U.S. patent application number 14/242432 was filed with the patent office on 2014-07-31 for unsaturated nitrogen heterocyclic compounds useful as pde10 inhibitors.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Jennifer R. Allen, Jian J. Chen, Michael J. Frohn, Essa Hu Harrington, Qingyian Liu, Alexander J. Pickrell, Shannon Rumfelt, Robert M. Rzasa, Wenge Zhong.
Application Number | 20140213572 14/242432 |
Document ID | / |
Family ID | 44278966 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140213572 |
Kind Code |
A1 |
Allen; Jennifer R. ; et
al. |
July 31, 2014 |
UNSATURATED NITROGEN HETEROCYCLIC COMPOUNDS USEFUL AS PDE10
INHIBITORS
Abstract
Unsaturated nitrogen heterocyclic compounds of formula (I):
##STR00001## as defined in the specification, 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, Huntington's
Disease, non-insulin dependent diabetes, schizophrenia, bipolar
disorder, obsessive-compulsive disorder, and the like.
Inventors: |
Allen; Jennifer R.; (Newbury
Park, CA) ; Chen; Jian J.; (Camarillo, CA) ;
Frohn; Michael J.; (Thousand Oaks, CA) ; Harrington;
Essa Hu; (Camarillo, CA) ; Liu; Qingyian;
(Camarillo, CA) ; Pickrell; Alexander J.;
(Westlake Village, CA) ; Rumfelt; Shannon;
(Camarillo, CA) ; Rzasa; Robert M.; (Ventura,
CA) ; Zhong; Wenge; (Thousand Oaks, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
44278966 |
Appl. No.: |
14/242432 |
Filed: |
April 1, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13105860 |
May 11, 2011 |
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14242432 |
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61334525 |
May 13, 2010 |
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Current U.S.
Class: |
514/210.18 ;
514/210.2; 514/210.21; 514/255.05; 514/318; 540/544; 540/598;
544/120; 544/356; 544/405; 546/194; 546/270.1; 546/273.4 |
Current CPC
Class: |
C07D 491/056 20130101;
A61P 43/00 20180101; C07D 403/14 20130101; A61P 25/00 20180101;
C07D 491/08 20130101; C07C 53/18 20130101; C07D 405/14 20130101;
A61P 25/16 20180101; C07D 491/107 20130101; A61P 25/24 20180101;
C07D 409/14 20130101; C07D 471/08 20130101; C07D 417/14 20130101;
C07D 513/04 20130101; A61P 3/04 20180101; C07D 413/14 20130101;
A61P 7/12 20180101; C07D 487/10 20130101; C07D 487/08 20130101;
C07D 471/04 20130101; C07D 487/04 20130101; A61P 25/18 20180101;
A61P 3/10 20180101; A61P 25/36 20180101; A61P 25/28 20180101; C07D
401/14 20130101; A61P 25/30 20180101; A61P 25/14 20180101 |
Class at
Publication: |
514/210.18 ;
546/273.4; 546/270.1; 544/405; 514/255.05; 544/356; 546/194;
514/318; 544/120; 540/598; 540/544; 514/210.21; 514/210.2 |
International
Class: |
C07D 403/14 20060101
C07D403/14; C07D 417/14 20060101 C07D417/14; C07D 409/14 20060101
C07D409/14; C07D 413/14 20060101 C07D413/14; C07D 487/08 20060101
C07D487/08; C07D 487/10 20060101 C07D487/10; C07D 405/14 20060101
C07D405/14; C07D 487/04 20060101 C07D487/04; C07D 491/08 20060101
C07D491/08; C07D 401/14 20060101 C07D401/14; C07D 491/107 20060101
C07D491/107 |
Claims
1. A compound of formula I: ##STR02406## or a pharmaceutically
acceptable salt thereof, wherein: X.sup.1 is N or CR.sup.6; X.sup.2
is N or CR.sup.2; X.sup.3 is N or CR.sup.3; X.sup.4 is N or
CR.sup.6; X.sup.5 is N or CR.sup.6; wherein 1 to 2 of X.sup.1,
X.sup.2, X.sup.3, X.sup.4 and X.sup.5 are N; R.sup.1 is halo,
C.sub.1-8alk, C.sub.1-4haloalk, --OR.sup.c,
--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 which are 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; Y is a C.sub.0-4alk, --C(.dbd.O),
SO, or SO.sub.2; each R.sup.2 and R.sup.3 is independently R.sup.1,
H, halo, CN, OH, --OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-4haloalk,
--C.sub.1-6alkOR.sup.a, --C(.dbd.O)C.sub.1-4alk,
--C(.dbd.O)NR.sup.aR.sup.a, --C.sub.0-4alkNH--C(.dbd.O)R.sup.a, or
R.sup.c; or alternatively the ring containing X.sup.1, X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 can be fused to ring A, ring B, or
ring C; each having the formula: ##STR02407## wherein each said
ring A, ring B, or ring C is a fused 4- to 6-membered-saturated,
-partially saturated, or -unsaturated-carbocyclic or -heterocyclic
ring containing 0, 1, 2, or 3 heteroatoms; and is substituted by 0,
1, or 2 R.sup.10 groups; R.sup.4a is H, OH, halo, C.sub.1-4alk, or
C.sub.1-4haloalk; R.sup.4b is halo, CN, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-4haloalk, or oxo; R.sup.5 is
--C.sub.1-6alkOR.sup.a, 5- to 6-membered heteroaryl, unsaturated 9-
to 10-membered bicyclo-heterocyclic ring, or 11- to 15-membered
tricyclo-heterocyclic ring; R.sup.5 ring is substituted by 0, 1, 2,
3, or 4 R.sup.8 groups; R.sup.6 is independently R.sup.1, H, halo,
CN, OH, OC.sub.1-4alk, C.sub.1-4alk or C.sub.1-4haloalk; m is 0, 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 contains 0, 1, or 2 double bonds; 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 substituted by 0,
1, 2 or 3 substituents which are, independently, 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.2;
each L.sup.1 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 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring,
said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms
which are O or S; L.sup.1 is independently substituted by 0, 1, 2
or 3 R.sup.9 groups; each L.sup.2 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 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 N
atoms and 0, 1, or 2 atoms which are O or S; L.sup.2 is
independently substituted by 0, 1, 2 or 3 R.sup.11 groups; R.sup.8
is halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-4haloalk,
OC.sub.1-4haloalk, --C(.dbd.O)R.sup.b, --C(.dbd.O)R.sup.c,
--C(.dbd.O)NHR.sup.b, --C(.dbd.O)NHR.sup.c,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2R.sup.c,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, R.sup.b, R.sup.c, NO.sub.2,
OR.sup.b, or OR.sup.c; R.sup.9 is halo, 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.1-6alkNR.sup.aR.sup.a, --OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, oxo, or R.sup.c; R.sup.10 is oxo,
C.sub.1-6alk, 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 R.sup.11 is halo, 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.1-6alkNR.sup.aR.sup.a, --OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, or oxo.
2. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the group ##STR02408##
##STR02409##
3. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the group ##STR02410##
##STR02411##
4. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein each of said Ring A, Ring B, and
Ring C is a fused 4- to 6-membered-saturated, -partially saturated,
or -unsaturated-carbocyclic which are fused phenyl, cyclobutyl,
cyclopentyl, or cyclohexyl; said Ring A, Ring B, and Ring C is
substituted by 0, 1, or 2 R.sup.10 groups which are oxo,
C.sub.1-6alk, 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.
5. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein each of said Ring A, Ring B, and
Ring C is a fused 5-membered-saturated, -partially saturated, or
-unsaturated-heterocyclic ring which are fused furanyl, thiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl,
thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, or isothiazolyl;
said Ring A, Ring B, and Ring C is substituted by 0, 1, or 2
R.sup.10 groups which are oxo, C.sub.1-6alk, 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.
6. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein each of said Ring A, Ring B, and
Ring C is a fused 6-membered-saturated, -partially saturated, or
-unsaturated-heterocyclic ring which are fused pyranyl, pyridinyl,
piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,
pyridazinyl, pyrazinyl, or piperazinyl; said Ring A, Ring B, and
Ring C is substituted by 0, 1, or 2 R.sup.10 groups which are oxo,
C.sub.1-6alk, 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.
7. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein each of p and q is independently
1.
8. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein each of p and q is independently
2.
9. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein the ring containing p and q
contains 0 or 1 double bond.
10. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the sum of p and q is 3; and the
ring containing p and q contains 0 or 1 double bond.
11. The compound according to claim 9, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4b is oxo and m is 1.
12. The compound according to claim 11, or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 is unsaturated 10-membered
bicyclo-heterocyclic ring; wherein each R.sup.5 ring is substituted
by 0, 1, or 2 R.sup.8 groups.
13. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the group ##STR02412## wherein
each ##STR02413## is substituted by 0, 1, or 2 R.sup.10 groups.
14. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein m is 1 or 2.
15. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is --NR.sup.aR.sup.c,
--OR.sup.c or --C.sub.0-4alk-L.sup.1.
16. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is a
carbon-linked-saturated or partially-saturated 3-, 4-, 5-, 6-, or
7-membered monocyclic ring, wherein each said ring contains 0, 1,
or 2 N atoms and 0 or 1 O atoms, and wherein each said L.sup.1 is
substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl, Br,
C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
17. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is a
carbon-linked-saturated or partially-saturated 5- to 6-membered
monocyclic ring, wherein each said ring contains 0, 1, or 2 N atoms
and 0 or 1 O atoms, and wherein each said L.sup.1 is substituted by
0, 1 or 2 R.sup.9 groups which are F, Cl, Br, C.sub.1-6alk,
--OR.sup.a, CN, --C(.dbd.O)R.sup.b, C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
18. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is a
carbon-linked-unsaturated 5- to 6-membered monocyclic ring, wherein
each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and
wherein each said L.sup.1 is substituted by 0, 1 or 2 R.sup.9
groups which are F, Cl, Br, C.sub.1-6alk, --OR.sup.a, CN,
--C(.dbd.O)R.sup.b, C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--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, --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, oxo, or R.sup.c.
19. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is a
carbon-linked-saturated, partially-saturated or unsaturated 6-, 7-,
8-, 9-, or 10-membered bicyclic ring, wherein each said ring
contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and wherein each
said L.sup.1 is substituted by 0, 1 or 2 R.sup.9 groups which are
F, Cl, Br, C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
20. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is a nitrogen-linked
saturated, partially-saturated or unsaturated 4-, 5-, 6-, or
7-membered monocyclic ring, wherein said ring contains 0, 1, 2, 3,
or 4 N atoms and 0 or 1 O atoms, and wherein each said L.sup.1 is
substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl, Br,
C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
21. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is a nitrogen-linked
saturated, partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-,
11-, or 12-membered bicyclic ring, wherein each said ring contains
0, 1, or 2 N atoms and 0 or 1 O atoms, and wherein each said
L.sup.1 is substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl,
Br, C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
22. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein L.sup.1 is
-3-azabicyclo[3.1.0]hexanyl, azetidinyl, indolyl, phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, piperazinonyl,
piperidinyl, pyrrolidinyl, dihydropyranyl, tetrahydropyridinyl,
octahydropyrrolo[3,4-c]pyrrolyl, tetrahydroisoquinolinyl, each of
which is substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl,
Br, C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
23. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is: Cl; Br;
--C.ident.C--CH.sub.3; --NH--CH(CH.sub.3).sub.2;
--NHCH.sub.2CH.sub.2OCH.sub.3; --NHCH.sub.2CH.sub.2OH; ##STR02414##
##STR02415## ##STR02416## ##STR02417## ##STR02418## ##STR02419##
##STR02420## ##STR02421## ##STR02422## ##STR02423## ##STR02424##
##STR02425## ##STR02426##
24. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is ##STR02427##
##STR02428## ##STR02429## ##STR02430## ##STR02431##
##STR02432##
25. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is: ##STR02433##
##STR02434## ##STR02435##
26. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein each R.sup.2 and R.sup.3 is
independently H, F, Cl, Br, CN, OH, OC.sub.1-4alk, C.sub.1-4alk or
C.sub.1-4haloalk.
27. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.6 is H, F, or
C.sub.1-4alk.
28. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4a is H, F, OH, or
methyl.
29. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4b is oxo and m is 1.
30. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4a is H and m is 0.
31. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 is pyridinyl.
32. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 is unsaturated 9- to
10-membered bicyclo-heterocyclic ring.
33. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 is 11- to 15-membered
tricyclo-heterocyclic ring.
34. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the group --Y--R.sup.5 is:
##STR02436## ##STR02437## ##STR02438## wherein each R.sup.5 is
substituted by 1 or 2 R.sup.8 groups.
35. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the group --Y--R.sup.5 is:
##STR02439## wherein each R.sup.5 is substituted by 1 or 2 R.sup.8
groups.
36. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein the group --Y--R.sup.5 is:
##STR02440## ##STR02441##
37. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is a bond or --C(.dbd.O).
38. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is a bond.
39. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.8 is independently F, Br,
Cl, CF.sub.3, methyl, methoxy, or CN.
40. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, 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.
41. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.c is a
C.sub.0-4alk-carbon-linked saturated, partially-saturated or
unsaturated 3-, 4-5-, or 6-membered monocyclic ring containing 0,
1, or 2 N atoms and 0 or 1 atom which are O or S, each R.sup.c is
substituted by 0 or 1 R.sup.11 groups which are independently F,
C.sub.1-6alk, C.sub.1-4haloalk, or --OR.sup.a.
42. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.c is pyridyl, phenyl, or
1,2,4-oxadiazolyl.
