U.S. patent application number 14/579733 was filed with the patent office on 2016-09-29 for heteroaryloxycarbocyclyl compounds as pde 10 inhibitors.
The applicant listed for this patent is Amgen Inc.. Invention is credited to Jennifer R. Allen, Michael J. Frohn, Essa Hu Harrington, Paul E. Harrington, Alexander J. Pickrell.
Application Number | 20160280703 14/579733 |
Document ID | / |
Family ID | 44342924 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160280703 |
Kind Code |
A1 |
Allen; Jennifer R. ; et
al. |
September 29, 2016 |
Heteroaryloxycarbocyclyl Compounds as PDE 10 Inhibitors
Abstract
Heteroaryloxycarbocyclyl compounds, and compositions containing
them, and processes for preparing such compounds. Provided herein
also are methods of treating disorders or diseases treatable by
inhibition of PDE10, such as obesity, non-insulin dependent
diabetes, schizophrenia, Huntington's Disease, bipolar disorder,
obsessive-compulsive disorder, and the like.
Inventors: |
Allen; Jennifer R.; (Newbury
Park, CA) ; Frohn; Michael J.; (Thousand Oaks,
CA) ; Harrington; Paul E.; (Camarillo, CA) ;
Harrington; Essa Hu; (Camarillo, CA) ; Pickrell;
Alexander J.; (Westlake Village, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amgen Inc. |
Thousand Oads |
CA |
US |
|
|
Family ID: |
44342924 |
Appl. No.: |
14/579733 |
Filed: |
December 22, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13105873 |
May 11, 2011 |
8952037 |
|
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14579733 |
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61334514 |
May 13, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 25/22 20180101; A61P 25/24 20180101; A61P 3/10 20180101; A61P
25/30 20180101; A61P 25/14 20180101; A61P 43/00 20180101; C07D
403/14 20130101; C07D 413/14 20130101; A61P 3/04 20180101; A61P
3/00 20180101; C07D 417/14 20130101; C07D 401/14 20130101; C07D
487/04 20130101; A61P 25/16 20180101; A61P 25/00 20180101; A61P
25/18 20180101; A61P 25/28 20180101; C07D 417/12 20130101; C07D
405/14 20130101 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 413/14 20060101 C07D413/14; C07D 471/04 20060101
C07D471/04; C07D 417/12 20060101 C07D417/12; C07D 487/04 20060101
C07D487/04; C07D 405/14 20060101 C07D405/14; C07D 401/14 20060101
C07D401/14 |
Claims
1. A compound of formula I: ##STR00373## a stereoisomer, or a
pharmaceutically-acceptable salt thereof, wherein: each of X.sup.1,
X.sup.2, and X.sup.3 is independently N or CR.sup.3; and X.sup.4 is
N; wherein no more than one of X.sup.1, X.sup.2, and X.sup.3 are N;
optionally, the ring containing X.sup.1, X.sup.2, X.sup.3, and
X.sup.4 may be fused to a saturated, partially saturated, or
unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0,
1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S;
wherein said monocyclic ring is independently substituted by 0, 1,
2, 3, or 4 R.sup.3 groups; m is 1, 2, 3, or 4; each of p and q is
independently 0, 1, 2, 3, 4, 5, or 6; wherein the sum of p and q is
2 to 6; the ring containing p and q is in cis or trans
configuration; R.sup.1 is F, Cl, Br, I, C.sub.1-8alk,
C.sub.1-4haloalk, --OR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --C(.dbd.O)R.sup.a,
--C(.dbd.O)R.sup.c, --C(.dbd.O)--O--R.sup.a, --OR.sup.c,
--NR.sup.aR.sup.c, --N(R.sup.c)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)R.sup.c, --C(.dbd.O)NR.sup.aR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.c, or C.sub.0-4alk-L.sup.1; wherein said
C.sub.1-8alk group is substituted by 0, 1, 2 or 3 groups selected
from halo, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk; R.sup.2 is --C(.dbd.O)R.sup.5,
--C(.dbd.O)OR.sup.5, --C(.dbd.O)NR.sup.5R.sup.6, or a group
--Y-L.sup.2; Y is a C.sub.0-4alk, O, NR.sup.7, S, SO, or SO.sub.2;
R.sup.3 is H, F, Cl, Br, CN, OH, OC.sub.1-4alk, C.sub.1-4alk, or
C.sub.1-4haloalk; R.sup.4a is H, C.sub.1-4alk, or C.sub.1-4haloalk;
each R.sup.4b is independently H, F, Cl, Br, CN, OH, OC.sub.1-4alk,
C.sub.1-4alk, or C.sub.1-4haloalk; R.sup.4a is R.sup.4b when
R.sup.2 is --C(.dbd.O)R.sup.5, --C(.dbd.O)OR.sup.5,
--C(.dbd.O)NR.sup.5R.sup.6, or said group --Y-L.sup.2; wherein Y is
C.sub.0-4alk, SO, or SO.sub.2; R.sup.4a is R.sup.4a when R.sup.2 is
said group --Y-L.sup.2, wherein Y is O, NR.sup.7, or S; each of
R.sup.5 and R.sup.6 is independently H, C.sub.1-8alk, or
C.sub.0-8alk-L.sup.3; R.sup.7 is independently H or R.sup.b;
R.sup.a is independently H or R.sup.b; R.sup.b is independently
phenyl, benzyl, or C.sub.1-6alk, wherein said phenyl, benzyl, and
C.sub.1-6alk are being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk, --OH,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk,
--OC(.dbd.O)C.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk; R.sup.c
is C.sub.0-4alk-L.sup.4; and each of L.sup.1, L.sup.2, L.sup.3, and
L.sup.4 is independently a carbon-linked or nitrogen-linked
saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or
7-membered monocyclic ring or a saturated, partially-saturated or
unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein
each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 0
or S atoms; wherein each L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is
independently substituted by 0, 1, 2 or 3 R.sup.8 groups which are
F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a,
--OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(10C(.dbd.NIONR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkOR.sup.a, --C.sub.1-6alkN(10C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a or oxo.
2. The compound as in claim 1 wherein the group ##STR00374##
3. The compound as in claim 1 wherein the ring containing X.sup.1,
X.sup.2, X.sup.3, and X.sup.4 is fused to a saturated, partially
saturated, or unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring
containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 O or S atoms;
wherein said monocyclic ring is independently substituted by 0, 1,
2, 3, or 4 R.sup.3 groups.
4. The compound as in claim 3 wherein said monocyclic ring is fused
phenyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, thiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl,
thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,
pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,
thiomorpholinyl, pyridazinyl, pyrazinyl, or piperazinyl.
5. The compound as in claim 1 wherein Y is a bond, NH, or
N--CH.sub.3.
6. The compound as in claim 1 wherein Y is NH.
7. The compound as in claim 1 wherein m is 1.
8. The compound as in claim 1 wherein p is 1 and q is 1.
9. The compound as in claim 1 wherein the ring containing p and q
is in cis configuration.
10. The compound as in claim 1 wherein the ring containing p and q
is in trans configuration.
11. The compound as as in claim 1 wherein R.sup.1 is F, Cl, Br, I,
--OR.sup.a, --NR.sup.aR.sup.c, --C(.dbd.O)--O--R.sup.a,
--C(.dbd.O)NR.sup.aR.sup.b, --OR.sup.a, or
--C(.dbd.O)NR.sup.aR.sup.b.
12. The compound as in claim 1 wherein R.sup.1 is
C.sub.0-4alk-L.sup.1; wherein said L.sup.1 is a carbon-linked or
nitrogen-linked saturated, partially-saturated or unsaturated 4-,
5-, 6-, or 7-membered monocyclic ring, wherein each said ring
contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 0 atoms, and wherein
each said ring is substituted by 0, 1, 2 or 3 R.sup.8 groups
selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OR.sup.a, --OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, and --C.sub.1-6alkOR.sup.a.
13. The compound as in claim 1 wherein R.sup.1 is
C.sub.0-4alk-L.sup.1; wherein said L.sup.1 is a carbon-linked or
nitrogen-linked saturated, partially-saturated or unsaturated 8-,
9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring
contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 O atoms, and wherein
each said ring is substituted by 0, 1, 2 or 3 R.sup.8 groups
selected from F, Cl, Br, C.sub.1 -6alk, C.sub.1-4haloalk,
--OR.sup.a, --OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, and --C.sub.1-6alkOR.sup.a.
14. The compound as in claim 1 wherein R.sup.1 is
C.sub.0-4alk-L.sup.1; wherein said L.sup.1 is cyclobutyl,
cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl,
azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl,
morpholinyl, pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl,
tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl,
tetrahydrothiopyranyl, oxaspiro[3.5]nonyl, azepanyl, oxepanyl, or
quinolinyl, all of which are substituted by 0, 1, 2 or 3 R.sup.8
groups selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OR.sup.a, --OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, and --C.sub.1-6alkOR.sup.a.
15. The compound as in claim 1 wherein R.sup.1 is
C.sub.0-4alk-L.sup.1; wherein said L.sup.1 is 3-pyridyl, 4-pyridyl,
tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrimidyl,
dihydropyranyl, or piperazinyl, all of which are substituted by 0,
1, 2 or 3 R.sup.8 groups selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a, and
--C.sub.1-6alkOR.sup.a.
16. The compound as as in claim 1 wherein R.sup.1 is not
methyl.
17. The compound as as in claim 1 wherein R.sup.1 is: ##STR00375##
##STR00376## wherein the dotted bond is an optional double
bond.
18. The compound as in claim 1 wherein R.sup.3 is H, F, Cl,
C.sub.1-4alk, or C.sub.1-4haloalk.
19. The compound as in claim 1 wherein R.sup.4a is H.
20. The compound as in claim 1 wherein each of R.sup.4a, R.sup.4b,
and R.sup.4a is H.
21. The compound as in claim 1 wherein R.sup.5 is C.sub.1-8alk or
C.sub.0-8alk-L.sup.3.
22. The compound as in as in claim 1 wherein R.sup.6 is
C.sub.1-8alk or C.sub.0-8alk-L.sup.3.
23. The compound as in claim 1 wherein R.sup.7 is H.
24. The compound as in claim 1 wherein R.sup.a is H or C.sub.1-6alk
substituted by 0 or 1 --OH, --OC.sub.1-4alk,
--OC(.dbd.O)C.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk.
25. The compound as in claim 1, wherein R.sup.c is a saturated,
partially-saturated or unsaturated 3-, 4-, 5-, or 6-membered
monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected
from O or S, which is substituted by 0 or 1 R.sup.8 groups which
are F, C.sub.1-6alk, C.sub.1-4haloalk, or --OR.sup.a.
26. The compound as in claim 1 wherein R.sup.2 is the group
--Y-L.sup.2 which are ##STR00377## ##STR00378## ##STR00379##
wherein Y is a NH.
27. The compound as in claim 1 wherein R.sup.2 is
--C(.dbd.O)R.sup.5, --C(.dbd.O)OR.sup.5, or
--C(.dbd.O)NR.sup.5R.sup.6.
28. The compound as in claim 1 wherein each R.sup.2 is the group
--Y-L.sup.2 selected from ##STR00380## wherein Y is NH; and L.sup.2
is independently substituted by 0, 1, or 2 R.sup.8 groups which are
F, Br, Cl, CF.sub.3, methyl, methoxy, or CN.
29. A compound of formula II: ##STR00381## or any
pharmaceutically-acceptable salt thereof, wherein: each of X.sup.1,
X.sup.2, and X.sup.3 is independently N or CR.sup.3; and X.sup.4 is
N; wherein no more than one of X.sup.1, X.sup.2, and X.sup.3 are N;
and wherein any adjacent X.sup.1, X.sup.2, and X.sup.3 may
optionally form an optionally substituted -saturated, -partially
saturated, or -unsaturated-heterocyclic or -heteroaryl ring fused
to the ring containing X.sup.1, X.sup.2, X.sup.3, and X.sup.4; m is
1, 2, 3, or 4; each of p and q is independently 0, 1, 2, 3, 4, 5,
or 6; wherein the sum of p and q is 2 to 6; the ring containing p
and q is in cis or trans configuration; Ring D is L.sup.1; R.sup.2
is --C(.dbd.O)R.sup.5, --C(.dbd.O)OR.sup.5,
--C(.dbd.O)NR.sup.5R.sup.6, or a group --Y-L.sup.2; Y is a
C.sub.0-4alk, O, NR.sup.7, S, SO, or SO.sub.2; R.sup.3 is H, F, Cl,
Br, CN, OH, OC.sub.1-4alk, C.sub.1-4alk, or C.sub.1-4haloalk;
R.sup.4a is H, C.sub.1-4alk, or C.sub.1-4haloalk; each R.sup.4b is
independently H, F, Cl, Br, CN, OH, OC.sub.1-4alk, C.sub.1-4alk, or
C.sub.1-4haloalk; R.sup.4a is R.sup.4b if R.sup.2 is
--C(.dbd.O)R.sup.5, --C(.dbd.O)OR.sup.5,
--C(.dbd.O)NR.sup.5R.sup.6, or said group --Y-L.sup.2; wherein Y is
C.sub.0-4alk, SO, or SO.sub.2; R.sup.4a is R.sup.4a if R.sup.2 is
said group --Y-L.sup.2, wherein Y is O, NR.sup.7, or S; each of
R.sup.5 and R.sup.6 is independently H, C.sub.1-8alk, or
C.sub.0-8alk-L.sup.3; R.sup.7 is independently H or R.sup.b;
R.sup.a is independently H or R.sup.b; R.sup.b is independently
phenyl, benzyl, or C.sub.1-6alk, wherein said phenyl, benzyl, and
C.sub.1-6alk are being substituted by 0, 1, 2 or 3 substituents
which are halo, C.sub.1-4alk, C.sub.1-3haloalk, --OH,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk,
--OC(.dbd.O)C.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk; and
each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is independently a
carbon-linked or nitrogen-linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a
saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or
12-membered bicyclic ring, wherein each said ring contains 0, 1, 2,
3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each L.sup.1,
L.sup.2, L.sup.3, and L.sup.4 is independently substituted by 0, 1,
2 or 3 R.sup.8 groups which are F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-Ahaloalk, CN,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(=NR.sup.a)NR.sup.aR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a, --N(10C(=NIONR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkOR.sup.a, --C.sub.1-6alkN(10C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
-C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a or oxo. ##STR00382##
30. The compound as in claim 29, wherein the group is cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl. ##STR00383##
31. The compound as in claim 29, wherein the group is in trans
configuration. ##STR00384##
32. The compound as in claim 29, wherein the group is in cis
configuration.
33. A method of treating conditions that may be treated with PDE10
inhibitors comprising the step of administering a pharmaceutically
effective amount of a compound as in claim 1 to a patient in need
thereof
34. A method of claim 33 wherein said condition is selected from
the group consisting of psychoses, Parkinson's disease, dementias,
obsessive compulsive disorder, tardive dyskinesia, choreas,
depression, mood disorders, impulsivity, drug addiction, attention
deficit/hyperactivity disorder (ADHD), depression with parkinsonian
states, personality changes with caudate or putamen disease,
dementia and mania with caudate and pallidal diseases, and
compulsions with pallidal disease.
35. The method of claim 33 wherein said condition is selected from
the group consisting of schizophrenia, Huntington's Disease,
bipolar disorder, and obsessive-compulsive disorder.
36. A pharmaceutical composition comprising a compound as in claim
1 and a pharmaceutically acceptable excipient thereof
37. A compound, a stereoisomer, or a pharmaceutically acceptable
salt thereof, which is:
N-(3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]th-
iazol-2-amine;
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)be-
nzo[d]thiazol-2-amine;
N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)be-
nzo[d]thiazol-2-amine;
5-methyl-N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cycl-
obutyl)pyridin-2-amine;
5-methyl-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cycl-
obutyl)pyridin-2-amine;
1-(4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)pi-
peridin-1-yl)ethanone;
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
peridin-1-yl)ethanone;
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-1-
H-benzo[d]imidazol-2-amine;
N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-1-
H-benzo[d]imidazol-2-amine;
1-(4-(3-((1R,3R)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-
-1-yl)ethanone;
N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
N-((1R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
1-(4-(3-((1S,3S)-3-((5-methylpyridin-2-yl)amino)cyclobutoxy)pyrazin-2-yl)-
piperidin-1-yl)ethanone;
1-(4-(3-((1R,3R)-3-((5-methylpyridin-2-yl)amino)cyclobutoxy)pyrazin-2-yl)-
piperidin-1-yl)ethanone;
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-5-
-(trifluoromethyl)pyridin-2-amine;
N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-5-
-(trifluoromethyl)pyridin-2-amine;
6-(((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)a-
mino)nicotinonitrile;
6-(((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)a-
mino)nicotinonitrile;
5-chloro-N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cycl-
obutyl)pyridin-2-amine;
5-chloro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cycl-
obutyl)pyridin-2-amine;
N-((1S,3S)-3-((3-(2-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine;
5-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
6-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
4-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
N-((1S,3S)-3-((3-(2-methoxypyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo-
[d]thiazol-2-amine;
7-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pipe-
ridin-4-yl)methanol;
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
perazin-1-yl)ethanone;
N-((1S,3S)-3-((3-(3-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine;
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idin-4-one;
N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine;
6-fluoro-N-((1S,3S)-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)o-
xy)cyclobutyl)benzo[d]thiazol-2-amine;
4-fluoro-N-((1S,3S)-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)o-
xy)cyclobutyl)benzo[d]thiazol-2-amine;
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idine-1-carboxylate;
5-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl-
)oxy)cyclobutyl)benzo[d]thiazol-2-amine;
7-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl-
)oxy)cyclobutyl)benzo[d]thiazol-2-amine; methyl
3-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)azeti-
dine-1-carboxylate;
N-((1S,3S)-3-((3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)oxy)cyclobutyl)ben-
zo[d]thiazol-2-amine;
N-((1R,3R)-3-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)cyclobutyl)-
-5-(trifluoromethyl)pyridin-2-amine;
N-((1S,3S)-3-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)cyclobutyl)-
-5-(trifluoromethyl)pyridin-2-amine;
N-((1R,3R)-3-((3-(1-acetylpiperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)-4-m-
ethylbenzenesulfonamide;
N-((1S,3S)-3-((3-(1-acetylpiperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)-4-m-
ethylbenzenesulfonamide;
N-((1R,3R)-3-((3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)oxy)cyclobutyl)ben-
zo[d]thiazol-2-amine;
2'-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3'-bipyridine]-6-
-carbonitrile;
N-(3-((3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thi-
azol-2-amine;
(1-(3-(3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-3--
yl)methanol;
2`-((1R,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3'-bipyridine]-6-
-carbonitrile;
N-((1S,3S)-3-((3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine; tert-butyl
4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-1-
-carboxylate; tert-butyl
2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-5',6'-dihydro
-[3,4'-bipyridine]-1'(2'H)-carboxylate;
1-(3-(3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrolidine-3-
-carbonitrile;
N-((1S,3S)-3-((3-(2-methylpyrimidin-5-yl)pyrazin-2-yl)oxy)cyclobutyl)benz-
o[d]thiazol-2-amine;
N-((1S,3S)-3-((3-(6-chloropyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine;
N-((1S,3S)-3-((3-(6-fluoropyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine;
5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)picol-
inonitrile;
1-(4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidin-
-1-yl)ethanone;
5-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinonitr-
ile;
(1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperid-
in-4-yl)methanol; methyl
4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piper-
idine-1-carboxylate;
2-methoxy-1-(4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl-
)piperidin-1-yl)ethanone;
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)qu-
inolin-2-amine;
1-(4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)pi-
peridin-1-yl)-2-methoxyethanone;
((R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)-
piperidin-3-yl)methanol;
((S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)-
piperidin-3-yl)methanol;
2'-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-[3,3'-bipyridine]-6-carbon-
itrile;
1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
perazin-1-yl)ethanone;
2-methoxy-1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl-
)piperidin-1-yl)ethanone;
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)qu-
inolin-2-amine;
N-((1S,3S)-3-((3-morpholinopyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2--
amine;
(R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)pyrrolidin-3-ol;
1-(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
peridin-4-yl)ethanol;
1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-
-1-yl)ethanone;
(S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)p-
yrrolidin-3-ol;
N-(3-((3-(3-methylpiperidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine;
N-((1S,3S)-3-((3-((R)-3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl-
)benzo[d]thiazol-2-amine;
N-((1R,3S)-3-((3-((S)-3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl-
)benzo[d]thiazol-2-amine;
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idine-4-carbonitrile;
1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidine-4-
-carbonitrile;
N-((1S,3S)-3-((6-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyc-
lobutyl)benzo[d]thiazol-2-amine;
5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)picol-
inamide;
(R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazi-
n-2-yl)pyrrolidine-3-carbonitrile;
(S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)p-
yrrolidine-3-carbonitrile;
5-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinamide-
;
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)p-
iperidin-1-yl)-2-hydroxyethanone;
N-((1S,3S)-3-((3-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl-
)benzo[d]thiazol-2-amine;
N-(3-((3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thi-
azol-2-amine;
2`-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-[3,3'-bipyridine]-6-carbox-
amide;
N-((1S,3S)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)cyclobuty-
l)benzo[d]thiazol-2-amine;
5-fluoro-N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobut-
yl)benzo[d]thiazol-2-amine;
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
peridin-1-yl)-2-methoxyethanone;
N-((1S,3S)-3-((6-fluoro-5-iodopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-
-2-amine;
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)thiomorpholine 1,1-dioxidecyclobutyl}-amine;
2'-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3'-bipyridine]-6-
-carboxamide;
N-((1S,3S)-34(3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)quinazo-
lin-2-amine;
N-((1S,3S)-3-46-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclo-
butyl)benzo[d]thiazol-2-amine;
5-(3-((1S,3S)-3-(quinazolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinoni-
trile;
N-((1S,3S)-3-((3-(2-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
1-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piper-
idine-4-carbonitrile;
1-(5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)py-
ridin-2-yl)ethanone;
N-((1S,3S)-3-((3-(1-methylpiperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benz-
o[d]thiazol-2-amine; N-((1S,3S)-3-((3-(5,6-dihydroimidazo
[1,5-a]pyrazin-7(8H)-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-ami-
ne;
N-((1S,3S)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)q-
uinazolin-2-amine; or
(1-(3-((1S,3S)-3-(quinazolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-
-4-yl)methanol.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/334,514, filed May 13, 2010 which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] Provided herein are certain heteroaryloxycarbocyclyl
compounds that are PDE10 inhibitors, pharmaceutical compositions
containing such compounds, and processes for preparing such
compounds. Provided herein also are methods of treating disorders
or diseases treatable by inhibition of PDE10, such as obesity,
non-insulin dependent diabetes, schizophrenia, bipolar disorder,
obsessive-compulsive disorder, and the like.
BACKGROUND
[0003] Neurotransmitters and hormones, as well as other types of
extracellular signals such as light and odors, create intracellular
signals by altering the amounts of cyclic nucleotide monophosphates
(cAMP and cGMP) within cells. These intracellular messengers alter
the functions of many intracellular proteins. Cyclic AMP regulates
the activity of cAMP-dependent protein kinase (PKA). PKA
phosphorylates and regulates the function of many types of
proteins, including ion channels, enzymes, and transcription
factors. Downstream mediators of cGMP signaling also include
kinases and ion channels. In addition to actions mediated by
kinases, cAMP and cGMP bind directly to some cell proteins and
directly regulate their activities.
[0004] Cyclic nucleotides are produced from the actions of adenylyl
cyclase and guanylyl cyclase, which convert ATP to cAMP and GTP to
cGMP. Extracellular signals, often through the actions of G
protein-coupled receptors, regulate the activities of the cyclases.
Alternatively, the amount of cAMP and cGMP may be altered by
regulating the activities of the enzymes that degrade cyclic
nucleotides. Cell homeostasis is maintained by the rapid
degradation of cyclic nucleotides after stimulus-induced increases.
The enzymes that degrade cyclic nucleotides are called 3',5'-cyclic
nucleotide-specific phosphodiesterases (PDEs).
[0005] Eleven PDE gene families (PDE1PDE11) have been identified
based on their distinct amino acid sequences, catalytic and
regulatory characteristics, and sensitivity to small molecule
inhibitors. These families are coded for by 21 genes; and further
multiple splice variants are transcribed from many of these genes.
Expression patterns of each of the gene families are distinct. PDEs
differ with respect to their affinity for cAMP and cGMP. Activities
of different PDEs are regulated by different signals. For example,
PDE1 is stimulated by Ca.sup.2+/calmodulin. PDE2 activity is
stimulated by cGMP. PDE3 is inhibited by cGMP. PDE4 is cAMP
specific and is specifically inhibited by rolipram. PDE5 is
cGMP-specific. PDE6 is expressed in retina.
[0006] PDE10 sequences were identified by using bioinformatics and
sequence information from other PDE gene families (Fujishige et
al., J. Biol. Chem. 274:18438-18445, 1999; Loughney et al., Gene
234:109-117, 1999; Soderling et al., Proc. Natl. Acad. Sci. USA
96:7071-7076, 1999). The PDE10 gene family is distinguished based
on its amino acid sequence, functional properties and tissue
distribution. The human PDE10 gene is large, over 200 kilobases,
with up to 24 exons coding for each of the splice variants. The
amino acid sequence is characterized by two GAF domains (which bind
cGMP), a catalytic region, and alternatively spliced N and C
termini. Numerous splice variants are possible because at least
three alternative exons encode N termini and two exons encode
C-termini. PDE10A1 is a 779 amino acid protein that hydrolyzes both
cAMP and cGMP. The K.sub.m values for cAMP and cGMP are 0.05 and
3.0 micromolar, respectively. In addition to human variants,
several variants with high homology have been isolated from both
rat and mouse tissues and sequence banks.
[0007] PDE10 RNA transcripts were initially detected in human
testis and brain. Subsequent immunohistochemical analysis revealed
that the highest levels of PDE10 are expressed in the basal
ganglia. Specifically, striatal neurons in the olfactory tubercle,
caudate nucleus and nucleus accumbens are enriched in PDE10.
Western blots did not reveal the expression of PDE10 in other brain
tissues, although immunoprecipitation of the PDE10 complex was
possible in hippocampal and cortical tissues. This suggests that
the expression level of PDE10 in these other tissues is 100-fold
less than in striatal neurons. Expression in hippocampus is limited
to the cell bodies, whereas PDE10 is expressed in terminals,
dendrites and axons of striatal neurons.
[0008] The tissue distribution of PDE10 indicates that PDE10
inhibitors can be used to raise levels of cAMP and/or cGMP within
cells that express the PDE10 enzyme, for example, in neurons that
comprise the basal ganglia and therefore would be useful in
treating a variety of neuropsychiatric conditions involving the
basal ganglia such as obesity, non-insulin dependent diabetes,
schizophrenia, bipolar disorder, obsessive compulsive disorder, and
the like.
[0009] Noninvasive, nuclear imaging techniques can be used to
obtain basic and diagnostic information about the physiology and
biochemistry of a variety of living subjects including experimental
animals, normal humans and patients. These techniques rely on the
use of sophisticated imaging instrumentation that is capable of
detecting radiation emitted from radiotracers administered to such
living subjects. The information obtained can be reconstructed to
provide planar and tomographic images that reveal distribution of
the radiotracer as a function of time. Use of appropriately
designed radiotracers can result in images which contain
information on the structure, function and most importantly, the
physiology and biochemistry of the subject. Much of this
information cannot be obtained by other means. The radiotracers
used in these studies are designed to have defined behaviors in
vivo which permit the determination of specific information
concerning the physiology or biochemistry of the subject or the
effects that various diseases or drugs have on the physiology or
biochemistry of the subject. Currently, radiotracers are available
for obtaining useful information concerning such things as cardiac
function, myocardial blood flow, lung perfusion, liver function,
brain blood flow, regional brain glucose and oxygen metabolism.
[0010] Compounds of the invention can be labeled with either
positron or gamma emitting radionuclides. For imaging, the most
commonly used positron emitting (PET) radionuclides are .sup.11C,
.sup.18F, .sup.15O, .sup.13N, .sup.76Br, .sup.77Br, .sup.123I, or
.sup.125I, wherein .sup.11C, .sup.18F, .sup.123I, or .sup.125I are
preferred, all of which are accelerator produced. In the last two
decades, one of the most active areas of nuclear medicine research
has been the development of receptor imaging radiotracers. These
tracers bind with high affinity and specificity to selective
receptors and neuroreceptors. For example, Johnson and Johnson has
synthesized and evaluated .sup.18F-JNJ41510417 as a selective and
high-affinity radioligand for in vivo brain imaging of PDE10A using
PET (The Journal Of Nuclear Medicine; Vol. 51; No. 10; October
2010).
SUMMARY OF THE INVENTION
[0011] The present invention comprises a new class of
heteroaryloxycarbocyclyl compounds useful in the treatment of
diseases, such as PDE10-mediated diseases and other maladies, such
as schizophrenia, Huntington's disease, bipolar disorder, or
obsessive-compulsive disorder. Accordingly, the invention also
comprises pharmaceutical compositions comprising the compounds,
methods for the treatment of PDE10-mediated diseases and other
maladies, such as schizophrenia, Huntington's disease, bipolar
disorder, or obsessive-compulsive disorder, using the compounds and
compositions of the invention, and intermediates and processes
useful for the preparation of the compounds of the invention.
[0012] Another aspect of the invention comprises a new class of
heteroaryloxycarbocyclyl compounds radiolabeled with a positron
emitting radionuclide selected from .sup.11C, .sup.18F, .sup.15O,
.sup.13N, .sup.76Br, .sup.77Br, .sup.123I, or .sup.125I, a
radiopharmaceutical composition comprising the radiolabelled
compound, a method for the diagnostic imaging of PDE10 receptors in
a mammal, including human, or tissues bearing PDE10 receptors in a
mammal, including human brain, which comprises administering to a
mammal in need of such diagnostic imaging an effective amount of
the radiolabeled compound, and a method for the detection or
quantification of PDE10 receptors in mammalian tissue, including
human tissue, which comprises contacting such mammalian tissue in
which such detection or quantification is desired with an effective
amount of the radiolabeled compound.
[0013] The compounds of the invention are represented by the
following general structure:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein m, p, q,
R.sup.1, R.sup.2, R.sup.4a, R.sup.4b, R.sup.4c, X.sup.1, X.sup.2,
and X.sup.4 are defined below.
[0014] Other compounds of the invention are represented by the
following general structure:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein m, p, q,
Ring D, .sub.R.sup.2, R.sup.4a, R.sup.4b,R.sup.4c, X.sup.1,
X.sup.2, X.sup.3, and X.sup.4 are defined below.
DETAILED DESCRIPTION OF THE INVENTION
[0015] One aspect of the current invention relates to compounds
having the general structure of formula (I):
##STR00003##
[0016] a stereoisomer, or a pharmaceutically-acceptable salt
thereof, wherein:
[0017] each of X.sup.1, X.sup.2, and X.sup.3 is independently N or
CR.sup.3; and X.sup.4 is N; wherein no more than one of X.sup.1,
X.sup.2, and X.sup.3 are N;
[0018] optionally, the ring containing X.sup.1, X.sup.2, X.sup.3,
and X.sup.4 may be fused to a saturated, partially saturated, or
unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0,
1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S;
wherein said monocyclic ring is independently substituted by 0, 1,
2, 3, or 4 R.sup.3 groups;
[0019] m is 1, 2, 3, or 4;
[0020] each of p and q is independently 0, 1, 2, 3, 4, 5, or 6;
wherein the sum of p and q is 2 to 6;
[0021] the ring containing p and q is in cis or trans
configuration;
[0022] R.sup.1 is F, Cl, Br, I, C.sub.1-8alk, C.sub.1-4haloalk,
--O.sup.a, --NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--C(.dbd.O)R.sup.a, --C(.dbd.O)R.sup.c, --C(.dbd.O)--O--R.sup.a,
--NR.sup.aR.sup.c, --N(R.sup.c)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)R.sup.c, --C(.dbd.O)NR.sup.aR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.c, or C.sub.0-4alk-L.sup.1; wherein said
C.sub.1-8alk group is substituted by 0, 1, 2 or 3 groups selected
from halo, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk;
[0023] R.sup.2 is --C(.dbd.O)R.sup.5, --C(.dbd.O)OR.sup.5,
--C(.dbd.O)NR.sup.5R.sup.6, or a group --Y-L.sup.2;
[0024] Y is a C.sub.1-4alk, O, NR.sup.7, S, SO, or SO.sub.2;
[0025] R.sup.3 is H, F, Cl, Br, CN, OH, OC.sub.1-4alk,
C.sub.1-4alk, or C.sub.1-4haloalk;
[0026] R.sup.4a is H, C.sub.1-4alk, or C.sub.1-4haloalk;
[0027] each R.sup.4b is independently H, F, Cl, Br, CN, OH,
OC.sub.1-4alk, C.sub.1-4alk, or C.sub.1-4haloalk;
[0028] R.sup.4c is R.sup.4b when R.sup.2 is --C(.dbd.O)R.sup.5,
--C(.dbd.O)OR.sup.5, --C(.dbd.O)NR.sup.5R.sup.6, or said group
--Y-L.sup.2; wherein Y is C.sub.0-4alk, SO, or SO.sub.2;
[0029] R.sup.4c is R.sup.4a when R.sup.2 is said group --Y-L.sup.2,
wherein Y is O, NR.sup.7, or S;
[0030] each of R.sup.5 and R.sup.6 is independently H,
C.sub.1-8alk, or C.sub.0-8alk-L.sup.3;
[0031] R.sup.7 is independently H or R.sup.b;
[0032] R.sup.a is independently H or R.sup.b;
[0033] R.sup.b is independently phenyl, benzyl, or C.sub.1-6alk,
wherein said phenyl, benzyl, and C.sub.1-6alk are being substituted
by 0, 1, 2 or 3 substituents selected from halo, C.sub.1-4alk,
C.sub.1-3haloalk --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk;
[0034] R.sup.c is C.sub.0-4alk-L.sup.4; and
[0035] each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is
independently a carbon-linked or nitrogen-linked saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered
monocyclic ring or a saturated, partially-saturated or unsaturated
8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said
ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms
selected from O or S; wherein each L.sup.1, L.sup.2, L.sup.3, and
L.sup.4 is independently substituted by 0, 1, 2 or 3 R.sup.8 groups
selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OR.sup.a, --OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkOR.sup.a, --C.sub.1-6alkN(R.sup.a)C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a and oxo.
[0036] In another embodiment, the group
##STR00004##
[0037] In another embodiment, the ring containing X.sup.1, X.sup.2,
X.sup.3, and X.sup.4 is fused to a saturated, partially saturated,
or unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring containing
0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S;
wherein said monocyclic ring is independently substituted by 0, 1,
2, 3, or 4 R.sup.3 groups.
[0038] In another embodiment, said monocyclic ring is selected from
fused phenyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl,
thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl,
oxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl,
isothiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl,
morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrazinyl,
and piperazinyl.
[0039] In another embodiment, Y is a bond, NH, or N--CH.sub.3
[0040] In another embodiment, Y is NH.
[0041] In another embodiment, R.sup.4b is H.
[0042] In another embodiment, p is 1 and q is 1.
[0043] In another embodiment, wherein the ring containing p and q
is in cis configuration.
[0044] In another embodiment, R.sup.1 is F, Cl, Br, I, --OR.sup.a,
--NR.sup.aR.sup.c, --C(.dbd.O)--O--R.sup.a,
--C(.dbd.O)NR.sup.aR.sup.b, --OR.sup.a, or
--C(.dbd.O)NR.sup.aR.sup.b.
[0045] In another embodiment, R.sup.1 is C.sub.-4alk-L.sup.1;
wherein said L.sup.1 is a carbon-linked or nitrogen-linked
saturated, partially-saturated or unsaturated 4-, 5-, 6-, or
7-membered monocyclic ring, wherein each said ring contains 0, 1,
2, or 3 N atoms and 0, 1, or 2 0 atoms, and wherein each said ring
is substituted by 0, 1, 2 or 3 R.sup.8 groups selected from F, Cl,
Br, C.sub.1-6alk, C.sub.1-4haloalk, --PR.sup.a,
--OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--NR.sup.aR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a, and
--C.sub.1-6alkOR.sup.a.
[0046] In another embodiment, R.sup.1 is C.sub.0-4alk-L.sup.1;
wherein said L.sup.1 is a carbon-linked or nitrogen-linked
saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or
12-membered bicyclic ring, wherein each said ring contains 0, 1, 2,
or 3 N atoms and 0, 1, or 2 O atoms, and wherein each said ring is
substituted by 0, 1, 2 or 3 R.sup.8 groups selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a, and
--C.sub.1-6alkOR.sup.a.
[0047] In another embodiment, R.sup.1 is C.sub.0-4alk-L.sup.1;
wherein said L.sup.1 is cyclobutyl, cyclohexyl, cyclopentyl,
cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl, phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, morpholinyl, pyrimidyl,
piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,
tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl,
oxaspiro[3.5]nonyl, azepanyl, oxepanyl, or quinolinyl, all of which
are substituted by 0, 1, 2 or 3 R.sup.8 groups selected from F, Cl,
Br, C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a,
--OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--NR.sup.aR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a, and
--C.sub.1-6alkOR.sup.a. /
[0048] In another embodiment, R.sup.1 is C.sub.0-4alk-L.sup.1;
wherein said L.sup.1 is 3-pyridyl, 4-pyridyl, tetrahydropyranyl,
tetrahydrofuranyl, piperidinyl, pyrimidyl, dihydropyranyl, or
piperazinyl, all of which are substituted by 0, 1, 2 or 3 R.sup.8
groups selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OR.sup.a, --OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, and --C.sub.1-6alkOR.sup.a.
[0049] In another embodiment, R.sup.1 is not methyl.
[0050] In another embodiment, R.sup.1 is:
##STR00005## ##STR00006##
wherein
[0051] the dotted bond is an optional double bond.
[0052] In another embodiment, R.sup.3 is H, F, Cl, C.sub.1-4alk, or
C.sub.1-4haloalk.
[0053] In another embodiment, R.sup.4a is H.
[0054] In another embodiment, R.sup.4a,R.sup.4b, and R.sup.4c is
H.
[0055] In another embodiment, R.sup.5 is C.sub.1-8alk or
C.sub.0-8alk-L.sup.3.
[0056] In another embodiment, R.sup.6 is C.sub.1-8alk or
C.sub.0-8alk-L.sup.3.
[0057] In another embodiment, R.sup.7 is H.
[0058] In another embodiment, IV is H or C.sub.1-6alk substituted
by 0 or 1 --OH, --OC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk.
[0059] In another embodiment, R.sup.c is a saturated,
partially-saturated or unsaturated 3-, 4-, 5-, or 6-membered
monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected
from O or S, which is substituted by 0 or 1 R.sup.8 groups selected
from F, C.sub.1-6alk, C.sub.1-4haloalk, or --OR.sup.a.
##STR00007## ##STR00008##
[0060] In another embodiment, R.sup.2 is the group Y-L.sup.2 which
are wherein Y is a NH.
[0061] In another embodiment, R.sup.2 is --C(.dbd.O)R.sup.5,
--C(.dbd.O)OR.sup.5, or --C(.dbd.O)NR.sup.5R.sup.6.
[0062] In another embodiment, each R.sup.2 is the group --Y-L.sup.2
which are
##STR00009##
wherein Y is NH; and L.sup.2 is independently substituted by 0, 1,
or 2 R.sup.8 groups which are F, Br, Cl, CF.sub.3, methyl, methoxy,
or CN.
[0063] Another aspect of the current invention relates to compounds
having the general structure of formula (II):
##STR00010##
or any pharmaceutically-acceptable salt thereof, wherein:
[0064] each of X.sup.1, X.sup.2, and X.sup.3 is independently N or
CR.sup.3; and X.sup.4 is N; wherein no more than one of X.sup.1,
X.sup.2, and X.sup.3 are N; and wherein any adjacent X.sup.1 ,
X.sup.2, and X.sup.3 may optionally form an optionally substituted
-saturated, -partially saturated, or -unsaturated-heterocyclic or
-heteroaryl ring fused to the ring containing X.sup.1, X.sup.2,
X.sup.3, and X.sup.4;
[0065] m is 1, 2, 3, or 4;
[0066] each of p and q is independently 0, 1, 2, 3, 4, 5, or 6;
wherein the sum of p and q is 2 to 6;
[0067] the ring containing p and q is in cis or trans
configuration;
[0068] Ring D is L.sup.1;
[0069] R.sup.2 is --C(.dbd.O)R.sup.5, --C(.dbd.O)OR.sup.5,
--C(.dbd.O)NR.sup.5R.sup.6, or a group --Y-L.sup.2;
[0070] Y is a C.sub.0-4alk, O, NR.sup.7, S, SO, or SO.sub.2;
[0071] R.sup.3 is H, F, Cl, Br, CN, OH, OC.sub.1-4alk,
C.sub.1-4alk, or C.sub.1-4haloalk;
[0072] R.sup.4a is H, C.sub.1-4alk, or C.sub.1-4haloalk;
[0073] each R.sup.4b is independently H, F, Cl, Br, CN, OH,
OC.sub.1-4alk, C.sub.1-4alk, or C.sub.1-4haloalk;
[0074] R.sup.4c is R.sup.4b if R.sup.2 is --C(.dbd.O)R.sup.5,
--C(.dbd.O)OR.sup.5, --C(.dbd.O)NR.sup.5R.sup.6, or said group
--Y-L.sup.2; wherein Y is C.sub.0-4alk, SO, or SO.sub.2;
[0075] R.sup.4c is R.sup.4a if R.sup.2 is said group --Y-L.sup.2,
wherein Y is O, NR.sup.7, or S;
[0076] each of R.sup.5 and R.sup.6 is independently H,
C.sub.1-8alk, or C.sub.0-8alk-L.sup.3;
[0077] R.sup.7 is independently H or R.sup.b;
[0078] R.sup.a is independently H or R.sup.b;
[0079] R.sup.b is independently phenyl, benzyl, or C.sub.1-6alk,
wherein said phenyl, benzyl, and C.sub.1-6alk are being substituted
by 0, 1, 2 or 3 substituents selected from halo, C.sub.1-4alk,
C.sub.1-3haloalk --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0080] each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is
independently a carbon-linked or nitrogen-linked saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered
monocyclic ring or a saturated, partially-saturated or unsaturated
8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said
ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms
selected from 0 or S; wherein each L.sup.1, L.sup.2, L.sup.3, and
L.sup.4 is independently substituted by 0, 1, 2 or 3 R.sup.8 groups
selected from F, Br, C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a,
--OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, C.sub.1-6alkNR.sup.aR.sup.a,
C.sub.1-6alkOR.sup.a, C.sub.1-6alkN(R.sup.a)C(.dbd.O)R.sup.b,
C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
C.sub.1-6alkC(.dbd.O)OR.sup.a and oxo.
