg, 65%). .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm 8.00 (1H,
s), 7.64 (1H, s), 7.04 (1H, m), 6.20 (3H, m), 4.03 (1H, m), 3.21
(1H, m), 2.5 (1H, m), 2.27 (2H, m), 2.05 (2H, m), 1.56-1.65 (4H,
m), 1.38 (6H, d, J=7.15 Hz). LC/MS, m/e 381 (M+1). HPLC Rt, 1.63
min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent
B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90%
H.sub.2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Example LXI (1)
N.sup.6-(trans-4-Aminocyclohexyl)-3-cyclopropyl-N.sup.8-phenylimidazo[1,2--
b]pyridazine-6,8-diamine
##STR00656##
[0389] (1a)
3-Bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine (200 mg, 0.45 mmol) from Example XXXI, step (1a) and
trans-1,4-cyclohexanediamine (1.1 g, 9.6 mmol) in NMP (2 mL) were
heated in a microwave reactor at 200.degree. C. for 1 h. After
cooling to room temperature, the resulting mixture was poured into
water and the resulting solid was collected and dried on a filter.
The dry solid was dissolved in dichloromethane (4 mL) and
Boc.sub.2O (159 mg) was added followed by stirring at room
temperature for 1 h. Concentration and purification by flash
chromatography provided tert-butyl
4-(3-bromo-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl-
amino)cyclohexylcarbamate as a light yellow solid (182 mg, 61%)
LCMS [M+H].sup.+621. (1b) tert-Butyl
4-(3-bromo-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl-
amino)cyclohexylcarbamate (30 mg, 0.048 mmol) from (1a) and
cyclopropylboronic acid (10 mg, 0.090 mmol) in toluene were purged
with argon for 15 min, then aq. K.sub.3PO.sub.4 (2M, 0.06 mL), EtOH
(0.04 mL) and tetrakis(triphenylphosphine)palladium(0) were added
sequentially. The mixture was heated at 120.degree. C. for 20 h.
After cooling to room temperature, the mixture was partitioned
between EtOAc (20 mL) and water (5 mL) and the organic layer was
washed with water, brine, dried over MgSO.sub.4 and concentrated.
The residue was purified by reverse phase preparative HPLC to
provide tert-butyl
4-(3-cyclopropyl-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazi-
n-6-ylamino)cyclohexylcarbamate as a cream colored oil (4.3 mg,
15%) LCMS [M+H].sup.+583. (1c) To tert-butyl
4-(3-cyclopropyl-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazi-
n-6-ylamino)cyclohexylcarb (4 mg) from (1b) in dichloromethane at
room temperature was added TFA and the resulting mixture was
stirred for 30 min. then concentrated. The resulting residue was
purified by reverse phase preparative HPLC to provide the titled
compound as a white solid (1.5 mg). H.sup.1 NMR (400 MHz,
MeOH-d.sub.4) .delta. ppm 7.42 (1H, s), 7.34 (2H, m), 7.23 (3H, m),
6.30 (1H, s), 3.64 (1H, m), 3.02 (1H, m), 2.18 (2H, m), 2.00-2.17
(3H, m), 1.43 (2H, m), 1.04 (2H, m). 0.82 (2H, m). LCMS, m/e 363
(M+1). HPLC Rt, 1.82 min. YMC S5 ODSC18 column (4.6.times.50 mm)
0%-100% B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.2%
H.sub.3PO.sub.4). Solvent A: (10% MeOH, 90% H.sub.2O, 0.2%
H.sub.3PO.sub.4). Gradient, start % B=0, final % B=100, gradient