43. A compound of formula II: ##STR02442## or a pharmaceutically
acceptable salt thereof, wherein: Ring D is -L.sup.1; X.sup.1 is N
or CR.sup.6; X.sup.2 is N or CR.sup.2; X.sup.3 is N or CR.sup.3;
X.sup.4 is N or CR.sup.6; wherein 1 to 2 of X.sup.1, X.sup.2,
X.sup.3, and X.sup.4 are N; Y is a C.sub.0-4alk, --C(.dbd.O), SO,
or SO.sub.2; each R.sup.2 and R.sup.3 is independently H, halo, CN,
OH, --OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-4haloalk,
--C.sub.1-6alkOR.sup.a, --C(.dbd.O)C.sub.1-4alk,
--C(.dbd.O)NR.sup.aR.sup.a, --C.sub.0-4alkNH--C(.dbd.O)R.sup.a, or
R.sup.c; or alternatively the ring containing X.sup.1, X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 can be fused to ring A, ring B, or
ring C; having the formula: ##STR02443## wherein each said ring A,
ring B, or ring C is a fused 4- to 6-membered-saturated, -partially
saturated, or -unsaturated-carbocyclic or -heterocyclic ring
containing 0, 1, 2, or 3 heteroatoms; and is substituted by 0, 1,
or 2 R.sup.10 groups; R.sup.4a is H, OH, halo, C.sub.1-4alk, or
C.sub.1-4haloalk; R.sup.4b is halo, CN, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-4haloalk, or oxo; R.sup.5 is pyridinyl or
unsaturated 9- to 10-membered bicyclo-heterocyclic ring; wherein
each R.sup.5 is substituted by 0, 1, 2 or 3 R.sup.8 groups; R.sup.6
is independently H, halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk or
C.sub.1-4haloalk; m is 0, 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 contains 0, 1, or 2 double
bonds; 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, or C.sub.1-6alk substituted by 0, 1, 2 or 3 substituents
which are, independently, 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.2; each L.sup.1 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 6-, 7-, 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 which are O or S;
wherein each L.sup.1 is independently substituted by 0, 1, 2 or 3
R.sup.9 groups; each L.sup.2 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 6-, 7-, 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 which are O or S; wherein each
L.sup.2 is independently substituted by 0, 1, 2 or 3 R.sup.11
groups; R.sup.8 is halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-4haloalk, OC.sub.1-4haloalk, --C(.dbd.O)R.sup.b,
--C(.dbd.O)R.sup.c, --C(.dbd.O)NHR.sup.b, --C(.dbd.O)NHR.sup.c,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2R.sup.c,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, R.sup.b, R.sup.c, NO.sub.2,
OR.sup.b, or OR.sup.c; R.sup.9 is 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.1-6alkNR.sup.aR.sup.a, --OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, oxo, or R.sup.c; R.sup.10 is oxo,
C.sub.1-6alk, 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 R.sup.11 is 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.1-6alkNR.sup.aR.sup.a, --OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, or oxo.
44. The compound according to claim 43, wherein the group
##STR02444## is azetidinyl, pyrrolidinyl, piperidinyl, or
azepanyl.
45. The compound according to claim 43, having the formula:
##STR02445##
46. The compound according to claim 43, having the formula:
##STR02446##
47. The compound according to claim 43, having the formula:
##STR02447##
48. The compound according to claim 47, wherein R.sup.4b is OXO; m
is 1; and R.sup.5 is unsaturated 10-membered bicyclo-heterocyclic
ring; wherein each R.sup.5 ring is substituted by 0, 1, or 2
R.sup.8 groups.
49. The compound according to claim 47, having the formula:
##STR02448## wherein m is 0; and R.sup.5 is unsaturated 10-membered
bicyclo-heterocyclic ring; wherein each R.sup.5 ring is substituted
by 0, 1, or 2 R.sup.8 groups.
50. The compound according to claim 45, wherein the group
--Y--R.sup.5 is: ##STR02449## Y is a bond; wherein each R.sup.5 is
substituted by 1 or 2 R.sup.8 groups; and R.sup.8 is independently
F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF.sub.3, OH, or
OCF.sub.3.
51. The compound according to claim 46, wherein the group
--Y--R.sup.5 is: ##STR02450## Y is a bond; wherein each R.sup.5 is
substituted by 1 or 2 R.sup.8 groups; and R.sup.8 is independently
F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF.sub.3, OH, or
OCF.sub.3.
52. The compound according to claim 47, wherein the group
--Y--R.sup.5 is: ##STR02451## Y is a bond; wherein each R.sup.5 is
substituted by 1 or 2 R.sup.8 groups; and R.sup.8 is independently
F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF.sub.3, OH, or
OCF.sub.3.
53. The compound according to claim 48, wherein the group
--Y--R.sup.5 is: ##STR02452## Y is a bond; wherein each R.sup.5 is
substituted by 1 or 2 R.sup.8 groups; and R.sup.8 is independently
F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF.sub.3, OH, or
OCF.sub.3.
54. 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 a compound
according to claim 1, or a pharmaceutically acceptable salt
thereof.
55. The method according to claim 54 wherein said condition 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.
56. 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 a compound
according to claim 43, or a pharmaceutically acceptable salt
thereof.
57. The method according to claim 56 wherein said condition is
schizophrenia, Huntington disease, obesity, bipolar disorder, or
obsessive-compulsive disorder.
58. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
59. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, which is:
(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methano-
ne;
(1H-Benzoimidazol-2-yl)-[3-(5-fluoro-3-phenyl-pyridin-2-yl)-azetidin-1-
-yl]-methanone;
(1H-benzoimidazol-2-yl)-[4-(3-phenyl-pyrazin-2-yl)-piperidin-1-yl]-methan-
one;
Benzothiazol-2-yl-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone-
;
(1H-Benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidin-1-
-yl]-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-quinoxalin-2-yl]-
-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-[3-(2,3-dihydro-indol-1-yl)-3',4',5',6'-tetrahydr-
o-2'H-[2,4']bipyridinyl-1'-yl]-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-quinolin-2-yl)-azetidin-1-yl]-methan-
one;
(1H-Benzoimidazol-2-yl)-(3-phenyl-3',4',5',6'-tetrahydro-2'H-[2,4']bi-
pyridinyl-1'-yl)-methanone;
(1H-Benzoimidazol-2-yl)-{4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2--
yl]-piperidin-1-yl}-methanone;
(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)(pyridin-2-yl)methanone;
(6-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;
(3-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;
(5-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;
(4-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-quinoxalin-2-yl)-azetidin-1-yl]-meth-
anone;
(1H-Benzoimidazol-2-yl)-[3-(3-morpholin-4-yl-pyrazin-2-yl)-azetidin-
-1-yl]-methanone;
(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-b-
enzoimidazol-2-yl]-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methano-
ne;
(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-dimethoxy-phenyl)-pyrazin-2-yl]-aze-
tidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-isopropyl-phenyl)-pyrazin-2-yl]-azetidin-
-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-trifluoromethoxy-phenyl)-pyrazin-2-yl]-a-
zetidin-1-yl}-methanone;
1H-Benzoimidazol-2-yl)-{3-[3-(3,5-dimethoxy-phenyl)-pyrazin-2-yl]-azetidi-
n-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-ethoxy-phenyl)-pyrazin-2-yl]-azetidin-1--
yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-isopropoxy-phenyl)-pyrazin-2-yl]-azetidi-
n-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-5-methoxy-phenyl)-pyrazin-2-yl]-a-
zetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(2-methoxy-pyridin-4-yl)-pyrazin-2-yl]-azet-
idin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(5-methoxy-pyridin-3-yl)-pyrazin-2-yl]-azet-
idin-1-yl}-methanone;
(1H-benzo[d]imidazol-2-yl)(3-(3-(4-fluoro-3-methylphenyl)pyrazin-2-yl)aze-
tidin-1-yl)methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxy-3-methyl-phenyl)-pyrazin-2-yl]-a-
zetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-5-methyl-phenyl)-pyrazin-2-yl]-az-
etidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(5-methyl-pyridin-3-yl)-pyrazin-2-yl]-azeti-
din-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-thiophen-2-yl)-pyrazin-2-yl]-azet-
idin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(1-methyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-az-
etidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-phenyl)-pyrazin-2-yl]-azet-
idin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxymethyl-phenyl)-pyrazin-2-yl]-azet-
idin-1-yl}-methanone;
1-(4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-ph-
enyl)-ethanone;
1-(3-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-ph-
enyl)-ethanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-methoxymethyl-phenyl)-pyrazin-2-yl]-azet-
idin-1-yl}-methanone;
4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N-d-
imethyl-benzamide;
3-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N-d-
imethyl-benzamide;
(1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)-
methanone;
(7-chloro-1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-3-yl)pyrazin--
2-yl)azetidin-1-yl)methanone;
(1H-benzo[d]imidazol-2-yl)(3-(3-(2-methylpyridin-4-yl)pyrazin-2-yl)azetid-
in-1-yl)methanone;
(1H-benzo[d]imidazol-2-yl)(3-(3-(m-tolyl)pyrazin-2-yl)azetidin-1-yl)metha-
none;
3-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)pyrazin-2-yl)-
benzonitrile
(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azeti-
din-1-yl]-methanone;
{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-(1-methyl-1-
H-benzoimidazol-2-yl)-methanone;
[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-eth-
yl)-1H-benzoimidazol-2-yl]-methanone;
{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-[1-(2,2,2-t-
rifluoro-ethyl)-1H-benzoimidazol-2-yl]-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-pyrrolidin-1-yl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-trifluoromethyl-piperidin-1-yl)-pyrazin--
2-yl]-azetidin-1-yl}-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-methyl-piperidin-1-yl)-pyrazin-2-yl]--
azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-piperidin-1-yl)-pyrazin-2-yl]-aze-
tidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-piperidin-1-yl)-pyrazin-2-yl]-aze-
tidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-dimethyl-piperidin-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2--
yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-y-
l]-pyrazin-2-yl}-azetidin-1-yl)-methanone;
(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-y-
l]-pyrazin-2-yl}-azetidin-1-yl)-methanone;
1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idine-4-carbonitrile;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxymethyl-piperidin-1-yl)-pyrazin-2--
yl]-azetidin-1-yl}-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-pyrazin-2-
-yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(1,3-dihydro-isoindol-2-yl)-pyrazin-2-yl]-a-
zetidin-1-yl}-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-cyclopentylamino-pyrazin-2-yl)-azetidin-1-y-
l]-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-cyclohexylamino-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-benzylamino-pyrazin-2-yl)-azetidin-1-yl]-me-
thanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxy-ethylamino)-pyrazin-2-yl-
]-azetidin-1-yl}-methanone;
(1H-benzo[d]imidazol-2-yl)(3-(3-((2-methoxyethyl)amino)pyrazin-2-yl)azeti-
din-1-yl)methanone;
1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idine-4-carboxylic acid amide; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-piperidin-1-yl)-pyrazin-
-2-yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-az-
etidin-1-yl}-methanone;
[3-(3-Azepan-1-yl-pyrazin-2-yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)-me-
thanone;
[3-(3-Azetidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-(1H-benzoimidazo-
l-2-yl)-methanone;
(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyraz-
in-2-yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-isopropylamino-pyrazin-2-yl)-azetidin-1-yl]-
-methanone;
(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyraz-
in-2-yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-(3-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-pyrazi-
n-2-yl}-azetidin-1-yl)-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-[1,4]oxazepan-4-yl-pyrazin-2-yl)-azetidin-1-
-yl]-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-[1,4]diazepan-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone;
1-(4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-[1-
,4]diazepan-1-yl)-ethanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-azepan-1-yl)-pyrazin-2-yl]-azeti-
din-1-yl}-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-pyrrolidin-1-yl)-pyrazi-
n-2-yl]-azetidin-1-yl}-methanone;
(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl-
]-azetidin-1-yl}-methanone;
(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl-
]-azetidin-1-yl}-methanone; (R &
S)-1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-pi-
peridine-3-carbonitrile;
1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idine-4-carboxylic acid methylamide;
1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idine-4-carboxylic acid dimethylamide;
1-(1-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)pyrazin-2-yl)pi-
peridin-4-yl)ethanone;
1-(4-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)pyrazin-2-yl)pi-
perazin-1-yl)ethanone;
(R)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-y-
l)azetidin-1-yl)methanone;
(S)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-y-
l)azetidin-1-yl)methanone;
(1H-benzo[d]imidazol-2-yl)(3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidin-1-y-
l)methanone;
(1H-benzo[d]imidazol-2-yl)(3-(3-(4-hydroxypiperidin-1-yl)pyrazin-2-yl)aze-
tidin-1-yl)methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-7-aza-spiro[3.5]non-7-yl)-pyrazin-2--
yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyrazin-2-
-yl]-azetidin-1-yl}-methanone;
1-(6-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-2,-
6-diaza-spiro[3.3]hept-2-yl)-ethanone;
2-(3-(3-(2-methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(6-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(2-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(6-fluoropyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quino-
line;
2-(3-(3-(2,6-dimethoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinol-
ine;
2-(3-(3-(5-fluoropyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(6-methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2--
trifluoroacetate;
2-(3-(3-(6-fluoro-5-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoli-
ne2,2,2-trifluoroacetate;
2-(3-(3-(pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoro-
acetate;
2-(3-(3-(4-(methylsulfonyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quin-
oline2,2,2-trifluoroacetate;
5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyridin-2-amine;
5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyridin-3-amine;
2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(2-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quino-
line2,2,2-trifluoroacetate;
N,N-dimethyl-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrimidin--
2-amine2,2,2-trifluoroacetate;
2-(3-(3-(4-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-t-
rifluoroacetate;
2-(3-(3-(5-(methylsulfonyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinol-
ine2,2,2-trifluoroacetate;
2-(3-(3-(5-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-t-
rifluoroacetate;
2-(3-(3-(5-methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2--
trifluoroacetate;
2-(3-(3-(4-chloro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-chloro-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenol;
2-(3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)q-
uinoline;
2-(3-(3-(4-ethoxy-3-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quin-
oline;
2-(3-(3-(3-chloro-4-ethoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoli-
ne;
2-(3-(3-(3-chloro-4-propoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline-
;
2-(3-(3-(3-fluoro-5-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)q-
uinoline;
2-(3-(3-(4-methoxy-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)qui-
noline;
2-(3-(3-(3-fluoro-5-isopropoxyphenyl)pyrazin-2-yl)azetidin-1-yl)qu-
inoline;
2-(3-(3-(3-fluoro-5-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quino-
line;
2-(3-(3-(3-chloro-4-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinolin-
e;
2-(3-(3-(3,4-difluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3,4-dichlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3,4-dimethylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-chloro-4-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-chloro-5-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-fluoro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(pyrimidin-5-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-chloro-3-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)qu-
inoline;
2-(3-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-yl)qui-
noline;
2-(3-(3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azeti-
din-1-yl)quinoline;
2-(3-(3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-y-
l)quinoline;
2-(3-(3-(1H-pyrazol-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-fluoro-5-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)qu-
inoline;
2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2-yl)azetidin-1-yl)quinoli-
ne; 2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(2-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(pyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;
methyl 3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate;
ethyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate;
2-(3-(3-(2-methoxypyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(2-fluoropyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-(methylthio)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;
2-(3-(3-(4-phenoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-fluoro-4-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)aniline;
N-methyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;
tert-butyl
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(-
2H)-carboxylate;
2-(3-(3-([1,1'-biphenyl]-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;
2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;
N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;
2-(3-(3-(2-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-ethoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
1-(3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;
(3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanol;
2-(3-(3-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-(benzyloxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
N-cyclopropyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide-
;
N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzenesu-
lfonamide;
2-(3-(3-(4-ethoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanol;
2-(3-(3-(4-propylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-ethylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
N,N-dimethyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)aniline;
2-(3-(3-(4-(trifluoromethoxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-isopropoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-methyl-2-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)prop-
anenitrile;
4-((4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)sulfonyl)mor-
pholine;
2-(3-(3-(4-(piperidin-1-ylsulfonyl)phenyl)pyrazin-2-yl)azetidin-1-
-yl)quinoline; (R-- &
S--)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)-
quinoline; (R-- &
S--)-2-(3-(3-(3-phenethylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quino-
line; (R-- &
S--)-2-(3-(3-(3-benzylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinolin-
e;
(R)--N,N-dimethyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyr-
rolidin-3-amine; (R-- & S--)-tert-butyl
methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)-
carbamate; (R-- &
S--)-N,N-dimethyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrro-
lidin-3-amine;
2-(3-(3-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoli-
ne; (R-- &
S--)-2-(3-(3-(3-(phenylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)az-
etidin-1-yl)quinoline; (R-- &
S--)-3-methyl-5-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrol-
idin-3-yl)-1,2,4-oxadiazole;
(R)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-ol;