[0081] In another embodiment, the group
##STR00011##
is cyclobutyl, cyclopentyl, cylohexyl, or cycloheptyl.
[0082] In another embodiment, the group
##STR00012##
is cyclobutyl.
[0083] In another embodiment, the group
##STR00013##
is cyclopentyl.
[0084] In another embodiment, the group
##STR00014##
is cyclohexyl.
[0085] In another embodiment, the group
##STR00015##
is in trans configuration.
[0086] In another embodiment, the group
##STR00016##
is in cis configuration.
[0087] In another embodiment, R.sup.3 is H, C.sub.1-4alk, or
C.sub.1-4haloalk.
[0088] In another embodiment, R.sup.4a is H or C.sub.1-4alk.
[0089] In another embodiment, R.sup.5 is C.sub.1-8alk or
C.sub.0-8alk-L.sup.3.
[0090] In another embodiment, R.sup.6 is C.sub.1-8alk or
C.sub.0-8alk-L.sup.3.
[0091] In another embodiment, R.sup.7 is H.
[0092] In another embodiment, R.sup.a is H or C.sub.1-6alk
substituted by 0 or 1 --OH, --OC.sub.1-4alk,
--OC(.dbd.O)C.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk.
[0093] In another embodiment, R.sup.c is a carbon-linked saturated,
partially-saturated or unsaturated 3-, 4-, 5-, or 6-membered
monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected
from O or S, which is substituted by 0 or 1 R.sup.8 groups selected
from F, C.sub.1-6alk, C.sub.1-4haloalk, or --OR.sup.a.
[0094] In another embodiment, R.sup.c is a nitrogen-linked
saturated, partially-saturated, or unsaturated 4-, 5-, 6- or
7-membered ring heterocycle containing the linking nitrogen and 0,
1 or 2 additional nitrogen atoms and containing 0 or 1 sulfur or
oxygen atom, the heterocycle being substituted by 0, 1, 2 or 3
R.sup.8 groups selected from F, Cl, Br, Cl, --OC.sub.1-4alk,
--NH.sub.2, --NHC.sub.1-4alk, --N(C.sub.1-4alk)C.sub.1-4alk, or
oxo.
[0095] In another embodiment, R.sup.c is a C.sub.0-4alk-linked
saturated, partially-saturated or unsaturated 3-, 5-, or 6-membered
monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected
from O and S, which is substituted by 0 or 1 R.sup.8 groups
selected from F, C.sub.1-6alk, C.sub.1-4haloalk, or --OR.sup.a.
[0096] In another embodiment, R.sup.2 is --C(.dbd.O)R.sup.5,
--C(.dbd.O)OR.sup.5, or --C(.dbd.O)NR.sup.5R.sup.6.
[0097] Another aspect of the invention relates to a method of
treating conditions that may be treated with PDE10 inhibitors
comprising the step of administering to a patient in need thereof a
therapeutically effective amount of any one of the above compounds,
or a pharmaceutically acceptable salt thereof
[0098] In one embodiment of the method, said conditions is
psychoses, Parkinson's disease, dementias, obsessive compulsive
disorder, tardive dyskinesia, choreas, depression, mood disorders,
impulsivity, drug addiction, attention deficit/hyperactivity
disorder (ADHD), depression with parkinsonian states, personality
changes with caudate or putamen disease, dementia and mania with
caudate and pallidal diseases, or compulsions with pallidal
disease.
[0099] In another embodiment of the method, said condition is
schizophrenia, Huntington's disease, bipolar disorder, or
obsessive-compulsive disorder.
[0100] In another embodiment of the method, said condition is
schizophrenia.
[0101] Another aspect of the invention relates to a pharmaceutical
composition comprising any one of the above compounds, or a
pharmaceutically acceptable salt thereof, and a
pharmaceutically-acceptable excipient.
[0102] Another aspect of the invention relates to the use of any
one of the above compounds, or a pharmaceutically acceptable salt
thereof, as a medicament.
[0103] Another aspect of the invention relates to the use of any
one of the above compounds, or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of
schizophrenia, bipolar disorder, or obsessive-compulsive
disorder.
[0104] Another aspect of the invention relates to a compound, or a
pharmaceutically acceptable salt thereof, which is listed
below:
[0105]
N-(3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benz-
o[d]thiazol-2-amine;
[0106]
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)benzo[d]thiazol-2-amine;
[0107]
N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)benzo[d]thiazol-2-amine;
[0108]
5-methyl-N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyl)pyridin-2-amine;
[0109]
5-methyl-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyppyridin-2-amine;
[0110]
1-(4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-
-yl)piperidin-1-yl)ethanone;
[0111]
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)piperidin-1-yl)ethanone;
[0112]
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)-1H-benzo[d]imidazol-2-amine;
[0113]
N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)-1H-benzo[d]imidazol-2-amine;
[0114]
1-(4-(3-((1R,3R)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)pip-
eridin-1-yl)ethanone;
[0115]
N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0116]
N-((1R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0117]
1-(4-(3-((1S,3S)-3-((5-methylpyridin-2-yl)amino)cyclobutoxy)pyrazin-
-2-yl)piperidin-1-yl)ethanone;
[0118]
1-(4-(3-((1R,3R)-3-((5-methylpyridin-2-yl)amino)cyclobutoxy)pyrazin-
-2-yl)piperidin-1-yl)ethanone;
[0119]
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)-5-(trifluoromethyl)pyridin-2-amine;
[0120]
N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)-5-(trifluoromethyl)pyridin-2-amine;
[0121]
6-(((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclob-
utyl)amino)nicotinonitrile;
[0122]
6-(((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclob-
utyl)amino)nicotinonitrile;
[0123]
5-chloro-N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyl)pyridin-2-amine;
[0124]
5-chloro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyl)pyridin-2-amine;
[0125]
N-((1S,3S)-3-((3-(2-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
[0126]
5-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0127]
6-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0128]
4-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0129]
N-((1S,3S)-3-((3-(2-methoxypyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl-
)benzo[d]thiazol-2-amine;
[0130]
7-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0131]
(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-y-
l)piperidin-4-yl)methanol;
[0132]
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)piperazin-1-yl)ethanone;
[0133]
N-((1S,3S)-3-((3-(3-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
[0134]
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl-
)piperidin-4-one;
[0135]
N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
[0136]
6-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridi-
n-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;
[0137]
4-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridi-
n-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;
[0138]
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl-
)piperidine-1-carboxylate;
[0139]
5-fluoro-N-41S,3S)-3-45-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin--
2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;
[0140]
7-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridi-
n-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;
[0141] methyl
3-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)azeti-
dine-1-carboxylate;
[0142]
N-((1S,3S)-3-((3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)oxy)cyclobut-
yl)benzo[d]thiazol-2-amine;
[0143]
N-((1R,3R)-3-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)cyclo-
butyl)-5-(trifluoromethyl)pyridin-2-amine;
[0144]
N-((1S,3S)-3-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)cyclo-
butyl-5-(trifluoromethyl)pyridin-2-amine;
[0145]
N-((1R,3R)-3-((3-(1-acetylpiperidin-4-yl)pyridin-2-yl)oxy)cyclobuty-
0-4-methylbenzenesulfonamide;
[0146]
N-((1S,3S)-3-((3-(1-acetylpiperidin-4-yl)pyridin-2-yl)oxy)cyclobuty-
l)-4-methylbenzenesulfonamide;
[0147]
N-((1R,3R)-3-((3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)oxy)cyclobut-
yl)benzo[d]thiazol-2-amine;
[0148]
2'-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3'-bipyrid-
ine]-6-carbonitrile;
[0149]
N-(3-((3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo-
[d]thiazol-2-amine;
[0150]
(1-(3-(3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperi-
din-3-yl)methanol;
[0151]
2'-((1R,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)[3,3'-bipyridi-
ne]-6-carbonitrile;
[0152]
N-((1S,3S)-3-((3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)oxy)cyclo-
butyl)benzo[d]thiazol-2-amine;
[0153] tert-butyl
4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-1-
-carboxylate;
[0154] tert-butyl
2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-5',6'-dihydro-[3,4'-bipyrid-
ine]-1'(2'H)-carboxylate;
[0155]
1-(3-(3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrroli-
dine-3-carbonitrile;
[0156]
N-((1S,3S)-3-((3-(2-methylpyrimidin-5-yl)pyrazin-2-yl)oxy)cyclobuty-
l)benzo[d]thiazol-2-amine;
[0157]
N-((1S,3S)-3-((3-(6-chloropyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
[0158]
N-((1S,3S)-3-((3-(6-fluoropyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
[0159]
5-(3-41S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)-
picolinonitrile;
[0160]
1-(4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)pip-
eridin-1-yl) ethanone;
[0161]
5-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picoli-
nonitrile;
[0162]
(1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idin-4-yl)methanol; methyl
4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piper-
idine-1-carboxylate;
[0163]
2-methoxy-1-(4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridi-
n-3-yl)piperidin-1-yl)ethanone;
[0164]
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobu-
tyl)quinolin-2-amine;
[0165]
1-(4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-
-yl)piperidin-1-yl)-2-methoxyethanone;
[0166]
((R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-
-2-yl)piperidin-3-yl)methanol;
[0167] ((S)-1-(3-((1S,
3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-3-yl)-
methanol;
[0168]
2'-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-[3,3'-bipyridine]-6--
carbonitrile;
[0169]
1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)pip-
erazin-1-yl)ethanone;
[0170]
2-methoxy-1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazi-
n-2-yl)piperidin-1-yl)ethanone;
[0171]
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)quinolin-2-amine;
[0172]
N-((1S,3S)-3-((3-morpholinopyrazin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine;
[0173]
(R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)pyrrolidin-3-ol;
[0174]
1-(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)piperidin-4-yl)ethanol;
[0175]
1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)pip-
eridin-1-yl)ethanone;
[0176]
(S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)pyrrolidin-3-ol;
[0177]
N-(3-((3-(3-methylpiperidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine;
[0178]
N-((1S,3S)-3-((3-((R)-3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
[0179]
N-((1R,3S)-3-((3-((S)-3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
[0180]
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl-
)piperidine-4-carbonitrile;
[0181]
1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperi-
dine-4-carbonitrile;
[0182]
N-((1S,3S)-3-((4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)o-
xy)cyclobutyl)benzo[d]thiazol-2-amine;
[0183]
5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl-
)picolinamide;
[0184]
(R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)pyrrolidine-3-carbonitrile;
[0185]
(S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)pyrrolidine-3-carbonitrile;
[0186]
5-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picoli-
namide;
[0187]
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)piperidin-1-yl)-2-hydroxyethanone;
[0188]
N-((1S,3S)-3-((3-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cycl-
obutyl)benzo[d]thiazol-2-amine;
[0189]
N-(3-((3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo-
[d]thiazol-2-amine;
[0190]
2'-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-[3,3'-bipyridine1-6--
carboxamide;
[0191]
N-((1S,3S)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)cyclobuty-
l)benzo[d]thiazol-2-amine;
[0192]
5-fluoro-N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cy-
clobutyl)benzo[d]thiazol-2-amine;
[0193]
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)piperidin-1-yl)-2-methoxyethanone;
[0194]
N-((1S,3S)-3-((6-fluoro-5-iodopyridin-2-yl)oxy)cyclobutyl)benzo[d]t-
hiazol-2-amine;
[0195]
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl-
)thiomorpholine 1,1-dioxidecyclobutyl 1-amine;
[0196]
2'-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3'-bipyrid-
ine]-6-carboxamide;
[0197]
N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)-
quinazolin-2-amine;
[0198]
N-((1S,3S)-3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine;
[0199]
5-(3-((1S,3S)-3-(quinazolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)pico-
linonitrile;
[0200]
N-((1S,3S)-3-((3-(2-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine;
[0201]
1-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl-
)piperidine-4-carbonitrile;
[0202]
1-(5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)pyridin-2-yl)ethanone;
[0203]
N-((1S,3S)-3-((3-(1-methylpiperidin-4-yl)pyrazin-2-yl)oxy)cyclobuty-
l)benzo[d]thiazol-2-amine;
[0204]
N-((1S,3S)-3-((3-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)pyrazin-
-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;
[0205]
N-((1S,3S)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)cyclobuty-
l)quinazolin-2-amine; or
[0206]
(1-(3-((1S,3S)-3-(quinazolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)pip-
eridin-4-yl)methanol.
[0207] Another aspect of the invention relates to the compounds of
Examples 118 to 127 as listed in Table 13 below, or a
pharmaceutically acceptable salt thereof
[0208] Yet another aspect of the current invention relates to any
compound of the present invention, or a pharmaceutically-acceptable
salt thereof, radiolabeled with a positron emitting radionuclide
selected from .sup.11C, .sup.18F, .sup.15O, .sup.13N, .sup.76Br,
.sup.77Br, .sup.123I, or .sup.125I.
[0209] Yet another aspect of the current invention relates to a
radiopharmaceutical composition comprising any compound of the
present invention, or a pharmaceutically-acceptable salt thereof,
radiolabeled with a positron emitting radionuclide selected from
.sup.11C, .sup.18F, .sup.15O, .sup.13N, .sup.76Br, .sup.77Br,
.sup.123I, or .sup.125I, and at least one pharmaceutically
acceptable carrier or excipient.
[0210] Yet another aspect of the current invention relates to a
method for the diagnostic imaging of PDE10 receptors in a mammal,
including human, or tissues bearing PDE10 receptors in a mammal,
including human brain, which comprises administering to a mammal in
need of such diagnostic imaging an effective amount of any any
compound of the present invention, or a pharmaceutically-acceptable
salt thereof, radiolabeled with a positron emitting radionuclide
selected from .sup.11C, .sup.18F, .sup.15O, .sup.13N, .sup.76Br,
.sup.77Br, .sup.123I, or .sup.125I.
[0211] Yet another aspect of the current invention relates to a
method for the diagnostic imaging of PDE10 receptors in a mammal,
including human, or tissues bearing PDE10 receptors in a mammal,
including human brain, which comprises administering to a mammal in
need of such diagnostic imaging an effective amount of any compound
of the present invention, or a pharmaceutically-acceptable salt
thereof, radiolabeled with a positron emitting radionuclide
selected from .sup.11C, .sup.18F, .sup.15O, .sup.13N, .sup.76Br,
.sup.77Br, .sup.123I, or .sup.125I.
[0212] Yet another aspect of the current invention relates to a
method for the detection or quantification of PDE10 receptors in
mammalian tissue, including human tissue, which comprises
contacting such mammalian tissue in which such detection or
quantification is desired with an effective amount of any compound
of the present invention, or a pharmaceutically-acceptable salt
thereof, radiolabeled with a positron emitting radionuclide
selected from .sup.11C, .sup.18F, .sup.15O, .sup.13N, .sup.76Br,
.sup.77Br, .sup.123I, or .sup.125I.
[0213] The compounds of this invention may have in general several
asymmetric centers and are typically depicted in the form of
racemic mixtures. This invention is intended to encompass racemic
mixtures, other racemic mixtures and separate enantiomers and
diasteromers.
[0214] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of the present invention
wherein one or more atoms are replaced by atoms having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number which predominates in nature.
[0215] Examples of isotopes suitable for inclusion in the compounds
of the invention include, but are not limited to, isotopes of
hydrogen, such as .sup.2H and .sup.3H, carbon, such as .sup.11C,
.sup.13C and .sup.14C, chlorine, such as .sup.38Cl, fluorine, such
as .sup.18F, iodine, such as .sup.123I and .sup.125I, nitrogen,
such as .sup.13N and .sup.15N, oxygen, such as .sup.15O, .sup.17O
and .sup.18O, phosphorus, such as .sup.32P, and sulphur, such as
.sup.35S.
[0216] Certain isotopically-labelled compounds of the present
invention, for example, those incorporating a radioactive isotope,
are useful in drug and/or substrate tissue distribution studies.
The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e.
u are particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0217] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0218] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0219] Isotopically-labeled compounds of the present invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples and Preparations using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0220] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0221] Specific embodiments of the present invention include the
compounds exemplified in the Examples below and their
pharmaceutically acceptable salts, complexes, solvates, polymorphs,
stereoisomers, metabolites, prodrugs, and other derivatives
thereof, Unless otherwise specified, the following definitions
apply to terms found in the specification and claims:
[0222] Heteroaryloxycarbocyclyl compounds of the invention may
possess one or more asymmetric carbon atoms. Rotation about
carbon-carbon bonds in carbocyclic compounds is limited by the ring
structure and therefore the compounds can exist as multiple
diastereomers. When two substituent groupsof a carbocyclic compound
are oriented in the same direction, the diastereomer is referred to
as cis, whereas, when the substituents are oriented in opposing
directions, the diastereomer is referred to as trans. For example,
there are two different 1,2-dichloro-cyclohexane diastereomers, one
with the two chloros on the same side (cis) of the ring and one
with the chloros on opposite sides (trans). Below are the
structures of trans and cis diastereoisomers of
1,2-dichloro-cyclobutane; 1,2-dichloro-cyclopentane, and
1,2-dichloro-cyclohexane, respectively:
##STR00017##
[0223] Similarly, a compound of formula (I):
##STR00018##
may exist in the following four stereoisomeric forms:
##STR00019##
[0224] It will be appreciated that in the compound of formula (I),
where m is not 0, all compounds of formula (a), (b), (c), and (d)
exist as 4 different stereoisomers, and each of which is
contemplated to be within the claimed invention.
It will also be appreciated that in the compound of formula (I),
where m is 0, and the sum of p and q is an odd number (3 or 5), all
compounds of formula (a), (b), (c), and (d) exist as 4 different
stereoisomers, and each of which is contemplated to be within the
claimed invention.
[0225] It will also be appreciated that the compound of formula
(I), where m is 0, and the sum of p and q is an even number (2, 4,
or 6), are symmetrical, and in the absence of any other
stereocenter elsewhere in the molecule, accordingly the compound of
formula (a) is identical to (b), and the compound of formula (c) is
identical to (d). Therefore said compound exists as 2 different
stereoisomers, and each of which is contemplated to be within the
claimed invention.
[0226] More specifically, for example, in the compound of Example
22, m is 0, and the sum of p and q is an even number (2); and the
compound is symmetrical. Therefore said compound may exist as two
different stereoisomers, cis and trans, as follows:
##STR00020##
[0227] Compounds (a) and (b) are called trans stereoisomers because
the substituents of the middle carbocyclic ring are oriented in the
same directions. Compounds (c) and (d) are called cis stereoisomers
because the substituents of the middle carbocyclic ring are
oriented in the opposite directions. Because the compound is
symmetrical, compound (a) is identical to compound (b) (trans
stereoisomers) and compound (c) is identical to compound (d) (cis
stereoisomers); each of which is contemplated to be within the
claimed invention.
[0228] The term "C.sub..alpha.-.beta.alk" means an alkyl group
comprising a minimum of a and a maximum of p carbon atoms in a
branched, cyclical or linear relationship or any combination of the
three, wherein a and p represent integers. The alkyl groups
described in this section may also contain one or two double or
triple bonds. A designation of C.sub.0alk indicates a direct bond.
Examples of C.sub.1-6alkyl include, but are not limited to the
following:
##STR00021##
[0229] The term "benzo group", alone or in combination, means the
divalent radical C.sub.4H.sub.4.dbd., one representation of which
is --CH.dbd.CH--CH.dbd.CH--, that when vicinally attached to
another ring forms a benzene-like ring--for example
tetrahydronaphthylene, indole and the like.
[0230] The terms "oxo" and "thioxo" represent the groups .dbd.O (as
in carbonyl) and .dbd.S (as in thiocarbonyl), respectively.
[0231] The term "halo" or "halogen" means a halogen atom selected
from F, Cl, Br or I.
[0232] The term "C.sub..alpha.-.beta.haloalk" means an alk group,
as described above, wherein one or more hydrogen atom of the alk
group is replaced by F, Cl, Br or I.
[0233] The term "carbon-linked" means a substituent is linked to
another group through a carbon atom. Examples of "carbon-linked"
substituents include, but are not limited to the following:
##STR00022##
[0234] The term "nitrogen-linked" means a substituent is linked to
another group through a nitrogen atom. Examples of
"nitrogen-linked" substituents include, but are not limited to the
following:
##STR00023##
[0235] The group N(R.sup.a)R.sup.a and the like include
substituents where the two R.sup.a groups together form a ring,
optionally including a N, O or S atom, and include groups such
as:
##STR00024##
[0236] The group N(C.sub..alpha.-.beta.alk)
C.sub..alpha.-.beta.alk, wherein a and p are as defined above,
include substituents where the two C.sub..alpha.-.beta.alk groups
together form a ring, optionally including a N, O or S atom, and
include groups such as:
##STR00025##
[0237] The term "carbocyclyl" means a ring comprising by itself or
in combination with other terms, represents, unless otherwise
stated, cyclic version of "C.sub..alpha.-.beta.alk". Thus, the term
"carbocyclyl" is meant to be included in the terms
"C.sub..alpha.-.beta.alk". Examples of carbocycle include
cyclopentyl, cyclohexyl, or partially unsaturated ring such as
1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene,
cyclohexylene and the like. Unless otherwise stated, carbocycle can
include fully saturated ring such as phenyl or naphthyl.
[0238] The term "heteroatom" means N, O and S.
[0239] The term "heterocyclyl" means a ring comprising at least one
carbon atom and at least one other atom selected from N, O and S.
"Heterocyclyl" includes aromatic heterocyclic ring which is
commonly known as heteroaryl. Thus, the term "heteroaryl" is meant
to be included in the terms "heterocyclyl". Examples of
heterocycles that may be found in the claims include, but are not
limited to, the following:
##STR00026## ##STR00027##
[0240] The term "pharmaceutically acceptable salt" means a salt
prepared by conventional means, and are well known by those skilled
in the art. The "pharmacologically acceptable salts" include basic
salts of inorganic and organic acids, including but not limited to
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic
acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric
acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
phenylacetic acid, mandelic acid and the like. When compounds of
the invention include an acidic function such as a carboxy group,
then suitable pharmaceutically acceptable cation pairs for the
carboxy group are well known to those skilled in the art and
include alkaline, alkaline earth, ammonium, quaternary ammonium
cations and the like. For additional examples of "pharmacologically
acceptable salts," and Berge et al., J. Pharm. Sci. 66:1
(1977).
[0241] The term "saturated, partially-saturated or unsaturated"
includes substituents saturated with hydrogens, substituents
completely unsaturated with hydrogens and substituents partially
saturated with hydrogens.
[0242] Representative examples of "saturated, partially-saturated
or unsaturated" five to eight membered rings, optionally having one
to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl and phenyl. Further exemplary five membered rings are
furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,
1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl,
2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,
pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl,
1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4oxadiazolyl,
1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl,
3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl,
1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, and 1,3-oxathiolyl.
[0243] Further exemplary six membered rings are 2H-pyranyl,
4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
pyndazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,
1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl,
4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl,
1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl,
1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl,
1,2,6-(3 oxathiazinyl, and 1,4,2-oxadiazinyl.
[0244] Further exemplary seven membered rings are azepinyl,
oxepinyl, thiepinyl and 1,2,4-triazepinyl.
[0245] Further exemplary eight membered rings are cyclooctyl,
cyclooctenyl and cyclooctadienyl.
[0246] The term "monocyclic" means a group having a single
saturated, partially-saturated, or unsaturated ring system.
Typically a monocyclic ring system can have from 3- to 8 atoms in
the ring system. The term includes, but is not limited to,
cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, phenyl, and the like.
[0247] The term "bicyclic" means a group having two interconnected
saturated, partially-saturated, or unsaturated rings that include
stable bridged, fused, or spiro rings. The bicyclic ring may be
attached at any carbon or heteroatom which affords a stable group.
Typically a bicyclic ring system can have from 6- to 14 atoms in
the ring system. The term includes, but is not limited to,
benzimidazole, naphthyl, bicyclo[3.1.0]hexane,
bicyclo[4.1.0]heptane, spiro[2.4]heptane, spiro[2.5]octane,
bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane, bicyclo[3.3.1]nonane,
bicyclo[3.2.1]octane, spiro[4.5]decane, spiro[3.5]nonane,
norbomane, bicyclo[2.1.0]pentane, bicyclo[3.3.0]octane,
bicyclo[2.2.2]octane, bicyclo[3.3.3]undecane, and the like.
[0248] The term "tricyclic" means a group having three
interconnected saturated, partially-saturated, or unsaturated rings
that include stable bridged, fused, or spiro rings. Typically a
tricyclic ring system can have from 11 to 18 ring atoms in the ring
system. The term includes, but is not limited to, adamantyl,
tricyclo[5.2.1.0.sup.2,6]decane, and the like.
[0249] Exemplary bicyclic rings consisting of two fused partially
saturated, fully saturated or fully unsaturated five and/or six
membered rings, optionally having one to four heteroatoms, are
indolizinyl, indolyl, isoindolyl, indolinyl,
cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl,
isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl,
indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl,
benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl,
2H-1-benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl,
pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,
1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and
4H-1,4-benzoxazinyl.
[0250] A cyclic ring group may be bonded to another group in more
than one way. If no particular bonding arrangement is specified,
then all possible arrangements are intended. For example, the term
"pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl"
includes 2-, or 3-thienyl.
[0251] The term "substituted" means that a hydrogen atom on a
molecule or group is replaced with a group or atom. Typical
substitutents include: halogen, C.sub.1-8alkyl, hydroxyl,
C.sub.1-8alkoxy, --NR.sup.xR.sup.x, nitro, cyano, halo or
perhaloC.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
SR.sup.x, S(.dbd.O).sub.2R.sup.x, C(.dbd.O)OR.sup.x,
C(.dbd.O)R.sup.x, wherein each R.sup.x is independently hydrogen or
C.sub.1-C.sub.8 alkyl. It is noted that when the substituent is
NRxRx, the Rx groups may be joined together with the nitrogen atom
to form a ring.
[0252] A group or atom that replaces a hydrogen atom is also called
a substituent.
[0253] Any particular molecule or group can have one or more
substituent depending on the number of hydrogen atoms that can be
replaced.
[0254] The symbol "-" represents a covalent bond and can also be
used in a radical group to indicate the point of attachment to
another group. In chemical structures, the symbol is commonly used
to represent a methyl group in a molecule.
[0255] The term "leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol or an
alcohol nucleophile. Such leaving groups are well known in the art.
Examples of such leaving groups include, but are not limited to,
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,
tosylates and the like. Preferred leaving groups are indicated
herein where appropriate.
[0256] The term "protecting group" generally refers to groups well
known in the art which are used to prevent selected reactive
groups, such as carboxy, amino, hydroxy, mercapto and the like,
from undergoing undesired reactions, such as nucleophilic,
electrophilic, oxidation, reduction and the like. Preferred
protecting groups are indicated herein where appropriate. Examples
of amino protecting groups include, but are not limited to,
aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted
cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl,
aralkoxycarbonyl, silyl and the like. Examples of aralkyl include,
but are not limited to, benzyl, ortho-methylbenzyl, trityl and
benzhydryl, which can be optionally substituted with halogen,
alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and
salts, such as phosphonium and ammonium salts. Examples of aryl
groups include phenyl, naphthyl, indanyl, anthracenyl,
9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl
radicals, preferably have 6-10 carbon atoms, include, but are not
limited to, cyclohexenyl methyl and the like. Suitable acyl,
alkoxycarbonyl and aralkoxycarbonyl groups include
benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,
substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro
acetyl, phthaloyl and the like. A mixture of protecting groups can
be used to protect the same amino group, such as a primary amino
group can be protected by both an aralkyl group and an
aralkoxycarbonyl group. Amino protecting groups can also form a
heterocyclic ring with the nitrogen to which they are attached, for
example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,
maleimidyl and the like and where these heterocyclic groups can
further include adjoining aryl and cycloalkyl rings. In addition,
the heterocyclic groups can be mono-, di- or tri-substituted, such
as nitrophthalimidyl. Amino groups may also be protected against
undesired reactions, such as oxidation, through the formation of an
addition salt, such as hydrochloride, toluenesulfonic acid,
trifluoroacetic acid and the like. Many of the amino protecting
groups are also suitable for protecting carboxy, hydroxy and
mercapto groups. For example, aralkyl groups. Alkyl groups are also
suitable groups for protecting hydroxy and mercapto groups, such as
tert-butyl.
[0257] The term "silyl protecting groups" means silicon atoms
optionally substituted by one or more alkyl, aryl and aralkyl
groups. Suitable silyl protecting groups include, but are not
limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl,
tert-butyldimethylsilyl, dimethylphenylsilyl,
1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and
diphenylmethylsilyl. Silylation of an amino groups provide mono- or
di-silylamino groups. Silylation of aminoalcohol compounds can lead
to a N,N,O-trisilyl derivative. Removal of the silyl function from
a silyl ether function is readily accomplished by treatment with,
for example, a metal hydroxide or ammonium fluoride reagent, either
as a discrete reaction step or in situ during a reaction with the
alcohol group. Suitable silylating agents are, for example,
trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride,
phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or
their combination products with imidazole or DMF. Methods for
silylation of amines and removal of silyl protecting groups are
well known to those skilled in the art. Methods of preparation of
these amine derivatives from corresponding amino acids, amino acid
amides or amino acid esters are also well known to those skilled in
the art of organic chemistry including amino acid/amino acid ester
or aminoalcohol chemistry.
[0258] Protecting groups are removed under conditions which will
not affect the remaining portion of the molecule. These methods are
well known in the art and include acid hydrolysis, hydrogenolysis
and the like. A preferred method involves removal of a protecting
group, such as removal of a benzyloxycarbonyl group by
hydrogenolysis utilizing palladium on carbon in a suitable solvent
system such as an alcohol, acetic acid, and the like or mixtures
thereof. A t-butoxycarbonyl protecting group can be removed
utilizing an inorganic or organic acid, such as HCl or
trifluoroacetic acid, in a suitable solvent system, such as dioxane
or methylene chloride. The resulting amino salt can readily be
neutralized to yield the free amine. Carboxy protecting group, such
as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the
like, can be removed under hydrolysis and hydrogenolysis conditions
well known to those skilled in the art.
[0259] It should be noted that compounds of the invention may
contain groups that may exist in tautomeric forms, such as cyclic
and acyclic amidine and guanidine groups, heteroatom substituted
aromatic heterocyclyl groups (Y'.dbd.O, S, NR), and the like, which
are illustrated in the following examples:
##STR00028##
and though one form is named, described, displayed and/or claimed
herein, all the tautomeric forms are intended to be inherently
included in such name, description, display and/or claim.
[0260] Prodrugs of the compounds of this invention are also
contemplated by this invention. A prodrug is an active or inactive
compound that is modified chemically through in vivo physiological
action, such as hydrolysis, metabolism and the like, into a
compound of this invention following administration of the prodrug
to a patient. The suitability and techniques involved in making and
using prodrugs are well known by those skilled in the art. For a
general discussion of prodrugs involving esters see Svensson and
Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of
Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion
include a variety of esters, such as alkyl (for example, methyl,
ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example,
benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example,
pivaloyloxymethyl). Amines have been masked as
arylcarbonyloxymethyl substituted derivatives which are cleaved by
esterases in vivo releasing the free drug and formaldehyde
(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an
acidic NH group, such as imidazole, imide, indole and the like,
have been masked with N-acyloxymethyl groups (Bundgaard Design of
Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as
esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses
Mannich-base hydroxamic acid prodrugs, their preparation and
use.
[0261] The term "therapeutically effective amount" means an amount
of a compound that ameliorates, attenuates or eliminates one or
more symptom of a particular disease or condition, or prevents or
delays the onset of one of more symptom of a particular disease or
condition.
[0262] The term "patient" means animals, such as dogs, cats, cows,
horses, sheep and humans. Particular patients are mammals. The term
patient includes males and females.
[0263] The term "pharmaceutically acceptable" means that the
referenced substance, such as a compound of Formula I, or a salt of
a compound of Formula I, or a formulation containing a compound of
Formula I, or a particular excipent, are suitable for
administration to a patient.
[0264] The terms "treating", "treat" or "treatment" and the like
include preventative (e.g., prophylactic) and palliative
treatment.
[0265] The term "excipient" means any pharmaceutically acceptable
additive, carrier, diluent, adjuvant, or other ingredient, other
than the active pharmaceutical ingredient (API), which is typically
included for formulation and/or administration to a patient.
Utility and Methods of Use
[0266] Provided herein are methods for treating a disorder or
disease by inhibiting PDE10 enzyme. The methods, in general,
comprises the step of administering a therapeutically effective
amount of a compounds of the present invention, or an individual
stereoisomer, a mixture of stereoisomers, or a pharmaceutically
acceptable salt or solvate thereof, to a patient in need thereof to
treat the disorder or disease.
[0267] In certain embodiments, this invention provides a use of a
compound as described herein in the manufacture of a medicament for
treating a disorder or disease treatable by inhibition of
PDE10.
[0268] The compounds of the present invention inhibit PDE10 enzyme
activity, and hence raise the levels of cAMP or cGMP within cells
that express PDE10. Accordingly, inhibition of PDE10 enzyme
activity would be useful in the treatment of diseases caused by
deficient amounts of cAMP or cGMP in cells. PDE10 inhibitors would
also be of benefit in cases wherein raising the amount of cAMP or
cGMP above normal levels results in a therapeutic effect.
Inhibitors of PDE10 may be used to treat disorders of the
peripheral and central nervous system, cardiovascular diseases,
cancer, gastro-enterological diseases, endocrinological diseases
and urological diseases.
[0269] Indications that may be treated with PDE10 inhibitors,
either alone or in combination with other drugs, include, but are
not limited to, those diseases thought to be mediated in part by
the basal ganglia, prefrontal cortex, and hippocampus. These
indications include psychoses, Parkinson's disease, dementias,
obsessive compulsive disorder, tardive dyskinesia, choreas,
depression, mood disorders, impulsivity, drug addiction, attention
deficit/hyperactivity disorder (ADHD), depression with parkinsonian
states, personality changes with caudate or putamen disease,
dementia and mania with caudate and pallidal diseases, and
compulsions with pallidal disease.
[0270] Psychoses are disorders that affect an individual's
perception of reality. Psychoses are characterized by delusions and
hallucinations. The compounds of the present invention are suitable
for use in treating patients suffering from all forms of psychoses,
including, but not limited to, schizophrenia, late-onset
schizophrenia, schizoaffective disorders, prodromal schizophrenia,
and bipolar disorders. Treatment can be for the positive symptoms
of schizophrenia as well as for the cognitive deficits and negative
symptoms. Other indications for PDE10 inhibitors include psychoses
resulting from drug abuse (including amphetamines and PCP),
encephalitis, alcoholism, epilepsy, Lupus, sarcoidosis, brain
tumors, multiple sclerosis, dementia with Lewy bodies, or
hypoglycemia. Other psychiatric disorders, like posttraumatic
stress disorder (PTSD), and schizoid personality can also be
treated with PDE10 inhibitors.
[0271] Obsessive-compulsive disorder (OCD) has been linked to
deficits in the frontal-striatal neuronal pathways (Saxena et al.,
Br. J. Psychiatry Suppl, 35:26-37, 1998). Neurons in these pathways
project to striatal neurons that express PDE10. PDE10 inhibitors
cause cAMP to be elevated in these neurons; elevations in cAMP
result in an increase in CREB phosphorylation and thereby improve
the functional state of these neurons. The compounds of the present
invention are therefore suitable for use in the indication of OCD.
OCD may result, in some cases, from streptococcal infections that
cause autoimmune reactions in the basal ganglia (Giedd et al., Am J
Psychiatry. 157:281-283, 2000). Because PDE10 inhibitors may serve
a neuroprotective role, administration of PDE10 inhibitors may
prevent the damage to the basal ganglia after repeated
streptococcal infections and thereby prevent the development of
OCD.
[0272] In the brain, the level of cAMP or cGMP within neurons is
believed to be related to the quality of memory, especially long
term memory. Without wishing to be bound to any particular
mechanism, it is proposed that, since PDE10 degrades cAMP or cGMP,
the level of this enzyme affects memory in animals, for example, in
humans. A compound that inhibits cAMP phosphodiesterase (PDE) can
thereby increase intracellular levels of cAMP, which in turn
activate a protein kinase that phosphorylates a transcription
factor (cAMP response binding protein). The phosphorylated
transcription factor then binds to a DNA promoter sequence to
activate genes that are important in long term memory. The more
active such genes are, the better is long-term memory. Thus, by
inhibiting a phosphodiesterase, long term memory can be
enhanced.
[0273] Dementias are diseases that include memory loss and
additional intellectual impairment separate from memory. The
compounds of the present invention are suitable for use in treating
patients suffering from memory impairment in all forms of dementia.
Dementias are classified according to their cause and include:
neurodegenerative dementias (e.g., Alzheimer's, Parkinson's
disease, Huntington's disease, Pick's disease), vascular (e.g.,
infarcts, hemorrhage, cardiac disorders), mixed vascular and
Alzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease,
multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic
brain injury), infectious (e.g., HIV), genetic (down syndrome),
toxic (e.g., heavy metals, alcohol, some medications), metabolic
(e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's
disease, psychiatric (e.g., depression and schizophrenia), and
hydrocephalus.
[0274] The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. The present
invention includes methods for dealing with memory loss separate
from dementia, including mild cognitive impairment (MCI) and
age-related cognitive decline. The present invention includes
methods of treatment for memory impairment as a result of disease.
Memory impairment is a primary symptom of dementia and can also be
a symptom associated with such diseases as Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and
head trauma as well as age-related cognitive decline. The compounds
of the present invention are suitable for use in the treatment of
memory impairment due to, for example, Alzheimer's disease,
multiple sclerosis, amylolaterosclerosis (ALS), multiple systems
atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's
disease, Pick's disease, Creutzfeld-Jakob disease, depression,
aging, head trauma, stroke, spinal cord injury, CNS hypoxia,
cerebral senility, diabetes associated cognitive impairment, memory
deficits from early exposure of anesthetic agents, multiinfarct
dementia and other neurological conditions including acute neuronal
diseases, as well as HIV and cardiovascular diseases.
[0275] The compounds of the present invention are also suitable for
use in the treatment of a class of disorders known as
polyglutamine-repeat diseases. These diseases share a common
pathogenic mutation. The expansion of a CAG repeat, which encodes
the amino acid glutamine, within the genome leads to production of
a mutant protein having an expanded polyglutamine region. For
example, Huntington's disease has been linked to a mutation of the
protein huntingtin. In individuals who do not have Huntington's
disease, huntingtin has a polyglutamine region containing about 8
to 31 glutamine residues. For individuals who have Huntington's
disease, huntingtin has a polyglutamine region with over 37
glutamine residues. Aside from Huntington's disease (HD), other
known polyglutamine-repeat diseases and the associated proteins
include dentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1);
spinocerebellar ataxia type-1 (ataxin-1); spinocerebellar ataxia
type-2 (ataxin-2); spinocerebellar ataxia type-3 (also called
Machado-Joseph disease or MJD) (ataxin-3); spinocerebellar ataxia
type-6 (alpha la-voltage dependent calcium channel);
spinocerebellar ataxia type-7 (ataxin-7); and spinal and bulbar
muscular atrophy (SBMA, also know as Kennedy disease).
[0276] The basal ganglia are important for regulating the function
of motor neurons; disorders of the basal ganglia result in movement
disorders. Most prominent among the movement disorders related to
basal ganglia function is Parkinson's disease (Obeso et al.,
Neurology. 62(1Suppl 1):517-30, 2004). Other movement disorders
related to dysfunction of the basal ganglia include tardive
dyskinesia, progressive supranuclear palsy and cerebral palsy,
corticobasal degeneration, multiple system atrophy, Wilson disease,
dystonia, tics, and chorea. The compounds of the invention are also
suitable for use to treat movement disorders related to dysfunction
of basal ganglia neurons.
[0277] PDE10 inhibitors are useful in raising cAMP or cGMP levels
and prevent neurons from undergoing apoptosis. PDE10 inhibitors may
be anti-inflammatory by raising cAMP in glial cells. The
combination of anti-apoptotic and anti-inflammatory properties, as
well as positive effects on synaptic plasticity and neurogenesis,
make these compounds useful to treat neurodegeneration resulting
from any disease or injury, including stroke, spinal cord injury,
Alzheimer's disease, multiple sclerosis, amylolaterosclerosis
(ALS), and multiple systems atrophy (MSA).