time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Example LXII(1)
N.sup.6-(4-Aminocyclohexyl)-N.sup.8-phenyl-3-((E)-2-(4-pyridinyl)vinyl)imi-
dazo[1,2-b]pyridazine-6,8-diamine
##STR00657##
[0390] (1a) To
6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine
(940 mg, 2.57 mmol) from Example X, step (1a) in chloroform (10 mL)
at room temperature was added NIS in one portion and the resulting
mixture was refluxed for 5 h. Concentration and purification by
flash chromatography provided
6-chloro-3-iodo-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyrida-
zin-8-amine as a foamy, yellow solid (960 mg, 76%). LCMS
[M+H].sup.+ 490. (1b)
6-chloro-3-iodo-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin--
8-amine (120 mg, 0.25 mmol) from (1a), 4-vinylpyridine(54 .mu.L,
0.50 mmol) and Pd(OAc).sub.2 (23 mg, 0.1 mmole) in acetonitrile (1
mL) were heated at 85.degree. C. for 2 h. After cooling to room
temperature, the mixture was partitioned between EtOAc (200 mL) and
water (20 mL) and the organic layer was washed with water, brine,
then dried over MgSO.sub.4 and concentrated. The resulting residue
was purified by flash chromatography to provide
6-chloro-N-(4-methoxybenzyl)-N-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,-
2-b]pyridazin-8-amine as a yellow solid (75 mg, 66%). LCMS
[M+H].sup.+ 468. (1c)
6-chloro-N-(4-methoxybenzyl)-N-phenyl-3-(2-(pyridin-4-yl)vinyl)-
imidazo[1,2-b]pyridazin-8-amine (75 mg, 0.16 mmol) from (1b),
sodium tert-butoxide (22 mg, 0.22 mmol),
trans-1,4-cyclohexanediamine (22 mg, 0.19 mmol) and
acetato(2'-di-tert-butylphosphino-1,1'-biphenyl-2-yl)palladium (II)
(7.4 mg, 0.01 mmole) were purged with argon for 15 min. then
toluene (0.6 mL) was added via syringe. The contents were sonicated
briefly and heated at 85.degree. C. for 2 h. After cooling to room
temperature, the mixture was partitioned between EtOAc (200 mL) and
water (20 mL), and the organic layer was washed with water, brine,
dried over MgSO4 and concentrated. The residue was purified by
reverse phase preparative HPLC to provide
N6-(trans-4-aminocyclohexyl)-N-8-(4-methoxybenzyl)-N-8-phenyl-3-(2-(pyrid-
in-4-yl)vinyl)imidazo[1,2-b]pyridazine-6,8-diamine as a yellow
solid (32 mg, 38%). LCMS[M+H].sup.+ 546. (1d) To
N6-(trans-4-aminocyclohexyl)-N-8-(4-methoxybenzyl)-N-8-phenyl-3-(2-(pyrid-
in-4-yl)vinyl)imidazo[1,2-b]pyridazine-6,8-diamine (30 mg) from
step (1c) in dichloromethane at room temperature was added excess
TFA. The mixture was stirred for 30 min, concentrated, and the
resulting residue was purified by reverse phase preparative HPLC to
provide the titled compound as a yellow solid (21 mg). NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 9.05 (1H, s), 8.66 (2H, m),
7.78-7.90 (8H, m), 7.39-7.44 (4H, m), 7.16 (1H, m), 6.68 (1H, m),
6.26 (1H, s), 3.62 (1H, m), 3.08 (1 H, m), 2.20 (2H, m), 2.02 (2H,
m), 1.51-1.54 (2H, m), 1.25-1.29 (2H, m). LC/MS, m/e 426 (M+1).
HPLC Rt, 1.89 min. YMC S5 ODSC18 column (4.6.times.50 mm) 0%-100%
B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.2% H.sub.3PO.sub.4).