(R-- &
S--)-2-(3-(3-(3-(pyridin-4-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidi-
n-1-yl)quinoline;
2-(3-(3-(pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
(3aR,6aS)-tert-butyl
5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]-
pyrrole-2(1H)-carboxylate; tert-butyl
5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]-
pyrrole-2(1H)-carboxylate; tert-butyl
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carbox-
ylate;
(R)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-
-yl)methanol; (R-- &
S--)-2-(3-(3-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-y-
l)quinoline;
(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)me-
thanol; (R)-tert-butyl
1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-ylcarbamat-
e;
(S)-2-(3-(3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoli-
ne;
2-(3-(3-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinol-
ine;
2-(3-(3-(4-isopropyl-1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)qui-
noline;
(1R,5R)-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-3-azabi-
cyclo[3.2.2]nonane;
2-(3-(3-(azepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]non-
ane;
1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepan-1--
yl)ethanone; (R-- &
S--)-2-(3-(3-(3-phenylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinolin-
e;
(3S,4S)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidine-3-
,4-diol;
N-(4-methoxybenzyl)-3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-a-
mine;
(1R,4R)-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-2-oxa-5-a-
zabicyclo[2.2.1]heptanes; (R-- &
S--)-2-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl-
)thiazole;
(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolid-
in-2-yl)methanol;
((2S,4S)-4-fluoro-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrro-
lidin-2-yl)methanol;
(R)-2-(3-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)-
quinoline;
2-(3-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrazin-2-yl)aze-
tidin-1-yl)quinoline; (R-- &
S--)-2-(3-(3-(3-isobutylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinol-
ine;
2-(3-(3-(3,3-dimethylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quino-
line; (R-- &
S--)-2-(3-(3-(3-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl-
)quinoline;
2-(3-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)qui-
noline;
1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-car-
bonitrile;
2-(3-(3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)-
quinoline;
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)morpholine;
2-(3-(3-(4-fluoropiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3-methoxyazetidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(3-(3-(3,3-difluoroazetidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
4-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-ol-
;
1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-pyrazole-4-carboni-
trile
2-(3-(3-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoli-
ne; tert-butyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)azetidin-3-yl)carbamat-
e;
2,2-dimethyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)morpholi-
ne;
2-(3-(3-(4-methyl-1H-imidazol-1-yl)pyrazin-2-yl)azetidin-1-yl)quinolin-
e;
1-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbon-
itrile;
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-pyrazol-4-y-
l)methanol;
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-imidazol-4-yl)meth-
anol;
1-methyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperazin-
-2-one;
N-(2,6-dimethylphenyl)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazi-
n-2-yl)piperidine-3-carboxamide; (S)-tert-butyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-3-yl)carbama-
te;
(4-(cyclopropylmethyl)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2--
yl)piperidin-4-yl)methanol;
2-(3-(3-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazin-2-yl)-
azetidin-1-yl)quinoline;
1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine;
(R-- & S--)-methyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbam-
ate; (R-- &
S--)--N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-y-
l)methanesulfonamide; (R-- & S--)-ethyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbam-
ate; (R-- &
S--)-2-methoxy-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrro-
lidin-3-yl)acetamide;
2-(3-(3-(1,4-Diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
Methyl
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carbox-
ylate; methyl
methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)-
carbamate;
N-methyl-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)p-
yrrolidin-3-yl)methanesulfonamide; Ethyl
methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)-
carbamate;
2-(3-(3-(4-chlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
2-(3-(3-(3-chlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
2-(3-(3-(2-chlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
2-(3-(3-(o-tolyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
1-(4-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;
1-(3-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;
N-(3-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)acetamide;
N-(4-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanesulf-
onamide;
N-(3-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)met-
hanesulfonamide;
2-(3-(3-(1H-indol-6-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
2-(3-(3-(1-methyl-1H-indol-5-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
2-(3-(3-(1-methyl-1H-indol-6-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-one;
1-methyl-5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-on-
e;
1-methyl-6-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-benzo[-
d]imidazol-2(3H)-one;
2-fluoro-4-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)aniline;
2-(3-(3-(p-tolyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;
2-methyl-6-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)isoquinolin--
1(2H)-one;
2-(3-(3-(1H-indazol-5-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline- ;
5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzo[d]thiazole;
(R &
S)-(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-
-yl}-azetidin-1-yl)-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-(3-{3-[3-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-y-
l}-azetidin-1-yl)-methanone; (R &
S)-(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-pyr-
azin-2-yl}-azetidin-1-yl)-methanone;
1-(4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-pi-
peridin-1-yl)-ethanone;
1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idin-4-one;
(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-difluoro-piperidin-1-yl)-pyrazin-2-yl]-
-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin-
-2-yl]-azetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-[3-(5-phenyl-pyrimidin-4-yl)-azetidin-1-yl]-metha-
none; 2-(3-(3-(prop-1-yn-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoline;
2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinazoline;
2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoxaline;
2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-benzothiazole;
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline;
2-{3-[3-(3-Methoxy-phenyl)-pyridin-2-yl]-azetidin-1-yl}-quinoline;
2-[3-(3-m-Tolyl-pyridin-2-yl)-azetidin-1-yl]-quinoline; (R &
S)-2-{3-[3-(3-Methyl-pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinol-
ine;
4-Methyl-2'-(1-quinolin-2-yl-azetidin-3-yl)-3,4,5,6-tetrahydro-2H-[1,-
3']bipyridinyl;
{1-[3-(1-Quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-meth-
anol;
{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}--
methanol;
{1-[3-(1-Quinazolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin--
4-yl}-methanol;
4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;
{1-[3-(1-Benzothiazol-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-m-
ethanol;
{1-[3-(1-Benzooxazol-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin--
4-yl-methanol;
(1-{3-[1-(5-Methyl-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-
-yl)-quinoline;
2-(4-benzylpiperidin-1-yl)-3-(1-(quinolin-2-yl)azetidin-3-yl)quinoxaline;
[5'-Fluoro-2'-(1-quinolin-2-yl-azetidin-3-yl)-3,4,5,6-tetrahydro-2H-[1,3'-
]bipyridinyl-4-yl]-quinoline;
{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyridazin-4-yl]-piperidin-4-yl}-qui-
noline; (R &
S)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
(S or
R)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quin-
oline; (R or
S)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;
2-(1-Quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline;
4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-quinoxalin-2-yl]-phenylamine;
3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-quinoxalin-2-yl]-phenol;
2-(3-Methoxy-phenyl)-3-(1-quinolin-2-yl-azetidin-3-yl)-quinoxaline;
2-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol;
3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol;
4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol;
2-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;
3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;
4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;
2-{3-[3-(4-Fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinolin-
e;
2-Fluoro-4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine
2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline;
2-{3-[3-(4-Methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxyli-
c acid amide;
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxyli-
c acid dimethylamide;
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxyli-
c acid methylamide;
1-[3'-(1-Quinolin-2-yl-azetidin-3-yl)-2,3,5,6-tetrahydro-[1,2']bipyraziny-
l-4-yl]-ethanone;
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-ol;
2-Methoxy-1-{4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-
-1-yl}-ethanone;
1-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-1-yl}-eth-
anone;
N-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenyl}-aceta-
mide;
1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyr-
idin-1(2H)-yl)ethanone; (R &
S)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}--
ethanol; (R or S, absolute stereospecificity not
determined)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperid-
in-4-yl}-ethanol; (S or R, absolute stereospecificity not
determined)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperid-
in-4-yl}-ethanol;
2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenol;
(1-{3-[1-(6-Methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin--
4-yl)-quinoline;
(1-{3-[1-(7-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin--
4-yl)-quinoline;
(1-{3-[1-(6-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin--
4-yl)-quinoline;
{1-[3-(1-[1,8]Naphthyridin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4--
yl}-quinoline;
(1-{3-[1-(6-Chloro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin--
4-yl)-quinoline;
(1-{3-[1-(6-Chloro-quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidi-
n-4-yl)-quinoline;
(1-{3-[1-(6-Methyl-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-
-yl)-quinoline;
(1-{3-[1-(5-Chloro-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-
-yl)-quinoline;
(1-(3-(1-(5-bromopyridin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)q-
uinoline;
(1-(3-(1-(8-methylquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piper-
idin-4-yl)quinoline;
(1-{3-[1-(8-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin--
4-yl)-quinoline;
(1-(3-(1-(8-chloroquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl-
)quinoline;
(1-{3-[1-(8-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidi-
n-4-yl)-quinoline;
(1-{3-[1-(7-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidi-
n-4-yl)-quinoline;
(1-{3-[1-(6-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidi-
n-4-yl)-quinoline;
(1-{3-[1-(5-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidi-
n-4-yl)-quinoline;
(1-{3-[1-(7-Chloro-quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidi-
n-4-yl)-quinoline;
2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-benzothiazole;
2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)-8-methylquinoline;
6-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazol-
ine
8-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quino-
line;
7-Fluoro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-qui-
noline;
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-6-methyl-q-
uinoline;
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-[1,8]nap-
hthyridine;
8-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazol-
ine;
5-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quin-
azoline;
2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)-4-phenylpyri-
midine;
2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazo-
le;
6-methoxy-2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]-
thiazole;
2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)-1,6-naphthy-
ridine;
6-chloro-2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quino-
line;
6-fluoro-2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d-
]thiazole;
2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;
-3-carbonitrile;
1-[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1-yl]-phthalazine;
6-chloro-2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)-1H-benzo[d]imidazole;
2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)-1H-benzo[d]imidazole;
2-((3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methyl)-1H-benzo[d]imidazole;
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;
2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;
2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;
2-(3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propan-2-ol;
2-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propan-2-ol;
2-(3-(3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinol-
ine; lithium
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate; (S or
R)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-
-yl)quinoline; (R or
S)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)qu-
inoline;
(1H-Benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenoxy)-pyrazin-2-yl]-a-
zetidin-1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(3-methoxy-phenoxy)-pyrazin-2-yl]-azetidin--
1-yl}-methanone;
(1H-benzoimidazol-2-yl)-{3-[3-(4-methoxy-phenoxy)-pyrazin-2-yl]-azetidin--
1-yl}-methanone;
(1H-Benzoimidazol-2-yl)-[3-(3-phenoxy-pyrazin-2-yl)-azetidin-1-yl]-methan-
one;
(1H-benzoimidazol-2-yl)-{3-[3-(tetrahydro-pyran-4-yl)-pyrazin-2-yl]-a-
zetidin-1-yl}-methanone;
(7-Chloro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(6-Chloro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(7-Fluoro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(6-Fluoro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl-
]-methanone;
(1H-benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-
-yl}-methanone;
(1H-benzoimidazol-2-yl)-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-
-yl}-methanone;
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-
-yl}-methanone;
(1H-benzoimidazol-2-yl)-[3-(2-phenyl-pyridin-3-yl)-azetidin-1-yl]-methano-
ne; or
2-(3-(3-(1H-indol-5-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 13/105,860, filed May 11, 2011, which claims
the benefit of U.S. Provisional Application No. 61/334,525, filed
May 13, 2010, which are hereby incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] Provided herein are certain unsaturated nitrogen
heterocyclic 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, Huntington's disease, 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 (PDE1-PDE11) 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 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 unsaturated
nitrogen heterocyclic 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
unsaturated nitrogen heterocyclic 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:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein m, p, q,
R.sup.1, R.sup.4a, R.sup.4b, R.sup.5, Y, X.sup.1, X.sup.2, X.sup.3,
X.sup.4, and X.sup.5 are defined below.
[0014] The compounds of the invention are represented by the
following general structure:
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein m, p, q,
R.sup.4a, R.sup.4b, R.sup.5, Y, X.sup.1, X.sup.2, X.sup.3, and
X.sup.4 are defined below.
[0015] The compounds of the invention are represented by the
following general structure:
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein m, p, q,
R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, Y, and
X.sup.1 are defined below.
[0016] Other compounds of the invention are represented by the
following general structure:
##STR00005##
or a pharmaceutically acceptable salt thereof, wherein m, p, q,
Ring D, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, Y, and
X.sup.1 are defined below.
DETAILED DESCRIPTION OF THE INVENTION
[0017] One aspect of the current invention relates to compounds
having the general structure of formula (I):
##STR00006##
or a pharmaceutically acceptable salt thereof, wherein:
[0018] X.sup.1 is N or CR.sup.6;
[0019] X.sup.2 is N or CR.sup.2;
[0020] X.sup.3 is N or CR.sup.3;
[0021] X.sup.4 is N or CR.sup.6;
[0022] X.sup.5 is N or CR.sup.6;
wherein 1 to 2 of X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5
are N;
[0023] R.sup.1 is halo, C.sub.1-8alk, C.sub.1-4haloalk, --OR.sup.c,
--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 which are 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;
[0024] Y is a C.sub.0-4alk, --C(.dbd.O), SO, or SO.sub.2;
[0025] each R.sup.2 and R.sup.3 is independently R.sup.1, H, halo,
CN, OH, --OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-4haloalk,
--C.sub.1-6alkOR.sup.a, --C(.dbd.O)C.sub.1-4alk,
--C(.dbd.O)NR.sup.aR.sup.a, --C.sub.0-4alkNH--C(.dbd.O)R.sup.a, or
R.sup.c;
[0026] or alternatively the ring containing X.sup.1, X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 can be fused to ring A, ring B, or
ring C; having the formula:
##STR00007##
wherein said ring A, ring B, or ring C is a fused 4- to
6-membered-saturated, -partially saturated, or
-unsaturated-carbocyclic or -heterocyclic ring containing 0, 1, 2,
or 3 heteroatoms; and is substituted by 0, 1, or 2 R.sup.10
groups;
[0027] R.sup.4a is H, OH, halo, C.sub.1-4alk, or
C.sub.1-4haloalk;
[0028] R.sup.4b is halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-4haloalk, or oxo;
[0029] R.sup.5 is --C.sub.1-6alkOR.sup.a, 5- to 6-membered
heteroaryl, unsaturated 9- to 10-membered bicyclo-heterocyclic
ring, or 11- to 15-membered tricyclo-heterocyclic ring; R.sup.5
ring is substituted by 0, 1, 2, 3, or 4 R.sup.8 groups;
[0030] R.sup.6 is independently R.sup.1, H, halo, CN, OH,
OC.sub.1-4alk, C.sub.1-4alk or C.sub.1-4haloalk;
[0031] m is 0, 1, 2, 3, or 4;
[0032] 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;
[0033] the ring containing p and q contains 0, 1, or 2 double
bonds;
[0034] R.sup.a is independently H or R.sup.b;
[0035] R.sup.b is independently phenyl, benzyl, or C.sub.1-6alk,
wherein said phenyl, benzyl, and C.sub.1-6alk are substituted by 0,
1, 2 or 3 substituents which are, independently, 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;
[0036] R.sup.c is C.sub.0-4alk-L.sup.2;
[0037] each L.sup.1 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 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 N
atoms and 0, 1, or 2 atoms which are O or S; L.sup.1 is
independently substituted by 0, 1, 2 or 3 R.sup.9 groups;
[0038] each L.sup.2 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 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 N
atoms and 0, 1, or 2 atoms which are O or S; L.sup.2 is
independently substituted by 0, 1, 2 or 3 R.sup.11 groups;
[0039] R.sup.8 is halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-4haloalk, OC.sub.1-4haloalk, --C(.dbd.O)R.sup.b,
--C(.dbd.O)R.sup.c, --C(.dbd.O)NHR.sup.b, --C(.dbd.O)NHR.sup.c,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2R.sup.c,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, R.sup.b, R.sup.c, NO.sub.2,
OR.sup.b, or OR.sup.c;
[0040] R.sup.9 is halo, 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.1-6alkNR.sup.aR.sup.a, --OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, oxo, or R.sup.c;
[0041] R.sup.10 is oxo, C.sub.1-6alk, 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
[0042] R.sup.11 is halo, 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.1-6alkNR.sup.aR.sup.a,
--OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, or oxo.