[0278] Autoimmune diseases or infectious diseases that affect the
basal ganglia may result in disorders of the basal ganglia
including ADHD, OCD, tics, Tourette's disease, Sydenham chorea. In
addition, any insult to the brain can potentially damage the basal
ganglia including strokes, metabolic abnormalities, liver disease,
multiple sclerosis, infections, tumors, drug overdoses or side
effects, and head trauma. Accordingly, the compounds of the
invention can be used to stop disease progression or restore
damaged circuits in the brain by a combination of effects including
increased synaptic plasticity, neurogenesis, anti-inflammatory,
nerve cell regeneration and decreased apoptosis.
[0279] The growth of some cancer cells is inhibited by cAMP and
cGMP. Upon transformation, cells may become cancerous by expressing
PDE10 and reducing the amount of cAMP or cGMP within cells. In
these types of cancer cells, inhibition of PDE10 activity inhibits
cell growth by raising cAMP. In some cases, PDE10 may be expressed
in the transformed, cancerous cell but not in the parent cell line.
In transformed renal carcinoma cells, PDE10 is expressed and PDE10
inhibitors reduce the growth rate of the cells in culture.
Similarly, breast cancer cells are inhibited by administration of
PDE10 inhibitors. Many other types of cancer cells may also be
sensitive to growth arrest by inhibition of PDE10. Therefore,
compounds disclosed in this invention can be used to stop the
growth of cancer cells that express PDE10.
[0280] The compounds of the invention are also suitable for use in
the treatment of diabetes and related disorders such as obesity, by
focusing on regulation of the cAMP signaling system. By inhibiting
PDE-10, especially PDE-10A, intracellular levels of cAMP are
increased, thereby increasing the release of insulin-containing
secretory granules and, therefore, increasing insulin secretion.
See, for example, WO 2005/012485. The compounds of Formula (I) can
also be used to treat diseases disclosed in US Patent application
publication No. 2006/019975.
Testing
[0281] The PDE10 inhibitory activities of the compounds of the
present invention can be tested, for example, using the in vitro
and in vivo assays described in the Biological Examples below.
Administration and Pharmaceutical Compositions
[0282] In general, the compounds of this invention can be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. The actual amount of a compound of this invention, i.e.,
the active ingredient, depends upon numerous factors, such as the
severity of the disease to be treated, the age and relative health
of the subject, the potency of the compound used, the route and
form of administration, and other factors.
[0283] Therapeutically effective amounts of compounds of formula
(I) may range from approximately 0.1-1000 mg per day; preferably
0.5 to 250 mg/day, more preferably 3.5 mg to 70 mg per day.
[0284] In general, compounds of this invention can be administered
as pharmaceutical compositions by any one of the following routes:
oral, systemic (e.g., transdermal, intranasal or by suppository),
or parenteral (e.g., intramuscular, intravenous or subcutaneous)
administration. The preferred manner of administration is oral
using a convenient daily dosage regimen, which can be adjusted
according to the degree of affliction. Compositions can take the
form of tablets, pills, capsules, semisolids, powders, sustained
release formulations, solutions, suspensions, elixirs, aerosols, or
any other appropriate compositions.
[0285] The choice of formulation depends on various factors, such
as the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills or capsules are
preferred) and the bioavailability of the drug substance. Recently,
pharmaceutical formulations have been developed especially for
drugs that show poor bioavailability based upon the principle that
bioavailability can be increased by increasing the surface area,
i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles
in the size range from 10 to 1,000 nm in which the active material
is supported on a crosslinked matrix of macromolecules. U.S. Pat.
No. 5,145,684 describes the production of a pharmaceutical
formulation in which the drug substance is pulverized to
nanoparticles (average particle size of 400 nm) in the presence of
a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high
bioavailability.
[0286] The compositions are comprised of, in general, a compounds
of the present invention in combination with at least one
pharmaceutically acceptable excipient. Acceptable excipients are
non-toxic, aid administration, and do not adversely affect the
therapeutic benefit of the compounds of the present invention. Such
excipient may be any solid, liquid, semi-solid or, in the case of
an aerosol composition, gaseous excipient that is generally
available to one of skill in the art.
[0287] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk and the like. Liquid
and semisolid excipients may be selected from glycerol, propylene
glycol, water, ethanol and various oils, including those of
petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,
soybean oil, mineral oil, sesame oil, etc. Preferred liquid
carriers, particularly for injectable solutions, include water,
saline, aqueous dextrose, and glycols.
[0288] Compressed gases may be used to disperse a compound of this
invention in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0289] Other suitable pharmaceutical excipients and their
formulations are described in Remington's Pharmaceutical Sciences,
Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
[0290] The level of the compound in a formulation can vary within
the full range employed by those skilled in the art. Typically, the
formulation contains, on a weight percent (wt %) basis, from about
0.01-99.99 wt % of a compounds of the present invention based on
the total formulation, with the balance being one or more suitable
pharmaceutical excipients. Preferably, the compound is present at a
level of about 1-80 wt %.
[0291] The compounds can be administered as the sole active agent
or in combination with other pharmaceutical agents such as other
agents used in the treatment of psychoses, especially schizophrenia
and bipolar disorder, obsessive-compulsive disorder, Parkinson's
disease, Alzheimer's disease, cognitive impairment and/or memory
loss, e.g., nicotinic a-7 agonists, PDE4 inhibitors, other PDE10
inhibitors, calcium channel blockers, muscarinic ml and m2
modulators, adenosine receptor modulators, ampakines, NMDA-R
modulators, mGluR modulators, dopamine modulators, serotonin
modulators, canabinoid modulators, and cholinesterase inhibitors
(e.g., donepezil, rivastigimine, and galanthanamine). In such
combinations, each active ingredient can be administered either in
accordance with their usual dosage range or a dose below their
usual dosage range, and can be administered either simultaneously
or sequentially.
[0292] Drugs suitable in combination with the compounds of the
present invention include, but are not limited to, other suitable
schizophrenia drugs such as Clozaril, Zyprexa, Risperidone, and
Seroquel; bipolar disorder drugs, including, but not limited to,
Lithium, Zyprexa, and Depakote; Parkinson's disease drugs,
including, but not limited to, Levodopa, Parlodel, Permax, Mirapex,
Tasmar, Contan, Kemadin, Artane, and Cogentin; agents used in the
treatment of Alzheimer's disease, including, but not limited to,
Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl,
Estrogen and Cliquinol; agents used in the treatment of dementia,
including, but not limited to, Thioridazine, Haloperidol,
Risperidone, Cognex, Aricept, and Exelon; agents used in the
treatment of epilepsy, including, but not limited to, Dilantin,
Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin,
Barbita, Solfeton, and Felbatol; agents used in the treatment of
multiple sclerosis, including, but not limited to, Detrol, Ditropan
XL, OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and
Copaxone; agents used in the treatment of Huntington's disease,
including, but not limited to, Amitriptyline, Imipramine,
Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline,
Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride,
Quetiapine, Clozapine, and Risperidone; agents useful in the
treatment of diabetes, including, but not limited to, PPAR ligands
(e.g. agonists, antagonists, such as Rosiglitazone, Troglitazone
and Pioglitazone), insulin secretagogues (e.g., sulfonylurea drugs,
such as Glyburide, Glimepiride, Chlorpropamide, Tolbutamide, and
Glipizide, and non-sulfonyl secretagogues), a-glucosidase
inhibitors (such as Acarbose, Miglitol, and Voglibose), insulin
sensitizers (such as the PPAR-y agonists, e.g., the glitazones;
biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and llbeta-HSD
inhibitors), hepatic glucose output lowering compounds (such as
glucagon antagonists and metaformin, e.g., Glucophage and
Glucophage XR), insulin and insulin derivatives (both long and
short acting forms and formulations of insulin); and anti-obesity
drugs, including, but not limited to, P-3 agonists, CB-1 agonists,
neuropeptide Y5 inhibitors, Ciliary Neurotrophic Factor and
derivatives (e.g., Axokine), appetite suppressants (e.g.,
Sibutramine), and lipase inhibitors (e.g., Orlistat).
Experimental
[0293] Unless otherwise noted, all materials were purchased from
Sinopharm Chemical Reagent Co., Ltd and used without further
purification. All microwave assisted reactions were conducted with
a Initiator Synthesizer.RTM. from Biotage.RTM.. All compounds
showed NMR spectra consistent with their assigned structures.
Melting points were determined on a Buchi apparatus and are
uncorrected. Mass spectral data was determined by electrospray
ionization technique. All examples were purified to >90% purity
as determined by high-performance liquid chromatography. Unless
otherwise stated, reactions were run at room temperature.
[0294] The following abbreviations are commonly used: [0295] Ac the
group CH.sub.3--(CO)-- [0296] AcOH or HOAc acetic acid [0297]
Ac.sub.2O acetic anhydride [0298] BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [0299] BnO Benzyloxy
[0300] Boc.sub.2O di-tent-butyl dicarbonate [0301] BTEA-Cl
benzyltriethylammonium chloride [0302] Bz Benzyl group [0303] Cbz
carboxylic acid benzyl ester [0304] CDI 1,1'-carbonyldiimidazole
[0305] d Day [0306] DCM Dichloromethane [0307] DIAD
(CH.sub.3).sub.2CHOOCN.dbd.NCOOCH(CH.sub.3).sub.2 [0308] DIEA
N,N-diisopropylethylamine [0309] Diox Dioxane [0310] DIPEA
diisopropylethyl amine [0311] DMA Dimethylamine [0312] DMAP
4-(dimethylamino)pyridine [0313] DME Dimethoxyethane [0314] DMF
N,N-dimethylformamide [0315] Dess martin Periodinane
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one [0316]
DMSO dimethyl sulfoxide [0317] DPPA diphenyl phosphoryl azide
[0318] EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride [0319] ESI-MS electrospray ionization mass
spectrometry [0320] Et.sub.2O diethyl ether [0321] EtOAc ethyl
acetate [0322] EtOH ethyl alcohol [0323] Et.sub.3N triethyl amine
[0324] g Grams [0325] h hour or hours [0326] HATU
O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0327] HBTU
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
hexafluorophosphate [0328] HCl Hydrochloric acid [0329] HPLC high
pressure liquid chromatography [0330] IPA isopropyl alcohol [0331]
i Pr.sub.2NEt diisopropylethylamine [0332] i PrOH Isopropyl alcohol
[0333] ISCO in-situ chemical oxidation [0334] Lawesson reagent
4-Methoxyphenylthiophosphoric cyclic di(thioanhydride), LR,
2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane,
2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane
2,4-disulfide [0335] LCMS liquid chromatography mass spectrometry
[0336] LDA Lithium diisopropyl amide [0337] LiHMDS Lithium
bis(trimethylsilyl)amide [0338] Me Methyl [0339] MeCN Acetonitrile
[0340] Mel Iodomethane [0341] MeOH methyl alcohol [0342] MeOD
deuteurated methyl alcohol [0343] mg Milligrams [0344] min Min
[0345] mL Milliliters [0346] Mo-(CO).sub.6 molybdenum hexacarbonyl
[0347] MTBE methyl tert-butyl ether [0348] NBS N-bromosuccinimide
[0349] NMP 1-methyl-2-pyrrolidinone [0350] NMR nuclear magnetic
resonance [0351] NOESY nuclear Overhauser effect spectroscopy
[0352] Pd(dppf)Cl.sub.2
[1,1'-Bis(diphenylphosphino)ferroceneldichloropalladium(II),
complex with dichloromethane [0353] PMBCl
1-(chloromethyl)-4-methoxybenzene [0354] PTSA p-toluenesulfonic
acid [0355] Py pyridine [0356] RT RT [0357] sat. saturated [0358]
t-bu tert-butyl group [0359] TFA trifluoroacetic acid [0360] THF
tetrahydrofuran [0361] TLC thin layer chromatography [0362] TMSCl
Trimethylsilyl chloride [0363] TBDPS Tert-Butylchlorodiphenyl
[0364] Tol Toluene [0365] TsCl 4-toluenesulfonyl chloride
(CH.sub.3C.sub.6H.sub.4SO.sub.2Cl) [0366] Xantphos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
General Synthetic Methodology
[0367] The compounds of the present invention can be prepared from
commercially available starting materials and by using general
synthetic techniques known to those of skill in the art. Outlined
below are general reaction schemes suitable for preparing the
compounds of the invention claimed herein. Further exemplification
is found in the specific examples provided. One skilled in the art
will understand that similar or related methods can be used for the
synthesis of the compounds. One skilled in the art will also
appreciate that in several instances it is possible to change the
order of the steps used in the preparation of these compounds and
obtain similar results.
##STR00029##
Alternatively, compounds of formula (I) can be prepared as
follows:
##STR00030##
[0368] General Scheme 1 above shows a general method for preparing
compounds of formula (I) of the invention, for example wherein
R.sup.2 is NH-L.sup.2, as defined herein, via key intermediate
compounds (1) and (2), which include the cis and trans isomers. A
cis isomer of compound (1) is depicted in the above scheme to
obtain the cis compound of formula (I). However, those skilled in
the art would appreciate that the trans isomer of (1) can produce
the trans isomer compound of formula (I) thereof
[0369] In the general schemes that follow, while the cis isomer is
specified, it can be appreciated that the trans isomers can be
produced by using the trans isomer starting material.
[0370] More specific examples of General Scheme 1 are depicted
below in General Schemes 1A-1B.
General Schemes 1A-1B:
##STR00031##
##STR00032##
[0371] PREPARATION 1
##STR00033##
[0372] PREPARATIOFLUORO 1A:
2-FLUORO-3-(TETRAHYDRO-PYRAN-4-YL)-PYRIDINE
STEP 1. 3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-2-FLUORO-PYRIDINE
[0373] A mixture of 3-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol),
4-(4,4,5,5-Tewtramethyl-[1,3]dlioxolan-2-yl)-3,6-dihydro-2H-pyran
(656 mg, 3.12 mmol), K.sub.3PO.sub.4 (1.2 g, 5.68 mmol), and Pd
(dppf)Cl.sub.2 (208 mg, 0.284 mmol) in 1,4-Dioxane/H.sub.2O
(5:1)(30 mL) was heated to reflux overnight under N.sub.2
atmosphere. The reaction mixture was filtered and the filtrate was
concentrated and purification by prep-TLC to give
2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine (260 mg, 1.45 mmol,
51.2%).
STEP 2. 2-FLUORO-3-(TETRAHYDRO-PYRAN-4-YL)-PYRIDINE
[0374] To a solution of
3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-pyridine (260 mg, 1.45 mmol)
in MeOH (20 mL) was added Pd/C (0.1 g), bubbled with H.sub.2 and
stirred at RT overnight. The reaction mixture was filtered and the
filtrate was concentrated to give
2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine (250 mg, 1.38 mmol,
95.3% yield).
PREPARATION 1B: 2-FLUORO-3-(2-METHYLPYRIDIN-4-YL)PYRIDINE
##STR00034##
[0375] STEP 1. 2-FLUORO-3-(2-METHYLPYRIDIN-4-YL)PYRIDINE
[0376] A mixture of 4-bromo-2-methylpyridine (25.0 g, 145 mmol),
2-fluoropyridin-3-ylboronic acid (22.5 g, 160 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (5.10 g, 7.27 mmol), and sodium
carbonate (46.2 g, 436 mmol) in 1,2-dimethoxyethane:ethanol:water
(7:2:0.75, 292.5 ml total volume) was heated to 80.degree. C. for 4
h. After cooling to room temperature, the mixture was diluted with
saturated aqueous sodium bicarbonate solution and water, then
extracted with dichloromethane (3.times.). The combined organic
extracts were then extracted with 2 N aqueous HCl solution
(4.times.). The combined aqueous layers were washed with
dichloromethane, then the pH was raised to 10 with 10 N NaOH. The
resulting suspension was extracted with dichloromethane (3.times.).
The combined extracts were concentrated in vacuo to give
2-fluoro-3-(2-methylpyridin-4-yl)pyridine (22.14 g, 118 mmol, 81%
yield).
PREPARATION 2: 3-(BENZLOXY)CYCLOBUTANAMINE
##STR00035##
[0377] STEP 1. ((1-BROMO-3-CHLOROPROPAN-2-YLOXY)METHYL)BENZENE
[0378] A mixture of mercury (II) chloride (0.05 g, 0.18 mmol),
epichlorohydrin (34.0 g, 367 mmol), and benzyl bromide (64.7 g, 378
mmol) in a 500 mL two necked flask with a reflux condenser and
thermometer (to measure internal temperature), under nitrogen
atmosphere, was slowly heated to 150.degree. C. internal
temperature over 6 h. Heating at that temperature continued for 12
h, and then the mixture was cooled to RT. Vacuum distillation gave
product as a colorless oil. (55.6 g, 57%). (BP=125-130.degree. C.
at <5 mmHg).
STEP 2. DIETHYL 3-(BENZYLOXY)CYCLOBUTATANE-1,1-DICARBOXYLATE
[0379] A solution of NaOEt in EtOH was prepared by dissolving
sodium (1.75 g, 76 mmol) in EtOH (30 mL) under nitrogen atmosphere.
This solution was added slowly to a solution of
((1-bromo-3-chloropropan-2-yloxy)methyl)benzene (8.0 g, 30.4 mmol)
and diethyl malonate (11.58 mL, 76 mmol) in EtOH (20 mL) under
nitrogen via addition funnel. This mixture was heated to reflux for
3 h, then cooled to RT. The resulting suspension was filtered and
the filtrate was concentrated by distillation. The resulting
mixture was heated to 125.degree. C. for 2 h, cooled to RT, and
filtered to remove the resulting solid, the solid was washed with
EtOH and the filtrate was concentrated in vacuo to give diester.
This material was taken to the next step without further
purification.
STEP 3. 3-(BENZYLOXY)CYCLOBUTANE-1,1-DICARBOXYLIC ACID
[0380] An aqueous solution of potassium hydroxide was prepared by
dissolving potassium hydroxide (8.52 g, 152 mmol) in water (11 mL).
This solution was added slowly to a solution of diethyl
3-(benzyloxy)cyclobutane-1,1-dicarboxylate (obtained in step 2) in
EtOH (30 mL) under nitrogen atmosphere and the mixture was then
heated to reflux for 45 min, then cooled to RT. The organic solvent
was removed in vacuo and water (20 mL) was added. The aqueous
suspension was then taken to pH 2-3 with conc. HCl (about 6 mL).
MeOtBu (35 mL) was added, the resulting biphasic mixture was
stirred vigorously for 10 minutes, and the layers were separated.
The aqueous layer was extracted with MeOtBu again, the combined
extracts were dried (MgSO.sub.4), filtered, and concentrated in
vacuo to give a yellow oil. Toluene (35 mL) was added and the
solution was concentrated in vacuo, during which time a solid
precipitated. After all the toluene had been removed, toluene (30
mL) was again added. The resulting suspension was heated to
90.degree. C. for 45 minutes, then cooled back to 15.degree. C.
with an ice bath. The suspension was filtered and the collected
solid was washed with cyclohexane and dried to give product as a
white solid (3.51 g, 46% for 2 steps).
STEP 4. 3-(BENZYLOXY)CYCLOBUTANECARBOXYLIC ACID
[0381] A solution of 3-(benzyloxy)cyclobutane-1,1-dicarboxylic acid
(1.5 g, 5.99 mmol) in pyridine (3 mL) was heated in a 120.degree.
C. oil bath for 12 h. The mixture was cooled to RT and the pyridine
was removed under vacuum. Toluene (10 mL) was added and the
solution was washed with IN HCl (3.times.), dried (MgSO.sub.4),
filtered, and concentrated in vacuo to give product as a brown oil
(1.17 g, 95%).
STEP 5. TERT-BUTYL 3-(BENZYLOXY)CYCLOBUTYLCARBAMATE
[0382] A solution of 3-(benzyloxy)cyclobutanecarboxylic acid (3.40
g, 16.49 mmol), DPPA (4.62 mL, 21.43 mmol), and
diisopropylethylamine (3.73 mL, 21.43 mmol) in toluene (35 mL)
under argon was warmed to 80.degree. C. and stirred for 7 h, then
cooled to RT. The mixture was cooled to 0.degree. C. and then added
slowly via canula to a suspension of potassium tert butoxide (3.70
g, 33.0 mmol) in THF (50 mL) under argon held at RT. The mixture
was then stirred for 1 h and EtOAc and water were then added. The
layers were separated, and the organic layer was dried
(MgSO.sub.4), filtered, and concentrated to give an oil. The oil
was purified by silica gel chromatography (0 to 50% EtOAc/hexane
gradient) to give product as a white solid (3.42 g, 75%).
STEP 6. 3-(BENZYLOXY)CYCLOBUTANAMINE
[0383] HCl (5-6 N in IPA, 3 mL) was added to a solution of
tert-butyl 3-(benzyloxy)cyclobutylcarbamate (1.07 g, 3.86 mmol) in
THF (10 mL). The mixture was stirred at 50.degree. C. for 3 h, then
cooled to RT. The solvent was removed in vacuo and EtOAc (10 mL)
was added. The resulting suspension was cooled to 0.degree. C. for
1 h, then the solid was collected by filtration to give the amine
as a white solid (601 mg, 73%).
PREPARATION 3:
1-(4-(3-CHLOROPYRAZIN-2-YL)PIPERIDIN-1-yl)ETHANONE
##STR00036##
[0384] STEP 1. TERT-BUTYL 4-IODOPIPERIDINE-1-CARBOXYLATE
[0385] A solution of N-Boc-4-hydroxypiperidine (246 g, 1.224 mol),
imidazole (100 g, 1.469 mol, 1.2 eq.) and triphenylphosphine (385
g, 1.469 mol, 1.2 eq.) in THF (750 mL) was cooled using an ice
bath. Then a solution of iodine (373 g, 1.469 mol, 1.2 eq.) in THF
(750 mL) was added slowly over a period of 1 h keeping the internal
temperature below 18.degree. C. The resulting mixture was allowed
to stir at room temperature for 5 h and the mixture was diluted
with ethyl acetate (2 L), brine (1 L) and water (500 mL). The
organic layer was separated and the aqueous layer was extracted
with ethyl acetate (1 L.times.2). The organic layers were combined,
washed with 15% aqueous sodium sulfite (1 L), brine (1 L), dried
and concentrated. The resulting residue was stirred with hexanes (2
L) and the solid was removed by filtration. The solid was stirred
with hexanes (2 L.times.2) and filtered. The filtrate was
concentrated to give 363 g of crude oil which was purified by
column chromatography (eluting with hexanes/ethyl acetate=50:1 to
20:1) to afford 319 g tert-butyl 4-iodopiperidine-1-carboxylate
Yield: 84%.
STEP 2. TERT-BUTYL
4-(3-CHLOROPYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE
[0386] To a suspension of activated zinc dust (84.4 g, 1.29 mol,
1.94 eq.) in anhydrous DMA (270 mL) was added 1,2-dibromoethane
(9.1 mL, 0.106 mol, 0.16 eq.), followed by the slow addition of
chlorotrimethylsilane (13.5 mL, 0.106 mol, 0.16 eq.) over a period
of 5 min. The resulting mixture was stirred for 15 min under
nitrogen. Then a solution of tert-butyl
4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (329 g, 1.06 mol,
1.59 eq.) in anhydrous DMA (670 mL) was added to the above
suspension over a period of 45 min keeping the internal temperature
below 65.degree. C. The resulting mixture was stirred for 1 h while
cooling back to room temperature. The prepared zinc reagent was
allowed to stand and the upper clear solution was transferred to a
degassed and well stirred solution of 2,3-dichloropyrazine (99 g,
0.664 mol, 1 eq.), PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 (16.3 g, 19.9
mmol, 0.03 eq.) and Cul (7.8 g, 41.2 mmol, 0.062 eq.) in anhydrous
DMA (670 mL) using a cannula. DMA (400 mL) was used to rinse the
remaining zinc dust and added to the above mixture. The resulting
mixture was heated to 80.degree. C. under nitrogen and stirred
overnight (19 h). The mixture was cooled to room temperature and
diluted with brine (1 L) and ethyl acetate (6 L). The aqueous phase
was extracted with ethyl acetate (4 L) and organic extracts were
combined, washed with brine (1 L), dried and concentrated. The
resulting residue was purified by column chromatography (eluting
with hexanes/ethyl acetate=9:1 to 6:1) to give 92 g tert-butyl
4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate. Yield: 47%.
STEP 3. 2-CHLORO-3-(PIPERIDIN-4-YL)PYRAZINE
[0387] To a well stirred solution of tert-butyl
4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (92 g, 0.309 mol,
1 eq.) in dichloromethane (1 L) was added trifluoroacetic acid (119
mL, 1.545 mol, 5 eq.). The resulting mixture was heated to reflux
overnight (16 h). The mixture was concentrated and the resulting
TFA salt was dried with toluene (500 mL) azetropically to give 150
g 2-chloro-3-(piperidin-4-yl)pyrazine.This was used in the next
step without further purification.
STEP 4. 1-(4-(3-CHLOROPYRAZIN-2-YL)PIPERIDIN-1-yl)ETHANONE
[0388] To an ice cooled solution of
2-chloro-3-(piperidin-4-yl)pyrazine3TFA (150 g, 0.278 mol) in
anhydrous dichloromethane (1.5 L) kept under nitrogen was added
triethylamine (194 mL, 1.39 mol, 5 eq.) over a period of 15 min.,
followed by acetic anhydride (53 mL, 0.556 mol, 2 eq.) over a
period of 10 min. The resulting mixture was allowed to stir at room
temperature for 2 h and quenched with 500 mL of water. After
separation, the organic phase was further washed with water (500
mL) and brine (500 mL). The aqueous phases were combined and back
extracted with dichloromethane (1 L). Organic extracts were
combined, dried and concentrated. The resulting residue was
purified by column chromatography (eluting with hexanes/ethyl
acetate=2:3 to 100% ethyl acetate) to give 70 g
1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone. Yield : 94% for
two steps.
PREPARATION 4A:
TERT-BUTYL((1S,3S)-3-HYDROXYCYCLOBUTYL)CARBAMATE
##STR00037##
[0389] STEP 1. TERT-BUTYL(3-OXOCYCLOBUTYL)CARBAMATE
[0390] A 22 L three neck flask was charged with
3-oxocyclobutanecarboxylic acid (630 g, 5.52 mol, 1.0 equiv),
toluene (12 L), and triethylamine (850 mL, 6.07 mol, 1.1 equiv).
The acid dissolved in toluene after the addition of triethylamine.
The solution was cooled below 10.degree. C. and diphenylphosphoryl
azide (DPPA) (1.32 L, 6.07 mol, 1.1 equiv) was added dropwise over
15 minutes under N.sub.2. The solution was then warmed up to RT and
stirred overnight. The reaction mixture was then transferred to 22
L separatory funnel, washed with aqueous NaHCO.sub.3 (2.times.4 L),
water (4 L), brine (2 L), dried over MgSO.sub.4 and filtered. The
filtrate was then transferred to a 22 L three neck flask and to it
was added tert-butanol (1260 mL, 13.2 mol, 2.4 equiv). The
resultant reaction mixture was then heated at reflux overnight.
Upon completion, the reaction mixture was cooled to RT and
concentrated under reduced pressure. Another 70 g batch was
combined prior to the column purification. The crude residue thus
obtained was then purified using column chromatography eluting with
ethyl acetate/hexanes (25:75 to 40:60) to afford 350 g of
tert-butyl (3-oxocyclobutyl)carbamate (30% yield).
STEP 2. TERT-BUTYL((1S,3S)-3-HYDROXYCYCLOBUTYL)CARBAMATE
[0391] Tert-butyl (3-oxocyclobutyl)carbamate (280 g, 1.51 mol, 1.0
equiv) was dissolved in anhydrous THF (6.0 L). To this solution
under N.sub.2 atmosphere at -74.degree. C. (acetone/dry ice bath)
was added L-selectride (1 M in THF, 1.82 L, 1.82 mol, 1.2 equiv)
drop-wise over 30 min. Upon completion of the addition, the
reaction mixture was stirred at -74.degree. C. for 2 h and allowed
to warm up to RT and stirred overnight. Disappearance of starting
material was monitored in LCMS. Upon completion, the reaction
mixture was cooled to -40.degree. C. and quenched with ice-cold
water (4.0 L). The crude reaction mixture was then extracted with
ethyl acetate (2.times.8.0 L) and the combined organic extracts was
washed with brine (4.0 L), dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The crude residue thus
obtained was then purified using column chromatography eluting with
ethyl acetate/hexanes (20:80) to ethyl acetate/MeOH (98:02) to
afford 201 g of the tert-butyl
((1S,3S)-3-hydroxycyclobutyl)carbamate (71% yield). .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 1.44 (s, 9H), 1.80-1.75 (m, 2H),
2.26 (bs, 1H), 2.80-2.72 (m, 2H), 3.67-3.64 (m, 1H), 4.05-3.98 (m,
1H), 4.69 (bs, 1H).
PREPARATION 4B: TERT-BUTYL(3-HYDROXYCYCLOBUTYL)CARBAMATE
##STR00038##
[0393] To tert-butyl (3-oxocyclobutyl)carbamate (see PREPARATION
4A, Step 1; 110 g, 0.594 mol, 1 eq) in ethanol (600 mL) was slowly
added sodium borohydride (11.23 g, 0.297 mol, 0.5 eq) at 0.degree.
C. Reaction mixture was warmed to RT and stirred at this
temperature for 2 h. It was quenched with water (1 L). Solvent was
removed under reduced pressure. Water layer was extracted with
EtOAc (3.times.2 L). Combined organic layer was washed with brine,
dried over magnesium sulfate, filtered and concentrated. Residue
was purified by column chromatography with aluminum oxide (Eluent:
20% EtOAc in hexane to 10% MeOH in DCM) to get 64 g of tert-butyl
(3-hydroxycyclobutyl)carbamate as a white solid in 58% yield.
PREPARATION 5A:
(1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
##STR00039##
[0394] STEP 1.
TERT-BUTYL((1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)CARBAMATE
[0395] To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and
tert-butyl ((1S,3S)-3-hydroxycyclobutYL)carbamate (see Preparation
4A; 3.65 g, 20 mmol) in DMSO (50 mL) was added Cs.sub.2CO.sub.3
(13.2 g, 40 mmol), and then the mixture was stirred at 80.degree.
C. overnight. The reaction mixture was diluted with water and
filtered. The filter cake was washed with water, and dried to give
tert-butyl
((1S,3S)-3-((3-chloropyrazin-2-YL)oxy)cyclobutyl)carbamate (5.7 g,
19.0 mmol, 96.6%). ESI-MS (M+1): 300 calc. for
C.sub.13H.sub.18ClN.sub.3O.sub.3 299.
STEP 2. (1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROXYCHLORIDE
[0396] To a mixture of tert-butyl
((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl) carbamate (2.8 g,
9.3 mmol) in MeOH (20 mL) was added HCl/MeOH (20 mL, saturated with
HCl gas), and then stirred at RT for 1 hour. The reaction mixture
was concentrated to give
(1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine hydrochloride
(2.18 g, 9.3 mmol, yield 100%). ESI-MS (M+1): 200 calc. for
C.sub.8H.sub.10ClN.sub.3O 199.
PREPARATION 5B:
N-((1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIAZOL-2-AMIN-
E
##STR00040##
[0398] A mixture of
(1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine hydrochloride
(see Preparation 5A; 1.42 g, 6.0 mmol), 2-chloro-benzothiazole
(purchased from ALDRICH.TM.) (1.07 g, 6.0 mmol) and DIEA (1.6 g,
12.0 mmol) in NMP (12 mL) was heated to 180.degree. C. for 2 hours
in microwave. The reaction mixture was diluted with water,
extracted with EtOAc (2.times.30 mL). The combined organic extracts
were washed with water (30 mL) and brine (30 mL), dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated in vacuo
and the residue was purified by flash column chromatography on
silica gel to give
N-(1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(1.80 g, 5.4 mmol, yield 90%). ESI-MS (M+1): 333 calc. for
C.sub.15H.sub.13ClN.sub.4OS 332.
PREPARATION 5C:
N-(3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIAZOL-2-AMINE
##STR00041##
[0399] STEP 1.
TERT-BUTYL(3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)CARBAMATE
[0400] To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and
tert-butyl (3-hydroxycyclobutyl)carbamate (see Preparation 4B; 3.65
g, 20 mmol) in DMSO (50 mL) was added Cs.sub.2CO.sub.3 (13.2 g, 40
mmol), and then the mixture was stirred at 80.degree. C. overnight.
The reaction mixture was diluted with water and filtered. The
filtrate cake was washed with water, and dried to give tert-butyl
(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2
mmol, 76%). ESI-MS (M+1): 300 calc. for
C.sub.13H.sub.18ClN.sub.3O.sub.3 299.
STEP 2. 3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
[0401] To a mixture of tert-butyl
(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (2.8 g, 9.61
mmol) in MeOH (20 mL) was added HCl/MeOH (20 mL, saturated with HCl
gas), and then stirred at RT for 1 hour. The reaction mixture was
concentrated to give 3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine
hydrochloride (2.2 g, 9.61 mmol, 100%). ESI-MS (M+1): 200 calc. for
C.sub.8H.sub.10ClN.sub.3O 199.
STEP 3.
N-(3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[D[THIAZOL-2-AMINE
[0402] A mixture of 3-(3-chloro-pyrazin-2-yloxy)-cyclobutylamine
hydrochloride (1.2 g, 6.28 mmol), 2-chloro-benzothiazole (purchased
from ALDRICH.TM.) (1.07 g, 6.28 mmol) and DIEA (1.8 g, 12.56 mmol)
in NMP (12 mL) was heated to 180.degree. C. for 2 hours in
microwave. The reaction mixture was extracted with EtOAc (40 mL)
and water, the organic phase was washed with brine and dried over
Na.sub.2SO.sub.4. The organic layers were concentrated and purified
by column chromatography on silica gel to give
N-(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(3.0 g, 6 mmol, 95.5%). ESI-MS (M+1): 333 calc. for
C.sub.15H.sub.13ClN.sub.4OS 332.
PREPARATION 5D:
(1S,3S)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)Pyrazin-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
##STR00042##
[0403] STEP 1.
TERT-BUTYL((1S,3S)-3-((3-(3,6-DIHYDRO-2H-PYRAN-4-YL)Pyrazin-2-YL)OXY)CYCL-
OBUTYL)CARBAMATE
[0404] To a solution of tert-butyl
41S,3S)-3-((3-chloropyrazin-2-YL)oxy)cyclobutyl)carbamate (see
Preparation 5A, step 1; 4 g, 11.2 mmol),
4-(3,3,4,4-tetramethyl-borolan-1-yl)-3,6-dihydro-2H-pyran (2.58 g,
12.4 mmol) and Na.sub.2CO.sub.3 (2.38 g, 22.4 mmol) in1,4-dioxane
(60 mL) and water (6 mL) was added Pd(dppf)Cl.sub.2 (410 mg, 0.56
mmol). The reaction mixture was stirred at 110.degree. C. under
N.sub.2 overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with CH.sub.2Cl.sub.2 (50 mL). The organic
layer was concentrated and the crude product was purified by silica
gel column chromatography to give tert-butyl
((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)car-
bamate (3.5 g, 8.7 mmol, 70%). ESI-MS (M+1): 348 calc. for
C.sub.18H.sub.25N.sub.3O.sub.4 347.
STEP 2.
TERT-BUTYL((1S,3S)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YL)OXY-
)CYCLOBUTYL)CARBAMATE
[0405] A mixture of tert-butyl
((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)car-
bamate (3.5 g, 9.6 mmol) and wet Pd--C (50%, 1.0 g) in MeOH (100
mL) was stirred under H.sub.2 atmosphere (40 psi) at 30.degree. C.
overnight. The reaction mixture was filtered through CELITE.RTM.
and washed with MeOH (100 mL). The filtrate was concentrated to
give tert-butyl
((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)carb-
amate (3.2 g, 8.1 mmol, 91%). ESI-MS (M+1): 350 calc. for
C.sub.18H.sub.27N.sub.3O.sub.4 349
STEP 3.
(1S,3S)-3-((3-(TETRAHYDRO-2H-PYRAN-4-YL)Pyrazin-2-YL)OXY)CYCLOBUTA-
NAMINE HYDROCHLORIDE
[0406] To tert-butyl
((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)carb-
amate (3.2 g, 8.8 mmol) was added 4 M HCl in MeOH (100 mL). The
solution was stirred at RT for 2 hours. The solvent was removed
under reduced pressure to give
(1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutanamine
hydrochloride (2 g, 9.8 mmol, 95%). ESI-MS (M+1): 250 calc. for
C.sub.13H.sub.19N.sub.3O.sub.2 249.
PREPARATION 5E:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIA-
ZOL-2-AMINE HYDROCHLORIDE
##STR00043##
[0407] STEP 1. TERT-BUTYL
4-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)-5,6--
DIHYDROPYRIDINE-1(2H)-CARBOXYLATE
[0408] To a mixture of
N-41S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(see Preparation 5B; 150 mg, 0.6 mmol) in 1,4-Dioxane/water (5:1,
12 mL) was added
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-
-pyridine-1-carboxylic acid tert-butyl ester (278 mg, 0.9 mmol),
K.sub.3PO.sub.4 (254 mg, 1.2 mmol) and Pd(dppf)Cl.sub.2 (44 mg,
0.06 mmol). The mixture was refluxed overnight. The reaction
mixture was filtered and concentrated. The residue was purification
by prep-HPLC to give tert-butyl
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)-5,6--
dihydropyridine-1(2H)-carboxylate (86 mg, 0.18 mmol, yield 30%).
ESI-MS (M+1): 480 calc. for C.sub.25H.sub.29N.sub.5O.sub.3S
479.
STEP 2. TERT-BUTYL
4-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPER-
DINE-1-CARBOXYLATE
[0409] A mixture of tert-butyl
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)-5,6--
dihydropyridine-1(2H)-carboxylate (479 mg, 1 mmol) and wet Pd--C
(50%, 500 mg) in MeOH (100 mL) was stirred under H.sub.2 (40psi) at
30.degree. C. overnight then the reaction mixture was filtered
through CELITE.RTM. and washed with MeOH. The filtrate was
concentrated to give the
tert-butyl4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)piperidine-1-carboxylate (438 mg, 0.91mmol, yield 91%). ESI-MS
(M+1): 482 calc. for C.sub.25H.sub.31N.sub.5O.sub.3S 481.
STEP 3.
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO-
[D]THIAZOL-2-AMINE HYDROCHLORIDE
[0410] To tert-butyl
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idine-1-carboxylate (481 mg, 1 mmol) was added 4 M HCl in MeOH (100
mL). The solution was stirred at RT for 2 hours. The solvent was
removed under reduced pressure to give
N-((1S,3S)-3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine hydrochloride (362 mg, 0.95 mmol, yield 95%). ESI-MS
(M+1): 382 calc. for C.sub.20H.sub.23N.sub.5OS 381.
PREPARATION 5F:
N-((1S,3S)-3-((3-(AZETIDIN-3-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIAZ-
OL-2-AMINE HYDROCHLORIDE
##STR00044##
[0411] STEP 1.
TERT-BUTYL((1S,3S)-3-(BENZYLOXY)CYCLOBUTYL)CARBAMATE
[0412] To a solution of tert-butyl
((1S,3S)-3-hydroxycyclobutyl)carbamate (see Preparation 4A; 187 mg,
1 mmol) in DMF (20 mL) at RT was added sodium hydride (60% wt in
mineral oil) (48 mg, 2 mmol). The mixture was stirred at RT for 10
mins and then bromomethyl-benzene (171 mg, 1 mmol) was added. The
reaction mixture was stirred at RT for 1 h and then diluted with
water (20 mL) and extracted with EtOAc (2.times.30 mL). The
combined organic extracts were washed with water (10 mL) and brine
(10 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by flash
column chromatography on silica gel (5% to 30% EtOAc in hexanes) to
give tert-butyl ((1S,3S)-3-(benzyloxy)cyclobutyl)carbamate (146 mg,
0.5 mmol, 50% yield). ESI-MS (M+1): 278 calc. for
C.sub.16H.sub.23NO.sub.3 277.
STEP 2. (1S,3S)-3-(BENZYLOXY)CYCLOBUTANAMINE HYDROCHLORIDE
[0413] To tert-butyl ((1S,3S)-3-(benzyloxy)cyclobutyl)carbamate
(277 mg, 1 mmol) was added 4 M HCl in MeOH (50 mL). The solution
was stirred at RT for 2 hours. The solvent was removed under
reduced pressure to give (1S,3S)-3-(benzyloxy)cyclobutanamine
hydrochloride (168 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 178
calc. for C.sub.1iH.sub.15NO 177. /
STEP 3.
N-((1S,3S)-3-(BENZYLOXY)CYCLOBUTYL)BENZO[D[THIAZOL-2-AMINE
[0414] A mixture of (1S,3S)-3-(benzyloxy)cyclobutanamine
hydrochloride (242 mg, 1 mmol), 2-chloro-benzothiazole (purchased
from ALDRICH) (169 mg, 1 mmol) and DIEA (286 mg, 2 mmol) in NMP (10
mL) was heated to 180.degree. C. for 2 hours in microwave. To the
reaction mixture was added water, and the residue was extracted
with EtOAc (40 mL). The combined organic phase was washed with
brine and dried over Na.sub.2SO.sub.4. The organic layers were
concentrated and purified by column chromatography on silica gel to
give N-((1S,3S)-3-(benzyloxy)cyclobutyl)benzo[d]thiazol-2-amine
(225 mg, 0.6 mmol, yield 60%). ESI-MS (M+1): 311 calc. for
C.sub.18H.sub.18N.sub.2OS 310.