Solvent A: (10% MeOH, 90% H.sub.2O, 0.2% H.sub.3PO.sub.4).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
Example LXIII(1)
N.sup.6-(trans-4-Aminocyclohexyl)-N.sup.8-phenyl-3-(1-propyn-1-yl)imidazo[-
1,2-b]pyridazine-6,8-diamine
##STR00658##
[0391] (1a) To a 2 dram vial was added trans-1,4-cyclohexyldiamine
(0.040 g, 0.1 mmol) and
3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine (0.5 g, 4.3 mmol) from Example XXXI step (1a). The reaction was
sealed and allowed to stir at 165.degree. C. for 16 hrs. Upon
cooling, the sample was dissolved in methylene chloride and washed
with water. Upon separation, the organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The brownish
residue was dissolved in methanol (25%)/water (75%) mixture with 4
drops of trifloroacetic acid. The solution was purified by HPLC
(5-60% methanol gradient), to provide
N6-((trans)-4-aminocyclohexyl)-3-bromo-N-8-(4-methoxybenzyl)-N-8-phenylim-
idazo[1,2-b]pyridazine-6,8-diamine TFA salt as a brown solid (0.060
g (21%). m/z=(521, M+1) (1b) To a 2 ml microwave vessel added
N6-((trans)-4-aminocyclohexyl)-3-bromo-N8-(4-methoxybenzyl)-N-8-phenylimi-
dazo[1,2-b]pyridazine-6,8-diamine TFA salt (0.060 g, 0.08 mmol)
from (1a), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.005 g, 0.002 mmol), CuI
(0.0015 g, 0.008 mmol) and TEA (1.6 ml, 0.05 M). The vessel was
sealed and pump/purged with nitrogen 3 times. Propyne gas was then
introduced via needle and the reaction was mixture was saturated
over a 2 minute time interval. The reaction was heated thermally
for 2 hours at 70.degree. C. Upon cooling, the solvent was removed
in vacuo and the reaction was diluted with ethyl acetate and
filtered through a plug of celite. The solvent was removed
providing crude
N6-((trans)-4-aminocyclohexyl)-N-8-(4-methoxybenzyl)-N-8-phenyl-3-(prop-1-
-ynyl)imidazo[1,2-b]pyridazine-6,8-diamine m/z=(481, M+1). (1c) To
a 2 dram vial was added crude
N6-((trans)-4-aminocyclohexyl)-N-8-(4-methoxybenzyl)-N-8-phenyl-3-(prop-1-
-ynyl)imidazo[1,2-b]pyridazine-6,8-diamine (0.065 g, 0.13 mmol)
from (1b) and a 1:1 mixture of TFA and CH.sub.2Cl.sub.2 (2 ml). The
reaction was stirred for 2 hours, concentrated, diluted with MeOH
and purified by preparative HPLC to provide the titled compound
(0.0025 g, 5%) as a TFA salt. 1H NMR (400 MHz, MeOD) .delta. ppm
7.44 (2H, dd, 8 Hz), 7.33 (2H, d, 8 Hz), 7.18-7.26 (1H, m),
7.18-7.25 (2H, m), 6.39 (1H, s), 3.68-3.82 (1H, m), 3.06-3.21 (1H,
m), 2.23-2.35 (2H, m), 2.18 (3H, s), 1.46-1.62 (2H, m), 1.25-1.41
(2H, m). LC/MS, m/z 361 (M+1). HPLC Rt, 2.30 min. Waters Sunfire
C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10%
H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
Example LXIV(1)
6-((trans-4-Aminocyclohexyl)amino)-8-anilino-N-4-pyridinylimidazo[1,2-b]py-
ridazine-3-carboxamide
##STR00659##
[0392] (1a) To an oven dried 25 ml shlenk flask under nitrogen was
added
3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-am-
ine (0.5 g, 1.1 mmol) from Example XXXI step (1a) and THF (5.0 ml).
The solution was cooled to -78.degree. C. and n-butyllithium was
added drop-wise over 10 minutes. The reaction was allowed to stir
at the depressed temperature for 1 hour. Carbon dioxide gas was
then introduced via a needle purging the solution for 2 minutes.
The reaction was allowed to warm to 25.degree. C. and stir for an
additional 30 minutes. Dilute 1N HCl was added taking the aqueous
portion to pH=5. Ethyl acetate was added and the layers separated.
The organic layer was washed with water (20 ml), then brine (10
ml), dried over Na.sub.2SO.sub.4, filtered and concentrated to
provide 0.47 g of 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)
imidazo[1,2-b]pyridazine-3-carboxylic acid (98%). m/z=(410, M+1).