[0043] In one embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the group
##STR00008## ##STR00009##
[0044] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the group
##STR00010## ##STR00011##
[0045] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, each of said Ring A, Ring
B, and Ring C is a fused 4- to 6-membered-saturated, -partially
saturated, or -unsaturated-carbocyclic which are fused phenyl,
cyclobutyl, cyclopentyl, or cyclohexyl; said Ring A, Ring B, and
Ring C is substituted by 0, 1, or 2 R.sup.10 groups which are oxo,
C.sub.1-6alk, 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.
[0046] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, each of said Ring A, Ring
B, and Ring C is a fused 5-membered-saturated, -partially
saturated, or -unsaturated-heterocyclic ring which are fused
furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,
dioxolanyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl,
imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,
pyrazolidinyl, isoxazolyl, or isothiazolyl; said Ring A, Ring B,
and Ring C is substituted by 0, 1, or 2 R.sup.10 groups which are
oxo, C.sub.1-6alk, 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.
[0047] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, each of said Ring A, Ring
B, and Ring C is a fused 6-membered-saturated, -partially
saturated, or -unsaturated-heterocyclic ring which are fused
pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,
thiomorpholinyl, pyridazinyl, pyrazinyl, or piperazinyl; said Ring
A, Ring B, and Ring C is substituted by 0, 1, or 2 R.sup.10 groups
which are oxo, C.sub.1-6alk, 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.
[0048] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, each of p and q is
independently 1.
[0049] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, each of p and q is
independently 2.
[0050] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the ring containing p and
q contains 0 or 1 double bond.
[0051] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, wherein the sum of p and
q is 3; and the ring containing p and q contains 0 or 1 double
bond.
[0052] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.4b is oxo and m is
1.
[0053] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.5 is unsaturated
10-membered bicyclo-heterocyclic ring; wherein each R.sup.5 ring is
substituted by 0, 1, or 2 R.sup.8 groups.
[0054] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the group
##STR00012##
wherein each
##STR00013##
is substituted by 0, 1, or 2 R.sup.10 groups.
[0055] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, m is 1 or 2.
[0056] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, m is 0.
[0057] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.1 is
--NR.sup.aR.sup.c, --OR.sup.c or --C.sub.0-4alk-L.sup.1.
[0058] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is a
carbon-linked-saturated or partially-saturated 3-, 4-, 5-, 6-, or
7-membered monocyclic ring, wherein each said ring contains 0, 1,
or 2 N atoms and 0 or 1 O atoms, and wherein each said L.sup.1 is
substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl, Br,
C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
[0059] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is a
carbon-linked-saturated or partially-saturated 5- to 6-membered
monocyclic ring, wherein each said ring contains 0, 1, or 2 N atoms
and 0 or 1 O atoms, and wherein each said L.sup.1 is substituted by
0, 1 or 2 R.sup.9 groups which are F, Cl, Br, C.sub.1-6alk,
--OR.sup.a, CN, --C(.dbd.O)R.sup.b, C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
[0060] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is a
carbon-linked-unsaturated 5- to 6-membered monocyclic ring, wherein
each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and
wherein each said L.sup.1 is substituted by 0, 1 or 2 R.sup.9
groups which are F, Cl, Br, C.sub.1-6alk, --OR.sup.a, CN,
--C(.dbd.O)R.sup.b, C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--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, --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, oxo, or R.sup.c.
[0061] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is a
carbon-linked-saturated, partially-saturated or unsaturated 6-, 7-,
8-, 9-, or 10-membered bicyclic ring, wherein each said ring
contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and wherein each
said L.sup.1 is substituted by 0, 1 or 2 R.sup.9 groups which are
F, Cl, Br, C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
[0062] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is a
nitrogen-linked saturated, partially-saturated or unsaturated 4-,
5-, 6-, or 7-membered monocyclic ring, wherein said ring contains
0, 1, 2, 3, or 4 N atoms and 0 or 1 O atoms, and wherein each said
L.sup.1 is substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl,
Br, C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
[0063] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is a
nitrogen-linked saturated, partially-saturated or unsaturated 6-,
7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each
said ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and
wherein each said L.sup.1 is substituted by 0, 1 or 2 R.sup.9
groups which are F, Cl, Br, C.sub.1-6alk, --OR.sup.a, CN,
--C(.dbd.O)R.sup.b, C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--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, --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, oxo, or R.sup.c.
[0064] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, L.sup.1 is
-3-azabicyclo[3.1.0]hexanyl, azetidinyl, indolyl, phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, piperazinonyl,
piperidinyl, pyrrolidinyl, dihydropyranyl, tetrahydropyridinyl,
octahydropyrrolo[3,4-c]pyrrolyl, tetrahydroisoquinolinyl, which are
substituted by 0, 1 or 2 R.sup.9 groups which are F, Cl, Br,
C.sub.1-6alk, --OR.sup.a, CN, --C(.dbd.O)R.sup.b,
C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a, --SR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b, --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,
--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, oxo, or R.sup.c.
[0065] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.1 is selected from
the group consisting of: Cl; Br; --C.ident.C--CH.sub.3;
--NH--CH(CH.sub.3).sub.2; --NHCH.sub.2CH.sub.2OCH.sub.3;
--NHCH.sub.2CH.sub.2OH;
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026## ##STR00027##
[0066] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.1 is selected from
the group consisting of:
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035##
[0067] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.1 is selected from
the group consisting of:
##STR00036## ##STR00037## ##STR00038##
[0068] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, each R.sup.2 and R.sup.3
is independently H, F, Cl, Br, CN, OH, OC.sub.1-4alk, C.sub.1-4alk
or C.sub.1-4haloalk.
[0069] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.6 is H, F, or
C.sub.1-4alk.
[0070] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.4a is H, F, OH, or
methyl.
[0071] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.4b is oxo and m is
1
[0072] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.4a is H and m is
0.
[0073] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.5 is pyridinyl.
[0074] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.5 is unsaturated 9-
to 10-membered bicyclo-heterocyclic ring.
[0075] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.5 is 11- to
15-membered tricyclo-heterocyclic ring.
[0076] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the group --Y--R.sup.5
is:
##STR00039## ##STR00040## ##STR00041## ##STR00042##
wherein each R.sup.5 is substituted by 1 or 2 R.sup.8 groups.
[0077] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the group --Y--R.sup.5
is:
##STR00043##
wherein each R.sup.5 is substituted by 1 or 2 R.sup.8 groups.
[0078] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, the group --Y--R.sup.5
is:
##STR00044## ##STR00045## ##STR00046##
[0079] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, Y is a bond or
--C(.dbd.O).
[0080] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, Y is a bond.
[0081] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.8 is independently
F, Br, Cl, CF.sub.3, methyl, methoxy, or CN.
[0082] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, 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.
[0083] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.c is a
C.sub.0-4alk-carbon-linked saturated, partially-saturated or
unsaturated 3-, 4- 5-, or 6-membered monocyclic ring containing 0,
1, or 2 N atoms and 0 or 1 atom which are O or S, which is
substituted by 0 or 1 R.sup.11 groups which are F, C.sub.1-6alk,
C.sub.1-4haloalk, or --OR.sup.a.
[0084] In another embodiment of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, R.sup.c is pyridyl,
phenyl, or 1,2,4-oxadiazolyl.
[0085] Another aspect of the current invention relates to compounds
having the general structure of formula (II):
##STR00047##
or a pharmaceutically acceptable salt thereof, wherein:
[0086] Ring D is -L.sup.1;
[0087] X.sup.1 is N or CR.sup.6;
[0088] X.sup.2 is N or CR.sup.2;
[0089] X.sup.3 is N or CR.sup.3;
[0090] X.sup.4 is N or CR.sup.6;
[0091] wherein 1 to 2 of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are
N;
[0092] Y is a C.sub.0-4alk, --C(.dbd.O), SO, or SO.sub.2;
[0093] each R.sup.2 and R.sup.3 is independently H, halo, CN, OH,
--OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-4haloalk,
--C.sub.1-6alkOR.sup.a, --C(.dbd.O)C.sub.1-4alk,
--C(.dbd.O)NR.sup.aR.sup.a, --C.sub.0-4alkNH--C(.dbd.O)R.sup.a, or
R.sup.c;
[0094] or alternatively the ring containing X.sup.1, X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 can be fused to ring A, ring B, or
ring C; having the formula:
##STR00048##
wherein each said ring A, ring B, or ring C is a fused 4- to
6-membered-saturated, -partially saturated, or
-unsaturated-carbocyclic or -heterocyclic ring containing 0, 1, 2,
or 3 heteroatoms; and is substituted by 0, 1, or 2 R.sup.10
groups;
[0095] R.sup.4a is H, OH, halo, C.sub.1-4alk, or
C.sub.1-4haloalk;
[0096] R.sup.4b is halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-4haloalk, or oxo;
[0097] R.sup.5 is pyridinyl or unsaturated 9- to 10-membered
bicyclo-heterocyclic ring; wherein each R.sup.5 is substituted by
0, 1, 2 or 3 R.sup.8 groups;
[0098] R.sup.6 is independently H, halo, CN, OH, OC.sub.1-4alk,
C.sub.1-4alk or C.sub.1-4haloalk;
[0099] m is 0, 1, 2, 3, or 4;
[0100] 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
contains 0, 1, or 2 double bonds;
[0101] R.sup.a is independently H or R.sup.b;
[0102] R.sup.b is independently phenyl, benzyl, or C.sub.1-6alk,
wherein said phenyl, benzyl, or C.sub.1-6alk substituted by 0, 1, 2
or 3 substituents which are, independently, 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;
[0103] R.sup.c is C.sub.0-4alk-L.sup.2;
[0104] each L.sup.1 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 6-, 7-, 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 which are O or S; wherein each
L.sup.1 is independently substituted by 0, 1, 2 or 3 R.sup.9
groups;
[0105] each L.sup.2 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 6-, 7-, 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 which are O or S; wherein each
L.sup.2 is independently substituted by 0, 1, 2 or 3 R.sup.11
groups;
[0106] R.sup.8 is halo, CN, OH, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-4haloalk, OC.sub.1-4haloalk, --C(.dbd.O)R.sup.b,
--C(.dbd.O)R.sup.c, --C(.dbd.O)NHR.sup.b, --C(.dbd.O)NHR.sup.c,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2R.sup.c,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, R.sup.b, R.sup.c, NO.sub.2,
OR.sup.b, or OR.sup.c;
[0107] R.sup.9 is 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.1-6alkNR.sup.aR.sup.a,
--OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, oxo, or R.sup.c;
[0108] R.sup.10 is oxo, C.sub.1-6alk, 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
[0109] R.sup.11 is 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.1-6alkNR.sup.aR.sup.a,
--OC.sub.1-6alkOR.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.1-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.1-6alkOR.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, or oxo.
[0110] In another embodiment of the compound of formula (II), or a
pharmaceutically acceptable salt thereof, the group
##STR00049##
is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.
[0111] In another embodiment of the compound of formula (II), or a
pharmaceutically acceptable salt thereof, the compound of formula
(II) has the formula:
##STR00050##
[0112] In another embodiment of the compound of formula (II), or a
pharmaceutically acceptable salt thereof, the compound of formula
(II) has the formula:
##STR00051##
[0113] In another embodiment of the compound of formula (II), or a
pharmaceutically acceptable salt thereof, the compound of formula
(II) has the formula:
##STR00052##
[0114] In another embodiment of the compound of formula (IIg),
R.sup.4b is oxo; m is 1; and R.sup.5 is unsaturated 10-membered
bicyclo-heterocyclic ring; wherein each R.sup.5 ring is substituted
by 0, 1, or 2 R.sup.8 groups.
[0115] In another embodiment of the compound of formula (IIg), said
compound has the formula
##STR00053##
wherein m is 0; and R.sup.5 is unsaturated 10-membered
bicyclo-heterocyclic ring; wherein each R.sup.5 ring is substituted
by 0, 1, or 2 R.sup.8 groups.
[0116] In another embodiment of any of the compound of the formula
(IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg), the group
--Y--R.sup.5 is:
##STR00054##
Y is a bond; wherein each R.sup.5 is substituted by 1 or 2 R.sup.8
groups; and R.sup.8 is independently F, Cl, Br, methyl, ethyl,
isopropyl, methoxy, CN, CF.sub.3, OH, or OCF.sub.3.
[0117] In another embodiment of any of the compound of the formula
(IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg), or a
pharmaceutically acceptable salt thereof, the group --Y--R.sup.5
is:
##STR00055## ##STR00056##
Y is a bond; wherein R.sup.8 is independently F, Cl, Br, methyl,
ethyl, isopropyl, methoxy, CN, CF.sub.3, OH, or OCF.sub.3.