STEP 4. (1S,3S)-3-(BENZO[D[THIAZOL-2-YLAMIN)CYCLOBUTANOL
[0415] A mixture of
N-((1S,3S)-3-(benzyloxy)cyclobutyl)benzo[d]thiazol-2-amine (310 mg,
1 mmol) and wet Pd--C (50%, 300 mg) in 2 M HCl in EtOH (100 mL) was
stirred under H.sub.2 (40psi) at 30.degree. C. overnight then the
reaction mixture was filtered through CELITE.RTM. and washed with
EtOH. The filtrate was concentrated to give
(1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (198 mg,
0.90mmol, yield 90%). ESI-MS (M+1): 221 calc. for
C.sub.11H.sub.12N.sub.2OS 220.
STEP 5. TERT-BUTYL
3-(3-((1S,3S)-3-(BENZO[D[THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)AZETI-
DINE-1-CARBOXYLATE
[0416] To a mixture of
(1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (220 mg, 1 mmol)
and tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (see
Preparation 10; 269 mg, 1 mmol) in DMSO (50 mL) was added
Cs.sub.2CO.sub.3 (652 mg, 2 mmol). The mixture was stirred at
80.degree. C. overnight. The reaction mixture was diluted with
water and filtered. The filtrate cake was washed with water, and
dried to give tert-butyl
3-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-y0azetid-
ine-1-carboxylate (272 mg, 0.6 mmol, yield 60%). ESI-MS (M+1): 454
calc. for C.sub.23H.sub.27N.sub.5O.sub.3S 453.
STEP 6.
N-((1S,3S)-3-((3-(AZETIDIN-3-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[-
D[THIAZOL-2-AMINE HYDROCHLORIDE
[0417] To tert-butyl
3-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)azeti-
dine-1-carboxylate (481 mg, 1 mmol) was added 4 M HCl in MeOH (100
mL). The solution was stirred at RT for 2 hours. The solvent was
removed under reduced pressure to give
N-((1S,3S)-3-((3-(azetidin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiaz-
ol-2-amine hydrochloride (362 mg, 0.95 mmol, yield 95%). ESI-MS
(M+1): 354 calc. for C.sub.18H.sub.19N.sub.5OS 353.
PREPARATION 5G:
N-((1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)QUINOLIN-2-AMINE
##STR00045##
[0419] A mixture of
(1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine hydrochloride
(see Preparation 5A; 1.2 g, 6.28 mmol), 2-chloro-quinoline
(purchased from Alfa Aesar.TM.) (1.02 g, 6.28 mmol) and DIEA (1.8
g, 12.56 mmol) in NMP (12 mL) was heated to 200.degree. C. for 2
hours in microwave. The reaction mixture was poured into water, and
extracted with EtOAc (40 mL). The organic phase was collected,
washed with brine and dried over Na.sub.2SO.sub.4. The organic
layers were concentrated and purified by column chromatography on
silica gel to give
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)quinolin-2-amine
(921 mg, 2.83 mmol, 45%). ESI-MS (M+1): 327 calc. for
C.sub.17H.sub.15ClN.sub.4O 326.
PREPARATION 5H:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)QUINOLIN-2-A-
MINE HYDROCHLORIDE
##STR00046##
[0420] STEP 1. TERT-BUTYL
4-(3-((1S,3S)-3-(QUINOLIN-2-ylamino)CYCLOBUTOXY)PYRAZIN-2-yl)-5,6-DIHYDRO-
PYRIDINE-1(2H)-CARBOXYLATE
[0421] To a mixture of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)quinolin-2-amine
(see Preparation 5G; 326 mg, 1 mmol) in 1,4-dioxane/H.sub.2O (5:1,
12 mL) was added tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (340 mg, 1.1 mmol), K.sub.3PO.sub.4 (424 mg, 2 mmol)
and Pd(dppf)Cl.sub.2 (37 mg, 0.05 mmol). The reaction mixture was
stirred at 110.degree. C. under N.sub.2 overnight. The reaction
mixture was filtered and concentrated. The residue was purified by
flash chromatography on silica gel (5% to 30% EtOAc in hexanes) to
give tert-butyl
4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)-5,6-dihydro-
pyridine-1(2H)-carboxylate (237mg, 0.5 mmol, yield 50%).
STEP 2: TERT-BUTYL
4-(3-((1S,3S)-3-(QUINOLIN-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPERIDINE-1-
-CARBOXYLATE
[0422] A mixture of tert-butyl
4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)-5,6-dihydro-
pyridine-1(2H)-carboxylate (473 mg, 1 mmol) and wet Pd--C (50%, 500
mg) in MeOH (100 mL) was stirred under H.sub.2 (40psi) at
30.degree. C. overnight then the reaction mixture was filtered
through CELITE.RTM. and washed with MeOH. The filtrate was
concentrated to give tert-butyl
4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidine-1-
-carboxylate (432 mg, 0.91mmol, yield 91%). ESI-MS (M+1): 476 calc.
for C.sub.27H.sub.33N.sub.5O.sub.3 475.
STEP 3:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)QUINO-
LIN-2-AMINE HYDROCHLORIDE
[0423] To tert-butyl
4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidine-1-
-carboxylate (475 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL).
The solution was stirred at RT for 2 hours. The solvent was removed
under reduced pressure to give
N-((1S,3S)-3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)quinolin-2-a-
mine hydrochloride (356 mg, 0.95 mmol, yield 95%). ESI-MS (M+1):
376 calc. for C.sub.22H.sub.25N.sub.5O 375.
PREPARATION 5I :
N-((1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)-5-FLUROBENZO[D[THIAZO-
L-2-AMINE
##STR00047##
[0425] A mixture of
(1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine hydrochloride
(see Preparation 5A; 470 mg, 2 mmol),
2-chloro-5-fluorobenzo[d]thiazole (see Preparation 6; 374 mg, 2
mmol) and DIEA (570 mg, 4 mmol) in NMP (2 mL) was heated to
180.degree. C. for 2 hours in microwave. The reaction mixture was
extracted with EtOAc (40 mL) and water, the organic phase was
washed with brine and dried over Na.sub.2SO.sub.4. The organic
layers were concentrated and purified by silica gel column
chromatography to give
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)-5-fluorobenzo[d]thiaz-
ol-2-amine (450 mg, 1.28 mmol, 64% yield). ESI-MS (M+1): 351 calc.
for C.sub.15H.sub.12ClFN.sub.4OS 350.
PREPARATION 5J:
N-((1S,3S)-3-((3-CHLOROPYRAZIN-2-YL)OXY)CYCLOBUTYL)QUINAZOLIN-2-AMINE
##STR00048##
[0427] A mixture of
(1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine hydrochloride
(see Preparation 5A; 1.2 g, 6.28 mmol), 2-chloroquinazoline (1.03
g, 6.28 mmol) and DIEA (1.8 g, 12.56 mmol) in NMP (12 mL) was
heated to 200.degree. C. for 2 hours in microwave. The reaction
mixture was poured into water, and extracted with EtOAc (40 mL).
The organic phase was collected, washed with brine and dried over
Na.sub.2SO.sub.4. The organic layers were concentrated and purified
by column chromatography on silica gel to give
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)quinazolin-2-amine
(925 mg, 2.83 mmol, 45%). ESI-MS (M+1): 328 calc. for
C.sub.16H.sub.14ClN.sub.5O 327.
PREPARATION 6: 2-CHLORO-5-FLUOROBENZO[D]THIAZOLE
##STR00049##
[0428] STEP 1. 5-FLUOROBENZO[D]THIAZOLE-2-THIOL
[0429] A mixture of 2,5-difluoro-phenylamine (129 mg, 1 mmol) and
potassium o-ethyl dithiocarbonate (352 mg, 2.2 mmol) in DMF (5 mL)
was heated to 120.degree. C. for 15 min in microwave. The reaction
mixture was cooled, diluted with 10 mL of ice water, and acidified
with 3 mL of HCl solution (1 mol/L). Then the mixture was extracted
with EtOAc (3.times.50 mL), washed with brine and dried over
Na.sub.2SO.sub.4. The dried organic layers were concentrated to
give 5-fluorobenzo[d]thiazole-2-thiol (120 mg, 0.67 mmol, 67%).
ESI-MS (M+1): 185 calc. for C.sub.7H.sub.4FN.sub.4S.sub.2 184.
STEP 2. 2-CHLORO-5-FLUOROBENZO[D]THIAZOLE
[0430] Sulfuryl chloride (0.3 mL, 4.41 mmol) was added neat to
5-fluoro-benzothiazole-2-thiol (680 mg, 3.67 mmol). The mixture was
stirred at RT for 1 hour, and then heated to 60.degree. C. for 40
mins. The resulting solution was cooled to room temperature, and
poured onto ice, extracted with EtOAc (3.times.50 mL), washed with
brine and dried over Na.sub.2SO.sub.4. The dried organic layers
were concentrated to give 2-chloro-5-fluorobenzo[d]thiazole (520
mg, 2.75 mmol, 75%). ESI-MS (M+1): 187 calc. for
C.sub.7H.sub.5ClFN.sub.4S 186.
PREPARATION 7A:
TERT-BUTYL((1S,3S)-3-((3-BROMO-5-FLUOROYRIDIN-2-YL)OXY)CYCLOBUTYL)CARBAMA-
TE
##STR00050##
[0432] To a mixture of 3-bromo-2,5-difluoro-pyridine (500 mg, 2.58
mmol) and tert-butyl ((1S,3S)-3-hydroxycyclobutyl)carbamate (see
Preparation 4A; 485 mg, 2.58 mmol) in DMSO (20 mL) was added
Cs.sub.2CO.sub.3 (1.68 g, 5.16 mmol), and then the mixture was
stirred at 80.degree. C. overnight. The reaction mixture was
diluted with water and extracted with EtOAc (3.times.50 mL), washed
with brine and dried over Na.sub.2SO.sub.4. The dried organic
layers were concentrated to tert-butyl
((1S,3S)-3-((3-bromo-5-fluoropyridin-2-yl)oxy)cyclobutyl)carbamate
(380 mg, 1.06 mmol, 41%). ESI-MS (M+1): 361 calc. for
C.sub.14H.sub.18BrFN.sub.2O.sub.3 360.
PREPARATION 7B:
TERT-BUTYL(3-((3-BROMOPRIDIN-2-YL)OXY)CYCLOBUTYL)CARBAMATE
##STR00051##
[0434] To a solution of tert-butyl (3-hydroxycyclobutyl)carbamate
(see Preparation 4B; 1.08 g, 3.8 mmol) in DMF (20 mL) at RT was
added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol).
The mixture was stirred at RT for 10 min and then
3-Bromo-2-fluoro-pyridine (665 mg, 3.8 mmol) was added. The
reaction mixture was stirred at RT for 1 h and then diluted with
water (20 mL) and extracted with EtOAc (2.times.30 mL). The
combined organic extracts were washed with water (10 mL) and brine
(10 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by flash
column chromatography on silica gel (5% to 30% EtOAc in hexanes) to
give tert-butyl
((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (391 mg,
1.14 mmol, 30% yield) as white solid. ESI-MS (M+1): 343 calc. for
C.sub.14H.sub.19BrN.sub.2O.sub.3 342.
PREPARATION 7C:
3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
##STR00052##
[0435] STEP 1:
TERT-BUTYL(3-((3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)C-
ARBAMATE
[0436] To a solution of tert-butyl
(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see Preparation
7B; 343 mg, 1 mmol),
4-(3,3,4,4-tetramethyl-borolan-1-yl)-3,6-dihydro-2H-pyran (2.27 mg,
1.1 mmol) and K.sub.3PO.sub.4 (424 mg, 2 mmol) in1,4-dioxane (60
mL) and H.sub.2O (6 mL) was added Pd(dppf)Cl.sub.2 (36.6 mg, 0.05
mmol) then the reaction mixture was stirred at 110.degree. C. under
N.sub.2 for overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with CH.sub.2Cl.sub.2. The organic layer was
concentrated and the crude product was purified by silica gel
column to give tert-butyl
(3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate
(242 mg, 0.7 mmol, yield 70%). ESI-MS (M+1): 347 calc. for
C.sub.19H.sub.26N.sub.2O.sub.4 346
STEP 2:
TERT-BUTYL(3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBU-
TYL)CARBAMATE
[0437] A mixture of tert-butyl
(3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate
(346 mg, 1 mmol) and wet Pd--C (50%, 200 mg) in MeOH (100 mL) was
stirred under H.sub.2 (40psi) at 30.degree. C. overnight then the
reaction mixture was filtered through CELITE.RTM. and washed with
MeOH. The filtrate was concentrated to give tert-butyl
(3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate
(331 mg, 0.95mmol, yield 95%). ESI-MS (M+1): 349 calc. for
C.sub.19H.sub.28N.sub.2O.sub.4 348.
STEP 3:
3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
[0438] To tert-butyl
(3-((3-(tetrahydro-2H-pyran-4-YL)pyridin-2-YL)oxy)cyclobutyl)carbamate
(348 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL). The solution
was stirred at RT for 2 hours. The solvent was removed under
reduced pressure to give
3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutanamine
hydrochloride (248 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 249
calc. for C.sub.19H.sub.28N.sub.2O.sub.4 248.
PREPARATION 7D:
(1S,3S)-3-((5-FLUORO-3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUT-
ANAMINE HYDROCHLORIDE
##STR00053##
[0439] STEP 1:
TERT-BUTYL((1S,3S)-3-((3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-5-FLUOROPYRIDIN-2-YL-
)OXY)CYCLOBUTYL)CARBAMATE
[0440] To a solution of tert-butyl
((1S,3S)-3-((3-bromo-5-fluoropyridin-2-yl)oxy)cyclobutyl)carbamate
(see Preparation 7A; 430 mg, 1.19 mmol),
4-(3,3,4,4-tetramethyl-borolan-1-yl)-3,6-dihydro-2H-pyran (372 mg,
1.79 mmol) and K.sub.3PO.sub.4 (505 mg, 2.38 mmol) in 1,4-dioxane
(30 mL) and H.sub.2O (6 mL) was added Pd(dppf)Cl.sub.2 (87 mg, 0.12
mmol), then the reaction mixture was stirred at 110.degree. C.
under N.sub.2 overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with CH.sub.2Cl.sub.2. The organic layer was
concentrated and the crude product was purified by silica gel
column to give tert-butyl
((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoropyridin-2-yl)oxy)cyclo-
butyl)carbamate (200 mg, 0.55 mmol, yield 46%). ESI-MS (M+1): 365
calc. for C.sub.19H.sub.25FN.sub.2O.sub.4 364.
STEP 2:
TERT-BUTYL((1S,3S)-3-((5-FLUORO-3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-
-2-YL)OXY)CYCLOBUTYL)CARBAMATE
[0441] A mixture of tert-butyl
((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoropyridin-2-yl)oxy)cyclo-
butyl)carbamate (100 mg, 0.275 mmol) and wet Pd--C (50%, 80 mg) in
MeOH (10 mL) was stirred under H.sub.2 (40 psi) at 30.degree. C.
overnight. The reaction mixture was filtered through CELITE.RTM.
and the filtrate was concentrated to give the desired compound (80
mg, 0.22 mmol, yield 80%). ESI-MS (M+1): 367 calc. for
C.sub.19H.sub.27FN.sub.2O.sub.4 366.
STEP 3:
(1S,3S)-3-((5-FLUORO-3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)C-
YCLOBUTANAMINE HYDROCHLORIDE
[0442] To tert-butyl
((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclob-
utyl)carbamate (200 mg, 0.546 mmol) in MeOH (10 mL) was added MeOH
(10 mL, saturated with HCl gas), and then stirred at RT for 2 hour.
The reaction mixture was concentrated to give
(1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tanamine hydrochloride (180 g, 0.535 mmol, 98%). ESI-MS (M+1): 267
calc. for C.sub.14H.sub.19FN.sub.2O.sub.2 266.
PREPARATION 7E:
N-(3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZO[D[THIAZOL-2-AMINE
##STR00054##
[0443] STEP 1: 3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
[0444] To tert-butyl
(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see Preparation
7B; 342 mg, 1 mmol) was added 4 M HCl in MeOH (50 mL). The solution
was stirred at RT for 2 hours. The solvent was removed under
reduced pressure to give
3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (223 mg,
0.95 mmol, yield 95%). ESI-MS (M+1): 243 calc. for
C.sub.9H.sub.11BrN.sub.2O 242.
STEP 2:
N-(3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIAZOL-2-AMINE
[0445] A mixture of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine
hydrochloride (242 mg, 1 mmol), 2-chloro-benzothiazole (169 mg, 1
mmol) and DIEA (286 mg, 2 mmol) in NMP (10 mL) was heated to
180.degree. C. for 2 hours in microwave. The reaction mixture was
added water, extracted with EtOAc (40 mL), washed with brine and
dried over Na.sub.2SO.sub.4. The organic layers were concentrated
and purified by column chromatography to give
N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(225 mg, 0.6 mmol, yield 60%). ESI-MS (M+1): 376 calc. for
C.sub.16H.sub.14BrN.sub.3OS 375.
PREPARATION 7F: (1S,3S)-3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
##STR00055##
[0446] STEP 1:
TERT-BUTYL((1S,3S)-3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTYL)CARBAMATE
[0447] To a solution of tert-butyl
((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see
Preparation 4A; 1.08 g, 3.8 mmol) in DMF (20 mL) at RT was added
sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The
mixture was stirred at RT for 10 min and then
3-bromo-2-fluoro-pyridine (665 mg, 3.8 mmol) was added. The
reaction mixture was stirred at RT for 1 h and then diluted with
water (20 mL) and extracted with EtOAc (2.times.30 mL). The
combined organic phases were washed with water (10 mL) and brine
(10 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by flash
chromatography on silica gel (5% to 30% EtOAc in hexanes) to give
tert-butyl
((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (391 mg,
1.14 mmol, 30%) as white solid. ESI-MS (M+1): 343 calc. for
C.sub.14H.sub.19BrN.sub.2O.sub.3 342.
STEP 2: (1S,3S)-3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
[0448] To a solution of tert-butyl
((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (342 mg,
1 mmol) was added 4 M HCl in MeOH (50 mL). The solution was stirred
at RT for 2 hours. The solvent was removed under reduced pressure
to give (1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutanamine
hydrochloride (223 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 243
calc. for C.sub.9H.sub.1iBrN.sub.2O 242.
PREPARATION 7G:
N-((1S,3S)-3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTYL)QUINOLIN-2-AMINE
##STR00056##
[0450] A mixture of
(1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride
(1.52 g, 6.28 mmol), 2-chloro-quinoline (purchased from Alfa
Aesar.TM.) (1.02 g, 6.28 mmol) and DIEA (1.8 g, 12.56 mmol) in NMP
(12 mL) was heated to 200.degree. C. for 2 hours in microwave. The
reaction mixture was added water, extracted with EtOAc (40 mL),
washed with brine and dried over Na.sub.2SO.sub.4. The organic
layers were concentrated and purified by column chromatography on
silica gel to give
N-((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)quinolin-2-amine
(1.04 g, 2.83 mmol, 45%). ESI-MS (M+1): 370 calc. for
C.sub.18H.sub.16BrN.sub.3O 369.
PREPARATION 7H:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)QUINOLIN-2-A-
MINE HYDROCHLORIDE
##STR00057##
[0451] STEP 1: TERT-BUTYL
2-((1S,3S)-3-(QUINOLIN-2-YLAMINO)CYCLOBUTOXY)-5',6'-DIHYDRO-[3,4'-BIPYRID-
INE]-1'(2'H)-CARBOXYLATE
[0452] To a mixture of
N-((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)quinolin-2-amine
(see Preparation 7G; 222 mg, 0.6 mmol) in 1,4-dioxane/H.sub.2O
(5:1, 12 mL) was added tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (278 mg, 0.9 mmol), K.sub.3PO.sub.4 (254 mg, 1.2 mmol)
and Pd(dppf)Cl.sub.2 (44 mg, 0.06 mmol). The mixture was refluxed
overnight. The reaction mixture was filtered and concentrated. The
residue was purification by prep-HPLC to give tert-butyl
2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-5',6'-dihydro-[3,4'-bipyrid-
ine]-1'(2'H)-carboxylate (86 mg, 0.18 mmol, yield 30%). ESI-MS
(M+1): 473 calc. for C.sub.28H.sub.32N.sub.4O.sub.3 472.
STEP 2: TERT-BUTYL
4-(2-((1S,3S)-3-(QUINOLIN-2-YLAMINO)CYCLOBUTOXY)PYRIDIN-3-YL)PIPERIDINE-1-
-CARBOXYLATE
[0453] A mixture of tert-butyl
2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-5',6'-dihydro-[3,4'-bipyrid-
ine]-1'(2'H)-carboxylate (472 mg, 1 mmol) and wet Pd--C (50%, 500
mg) in MeOH (100 mL) was stirred under H.sub.2 (40 psi) at
30.degree. C. overnight then the reaction mixture was filtered
through CELITE.RTM. and washed with MeOH. The filtrate was
concentrated to give tert-butyl
4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-1-
-carboxylate (431 mg, 0.91mmol, yield 91%). ESI-MS (M+1): 475 calc.
for C.sub.27H.sub.33N.sub.5O.sub.3 474
STEP 3:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)QUINO-
LIN-2-AMINE HYDROCHLORIDE
[0454] To tert-butyl
4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-1-
-carboxylate (474 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL).
The solution was stirred at RT for 2 hours. The solvent was removed
under reduced pressure to give
N-((1S,3S)-3-((3-(piperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)quinolin-2-a-
mine hydrochloride (356 mg, 0.95 mmol, yield 95%). ESI-MS (M+1):
375 calc. for C.sub.22H.sub.25N.sub.5O 374.
PREPARATION 7I:
N-((1S,3S)-3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIAZOL-2-AMINE
##STR00058##
[0456] A mixture of
(1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride
(see Preparation 7F) (242 mg, 1 mmol), 2-chloro-benzothiazole (169
mg, 1 mmol) and DIEA (286 mg, 2 mmol) in NMP (10 mL) was heated to
180.degree. C. for 2 hours in microwave. The reaction mixture was
extracted with EtOAc (40 mL) and water. The organic phase was
collected, washed with brine and dried over Na.sub.2SO.sub.4. The
organic layers were concentrated and purified by column
chromatography on silica gel to give
N-((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(225 mg, 0.6 mmol, yield 60%). ESI-MS (M+1): 376 calc. for
C.sub.16H.sub.14BrN.sub.3OS 375.
PREPARATION 7J:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]THIA-
ZOL-2-AMINE HYDROCHLORIDE
##STR00059##
[0457] STEP 1: TERT-BUTYL
2-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)-5',6'-DIHYDRO-[3,4'--
BIPYRIDINE]-1'(2'H)-CARBOXYLATE
[0458] To a mixture of
N-((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(see Preparation 71; 225 mg, 0.6 mmol) in 1,4-dioxane/H.sub.2O
(5:1, 12 mL) was added tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (278 mg, 0.9 mmol), K.sub.3PO.sub.4 (254 mg, 1.2 mmol)
and Pd(dppf)Cl.sub.2 (44 mg, 0.06 mmol). The mixture was refluxed
overnight. The reaction mixture was filtered and concentrated. The
residue was purification by flash chromatography on silica gel (5%
to 30% EtOAc in hexanes) to give tert-butyl
2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-5',6'-dihydro-[3,4'--
bipyridine]-l'(2'H)-carboxylate (86 mg, 0.18 mmol, yield 30%).
ESI-MS (M+1): 479 calc. for C.sub.26H.sub.30N.sub.4O.sub.3S
478.
STEP 2: TERT-BUTYL
4-(2-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBOTY)PYRIDIN-3-YL)PIPERID-
INE-1-CARBOXYLATE
[0459] A mixture of tert-butyl
2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-5',6'-dihydro-[3,4'--
bipyridine]-1'(2'H)-carboxylate (478 mg, 1 mmol) and wet Pd--C
(50%, 500 mg) in MeOH (100 mL) was stirred under H.sub.2 (40 psi)
at 30.degree. C. overnight then the reaction mixture was filtered
through CELITE.RTM. and washed with MeOH. The filtrate was
concentrated to give tert-butyl
4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piper-
idine-1-carboxylate (437 mg, 0.91mmol, yield 91%). ESI-MS (M+1):
481 calc. for C.sub.26H.sub.32N.sub.4O.sub.3S 480.
STEP3:
N-((1S,3S)-3-((3-(PIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZO[-
D]THIAZOL-2-AMINE HYDROCHLORIDE
[0460] To tert-butyl
4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-YL)piper-
idine-1-carboxylate (480 mg, 1 mmol) was added 4 M HCl in MeOH (100
mL). The solution was stirred at RT for 2 hours. The solvent was
removed under reduced pressure to give
N-((1S,3S)-3-((3-(piperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine hydrochloride (361 mg, 0.95 mmol, yield 95%). ESI-MS
(M+1): 381 calc. for C.sub.21H.sub.24N.sub.4OS 380.
PREPARATION 7K:
(1S,3S)-3-((6-CHLORO-3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOB-
UTANAMINE HYDROCHLORIDE
##STR00060##
[0461] STEP 1.
TERT-BUTYL((1S,3S)-3-((3-BROMO-6-CHLOROPYRIDIN-2-YL)OXY)CYCLOBUTYL)CARBAM-
ATE
[0462] To a mixture of 3-bromo-2,6-dichloropyridine (4.5 g, 20
mmol) and tert-butyl ((1S,3S)-3-hydroxycyclobutyl)carbamate (see
Preparation 4A; 3.65 g, 20 mmol) in acetonitrile (50 mL) was added
Cs.sub.2CO.sub.3 (13.2 g, 40 mmol), and then the mixture was
stirred at RT overnight. The reaction mixture was filtered and
concentrated under vacuum to give tert-butyl
((1S,3S)-3-((3-bromo-6-chloropyridin-2-yl)oxy)cyclobutyl)carbamate
(4.2 g, 11.2 mmol, 56%). ESI-MS (M+1): 377 calc. for
C.sub.14H.sub.18BrClN.sub.2O.sub.3 376.
STEP 2.
TERT-BUTYL((1S,3S)-3-46-CHLORO-3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDI-
N-2-YL)OXY)CYCLOBUTYL)CARBAMATE
[0463] To a solution of tert-butyl
((1S,3S)-3-((3-bromo-6-chloropyridin-2-yl)oxy)cyclobutyl)carbamate
(375 mg, 1 mmol),
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(250 mg, 1.2mmol) and Na.sub.2CO.sub.3 (212 mg, 2 mmol)
in1,4-dioxane (60 mL) and H.sub.2O (6 mL) was added
Pd(dppf)Cl.sub.2 (36.6 mg, 0.05 mmol) then the reaction mixture was
stirred at 110.degree. C. under N.sub.2 overnight. The reaction
mixture was filtered through CELITE.RTM. and washed with
CH.sub.2Cl.sub.2 (50 mL). The organic layer was concentrated and
the crude product was purified by silica gel column to give
tert-butyl
((1S,3S)-3-46-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclob-
utyl)carbamate (265 mg, 0.7 mmol, yield 70%). ESI-MS (M+1): 381
calc. for C.sub.19H.sub.25ClN.sub.2O.sub.4 380.
STEP 3.
(1S,3S)-3-((6-CHLORO-3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY-
)CYCLOBUTANAMINE HYDROCHLORIDE
[0464] To tert-butyl
((1S,3S)-3-((6-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclo-
butyl)carbamate (379 mg, 1 mmol) was added 4 M HCl in MeOH (100
mL). The solution was stirred at RT for 2 hours. The solvent was
removed under reduced pressure to give
(1S,3S)-3-((6-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclob-
utanamine hydrochloride (265 mg, 0.95 mmol, yield 95%). ESI-MS
(M+1): 281 calc. for C.sub.14H.sub.17ClN.sub.2O.sub.2 280.
PREPARATION 7L:
1-(2-((1S,3S)-3-AMINOCYCLOBUTOXY)PYRIDIN-3-YL)PIPERIDINE-4-CARBONITRILE
HYDROCHLORIDE
##STR00061##
[0465] STEP 1.
TERT-BUTYL((1S,3S)-3-((3-(4-CYANPIPERIDIN-1-YL)PYRIDIN-2-YL)OXY)CYCLOBUTY-
L)CARBAMATE
[0466] The mixture of tert-butyl
((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see
Preparation 7F, step 1; 684 mg, 2 mmol, 1.0 eqv),
piperidine-4-carbonitrile (220 mg, 2 mmol, 1.0 eqv),
Pd.sub.2(dba).sub.3 (91 mg, 0.1 mmol),
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) (248 mg, 0.4
mmol), potassium tert-butoxide (224 mg, 2 mmol) and toluene (10 ml)
was stirred at 100.degree. C. overnight. The mixture was
concentrated and purified by silica gel chromatography to give the
title compound (420 mg, 1.1 mmol, 55% yield) ESI-MS (M+1): 373
calc. for C.sub.20H.sub.28N.sub.4O.sub.3 372.
STEP 2.
1-(2-((1S,3S)-3-AMINOCYCLOBUTOXY)PYRIDIN-3-YL)piperidine-4-CARBONI-
TRILE HYDROCHLORIDE
[0467] The mixture of tert-butyl
((1S,3S)-3-((3-(4-cyanopiperidin-1-yl)pyridin-2-yl)oxy)cyclobutyl)carbama-
te (420 mg, 1.1 mmol, 1.0 eqv) in HCFmethanol 4N (20 ml) was
stirred at RT overnight. The mixture was concentrated to give the
title compound (320 mg, 1.04 mmol, 95% yield) ESI-MS (M+1): 273
calc. for C.sub.15H.sub.20N.sub.4O 272
PREPARATION 8: 2,6-DIFLUORO-3-IODOPRIDINE
##STR00062##
[0469] To a mixture of 2,6-difluoropyridine (1.15 g, 10 mmol, 10.
eqv) in toluene (300 ml) was added n-BuLi (4.8 ml, 12 mmol, 1.2
eqv) at -78.degree. C. under nitrogen and the mixture was stirred
at the same temperature for 4 hrs. Iodine (2.53 g,10 mmol) was
added with the temperature still below -70.degree. C. The mixture
was allowed to warm up to RT and quenched with 10 ml water. The
organic solvent was removed under vacuum and the product was
collected by filtration. Chromatography by silica gel (petroleum
ether: EtOAc=50:1 to 5:1) to give 2,6-difluoro-3-iodopyridine as
solid (1.49 g, 6.1 mmol, 61% yield) ESI-MS (M+1): 242 calc. for
C.sub.5H.sub.2F.sub.2IN 241.
PREPARATION 9:
1-(5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDIN-2-YL)EETHANONE
##STR00063##
[0471] The a mixture of 1-(5-bromo-pyridin-2-yl)-ethanone (199 mg,
1 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (254
mg, 1 mmol), potassium acetate (AcOK) (196 mg, 2 mmol),
Pd(dppf)Cl.sub.2 (73mg, 0.1 mmol) in 1,4-dioxane (2 ml) was stirred
at 100.degree. C. for 2.5 h. The mixture was used in the next step
without purification.
PREPARATION 10: TERT-BUTYL
3-(3-CHLOROPYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE
##STR00064##
[0472] PREPARATION OF TERT-BUTYL
3-(3-CHLOROPYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE
[0473] A 12 L 3-neck round bottom flask fitted with a magnetic
stirrer under nitrogen was charged with zinc dust (745 g,
pre-activated, 11.4 mol, 2 eq.) and DMA (2 L, anhydrous). 1,
2-dibromoethane (71 mL, 0.855 mol, 0.15 eq, Aldrich) was then added
over 10 minutes, followed by TMSC1 (108 mL, 0.855 mol, 0.15 eq,
Acros) over 20 minutes. The reaction mixture was stirred for 25
minutes at room temperature. A solution of N-Boc-3-iodoazetidine
(2420 g, 8.55 mol, 1.5 eq, CNH Technologies) in DMA (5 L,
anhydrous) was added via a 2L addition funnel over 2 h keeping the
internal temperature below 65.degree. C. using a water bath. The
suspension was stirred for 1 hour at RT at which point it was
degassed with nitrogen. Stirring was stopped and the suspension was
allowed to stand. A 22L 3-neck round bottom flask fitted with a
mechanical stirrer was charged with 2, 3-dichloropyrazine (850 g,
5.70 mol, 1.0 eq, AK Scientific), PdCl.sub.2dpplCH.sub.2Cl.sub.2
(140 g, 171 mmol, 0.03 eq, Aldrich), Cul (67.3 g, 353 mmol, 0.062
eq, Aldrich), and DMA (5 L, anhydrous). The solution was degassed
with nitrogen. The clear zinc reagent solution above the residual
solid zinc was poured into the 22L flask under nitrogen. The brown
solution was degassed with nitrogen and heated to 80.degree. C. for
16 hours at which point LCMS indicated complete conversion of 2,
3-dichloropyrazine. The reaction mixture was transferred to brine
(8 L) in SOL separatory funnel. Water (8 L) and EtOAc (15 L) were
added and the layers were separated. The aqueous layer was
extracted with EtOAc (2.times.10 L). The combined organics were
washed with water (3.times.10 L) and brine (5 L), dried over sodium
sulfate and evaporated. The resulting residue was purified by
column chromatography (eluting with hexanes/ethyl acetate=10:1) to
get 536 g of pure tert-butyl
3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate and 121 g of mixed
fractions. The impure material was distilled under high vacuum to
remove the impurity (N-Boc-azetidine) to give 81 g of pure
tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate.
[0474] Total: 617 g, Yield: 40%.
##STR00065##
EXAMPLE 1
TRANS/CIS-2-{4-[3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-Cyclohexyl}-1H-B-
ENZOIMIDAZOLE
STEP 1. 2-(4-METHOXY-CYCLOHEXYL)-1H-BENZOIMIDAZOLE
[0475] 4-Hydroxy-cyclohexanecarboxylic acid(2 g, 13.8 mmol) in a
mixture of DMF (4 mL) and pyridine (4 mL) was treated with
1,1-carbonyldiimidazole (2.26 g, 213.8 mmol) at RT and the
resulting solution was stirred at 45.degree. C. for 2 h. The
mixture was treated with benzene-1, 2-diamine (1.5 g, 13.8 mmol)
and stirred at RT overnight. After completion, the mixture was
concentrated and the obtained residue was treated with glacial
acetic acid (20 mL) and heated at 110.degree. C. for 0.5 h. The
solution was allowed to cool to RT and concentrated to get a
residue, which was purified by flash chromatography on silica gel
to provide the title compound (3.0 g, 13.0 mmol, 71% yield) as
yellow solid.
STEP 2. 4-(1H-BENZOIMIDAZOL-2-YL)-CYCLOHEXANOL
[0476] A solution of 2-(4-methoxy-cyclohexyl)-1H-benzoimidazole
(500 mg, 2.17 mmol) in HI (35%) (5 mL) was heated to 90.degree. C.
for 1 h. The reaction mixture was diluted with water (20 mL) and
extracted with EtOAc (2.times.10 mL); the organic layers was
combined and washed with brine (2.times.10 mL), dried over
Na.sub.2SO.sub.4, and concentrated to give the desired product (400
mg, 1.85 mmol, 85% yield) as brown solid.
STEP 3.
2-14-(3-BROMO-PYRIDIN-2-YLOXY)-CYCLOHEXYL]-1H-BENZOIMIDAZOLE
[0477] The mixture of 4-(1H-benzoimidazol-2-yl)-cyclohexanol (0.36
g, 1.67 mmol), 3-bromo-2-chloro-pyridine (0.64 g, 3.34 mmol),
t-BuONa (0.37 g, 3.34 mmol) and DMSO (5 mL) was heated at
60.degree. C. for 2 days under N.sub.2 atmosphere. Then the mixture
was concentrated under vacuum and the obtained residue was purified
by silica gel chromatograph (DCM: MeOH=10:1) to give
2-[4-(3-bromo-pyridin-2-yloxy)-cyclohexyl]-1H-benzoimidazole (0.15
g, 0.403 mmol, 36% yield) as white solid.
STEP 4.
2-{4-[3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOHEXYL}-1-
H-BENZOIMIDAZOLE
[0478] The mixture of
2-[4-(3-bromo-pyridin-2-yloxy)-cyclohexyl]-1H-benzoimidazole (0.15
g, 0.40 mmol),
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran
(0.09, 0.40 mmol), Pd(dppOCl.sub.2, Na.sub.2CO.sub.3, dioxane and
H.sub.2O was heated at 90.degree. C. for 10 h under N.sub.2
atmosphere. Then the mixture was concentrated and the obtained
residue was purified by silica gel chromatography (DCM:MeOH=10:1)
to give
2-{4-[3-(3,6-dihydro-2H-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-benzo-
imidazole (0.10 g, 0.267 mmol, 75% yield) as light yellow oil.
STEP 5. TRANS/CIS
2-{4-[3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOHEXYL}-1H-BENZOIMIDA-
ZOLE
[0479] The mixture of
2-{4-[3-(3,6-dihydro-2H-pyran-4-yl)-pyridin-2-YLOXY]-cyclohexyl}-1H-benzo-
imidazole (0.15 g, 0.45 mmol), Pd/C (0.5 g) in MeOH (50 mL) was
stirred under H.sub.2 atmosphere at 40.degree. C. for 24 h. Then
the reaction mixture was filtrated and the filtrate was
concentrated and purified by prep-HPLC to give
trans-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-ben-
zoimidazole (0.11 g, 0.292 mmol, 65% yield) and
cis-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-benzo-
imidazole (0.1 g, 0.265 mmol, 60% yield) as white solid. [M+1]378
each. IC50 (uM): (trans) 0.023 and (cis) 0.025.
##STR00066##
EXAMPLE 2
TRANS/CIS
2-{4-[3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOHEXYL}-BENZ-
OTHIAZOLE
STEP 1. 2-(4-METHOXY-CYCLOHEXYL)-BENZOTHIAZOLE
[0480] A mixture of 2-amino-benzenethiol (796 mg, 6.32 mmol),
4-methoxy-cyclohexanecarboxylic acid (1.0 g, 6.32 mmol) and
Lawesson reagent (889 mg, 2.2 mmol) was heated to 160190.degree. C.
for 1 h. Then the mixture was diluted with DCM (100 ml) and washed
with 10% aqueous NaOH solution (2.times.10 mL), brine, and dried
over Na.sub.2SO.sub.4. The organic layer was concentrated and
purified by flash column chromatography to give
2-(4-methoxy-cyclohexyl)-benzothiazole which was used in the next
step without further purification.
STEP 2. 4-BENZOTHIAZOL-2-YL-CYCLOHEXANOL
[0481] A solution of 2-(4-methoxy-cyclohexyl)-benzothiazole (1.2 g,
5.15 mmol) in HI (35%)(12 mL) was heated to 90.degree. C. for 1 h.
Then the reaction mixture was diluted with water (20 mL), extracted
with EtOAc (2 .times.) and the separated organic layer was washed
with brine (2 .times.), dried over Na.sub.2SO.sub.4, and
concentrated to give the desired product (960 mg, 4.12 mmol, 85%
yield) as brown solid.
STEP 3. TRANS/CIS
2-{4-[3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOHEXYL}-BENZOTHIAZOLE
[0482] A mixture of 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as
prepared in preparation la, (200 mg, 1.1 mmol),
4-benzothiazol-2-yl-cyclohexanol (257 mg, 1.1 mmol) and NaH
(60%)(53 mg, 2.2 mmol) in DMA (4 mL) was heated to 120.degree. C.
for 2 h. Then the reaction mixture was diluted with water (10 mL)
and extracted with EtOAc (3.times.15 mL), washed with brine, dried
over Na.sub.2SO.sub.4. After concentration, the residue was
purified by Prep-TLC and then Prep-HPLC to give
trans-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-b-
enzothiazole (14 mg, 0.036 mmol, 3.2% yield) and
cis-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyll-benzothi-
azole (15 mg, 0.038 mol, 3.5%). [M+1] 395 each. IC.sub.50 (uM):
(trans) 0.408 and (cis) 0.584.
##STR00067##
EXAMPLE 3A
TRANS
(5-METHYL-PYRIDIN-2-YL)-{4-[3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY-
]-CYCLOHEXYL}-AMINE
STEP 1. TRANS 4-(5-METHYL-PYRIDIN-2-YLAMINO)-CYCLOHEXANOL
[0483] A mixture of 2-Chloro-5-methyl-pyridine (0.1 g, 0.78 mmol),
4-amino-cyclohexanol (0.117 g, 0.78 mmol),
Pd.sub.2(dba).sub.3(0.057 g, 0.0624 mmol), t-BuONa(0.262
g,2.73mmol) and Binap (0.076 g, 0.1248 mmol) in toluene (10 mL) was
stirred at 85.degree. C. until TLC analysis confirmed the absence
of starting materials. Then the mixture was diluted with water (10
mL), and extracted with EtOAc (3.times.20 mL). The combined organic
extracts were washed with water (5 mL) and brine (10 mL), dried
over Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated in
vacuo and the residue was purified by column chromatography
(EtOAc:Petrol ether=1:2) to provide
4-(5-methyl-pyridin-2-ylamino)-cyclohexanol (0.06 g, yield 60%) as
a solid.