(1b) To a 2 dram vial was added
6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-imidazo[1,2-b]pyridazine-3-ca-
rboxylic acid (0.025 g, 0.06 mmol) from (1a), EDCI (0.018 g, 0.09
mmol), HOBT (0.012 g, 0.09 mmol), 4-aminopyridine (8.46 mg, 0.09
mmol), TEA (0.025 ml, 0.18 mmol) and CH.sub.3CN (1.0 ml). The
reaction was stirred at 25.degree. C. for 48 hours then
concentrated to give crude
6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(pyridin-4-yl)imidazo[1,2-b-
]pyridazine-3-carboxamide. To this residue was added
trans-1,4-cyclohexyldiamine (0.5 g, 4.3 mmol) and the resulting
mixture was allowed to heat at 165.degree. C. for 5 hrs. Upon
cooling, the sample was dissolved in methylene chloride, and washed
with water. The organics were separated, then dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. To this
residue was added a 1:1 mixture of CH.sub.2Cl.sub.2/TFA (2 ml). The
solution was stirred at 25.degree. C. for 3 hours, concentrated,
diluted with MeOH and purified by preparative HPLC to provide the
titled compound (0.008 g, 22%) as a TFA salt. 1H NMR (500 MHz,
MeOH) .delta. ppm 8.74 (2H, d, J=7.15 Hz), 8.30 (2H, d, J=7.15 Hz),
8.19 (1H, s), 7.41-7.50 (2H, m), 7.31-7.41 (2H, m), 7.17-7.26 (1H,
m), 6.26-6.33 (1H, m), 3.71-3.87 (1H, m), 3.10-3.23 (1H, m),
2.25-2.39 (2H, m), 2.06-2.24 (2H, m), 1.53-1.66 (2H, m), 1.35-1.52
(2H, m). LC/MS, m/z 443 (M+1). HPLC Rt, 2.34 min. Waters Sunfire
C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90% MeOH, 10%
H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O, 0.1% TFA).
Gradient, start % B=0, final % B=100, gradient time 4 min, hold at
100% B 1 min, flow rate 4 mL/min.
Example LXV(1)
6-((4-Amino-1-piperidinyl)methyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine
##STR00660##
[0393] (1a) To a 20 ml microwave vial was added
6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine
(0.66 g, 1.8 mmol) from Example XXXI, step (1a), zinc cyanide (0.13
g, 1.1 mmol), Pd.sub.2(dba).sub.3 (0.033 g, 0.036 mmol),
1,1'-bis(diphenylphosphino)-ferrocene [dppf] (0.040 g, 0.07 mmol),
zinc dust (0.012 g, 0.18 mmol) and DMA (11.0 ml, 0.17 M). The
reaction mixture was sealed and pump/purged 3.times. with nitrogen
then heated in a microwave for 20 minutes at 150.degree. C. Upon
cooling, the suspension was diluted with ethyl acetate (50 ml) and
filtered through a plug of celite. To the resulting solution was
added 10% LiCl solution and the layers separated. The organic layer
was washed two additional times with 10% LiCl solution, then brine
(1.times.), dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. This residue was purified on silica gel (ISCO-80 gram)
using a 30-100% ethyl acetate/heptane gradient over 20 minutes. To
provide
8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-6-carbonitrile
(0.63 g, 98%). m/z=(357, M+1). (1b) To a 25 ml round bottom flask
was added
8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-6-carbon-
itrile (0.62 g, 1.7 mmol) from (1a) and toluene (3.4 ml, 0.5 M) and
the solution cooled to -5.degree. C. To this was added dropwise, a
1.0 M solution of diisobutylaluminum hydride [DIBAL] in toluene
(3.5 ml, 3.5 mmol) over a period of 10 minutes. The reaction was
stirred at -5.degree. C. for 1 hour and then warmed to room
temperature and allowed to stir for an additional 2 hours. Dilute
1N HCl and ethyl acetate were added and the layers separated. The
acidic aqueous layer was extracted 1 additional time with ethyl
acetate and then basified with a 50% NaOH solution. The aqueous
layer was extracted 2.times. with ethyl acetate and the combined
organics were washed with brine (20 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide
crude
6-(aminomethyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-ami-
ne (0.44 g) which was used as such in the subsequent step.