[0118] Another aspect of the current invention relates to compounds
having the general structure of formula (III):
##STR00057##
[0119] or a pharmaceutically-acceptable salt thereof, wherein:
[0120] X.sup.1 is N or CR.sup.6;
[0121] R.sup.1 is F, Cl, Br, I, C.sub.1-8alk, C.sub.1-4haloalk,
--OR.sup.a, --OR.sup.c, --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;
[0122] Y is a C.sub.0-4alk, --C(.dbd.O), SO, or SO.sub.2;
[0123] each of R.sup.2, R.sup.3, R.sup.4b, R.sup.6 and R.sup.8 is
independently H, F, Cl, Br, I, CN, OH, OC.sub.1-4alk, C.sub.1-4alk
or C.sub.1-4haloalk;
[0124] or alternatively R.sup.2 and R.sup.3 can form an optionally
substituted 5- to 6-membered-saturated, -partially saturated, or
-unsaturated-heterocyclic ring fused to the ring containing
X.sup.1;
[0125] R.sup.4a is H, C.sub.1-4alk, or C.sub.1-4haloalk;
[0126] R.sup.5 is pyridinyl or unsaturated 9- or 10-membered
bicyclo-heterocyclic ring;
[0127] wherein each R.sup.5 is substituted by 0, 1, 2 or 3 R.sup.8
groups; and is not substituted by oxo;
[0128] m is 1, 2, 3, or 4;
[0129] 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;
[0130] R.sup.a is independently H or R.sup.b;
[0131] 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;
[0132] R.sup.c is C.sub.0-4alk-L.sup.2; and
[0133] each of L.sup.1 and L.sup.2 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 and S; wherein each
L.sup.1 and L.sup.2 is independently substituted by 0, 1, 2 or 3
R.sup.9 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 or oxo;
[0134] with the proviso that: when all X.sup.1, X.sup.2, and
X.sup.3 are CR.sup.3; each of p and q is 2; and R.sup.3 is methyl;
then R.sup.1 is F, Cl, Br, I, C.sub.1-8alk, C.sub.1-4haloalk,
--OR.sup.a, --OR.sup.c, --N(R.sup.a)C(.dbd.O)R.sup.b,
--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, 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.
[0135] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.5 is not
substituted by oxo.
[0136] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the group:
##STR00058##
[0137] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, M.sub.1, M.sub.2,
M.sub.3, and M.sub.4 is independently CR.sup.10 or a heteroatom
selected from S, O, or NR.sup.11; wherein no more than of Y.sub.1,
Y.sub.2, Y.sub.3, M.sub.1, M.sub.2, M.sub.3, and M.sub.4 are N;
and
[0138] wherein R.sup.10 is H, 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
R.sup.11 is H, C.sub.1-4alk, or C.sub.1-3haloalk.
[0139] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the group
##STR00059##
[0140] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the group
##STR00060##
each of p and q is 2; R.sup.5 is unsaturated 9-membered
bicyclo-heterocyclic ring; and Y is C.sub.0-4alk; and R.sup.1 is
C.sub.0-4alk-L.sup.1.
[0141] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the group
##STR00061##
[0142] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, m is 1 or 2.
[0143] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, p is 0, 1, or 2.
[0144] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, q is 0, 1, or 2.
[0145] In another embodiment of the compound of formula (II), or a
pharmaceutically acceptable salt thereof, R.sup.1 is F, Cl, Br, I,
--OR.sup.a, --C(.dbd.O)--O--R.sup.a, --C(.dbd.O)NR.sup.aR.sup.b,
--OR.sup.c, or --C(.dbd.O)NR.sup.aR.sup.c.
[0146] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.1 is a 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 O atoms, and wherein each said ring is
substituted by 0, 1, 2 or 3 R.sup.9 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,
SR.sup.a, or oxo.
[0147] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.1 is a saturated or
partially-saturated 5- to 6-membered monocyclic 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.9
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, SR.sup.a, or oxo.
[0148] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.1 is a 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.9 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,
SR.sup.a, or oxo.
[0149] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.1 is a
nitrogen-linked saturated, partially-saturated or unsaturated 4-,
5-, 6-, or 7-membered monocyclic ring wherein each said ring
contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms selected
from O and S; substituted by 0, 1, 2 or 3 R.sup.9 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, SR.sup.a, or oxo.
[0150] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.1 is cyclohexyl,
cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl,
phenyl, 2-pyridyl, 3-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.9 groups selected from F, Cl,
Br, C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, CN,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a, --SR.sup.a, or oxo.
[0151] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.1 is:
##STR00062## ##STR00063##
wherein the dotted bond is an optional double bond.
[0152] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, each R.sup.2 and R.sup.3
is independently H, F, Cl, Br, CN, OH, OC.sub.1-4alk, C.sub.1-4alk
or C.sub.1-4haloalk.
[0153] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, each R.sup.2 and R.sup.3
is H, C.sub.1-4alk, or C.sub.1-4haloalk.
[0154] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.2 and R.sup.3 are
H.
[0155] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.2 and R.sup.3 form
an optionally substituted 5- to 6-membered-saturated, -partially
saturated, or -unsaturated-heterocyclic ring fused to the ring
containing X.sup.1.
[0156] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, X.sup.1 is N.
[0157] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, X.sup.1 is CR.sup.6;
wherein R.sup.6 is H, F, Cl, Br, I, OC.sub.1-4alk, or
C.sub.1-4alk.
[0158] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.6 is H or
C.sub.1-4alk.
[0159] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.4a is H or
C.sub.1-4alk.
[0160] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.4b is independently
H, F, CN, OC.sub.1-4alk, C.sub.1-4alk or C.sub.1-4haloalk.
[0161] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, each of R.sup.4a and
R.sup.4b is H.
[0162] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.5 is pyridinyl.
[0163] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.5 is unsaturated 9-
or 10-membered bicyclo-heterocyclic ring; wherein the ring is
aromatic.
[0164] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.5 is unsaturated
9-membered bicyclo-heterocyclic ring; wherein the ring is
aromatic.
[0165] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.5 is unsaturated
10-membered bicyclo-heterocyclic ring; wherein the ring is
aromatic.
[0166] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the group --Y--R.sup.5
is:
##STR00064##
[0167] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the group --Y--R.sup.5
is:
##STR00065##
and Y is C(.dbd.O).
[0168] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, Y is --C(.dbd.O).
[0169] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, Y is a bond or
C.sub.1-3alk.
[0170] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.5 is:
##STR00066##
[0171] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.8 is independently
H, F, CN, OC.sub.1-4alk, C.sub.1-4alk or C.sub.1-4haloalk.
[0172] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.8 is H.
[0173] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, 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.
[0174] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, 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 and S, which is substituted by 0 or 1
R.sup.9 groups selected from F, C.sub.1-6alk, C.sub.1-4haloalk, or
--OR.sup.a.
[0175] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, 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.9 groups selected from F, Cl, Br, C.sub.1-4alk,
C.sub.1-4haloalk, --OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk,
--N(C.sub.1-4alk)C.sub.1-4alk, or oxo.
[0176] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, R.sup.c is a
C.sub.0-4alk-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.9
groups selected from F, C.sub.1-6alk, C.sub.1-4haloalk, or
--OR.sup.a.
[0177] In another embodiment of the compound of formula (III), or a
pharmaceutically acceptable salt thereof, the compound has the
following formula (IIIa):
##STR00067##
wherein R.sup.1 is F, Cl, Br, I, C.sub.1-8alk, C.sub.1-4haloalk,
--OR.sup.a, --OR.sup.c, --N(R.sup.a)C(.dbd.O)R.sup.b,
--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, 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; and R.sup.3 is not methyl.
[0178] Another aspect of the current invention relates to compounds
having the general structure of formula (IV):
##STR00068##
or any pharmaceutically-acceptable salt thereof, wherein:
[0179] Ring D is -L.sup.1;
[0180] X.sup.1 is N or CR.sup.6;
[0181] Y is a C.sub.0-4alk, --C(.dbd.O), SO, or SO.sub.2;
[0182] each of R.sup.2, R.sup.3, R.sup.4b, R.sup.6 and R.sup.8 is
independently H, F, Cl, Br, I, CN, OH, OC.sub.1-4alk, C.sub.1-4alk
or C.sub.1-4haloalk;
[0183] or alternatively R.sup.2 and R.sup.3 can form an optionally
substituted 5- to 6-membered-saturated, -partially saturated, or
-unsaturated-heterocyclic ring fused to the ring containing
X.sup.1;
[0184] R.sup.4a is H, C.sub.1-4alk, or C.sub.1-4haloalk;
[0185] R.sup.5 is pyridinyl or unsaturated 9- or 10-membered
bicyclo-heterocyclic ring; wherein each R.sup.5 is substituted by
0, 1, 2 or 3 R.sup.8 groups; and is not substituted by oxo;
[0186] m is 1, 2, 3, or 4;
[0187] 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;
[0188] R.sup.a is independently H or R.sup.b;
[0189] 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
[0190] each of L.sup.1 and L.sup.2 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 and S; wherein each
L.sup.1 and L.sup.2 is independently substituted by 0, 1, 2 or 3
R.sup.9 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.
[0191] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00069##
is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl; wherein each
group is not substituted by oxo.
[0192] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00070##
is azetidinyl; which is not substituted by oxo.
[0193] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00071##
is pyrrolidinyl; which is not substituted by oxo.
[0194] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00072##
is piperidinyl; which is not substituted by oxo.
[0195] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00073##
is azepanyl; which is not substituted by oxo.
[0196] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00074##
is azetidinyl or piperidinyl; which is not substituted by oxo; and
Y is --C(.dbd.O), SO, or SO.sub.2.
[0197] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, the group
##STR00075##
is azetidinyl; which is not substituted by oxo; and Y is
--C(.dbd.O), SO, or SO.sub.2.
[0198] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is a carbon-linked
saturated, partially-saturated or unsaturated 4-, 5-, 6-, or
7-membered monocyclic ring, wherein each said ring contains 0, 1,
2, 3, or 4 N atoms and 0, 1, or 2 atoms selected from O and S;
independently substituted by 0, 1, 2 or 3 R.sup.9 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.
[0199] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is a
carbon-linked-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 and S; independently substituted by 0, 1, 2 or 3 R.sup.9
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.
[0200] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is a
nitrogen-linked saturated, partially-saturated or unsaturated 4-,
5-, 6-, or 7-membered monocyclic ring, wherein each said ring
contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms selected
from O and S; independently substituted by 0, 1, 2 or 3 R.sup.9
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.
[0201] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is a
nitrogen-linked-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 and S; independently substituted by 0, 1, 2 or 3 R.sup.9
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.
[0202] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is cyclohexyl,
cyclopentyl, cyclopentenyl, cyclohexenyl, or cycloheptyl.
[0203] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is azetidinyl,
phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl, pyrimidyl,
piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,
tetrahydrofuranyl, tetrahydropyridinyl, or
tetrahydrothiopyranyl.
[0204] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is
oxaspiro[3.5]nonyl, azepanyl, oxepanyl, or quinolinyl.
[0205] In another embodiment of the compound of formula (IV), or a
pharmaceutically acceptable salt thereof, ring D is cyclohexyl,
cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl,
phenyl, 2-pyridyl, 3-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.9 groups selected from F, Cl,
Br, C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, CN,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a, --NR.sup.aR.sup.a,
--SR.sup.a, and oxo.
[0206] Another aspect of the invention relates to a compound of
formula (IV) having the formula:
##STR00076##
wherein m, Ring D, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5,
Y, and X.sup.1 are defined above.
[0207] Another aspect of the invention relates to a compound having
the formula:
##STR00077##
wherein m, Ring D, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5,
Y, and X.sup.1 are defined above.
[0208] Another aspect of the invention relates to a compound having
the formula:
##STR00078##
wherein m, Ring D, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5,
Y, and X.sup.1 are defined above.
[0209] 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.
[0210] 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.
[0211] In another embodiment of the method, said condition is
schizophrenia, Huntington's disease, bipolar disorder, or
obsessive-compulsive disorder.
[0212] In another embodiment of the method, said condition is
schizophrenia.
[0213] 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.
[0214] 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.
[0215] 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.