STEP 2. TRANS
(5-METHYL-PYRIDIN-2-YL)-{4-[3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYC-
LOHEXYL}-AMINE
[0484] 4-(5-methyl-pyridin-2-ylamino)-cyclohexanol (50 mg) was
added to a solution of 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine,
as prepared in preparation la, (50 mg) in DMSO (15 mL) and the
reaction mixture was stirred until TLC analysis confirmed the
absence of starting materials. Then the mixture was diluted with
water (10 mL), and extracted with EtOAc (3.times.20 mL). The
combined organic extracts were washed with water (5 mL) and brine
(10 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by column
chromatography (EtOAc:Petrol ether=1:1) to provide
(5-methyl-pyridin-2-yl)-{4-[3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cy-
clohexyl}-amine (0.03 g, yield 60%) as a solid. [M+1] 368.
IC.sub.50 (uM): 0.057.
EXAMPLES 3B AND 3C
N-(TRANS-4-(3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CyclohexYL)BENZO[-
D]THIAZOL-2-AMINE AND
N-(TRANS-4-(3-(3,4-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOHEXYL)BENZO-
[D]THIAZOL-2-AMINE
##STR00068##
[0485] STEP 1.
N-(TRANS-4-(3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOHEXYL)BENZO-
[D]THIAZOL-2-AMINE and
N-(TRANS-4-(3-(3,4-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOHEXYL)BENZO-
[D]THIAZOL-2-AMINE
[0486] Sodium hydride (0.054 g, 1.3 mmol, 60% dispersion in mineral
oil) was added to a mixture of
trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (0.17 g, 0.67 mmol)
in NMP (1.5 mL) in a microwave tube. The tube was sealed and placed
under an argon atmosphere. The mixture was stirred at RT for 45 min
before 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine, as prepared
in preparation la, step 1, (0.10 g, 0.56 mmol) was added via
syringe. The reaction mixture was warmed to 120.degree. C. and
stirred for 1 h. Water was added, and the aqueous mixture was
extracted with EtOAc (2.times.). The organic extracts were
combined, washed with saturated sodium chloride, dried over
magnesium sulfate, filtered, and concentrated. The resulting crude
product was purified via silica gel chromatography to give both
N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo-
[d]thiazol-2-amine and
N-(trans-4-(3-(3,4-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo-
[d]thiazol-2-amine as white solids. [M+1] 408.1 each. IC.sub.50
(uM): 0.007281 (Example 3b) and 0.9154 (Example 3c).
##STR00069## ##STR00070##
EXAMPLE 4
TRANS/CIS-(1H-BENZOIMIDAZOL-2-yl)-{3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-YL)-PY-
RIDIN-2-YLOXY]-CYCLOBUTYL}-METHANONE
STEP 1. 3-BROMO-5-FLUORO-PYRIDIN-2-YLAMINE
[0487] NBS (10 g, 56.2 mmol) was added slowly to a solution of
5-fluoro-pyridin-2-ylamine (12.4 g, 56.2 mmol) in MeCN (200 mL).
The reaction mixture was stirred at RT overnight. After completion,
the solution was filtered and the filtrate was concentrated to get
a residue, which was purified by silica gel chromatography to give
the product (5.2 g, 31%) as a yellow solid.
STEP 2. 3-BROMO-2,5-DIFLUOR-PYRIDINE
[0488] NaNO.sub.2 (1.4 g, 14.4 mmol) was added in portions to a
solution of 3-bromo-5-fluoro-pyridin-2-ylamine (5.2 g, 17.3 mmol)
in a HF/pyridine mixture (40 mL) in a polyethylene reaction vessel.
The resulting mixture was stirred at 0.degree. C. for 0.5 h, then
heated to 50.degree. C. and stirred for 1 h. The reaction mixture
was poured onto crushed ice, partially neutralized with
Na.sub.2CO.sub.3, and extracted with EtOAc. The organic phase was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the product (4.1 g, 68%) as a white solid.
STEP 3. 3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-2,5-DIFLUORO-PYRIDINE
[0489] To a solution of 3-bromo-2,5-difluoro-pyridine (4.1 g, 20.8
mmol) in dioxane (60 mL) was treated with Na.sub.2CO.sub.3 (4.4 g,
41.6 mmol) in 20 mL of H.sub.2O as a solution, followed by
additional of
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran
(4.8 g 22.9 mmol) and Pd(dppf)Cl.sub.2 (761 mg). The resulting
mixture was heated at refluxing overnight under N.sub.2 atmosphere.
TLC showed that most of the staring materials were consumed. The
solution was filtered and the filtrate was concentrated to get a
residue, which was purified by silica gel chromatography to give
the product (3.7 g).
STEP 4. 2,5-DIFLUORO-3-(TETRHYDRO-PYRAN-4-YL)-PYRIDINE
[0490] To a solution of
3-(3,6-dihydro-2H-pyran-4-yl)-2,5-difluoro-pyridine (3.7 g, 18.8
mmol) in MeOH (40 mL) was added Pd/C (1.0 g). The reaction solution
was stirred at RT overnight under H.sub.2 atmosphere until LCMS
showed that the starting material was consumed completely. The
mixture was filtered and the filtrate was concentrated to give the
product (2.9 g, 78%).
STEP 5.
3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOBUTANEC-
ARBOXYLIC ACID METHYL ESTER
[0491] To a solution of methyl 3-hydroxycyclobutanecarboxylate (1.2
g, 9.0 mmol) in DMF (20 mL) was added sodium hydride (60% wt in
mineral oil) (1.8 g, 45 mmol) at RT. The mixture was stirred for 1
h and then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine (1.8 g,
9.0 mmol) was added. The reaction mixture was heated to 60.degree.
C. for 3 h and then quenched with saturated NH.sub.4Cl. The
solution was diluted with EtOAc and water and extracted with EtOAc
(2.times.10 mL). The organic extracts were combined, washed with
brine (10 mL), dried over MgSO.sub.4, filtered, and concentrated to
get a residue, which was purified by flash column chromatography on
silica gel (5% to 30% EtOAc in hexanes) to give the product (3.2 g)
as yellow oil.
STEP 6.
3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOBUTANEC-
ARBOXYLIC ACID
[0492] To a solution of
345-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-YLOXY]-cyclobutanecarboxyl-
ic acid methyl ester (3.2 g) in MeOH (60 mL) and water (15 mL) at
RT was added lithium hydroxide (1.0 g, 41.6 mmol). The reaction
mixture was heated to 50.degree. C. for 2 h and then additional
LiOH (400 mg) was added. Stirring was continued at 50.degree. C.
for 1 h. The reaction was neutralized with 5 M HCl and
concentrated. The concentrated solution was extracted with EtOAc
(50 mL) and the organic layer was washed with water (10 mL), brine
(10 mL), dried over MgSO.sub.4 and concentrated to give the product
(1.5 g), which was used in the next step without further
purification.
STEP 7.
3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOBUTANEC-
ARBOXYLIC ACID METHOXY-METHYL-AMIDE
[0493] To a solution of
345-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxyl-
ic acid (1.5 g, 4.68 mmol) was added DMF (20 mL), triethylamine (1
mL, 7.02 mmol), and
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (2.24 g, 5.90 mmol). The reaction mixture
was stirred at RT for 1 d. Then it was diluted with water and
EtOAc. The organic layer was separated and the aqueous phase was
extracted with EtOAc (2.times.10 mL). All the organic layers were
combined and washed with brine (1.times.10 mL), dried over
MgSO.sub.4, filtered, and concentrated to get a crude, which was
purified by flash column chromatography on silica gel (30% to 70%
EtOAc in hexanes) to give the product (2.2 g) as yellow oil.
STEP 8.
{3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-YL)-PYRIDIN-2-YLOXY]-CYCLOBUTYL}-
-(1-METHOXYMETHY-1H-BENZOIMIDAZOL-2-YL)-METHANONE
[0494] To a solution of 1-(methoxymethyl)-1H-benzo[d]imidazole (1.5
g, 9.04 mmol) in THF (20 mL) at -78.degree. C. was added
butyllithium (2.5 M in hexane) (3.7 mL, 9.16 mmol). The solution
was stirred at -78.degree. C. for 30 min and a solution of
3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxy-
lic acid methoxy-methyl-amide (2.2 g, 6.87 mmol) in THF (20 mL) was
added dropwise via cannula. The reaction mixture was stirred at
-78.degree. C. for 30 min and then warmed to RT and quenched with
water. The reaction mixture was extracted with EtOAc (3.times.25
mL) and the organic phases were combined and washed with water
(1.times.10 mL), brine (1.times.10 mL), dried over MgSO.sub.4,
filtered, and concentrated to get a residue, which was purified by
flash column chromatography on silica gel (10% to 60% EtOAc in
hexanes) to give the product (1.2 g) as yellow oil.
STEP 9.
TRANS/CIS-(1H-BENZOIMIDAZOL-2-YL)-{3-[5-FLUORO-3-(TETRHYDRO-PYRAN--
4-YL)-PYRIDIN-2-YLOXY]-CYCLOBUTYL}-METHANONE
[0495] To a solution of
{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-(1-me-
thoxymethyl-1H-benzoimidazol-2-yl)-methanone (1.2 g) in THF (20 mL)
at RT was added concentrated HCl (20 mL). The reaction mixture was
stirred at RT for 1 h and then heated to 60.degree. C. for 6 h. The
mixture was partially concentrated, neutralized with saturated
NaHCO.sub.3 and diluted with EtOAc. The aqueous phase was extracted
with EtOAc (2.times.10 mL) and the combined organic extracts were
washed with brine (10 mL), dried over MgSO.sub.4, filtered, and
concentrated to get a residue, which was purified by flash column
chromatography on silica gel (5% to 30% EtOAc in DCM) gave
cis-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridi-
n-2-yloxy]-cyclobutyll-methanone and
trans-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyri-
din-2-yloxy]-cyclobutyll-methanone (196 mg) as white solid. [M+1]
396 each. IC.sub.50 (uM) 0.00003 (cis) and 0.0005 (trans).
##STR00071##
##STR00072##
EXAMPLE 5A
CIS-BENZOTHIAZOL-2-YL-{3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-yl)-PYRIDIN-2-YL]--
CYCLOBUTYL}-AMINE
STEP 1. TRANS/CIS
BENZOTHIAZOL-2-YL-(3-BENZYLOXY-CYCLOBUTYL)-AMINE
[0496] A mixture of N-ethyl-N-isopropylpropan-2-amine (3 g, 24
mmol), 2-chlorobenzo[d]thiazole (2.0 g, 12 mmol), and
3-benzyloxy-cyclobutylamine (2.08 g, 12 mmol) in DMA (20 mL) was
heated to 130.degree. C. for 20 h. Then it was cooled to RT and
diluted with EtOAc (50 mL). The mixture was washed with water
(2.times.25 mL), brine (25 mL), dried over MgSO.sub.4, filtered,
and concentrated in vacuo to give an oil. The oil was purified by
silica gel chromatography (0 to 30% EtOAc/hexane gradient) to give
two products as a white solid.
[0497] Top spot on TLC is cis stereoeisomer according to NOESY.
LC-MS (102289-80-1X). ESI-MS (M+1) 311, calc. for
C.sub.18H.sub.18N.sub.2OS MW: 310; (102289-80-1) .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. (ppm) 7.57 (t, 2H, J=8.4 Hz),
7.34-7.26 (m, 6 H), 7.08 (t, 1H, J=7.2 Hz), 6.06 (s, 1H), 4.44 (s,
2H), 3.88-3.81 (m, 2H), 2.90 (d, 2H, J=5.2 Hz), 2.01 (d, 2H, J=7.2
Hz).
[0498] Bottom spot on TLC is trans stereoeisomer according to
NOESY. LC-MS (102289-80-1X) ESI-MS (M+1) 311, calc. for
C.sub.18H.sub.18N.sub.2OS MW: 310; (102289-80-2) .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. (ppm) 7.52 (d, 1H, J=8.0 Hz), 7.45
(d, 1H, J=8.0 Hz), 7.29-7.17 (m, 6 H), 7.01 (t, 1H, J=6.4 Hz), 6.22
(br, 1H), 4.35 (s, 2H), 4.21-4.16 (m, 2H), 2.53-2.47 (m, 2H),
2.25-2.19 (m, 2H).
STEP 2. CIS-3-(BENZOTHIAZOL-2-YLAMINO)-CYCLOBUTANOL
[0499] A mixture of hydrogen chloride (5-6 N) in isopropyl alcohol
(5 mL, 25 mmol),
cis-benzothiazol-2-yl-(3-benzyloxy-cyclobutyl)-amine (500 mg, 1.6
mmol), and palladium black (250 mg, 50%wt percent) in EtOH (20 mL)
under hydrogen atmosphere (balloon) was heated to 70.degree. C. for
20 h. Then it was cooled to RT and solid NaHCO.sub.3 (500 mg) was
added. The mixture was stirred until gas evolution ceased. The
palladium was filtered off using Celite.RTM. and the filtrate was
concentrated in vacuo to give oil (400 mg), which was used for next
step without further purification.
STEP 3.
CIS-BENZOTHIAZOL-2-yl-{3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-yl)-PYRIDI-
N-2-YL]-CYCLOBUTYL}-AMINE
[0500] Sodium hydride (81.8 mg, 2.0 mmol) was added to a solution
of cis-3-(benzothiazol-2-ylamino)-cyclobutanol (150 mg, 0.68 mmol)
in DMF (3 mL) under argon and the mixture was stirred for 1 h at
RT. Then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as
prepared in Example 4, steps 1-4, (162 mg, 0.82 mmol) was added and
the resulting mixture was heated to 100.degree. C. for 2 h. It was
cooled to RT and EtOAc and saturated NH.sub.4Cl were added. The
organic layer was separated, washed with water (2.times.25 mL),
brine (25 mL), dried over MgSO.sub.4, filtered and concentrated in
vacuo to give oil, which was purified by prep-HPLC to give product
(20 mg). [M+1] 400. IC.sub.50 (uM) 0.0002.
EXAMPLE 5B
TRANS-BENZOTHIAZOL-2-YL-{3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-yl)-PYRIDIN-2-yl-
]-CYCLOBUTYL}-AMINE
STEP 1. TRANS-3-(BENZOthiazol-2-YLAMINO)-Cyclobutanol
[0501] A mixture of hydrogen chloride (5-6N) in isopropyl alcohol
(5 mL, 25 mmol), trans-benzothiazol-2-yl-(3-benzyloxy-cyclobutyl)
amine (500 mg, 1.6 mmol), and palladium black (250 mg, 50%wt
percent) in EtOH (20 mL) under hydrogen atmosphere (balloon) was
heated to 70.degree. C. for 20 h. Then it was cooled to RT and
solid NaHCO.sub.3 (500 mg) was added. The mixture was stirred until
gas evolution ceased. The palladium was filtered off using
Celite.RTM. and the filtrate was concentrated in vacuo to give an
oil (400 mg), which was used to next step without further
purification.
STEP 2.
TRANS-BENZOTHIAZOL-2-yl-{3-[5-FLUORO-3-(TETRHYDRO-PYRAN-4-yl)-PYRI-
DIN-2-YL]-CYCLOBUTYL}-AMINE
[0502] Sodium hydride (81.8 mg, 2.0 mmol) was added to a solution
of cis-3-(benzothiazol-2-ylamino)-cyclobutanol (150 mg, 0.68 mmol)
in DMF (3 mL) under argon and the mixture was stirred for 1 h at
RT. Then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine (162 mg,
0.82 mmol) was added and the mixture was heated to 100.degree. C.
for 2 h. It was cooled to RT and EtOAc (25 mL) and saturated
NH.sub.4Cl (15 mL) were added. The organic layer was separated,
washed with water (2.times.25 mL), brine (25 mL), dried over
MgSO.sub.4, filtered and concentrated in vacuo to give an oil,
which was purified by prep-HPLC to give
trans-benzothiazol-2-yl-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2--
yl]-cyclobutyll-amine (30 mg, yield 10%). [M+1] 400. IC.sub.50 (uM)
0.0001.
TABLE-US-00001 TABLE 1A EXAMPLES 6-26 PREPARED ANALOGOUS TO SCHEMES
3-5. Example No. Chemical Structure Chemical Name M + 1 IC.sub.50
(uM) 6 ##STR00073## (4-methyl-pyridin-2- yl)-{4-[3-(tetrahydro-
pyran-4-yl)-pyridin- 2-yloxy]- cyclohexyl}-amine 368 0.150 7
##STR00074## (3-methyl-pyridin-2- yl)-{4-[3-(tetrahydro-
pyran-4-yl)-pyridin- 2-yloxy]- cyclohexyl}-amine 368 0.046 8
##STR00075## (6-methyl-pyridin-2- yl)-{4-[3-(tetrahydro-
pyran-4-yl)-pyridin- 2-yloxy]- cyclohexyl}-amine 368 1.75 9
##STR00076## Quinolin-2-yl-{4-[3- (tetrahydro-pyran-4-
yl)-pyridin-2-yloxy]- cyclohexyl}-amine 404 0.091 10 ##STR00077##
Benzooxazol-2-yl-{4- [3-(tetrahydro-pyran- 4-yl)-pyridin-2-
yloxy]-cyclohexyl}- amine 394 0.012 11 ##STR00078## N-(trans-4-(3-
(tetrahydro-2H- pyran-4-yl)pyridin-2- yloxy)cyclohexyl)
benzo[d]thiazol-2-amine 410.1 0.03252 12 ##STR00079##
5-methyl-N-(trans-3- (3-(tetrahydro-2H- pyran-4-yl)pyridin-2-
yloxy)cyclobutyl) pyridin-2-amine 340.2 0.01763 13 ##STR00080##
5-methyl-N-(cis-3-(3- (tetrahydro-2H- pyran-4-yl)pyridin-2-
yloxy)cyclobutyl) pyridin-2-amine 340.2 0.008249 14 ##STR00081##
1-(4-(3-(cis-3- (benzo[d]thiazol-2- ylamino)cyclobutoxy) pyrazin-2-
yl)piperidin-1- yl)ethanone 424.0 0.002766 15 ##STR00082##
1-(4-(2-(trans-3- (quinolin-2- ylamino)cyclobutoxy) pyrazin-2-
yl)piperidin-1- yl)ethanone 418.0 0.01582 16 ##STR00083## (1H-
benzo[d]imidazol-2- yl)(trans-3-(3- (tetrahydro-2H-
pyran-4-yl)pyridin-2- yloxy)cyclobutyl) methanone 378 0.007153 17
##STR00084## (1H- benzo[d]imidazol-2- yl)(cis-3-(3- (tetrahydro-2H-
pyran-4-yl)pyridin-2- yloxy)cyclobutyl) methanone 378 0.000413 18
##STR00085## pyridin-2-yl(3-(3- (tetrahydro-2H-
pyran-4-yl)pyridin-2- yloxy)cyclobutyl) methanone 339 0.2496 19
##STR00086## 1-(4-(3-(cis-3-(5- methylpyridin-2-
ylamino)cyclobutoxy) pyrazin-2- yl)piperidin-1- yl)ethanone 382
0.06606 20 ##STR00087## 1-(4-(3-(trans-3-(5- methylpyridin-2-
ylamino)cyclobutoxy) pyrazin-2- yl)piperidin-1- yl)ethanone 382
0.08455 21 ##STR00088## N-(cis-3-(3- (tetrahydro-2H-
pyran-4-yl)pyridin-2- yloxy)cyclobutyl)- 1H- benzo[d]imidazol-2-
amine 365 0.001529 22 ##STR00089## N-(trans-3-(3- (tetrahydro-2H-
pyran-4-yl)pyridin-2- yloxy)cyclobutyl)- 1H- benzo[d]imidazol-2-
amine 365 0.002627 23 ##STR00090## 1-(4-(3-(trans-4-
(benzo[d]thiazol-2- ylamino)cyclohexyloxy) pyrazin-2-
yl)piperidin-1- yl)ethanone 452.3 0.04551 24 ##STR00091##
N-(trans-4-(2'- methyl-3,4'- bipyridin-2- yloxy)cyclohexyl)
benzo[d]thiazol-2-amine 417.2 0.01961 25 ##STR00092##
N-(trans-3-(3- (tetrahydro-2H- pyran-4-yl)pyridin-2-
yloxy)cyclobutyl) benzo[d]thiazol-2-amine 382.2 0.003195 26
##STR00093## N-(cis-3-(3- (tetrahydro-2H- pyran-4-yl)pyridin-2-
yloxy)cyclobutyl) benzo[d]thiazol-2-amine 382.2 0.000751
TABLE-US-00002 TABLE 1B STARTING MATERIALS AND CONDITIONS USED IN
PREPARATION AND NMR DATA OF EXAMPLE 6-26. Example Principle
reagents No. Scheme Starting Material 1 Starting Material 2 and
solvents 6 3 ##STR00094## ##STR00095## t-BuONa, DMSO 7 3
##STR00096## ##STR00097## t-BuONa, DMSO 8 3 ##STR00098##
##STR00099## t-BuONa, DMSO 9 3 ##STR00100## ##STR00101## t-BuONa,
DMSO 10 3 ##STR00102## ##STR00103## t-BuONa, DMSO 11 3 ##STR00104##
##STR00105## NaH, NMP, 60.degree. C. 12 5 ##STR00106## ##STR00107##
NaH, DMF 13 5 ##STR00108## ##STR00109## NaH, DMF 14 5 ##STR00110##
##STR00111## 15 5 ##STR00112## ##STR00113## 16 4 ##STR00114##
##STR00115## n-BuLi 17 4 ##STR00116## ##STR00117## n-BuLi 18 4
##STR00118## ##STR00119## n-BuLi 19 5 ##STR00120## ##STR00121##
NaH, DMF 20 5 ##STR00122## ##STR00123## NaH, DMF 21 5 ##STR00124##
##STR00125## NaH, DMF 22 5 ##STR00126## ##STR00127## NaH, DMF 23 3
##STR00128## ##STR00129## NaH, DMF 24 5 ##STR00130## ##STR00131##
NaH, DMF 25 5 ##STR00132## ##STR00133## NaH, DMF 26 5 ##STR00134##
##STR00135## NaH, DMF
##STR00136##
EXAMPLE 27
N-(TRANS-4-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)CYCLOHEXYL)PYRIDIN--
2-AMINE
STEP 1. TRANS-4-(Bis(4-METHOXYBENZYL)AMINO)CYCLOHEXANOL
[0503] 1-(Chloromethyl)-4-methoxybenzene (0.28 mL, 2.00 mmol) was
added to a solution of triethylamine (0.31 mL, 2.20 mmol) and
trans-4-aminocyclohexanol (0.12 g, 1.00 mmol) in DMF (4 mL) under
an argon atmosphere. The reaction mixture was stirred at 60.degree.
C. for 16 h. The mixture was diluted with water and extracted with
EtOAc. The organic layer was separated, washed with water
(2.times.), washed with saturated sodium chloride, dried over
magnesium sulfate, filtered, and concentrated. The resulting crude
oil was purified by silica gel chromatography to give
trans-4-(bis(4-methoxybenzyl)amino)cyclohexanol as a white
solid.
STEP 2.
TRANS-4-(3-CHLOROPYRAZIN-2-YLOXY)-N,N-BIS(4-METHOXYBENZYL)CYCLOHEX-
AMINE
[0504] Sodium hydride (0.58 g, 14.5 mmol, 60% dispersion in mineral
oil) was added to a solution of
trans-4-(bis(4-methoxybenzyl)amino)cyclohexanol (4.30 g, 12.1 mmol)
in DMF (50 mL). The mixture was stirred for 30 min at RT before
2,3-dichloropyrazine (1.89 mL, 12.7 mmol) was added dropwise via
syringe. The reaction mixture was warmed to 60.degree. C. and
stirred overnight. The mixture was diluted with water and extracted
with EtOAc (3.times.). The extracts were combined, washed with
water (3.times.), washed with saturated sodium chloride, dried over
magnesium sulfate, filtered, and concentrated. The resulting crude
oil was purified by silica gel chromatography to give
trans-4-(3-chloropyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine
as a white solid.
STEP 3.
TRANS-4-(3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)-N,N-BIS(4-M-
ETHOXYBENZYL)CYCLOHEXAMINE
[0505]
trans-4-(3-CHLOROPYRAZIN-2-YLOXY)-N,N-bis(4-methoxybenzyl)cyclohexa-
namine (0.810 g, 1.73 mmol),
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.455 g, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0)
(0.100 g, 0.087 mmol) were mixed in DME (2 mL) under a nitrogen
atmosphere. Sodium carbonate (2.60 mL, 5.19 mmol, 2 M in water) was
added via syringe, and the reaction mixture was then heated to
80.degree. C. and stirred for 5 h. The mixture was cooled to RT and
partitioned between EtOAc and water. The layers were separated, and
the aqueous layer was extracted with EtOAc (2.times.). The extracts
were combined, dried over magnesium sulfate, filtered, and
concentrated. The resulting crude product was purified by silica
gel chromatography to give
trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)-N,N-bis(4-methoxyb-
enzyl)cyclohexanamine as a light yellow solid.
STEP 4.
TRANS-4-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)CYCLOHEXYL)CYC-
LOHEXAMINE
[0506] Palladium hydroxide (0.040 g, 0.057 mmol, 20 weight % on
carbon) was added to a stirred mixture of
trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)-N,N-bis(4-methoxyb-
enzyl)cyclohexanamine (0.40 g, 0.77 mmol) in ethanol (4 mL). The
reaction mixture was placed under a hydrogen atmosphere (balloon)
and stirred at 50.degree. C. for 18 h. Additional palladium
hydroxide (0.040 g) and methanol (1 mL) were added, and the
reaction mixture was stirred at 50.degree. C. for an additional 5
h. The reaction mixture was filtered, and the filtrate was
concentrated. The resulting crude product was purified via silica
gel chromatography to give trans-4-(3-(tetrahy
dro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexanamine as a colorless
oil.
STEP 5.
N-(TRANS-4-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)CYCLOHEXYL)-
PYRIDIN-2-AMINE
[0507] trans-4-(3-(Tetrahy
dro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexanamine (0.053 g, 0.19
mmol) and 2-fluoropyridine (0.033 mL, 0.38 mmol) were mixed in a
microwave tube. The tube was sealed, and the mixture was stirred
neat at 160.degree. C. for 3 d. The crude mixture was purified via
silica gel column chromatography to give
N-(trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)pyridi-
n-2-amine as a brown solid. [M+1] 355.2. IC.sub.50 (UM): 2.665.
##STR00137##
EXAMPLE 28A
TRANS-N-(PYRIDIN-2-YL)-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLO-
BUTANECARBOXAMIDE
##STR00138##
[0508] STEP 1.
TRANS/CIS-3-(BENZYLOXY)-N-(PYRIDIN-2-YL)CYCLOBUTANECARBOXAMIDE AND
CIS-3-(BENZYLOXY)-N-(PYRIDIN-2-YL)CYCLOBUTANECARBOXAMIDE
[0509]
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (2.21 g, 5.82 mmol) was added to a stirred
mixture of 3-(benzyloxy)cyclobutanecarboxylic acid (0.80 g, 3.88
mmol), 2-aminopyridine (0.73 g, 7.76 mmol), and triethylamine (1.08
mL, 7.76 mmol) in DMF (15 mL). The reaction mixture was stirred at
RT for 16 h. The reaction mixture was diluted with water and
extracted with EtOAc. The organic extract was separated, washed
with saturated sodium chloride, dried over magnesium sulfate,
filtered, and concentrated. The resulting crude product was
purified via silica gel chromatography to give the separated
diastereomers
trans-3-(benzyloxy)-N-(pyridin-2-yl)cyclobutanecarboxamide and
cis-3-(benzyloxy)-N-(pyridin-2-yl)cyclobutanecarboxamide.
STEP 2. TRANS-3-HYDROXY-N-(PYRIDIN-2-yl)CYCLOBUTANECARBOXAMIDE
[0510] trans-3-(benzyloxy)-N-(pyridin-2-yl)cyclobutanecarboxamide
(0.394 g, 1.40 mmol) and palladium hydroxide (0.098 g, 0.14 mmol,
20 weight % on carbon) were mixed in ethanol (5 mL). The reaction
mixture was placed under a hydrogen atmosphere (balloon) and
stirred at 70.degree. C. for 20 h. The reaction mixture was cooled
to RT and filtered. The filtrate was concentrated, and the
resulting crude product was purified via silica gel chromatography
to give trans-3-hydroxy-N-(pyridin-2-yl)cyclobutanecarboxamide as
an off white solid.
STEP 3.
TRANS-N-(PYRIDIN-2-YL)-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLO-
XY)CYCLOBUTANECARBOXAMIDE
[0511] Sodium hydride (0.073 g, 1.8 mmol, 60% dispersion in mineral
oil) was added to a stirred solution of
trans-3-hydroxy-N-(pyridin-2-yl)cyclobutanecarboxamide (0.18 g,
0.92 mmol) in DMF (3.5 mL) under an argon atmosphere. The mixture
was stirred at RT for 1 h.
2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.17 g, 0.92 mmol)
was added, and the reaction mixture was stirred at 60.degree. C.
for 18 h. The reaction mixture was diluted with EtOAc and washed
with saturated ammonium chloride. The organic layer was separated,
washed with saturated sodium chloride, dried over magnesium
sulfate, filtered, and concentrated. The resulting crude product
was purified via silica gel chromatography to give
trans-N-(pyridin-2-yl)-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyc-
lobutanecarboxamide as a white solid. [M+1]=354.0. IC.sub.50 (uM):
3.066.
##STR00139##
EXAMPLE 28B
Cis-N-(PYRIDIN-2-YL)-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOBU-
TANECARBOXAMIDE
[0512] The cis isomer was prepared according to Scheme 7b by using
the appropriate cis starting materials. [M+1]=354.2. IC.sub.50
(uM): 3.671.
##STR00140##
EXAMPLE 29A
4-(3-(TRANS-4-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOHEXYLOXY)PYRAZIN-2-YL)-1-MET-
HYLPIPERAZIN-2-ONE
STEP 1. N-(TRANS-4-(3-CHLOROPYRAZIN-2-YLOXY)
CYCLOHEXYL)BENZO[D]THIAZOL -2-AMINE
[0513] Sodium hydride (60% dispersion, 0.41 g, 10.2 mmol) was added
to a solution of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol
(as prepared according to Scheme 5) (1.10 g, 4.43 mmol) in DMF (20
mL) under argon. The mixture was stirred for 45 min and then
2,3-dichloropyrazine (0.66 g, 4.43 mmol) was added via syringe.
This mixture was heated to 60.degree. C. for 16 h, cooled to room
temperature, then water was added slowly. The resulting suspension
was filtered and the collected solid was purified by silica gel
chromatography to give
N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine
(0.92 g, 2.54 mmol, 57% yield) as a white solid.
STEP 2.
4-(3-(TRANS-4-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOHEXYLOXY)PYRAZIN-2-Y-
L)-1-METHYLPIPERAZIN-2-One
[0514]
N-(trans-4-(3-CHLOROPYRAZIN-2-yloxy)cyclohexyl)benzo[d]thiazol-2-am-
ine (0.080 g, 0.22 mmol), 1-methylpiperazin-2-one hydrochloride
(0.10 g, 0.67 mmol), and triethylamine (0.093 mL, 0.67 mmol) were
mixed in DMSO (2 mL) under an argon atmosphere. The reaction
mixture was stirred at 80.degree. C. for 24 h. The reaction mixture
was then warmed to 120.degree. C. and stirred for an additional 72
h. The reaction mixture was cooled to RT, diluted with water, and
extracted with EtOAc (2.times.). The organic extracts were
combined, washed with saturated sodium chloride, dried over
magnesium sulfate, filtered, and concentrated. The resulting crude
product was purified via silica gel chromatography to give
4-(3-(trans-4-(benzo[d]thiazol-2-ylamino)cyclohexyloxy)pyrazin-2-yl)-1-me-
thylpiperazin-2-one as a light orange solid. [M+1] 439.2. IC.sub.50
(uM): 0.5369.
##STR00141##
EXAMPLE 29B
N-(TRANS-4-(3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)CYCLOHEXYL)BENZO[-
D]THIAZOL-2-AMINE
[0515] A mixture of
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.10 g, 0.49 mmol) and
N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine
(0.14 g, 0.39 mmol), prepared as in step 1 of example 9a, in
1,2-dimethoxyethane (2 mL) and aqueous sodium carbonate (2 M, 0.58
mL, 1.16 mmol) was placed under nitrogen atmosphere using 3
evacuation/backfill cycles. Tetrakis triphenylphosphine(palladium)
(0.022 g, 0.019 mmol) was added and one more evacuation/backfill
cycle was executed. The mixture was then heated to 80.degree. C.
After 4 h the mixture was cooled to RT and partitioned between
ethyl acetate and water. The layers were separated and the aqueous
layer was extracted with ethyl acetate twice. The combined extracts
were dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The resulting oil was purified by silica gel
chromatography to give
N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo-
[d]thiazol-2-amine (0.13 g, 0.32 mmol, 83% yield). [M+1] 409.2.
IC.sub.50 (uM): 0.03702.
##STR00142##
EXAMPLE 29C
N-(TRANS-4-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)CYCLOHEXYL)BENZO[D]-
THIAZOL-2-AMINE
[0516] A mixture of
N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo-
[d]thiazol-2-amine. As prepared in Example 30b, (0.22 g, 0.54
mmol), palladium hydroxide on carbon (20 wt % Pd dry basis, wet,
Degussa type E101 NE/W) (0.60 g), and ammonium formate (0.51 g,
8.11 mmol) in methanol (3 mL) was heated to 65.degree. C. for 12 h,
then cooled to RT. The palladium was filtered off and the filtrate
was concentrated in vacuo to give a white solid. This solid was
partitioned between ethyl acetate and water, the layers were
separated, and the organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give an oil. The
oil was then purified by silica gel chromatography to give
N-(trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo[-
d]thiazol-2-amine (0.030 g, 0.073 mmol, 14% yield) as a white
solid. [M+1] 411.2. IC.sub.50 (uM): 0.0635.
##STR00143##
EXAMPLE 30
1-(4-(2-(CIS-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRIDIN-3-YL)PIPERID-
IN-1-YL)ETHANONE
STEP 1. TERT-BUTYL
4-(2-FLUOROPYRIDIN-3-YL-5,6-DIHYDROPYRIDINE-1(2H)-CARBOXYLATE
[0517] 3-Bromo-2-fluoropyridine (1.5 g, 8.5 mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (3.16 g, 10.2 mmol),
trans-dichlorobis(triphenylphosphine)palladium (II) (0.48 g, 0.68
mmol), sodium carbonate (4.44 g, 41.9 mmol), and 6:1:1
DME-H.sub.2O-EtOH (20 mL) were combined in a sealed tube and
stirred at 80.degree. C. for 18 h. The cooled reaction was diluted
with CH.sub.2Cl.sub.2 and washed with aqueous saturated NaHCO.sub.3
solution; the aqueous layer was back-washed with CH.sub.2Cl.sub.2
(1.times.). The combined organic extracts were dried (MgSO.sub.4),
filtered, and concentrated in vacuo. Flash column chromatography
(10% to 40% EtOAc/Hexanes) gave tert-butyl
4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a
golden yellow oil. [M+1]=279.2.
STEP 2.
1-(4-(2-FLUOROPYRIDIN-3-yl)-5,6-DIHYDROPYRIDIN-1(2H)-YL)ETHANONE
[0518] A solution of tert-butyl
4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate
(2.69 g, 9.67 mmol) in CH.sub.2Cl.sub.2 (8 mL) was added
trifluoroacetic acid (7.45 mL, 97 mmol) and stirred at RT for 2 h.
The reaction was concentrated in vacuo, and the residue was
partitioned between CH.sub.2Cl.sub.2 and aqueous saturated
NaHCO.sub.3 solution. The organic layer was dried (MgSO.sub.4),
filtered, and concentrated in vacuo to give a golden yellow oil. A
solution of the crude golden yellow oil in CH.sub.2Cl.sub.2 (10 mL)
was cooled to 0.degree. C. and added acetic anhydride (4.5 mL, 48.3
mmol). The reaction was gradually allowed to warm to RT and stirred
for 16 h. The reaction was diluted with CH.sub.2Cl.sub.2 and washed
with aqueous saturated NaHCO.sub.3 solution; the aqueous layer was
back-extracted with CH.sub.2Cl.sub.2 (1.times.). The organic
extracts were combined, dried (MgSO.sub.4), and concentrated in
vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes)
afforded
1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as
a colorless oil. [M+11=221.1.
STEP 3.
1-(4-(2-(Cis-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRIDIN-3-YL-
-5,6-DIHYDROPYRIDIN-1(2H)-YL)ETHANONE
[0519] Sodium hydride, 60% dispersion in mineral oil (0.13 g, 3.18
mmol) was added to a solution of
cis-3-(benzo[d]thiazol-2-ylamino)cyclobutanol hydrochloride (0.20
g, 0.795 mmol) in N,N-dimethylformamide (2.7 mL) under argon and
the mixture was stirred for 30 min at RT.
1-(4-(2-Fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone
(0.17 g, 0.79 mmol) was next added, and the resulting mixture was
heated at 100.degree. C. for 2 h. The cooled reaction was diluted
with EtOAc and washed with water. The organic layer was dried
(MgSO.sub.4), filtered, and concentrated in vacuo. Flash column
chromatography (20% to 80% EtOAc/Hexanes) afforded
1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl-5,6-di-
hydropyridin-1 (2H)-yl)ethanone as an off-white amorphous solid.
[M+1]=421.0.
STEP 4.
1-(4-(2-(Cis-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRIDIN-3-YL-
)PIPERIDIN-1-YL)ETHANONE
[0520] A solution of
1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)-5,6-d-
ihydropyridin-1(2H)-yl)ethanone (0.12 g, 0.28 mmol) in ethanol (2
mL) was added palladium hydroxide, 20 wt. % Pd (dry basis) on
carbon, wet, Degussa type E101 NE/W (0.039 g, 0.056 mmol) and
hydrogenated (double-walled balloon pressure) at 50.degree. C. for
3 days. The cooled reaction was filtered via a pad of Celite.RTM.,
and the filtrate was concentrated in vacuo and purified via flash
column chromatography (20% EtOAc/Hexanes to 100% EtOAc) to afford
1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piperi-
din-1-yl)ethanone as a white solid. [M+1]=423.0. IC.sub.50 (uM):
0.001566.
##STR00144##
EXAMPLES 31A AND 31B
TRANS AND CIS
2-(-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOBUTYL)BENZO[D]THIA-
ZOLE
[0521] To a solution of
3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutanecarboxylic
acid (prepared according to Scheme 4) (0.236 g, 0.851 mmol) in DCM
(0.5 mL) at RT was added DMF (1 drop) and oxalyl dichloride (0.50
mL, 5.6 mmol). The reaction mixture was stirred at RT for 10 min
and the solvent was removed under reduced pressure. The concentrate
was dissolved in toluene (3 mL), cooled to 0.degree. C., and
2-aminobenzenethiol (0.10 mL, 0.94 mmol) was added. The reaction
mixture was warmed to RT and stirred for 2 h. The reaction was
neutralized with saturated NaHCO.sub.3 and diluted with EtOAc. The
organic phase was washed with water (1.times.), brine (1.times.),
dried over MgSO.sub.4, filtered, and concentrated. Purification by
flash column chromatography on silica gel (5% to 30% EtOAc in
hexanes) followed by purification by flash column chromatography on
silica gel (5% to 30% DCM in hexanes) gave
2-(trans-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)benzo[-
ci]thiazole (0.018 g, 0.049 mmol, 6% yield) and
2-(cis-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)benzo[d]-
thiazole (0.029 g, 0.079 mmol, 9% yield) as colorless oils.
[M+11=367 each. IC.sub.50 (uM): 0.01497 (trans) and 0.0633
(cis).
##STR00145##
##STR00146##
EXAMPLE 32A
2-(TRANS-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOBUTYL)-1H-BENZ-
O[D[IMIDAZOLE
STEP 1. N-(2-AMINIPHENYL-3-(BENZYLOXY)CYCLOBUTANECARBOXAMIDE
[0522] HBTU (2.06 g, 5.44 mmol) was added to a solution of
diisopropyl ethylamine(1.03 mL, 5.93 mmol), o-phenylenediamine
(0.54 g, 4.95 mmol), and 3-(benzyloxy)cyclobutanecarboxylic acid
(1.02 g, 4.95 mmol) in DMF (20 mL) under argon atmosphere at
0.degree. C. The mixture was stirred overnight with gradual warming
to RT, then poured into water. The resulting suspension was
filtered and the solid was air-dried to give
N-(2-aminophenyl)-3-(benzyloxy)cyclobutanecarboxamide (1.17 g, 3.95
mmol, 80% yield) as an off-white solid.
STEP 2. 2-(3-(BENZYLOXY)CYCLOBUTYL)-1H-BENZO[D[IMIDAZOLE
[0523] A solution of
N-(2-aminophenyl)-3-(benzyloxy)cyclobutanecarboxamide (1.78 g, 6.01
mmol) in acetic acid was heated to 100.degree. C. for 1 h, then
cooled to RT. The acetic acid was removed in vacuo and ethyl
acetate was added to the resulting oil. The resulting suspension
was filtered and the collected solid was air dried to give
2-(3-(Benzyloxy)cyclobutyl)-1H-benzo[d]imidazole. The filtrate was
concentrated in vacuo to give another suspension, which was
filtered, air dried, and added to the first crop of product to give
a total of 0.96 g (3.43 mmol, 57% yield) of
2-(3-(Benzyloxy)cyclobutyl)-1H-benzo[d]imidazole as a white
solid.