m/z=(360, M+1). (1c) To a 40 ml reaction vial was added
6-(aminomethyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-ami-
ne (0.437 g, 1.2 mmol) from (1b), ethanol (5.0 ml, 0.2 M) and
methyl acrylate (0.33 ml, 3.6 mmol). The vial was sealed and the
reaction was heated 90.degree. C. for 72 hours. Upon cooling, the
volatiles were evaporated and the crude material was purified on
silica gel (ISCO--40 gram) using a 10-70% ethyl acetate/heptane
gradient over 20 minutes. This gave 0.44 g of the di-substituted
product as a mixture of the methyl and ethyl esters. m/z=(532, M+1,
methyl ester) and m/z=(546, M+1, ethyl ester). (1d) The product of
step (1c) (0.440 g, .about.0.83 mmol) was diluted in THF (1.0 ml),
cooled to 0.degree. C. and then dropwise treated with potassium
tert-butoxide (1.655 mL, 1.655 mmol). The reaction was stirred
overnight at room temperature. 1 N NaOH (1.655 mL, 1.655 mmol) was
added and the mixture was allowed to stir at 50.degree. C. for 1
hour. To this was added 1 N HCl (3.31 mL, 3.31 mmol) and stirring
was continued at room temperature for 4 hrs. A 50% NaOH solution
was then added taking the mixture to pH .about.10 and this was
followed by dilution with ethyl acetate. The layers were separated
and the organic was washed with water, then brine, dried over
Na.sub.2SO.sub.4, and concentration to dryness to provide
1-((8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)methyl-
)piperidin-4-one (0.229 g, 62.7% yield). m/z=(442, M+1). (1e) In a
2 dram vial was added
1-((8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)methyl-
)piperidin-4-one (0.048 g, 0.109 mmol) from (1d), THF (0.362 mL)
and benzylamine (0.013 mL, 0.120 mmol). The reaction was allowed to
stir at room temperature for 1 hr. Sodium triacetoxyborohydride
(0.092 g, 0.435 mmol) was then added and the reaction stirred for
48 hours at ambient temperature. The mixture was diluted with ethyl
acetate and 1N NaOH solution and the layers separated. The organics
were washed with water and the resulting aqueous solution was
back-extracted with ethyl acetate (2.times.). The combined organics
were collected, dried over Na.sub.2SO.sub.4, filtered and
concentrated to provide
6-((4-(benzylamino)piperidin-1-yl)methyl)-N-(4-methoxybenzyl)-N-phenylimi-
dazo[1,2-b]pyridazin-8-amine (0.05 g, 86% yield) which was
subsequently used without further purification m/z=(532, M+1). (1f)
In a Parr bottle was added
6-((4-(benzylamino)piperidin-1-yl)methyl)-N-(4-methoxybenzyl)-N-
-phenylimidazo[1,2-b]pyridazin-8-amine (0.030 g, 0.056 mmol) from
(1e), MeOH (7 ml), Pd/C (0.030 mg, 0.282 .mu.mol) and AcOH (0.020
ml, 0.349 mmol). Added hydrogen to a pressure of 55 psi and let
shake overnight. The suspension was filtered through celite and
rinsed with MeOH, concentrated, and then diluted with TFA (1 ml).
The mixture was allowed to stir at room temperature for 6 hours,
concentrated and diluted with MeOH (2 ml) and purified by HPLC
(10-75% MeOH/Water) to provide the title compound (0.009 g, 49.6%
yield) as a TFA salt. 1H NMR (500 MHz, MeOH) .delta. ppm 8.08 (1H,
d, J=2.75 Hz), 7.76 (1H, d, J=2.75 Hz), 7.47 (2H, dd, J=7.56, 3.44
Hz), 7.40-7.45 (2H, m), 7.25-7.31 (1H, m), 6.78 (1H, d, J=3.67 Hz),
4.40 (2H, d, J=3.21 Hz), 3.74 (2H, d, J=11.00 Hz), 3.46 (1H, d,
J=3.67 Hz), 3.22 (2H, t, J=12.14 Hz), 2.25 (2H, d, J=14.20 Hz),
2.00 (2H, m). LC/MS, m/z 323 (M+1). HPLC Rt, 1.04 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
Example LXVI(1)
6-((trans-4-Aminocyclohexyl)amino)-8-anilinoimidazo[1,2-b]pyridazine-7-car-
bonitrile
##STR00661##
[0394] (1a) To a solution of ethyl 1H-imidazole-2-carboxylate (701
mg, 5 mmol) in DMF (20 ml) was dropwise added potassium
tert-butoxide (5.50 ml, 5.50 mmol). The reaction turned cloudy in
the middle of the addition. The mixture was stirred for 30 minutes
before O-(4-nitrobenzoyl)hydroxylamine (911 mg, 5.00 mmol) in DMF
(10 mL) was added dropwise. The reaction turned dark blue and then
brown and finally orange as the addition continued. The reaction
was stirred at room temperature overnight and poured into aqueous
NaHCO.sub.3 (150 mL) to form a clear yellow solution which was
extracted with CH.sub.2Cl.sub.2 (4.times.200 ml). The organic
layers were combined and evaporated in vacuo to provide ethyl
1-amino-1H-imidazole-2-carboxylate (760 mg, 98% yield) as a yellow
solid. (1b) In a 100 ml RB flask was added ethyl
1-amino-1H-imidazole-2-carboxylate (0.4 g, 2.58 mmol) from (1a),
DCE (12.0 mL), 2-cyanoacetyl chloride (0.320 g, 3.09 mmol) and
pyridine (0.417 mL, 5.16 mmol). The resulting mixture was stirred
overnight under nitrogen at room temperature. The reaction was
concentrated and diluted with ethyl acetate and washed with water
(2.times.), then the aqueous was back-extracted with ethyl acetate.