[0216] Another aspect of the invention relates to a compound, or a
pharmaceutically acceptable salt thereof, which is tabulated
below:
TABLE-US-00001 Chemical Structure Chemical Name ##STR00079##
(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-
pyridin-2-yl)-azetidin-1-yl]-methanone ##STR00080##
(1H-Benzoimidazol-2-yl)-[3-(5-fluoro-3-
phenyl-pyridin-2-yl)-azetidin-1-yl]- methanone ##STR00081##
(1H-benzoimidazol-2-yl)-[4-(3-phenyl-
pyrazin-2-yl)-piperidin-1-yl]-methanone ##STR00082##
Benzothiazol-2-yl-[3-(3-phenyl-pyrazin-2-
yl)-azetidin-1-yl]-methanone ##STR00083##
(1H-Benzoimidazol-2-yl)-[3-(3-piperidin-
1-yl-quinoxalin-2-yl)-azetidin-1-yl]- methanone ##STR00084##
(1H-Benzoimidazol-2-yl)-{3-[3-(4-
hydroxy-piperidin-1-yl)-quinoxalin-2-yl]- azetidin-1-yl}-methanone
##STR00085## (1H-Benzoimidazol-2-yl)-[3-(2,3-dihydro-
indol-1-yl)-3',4',5',6'-tetrahydro-2'H-
[2,4']bipyridinyl-1'-yl]-methanone ##STR00086##
(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-
quinolin-2-yl)-azetidin-1-yl]-methanone ##STR00087##
(1H-Benzoimidazol-2-yl)-(3-phenyl-
3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl- 1'-yl)-methanone
##STR00088## (1H-Benzoimidazol-2-yl)-{4-[3-(4-
hydroxymethyl-piperidin-1-yl)-pyrazin-2-
yl]-piperidin-1-yl}-methanone ##STR00089##
(3-(3-phenylpyrazin-2-yl)azetidin-1- yl)(pyridin-2-yl)methanone
##STR00090## (6-methylpyridin-2-yl)(3-(3-
phenylpyrazin-2-yl)azetidin-1- yl)methanone ##STR00091##
(3-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin-1-
yl)methanone ##STR00092## (5-methylpyridin-2-yl)(3-(3-
phenylpyrazin-2-yl)azetidin-1- yl)methanone ##STR00093##
(4-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin-1-
yl)methanone ##STR00094## (1H-Benzoimidazol-2-yl)-[3-(3-phenyl-
quinoxalin-2-yl)-azetidin-1-yl]-methanone ##STR00095##
(1H-Benzoimidazol-2-yl)-[3-(3-morpholin-
4-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00096##
(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00097##
[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1-yl]-
[1-(2,2,2-trifluoro-ethyl)-1H- benzoimidazol-2-yl]-methanone
##STR00098## (1H-Benzoimidazol-2-yl)-[3-(3-phenyl-
pyrazin-2-yl)-azetidin-1-yl]-methanone ##STR00099##
(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-
dimethoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00100## (1H-Benzoimidazol-2-yl)-{3-[3-(3-
isopropyl-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00101## (1H-Benzoimidazol-2-yl)-{3-[3-(3-
trifluoromethoxy-phenyl)-pyrazin-2-yl]- azetidin-1-yl)-methanone
##STR00102## 1H-Benzoimidazol-2-yl)-{3-[3-(3,5-
dimethoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00103## (1H-Benzoimidazol-2-yl)-{3-[3-(3-ethoxy-
phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone ##STR00104##
(1H-Benzoimidazol-2-yl)-{3-[3-(3-
isopropoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00105## (1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-
5-methoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00106## (1H-Benzoimidazol-2-yl)-{3-[3-(2-
methoxy-pyridin-4-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00107## (1H-Benzoimidazol-2-yl)-{3-[3-(5-
methoxy-pyridin-3-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00108## (1H-benzo[d]imidazol-2-yl)(3-(3-(4-
fluoro-3-methylphenyl)pyrazin-2- yl)azetidin-1-yl)methanone
##STR00109## (1H-Benzoimidazol-2-yl)-{3-[3-(4-
methoxy-3-methyl-phenyl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00110## (1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-
5-methyl-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00111## (1H-Benzoimidazol-2-yl)-{3-[3-(5-methyl-
pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl- methanone ##STR00112##
(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-
thiophen-2-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone ##STR00113##
(1H-Benzoimidazol-2-yl)-{3-[3-(1-methyl-
1H-pyrazol-4-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00114## (1H-Benzoimidazol-2-yl)-{3-[3-(3-
hydroxymethyl-phenyl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00115## (1H-Benzoimidazol-2-yl)-{3-[3-(4-
hydroxymethyl-phenyl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00116## 1-(4-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- phenyl)-ethanone
##STR00117## 1-(3-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- phenyl)-ethanone
##STR00118## (1H-Benzoimidazol-2-yl)-{3-[3-(3-
methoxymethyl-phenyl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00119## 4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-N,N- dimethyl-benzamide ##STR00120##
3-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-N,N- dimethyl-benzamide ##STR00121##
(1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-
4-yl)pyrazin-2-yl)azetidin-1-yl)methanone ##STR00122##
(7-chloro-1H-benzo[d]imidazol-2-yl)(3-(3-
(pyridin-3-yl)pyrazin-2-yl)azetidin-1- yl)methanone ##STR00123##
(1H-benzo[d]imidazol-2-yl)(3-(3-(2-
methylpyridin-4-yl)pyrazin-2-yl)azetidin- 1-yl)methanone
##STR00124## (1H-benzo[d]imidazol-2-yl)(3-(3-(m-
tolyl)pyrazin-2-yl)azetidin-1-yl)methanone ##STR00125##
3-(3-(1-(1H-benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-
yl)benzonitrile ##STR00126##
(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-
piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00127##
{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-
2-yl]-azetidin-1-yl}-(1-methyl-1H- benzoimidazol-2-yl)-methanone
##STR00128## [3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-
1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H- benzoimidazol-2-yl]-methanone
##STR00129## {3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-
2-yl]-azetidin-1-yl}-[1-(2,2,2-trifluoro-
ethyl)-1H-benzoimidazol-2-yl]-methanone ##STR00130##
(1H-Benzoimidazol-2-yl)-[3-(3-pyrrolidin-
1-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00131##
(1H-Benzoimidazol-2-yl)-{3-[3-(4-
trifluoromethyl-piperidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone ##STR00132## (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(2-methyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00133## (1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-
piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00134## (1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-
piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00135## (1H-Benzoimidazol-2-yl)-{3-[3-(4,4-
dimethyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00136## (1H-Benzoimidazol-2-yl)-{3-[3-(4-
hydroxymethyl-piperidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone ##STR00137##
(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-
hydroxy-1-methyl-ethyl)-piperidin-1-yl]-
pyrazin-2-yl}-azetidin-1-yl)-methanone ##STR00138##
(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-
hydroxy-1-methyl-ethyl)-piperidin-1-yl]-
pyrazin-2-yl}-azetidin-1-yl)-methanone ##STR00139##
1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carbonitrile
##STR00140## (1H-Benzoimidazol-2-yl)-{3-[3-(4-
methoxymethyl-piperidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone ##STR00141## (R &
S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00142## (R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(2-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00143## (1H-Benzoimidazol-2-yl)-{3-[3-(3,4-
dihydro-1H-isoquinolin-2-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone ##STR00144##
(1H-Benzoimidazol-2-yl)-{3-[3-(1,3-
dihydro-isoindol-2-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00145## (R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(3-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00146## (R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(2-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00147## (1H-Benzoimidazol-2-yl)-[3-(3-
cyclopentylamino-pyrazin-2-yl)-azetidin- 1-yl]-methanone
##STR00148## (1H-Benzoimidazol-2-yl)-[3-(3-
cyclohexylamino-pyrazin-2-yl)-azetidin-1- yl]-methanone
##STR00149## (1H-Benzoimidazol-2-yl)-[3-(3-
benzylamino-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00150##
(1H-Benzoimidazol-2-yl)-{3-[3-(2-
hydroxy-ethylamino)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00151## (1H-benzo[d]imidazol-2-yl)(3-(3-((2-
methoxyethyl)amino)pyrazin-2- yl)azetidin-1-yl)methanone
##STR00152## 1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carboxylic acid amide
##STR00153## (R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(3-hydroxymethyl-piperidin-1-yl)-pyrazin-
2-yl]-azetidin-1-yl}-methanone ##STR00154##
(1H-Benzoimidazol-2-yl)-{3-[3-(3-
hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00155## [3-(3-Azepan-1-yl-pyrazin-2-yl)-azetidin-
1-yl]-(1H-benzoimidazol-2-yl)-methanone ##STR00156##
[3-(3-Azetidin-1-yl-pyrazin-2-yl)-azetidin-
1-yl]-(1H-benzoimidazol-2-yl)-methanone ##STR00157##
(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-
hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone ##STR00158##
(1H-Benzoimidazol-2-yl)-[3-(3-
isopropylamino-pyrazin-2-yl)-azetidin-1- yl]-methanone ##STR00159##
(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-
hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone
##STR00160## (1H-Benzoimidazol-2-yl)-(3-{3-[4-(2-
hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2-
yl}-azetidin-1-yl)-methanone ##STR00161##
(1H-Benzoimidazol-2-yl)-[3-(3-
[1,4]oxazepan-4-yl-pyrazin-2-yl)-azetidin- 1-yl]-methanone
##STR00162## (1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-
[1,4]diazepan-1-yl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00163## 1-(4-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-
[1,4]diazepan-1-yl)-ethanone ##STR00164##
(1H-Benzoimidazol-2-yl)-{3-[3-(4-
hydroxy-azepan-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00165## (R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-
(3-hydroxymethyl-pyrrolidin-1-yl)-
pyrazin-2-yl]-azetidin-1-yl}-methanone ##STR00166##
(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-
hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00167## (S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-
hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00168## (R & S)-1-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- piperidine-3-carbonitrile
##STR00169## 1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carboxylic acid
methylamide ##STR00170## 1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carboxylic acid
dimethylamide ##STR00171## 1-(1-(3-(1-(1H-benzo[d]imidazole-2-
carbonyl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)ethanone
##STR00172## 1-(4-(3-(1-(1H-benzo[d]imidazole-2-
carbonyl)azetidin-3-yl)pyrazin-2- yl)piperazin-1-yl)ethanone
##STR00173## (R)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-
hydroxypyrrolidin-1-yl)pyrazin-2- yl)azetidin-1-yl)methanone
##STR00174## (S)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-
hydroxypyrrolidin-1-yl)pyrazin-2- yl)azetidin-1-yl)methanone
##STR00175## (1H-benzo[d]imidazol-2-yl)(3-(3-
(piperidin-1-yl)pyrazin-2-yl)azetidin-1- yl)methanone ##STR00176##
(1H-benzo[d]imidazol-2-yl)(3-(3-(4-
hydroxypiperidin-1-yl)pyrazin-2- yl)azetidin-1-yl)methanone
##STR00177## (1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-7-
aza-spiro[3.5]non-7-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00178## (1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-6-
aza-spiro[3.3]hept-6-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00179## 1-(6-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-2,6-
diaza-spiro[3.3]hept-2-yl)-ethanone ##STR00180##
2-(3-(3-(2-methoxypyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00181##
2-(3-(3-(6-methylpyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00182## 2-(3-(3-(2-methylpyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00183##
2-(3-(3-(6-fluoropyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00184## 2-(3-(3-(6-(trifluoromethyl)pyridin-3-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00185##
2-(3-(3-(2,6-dimethoxypyridin-3-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00186##
2-(3-(3-(5-fluoropyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00187## 2-(3-(3-(6-methoxypyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate ##STR00188##
2-(3-(3-(6-fluoro-5-methylpyridin-3-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate
##STR00189## 2-(3-(3-(pyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate ##STR00190##
2-(3-(3-(4- (methylsulfonyl)phenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate ##STR00191##
5-(3-(1-quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyridin-2-amine
##STR00192## 5-(3-(1-quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyridin-3-amine ##STR00193##
2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00194##
2-(3-(3-(2-(trifluoromethyl)pyridin-3-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate
##STR00195## N,N-dimethyl-5-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrimidin-2- amine
2,2,2-trifluoroacetate ##STR00196##
2-(3-(3-(4-methylpyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
2,2,2- trifluoroacetate ##STR00197##
2-(3-(3-(5-(methylsulfonyl)pyridin-3-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate
##STR00198## 2-(3-(3-(5-methylpyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate ##STR00199##
2-(3-(3-(5-methoxypyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate ##STR00200##
2-(3-(3-(4-chloro-3-methylphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00201##
2-(3-(3-(3-fluoro-4-methylphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00202##
2-chloro-4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenol
##STR00203## 2-(3-(3-(3-methoxy-5-
(trifluoromethyl)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00204## 2-(3-(3-(4-ethoxy-3-fluorophenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00205##
2-(3-(3-(3-chloro-4-ethoxyphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00206## 2-(3-(3-(3-chloro-4-
propoxyphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline ##STR00207##
2-(3-(3-(3-fluoro-5- (trifluoromethyl)phenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00208## 2-(3-(3-(4-methoxy-3-
methylphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline ##STR00209##
2-(3-(3-(3-fluoro-5- isopropoxyphenyl)pyrazin-2-yl)azetidin-1-
yl)quinoline ##STR00210## 2-(3-(3-(3-fluoro-5-methylphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00211##
2-(3-(3-(3-chloro-4-fluorophenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00212##
2-(3-(3-(3,4-difluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00213## 2-(3-(3-(3,4-dichlorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00214##
2-(3-(3-(3,4-dimethylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00215## 2-(3-(3-(3-chloro-4-methylphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00216##
2-(3-(3-(3-chloro-5-methylphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00217##
2-(3-(3-(4-fluoro-3-methylphenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00218##
2-(3-(3-(pyrimidin-5-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00219## 2-(3-(3-(4-chloro-3-
(trifluoromethyl)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00220## 2-(3-(3-(3,6-dihydro-2H-pyran-4-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00221##
2-(3-(3-(2,2-dimethyl-3,6-dihydro-2H-
pyran-4-yl)pyrazin-2-yl)azetidin-1- yl)quinoline and
2-(3-(3-(6,6-dimethyl-3,6- dihydro-2H-pyran-4-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00222##
2-(3-(3-(1H-pyrazol-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00223## 2-(3-(3-(3-fluoro-5-
(trifluoromethyl)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00224## 2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00225##
2-(3-(3-phenylpyrazin-2-yl)azetidin-1- yl)quinoline ##STR00226##
2-(3-(3-(4-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00227## 2-(3-(3-(4-fluorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00228##
2-(3-(3-(2-fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00229## 2-(3-(3-(3-fluorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00230##
2-(3-(3-(pyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00231## 3-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzonitrile ##STR00232##
4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile
##STR00233## methyl 3-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzoate ##STR00234## ethyl
4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzoate
##STR00235## 2-(3-(3-(2-methoxypyridin-4-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00236##
2-(3-(3-(2-fluoropyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00237## 2-(3-(3-(3-(methylthio)phenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00238##
1-(4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)ethanone ##STR00239##
2-(3-(3-(4-phenoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00240## 2-(3-(3-(4- (trifluoromethyl)phenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00241## 2-(3-(3-(3-fluoro-4-
methoxyphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline ##STR00242##
N,N-dimethyl-3-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)aniline
##STR00243## N-methyl-3-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)benzamide ##STR00244## tert-butyl
4-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate
##STR00245## 2-(3-(3-([1,1'-biphenyl]-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00246##
2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzonitrile ##STR00247##
2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzonitrile ##STR00248##
N,N-dimethyl-3-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)benzamide ##STR00249##
2-(3-(3-(2-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00250## 2-(3-(3-(3- (trifluoromethyl)phenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00251##
2-(3-(3-(3-ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00252## 1-(3-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)ethanone ##STR00253##
(3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)methanol
##STR00254## 2-(3-(3-(3- (trifluoromethoxy)phenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00255##
2-(3-(3-(3-(benzyloxy)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00256## N-cyclopropyl-3-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)benzamide ##STR00257##
N,N-dimethyl-3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)benzenesulfonamide ##STR00258##
2-(3-(3-(4-ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00259## (4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)methanol ##STR00260##
2-(3-(3-(4-propylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00261## 2-(3-(3-(4-ethylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00262##
N,N-dimethyl-4-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)aniline ##STR00263## 2-(3-(3-(4-
(trifluoromethoxy)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00264## 2-(3-(3-(4-isopropoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00265##
2-methyl-2-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)propanenitrile ##STR00266##
4-((4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-
yl)phenyl)sulfonyl)morpholine ##STR00267## 2-(3-(3-(4-(piperidin-1-
ylsulfonyl)phenyl)pyrazin-2-yl)azetidin-1- yl)quinoline
##STR00268## (R- & S-)-2-(3-(3-(3-(pyridin-3-
yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline
##STR00269## (R- & S-)-2-(3-(3-(3-phenethylpyrrolidin-
1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00270## (R- &
S-)-2-(3-(3-(3-benzylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00271##