STEP 3. TERT-BUTYL
2-(CIS-3-(BENZYLOXY)CYCLOBUTYL)-1H-BENZO[D]IMIDDAZOLE-1-CARBOXYLATE
AND TERT-BUTYL
2-(TRANS-3-(BENZYLOXY)CYCLOBUTYL)-1H-BENZO[D]IMIDAZOLE-1-CARBOXYLATE
[0524] DMAP (0.020 g, 0.16 mmol) and di-tert-butyldicarbonate (0.83
g, 3.77 mmol) were added to a suspension of
2-(3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole (0.96 g, 3.43
mmol) and triethylamine (1.20 mL, 8.58 mmol) in dichloromethane (15
mL) and the mixture was stirred for 16 h. Water was added, the
resulting layers were separated, and the organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo to give an oil. The oil was purified by silica gel
chromatography to give tert-butyl 2-(cis
-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.43
g, 1.14 mmol, 33% yield) and tert-butyl
2-(trans-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate
(0.47 g, 1.23 mmol, 36% yield).
STEP 4. TERT-BUTYL
2-(TRANS-3-HYDROXYCYCLOBUTYL)-1H-BENZO[D]IMIDAZOLE-1-CARBOXYLATE
[0525] A mixture of tert-butyl 2-(trans
-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.47
g, 1.23 mmol), cyclohexene (0.080 g, 0.91 mmol), and 20 wt % Pd
(dry basis) on carbon, Degussa type E101 NE/W (2.45 g) in ethanol
(5 mL) under argon was heated to 65.degree. C. for 6 h, cooled to
RT, and filtered through Celite.RTM.. The filtrate was concentrated
in vacuo and the resulting oil was purified by silica gel
chromatography to give tert-butyl
2-(trans-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-1-carboxylate
(0.31 g, 1.09 mmol, 88% yield) as a white solid.
STEP 5. TRANS-3-(1H-BENZO[D]IMIDAZOL-2-yl)CYCLOBUTANOL
[0526] tert-Butyl
2-(trans-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-1-carboxylate
(0.31 g, 1.09 mmol) was stirred in a mixture of dichloromethane (5
mL) and TFA (5 mL) at RT for 4 h, then the mixture was concentrated
in vacuo. The residue was partitioned between saturated aqueous
sodium bicarbonate solution and 10:1 DCM /MeOH the layers were
separated and the aqueous layer was extracted with 10:1 DCM/MeOH (3
.times.). The combined extracts were dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give
trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol,
54% yield) as a white solid.
STEP 6.
2-(TRANS-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOBUTYL)-
-1H-BENZO[D[IMIDAZOLE
[0527] Sodium hydride (60% dispersion, 0.049 g, 1.2 mmol) was added
to a solution of trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol
(0.11 g, 0.58 mmol) in DMF (1.5 mL) under argon and the mixture was
stirred for 45 min at RT.
2-Fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.58 mmol)
was added and the mixture was stirred for 16 h at 110.degree. C.
Ethyl acetate was added and the mixture was washed with water
(2.times.), saturated aqueous sodium chloride (1.times.), dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo. The resulting oil was purified by silica gel chromatography
to give
2-(trans-3-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)-1H-be-
nzo[d]imidazole (37 mg, 0.11 mmol, 18% yield) as a white solid.
[M+1]: 350.3. IC.sub.50 (uM) 0.01041.
##STR00147##
EXAMPLE 32B
2-(Cis-3-(3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YLOXY)CYCLOBUTYL)-1H-BENZO[-
D[IMIDAZOLE
[0528] The cis isomer was prepared according to scheme 12b by using
the appropriate cis starting materials. [M+1]=350.2. IC.sub.50
(uM): 0.2068.
##STR00148##
EXAMPLE 33
4-FLUORO-N-((1S,3S)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YL)OXY)CYCLOB-
UTYL)BENZO[D]THIAZOL-2-AMINE
[0529] To a mixture of (1S,3S)-3-((3-(tetrahy
dro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutanamine hydrochloride
(see Preparation 5D, 200 mg, 0.8 mmol) in NMP (4 mL) was added
2-chloro-4-fluoro-benzothiazole (150 mg, 0.8 mmol) and DIEA (229
mg, 1.6 mmol), then heated to 180.degree. C. for 2 h in microwave.
The reaction mixture was diluted with water (10 mL), extracted with
ethyl acetate (20 mL), washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purification by
prep-HPLC to give the title compound (30 mg, yield 9%).
TABLE-US-00003 TABLE 2A EXAMPLES 33-41 PREPARED ANALOGOUS TO SCHEME
12 IC.sub.50 Ex. # Structure Chemical Name M + 1 (.mu.M) 33
##STR00149## 4-fluoro-N-((1S,3S)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 401 0.013
34 ##STR00150## 5-fluoro-N-((1S,3S)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 401 0.0183
35 ##STR00151## 6-fluoro-N-((1S,3S)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 401 0.0151
36 ##STR00152## 7-fluoro-N-((1S,3S)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 401 0.0271
37 ##STR00153## 4-fluoro-N-((1S,3S)-3-((5- fluoro-3-(tetrahydro-2H-
pyran-4-yl)pyridin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine
418 0.00543 38 ##STR00154## 5-fluoro-N-((1S,3S)-3-((5-
fluoro-3-(tetrahydro-2H- pyran-4-yl)pyridin-2-
yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 418 0.00349 39
##STR00155## 6-fluoro-N-((1S,3S)-3-((5- fluoro-3-(tetrahydro-2H-
pyran-4-yl)pyridin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine
418 0.00144 40 ##STR00156## 7-fluoro-N-((1S,3S)-3-((5-
fluoro-3-(tetrahydro-2H- pyran-4-yl)pyridin-2-
yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 418 0.00245 41
##STR00157## N-((1S,3S)-3-((6-chloro-3- (3,6-dihydro-2H-pyran-4-
yl)pyridin-2- yl)oxy)cyclobutyl)benzo[d] thiazol-2-amine 414
0.00355
TABLE-US-00004 TABLE 2B PREPARATION AND NMR DATA OF EXAMPLES 33-41
Starting Starting Reaction .sup.1H NMR (CDCl.sub.3, 400 Ex. #
Material (1) Material (2) Condition MHz) .delta. (ppm) 33
##STR00158## ##STR00159## DIEA, NMP, MW 180.degree. C. 8.09 (s,
1H); 7.89-7.88 (d, J = 2.4 Hz, 1H); 7.51-7.48 (m, 1H); 7.35-7.33
(m, 1H); 7.24-7.15 (m, 1H); 5.07-5.00 (m, 1H); 4.10- 4.06 (m, 2H);
3.67-3.56 (m, 3H); 3.30-3.17 (m, 3H); 2.47-2.41 (m, 2H); 2.05-1.90
(m, 2H); 1.77- 1.74 (d, J = 13.2 Hz, 2H) 34 ##STR00160##
##STR00161## DIEA NMP, MW 180.degree. C. 8.08-8.07 (d, J = 2.8 Hz,
1H); 7.87-7.86 (d, J = 2.8 1H); 7.55-7.52 (m, 1H); 7.29-7.24 (m,
1H); 7.04-6.99 (m, 1H); 5.05- 5.02 (m, 1H); 4.09-4.05 (m, 2H);
3.67-3.55 (m, 3H); 3.29-3.15 (m, 3H); 2.48-2.41 (m, 2H); 1.99- 1.88
(m, 2H); 1.77-1.74 (m, 2H). 35 ##STR00162## ##STR00163## DIEA, NMP,
MW 180.degree. C. 8.06-8.05 (d, J = 2.4 Hz, 1H); 7.86-7.85 (d, J =
2.8 Hz, 1H); 7.37-7.35 (m, 1H); 7.17-7.10 (m, 2H); 5.04-5.01 (m,
1H); 4.08- 4.04 (m, 2H); 3.75-3.71 (m, 1H); 3.58-3.53 (m, 2H);
3.28-3.14 (m, 3H); 2.41-2.34 (m, 2H); 1.98- 1.88 (m, 2H); 1.77-1.73
(m, 2H). 36 ##STR00164## ##STR00165## DIEA, NMP, MW 180.degree. C.
8.08-8.07 (d, J = 2.8 Hz, 1H); 7.87-7.86 (d, J = 2.8 Hz, 1H);
7.43-7.38 (m, 1H); 7.35-7.33 (d, J = 8 Hz, 1H); 7.02-6.98 (m, 1H);
5.08-5.01 (m, 1H); 4.08-4.05 (m, 2H); 3.72- 3.55 (m, 3H); 3.29-3.17
(m, 3H); 2.48-2.41 (m, 2H); 1.98-1.88 (m, 4H). 37 ##STR00166##
##STR00167## DIEA, NMP, MW 180.degree. C. 7.77-7.76 (d, J = 2.8 Hz,
1H); 7.39-7.37 (m, 1H); 7.24-7.17 (m, 3H); 5.02- 4.98 (m, 1H);
4.08-4.04 (m, 2H); 3.66-3.53 (m, 3H); 3.19-3.13 (m, 2H); 3.07-3.05
(m, 1H); 2.42- 2.35 (m, 2H); 1.79-1.63 (m, 4H). 38 ##STR00168##
##STR00169## DIEA, NMP, MW 180.degree. C. 7.77-7.76 (d, J = 2.8 Hz,
1 H); 7.53-7.49 (m, 1 H); 7.26-7.18 (m, 2 H); 6.97- 6.93 (m, 1 H);
5.02-4.98 1 H); 4.07-4.04 (m, 2 H); 3.73-3.69 (m, 1 H); 3.58-3.52
(m, 2 H); 3.18- 3.12 (m, 2 H); 3.05-3.03 (m, 1 H); 2.35-2.27 (m, 2
H); 1.78-1.60 (m, 4 H). 39 ##STR00170## ##STR00171## DIEA, NMP, MW
180.degree. C. 7.73-7.71 (m, 1H); 7.45- 7.43 (m, 1H); 7.30-7.28 (d,
J = 6.8 Hz, 1H); 7.21- 7.08 (m, 2H); 4.99-4.93 (m, 1H); 4.03-4.00
(d, J = 11.6 Hz, 2H); 3.65-3.49 (m, 3H); 3.14-2.98 (m, 3H);
2.35-2.29 (m, 2H); 1.74-1.57 (m, 4H). 40 ##STR00172## ##STR00173##
DIEA, NMP, MW 180.degree. C. 7.73-7.72 (d, J = 3.2 Hz, 1H);
7.39-7.29 (m, 2H); 7.19-7.14 (m, 1H); 6.98- 6.94 (m, 1H); 4.98-4.94
(m, 1H); 4.03-4.00 (m, 2H); 3.63-3.49 (m, 3H); 3.17-3.10 (m, 2H);
3.04- 2.98 (m, 1H); 2.39-2.32 (m, 2H); 1.74-1.56 (m, 4H). 41
##STR00174## ##STR00175## DIEA, NMP MW, 180.degree. C. 7.61 (d, J =
8 Hz, 1 H); 7.54 (d, J = 8 Hz, 1 H); 7.45-7.40 (m, 2 H); 7.30- 7.25
(m, 1 H); 6.89 (d, J = 7.6 Hz, 1 H); 6.07-6.06 (m, 1 H); 5.07-5.00
(m, 1H); 4.31-4.29 (m, 2H); 3.91-3.88 (m, 2H); 3.66- 3.65 (m, 1H);
3.23-3.17 (m, 2H); 2.48-2.38 (m, 4H). Prep. = Preparation
##STR00176##
EXAMPLE 42
N-((1S,3S)-3-((3-(3-METHYLPYRIDIN-4-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO[D-
]THIAZOL-2-AMINE
[0530] To a mixture of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amin-
e (see Preparation 5B; 150 mg, 0.6 mmol) in 1,4-Dioxane/H.sub.2O
(5:1) (12 mL) was added
3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
(197 mg, 0.9 mmol), K.sub.3PO.sub.4 (254 mg, 1.2 mmol) and
Pd(dppf)Cl.sub.2 (44 mg, 0.06 mmol), and then heated to reflux
overnight. The reaction mixture was filtered and concentrated. The
residue was purification by prep-HPLC to
N-((1S,3S)-3-((3-(3-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[-
d]thiazol-2-amine (70 mg, 0.18 mmol, yield 30%).
TABLE-US-00005 TABLE 3A EXAMPLES 42-55 PREPARED ANALOGOUS TO SCHEME
13 IC.sub.50 Ex. # Structure Chemical Name M + 1 (.mu.M) 42
##STR00177## N-((1S,3S)-3-((3-(3- methylpyridin-4-yl)pyrazin-2-
yl)oxy)cyclobutyl)benzo[d]thia zol-2-amine 390 0.00423 43
##STR00178## N-((1S,3S)-3-((3-(2- methylpyridin-4-yl)pyrazin-2-
yl)oxy)cyclobutyl)benzo[d]thia zol-2-amine 390 0.0205 44
##STR00179## N-((1S,3S)-3-((3-(6- methylpyridin-3-yl)pyrazin-2-
yl)oxy)cyclobutyl)benzo[d]thia zol-2-amine 390 0.00339 45
##STR00180## N-((1S,3S)-3-((3-(2- methoxypyridin-3-yl)pyrazin- 2-
yl)oxy)cyclobutyl)benzo[d]thia zol-2-amine 406 0.00411 46
##STR00181## N-((1S,3S)-3-((3-(2- methylpyrimidin-5-yl)pyrazin-
2-yl)oxy) cyclobutyl)benzo[d]thiazol-2- amine 391 0.00325 47
##STR00182## N-((1S,3S)-3-((3-(6- chloropyridin-3-yl)pyrazin-2-
yl)oxy)cyclobutyl)benzo[d]thia zol-2-amine 410 0.00766 48
##STR00183## 5-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)picolinonitrile 401 0.0074 49
##STR00184## N-((1S,3S)-3-((3-(2- methylpyridin-3-yl)pyrazin-2-
yl)oxy)cyclobutyl)benzo[d]thia zol-2-amine 390 0.00194 50
##STR00185## 1-(5-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)pyridin-2-yl)ethanone 418 0.00274
51 ##STR00186## 5-fluoro-N-((1S,3S)-3-((3-(6-
methylpyridin-3-yl)pyrazin-2- yl)oxy)cyclobutyl)benzo[d]thia
zol-2-amine 408 0.0197 52 ##STR00187## 5-(3-((1S,3S)-3-(quinolin-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)picolinonitrile 395 0.00835 53
##STR00188## N-((1S,3S)-3-((3-(6- methylpyridin-3-yl)pyrazin-2-
yl)oxy)cyclobutyl)quinazolin- 2-amine 385 0.00243 54 ##STR00189##
5-(3-((1S,3S)-3-(quinazolin-2- ylamino)cyclobutoxy)pyrazin-
2-yl)picolinonitrile 396 0.00771 55 ##STR00190##
2'-((1S,3S)-3-(quinolin-2- ylamino)cyclobutoxy)-[3,3'-
bipyridine]-6-carbonitrile 394 0.00129
TABLE-US-00006 TABLE 3B PREPARATION AND NMR DATA OF EXAMPLES 42-55
Starting Reaction .sup.1H NMR (CDCl.sub.3, 400 Ex. # Starting
Material (1) Material (2) Condition MHz) .delta. (ppm) 42
##STR00191## ##STR00192## Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4,
Dioxane/ H.sub.2O 8.77 (s, 1H); 8.72-8.70 (d, J = 5.6 Hz, 1H);
8.37-8.36 (d, J = 2.8 Hz, 2H); 8.26-8.25 (d, J = 2.8 Hz, 1H); 7.95-
7.94 (d, J = 6 Hz, 1H); 7.60-7.58 (d, J = 7.6 Hz, 1H); 7.51-7.49
(d, J = 8 Hz, 1H); 7.43- 7.40 (m, 1H); 7.29-7.24 (m, 1H); 5.13-5.06
(m, 1H); 3.72 (s, 1H); 3.23- 3.17 (m, 2H); 2.50 (s, 3H); 2.45-2.36
(m, 2H). 43 ##STR00193## ##STR00194## Pd(dppf) Cl.sub.2,
K.sub.3PO.sub.4 Dioxane/ H.sub.2O 8.75-8.73 (d, J = 6.4 Hz, 1 H);
8.64-8.63 (d, J = 7.2 Hz, 2 H); 8.45- 8.44 (d, J = 2.4 Hz, 1 H);
8.37-8.36 (d, J = 2.4 Hz, 1 H); 7.75-7.73 (d, J = 8 Hz, 1 H);
7.51-7.49 (d, J = 8.4 Hz, 1 H); 7.46-7.42 (m, 1 H); 7.30-7.26 (m, 1
H); 5.32-5.26 (m, 1 H); 4.15-4.11 (m, 1 H); 3.31-3.24 (m, 2 H);
2.85 (s, 3 H); 2.53-2.45 (m, 2 H). 44 ##STR00195## ##STR00196##
Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4 Dioxane/ H.sub.2O 9.23-9.22 (d,
J = 1.6 Hz, 1H); 8.27-8.22 (m, 2H); 8.01-8.00 (d, J = 2.4 Hz, 1H);
7.54-7.48 (m, 2H); 7.24-7.14 (m, 2H); 7.04-7.00 (m, 1H); 5.12-5.06
(m, 1H); 4.07-3.99 (m, 1H); 3.20-3.13 (m, 2H); 2.61 (s, 3H); 2.23-
2.16 (m, 2H). 45 ##STR00197## ##STR00198## Pd(dppf) Cl.sub.2,
K.sub.3PO.sub.4, Dioxane/ H.sub.2O 8.25-8.21 (m, 2H); 8.07-8.06 (d,
J = 2.8 Hz, 2H); 7.71-7.69 (m, 1H); 7.57-7.55 (d, J = 8 Hz, 1H);
7.51-7.49 (d, J = 8 Hz, 1H); 7.27- 7.23 (m, 1H); 7.09-7.05 (m, 1H);
7.01-6.98 (m, 1H); 5.10-5.03 (m, 1H); 3.99-3.96 (m, 1H); 3.93 (s,
3H); 3.16- 3.09 (m, 2H); 2.11-2.04 (m, 2H). 46 ##STR00199##
##STR00200## Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4, Dioxane/ H.sub.2O
8.33-8.21 (m, 1H); 8.02-8.01 (m, 1H); 7.80-7.78 (d, J = 7.6 Hz,
1H); 7.55-7.48 (m, 2H); 7.37-7.33 (m, 1H); 5.27-5.23 (m, 1H);
4.16-4.12 (m, 1H); 3.32-3.25 (m, 2H); 2.76 (s, 3H); 2.52-2.41 (m,
2H). 47 ##STR00201## ##STR00202## Pd(dppf) Cl.sub.2,
K.sub.3PO.sub.4, Dioxane/ H.sub.2O 9.11 (d, J = 2.4 Hz, 1H);
8.42-8.39 (m, 1H); 8.30-8.29 (m, 1H); 8.08-8.07 (m, 1H); 7.62 (d, J
= 8 Hz, 1H); 7.56 (d, J = 8 Hz, 1H); 7.47-7.43 (m, 2H); 7.31-7.26
(m, 1H); 5.16-5.09 (m, 1H); 3.77-3.72 (m, 1H); 3.28-3.21 (m, 2H);
2.61-2.47 (m, 2H). 48 ##STR00203## ##STR00204## Pd(dppf) Cl.sub.2,
K.sub.3PO.sub.4, Dioxane/ H.sub.2O 9.41 (s, 1H); 8.60-8.58 (m, 1H);
8.34 (d, J = 2.4 Hz, 1H); 8.13 (d, J = 2.4 Hz, 1H); 7.80- 7.78 (m,
1H); 7.61 (d, J = 8 Hz, 1H); 7.53 (d, J = 8 Hz, 1H ); 7.45-7.41 (m,
1H); 7.30-7.24 (m, 1H); 5.16-5.12 (m, 1H); 3.75-3.71 (m, 1H);
3.28-3.21 (m, 2H); 2.53-2.46 (m, 2H). 49 ##STR00205## ##STR00206##
Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4, Dioxane/ H.sub.2O 8.85 (d, J =
5.6 Hz, 1 H); 8.73 (d, J = 8 Hz, 1 H); 8.42 (s, 1H); 8.37 (s, 1H);
8.06-8.03 (m, 1 H); 7.78 (d, J = 7.6 Hz, 1 H); 7.54-7.46 (m, 2 H);
7.36-7.32 (m, 1 H); 5.24-5.20 (m, 1 H); 4.13-4.09 (m, 1 H);
3.28-3.21 (m, 2 H); 2.77 (s, 3 H);2.43-2.36 (m, 2 H). 50
##STR00207## ##STR00208## Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4,
Dioxane/ H.sub.2O 9.41 (s, 1H); 8.55-8.53 (m, 1H); 8.35-8.34 (m,
1H); 8.16-8.12 (m, 2H); 7.63-7.56 (m, 2H); 7.46-7.42 (m, 1H);
7.29-7.27 (m, 1H); 5.20-5.12 (m, 1H); 3.82-3.75 (m, 1H); 3.29-3.24
(m, 3H); 2.78 (s, 3H); 2.53-2.46 (m, 2H). 51 ##STR00209##
##STR00210## Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4, 1,4-Dioxane
(CD.sub.3OD) 9.47 (s, 1H); 9.27-9.25 (m, 1H); 8.42 (s, 1H); 8.32
(s, 1H); 8.05-8.02 (m, 1H); 7.71-7.68 (m, 1H); 7.25-7.22 (m, 1H);
7.04-6.99 (m, 1H); 5.32-5.25 (m, 1H); 4.21-4.13 (m, 1H); 3.28-3.24
(m, 2H); 2.88 (s, 3H); 2.48-2.41 (m, 2H). 52 ##STR00211##
##STR00212## Pd(dppf) Cl.sub.2, K.sub.3PO.sub.4 Dioxane/ H.sub.2O
9.45 (s, 1H); 8.67-8.64 (m, 1H); 8.34-8.33 (d, J = 2.8 Hz, 1H);
8.20- 8.14 (m, 2H); 7.82-7.69 (m, 4H); 7.45-7.41 (m, 1H); 6.84-6.81
(d, J 9.2 Hz, 1H); 5.20-5.16 (m, 1H); 3.96 (s, 1H); 3.24-3.21 (m,
2H); 2.51-2.46 (m, 2H). 53 ##STR00213## ##STR00214## Pd(dppf)
Cl.sub.2, K.sub.3PO.sub.4 Dioxane/ H.sub.2O (d.sub.6-DMSO)
9.12-9.08 (m, 2H); 8.35-8.20 (m, 3H); 7.80-7.61 (m, 3H); 7.48-7.37
(m, 2H); 7.23-7.19 (m, 1H); 5.12-5.04 (m, 1H); 4.33-4.27 (m, 1H);
2.98-2.91 (m, 2H); 2.53 (s, 3H); 2.27-2.20 (m, 2H). 54 ##STR00215##
##STR00216## K.sub.3PO.sub.4, Pd(dppf)Cl.sub.2 1,4- Dioxane/
H.sub.2O (d.sub.6-DMSO) 9.40 (s, 1H); 9.12 (s, 1H); 8.68-8.66 (m,
1H); 8.45-8.36 (m, 2H); 8.21-8.19 (m, 1H); 7.81-7.68 (m, 3H);
7.48-7.45 (m, 1H); 7.26-7.22 (m 1H); , 5.15-5.12 (m, 1H); 4.36-4.32
(m, 1H); 2.99-2.96 (m, 2H); 2.31-2.25 (m, 2H). 55 ##STR00217##
##STR00218## K.sub.3PO.sub.4, Pd(dppf)Cl.sub.2 1,4- Dioxane/
H.sub.2O (CD.sub.3OD) 8.91-8.90 (m, 1 H); 8.23-8.20 (m, 3 H); 7.91
(d, J = 8.4 Hz, 1 H); 7.87-7.82 (m, 3 H ); 7.78-7.74 (m, 1 H);
7.51-7.47 (m, 1 H); 7.14-7.12 (m, 1 H); 7.00 (s, 1 H); 5.23-5.20
(m, 1 H); 4.29-4.27 (m, 1 H); 3.24-3.22 (m, 2 H); 2.33-2.26 (m, 2
H).
##STR00219##
EXAMPLES 56 AND 57
N-((1S,3S)-3-((3-(3-FLUORO-4-METHYLPHENYL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZ-
O[D]THIAZOL-2-AMINE AND
N-(1R,3R)-3-((3-(3-FLUORO-4-METHYLPHENYL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZ-
O[D]THIAZOL-2-AMINE
[0531] To a mixture of
N-(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine
(see Preparation 5C, 150 mg, 0.6 mmol) in 1,4-Dioxane/water (5:1)
(12 mL) was added
2-(3-Fluoro-4-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,21dioxaborola-
ne (212 mg, 0.9 mmol), K.sub.3PO.sub.4 (254 mg, 1.2 mmol) and
Pd(dppf)Cl.sub.2 (44 mg, 0.06 mmol). The mixture was heated to
reflux overnight. The reaction mixture was filtered and
concentrated. The residue was purification by prep-HPLC to give
Examples 56 and 57.
TABLE-US-00007 TABLE 4A EXAMPLES 56-59 PREPARED ANALOGOUS TO SCHEME
14 IC.sub.50 Ex. # Structure Chemical Name M + 1 (.mu.M) 56
##STR00220## N-((1S,3S)-3-((3-(3- fluoro-4- methylphenyl)pyrazin-2-
yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 407 0.0362 57
##STR00221## N-((1R,3R)-3-((3-(3- fluoro-4- methylphenyl)pyrazin-2-
yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 407 0.0444 58
##STR00222## 2'-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)- [3,3'-bipyridine]-6- carbonitrile 400 0.00056
59 ##STR00223## 2'-((1R,3R)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)- [3,3'-bipyridine]-6- carbonitrile 400
0.00297
TABLE-US-00008 TABLE 4B PREPARATION AND NMR DATA OF EXAMPLES 56-59
Starting Reaction .sup.1H NMR (CDCl.sub.3, 400 Ex. # Starting
Material (1) Material (2) Condition MHz) .delta. (ppm) 56
##STR00224## ##STR00225## K3PO4, Pd(dppf)Cl.sub.2 1.4- Dioxane/
H.sub.2O 8.19-8.18 (m, 1H); 7.94-7.93 (d, J = 2.4 Hz, 1H);
7.74-7.67 (m, 2H); 7.54-7.49 (m, 2H); 7.41-7.37 (m, 1H); 7.23-7.19
(m, 2H); 5.08-5.01 (m, 1H); 3.66-3.60 (m, 1H); 3.20-3.14 (m, 2H);
2.49-2.42 (m, 2H); 2.27 (s, 3H). 57 ##STR00226## ##STR00227##
K3PO4, Pd(dppf)Cl.sub.2 1.4- Dioxane/ H.sub.2O 8.25-8.24 (d, J = 2
Hz, 1H); 8.03-8.02 (d, J = 2 Hz, 1H); 7.82- 7.78 (m, 2H); 7.62-
7.55 (m, 2H); 7.47- 7.43 (m, 1H); 7.31- 7.26 (m, 2H); 5.55 (s, 1H);
4.16 (s, 1H); 2.90-2.77 (m, 4H); 2.35 (s, 3H). 58 ##STR00228##
##STR00229## Pd(dppf)Cl.sub.2, K.sub.3PO.sub.4 dioxane/H.sub.2O
(CD.sub.3OD) 8.95-8.94 (m, 1H); 8.23-8.20 (m, 2H); 7.92-7.90 (m,
1H); 7.85-7.83 (m, 1H); 7.57-7.56 (m, 1H); 7.55-7.54 (m, 1H);
7.43-7.41 (m, 1H); 7.26-7.22 (m, 1H); 7.12-7.02 (m, 1H); 5.13 (s,
1H); 4.10 (s, 1H); 3.12- 3.09 (m, 2H); 2.14- 2.10 (m, 2H). 59
##STR00230## ##STR00231## Pd(dppf)Cl.sub.2, K.sub.3PO.sub.4
dioxane/H.sub.2O (CD.sub.3OD) 9.01 (s, 1H); 8.30-8.21 (m, 2H);
7.97-7.95 (m, 1H); 7.90-7.88 (m, 1H); 7.79-7.77 (m, 1H); 7.51-7.48
(m, 2H); 7.37-7.33 (m, 1H); 7.17-7.14 (m, 1H); 5.56-5.53 (m, 1H);
4.47-4.44 (m, 1H); 2.77-2.74 (m, 4H).
##STR00232##
EXAMPLE 60
5-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PICOLI-
NAMIDE
[0532] A mixture of
5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)picol-
inonitrile (see Example 48; 200 mg, 0.5 mmol), DMSO (1 mL),
K.sub.2CO.sub.3 (138 mg, 1 mmol) and H.sub.2O.sub.2.aq (0.5 mL) was
stirred at ambient termperature for 2 h. The solid was filtered and
washed by methanol (2 mL) and dried to give
5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)picol-
inamide (100 mg, 0.24 mmol, 48%).
TABLE-US-00009 TABLE 5A EXAMPLES 60-63 PREPARED ANALOGOUS TO SCHEME
15 IC.sub.50 Ex. # Structure Chemical Name M + 1 (.mu.M) 60
##STR00233## 5-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)picolinamide 419 0.00296 61
##STR00234## 5-(3-((1S,3S)-3-(quinolin-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)picolinamide 413 0.0038 62
##STR00235## 2'-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)-[3,3'- bipyridine]-6-carboxamide 418 0.000129
63 ##STR00236## 2'-((1S,3S)-3-(quinolin-2-
ylamino)cyclobutoxy)-[3,3'- bipyridine]-6-carboxamide 412
0.00026
TABLE-US-00010 TABLE 5B PREPARATION AND NMR DATA OF EXAMPLES 60-63
Reaction .sup.1H NMR (d-DMSO 400 MHz) .delta. Ex. # Starting
Material (1) Condition (ppm) 60 ##STR00237## K.sub.2CO.sub.3, DMSO,
H.sub.2O.sub.2 9.28-9.27 (m, 1 H); 8.59-8.57 (m, 1 H); 8.41 (d, J =
2.8 Hz, 1 H); 8.34 (d, J = 7.2 Hz, 1 H); 8.29 (d, J = 2.4 Hz, 1 H);
8.19 (s, 1 H); 8.16-8.14 (m, 1 H); 7.65-7.64 (m, 2 H); 7.38-7.36
(m, 1 H); 7.22- 7.18 (m, 1 H); 7.02-6.98 (m, 1 H); 5.13-5.10 (m, 1
H); 4.16-4.10 (m, 1 H); 3.05-2.98 (m, 2 H); 2.23- 2.16 (m, 2 H). 61
##STR00238## K.sub.2CO.sub.3, DMSO, H.sub.2O.sub.2 9.28 (s, 1H);
8.59-8.57 (m, 1 H); 8.39-8.15 (m, 4 H); 7.83 (d, J = 9.0 Hz, 1 H);
7.72 (s, 1 H); 7.58 (d, J = 7.9 Hz, 1 H); 7.49-7.34 (m, 3 H); 7.12
(t, J = 7.0 Hz, 1 H); 6.69 (d, J = 8.8 Hz, 1 H); 5.20-5.10 (m, 1H);
4.40-4.30 (m, 1H); 3.07-2.96 (m, 2H); 2.21- 2.09 (m, 2H). 62
##STR00239## K.sub.2CO.sub.3, DMSO, H.sub.2O.sub.2 8.87-8.86 (m,
1H); 8.30-8.08 (m, 5H); 7.94-7.91 (m, 1H); 7.66- 7.64 (m, 2H);
7.37-7.35 (m, 1H); 7.21-7.13 (m, 2H); 7.01-6.97 (m, 1H); 5.08-5.02
(m, 1H); 4.08- 4.01 (m, 1H); 2.99-2.92 (m, 2H); 2.10-2.03 (m, 2H).
63 ##STR00240## K.sub.2CO.sub.3, DMSO, H.sub.2O.sub.2 8.88-8.87 (m,
1 H); 8.19-8.09 (m, 4 H), 7.94-7.91 (m, 1 H); 7.83- 7.81 (m, 1 H);
7.66 (brs, 1 H); 7.59-7.57 (m, 1 H); 7.48-7.45 (m, 2 H); 7.30-7.29
(m, 1 H); 7.16- 7.14 (m, 2 H); 6.68-6.66 (m, 1 H); 5.13-5.11 (m, 1
H); 4.34-4.30 (m, 1 H); 2.98-2.94 (m, 2 H), 2.06- 2.01 (m, 2
H).
##STR00241##
EXAMPLE 64
METHYL
4-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL-
)PIPERIDINE-1-CARBOXYLATE
[0533] To a solution of
N-((1S,3S)-3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine hydrochloride (see Preparation 5E; 381 mg, 1 mmol) in
dry DCM (10 mL) was added Et.sub.3N (1 mL). The reaction mixture
was cooled to 0.degree. C. with an ice bath, and methyl
chloroformate (188 mg, 2 mmol) was added dropwise. After 1 hour,
the reaction mixture was warmed to room temperature, and stirred
overnight. Then the reaction mixture was washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to
give the crude product. The residue was purified by prep-HPLC to
give methyl
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idine-1-carboxylate (307 mg, 0.7 mmol, 70% yield).
TABLE-US-00011 TABLE 6A EXAMPLES 64-72 PREPARED ANALOGOUS TO SCHEME
16 Ex. # Structure Chemical Name M + 1 IC.sub.50 (uM) 64
##STR00242## 4-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)piperidine-1-carboxylate 440
0.00424 65 ##STR00243## 1-(4-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)piperidin-1-yl)-2-
methoxyethanone 454 0.00657 66 ##STR00244## methyl 3-(3-((1S,3S)-3-
(benzo[d]thiazol-2- ylamino)cyclobutoxy)pyrazin-
2-yl)azetidine-1-carboxylate 412 0.0175 67 ##STR00245##
1-(4-(3-((1S,3S)-3-(quinolin- 2- ylamino)cyclobutoxy)pyrazin-
2-yl)piperidin-1-yl)ethanone 418 0.00493 68 ##STR00246##
2-methoxy-1-(4-(3-((1S,3S)- 3-(quinolin-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)piperidin-1-yl)ethanone 448
0.00506
TABLE-US-00012 TABLE 6B PREPARATION AND NMR DATA OF EXAMPLES 64-72
Starting Reaction .sup.1H NMR (CD.sub.3OD, 400 Ex. # Starting
Material (1) Material (2) Condition MHz) .delta. (ppm) 64
##STR00247## ##STR00248## Et.sub.3N, DCM 7.98-7.97 (d, J = 2.8 Hz,
1 H); 7.83-7.82 (d, J = 2.8 Hz, 1 H); 7.52 (d, J = 7.6 Hz, 1 H);
7.47 (d, J = 7.6 Hz, 1 H); 7.22-7.20 (m, 1 H); 7.07-7.01 (m, 1 H);
4.99-4.92 (m, 1 H); 4.35-4.10 (br, 2 H); 3.99- 3.91 (m, 1 H); 3.64
(s, 3 H); 3.20-3.08 (m, 3 H); 2.91-2.80 (m, 2 H), 2.17- 2.04 (m, 2
H); 1.82-1.73 (m, 4 H). 65 ##STR00249## ##STR00250## Et.sub.3N, DCM
8.06 (d, J = 2.8 Hz, 1 H); 7.98-7.97 (m, 1 H ); 7.79 (d, J = 8.0
Hz, 1 H); 7.55-7.48 (m, 2 H); 7.37- 7.33 (m, 1 H); 5.14-5.10 1 H);
4.59 (d, J = 13.6 Hz, 1 H); 4.22-4.08 (m, 3 H); 3.98 (d, J = 15.2
Hz, 1 H); 3.40-3.34 (m, 4 H); 3.27-3.19 (m, 3 H); 2.83 (d, J = 2.4
Hz, 1 H); 2.42-2.40 (m, 2 H); 1.93-1.90 (m, 2 H); 1.82-1.75 (m, 2
H). 66 ##STR00251## ##STR00252## Et.sub.3N, DCM 8.09-8.08 (d, J =
2.4 Hz, 1 H); 7.89-7.88 (d, J = 2.8 Hz, 1 H); 7.57-7.50 (m, 2 H);
7.42-7.38 (m, 1 H); 7.26-7.20 (m, 1 H); 4.99-4.95 (m, 1 H); 4.30-
4.20 (m, 4 H); 4.10-4.06 (m, 1 H); 3.66-3.54 (m, 4 H); 3.16-3.09
(m, 2 H); 2.41-2.34 (m, 2 H). 67 ##STR00253## ##STR00254##
Et.sub.3N, DCM 8.28-8.21 (s, 1 H); 8.08- 8.07 (d, J = 2.8 Hz, 1 H);
7.99-7.96 (m, 1 H); 7.95- 7.83 (m, 2 H); 7.81-7.75 (m, 1 H);
7.54-7.50 (m, 1 H); 7.12-7.01 (s, 1 H); 5.18-5.14 (m, 1 H); 4.63-
4.60 (m, 1 H); 4.31 (s, 1 H); 4.07-4.03 (d, J = 13.6 Hz, 1 H);
3.38-3.33 (m, 1 H); 3.27-3.24 (m, 3 H); 2.83-2.76 (m, 1 H);
2.41-2.34 (m, 2 H); 2.13 (s, 3 H); 1.96-1.83 (m, 3 H); 1.74-1.68
(m, 1 H). 68 ##STR00255## ##STR00256## Et.sub.3N, DCM 8.25 (s, 1H);
8.05 (s, 1H); 7.97 (s, 1H); 7.86- 7.77 (m, 3H); 7.50 (s, 1H); 7.03
(s, 1H); 5.14 (s, 1H); 4.59-4.56 (d, J = 11.6 Hz, 1H); 4.27-4.16
(m, 3H); 3.99-3.96 (m, 1H); 3.39 (s, 4H); 3.23 (s, 3H); 2.85-2.79
(m, 1H); 2.36 (s, 2H); 1.89- 1.69 (m, 4H). 69 ##STR00257##
##STR00258## Et3N, DCM 7.87-7.86 (m, 1 H); 7.50- 7.49 (m, 1 H );
7.48-7.42 (m, 1 H); 7.35-7.33 (m, 1 H); 7.18-7.14 (m, 1 H);
6.98-6.94 (m, 1 H); 6.83- 6.80 (m, 1 H); 4.98-4.96 (m, 1 H);
4.58-4.56 (m, 1 H); 4.12-4.10 (m, 2 H); 4.07-4.06 (m, 1 H); 4.02-
4.01 (m, 1 H); 3.31 (s, 3 H); 3.05-2.99 (m, 4 H); 2.62-2.60 (m, 1
H); 2.08- 2.01 (m, 2 H); 1.82 (d, J = 13.2 Hz, 2 H); 1.58- 1.53 (m,
2 H). 70 ##STR00259## ##STR00260## Et.sub.3N, DCM 7.97-7.95 (m, 1
H); 7.81- 7.79 (m, 1 H ); 7.55-7.51 (m, 3 H); 7.49-7.34 (m, 1 H);
6.94-6.91 (m, 1 H); m, 1 H ); 4.25 (d, J = 12.8 Hz, 2 H); 4.09-4.08
(m, 1 H); 3.69 (s, 3 H); 3.23-3.20 (m, 2 H); 3.02 (s, 3 H); 2.35-
2.30 (m, 2 H); 1.84 (d, J = 12.4 Hz, 2 H); 1.64- 1.60 (m, 2 H). 71
##STR00261## ##STR00262## Et3N, DCM 8.16 (d, J = 9.2 Hz, 1 H); 8.03
(d, J = 4 Hz, 1 H); 7.79 (d, J = 8.4 Hz, 1 H); 7.71-7.68 (m, 2 H);
7.48- 7.46 (m, 2 H); 6.97-6.94 (m, 1 H); 6.83 (d, J = 9.2 Hz, 1 H);
5.20-5.16 (m, 1 H); 4.79 (d, J = 12 Hz, 1 H); 3.94 (s, 2 H); 3.32-
3.10 (m, 4 H); 2.78-2.72 (m, 1 H); 2.42 (d, J = 8.4 Hz, 2 H); 2.19
(s, 3 H); 2.07-1.86 (m, 2 H); 1.63- 1.51 (m, 2 H). 72 ##STR00263##
##STR00264## Et.sub.3N, DCM 8.26-8.24 (m, 1 H); 7.97- 7.96 (m, 1
H); 7.87-7.80 (m, 2 H); 7.78-7.76 (m, 1 H ); 7.55-7.50 (m, 2 H);
7.01-6.99 (m, 1 H); 6.94- 6.91 (m, 1 H); 5.15-5.12 (m, 1 H);
4.65-4.62 (m, 1 H); 4.25-4.11 (m, H); 3.97-3.95 (m, 1 H) 3; 3.39
(s, 3 H); 3.25-3.09 (m, 4 H); 2.74-2.73 (m, 1 H); 2.33-2.26 (m, 2
H); 1.91- 1.87 (m, 2 H); 1.72-1.62 (m, 2 H).
##STR00265##
EXAMPLE 73
1-(4-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIP-
ERIDIN-1-YL)-2-HYDROXYETHANONE
STEP 1.