The organics were collected, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide
ethyl 1-(2-cyanoacetamido)-1H-imidazole-2-carboxylate (0.38 g,
66.3% yield). (1c) In a 40 ml reaction vial was added ethyl
1-(2-cyanoacetamido)-1H-imidazole-2-carboxylate (3.00 g, 13.50
mmol) prepared as described in (1b) and THF (2 ml). The mixture was
cooled to 0.degree. C. and potassium tert-butoxide (40.5 ml, 40.5
mmol) was added dropwise. The mixture was stirred at room
temperature for 16 hours. 4.0 M HCl (10.13 ml, 40.5 mmol) in
dioxane was added and the mixture was stirred for 30 min. The
volatiles were evaporated to provide
6,8-dioxo-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-7-carbonitrile
which was used without purification in the following step.
m/z=(177, M+1). (1d) In a 40 ml reaction vial was added crude
6,8-dioxo-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-7-carbonitrile
(0.3 g, 1.7 mmol) from (1c) and POCl.sub.3 (7.0 ml, 75.0 mmol) and
the reaction was heated to 120.degree. C. for 24 hours. The mixture
was then concentrated, ice and solid sodium carbonate were added
and the resulting suspension stirred for 1 hour. The mixture was
filtered to provide
6,8-dichloroimidazo[1,2-b]pyridazine-7-carbonitrile (0.14 g, 39%
yield) as a brown solid. m/z=(213, M+1). (1e) In a 1 dram vial,
under argon, was added
6,8-dichloroimidazo[1,2-b]pyridazine-7-carbonitrile (0.050 g, 0.235
mmol) from (1d), N-(4-methoxy)benzylaniline (0.052 g, 0.282 mmol),
potassium carbonate (0.1 g, 0.704 mmol) and acetonitrile (1.0 ml).
The mixture was heated to 100.degree. C. for 6 hours, filtered
through a frit and rinsed with methylene chloride. The resulting
material was dry loaded onto silica and purified by ISCO (12 gram,
10-30% ethyl acetate/heptane gradient over 20 minutes) to provide
6-chloro-8-((4-methoxyphenyl)(phenyl)amino)imidazo[1,2-b]pyridazine-7-car-
bonitrile (0.05 g, 56.7% yield) as a yellowish solid. m/z=(390,
M+1). (1f) In a 1 dram vial was added
6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-7-car-
bonitrile (0.019 g, 0.049 mmol) from (1e),
(trans)-cyclohexane-1,4-diamine (0.011 g, 0.097 mmol), cesium
carbonate (0.048 g, 0.146 mmol), Pd(OAc).sub.2 (0.547 mg, 2.437
.mu.mol),
(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphos-
pine [JOSI-Phos] (1.351 mg, 2.437 .mu.mol) and the solids were
pump/purged with argon (3.times.). Dioxane (1.0 ml, 0.05 M) was
added and the reaction was heated at 100.degree. C. overnight. Upon
cooling, the mixture was filtered through a frit and the resulting
solution was concentrated to dryness. To this residue was added TFA
(1.0 ml) and the solution was stirred for 18 hours, concentrated
and purified by HPLC to provide the titled compound (0.0031 g, 18%
yield) as a TFA salt. 1H NMR (500 MHz, MeOH) .delta. ppm 7.78 (1H,
s), 7.57 (1H, s), 7.43-7.51 (2H, m), 7.31-7.40 (3H, m), 3.77-3.89
(1 H, m), 3.06-3.20 (1H, m), 2.18-2.29 (2H, m), 2.09 (2H, m),
1.36-1.62 (4H, m). LC/MS, m/z 348 (M+1). HPLC Rt, 1.78 min. Waters
Sunfire C18 column (4.6.times.50 mm) 0%-100% B. Solvent B: (90%
MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H.sub.2O,
0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4
min, hold at 100% B 1 min, flow rate 4 mL/min.