(R)-N,N-dimethyl-1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- amine ##STR00272## (R-
& S-)-tert-butyl methyl(1-(3-(1-
(quinolin-2-yl)azetidin-3-yl)pyrazin-2-
yl)pyrrolidin-3-yl)carbamate ##STR00273## (R- &
S-)-N,N-dimethyl-1-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin- 3-amine ##STR00274##
2-(3-(3-(3-azabicyclo[3.1.0]hexan-3-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00275## (R- &
S-)-2-(3-(3-(3- (phenylsulfonyl)pyrrolidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00276## (R- &
S-)-3-methyl-5-(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)-1,2,4-oxadiazole
##STR00277## (R)-1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3-ol ##STR00278## (R- &
S-)-2-(3-(3-(3-(pyridin-4-
yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline
##STR00279## 2-(3-(3-(pyrrolidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00280## (3aR,6aS)-tert-butyl
5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate ##STR00281##
tert-butyl 5-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate
##STR00282## tert-butyl 4-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)-1,4-diazepane-1- carboxylate ##STR00283##
(R)-(1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol ##STR00284## (R- &
S-)-2-(3-(3-(3- (methylsulfonyl)pyrrolidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00285##
(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol ##STR00286##
(R)-tert-butyl 1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- ylcarbamate
##STR00287## (S)-2-(3-(3-(3-fluoropyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00288##
2-(3-(3-(3,3-difluoropyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00289##
2-(3-(3-(4-isopropyl-1,4-diazepan-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00290##
(1R,5R)-3-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane ##STR00291##
2-(3-(3-(azepan-1-yl)pyrazin-2-yl)azetidin- 1-yl)quinoline
##STR00292## 2-(3-(3-(4-methyl-1,4-diazepan-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00293##
3-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane ##STR00294##
1-(4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-1,4-diazepan-1- yl)ethanone ##STR00295## (R- &
S-)-2-(3-(3-(3-phenylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00296##
(3S,4S)-1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidine-3,4-diol ##STR00297##
N-(4-methoxybenzyl)-3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-amine ##STR00298##
(1R,4R)-5-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-2-oxa-5- azabicyclo[2.2. l]heptane ##STR00299##
(R- & S-)-2-(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)thiazole
##STR00300## (S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol ##STR00301##
((2S,4S)-4-fluoro-1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2- yl)methanol
##STR00302## (R)-2-(3-(3-(2-(methoxymethyl)pyrrolidin-
1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00303##
2-(3-(3-(hexahydrocyclopenta[c]pyrrol-
2(1H)-yl)pyrazin-2-yl)azetidin-1- yl)quinoline ##STR00304## (R-
& S-)-2-(3-(3-(3-isobutylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00305##
2-(3-(3-(3,3-dimethylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00306## (R- &
S-)-2-(3-(3-(3- (methoxymethyl)pyrrolidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00307##
2-(3-(3-(4-(trifluoromethyl)piperidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00308##
1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4-carbonitrile ##STR00309##
2-(3-(3-(4,4-difluoropiperidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00310##
4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)morpholine
##STR00311## 2-(3-(3-(4-fluoropiperidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00312##
2-(3-(3-(3-methoxyazetidin-1-yl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00313##
2-(3-(3-(3,3-difluoroazetidin-1-yl)pyrazin-
2-yl)azetidin-1-yl)quinoline ##STR00314##
4-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidin-4-ol ##STR00315##
1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-1H-pyrazole-4-
carbonitrile ##STR00316## 2-(3-(3-(4-methyl-1H-pyrazol-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00317## tert-butyl
(1-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)azetidin-3-yl)carbamate ##STR00318##
2,2-dimethyl-4-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)morpholine ##STR00319##
2-(3-(3-(4-methyl-1H-imidazol-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00320##
1-(3-(1-(quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4-carbonitrile ##STR00321##
(1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-1H-pyrazol-4-yl)methanol ##STR00322##
(1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-1H-imidazol-4-
yl)methanol ##STR00323##
1-methyl-4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperazin-2-one ##STR00324##
N-(2,6-dimethylphenyl)-1-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine- 3-carboxamide
##STR00325## (S)-tert-butyl (1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)piperidin-3- yl)carbamate
##STR00326## (4-(cyclopropylmethyl)-1-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin- 4-yl)methanol
##STR00327## 2-(3-(3-((1R,5S)-8-methyl-3,8-
diazabicyclo[3.2.1]octan-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00328## 1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3-amine ##STR00329## (R- &
S-)-methyl (1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate
##STR00330## (R- & S-)-N-(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide
##STR00331## (R- & S-)-ethyl (1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate
##STR00332## (R- & S-)-2-methoxy-N-(1-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin- 3-yl)acetamide
##STR00333## 2-(3-(3-(1,4-Diazepan-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline ##STR00334## Methyl
4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-1,4-diazepane-1- carboxylate ##STR00335## methyl
methyl(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate
##STR00336## N-methyl-N-(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide
##STR00337## Ethyl methyl(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate
##STR00338## 2-(3-(3-(4-chlorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinazoline ##STR00339##
2-(3-(3-(3-chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline
##STR00340## 2-(3-(3-(2-chlorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinazoline ##STR00341##
2-(3-(3-(o-tolyl)pyrazin-2-yl)azetidin-1- yl)quinazoline
##STR00342## 1-(4-(3-(1-(quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)ethanone ##STR00343##
1-(3-(3-(1-(quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)ethanone ##STR00344##
N-(3-(3-(1-(quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)acetamide ##STR00345##
N-(4-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-
yl)phenyl)methanesulfonamide ##STR00346##
N-(3-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-
yl)phenyl)methanesulfonamide ##STR00347##
2-(3-(3-(1H-indol-6-yl)pyrazin-2- yl)azetidin-1-yl)quinazoline
##STR00348## 2-(3-(3-(1-methyl-1H-indol-5-yl)pyrazin-
2-yl)azetidin-1-yl)quinazoline ##STR00349##
2-(3-(3-(1-methyl-1H-indol-6-yl)pyrazin-
2-yl)azetidin-1-yl)quinazoline ##STR00350##
5-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)indolin-2-one
##STR00351## 1-methyl-5-(3-(1-(quinazolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-one ##STR00352##
1-methyl-6-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1H-
benzo[d]imidazol-2(3H)-one ##STR00353##
2-fluoro-4-(3-(1-(quinazolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)aniline ##STR00354##
2-(3-(3-(p-tolyl)pyrazin-2-yl)azetidin-1- yl)quinazoline
##STR00355## 2-methyl-6-(3-(1-(quinazolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)isoquinolin- 1(2H)-one ##STR00356##
2-(3-(3-(1H-indazol-5-yl)pyrazin-2- yl)azetidin-1-yl)quinazoline
##STR00357## 5-(3-(1-(quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzo[d]thiazole ##STR00358## (R &
S)-(1H-Benzoimidazol-2-yl)-(3-{3-
[4-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-
yl}-azetidin-1-yl)-methanone ##STR00359## (R &
S)-(1H-Benzoimidazol-2-yl)-(3-{3-
[3-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-
yl}-azetidin-1-yl)-methanone ##STR00360## (R &
S)-(1H-Benzoimidazol-2-yl)-(3-{3-
[4-(1-hydroxy-ethyl)-piperidin-1-yl]-
pyrazin-2-yl}-azetidin-1-yl)-methanone ##STR00361##
1-(4-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- piperidin-1-yl)-ethanone
##STR00362## 1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- one ##STR00363##
(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-
difluoro-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00364## (1H-Benzoimidazol-2-yl)-{3-[3-(4-
hydroxy-4-methyl-piperidin-1-yl)-pyrazin-
2-yl]-azetidin-1-yl}-methanone ##STR00365##
(1H-Benzoimidazol-2-yl)-[3-(5-phenyl-
pyrimidin-4-yl)-azetidin-1-yl]-methanone ##STR00366##
2-(3-(3-(prop-1-yn-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline
##STR00367## 2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-
yl]-quinoline ##STR00368##
2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1- yl]-quinazoline
##STR00369## 2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-
yl]-quinoxoline ##STR00370##
2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1- yl]-benzothiazole
##STR00371## 2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-quinoline ##STR00372##
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-quinazoline ##STR00373##
2-{3-[3-(3-Methoxy-phenyl)-pyridin-2-yl]- azetidin-1-yl}-quinoline
##STR00374## 2-[3-(3-m-Tolyl-pyridin-2-yl)-azetidin-1-
yl]-quinoline ##STR00375## (R &
S)-2-{3-[3-(3-Methyl-pyrrolidin-1-
yl]-pyridin-2-yl]-azetidin-1-yl}-quinoline ##STR00376##
4-Methyl-2'-(1-quinolin-2-yl-azetidin-3-
yl)-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl ##STR00377##
{1-[3-(1-Quinolin-2-yl-piperidin-4-yl)-
pyrazin-2-yl]-piperidin-4-yl}-methanol ##STR00378##
{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin-4-yl}-methanol ##STR00379##
{1-[3-(1-Quinazolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin-4-yl}-methanol ##STR00380##
4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenylamine
##STR00381## {1-[3-(1-Benzothiazol-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin-4-yl}-methanol ##STR00382##
{1-[3-(1-Benzooxazol-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin-4-yl}-methanol ##STR00383##
(1-{3-[1-(5-Methyl-pyridin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00384##
2-(4-benzylpiperidin-1-yl)-3-(1-(quinolin-
2-yl)azetidin-3-yl)quinoxaline ##STR00385##
[5'-Fluoro-2'-(1-quinolin-2-yl-azetidin-3-
yl)-3,4,5,6-tetrahydro-2H- [1,3']bipyridinyl-4-yl]-methanol
##STR00386## {1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyridazin-4-yl]-piperidin-4-yl}-methanol ##STR00387## (R &
S)-2-(3-(3-(3-methylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00388## (S or
R)-2-(3-(3-(3-methylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00389## (R or
S)-2-(3-(3-(3-methylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00390##
2-(1-Quinolin-2-yl-azetidin-3-yl)-3-m- tolyl-quinoxaline
##STR00391## 4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
quinoxalin-2-yl]-phenylamine ##STR00392##
3-[3-(1-Quinolin-2-yl-azetidin-3-yl)- quinoxalin-2-yl]-phenol
##STR00393## 2-(3-Methoxy-phenyl)-3-(1-quinolin-2-yl-
azetidin-3-yl)-quinoxaline ##STR00394##
2-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenol
##STR00395## 3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-phenol ##STR00396##
4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenol
##STR00397## 2-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-phenylamine ##STR00398##
3-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenylamine
##STR00399## 4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-phenylamine ##STR00400##
2-{3-[3-(4-Fluoro-3-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}-quinoline ##STR00401##
2-Fluoro-4-[3-(1-quinolin-2-yl-azetidin-3-
yl)-pyrazin-2-yl]-phenylamine ##STR00402##
2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)- azetidin-1-yl]-quinoline
##STR00403## 2-{3-[3-(4-Methyl-piperidin-1-yl)-pyrazin-
2-yl]-azetidin-1-yl}-quinoline ##STR00404##
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidine-4-carboxylic acid amide ##STR00405##
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidine-4-carboxylic acid dimethylamide
##STR00406## 1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidine-4-carboxylic acid methylamide ##STR00407##
1-[3'-(1-Quinolin-2-yl-azetidin-3-yl)-
2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl]- ethanone ##STR00408##
1-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-piperidin-4-ol
##STR00409## 2-Methoxy-1-{4-[3-(1-quinolin-2-yl-
azetidin-3-yl)-pyrazin-2-yl]-piperidin-1- yl}-ethanone ##STR00410##
1-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin-1-yl}-ethanone ##STR00411##
N-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-
pyrazin-2-yl]-phenyl}-acetamide ##STR00412##
1-(4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)- yl)ethanone
##STR00413## (R & S)-1-{1-[3-(1-Quinolin-2-yl-azetidin-
3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol ##STR00414## (R or S,
absolute stereospecificity not
determined)-1-{1-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2-yl]-piperidin-4- yl}-ethanol ##STR00415##
2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenol
##STR00416## (1-{3-[1-(6-Methyl-quinolin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00417##
(1-{3-[1-(7-Fluoro-quinolin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00418##
(1-{3-[1-(6-Fluoro-quinolin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00419##
{1-[3-(1-[1,8]Naphthyridin-2-yl-azetidin-
3-yl)-pyrazin-2-yl]-piperidin-4-yl}- methanol ##STR00420##
(1-{3-[1-(6-Chloro-quinolin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00421##
(1-{3-[1-(6-Chloro-quinoxalin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00422##
(1-{3-[1-(6-Methyl-pyridin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00423##
(1-{3-[1-(5-Chloro-pyridin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00424##
(1-(3-(1-(5-bromopyridin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidin-4-yl)methanol ##STR00425##
(1-(3-(1-(8-methylquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidin-4-yl)methanol ##STR00426##
(1-{3-[1-(8-Fluoro-quinolin-2-yl)-azetidin-
3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol ##STR00427##
(1-(3-(1-(8-chloroquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidin-4-yl)methanol ##STR00428##
(1-{3-[1-(8-Chloro-quinazolin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00429##
(1-{3-[1-(7-Chloro-quinazolin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00430##
(1-{3-[1-(6-Chloro-quinazolin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00431##
(1-{3-[1-(5-Chloro-quinazolin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00432##
(1-{3-[1-(7-Chloro-quinoxalin-2-yl)-
azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol ##STR00433##
2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)- azetidin-1-yl]-benzothiazole
##STR00434## 2-(3-(3-(3-methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)-8-methylquinoline ##STR00435##
6-Chloro-2-{3-[3-(3-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}-quinazoline ##STR00436##
8-Chloro-2-{3-[3-(3-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}-quinoline ##STR00437##
7-Fluoro-2-{3-[3-(3-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}-quinoline ##STR00438##
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-6-methyl-quinoline ##STR00439##
2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-[1,8]naphthyridine ##STR00440##
8-Chloro-2-{3-[3-(3-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}-quinazoline ##STR00441##
5-Chloro-2-{3-[3-(3-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}-quinazoline ##STR00442##
2-(3-(3-(3-methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)-4-phenylpyrimidine ##STR00443##
2-(3-(3-(3-methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)benzo[d]thiazole ##STR00444##
6-methoxy-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-
yl)benzo[d]thiazole ##STR00445##
2-(3-(3-(3-methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)-1,6-naphthyridine ##STR00446##
6-chloro-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-
yl)quinoline ##STR00447## 6-fluoro-2-(3-(3-(3-
methoxyphenyl)pyrazin-2-yl)azetidin-1- yl)benzo[d]thiazole
##STR00448## 2-(3-(3-(3-methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline-3-carbonitrile ##STR00449##
1-[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1- yl]-phthalazine
##STR00450## 6-chloro-2-(3-(3-phenylpyrazin-2-
yl)azetidin-1-yl)-1H-benzo[d]imidazole ##STR00451##
2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)- 1H-benzo[d]imidazole
##STR00452## 2-((3-(3-phenylpyrazin-2-yl)azetidin-1-
yl)methyl)-1H-benzo[d]imidazole ##STR00453##
3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzamide
##STR00454## 4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzamide ##STR00455##
2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzamide ##STR00456##
2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzamide ##STR00457##
2-(3-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)propan-2-ol ##STR00458##
2-(4-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)phenyl)propan-2-ol ##STR00459##
2-(3-(3-(1,2,3,6-tetrahydropyridin-4-
yl)pyrazin-2-yl)azetidin-1-yl)quinoline ##STR00460## lithium
3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzoate
##STR00461## (S or R)-2-(3-(3-(3-(pyridin-3-
yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline
##STR00462## (R or S)-2-(3-(3-(3-(pyridin-3-
yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline
##STR00463## (1H-Benzoimidazol-2-yl)-{3-[3-(2-
methoxy-phenoxy)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00464## (1H-Benzoimidazol-2-yl)-{3-[3-(3-
methoxy-phenoxy)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00465## (1H-benzoimidazol-2-yl)-{3-[3-(4-
methoxy-phenoxy)-pyrazin-2-yl]-azetidin- 1-yl}-methanone
##STR00466## (1H-Benzoimidazol-2-yl)-[3-(3-phenoxy-
pyrazin-2-yl)-azetidin-1-yl]-methanone ##STR00467##
(1H-benzoimidazol-2-yl)-{3-[3-
(tetrahydro-pyran-4-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone
##STR00468## (7-Chloro-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00469##
(6-Chloro-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00470##
(7-Fluoro-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00471##
(6-Fluoro-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00472##
(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00473##
(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-
phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone ##STR00474##
(1H-benzoimidazol-2-yl)-{3-[3-(2-
methoxy-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00475## (1H-benzoimidazol-2-yl)-{3-[3-(3-
methoxy-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00476## (1H-Benzoimidazol-2-yl)-{3-[3-(4-
methoxy-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone
##STR00477## (1H-benzoimidazol-2-yl)-[3-(2-phenyl-
pyridin-3-yl)-azetidin-1-yl]-methanone ##STR00478##
2-(3-(3-(1H-indol-5-yl)pyrazin-2- yl)azetidin-1-yl)quinazoline
[0217] Another aspect of the invention relates to the compounds of
Examples 36.1 to 36.190 as listed in Table 36 below, or a
pharmaceutically acceptable salt thereof.