2-(4-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN--
2-YL)PIPERIDIN-1-YL)-2-HYDROXYETHANONE
[0534] To a solution of
N-((1S,3S)-3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine hydrochloride (see Preparation 5E; 381 mg, 1 mmol) in
dry DCM (10 mL) was added Et.sub.3N (1 mL). The reaction mixture
was cooled to 0.degree. C. with an ice bath, and
2-chloro-2-oxoethyl acetate (272 mg, 2 mmol) was added droppwise to
the reaction mixture, 1 hour later, the reaction mixture was warmed
to room temperature, and stirred overnight. Then the reaction
mixture was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to give the crude product
(337 mg, 0.7 mmol, 70% yield). ESI-MS (M+1): 482 calc. for
C.sub.24H.sub.27N.sub.5O.sub.4S 481.
STEP 2.
1-(4-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN--
2-YL)PIPERIDIN-1-YL)-2-HYDROXYETHANONE
[0535] A solution of
2-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
peridin-1-yl)-2-oxoethyl acetate (240 mg, 0.5 mmol) and LiOH (24
mg, 1.0 mmol) in THF/MeOH/H.sub.2O (3:3:1) (21 mL) was stirred at
RT for 1 hour. Then the reaction mixture was filtered and
concentrated under vacuum to give the crude product. The crude
product was purified by prep-HPLC to give
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2--
yl)piperidin-1-yl)-2-hydroxyethanone (175 mg, 0.8 mmol, 80% yield).
M+1: 440. PDE10 IC.sub.50 (uM): 0.00481. .sup.1H NMR (CD.sub.3OD,
400 MHz) .delta. (ppm): 8.06 (d, J=2.8 Hz, 1H); 7.97 (d, J=2.8 Hz,
1H); 7.78 (d, J=7.6 Hz, 1H); 7.54-7.46 (m, 2 H); 7.35-7.31 (m, 1H);
5.13-5.10 (m, 1H); 4.61-4.57 (m, 1H); 4.26-4.15 (m, 2H); 4.10-4.09
(m, 1H); 3.85 (d, J=13.6 Hz, 1H); 3.37-3.32 (m, 1H); 3.26-3.19 (m,
3 H); 2.86 (d, J=2Hz, 1 H); 2.39-2.33 (m, 2H);1.94-1.70 (m, 4
H).
##STR00266##
EXAMPLE 74
N-((1S,3S)-3-((3-(1-METHYLPIPERIDIN-4-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO-
IDITHIAZOL-2-AMINE
[0536] To the solution of tert-butyl
4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idine-1-carboxylate (see Preparation 5E, step 2; 482 mg, 1 mmol)in
THF (10 ml) was added the diisobutylaluminum hydride (DIBAL-H) (1N
in toluene) (1 ml). The mixture was stirred at RT for 2 h and
quenched by water (1 ml). Reaction mixture was concentrated and the
residue was purified by silica gel chromatography to give
N-((1S,3S)-3-((3-(1-methylpiperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benz-
o[d]thiazol-2-amine. M+1: 396. PDE10 IC.sub.50 (uM): 0.0498.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. (ppm): 8.05-7.97 (m, 2H);
7.59-7.53 (m, 2H); 7.30-7.23 (m, 1H); 7.10-7.06 (m, 1H); 5.27-5.24
(m, 1H); 4.24-4.20 (m, 1H); 3.51-3.42 (m, 3H); 3.21-3.04 (m, 3H);
2.84-2.52 (m, 6H); 2.49-2.31 (m, 2H); 2.14-2.01 (m, 2H).
##STR00267##
EXAMPLE 75
(1-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPER-
IDIN-4-YL)METHANOL
[0537] To a mixture of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amin-
e (see Preparation 5B; 332 mg, 1 mmol) and piperidin-4-yl-methanol
(115 mg, 1 mmol) and K.sub.2CO.sub.3 (276 mg, 2 mmol) was added
isopropyl alcohol (i-PrOH) (2 mL) and water (0.5 mL). The solution
was heated to 160.degree. C. under microwave for 5 h. Then the
mixture was diluted with water (20 mL) and extracted with EtOAc
(2.times.30 mL). The combined organic extracts were washed with
water (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, and
filtered. The filtrate was evaporated in vacuo and the residue was
purified by prep-HPLC to give
(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pipe-
ridin-4-yl)methanol. (111 mg, 0.27 mmol, 27% yield).
TABLE-US-00013 TABLE 7A EXAMPLES 75-90 PREPARED ANALOGOUS TO SCHEME
19 ESI-MS IC.sub.50 Ex. # Structure Chemical Name (M + 1) (.mu.M)
75 ##STR00268## (1-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)piperidin- 4-yl)methanol 412
0.00316 76 ##STR00269## N-((1S,3S)-3-((3- morpholinopyrazin-2-
yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 384 0.0224 77
##STR00270## N-((1S,3S)-3-((3-(3- methylpyrrolidin-1- yl)pyrazin-2-
yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 382 0.00692 78
##STR00271## 1-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)pyrrolidine- 3-carbonitrile 393
0.00107 79 ##STR00272## N-((1S,3S)-3-((3-(3- methylpiperidin-1-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 396 0.0294
80 ##STR00273## (1-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)piperidin-3- yl)methanol 412
0.00362 81 ##STR00274## N-((1S,3S)-3-((3-(3,3-
difluoropyrrolidin-1- yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine
404 0.0111 82 ##STR00275## 4-(3-((1S,3S-)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2- yl)thiomorpholine 1,1-
dioxidecyclobutyl}- amine 432 0.0185 83 ##STR00276##
N-((1S,3S)-3-((3-(5,6- dihydroimidazo[1,5- a]pyrazin-7(8H)-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 420
0.00699 84 ##STR00277## (R)-1-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)pyrrolidin- 3-ol 384 0.0142 85
##STR00278## (S)-1-(3-((1S,3R)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)pyrrolidin- 3-ol 384 0.0175 86
##STR00279## 1-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)piperidine- 4-carbonitrile 407
0.00231 87 ##STR00280## N-((1S,3S)-3-((3-(4- methylpiperazin-1-
yl)pyrazin-2- yl)oxy)cyclobutyl)benzo [d]thiazol-2-amine 397 0.122
88 ##STR00281## 1-(3-((1S,3S)-3- (quinolin-2- ylamino)cyclobutoxy)
pyrazin-2-yl)piperidine- 4-carbonitrile 401 0.00226 89 ##STR00282##
N-((1S,3S)-3-((3-(4- methylpiperazin-1- yl)pyrazin-2-
yl)oxy)cyclobutyl) quinazolin-2-amine 392 0.316 90 ##STR00283##
(1-(3-((1S,3S)-3- (quinazolin-2- ylamino)cyclobutoxy)
pyrazin-2-yl)piperidin-4- yl)methanol 407 0.01089
TABLE-US-00014 TABLE 7B PREPARATION AND NMR DATA OF EXAMPLES 75-90
Ex. Starting Reaction .sup.1H NMR (CDCl.sub.3, 400 # Starting
Material (1) Material (2) Condition MHz) .delta. (ppm) 75
##STR00284## (see Preparation 5B) ##STR00285## K.sub.2CO.sub.3,
iPrOH, H.sub.2O, MW 160.degree. C. 7.70-7.69 (d, J = 2.8 Hz, 1H);
7.59-7.53 (m, 2H); 7.47-7.46 (d, J = 3.2 Hz, 1H); 7.32-7.24 (m,
1H); 7.12-7.08 (m, 12H); 5.04-5.00 (m, 1H); 4.20-4.17 (d, J = 12.8
Hz, 2H); 4.00-3.97 (m, 1H); 3.55- 3.53 (d, J = 6 Hz, 2H); 3.22-3.15
(m, 2H); 2.83- 2.76 (m, 2H); 2.20-2.15 (m, 2H); 1.83-1.71 (m, 3H);
1.44-1.34 (m, 2H). 76 ##STR00286## (see Preparation 5B)
##STR00287## Et.sub.3N, DMSO, MW 140.degree. C. 7.67 (d, J = 2.8
Hz, 1H); 7.53 (d, J = 5.6 Hz, 1H); 7.49-7.47 (m, 2H); 7.24-7.19 (m,
1H); 7.05-7.01 (m, 1H); 5.00-4.93 (m, 1H); 4.02-3.85 (m, 1H);
3.78-3.76 (m, 4H); 3.46-3.43 (m, 4H); 3.17-3.10 (m, 2H); 2.16-2.09
(m, 2H). 77 ##STR00288## (see Preparation 5B) ##STR00289##
Et.sub.3N, DMSO, MW 140.degree. C. 7.75-7.73 (m, 1H), 7.51 (d, J =
8.0 Hz, 1H), 7.46- 7.41 (m, 1H), 7.34 (s, 2H), 7.30-7.26 (m, 1H),
5.13- 5.07 (m, 1H), 4.13-3.98 (m, 3H), 3.88-3.81 (m, 1H), 3.40-3.35
(m, 1H), 3.24-3.17 (m, 2H), 2.45- 2.35 (m, 3H), 2.35-2.26 (m, 1H),
2.70-1.65 (m, 1H), 1.15 (J = 6.8 Hz, 3H). 78 ##STR00290## (see
Preparation 5B) ##STR00291## Et.sub.3N, DMSO, MW 140.degree. C.
7.80 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 3H), 7.49 (d, J = 3.2 Hz,
2H), 5.12-5.08 (m, 1H), 4.15-4.09 (m, 2H), 4.08-4.00 (m, 1H),
4.00-3.90 (m, 1H), 3.89-3.80 (m, 1H), 3.50-3.40 (m, 1H), 3.25-3.22
(m, 2H), 2.45-2.39 (m, 3H), 2.35-2.26 (m, 1H). 79 ##STR00292## (see
Preparation 5B) ##STR00293## Et.sub.3N, DMSO, MW 140.degree. C.
7.65-7.56 (m, 3H); 7.45-7.46 (m, 2H); 7.29 (m, 1H); 5.07 (m, 1H);
4.22-4.21 (m, 1H); 4.13-4.11 (m, 1H); 3.71-3.69 (m, 1H); 3.21-3.19
(m, 2H); 3.06-3.03 (m, 1H); 2.74-2.70 (m, 1H); 2.48-2.50 (m, 2H);
1.84-1.81 (m, 3H); 1.71-1.70 (m, 1H); 1.23-1.14 (m, 1H); 0.95 (d, J
= 5.6 Hz, 3H). 80 ##STR00294## (see Preparation 5B) ##STR00295##
Et.sub.3N, DMSO, MW 140.degree. C. 7.79 (d, J = 8.0 Hz, 1H),
7.68-7.60 (m, 1H), 7.55- 7.47 (m, 3H), 7.37-7.32 (m, 1H), 5.16-5.08
(m, 1H), 4.41-4.25 (m, 1H), 4.14-4.02 (m, 2H), 3.55- 3.51 (m, 1H),
3.46-3.41 (m, 1H), 3.26-3.19 (m, 2H), 3.04-2.97 (m, 1H), 2.91-2.76
(m, 1H), 2.44- 2.31 (m, 2H), 1.90-1.78 (m, 3H), 1.74-1.63 (m, 1H),
1.45-1.23 (m, 1H). 81 ##STR00296## (see Preparation 5B)
##STR00297## Et.sub.3N, DMSO, MW 140.degree. C. 7.66 (d, J = 2.8
Hz, 1H); 7.62 (d, J = 7.6 Hz, 1H); 7.56 (d, J = 8.0 Hz, 1H); 7.39
(d, J = 2.8 Hz, 1H); 7.29-7.25 (m, 1H); 7.11-7.08 (m, 1H);
5.01-4.98 (m, 1H); 4.04-3.92 (m, 3H); 3.89-3.86 (m, 2H); 3.22-3.16
(m, 2H); 2.43-2.36 (m, 2H); 2.24-2.17 (m, 2H). 82 ##STR00298## (see
Preparation 5B) ##STR00299## DIEA, NMP, MW 200.degree. C. 7.78-7.77
(m, 2H); 7.62-7.61 (m, 1H); 7.49-7.48 (m, 2H); 7.35-7.31 (m, 1H);
5.10-5.07 (m, 1H); 4.35-4.31 (m, 1H); 4.12-4.09 (m, 4H); 3.96-3.92
(m, 1H); 3.14-3.11 (m, 6H); 2.37 (s, 1H). 83 ##STR00300## (see
Preparation 5B) ##STR00301## DIEA, NMP, MW 200.degree. C. 8.67 (s,
1H), 7.80-7.64 (m, 1H), 7.66-7.64 (m, 2H), 7.59-7.57 (m, 1H),
7.51-7.46 (m, 1H), 7.35- 7.31 (m, 1H), 7.26 (s, 1H), 5.20-5.16 (m,
1H), 4.84 (s, 2H), 4.48-4.45 (m, 2H), 4.13-4.10 (m, 2H), 3.78-3.77
(m, 1H), 3.33-3.26 (m, 2H), 2.56-2.49 (m, 2H). 84 ##STR00302## (see
Preparation 5B) ##STR00303## Et.sub.3N, DMSO, MW 140.degree. C.
7.57 (d, J = 8.0 Hz, 1H); 7.51 (d, J = 8.4 Hz, 1H); 7.42 (t, J =
7.6 Hz, 1H); 7.36 (d, J = 4.0 Hz, 1H); 7.28-7.24 (m, 2H); 5.08-5.01
(m, 1H); 4.59 (s, 1H); 4.13-4.03 (m, 3H); 3.98-3.95 (m, 1H); 3.72
(br, 1H); 3.22-3.16 (m, 2H); 2.51-2.43 (m, 2H); 2.13-2.10 (m, 1H);
2.07-1.99 (m, 1H). 85 ##STR00304## (see Preparation 5B)
##STR00305## Et.sub.3N, DMSO, MW 140.degree. C. 7.57 (d, J = 8.0
Hz, 1H); 7.51 (d, J = 8.4 Hz, 1H); 7.44-7.41 (m, 1H); 7.37-7.36 (m,
1H); 7.28-7.24 (m, 2H); 5.08-5.01 (m, 1H); 4.59 (s, 1H); 4.13- 4.03
(m, 3H); 3.98-3.95 (m, 1H); 3.72 (br, 1H); 3.22-3.16 (m, 2H);
2.51-2.43 (m, 2H); 2.13-2.11 (m, 1H); 2.07-1.99 (m, 1H). 86
##STR00306## (see Preparation 5B) ##STR00307## Et.sub.3N, DMSO, MW
140.degree. C. 7.64 (d, J = 2.8 Hz, 1 H); 7.53-7.51 (m, 1 H); 7.49-
7.47 (m, 2 H); 7.19-7.15 (m, 1 H); 7.02-6.98 (m, 1 H); 4.96-4.93
(m, 1 H); 3.89 (s, 1 H); 3.70-3.65 (m, 2 H); 3.28-3.24 (m, 2 H);
3.22-3.10 (m, 2 H); 2.74-2.72 (m, 1 H); 2.16-2.10 (m, 2 H);
1.91-1.82 (m, 4 H). 87 ##STR00308## (see Preparation 5B)
##STR00309## Neat, MW 150.degree. C. 7.75 (d, J = 2.8 Hz, 1 H);
7.63-7.55 (m, 3 H); 7.32 (t, J = 7.8 Hz, 1 H); 7.12 (t, J = 7.8 Hz,
1 H); 5.89 (br, 1 H); 5.10-5.02 (m, 1 H); 4.11-4.02 (m, 1 H); 3.73
(br, 4 H); 3.27-3.17 (m, 2 H); 2.79 (br, 4 H); 2.52 (s, 3 H);
2.25-2.16 (m, 2 H). 88 ##STR00310## (see Preparation 5G)
##STR00311## Et.sub.3N, DMSO, MW 150.degree. C. 8.17 (d, J = 9.2
Hz, 1 H); 7.72-7.68 (m, 4 H); 7.51 (d, J = 2.8 Hz, 1 H); 7.41-7.38
(m, 1 H); 6.82 (d, J = 9.2 Hz, 1 H); 5.09-5.05 (m, 1 H); 3.93-3.92
(m, 1 H); 3.82-3.78 (m, 2 H); 3.49-3.44 (m, 2 H); 3.18 (s, 2 H);
2.88-2.86 (m, 1 H); 2.43-2.42 (m, 2 H); 2.04-2.03 (m, 2 H);
1.96-1.95 (m, 2 H). 89 ##STR00312## (see Preparation 5J)
##STR00313## NMP, MW 180.degree. C. 8.99 (s, 1H); 7.74-7.72 (m,
1H); 7.70-7.68 (m, 2H); 7.68-7.66 (m, 1H); 7.62-7.60 (m, 1H); 7.29-
7.24 (m, 1H); 5.55-5.53 (m, 1H); 5.11-5.04 (m, 1H); 4.48-4.38 (m,
1H); 3.64-3.54 (m, 4H); 3.23- 3.17 (m, 2H); 2.63-2.61 (m, 4H); 2.39
(s, 3H); 2.19-2.12 (m, 2H). 90 ##STR00314## (see Preparation 5J)
##STR00315## NMP, MW 180.degree. C. 8.91 (s, 1H); 7.64-7.63 (m,
1H); 7.62-7.60 (m, 2H); 7.59-7.51 (m, 1H); 7.44-7.43 (m, 1H); 7.18-
7.16 (m, 1H); 5.36-5.34 (m, 1H); 5.01-4.98 (m, 1H); 4.36-4.14 (m,
2H); 3.50-3.49 (m, 2H); 3.15- 3.08 (m, 2H); 2.78-2.72 (m, 2H);
2.10-2.03 (m, 2H); 1.98-1.51 (m, 3H); 1.39-1.33 (m, 2H).
##STR00316##
EXAMPLES 91 AND 92
((S)-1-(3-((1S,3R)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)P-
IPERIDIN-3-YL)METHANOL AND
((R)-1-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)-
PIPERIDIN-3-yl)METHANOL
[0538] Racemic mixture
(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pipe-
ridin-3-yl)methanol , made according to Example 80, (0.054 g, 0.13
mmol) was separated by chiral prep-HPLC (Column: Chiralcel OD-H
250*30 mm, 5u; Mobile phase: 85% hexane in EtOH (0.05%diethyl
amine); Flow rate: 30 mL/minute) to give examples 91 and 92 as
separated enantiomers. ESI-MS (M+1): 412 calc. for
C.sub.IIH.sub.25N.sub.5O.sub.2S 411
TABLE-US-00015 TABLE 8A EXAMPLES 91-96 PREPARED ANALOGOUS TO SCHEME
20 ESI-MS IC.sub.50 Ex. # Structure Chemical Name (M + 1) (uM) 91
and 92 ##STR00317## and ##STR00318## as separated enantiomers
((S)-1-(3-((1S,3R)-3- (benzo[d]thiazol-2- ylamino)cyclobutoxy)
pyrazin-2-yl)piperidin- 3-yl)methanol and ((R)-1-(3-((1S,3S)-3-
(benzo[d]thiazol-2- ylamino)cyclobutoxy) pyrazin-2-yl)piperidin-
3-yl)methanol 412 0.026 and 0.00281 93 and 94 ##STR00319## and
##STR00320## As separated single enantiomer N-((1S,3S)-3-((3-((R)-
3-methylpyrreolidin-1- yl)pyrazin-2- yl)oxy)cyclobutyl)
benzo[d]thiazol-2- amine and N-((1R,3S)-3-((3-((S)-
3-methylpyrrolidin-1- yl)pyrazin-2- yl)oxy)cyclobutyl)
benzo[d]thiazol-2- amine 382 0.00324 and 0.00802 95 and 96
##STR00321## and ##STR00322## As separated single enantiomer
(R)-1-(3-((1S,3S)-3- (benzo[d]thiazol-2- ylamino)cyclobutoxy)
pyrazin-2- yl)pyrrolidine-3- carbonitrile and (S)-1-(3-((1S,3R)-3-
(benzo[d]thiazol-2- ylamino)cyclobutoxy) pyrazin-2-
yl)pyrrolidine-3- carbonitrile 393 0.000728 and 0.00527 Note: The
absolute stereospecificity of each enantiomer was not determined in
the examples below and therefore the IC.sub.50 and NMR data
reported herein can be for either enantiomer.
TABLE-US-00016 TABLE 8B PREPARATION AND NMR DATA OF EXAMPLES 91-96,
AS SEPARATED SINGLE ENANTIOMER. Ex. Separation # Starting material
(1) Condition .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. (ppm) 91
and 92 ##STR00323## Column: Chiracel OD-H 250 * 30 mm, 5u; Mobile
phase: 85% hexane in EtOH (0.05% diethyl amino); Flow rate: 30
mL/minute 7.62 (d, J = 2.8 Hz, 1H); 7.53 (d, J = 8.1 Hz, 1H); 7.50
(d, J = 8.1 Hz, 1H); 7.49 (d, J = 2.8 Hz, 1H); 7.25-7.20 (m, 1H);
7.04-7.00 (m, 1H); 5.95 (br, 1H); 5.08-5.05 (m, 1H); 3.99-3.95 (m,
2H); 3.60-3.49 (m, 3H); 3.17-3.06 (m, 3H); 2.98-2.93 (m, 1H);
2.31-2.10 (m, 2H); 1.95 (br, 1H); 1.80-1.58 (m, 2H); 1.27-1.25 (m,
1H); and 7.67 (d, J = 2.8 Hz, 1H); 7.57 (d, J = 8.2 Hz, 1H); 7.51
(d, J = 8.4 Hz, 1H); 7.45-7.44 (m, 1H); 7.29-7.27 (m, 1H);
7.09-7.05 (m, 1H); 6.58 (brs, 1H); 5.13-5.10 (m, 1H); 4.07-4.0 (m,
2H); 3.78-3.74 (m, 2H); 3.65-3.53 (m, 2H); 3.21-3.14 (m, 3H);
3.05-3.00 (m, 1H); 2.27-2.23 (m, 2H); 1.97-1.96 (m, 1H); 1.77-1.65
(m, 2H); 1.31-1.25 (m, 1H). 93 and 94 ##STR00324## Column:
ChiralPak AD- H, 250 .times. 30 mm I.D; Mobile phase: A for SF
CO.sub.2 and B for Ethanol (0.2% DE A); Gradient: B 40%; Flow rate:
40 mL/min 7.54-7.47 (m, 3H); 7.25-7.16 (m, 2H); 7.05-7.01 (m, 1H);
5.49-5.47 (m, 1H); 4.93-4.90 (m, 1H); 3.96-3.92 (m, 1H); 3.81-3.63
(m, 2H); 3.63-3.58 (m, 1H); 3.18-3.10 (m, 3H); 2.24-2.22 (m, 1H);
2.10-1.97 (m, 3H); 1.50-1.47 (m, 1H); 1.41 (d, J = 6.4 Hz, 3H); and
7.60-7.58 (m, 2H); 7.57 (d, J = 12.0 Hz, 1H); 7.30-7.22 (m, 2H);
7.11-7.07 (m, 1H); 5.59 (br, 1H); 4.99-4.96 (m, 1H); 4.01-3.98 (m,
1H); 3.87-3.71 (m, 2H); 3.69-3.66 (m, 1H); 3.24-3.14 (m, 3H);
2.31-2.26 (m, 1H); 2.18-2.09 (m, 2H); 2.07-2.03 (m, 1H); 1.58-1.51
(m, 1H); 95 and 96 ##STR00325## Column: ChiralPak AD- H, 250
.times. 30 mm I.D; Mobile phase: A for SF CO.sub.2 and B for
Ethanol (0.2% DE A); Gradient: B 40%; Flow rate: 40 mL/min 7.57 (d,
J = 2.8 Hz, 1H); 7.53 (d, J = 7.6 Hz, 1H); 7.48 (d, J = 8.4 Hz,
1H); 7.30 (d, J = 3.2 Hz, 1H); 7.23-7.21 (m, 1H); 7.03-7.01 (m,
1H); 5.54 (brs, 1H); 4.97-4.90 (m, 1H); 3.99-3.83 (m, 4H);
3.77-3.71 (m, 1H); 3.16-3.08 (m, 3H); 2.30-2.20 (m, 2H); 2.11-2.07
(m, 2H); and 7.63 (d, J =2.8 Hz, 1H); 7.60 (d, J = 0.4 Hz, 1H);
7.58 (d, J = 0.8 Hz, 1H); 7.54 (d, J = 8.4 Hz, 1H); 7.29-7.27 (m,
1H); 7.10-7.08 (m, 1H); 5.52 (s, 1H); 5.20-4.98 (m, 1H); 4.06-4.88
(m, 4H); 3.83-3.77 (m, 1H); 3.22-3.14 (m, 3H); 2.35-2.28 (m, 2H);
2.18-2.11 (m, 2H).
##STR00326##
EXAMPLE 97
N-((1S,3S)-3-((3-(3-FLUOROPYRROLIDIN-1-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZ-
O[D]THIAZOL-2-AMINE AS RACEMIC MIXTURE
STEP 1.
1-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-Y-
L)PYRROLIDIN-3-OL AS RACEMIC MIXTURE
[0539] To a mixture of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amin-
e (see Preparation 5B; 0.083 g, 0.25 mmol) and pyrrolidin-3-ol
(0.022 g, 0.25 mmol) was added triethylamine (0.05 g, 0.50 mmol)
and DMSO (3 mL). The solution was heated to 150.degree. C. in
microwave for 3 h. Then the mixture was diluted with water (10 mL)
and extracted with EtOAc (2.times.20 mL). The combined organic
extracts were washed with water (10 mL) and brine (10 mL), dried
over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated in
vacuo and the residue was purified by reverse phase prep-HPLC (10%
to 80% water/MeCN) to give racemic mixture
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrro-
lidin-3-ol (0.050 g, 0.13 mmol, 54% yield) as white solid. ESI-MS
(M+1): 384 calc. for C.sub.19H.sub.2iN.sub.5O.sub.2S 383.
STEP 2.
N-((1S,3S)-3-((3-(3-FLUOROPYRROLDIN-1-YL)PYRAZIN-2-YL)OXY)CYCLOBUT-
YL)BENZOIDITHIAZOL-2-AMINE AS RACEMIC MIXTURE
[0540] In a 50 mL flask,
1-(3-41S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrol-
idin-3-ol (0.050 g, 0.13 mmol) was dissolved in anhyd DCM (15 mL).
The solution was cooled to 10.degree. C. under nitrogen atmosphere
and diethylaminosulfur trifluoride (DAST, purchased from Alfa
Aesar.TM.) (0.26 g, 0.10 mmol) was added dropwise. The reaction
mixture was allowed to warm to r.t and stirred for 2 h. The mixture
was poured into cold water (10 mL). The separated aqueous phase was
extracted twice with DCM (20 mL), and the combined organic phases
were dried over MgSO.sub.4. After filtration, the solvent was
evaporated in vacuo, and the concentrate was purified by flash
chromatography on silica gel (20% to 45% EtOAc in petroleum ether)
to give racemic mixture
N-((1S,3S)-3-((3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)ben-
zo[d]thiazol-2-amine (0.039 g, 0.10 mmol, 75% yield) as a white
solid. PDE10 IC.sub.50 (uM): 0.00335. M+1: 386. .sup.11-INMR
(CDCl.sub.3, 400 MHz) .delta. (ppm): 7.54-7.45 (m, 3H); 7.21-7.15
(m, 1H); 7.01-6.89 (m, 2H); 5.25-5.12 (m, 1H); 4.92-4.88 (m, 1H);
393-3.72 (m, 5H); 3.10-3.07 (m, 2H); 2.24-1.89 (m, 4H).
##STR00327##
EXAMPLE 98:
1-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPERI-
DIN-4-ONE
STEP 1
1-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPERI-
DIN-4-OL AS RACEMIC MIXTURE
[0541] To a mixture of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amin-
e (see Preparation 5B; 332 mg, 1.0 mmol) and piperidin-4-ol (101
mg, 1.0 mmol) and Et.sub.3N (202 mg, 2.0 mmol) was added DMSO (2
mL). The solution was heated to 150.degree. C. under microwave for
2 h. Then the mixture was diluted with water (10 mL) and extracted
with EtOAc (2.times.30 mL). The combined organic extracts were
washed with water (10 mL) and brine (10 mL), dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated in
vacuo and the residue was purified by flash column chromatography
on silica gel (20% to 60% EtOAc in petroleum ether) to give the
title product (311 mg, 0.80 mmol, 80% yield). ESI-MS (M+1): 398
calc. for C.sub.20H.sub.23N.sub.5O.sub.2S 397.
STEP 2:
1-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-Y-
L)PIPERIDIN-4-ONE
[0542] The
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin--
2-yl)piperidin-4-ol (397 mg, 1 mmol) was dissolved in anhydrous
CH.sub.2Cl.sub.2 (10 mL), treated with DessMartin periodinane (DMP)
(800 mg, 2 mmol, 2.0 equiv) and stirred at RT until complete
conversion. The organic layer was washed with an aq solution of
NaHCO.sub.3/Na.sub.2S.sub.2O.sub.3 (3.times.10 mL)), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The resulting residue
was purified by prep-HPLC to give
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idin-4-one (288 mg, 0.73 mmol, 73% yield). PDE10 IC.sub.50 (uM):
0.0211. M+1: 396. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. (ppm):
7.74-7.73 (d, J=3.2 Hz, 1H); 7.61-7.59 (d, J=7.6 Hz, 1H); 7.54-7.52
(m, 2H); 7.46-7.41 (m, 1H); 7.30-7.24 (m, 1H); 5.10-5.02 (m, 1H);
3.89-3.87 (m, 4H); 3.71-3.67 (m, 1H); 3.25-3.18 (m, 2H); 2.62-2.55
(m, 4H); 2.49-2.42 (m, 2H).
##STR00328##
EXAMPLE 99
N-((1S,3S)-3-((3-(4,4-DIFLUOROPIPERIDIN-1-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)B-
ENZOIDITHIAZOL-2-AMINE
[0543] In a 50 mL flask,
1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piper-
idin-4-one (0.10 g, 0.25 mmol) was dissolved in anhydous DCM (15
mL). The solution was cooled to 10.degree. C. under nitrogen
atmosphere and diethylaminosulfur trifluoride (DAST, purchased from
Alfa Aesar.TM.) (0.78 g, 0.30 mmol) was added dropwise. The
reaction mixture was allowed to warm to RT and stirred for 2 h. The
mixture was poured into cold water (10 mL). The separated aqueous
phase was extracted twice with DCM (20 mL), and the combined
organic phases were dried over MgSO.sub.4. After filtration, the
solvent was evaporated in vacuo, and the residue was purified by
flash chromatography on silica gel (20% to 45% EtOAc in petroleum
ether) to give
N-((1S,3S)-3-((3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)-
benzo[d]thiazol-2-amine (0.050 g, 0.12 mmol, 49% yield) as a white
solid. PDE10 IC.sub.50 (uM): 0.0177. M+1: 418. .sup.1H NMR:
(CD.sub.3OD, 400 MHz) .delta. (ppm): 7.78-7.75 (m, 1H), 7.72 (d,
J=2.8 Hz, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.49-7.45
(m, 1H), 7.34-7.29 (m, 1H), 5.13-5.09 (m, 1H), 4.16-4.09 (m, 1H),
3.67-3.65 (m, 4H), 3.24-3.20 (m, 2H), 2.35-2.31 (m, 2H), 2.09-2.02
(m, 4H).
##STR00329##
EXAMPLE 100
1-(4-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIP-
ERAZIN-1-YL)ETHANONE
STEP 1.
N-((1S,3S)-3-((3-(PIPERAZIN-1-YL)PYRAZIN-2-YL)OXY)CYCLOBUTYL)BENZO-
[D[THIAZOL-2-AMINE
[0544] A solution of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amin-
e (see Preparation 5B; 332 mg, 1 mmol) and piperazine (860 mg, 10
mmol) was heated to 150.degree. C. in microwave for 2 hrs. Then the
mixture was diluted with water (10 mL) and extracted with EtOAc
(2.times.30 mL). The combined organic extracts were washed with
water (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, and
filtered. The filtrate was evaporated in vacuo and the residue was
purified by flash column chromatography on silica gel (20% to 60%
EtOAc in petroleum ether) to give the title product (115 mg, 0.3
mmol, 30% yield). ESI-MS (M+1): 383 calc. for
C.sub.19H.sub.22N.sub.6OS 382.
STEP 2.
1-(4-(3-((1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN--
2-YL)PIPERAZIN-1-YL)ETHANONE
[0545] To a solution of
N-((1S,3S)-3-((3-(piperazin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thia-
zol-2-amine (382 mg, 1 mmol) in dry DCM (10 mL) was added Et.sub.3N
(1 mL). The reaction mixture was cooled to 0.degree. C. with an ice
bath, and acetic anhydride (204 mg, 2 mmol) was added dropped to
the reaction mixture. After 1 hour, the reaction mixture was warmed
to room temperature, and stirred overnight. Then the reaction
mixture was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to give the crude product.
The crude product was purified by prep-HPLC to give
1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pi-
perazin-1-yl)ethanone (297 mg, 0.7 mmol, 70% yield).
TABLE-US-00017 TABLE 9A EXAMPLES 101-102 PREPARED ANALOGOUS TO
SCHEME 24 Ex. # Structure Chemical name M + 1 IC.sub.50 (uM) 100
##STR00330## 1-(4-(3-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy) pyrazin-2-yl)piperazin-1- yl)ethanone 425
0.00926 101 ##STR00331## 1-(4-(3-((1S,3S)-3-(quinolin- 2-ylamino)
cyclobutoxy)pyrazin-2-yl) piperazin-1-yl)ethanone 419 0.0237
TABLE-US-00018 TABLE 9B PREPARATION AND NMR DATA OF EXAMPLES
100-101 Starting Reaction .sup.1H NMR (CDCl.sub.3, 400 Ex. #
Starting Material (1) Material (2) Condition MHz) .delta. (ppm) 100
##STR00332## ##STR00333## Et.sub.3N, DCM 7.71-7.70 (d, J = 2.8 Hz,
1H); 7.60-7.58 (d, J = 8 Hz, 1H); 7.52-7.49 (m, 2H); 7.43-7.39 (m,
1H); 7.28-7.24 (m, 1H); 5.09- 5.02 (m, 1H); 3.75-3.74 (d, J = 5.2
Hz, 3H); 3.70 (s, 4H); 3.61-3.60 (d, J = 5.2 Hz, 2H); 3.24- 3.17
(m, 2H); 2.47-2.40 (m, 2H); 2.15 (s, 3H). 101 ##STR00334##
##STR00335## Et.sub.3N, DCM (CD.sub.3OD) 8.26 (s, 1 H); 7.85 (d, J
= 8.0 Hz, 2 H); 7.79-7.75 (m, 1 H); 7.72 (d, J = 2.8 Hz, 1 H); 7.56
(d, J = 2.8 Hz, 1 H); 7.53-7.48 (m, 1 H); 7.03 (s, 1 H); 5.16- 5.12
(m, 1 H); 3.70-3.64 (m, 4 H); 3.57-3.50 (m, 5 H); 3.25-3.23 (m, 2
H); 2.40-2.33 (m, 2 H); 2.12 (s, 3 H).
##STR00336##
EXAMPLE 102
1-(1-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIP-
ERIDIN-4-YL)METHANOL
STEP 1.
1-(1-(3-((1S,3S)-3-(BENZOIDITHIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN--
2-YL)PIPERIDIN-4-YL)ETHANONE
[0546] To a mixture of
N-((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amin-
e (see Preparation 5B; 332 mg, 1 mmol) and
1-(piperidin-4-yl)ethanone (127 mg, 1 mmol) and Et.sub.3N (202 mg,
2 mmol) was added DMSO (2 mL). The solution was heated to
150.degree. C. under microwave for 3h. Then the mixture was
concentrated and extracted with EtOAc (2.times.30 mL). The combined
organic extracts were washed with water (10 mL) and brine (10 mL),
dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
evaporated in vacuo and the residue was purified by flash column
chromatography on silica gel (20% to 60% EtOAc in petroleum ether)
to give the title product (127 mg, 0.3 mmol, 30% yield). ESI-MS
(M+1): 424 calc. for C.sub.22H.sub.25N.sub.5O.sub.2S 423.
STEP 2.
1-(1-(3-((1S,3S)-3-(BENZO[D[THIAZOL-2-YLAMINO)CYCLOBUTOXY)PYRAZIN--
2-YL)PIPERIDIN-4-YL)ETHANOL AS RACEMIC MIXTURE
[0547]
1-(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-
-yl)piperidin-4-yl)ethanone (423 mg, 1 mmol) was dissolved in 20 ml
of methanol. This solution was cooled down to 0.degree. C. using an
ice bath and sodium tetraborohydride (76 mg, 2 mmol) was added by
portions. The reaction mixture was stirred for 4 h at ambient
temperature, and then saturated aqueous solution of ammonium
chloride (10 mL) was added. The methanol was evaporated under
vacuum and then the reaction mixture was diluted in ethyl acetate.
The organic layer was separated from the aqueous layer. The aqueous
layer was extracted one more time with ethyl acetate. The organic
layers were combined and dried over magnesium sulphate, followed by
concentration under reduced pressure. The residue was purified by
column chromatography on silica gel to give racemic mixture
1-(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-
-2-yl)piperidin-4-yl)ethanol as racemix mixture (298 mg, 0.7 mmol,
70% yield). PDE10 IC.sub.50 (uM): 0,0108. M+1: 426. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. (ppm): 7.63-7.62 (d, J=3.2 Hz, 1H);
7.57-7.56 (m, 1H); 7.47-7.46 (d, J=3.2 Hz, 1H); 7.43-7.40 (m, 1H);
7.25-7.21 (m, 1H); 7.06-7.01 (m, 1H); 5.04-5.00 (m, 1H); 4.23-4.19
(m, 2H); 4.12-4.08 (m, 1H); 3.52-3.49 (m, 1H); 3.12-3.09 (m, 2H);
2.74-2.72 (m, 2H); 2.17-2.14 (m, 2H); 1.89-1.81 (m, 1H); 1.71-1.60
(m, 1H); 1.44-1.39 (m, 3H); 1.16-1.14 (d, J=6 Hz, 3H).
##STR00337##
EXAMPLE 103
(1-(3-((1S,3S)-3-(QUINOLIN-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPERIDIN-4--
YL)METHANOL
STEP 1.
TERT-BUTYL((1S,3S)-3-((3-(4-(HYDROXYMETHYL)PIPERIDIN-1-YL)PYRAZIN--
2-YL)OXY)CYCLOBUTYL)CARBAMATE
[0548] To a mixture of tert-butyl
((1S,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (see
Preparation 5A, step 1; 299 mg, 1 mmol) and piperidin-4-yl-methanol
(115 mg, 1 mmol) and Et.sub.3N (202 mg, 2 mmol) was added DMSO (6
mL). The solution was heated to 140.degree. C. under microwave for
3 h. Then the mixture was concentrated and extracted with EtOAc
(2.times.30 mL). The combined organic extracts were washed with
water (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, and
filtered. The filtrate was evaporated in vacuo and the residue was
purified by flash column chromatography on silica gel (20% to 60%
EtOAc in petroleum ether) to give
tert-butyl((1S,3S)-3-((3-(4-(hydroxymethyl)piperidin-1-yl)pyrazin-2--
yl)oxy)cyclobutyl)carbamate (113 mg, 0.3 mmol, 30% yield). ESI-MS
(M+1): 379 calc. for C.sub.19H.sub.30N.sub.4O.sub.4 378.
STEP 2.
(1-(3-((1S,3S)-3-AMINOCYCLOBUTOXY)PYRAZIN-2-YL)PIPERIDIN-4-YL)METH-
ANOL HYDROCHLORIDE
[0549] To tert-butyl
41S,3S)-3-((3-(4-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)oxy)cyclobuty-
l)carbamate (378 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL).
The solution was stirred at RT for 2 h. The solvent was removed
under reduced pressure to give (1-(3-((1S,3S)-3-amino
cyclobutoxy)pyrazin-2-yl)piperidin-4-yl)methanol hydrochloride (299
mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 279 calc. for
C.sub.14H.sub.22N.sub.4O.sub.2 278.
STEP 3.
(1-(3-((1S,3S)-3-(QUINOLIN-2-YLAMINO)CYCLOBUTOXY)PYRAZIN-2-YL)PIPE-
RIDIN-4-YL)METHANOL
[0550] A mixture of
(1-(3-((1S,3S)-3-aminocyclobutoxy)pyrazin-2-yl)piperidin-4-yl)methanol
hydrochloride (278 g, 1 mmol), 2-chloro-quinoline (163 mg, 1 mmol)
and DIEA (286 mg, 2 mmol) in NMP (12 mL) was heated to 200.degree.
C. for 2 h in microwave. The reaction mixture was diluted with
water, extracted with EtOAc (40 mL), washed with brine and dried
over Na.sub.2SO.sub.4. The organic layers were concentrated and
purified by column chromatography on silica gel to give
(1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-4-
-yl)methanol (182 mg, 0.45 mmol, 45%).