[0395] Compounds having the formula (Ia) were prepared according to
procedures similar to Example LXVI(1), where in R.sub.1, R.sub.2,
R.sub.3, X and Y have the values listed in Table 15, using the
appropriate starting materials and substantially the same
procedures as indicated.
TABLE-US-00015 TABLE 15 LC/MS m/z Exp Name R.sub.1 R.sub.2 R.sub.3
X Y (M + 1) LXVI(1) 8-Anilino-6-((3S)-3-
piperidinylamino)imidazo[1,2- b]pyridazine-7-carbonitrile H H CN
##STR00662## ##STR00663## 334 *For substituents X and Y,
substitution on the core (formula Ia) occurs at the available
nitrogen atom
Example LXVII(1)
4-((6-((trans-4-Aminocyclohexyl)amino)-3-cyanoimidazo[1,2-b]pyridazin-8-yl-
)amino)-N-methylbenzenesulfonamide
##STR00664##
[0396] (1a) In a 100 ml round bottom flask was added
3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.122 g, 0.391 mmol)
from Example XXIV, step (1a), 4-amino-N-methylbenzenesulfonamide
(0.080 g, 0.430 mmol), and THF (3.9 ml, 0.1 M). Potassium
tert-butoxide (0.976 mL, 0.976 mmol) was added drop-wise and the
reaction was stirred at 25.degree. C. overnight. The mixture was
concentrated and diluted with ethyl acetate and water. The layers
were separated and the organic was washed water (20 ml), then brine
(10 ml), dried over Na.sub.2SO.sub.4, filtered and concentrated to
provide
4-(3-bromo-6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenzenesulf-
onamide (0.090 g, 55.3% yield) as a brownish solid. m/z=(417, M+1).
(1b) In a microwave vial was added
4-(3-bromo-6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenzenesulf-
onamide (0.068 g, 0.163 mmol) from (1a), DPPF (3.62 mg, 6.53
.mu.mol), Pd.sub.2(dba).sub.3 (2.99 mg, 3.26 .mu.mol), and
Zn(CN).sub.2 (0.031 mL, 0.490 mmol) The solids were pump/purged
with nitrogen. DMA (0.326 mL) was added and the reaction was heated
to 180.degree. C. for 30 minutes, filtered through a frit and
concentrated. The resulting residue was purified by HPLC (30-100%
MeOH/Water) to provide
4-(6-chloro-3-cyanoimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenzenesulf-
onamide (0.025 g, 42% yield). m/z=(363, M+1). (1c) In a 2 dram vial
was added
4-(6-chloro-3-cyanoimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenze-
nesulfonamide (0.025 g, 0.069 mmol) from (1b) and
(trans)-cyclohexane-1,4-diamine (0.700 g, 6.13 mmol). The mixture
was heated to 165.degree. C. for 1 hour. Upon cooling, the mixture
was diluted with CH.sub.2Cl.sub.2, then washed with water, dried
over Na.sub.2SO.sub.4, filtered, concentrated and purified by HPLC
to provide the titled compound (0.008 g, 26.4% yield). 1H NMR (400
MHz, MeOD) .delta. ppm 7.91-7.99 (1H, s), 7.82-7.88 (2H, m),
7.48-7.55 (2H, m), 6.42-6.56 (1H, s), 3.68-3.84 (1H, m), 3.06-3.21
(1H, m), 2.49-2.59 (3H, s), 2.23-2.38 (2H, m), 2.04-2.17 (2H, m),
1.48-1.66 (2H, m), 1.28-1.45 (2H, m). LC/MS, m/z 441 (M+1). HPLC
Rt, 2.30 min. Waters Sunfire C18 column (4.6.times.50 mm) 0%-100%
B. Solvent B: (90% MeOH, 10% H.sub.2O, 0.1% TFA). Solvent A: (10%
MeOH, 90% H.sub.2O, 0.1% TFA). Gradient, start % B=0, final %
B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4
mL/min.
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