TABLE-US-00019 TABLE 10A EXAMPLES 103-104 PREPARED ANALOGOUS TO
SCHEME 26 Ex. # Structure Chemical Name M + 1 IC.sub.50 (uM) 103
##STR00338## (1-(3-((1S,3S)-3-(quinolin-2-
ylamino)cyclobutoxy)pyrazin- 2-yl)piperidin-4-yl)methanol 406 Not
yet taken 104 ##STR00339## 1-(2-((1S,3S)-3- (benzo[d]thiazol-2-
ylamino)cyclobutoxy)pyridin- 3-yl)piperidin-4- carbonitrile 406
0.00125
TABLE-US-00020 TABLE 10B PREPARATION AND NMR DATA OF EXAMPLES
103-104 Starting Reaction .sup.1H NMR (CD.sub.3OD, 400 Ex. #
Starting Material (1) Material (2) Condition MHz) .delta. (ppm) 103
##STR00340## (See Preparation 5A) ##STR00341## DIEA, NMP MW 7.79
(d, J = 8.8 Hz, 1 H); 7.62-7.53 (m, 3 H); 7.48-7.43 (m, 2 H);
7.16-7.12 (m, 1 H); 6.70-6.68 (d, J = 8.8 Hz, 1 H); 5.05-5.01 (m, 1
H); 4.31 (s, 1 H); 4.19- 4.16 (d, J = 13.2 Hz, 2 H); 3.41 (d, J =
6.4 Hz, 2 H); 3.11-3.07 (m, 2 H); 2.79-2.73 (m, 2 H); 2.13-2.06 (m,
2 H); 1.79- 1.75 (m, 2 H); 1.62-1.60 (m, 1 H); 1.33-1.29 (m, 2 H).
104 ##STR00342## (See Preparation 7L) ##STR00343## DIEA, NMP MW
(CDCl.sub.3) 7.81-7.79 (m, 1H); 7.64-7.56 (m, 2H); 7.34-7.30 (m,
1H); 7.14-7.10 (m, 2H); 6.89-6.86 (m, 1H); 5.50 (br, 1H); 5.13-5.06
(m, 1H); 4.07-4.03 (m, 1H); 3.31-3.20 (m, 4H); 3.06-3.00 (m, 2H);
2.88-2.83 (m, 1H); 2.21-2.05 (m, 6H).
##STR00344##
EXAMPLE 105
N-((1S,3S)-3-((6-FLUORO-3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOB-
UTYL)BENZO[D]THIAZOL-2-AMINE
STEP 1. (1S,3S)-3-AMINOCYCLOBUTANOL HYDROCHLORIDE
[0551] The mixture of tert-butyl
((1S,3S)-3-hydroxycyclobutyl)carbamate (see Preparation 4A; 187 mg,
1 mmol, 1.0 eqv) in HCl/MeOH 4 N (15 ml) was stirred at room
temperature for 4 hours. Reaction mixture was concentrated to give
(1S,3S)-3-aminocyclobutanol hydrochloride. (120 mg, 0.98 mmol, 98%
yield) ESI-MS (M+1): 88 calc. for C.sub.4H.sub.9NO 87.
STEP 2. (1S,3S)-3-(BENZO[D]THIAZOL-2-YLAMINO)CYCLOBUTANOL
[0552] A mixture of (1S,3S)-3-aminocyclobutanol hydrochloride (120
mg, 0.98 mmol, 1.0 eqv), 2-chloro-benzothiazole (purchased from
ALDRICH) (169 mg, 1 mmol, 1.02 eqv) and DIEA (286 mg, 2 mmol, 2.04
eqv) in NMP (2 mL) was heated to 180.degree. C. for 2 hours in
microwave. To the reaction mixture was added water, and the residue
was extracted with EtOAc (30 mL). The combined organic layer was
washed with brine and dried over Na.sub.2SO.sub.4. The organic
layers were concentrated and purified by column chromatography on
silica gel to give
(1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (160 mg, 0.72
mmol, yield 73%). ESI-MS (M+1): 221 calc. for
C.sub.11H.sub.12N.sub.2OS 221.
STEP 3.
N-((1S,3S)-3-((6-FLUORO-3-IODOPYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZO[D]-
THIAZOL-2-AMINE
[0553] To the mixture of
(1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (160 mg, 0.72
mmol, 1.0 eqv), 2,6-difluoro-3-iodopyridine (see Preparation 8; 374
mg, 1.44 mmol, 2.0 eqv) and DMF (2 ml) was added sodium hydride 60%
(29 mg, 0.72 mmol, 1.0 eqv) at 0.degree. C. The mixture was stirred
at room temperature for 1 hour. The mixture was poured into water
(50 ml) and extracted with ethyl acetate. The organic layer was
dried and concentrated. The residue was purified by silica gel
chromatography to give
N-((1S,3S)-3-((6-fluoro-3-iodopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-
-2-amine (105 mg, 0.22 mmol, 31% yield). ESI-MS (M+1): 442 calc.
for C.sub.16H.sub.13FIN.sub.3OS 441.
STEP 4.
N-((1S,3S)-3-((3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-6-FLUOROPYRIDIN-2-YL)-
OXY)CYCLOBUTYL)BENZO[D]THIAZOL-2-AMINE
[0554] The mixture of
N-((1S,3S)-3-((6-fluoro-3-iodopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-
-2-amine (100 mg, 0.22 mmol, 1.0 eqv),
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(70 mg, 0.33 mmol, 1.5 eqv) K.sub.3PO.sub.4 (212 mg, 1 mmol, 5 eqv)
and Pd(dppf)Cl.sub.2 (50 mg) in 1,4-dioxane (3 ml) was stirred at
80.degree. C. overnight. The mixture was cool down to room
temperature and concentrated. The residue was purified by silica
gel chromatography to give
N-((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)-6-fluoropyridin-2-yl)ox-
y)cyclobutyl)benzo[d]thiazol-2-amine (80 mg, 0.2 mmol, 90% yield)
ESI-MS (M+1): 398 calc. for C.sub.21H.sub.20FN.sub.3O.sub.2S
398.
STEP 5.
N-((1S,3S)-3-((6-FLUORO-3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OX-
Y)CYCLOBUTYL)BENZO[D]THIAZOL-2-AMINE
[0555] The mixture of
N-((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)-6-fluoropyridin-2-yl)oxy)cyc-
lobutyl)benzo[d]thiazol-2-amine (80 mg, 0.2 mmol, 1 eqv) Pd/C 10%
wet (0.3 g) in THF (10 ml) was stirred at 40 psi for 48 hours under
H.sub.2. The reaction mixture was filtered and concentrated to give
N-((1S,3S)-3-46-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclo-
butyl)benzo[d]thiazol-2-amine (60 mg, 0.15 mmol, 75% yield). PDE10
IC.sub.50 (uM): 0.000758. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta.
(ppm): 7.79-7.77 (m, 1H); 7.73-7.68 (m, 1H); 7.56-7.47 (m, 2H);
7.35-7.32 (m, 1H); 6.58-6.55 (m, 1H); 5.09-5.03 (m, 1H); 4.14-4.04
(m, 3H); 3.61-3.55 (m, 2H); 3.27-3.05 (m, 3H); 2.35-2.28 (m, 2H);
1.83-1.77 (m, 4H).
##STR00345##
EXAMPLE 106 AND EXAMPLE 107
6-(((1R,3R)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)AMI-
NO)NICOTINONITRILE AND
6-(((1S,3S)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)Am-
ino)NICOTINONITRILE
[0556] To a mixture of Cs.sub.2CO.sub.3 (652 mg, 2 mmol) and
3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutanamine
hydrochloride (see Preparation 7C; 248 mg, 1 mmol) was added DMF
(20 mL) and 6-chloro-nicotinonitrile (138 mg, 1 mmol). The reaction
mixture was heated to 120.degree. C. for 10 hours. The mixture was
diluted with water (60 mL) and extracted with EtOAc (2.times.50
mL). The combined organic extracts were washed with water (60 mL)
and brine (60 mL), dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was evaporated in vacuo and the residue was purified by
prep-HPLC to give examples 105 (175 mg, 0.5 mmol, 50% yield) and
106 (55 mg, 0.156 mmol, 39% yield) as a pair of separated
stereoisomers.
TABLE-US-00021 TABLE 11A EXAMPLES 106-111 PREPARED ANALOGOUS TO
SCHEME 28. Ex. # Structure Chemical Name M + 1 IC.sub.50 (uM) 106
and 107* ##STR00346## and ##STR00347##
6-(((1S,3S)-3-((3-(tetrahydro- 2H-pyran-4-yl)pyridin-2-
yl)oxy)cyclobutyl)amino) nicotinonitrile and
6-(((1R,3R)-3-((3-(tetrahydro- 2H-pyran-4-yl)pyridin-2-
yl)oxy)cyclobutyl) nicotinonitrile; respectively. 351 0.59 and
0.865, respectively 108 and 109* ##STR00348## and ##STR00349##
N-((1R,3R)-3-((3-(tetrahydro- 2H-pyran-4-yl)pyridin-2-
yl)oxy)cyclobutyl)-5- (trifluoromethyl)pyridin-2-amine and
N-((1S,3S)-3-((3-(tetrahydro- 2H-pyran-4-yl)pyridin-2-
yl)oxy)cyclobutyl)-5- (trifluoromethyl)pyridin-2- amine;
respectively. 394 0.436 and 0.106; 0.59 and 0.865, respectively 110
and 111* ##STR00350## and ##STR00351## 5-chloro-N-((1S,3S)-3-((3-
(tetrahydro-2H-pyran-4- yl)pyridin-2- yl)oxy)cyclobutyl)pyridin-2-
amine and 5-chloro-N-((1R,3R)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyridin-4- yl)oxy)cyclobutyl)pyridin-2- amine; respectively. 360
0.0262 and 0.0837; 0.59 and 0.865, respectively *as a pair of
separated stereoisomers having the same mass.
TABLE-US-00022 TABLE 11B PREPARATION AND NMR OF EXAMPLES 106-111
Starting Reaction Ex. # Materials (1) and (2) Condition .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. (ppm) 106 and 107 ##STR00352##
Cs.sub.2CO.sub.3, DMF 120.degree. C. 8.25 (s, 1H); 7.97-7.96 (d, J
= 5.2 Hz, 1H); 7.72-7.70 (d, J = 9.2 Hz, 1H); 7.44-7.43 (d, J = 7.2
Hz, 1H); 6.89- 6.86 (m, 1H); 6.52-6.50 (m, 1H); 5.12- 5.08 (m, 1H);
4.08-4.06 (d, J = 11.2 Hz, 2H); 3.89 (s, 1H); 3.59-3.53 (m, 2H);
3.15-3.12 (m, 2H); 3.11-3.01 (m, 1H); 2.22-2.16 (m, 2H); 1.77-1.72
(m, 4H) and 8.35-8.34 (d, J = 0.8 Hz, 1H); 7.98- 7.96 (m, 1H);
7.65-7.63 (d, J = 7.6 Hz, 1H); 7.45-7.43 (m, 1H); 6.89-6.85 (m,
1H); 6.42-6.36 (m, 1H); 5.47-5.44 (m, 1H); 4.35 (s, 1H); 4.11-4.06
(m, 2H); 3.61-3.55 (m, 2H); 3.11-3.03 (m, 1H); 2.70-2.64 (m, 2H);
2.57-2.51 (m, 2H); 1.79-1.75 (m, 4H); respectively. 108 and 109
##STR00353## Cs.sub.2CO.sub.3, DMF 120.degree. C. 8.22 (s, 1H);
7.94-7.92 (m, 1H); 7.83- 7.80 (m, 1H); 7.58-7.56 (m, 1H); 6.94-
6.91 (m, 1H); 6.86-6.83 (d, J = 9.2 Hz, 1H); 5.42 (s, 1H); 4.46 (s,
1H); 4.08- 4.04 (m, 2H); 3.63-3.56 (m, 2H); 3.13 (s, 1H); 2.66-2.58
(m, 4H); 1.83-1.77 (m, 4H) and 8.23-8.22 (d, J = 0.8 Hz, 1H); 7.96-
7.94 (m, 1H); 7.81-7.78 (m, 1H); 7.56- 7.53 (m, 1H); 6.94-6.90 (m,
1H); 6.81- 6.79 (d, J = 9.2 Hz, 1H); 5.10-5.06 (m, 1H); 4.09-4.02
(m, 3H); 3.59-3.53 (m, 2H); 3.12-3.07 (m, 3H); 2.16-2.13 (m, 2H);
1.81-1.75 (m, 4H); respectively. 110 and 111 ##STR00354## t-BuONa,
DMF (CD.sub.3OD) 7.94-7.93 (d, J = 4.8 Hz, 1H); 7.89-7.88 (d, J = 2
Hz, 1H); 7.53- 7.51 (m, 1H); 7.40-7.37 (m, 1H); 6.91- 6.88 (m, 1H);
6.48-6.46 (d, J = 8.8 Hz, 1H); 5.05-5.01 (m, 1H); 4.04-3.96 (m,
3H); 3.59-3.52 (m, 2H); 3.07-3.01 (m, 3H); 2.05-1.99 (m, 2H);
1.79-1.75 (m, 4H) and (CD.sub.3OD) 7.94-7.93 (d, J =4.8 Hz, 1H);
7.89-7.88 (d, J = 2 Hz, 1H); 7.53- 7.51 (m, 1H); 7.40-7.37 (m, 1H);
6.91- 6.88 (m, 1H); 6.48-6.46 (d, J = 8.8 Hz, 1H); 5.05-5.01 (m,
1H); 4.04-3.96 (m, 3H); 3.59-3.52 (m, 2H); 3.07-3.01 (m, 3H);
2.05-1.99 (m, 2H); 1.79-1.75 (m, 4H); respectively.
##STR00355##
EXAMPLE 112
N-((1S,3S)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)QUIN-
OLIN-2-AMINE
STEP 1.
N-((1S,3S)-3-((3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLO-
BUTYL)QUINOLIN-2-AMINE
[0557] To the mixture of
N-((1S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)quinolin-2-amine
(see Preparation 7G; 370 mg, 1 mmol, 1.0 eqv),
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(315 mg, 1.5 mmol, 1.5 eqv) and NaCO .sub.3 (212 mg, 2 mmol)
in1,4-dioxane (60 mL) and H.sub.2O (6 mL) was added
Pd(dppf)Cl.sub.2 (36.6 mg, 0.05 mmol). The reaction mixture was
stirred at 110.degree. C. under N.sub.2 overnight. The reaction
mixture was filtered through CELITE.RTM. and washed with
CH.sub.2Cl.sub.2. The organic layer was concentrated and the crude
product was purified by silica gel column to give
N-((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobu-
tyl)quinolin-2-amine (188 mg, 0.52mmol, yield 52%). ESI-MS (M+1):
374 calc. for C.sub.23H.sub.23N.sub.3O.sub.2 373.
STEP 2.
N-((1S,3S)-3-((3-(TETRHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBU-
TYL)QUINOLIN-2-AMINE
[0558] A mixture of
N-((1S,3S)-3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)q-
uinolin-2-amine (373 mg, 1 mmol) and wet Pd--C (50%, 200 mg) in
MeOH (100 mL) was stirred under H.sub.2 (40 psi) at 30.degree. C.
overnight then the reaction mixture was filtered through
CELITE.RTM. and washed with MeOH (100 mL). The filtrate was
concentrated to give
N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)qu-
inolin-2-amine (336 mg, 0.9 mmol, yield 90%).
TABLE-US-00023 TABLE 12A EXAMPLES 112-113 PREPARED ANALOGOUS TO
SCHEME 29 Ex. # Structure Chemical Name M + 1 IC.sub.50 (uM) 112
##STR00356## N-((1S,3S)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyridin-2- yl)oxy)cyclobutyl)quinolin- 2-amine 376 0.0015 113
##STR00357## N-((1S,3S)-3-((3- (tetrahydro-2H-pyran-4-
yl)pyrazin-2- yl)oxy)cyclobutyl)quinolin- 2-amine 377 0.0075
TABLE-US-00024 TABLE 12B PREPARATION AND NMR OF EXAMPLES 112-113
Reaction .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. Ex. # Strating
Material (1) Condition (ppm) 112 ##STR00358## (See Preparation 7G)
H.sub.2, Pd/C, MeOH 8.13 (d, J = 8.0 Hz, 1 H); 7.97- 7.95 (m, 1 H);
7.78 (d, J = 8.0 Hz, 1 H); 7.68-7.64 (m, 2 H); 7.47-7.44 (m, 1 H);
7.40-7.36 (m, 1 H); 6.90-6.88 (m, 1 H); 6.87-6.78 (m, 1 H);
5.13-5.10 (m, 1 H); 4.07-4.03 (m, 2 H); 3.88-3.85 (m, 1 H);
3.60-3.53 (m, 2 H); 3.17-3.08 (m, 3 H); 2.41 (d, J = 12.0 Hz, 2 H);
1.77- 1.67 (m, 4 H). 113 ##STR00359## (See Preparation 5G) H.sub.2,
Pd/C, MeOH (CD.sub.3OD) 8.35-8.24 (m, 1H); 8.08 (s, 1H); 7.98 (s,
1H); 7.88- 7.80 (m, 3H); 7.53 (s, 1H); 7.28- 6.99 (m, 1H); 5.16 (s,
1H); 4.30- 4.29 (m, 1H); 4.05 (d, J = 7.2 Hz, 2H); 3.60-3.55 (m,
2H); 3.26-3.22 (m, 3H); 2.39 (d, J = 12 Hz, 2H); 1.94 (d, J = 12
Hz, 2H); 1.79 (s, 2H).
##STR00360## ##STR00361##
EXAMPLES 114 AND 115
N-((1S,3S)-3-((3-(1-ACETYLPIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)-4-ME-
THYLBENZENSULFONAMIDE AND
N-((1R,3R)-3-((3-(1-ACETYLPIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)-4-M-
ETHYLBENZENESULFONAMIDE
STEP 1: 3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTANAMINE
HYDROCHLORIDE
[0559] To a solution of tert-butyl
(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see Preparation
7B; 342 mg, 1 mmol) was added 4 M HCl in MeOH (50 mL). The solution
was stirred at room temperature for 2 hours. The solvent was
removed under reduced pressure to give
3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (223 mg,
0.95 mmol, yield 95%). ESI-MS (M+1): 243 calc. for
C.sub.9H.sub.11BrN.sub.2O 242.
STEP 2.
N-(3-((3-BROMOPYRIDIN-2-YL)OXY)CYCLOBUTYL)-4-METHYLBENZENESULFONAM-
IDE
[0560] To a solution of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine
hydrochloride (243 mg, 1 mmol) in dry DCM (10 mL) was added
Et.sub.3N (1 mL). The reaction mixture was cooled to 0.degree. C.
with an ice bath, and p-toluenesulfonyl chloride (380 mg, 2 mmol)
was added dropwise. After 1 hour, the reaction mixture was warmed
to room temperature, and stirred overnight. Then the reaction
mixture was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to give the crude product.
The crude product was purified by flash chromatography on silica
gel (20% to 45% EtOAc in petroleum ether) to give
N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide
(318 mg, 0.8 mmol, yield 80%). ESI-MS (M+1): 397 calc. for
C.sub.16H.sub.17BrN.sub.2O.sub.3S 396.
STEP 3. TERT-BUTYL
2-(3-(4-METHYLPHENYLSULFONAMIDO)CYCLOBUTOXY)-5',6'-DIHYDRO-[3,4'-BIPYRIDI-
NE]-1'(2'H)-CARBOXYLATE
[0561] To a solution of
N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide
(397 mg, 1 mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (335 mg, 1.1 mmol) and NaCO.sub.3 (212 mg, 2 mmol)
in1,4-dioxane (60 mL) and H.sub.2O (6 mL) was added
Pd(dppf)Cl.sub.2 (36.6 mg, 0.05 mmol). The reaction mixture was
stirred at 110.degree. C. under N.sub.2 overnight. The reaction
mixture was filtered through CELITE.RTM. and washed with
CH.sub.2Cl.sub.2. The organic layer was concentrated and the crude
product was purified by silica gel column to give tert-butyl
2-(3-(4-methylphenylsulfonamido)cyclobutoxy)-5',6'-dihydro-[3,4'-bipyridi-
ne]-1'(2'H)-carboxylate (351 mg, 0.7 mmol, yield 70%). ESI-MS
(M+1): 500 calc. for C.sub.26H.sub.33N.sub.3O.sub.5S 499.
STEP 4. TERT-BUTYL
4-(2-(3-(4-METHYLPHENYLSULFONAMIDO)CYCLOBUTOXY)PYRIDIN-3-YL)PIPERIDINE-1--
CARBOXYLATE
[0562] A mixture of tert-butyl
2-(3-(4-methylphenylsulfonamido)cyclobutoxy)-5',6'-dihydro-[3,4'-bipyridi-
ne]-1'(2'H)-carboxylate (499 mg, 1 mmol) and wet Pd--C (50%, 1.0 g)
in MeOH (50 mL) was stirred under H.sub.2 (40psi) at 30.degree. C.
overnight then the reaction mixture was filtered through
CELITE.RTM. and washed with MeOH. The filtrate was concentrated to
give tert-butyl
4-(2-(3-(4-methylphenylsulfonamido)cyclobutoxy)pyridin-3-yl)piperidine-1--
carboxylate (476 mg, 0.95mmol, yield 95%). ESI-MS (M+1): 502 calc.
for C.sub.26H.sub.35N.sub.3O.sub.5S 501.
STEP 5.
4-METHYL-N-(3-((3-(PIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)BENZ-
ENESULFONAMIDE HYDROCHLORIDE
[0563] To tert-butyl
4-(2-(3-(4-methylphenylsulfonamido)cyclobutoxy)pyridin-3-yl)piperidine-1--
carboxylate (501 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL).
The solution was stirred at room temperature for 2 hours. The
solvent was removed under reduced pressure to give
4-methyl-N-(3-((3-(piperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzenesulf-
onamide hydrochloride (381 mg, 0.95 mmol, yield 95%). ESI-MS (M+1):
402 calc. for C.sub.21H.sub.27N.sub.3O.sub.3S 401.
STEP 6.
N-((1S,3S)-3-((3-(1-ACETYLPIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUT-
YL)-4-METHYLBENZENESULFONAMIDE AND
N-((1R,3R)-3-((3-(1-ACETYLPIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)-4-M-
ETHYLBENZENESULFONAMIDE
[0564] To a solution of
4-methyl-N-(3-((3-(piperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzenesulf-
onamide hydrochloride (401 mg, 1 mmol) in dry CH.sub.2Cl.sub.2 (10
mL) was added Et.sub.3N (1 mL). The reaction mixture was cooled to
0.degree. C. with an ice bath, and acetyl chloride (156 mg, 2 mmol)
was added dropwise. After 1 hour, the reaction mixture was warmed
to room temperature, and stirred overnight. Then the reaction
mixture was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to give the crude product.
The crude product was purified by chiral-prep-HPLC (Column:
Chiralcel OD-H 250*30 mm, 5u; Mobile phase: 80% hexane in EtOH
(0.05% diethyl amine); Flow rate: 30 mL/minute) to give examples
114 and 115.
EXAMPLE 114
N-((1S,3S)-3-((3-(1-ACETYLPIPERIDIN-4-yl)PYRIDIN-2-yl)oxy)cyclobutyl)-4-ME-
THYLBENEZENSULFONAMIDE
[0565] PDE10 IC.sub.50 (uM): 12.4. M+1: 444. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. (ppm): 7.89-7.87 (m, 1H); 7.74-7.72
(m, 2H); 7.50-7.48 (m, 1H); 7.37-7.35 (d, J=8 Hz, 2H); 6.89-6.87
(m, 1H); 4.87-4.78 (m, 1H); 4.70-4.60 (m, 1H); 4.02-3.99 (m, 1H);
3.50-3.46 (m, 1H); 3.30-3.29 (m, 1H); 3.10-2.96 (m, 1H); 2.67-2.61
(m, 3 H); 2.41 (s, 3 H); 2.11(s, 3 H); 1.90-1.79 (m, 4 H);
1.65-1.51 (m, 2H).
EXAMPLE 115
N-((1R,3R)-3-((3-(1-ACETYLPIPERIDIN-4-YL)PYRIDIN-2-YL)OXY)CYCLOBUTYL)-4-ME-
THYLBEBZENESULFONAMIDE
[0566] PDE10 IC.sub.50 (uM): 0.916. M+1: 444. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. (ppm): 7.90-7.88 (m, 1 H); 7.73-7.70
(m, 2H); 7.54-7.52 (m, 1H); 7.37-7.35 (m, 2H); 6.92-6.89 (m, 1H);
5.20-5.18 (m, 1H); 3.96-3.93 (m, 2H); 3.23-3.22 (d, J=2.4 Hz, 2H);
3.01 (s, 1H); 2.71-2.70 (d, J=2.8 Hz, 1H); 2.41 (s, 3 H); 2.31-2.26
(m, 4 H); 2.13 (s, 3 H); 1.86-1.80 (m, 2H); 1.66-1.53 (m, 2 H).
##STR00362##
EXAMPLES 116 AND 117
N-((1R,3R)-3-((5-(TETRHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4-YL)OXY)CYCLOBUTYL)-5-
-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE AND
N-((1S,3S)-3-((5-(TETRHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4-YL)OXY)CYCLOBUTYL)--
5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE
STEP 1.
[3-(5-BROMO-2-CHLORO-PYRIMIDIN-4-YLOXY)-CYCLOBUTYL]-CARBAMIC ACID
TERT-BUTYL ESTER
[0567] To a solution of (3-hydroxy-cyclobutyl)-carbamic acid
tert-butyl ester (2.5 g, 13.3 mmol) in THF (40 mL) were added
Cs.sub.2CO.sub.3 (8.6 g, 26.6 mmol) and
5-bromo-2,4-dichloro-pyrimidine (3 g, 13.3 mmol). The reaction
mixture was heated at reflux overnight. The reaction mixture was
filtered and concentrated, diluted with EtOAc and water. The
aqueous phase was extracted with EtOAc (3.times.100 mL) and the
combined organic extracts were washed with brine (60 mL), dried
over MgSO.sub.4, filtered, and concentrated. Purification by flash
column chromatography on silica gel to give the product (4.75 g,
12.6 mmol, yield: 95%). ESI-MS (M+1): 378 calc. for
C.sub.13H.sub.17BrClN.sub.3O.sub.3 377.
STEP 2.
{3-[2-CHLORO-5-(3,6-DIHYDRO-2H-PYRAN-4-YL)-PYRIMIDIN-4-YLOXY]-CYCL-
OBUTYL}-CARBAMIC ACID TERT-BUTYL ESTER
[0568] To a solution of
[3-(5-bromo-2-chloro-pyrimidin-4-yloxy)-cyclobutyl]-carbamic acid
tert-butyl ester (5.1 g, 13.3 mmol) in dioxane (80 mL) was treated
with Na.sub.2CO.sub.3 (2.8 g, 26.6 mmol) in 15 mL of H.sub.2O as a
solution, followed by additional of
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran
(3.3 g 16.0 mmol) and Pd(dppf)Cl.sub.2 (974 mg, 1.33mmol). The
resulting mixture was heated at refluxing overnight under N.sub.2
atmosphere. TLC showed that most of the staring materials were
consumed completely. The solution was filtered, and the filter was
concentrated. And the residue was purified by silica gel
chromatography to give the product (2.2 g, 5.76 mmol, 43%). ESI-MS
(M+1): 382 calc. for C.sub.18H.sub.24ClN.sub.3O.sub.4 381.
STEP 3.
{3-[5-(TETRHYDRO-PYRAN-4-YL)-PYRIMIDIN-4-YLOXY]-CYCLOBUTYL}-CARBAM-
IC ACID TERT-BUTYL ESTER
[0569] To a solution of
{3-[2-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutyl}-
-carbamic acid tert-butyl ester (2.2 g, 5.76 mmol) in MeOH (40 mL)
was added Pd/C (1.0 g). The reaction solution was stirred at room
temperature overnight under H.sub.2 atmosphere. LCMS showed that
the staring material was consumed completely. The mixture was
filtered and concentrated to give the product (1.2 g, 3.44 mmol,
yield: 60%). ESI-MS (M+1): 350 calc. for
C.sub.18H.sub.27N.sub.3O.sub.4 349.
STEP 4.
3-[5-(TETRHYDRO-PYRAN-4-yl)-PYRIMIDIN-4-YLOXY]-CYCLOBUTYLAMINE
[0570] The mixture of
{3-[5-(tetrahydro-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutyl}-carbamic
acid tert-butyl ester (1.2 g, 3.21 mmol) in HCl/MeOH (20 mL) was
stirred at room temperature for 1 hour. Then it was concentrated to
give 3-[5-(tetrahydro
-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutylamine (916 mg, 3.21 mmol,
yield: 93%) which was used in the next step without further
purification. ESI-MS (M+1): 250 calc. for
C.sub.13H.sub.19N.sub.3O.sub.2 249.
STEP 5.
N-((1R,3R)-3-((5-(TETRHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4-YL)OXY)CYCLO-
BUTYL)-5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE AND
N-((1S,3S)-3-((5-(TETRHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4-YL)OXY)CYCLOBUTYL)--
5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE
[0571] To a solution of
3-[5-(tetrahydro-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutylamine
(916 mg, 3.21 mmol) in DMF (20 mL) were added Cs.sub.2CO.sub.3 (2.1
g, 6.42 mmol) and 2-chloro-5-trifluoromethyl-pyridine (697 mg, 3.85
mmol). The mixture was heated at 120.degree. C. for 2 hours. The
reaction mixture was concentrated, diluted with EtOAc and water.
The aqueous layer was extracted with EtOAc (3.times.) and the
combined organic extracts were washed with brine (1.times.), dried
over MgSO.sub.4, filtered, and concentrated. Purification by flash
column chromatography on silica gel, and followed by supercritical
fluid chromatography (SFC) to give the products.
EXAMPLE 116
N-((1R,3R)-3-((5-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4-YL)OXY)CYCLOBUTYL)--
5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE PDE10 IC.sub.50 (uM): 0.959.
M+1: 395. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. (ppm): 8.47 (s,
1H), 8.24 (s, 1H), 8.12-8.11 (m, 1H), 7.51 (dd, J=8.8 Hz, 2.4 Hz,
1H), 6.49(d, J=9.2 Hz, 1H), 5.48-5.40 (m, 1H), 4.64-4.60 (m, 1H),
3.99-3.95 (m, 2H), 3.54-3.47 (m, 2H), 3.03-2.96 (m, 1H), 2.59-2.52
(m, 2H), 2.47-2.41 (m, 2H), 1.82-1.71 (m, 4H).
EXAMPLE 117
N-((1S,3S)-3-((5-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4-YL)OXY)CYCLOBUTYL)--
5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE
[0572] PDE10 IC.sub.50 (uM): 0.321. M+1: 395. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. (ppm): 8.60 (s, 1H), 8.35 (s, 1H),
8.22-8.21 (m, 1H), 7.59 (d, J=9.2 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H),
5.20-5.16 (m, 1H), 4.20-4.10 (m, 1H), 4.06-4.02 (m, 2H), 3.59-3.52
(m, 2H), 3.12-3.03 (m, 3H), 2.16-2.09 (m, 2H), 1.90-1.76 (m,
4H).
[0573] The following Examples 118-127 can be prepared according to
the above schemes and preparations from starting materials
available to those skilled in the art.
TABLE-US-00025 TABLE 13 EXAMPLES 118-127 Ex. # Structure Chemical
Name 118 ##STR00363## N-(3-((5-fluoro-3-(indolin-5-yl)pyridin-2-
yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine 119 ##STR00364##
1-(6-(3-(hydroxymethyl)piperidin-1-yl)-5-(3-
(quinoxalin-2-ylamino)cyclobutoxy)pyran-2- yl)ethanone 120
##STR00365## 1-(4-(3-(1-methyl-3-((5-methylpyridin-2-
yl)amino)cyclobutoxy)-6-(tetrahydrofuran-3-
yl)pyrazin-4-yl)-5,6-dihydropyridin-1(2H)-
yl)-2-(methylamino)ethanone 121 ##STR00366##
1-(4-(2-chloro-4-(3-methyl-3-((1-methyl-1H- benzo[d]imidazol-2-
yl)amino)cyclobutoxy)pyrimidin-5- yl)piperidin-1-yl)ethanone 122
##STR00367## 5-(5-(3-(imidazo[1,2-a]pyridin-2-
ylamino)cyclobutoxy)-2-oxo-2,3-dihydro-1H-
pyrrolo[3,2-b]pyridin-6-yl)pyrimidine-2- carbonitrile 123
##STR00368## 4-(5-fluoro-2-(3-((7-methylquinazolin-2-
yl)amino)cyclobutoxy)pyridin-3-yl)tetrahydro- 2H-pyran-4-ol 124
##STR00369## N-(3-((5-fluoro-4-(1-methylpyrrolidin-3-
yl)pyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-
pyrrolo[2,3-b]pyridin-6-amine 125 ##STR00370##
2-(1-(3-(1-fluoro-3-(quinolin-2- ylamino)cyclobutoxy)quinoxalin-2-
yl)pyrrolidin-3-yl)propan-2-ol 126 ##STR00371## methyl
3-fluoro-3-(4-(3-((3-methyl-1,6-
naphthyridin-2-yl)amino)cyclobutoxy)pyridin-
3-yl)pyrrolidine-1-carboxylate 127 ##STR00372##
5-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-
yl)-6-((1-(isoquinolin-3-yl)azetidin-3- yl)oxy)picolinonitrile
BIOLOGICAL EXAMPLES
[0574] The above PDE10 IC.sub.50 data were obtained by using the
following assays.
EXAMPLE A
MPDE10A7 Enzyme Activity and Inhibition
[0575] Enzyme Activity. An IMAP TR-FRET assay was used to analyze
the enzyme activity (Molecular Devices Corp., Sunnyvale CA). 5
.mu.L of serial diluted PDE10A (BPS Bioscience, San Diego, Calif.)
or tissue homogenate was incubated with equal volumes of diluted
fluorescein labeled cAMP or cGMP for 60 min in 384-well polystyrene
assay plates (Corning, Corning, N.Y.) at room temperature. After
incubation, the reaction was stopped by adding 60 .mu.L of diluted
binding reagents and was incubated for 3 hours to overnight at room
temperature. The plates were read on an Envision (Perkin Elmer,
Waltham, Massachusetts) for time resolved fluorescence resonance
energy transfer. The data were analyzed with GraphPad Prism (La
Jolla, Calif.).
[0576] Enzyme Inhibition. To check the inhibition profile, 5 pt of
serial diluted compounds were incubated with 5 .mu.L of diluted
PDE10 enzyme (BPS Bioscience, San Diego, Calif.) or tissue
homogenate in a 384-well polystyrene assay plate (Coming, Corning,
N.Y.) for 30 min at room temperature. After incubation, 10 .mu.L of
diluted fluorescein labeled cAMP or cGMP substrate were added and
incubated for 60 min at room temperature. The reaction was stopped
by adding 60 pt of diluted binding reagents and plates were read on
an Envision (Perkin Elmer, Waltham, Massachusetts) for time
resolved fluorescence resonance energy transfer. The data were
analyzed with GraphPad Prism (La Jolla, Calif.).
EXAMPLE B
Apomorphine Induced Deficits in Prepulse Inhibition of the Startle
Response in Rats, and In Vivo Test for Antipsychotic Acticity
[0577] The thought disorders that are characteristic of
schizophrenia may result from an inability to filter, or gate,
sensorimotor information. The ability to gate sensorimotor
information can be tested in many animals as well as in humans. A
test that is commonly used is the reversal of apomorphine-induced
deficits in the prepulse inhibition of the startle response. The
startle response is a reflex to a sudden intense stimulus such as a
burst of noise. In this example, rats can be exposed to a sudden
burst of noise, at a level of 120 db for 40 msec, e.g., the reflex
activity of the rats can be measured. The reflex of the rats to the
burst of noise may be attenuated by preceding the startle stimulus
with a stimulus of lower intensity, at 3 db to 12 db above
background (65 db), which attenuates the startle reflex by 20% to
80%.
[0578] The prepulse inhibition of the startle reflex, described
above, may be attenuated by drugs that affect receptor signaling
pathways in the CNS. One commonly used drug is the dopamine
receptor agonist apomorphine. Administration of apomorphine reduces
the inhibition of the startle reflex produced by the prepulse.
Antipsychotic drugs such as haloperidol prevents apomorphine from
reducing the prepulse inhibition of the startle reflex. This assay
can be used to test the antipsychotic efficacy of PDE10 inhibitors,
as they reduce the apomorphine-induced deficit in the prepulse
inhibition of startle.
EXAMPLE C
Conditioned Avoidance Responding (CAR) in Rats, and In Vivo Test
for Antipsychotic Activity
[0579] Conditioned avoidance responding (CAR) occurs, for instance,
when an animal learns that a tone and light predict the onset of a
mild foot shock. The subject learns that when the tone and light
are on, it must leave the chamber and enter a safe area. All known
antipsychotic drugs reduce this avoidance response at doses which
do not cause sedation. Examining the ability of test compounds to
suppress the conditioned avoidance has been widely used for close
to fifty years to screen for drugs with useful antipsychotic
properties.
[0580] In this example, an animal can be placed in a two-chambered
shuttle box and presented with a neutral conditioned stimulus (CS)
consisting of a light and tone, followed by an aversive
unconditioned stimulus (US) consisting of a mild foot shock through
a floor grid in the shuttle box chamber. The animal can be free to
escape the US by running from one chamber to the other, where the
grid is not electrified. After several presentations of the CS-US
pair, the animal typically learns to leave the chamber during the
presentation of the CS and avoid the US altogether. Animals treated
with clinically-relevant doses of antipsychotic drugs have a
suppression of their rate of avoidances in the presence of the CS
even though their escape response to the shock itself is
unaffected.
[0581] Specifically, conditioned avoidance training can be
conducted using a shuttle box (Med Associates, St. Albans, Vt.).
The shuttle box is typically divided into 2 equal compartments that
each contain a light source, a speaker that emits an 85 dB tone
when activated and an electrified grid that can deliver a scrambled
foot shock. Sessions can consist of 20 trials per day (intertrial
interval of 25-40 sec) during which a 10 sec illumination and a
concurrent 10 sec tone signals the subsequent delivery of a 0.5 mA
shock applied for a maximum of 10 sec. Active avoidance, defined as
the crossing into the opposite compartment during the 10 sec
conditioning stimuli (light and tone) prevents the delivery of the
shock. Crossing over to the other compartment after the delivery of
the shock terminates shock delivery and may be recorded as an
escape response. If an animal does not leave the conditioning
chamber during the delivery of the shock it is recorded as an
escape failure. Training can be continued daily until the avoidance
of 16 or more shocks out of 20 trials (80% avoidance) on 2
consecutive days is achieved. After this criterion is reached the
rats may be given one day of pharmacological testing. On test day,
rats can be randomly assigned to experimental groups, weighed and
injected intraperitoneally (i.p.) (1 cc tuberculin syringe, 26 3/8
gauge needle) or per os (p.o.) (18 gauge feeding needle) with
either control or compound solutions. Compounds can be injected at
1.0m1/kg for i.p. and 10 mL/kg for p.o. administration. Compounds
can be administered either acutely or chronically. For testing,
each rat may be placed in the shuttle box, and given 20 trials with
the same parameters as described above for training trials. The
number of avoidances, escapes, and escape failures can be
recorded.
EXAMPLE D
PCP-Induced Hyperactivity (PCP-LMA)
[0582] Equipment Used: 4.times.8 home cage photobeam activity
system (PAS) frame from San Diego Instruments. Open PAS program and
prepare an experimental session using the following variables:
[0583] Multiphase experiment
[0584] 300 sec/interval (5 min)
[0585] 12 intervals (1 h)
[0586] Individual on screen switches.
[0587] Start recording after first beam break.
[0588] End session after end of interval.
Cage Preparation:
[0589] Techniplast rat cage with filter top, but no wire lid. Place
400 mL bedding and one food pellet in cage and place 250 mL
techniplast water bottle in holder on filter top. Place the prepped
cage in the PAS frame. Make sure bedding or pellet doesn't block
the photobeams.
Animal Preparation:
[0590] Mark rats and record their weights. Bring rats to testing
room.
Phase I: Habituation
[0591] Start the experiment session. Place the rat in the
enclosure. The computer should start recording when it detects the
rat breaking the beam. The computer will record for 1 h. During the
habituation phase, prepare risperidone (positive control): Measure
out risperidone, calculate final volume at 1 mg/mL concentration
and add 1% glacial acetic acid of the final volume to dissolve
risperidone. When risperidone is dissolved, add saline to final
volume to make a concentration of 1 mg/mL. Fill syringes (3 mL
syringes with 23 g1/2 needle or oral gavage needle) with Amgen
compound solution (5 mL/kg) or risperidone (1 mL syringe with 23
g1/2 needle) control (1 mL/kg) s.c.
Phase II: Compound Pre-Treatment
[0592] Make sure Phase I has ended. Remove rat from enclosure,
start the next phase using on-screen individual switch, administer
compound p.o or i.p. and control s.c. and place rat back in the
enclosure. The computer should start recording when it detects the
rat breaking the beam. The computer will record for 1 h.
[0593] During phase II, prepare pcp: Dissolve pcp in saline to a
concentration of 5 mg/mL.
[0594] Fill syringes (1 mL syringes with 26 g3/8 needle) with pcp
solution (1 mL/kg).
Phase III: PCP Administration
[0595] Make sure phase II is ended. Remove rat from enclosure,
start the next phase using on-screen individual switch, administer
pcp s.c. and place rat back in the enclosure. The computer will
record for 1 h.
Clean-Up:
[0596] End-session to terminate experiment and so that computer
will compile data. Export raw data to excel file for data analysis.
Euthanize rats and take necessary tissue/sample for PK.
Data Generation:
[0597] Export raw data to excel file for data analysis. Total time
of movement is recorded as the number of photobeam breaks by the
computer. Total time of movement (seconds) is combined into 5
minute bins and averaged for each treatment group for an N of 7-10
animals. Data are analyzed for statistical significance using a
two-way ANOVA followed by a Bonferroni's post-hoc test for multiple
comparisons.
[0598] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed compounds.
Variations and changes which are obvious to one skilled in the art
are intended to be within the scope and nature of the invention
which are defined in the appended claims. All patents, patent
applications, and other publications recited herein are hereby
incorporated by reference in their entirety.
* * * * *