[0218] 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, F, .sup.15O, .sup.13N, .sup.76Br,
.sup.77Br, .sup.123I, or .sup.125I.
[0219] 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.
[0220] 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.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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.
[0225] 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.
[0226] 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.
.sup.14C, are particularly useful for this purpose in view of their
ease of incorporation and ready means of detection.
[0227] 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.
[0228] Substitution with positron emitting isotopes, such as
.sup.11C, F, .sup.15O and .sup.13N, can be useful in Positron
Emission Topography (PET) studies for examining substrate receptor
occupancy.
[0229] 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.
[0230] 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.
[0231] 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
[0232] The term "C.sub..alpha.-.beta.alk" means an alkyl group
comprising a minimum of .alpha. and a maximum of .beta. carbon
atoms in a branched, cyclical or linear relationship or any
combination of the three, wherein .alpha. and .beta. 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
##STR00479##
[0233] 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.
[0234] The terms "oxo" and "thioxo" represent the groups .dbd.O (as
in carbonyl) and .dbd.S (as in thiocarbonyl), respectively.
[0235] The term "halo" or "halogen" means a halogen atoms selected
from F, Cl, Br or I.
[0236] 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.
[0237] 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:
##STR00480##
[0238] 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:
##STR00481##
[0239] 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:
##STR00482##
[0240] The group N(C.sub..alpha.-.beta.alk)
C.sub..alpha.-.beta.alk, wherein .alpha. and .beta. 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:
##STR00483##
[0241] 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 unsaturated ring such as phenyl or naphthyl.
[0242] The term "heteroatom" means N, O and S.
[0243] 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:
##STR00484## ##STR00485##
[0244] 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).
[0245] The term "saturated, partially-saturated or unsaturated"
includes substituents saturated with hydrogens, substituents
completely unsaturated with hydrogens and substituents partially
saturated with hydrogens.
[0246] 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-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
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.
[0247] 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,
pyridazinyl, 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-(oxathiazinyl, and 1,4,2-oxadiazinyl.
[0248] Further exemplary seven membered rings are azepinyl,
oxepinyl, thiepinyl and 1,2,4-triazepinyl.
[0249] Further exemplary eight membered rings are cyclooctyl,
cyclooctenyl and cyclooctadienyl.
[0250] 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.
[0251] 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,
norbornane, bicyclo[2.1.0]pentane, bicyclo[3.3.0]octane,
bicyclo[2.2.2]octane, bicyclo[3.3.3]undecane, and the like.
[0252] 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(2,6)]decane, and the like.
[0253] 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.
[0254] 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.
[0255] 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.1-8-alkyl, 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
--NR.sup.xR.sup.x, the R.sup.x groups may be joined together with
the nitrogen atom to form a ring.
[0256] A group or atom that replaces a hydrogen atom is also called
a substituent.
[0257] Any particular molecule or group can have one or more
substituent depending on the number of hydrogen atoms that can be
replaced.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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:
##STR00486##
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.
[0264] 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, Apr. 11, 1981)
discloses Mannich-base hydroxamic acid prodrugs, their preparation
and use.
[0265] 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.
[0266] 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.
[0267] 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 excipient, are suitable for
administration to a patient.
[0268] The terms "treating", "treat" or "treatment" and the like
include preventative (e.g., prophylactic) and palliative
treatment.
[0269] 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
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] 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 1a-voltage dependent calcium channel);
spinocerebellar ataxia type-7 (ataxin-7); and spinal and bulbar
muscular atrophy (SBMA, also know as Kennedy disease).
[0280] 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(1 Suppl 1):S17-30, 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.
[0281] 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).
[0282] 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.
[0283] 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.
[0284] 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
[0285] 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
[0286] 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.
[0287] 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.
[0288] 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.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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.
[0293] Other suitable pharmaceutical excipients and their
formulations are described in Remington's Pharmaceutical Sciences,
Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
[0294] 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 %.
[0295] 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 .alpha.-7 agonists, PDE4 inhibitors, other
PDE10 inhibitors, calcium channel blockers, muscarinic m1 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.
[0296] 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), .alpha.-glucosidase
inhibitors (such as Acarbose, Miglitol, and Voglibose), insulin
sensitizers (such as the PPAR-.gamma. agonists, e.g., the
glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and
11beta-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, .beta.-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
[0297] 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.
[0298] The following abbreviations are commonly used: [0299] Ac the
group CH.sub.3--(CO)-- [0300] AcOH or HOAc acetic acid [0301]
Ac.sub.2O acetic anhydride [0302] BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [0303] BnO Benzyloxy
[0304] Boc.sub.2O di-tert-butyl dicarbonate [0305] BTEA-Cl
benzyltriethylammonium chloride [0306] Bz Benzyl group [0307] Cbz
carboxylic acid benzyl ester [0308] CDI 1,1'-carbonyldiimidazole
[0309] d Day [0310] DCM Dichloromethane [0311] DIAD
(CH.sub.3).sub.2CHOOCN.dbd.NCOOCH(CH.sub.3).sub.2 [0312] DIEA
N,N-diisopropylethylamine [0313] Diox Dioxane [0314] DIPEA
diisopropylethyl amine [0315] DMA Dimethylamine [0316] DMAP
4-(dimethylamino)pyridine [0317] DME Dimethoxyethane [0318] DMF
N,N-dimethylformamide [0319] Dess-Martin Periodinane
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one [0320]
DMSO dimethyl sulfoxide [0321] DPPA diphenyl phosphoryl azide
[0322] EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride [0323] ESI-MS electrospray ionization mass
spectrometry [0324] Et.sub.2O diethyl ether [0325] EtOAc ethyl
acetate [0326] EtOH ethyl alcohol [0327] Et.sub.3N triethyl amine
[0328] g Grams [0329] h hour or hours [0330] HATU
O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0331] HBTU
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
hexafluorophosphate [0332] HCl Hydrochloric acid [0333] HPLC high
pressure liquid chromatography [0334] IPA isopropyl alcohol [0335]
iPr.sub.2NEt diisopropylethylamine [0336] iPrOH Isopropyl alcohol
[0337] ISCO in-situ chemical oxidation [0338] 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 [0339] LCMS liquid chromatography mass spectrometry
[0340] LDA Lithium diisopropyl amide [0341] LiHMDS Lithium
bis(trimethylsilyl)amide [0342] Me Methyl [0343] MeCN Acetonitrile
[0344] MeI Iodomethane [0345] MeOH methyl alcohol [0346] MeOD
deuteurated methyl alcohol [0347] mg Milligrams [0348] min Min
[0349] mL Milliliters [0350] Mo--(CO).sub.6 molybdenum hexacarbonyl
[0351] MTBE methyl tert-butyl ether [0352] NBS N-bromosuccinimide
[0353] NMP 1-methyl-2-pyrrolidinone [0354] NMR nuclear magnetic
resonance [0355] NOESY nuclear Overhauser effect spectroscopy
[0356] Pd(dppf)Cl.sub.2
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane [0357] PMBCl
1-(chloromethyl)-4-methoxybenzene [0358] PTSA p-toluenesulfonic
acid [0359] Py pyridine [0360] RT RT [0361] sat. saturated [0362]
t-bu tert-butyl group [0363] TFA trifluoroacetic acid [0364] THF
tetrahydrofuran [0365] TLC thin layer chromatography [0366] TMSCl
Trimethylsilyl chloride [0367] TBDPS Tert-Butylchlorodiphenyl
[0368] Tol Toluene [0369] TsCl 4-toluenesulfonyl chloride
(CH.sub.3C.sub.6H.sub.4SO.sub.2Cl) [0370] Xantphos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
General Schemes
[0371] In general, the compounds of the formula I can be prepared
according to the following General Schemes A to H, wherein m, p, q,
R.sup.1, R.sup.4a, R.sup.4b, R.sup.5, Y, X.sup.1, X.sup.2, X.sup.3,
X.sup.4, and X.sup.5 are defined herein.
##STR00487##
##STR00488##
##STR00489##
##STR00490##
##STR00491##
##STR00492##
##STR00493##
##STR00494##
##STR00495##
Zinc Dust Preactivation Procedure
[0372] Zinc dust (Acros) was slowly added to a well stirred
solution of aqueous 2N HCl. The material was allowed to stir for 30
min at which point it was filtered, washed with water, EtOH, and
diethyl ether. The material was dried using a rotavapor.
##STR00496##
STEP 1: TERT-BUTYL 3-(3-BROMOPYRIDIN-2-YL)AZETIDINE-1-CARBOXYLATE
(3)
[0373] A 5 L 3-neck round bottom flask fitted with a magnetic
stirrer under nitrogen was charged with zinc dust (138 g,
preactivated according to the above Preparation 1, 2.11 mol, 2 eq.)
and DMA (370 mL, anhydrous). 1,2-dibromoethane (13 mL, 0.158 mol,
0.15 eq, Aldrich) was then added over 5 min, followed by TMSCl (20
mL, 0.158 mol, 0.15 eq, Acros) over 5 min. The reaction mixture was
stirred for 20 min at RT. A solution of N-Boc-3-iodoazetidine (2)
(448 g, 1.583 mol, 1.5 eq, CNH Technologies) in DMA (925 mL,
anhydrous) was added over 25 min keeping the internal temperature
below 65.degree. C. using a water bath. The suspension was stirred
for 1 h at RT at which point it was degassed with nitrogen.
Stirring was stopped and the suspension was allowed to stand. A 12
L 3-neck round bottom flask fitted with a mechanical stirrer was
charged with 2,3-dibromopyridine (1) (250 g, 1.055 mol, 1.0 eq,
Frontier Scientific), PdCl.sub.2dppf.CH.sub.2Cl.sub.2 (25.8 g,
31.65 mmol, 0.03 eq, Aldrich), CuI (12.5 g, 65.41 mmol, 0.062 eq,
Aldrich), and DMA (925 mL, anhydrous). The solution was degassed
with nitrogen. The clear zinc reagent solution above the residual
solid zinc was poured into the 12 L flask under nitrogen. The brown
solution was degassed with nitrogen and heated to 80.degree. C. for
17 h at which point LCMS indicated complete conversion of
2,3-dibromopyridine (1). The reaction mixture was transferred to
brine (2 L) in 22 L separatory funnel. Water (2 L) and EtOAc (4 L)
were added and the layers were separated. The aqueous layer was
extracted with EtOAc (2.times.3 L). The combined organics were
washed with water (3.times.3 L) and brine (2 L), dried over sodium
sulfate and evaporated. The resulting residue was purified by
column chromatography (eluting with hexanes/ethyl acetate=9:1 to
5:1) to obtain 289 g of impure tert-butyl
3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) which was
distilled under high vacuum to remove the impurity
(N-Boc-azetidine) to give 281 g of pure tert-butyl
3-(3-bromopyridin-2-yl)azetidine-1-carboxylate. Yield: 85%.
##STR00497##
STEP 2: 2-(AZETIDIN-3-YL)-3-BROMOPYRIDINE HYDROCHLORIDE (4)
[0374] To a solution of tert-butyl
3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) (266 g, 0.849
mol, 1 eq.) in methanol (6 L) was added concentrated HCl (350 mL,
4.2 mol, 4.95 eq.) and the resulting mixture was stirred at RT for
92 hrs. The mixture was concentrated and dried using a rotavapor to
obtain 230 g of 2-(azetidin-3-yl)-3-bromopyridine hydrochloride
(4).
##STR00498##
STEP 3: 2-(3-(3-BROMOPYRIDIN-2-YL)AZETIDIN-1-YL)QUINOLINE (5)
[0375] A mixture of 2-(azetidin-3-yl)-3-bromopyridine hydrochloride
(4) (221 g, 0.886 mol), 2-chloroquinoline (133.5 g, 0.816 mol, 0.92
eq., Combi-Blocks) and cesium carbonate (866 g, 2.658 mol, 3 eq.)
in anhydrous DMF (7 L) was heated to 110.degree. C. and stirred for
16 hrs. After cooling to RT, the mixture was transferred to 50 L
separatory funnel and diluted with water (14 L). The precipitated
solid was filtered, stirred in water (4 L), filtered and dried to
obtain 222 g of 2-(3-(3-bromopyridin-2-yl)azetidin-1-yl)quinoline.
Yield: 80% over two steps.
[0376] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. ppm 8.58 (d,
J=4.8 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.71
(d, J=8.1 Hz, 1H), 7.65-7.50 (m, 2H), 7.35-7.15 (m, 2H), 6.81 (d,
J=9.0 Hz, 1H), 4.55-4.30 (m, 5H). HPLC purity: >98% (215 nm and
254 nm)
[0377] LCMS: m/z: 340.1 for .sup.79Br (M+1), Calcd. for
C.sub.17H.sub.14.sup.79BrN.sub.3: 339.04; 342.1 for .sup.81Br
(M+1), Calcd. for C.sub.17H.sub.14.sup.81BrN.sub.3: 341.04.
##STR00499##
STEP 1: TERT-BUTYL 3-(3-CHLOROPYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE
(7)
[0378] A 12 L 3-neck round bottom flask fitted with a magnetic
stirrer under nitrogen was charged with zinc dust (745 g,
preactivated according to the above Preparation 1, 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 min, followed by TMSCl (108 mL,
0.855 mol, 0.15 eq, Acros) over 20 min. The reaction mixture was
stirred for 25 min at RT. A solution of N-Boc-3-iodoazetidine (2)
(2420 g, 8.55 mol, 1.5 eq, CNH Technologies) in DMA (5 L,
anhydrous) was added via a 2 L addition funnel over 2 h keeping the
internal temperature below 65.degree. C. using a water bath. The
suspension was stirred for 1 h at RT at which point it was degassed
with nitrogen. Stirring was stopped and the suspension was allowed
to stand. A 22 L 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dichloropyrazine (6) (850 g, 5.70 mol,
1.0 eq, AK Scientific), PdCl.sub.2dppf.CH.sub.2Cl.sub.2 (140 g, 171
mmol, 0.03 eq, Aldrich), CuI (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 22 L flask under nitrogen. The brown solution was
degassed with nitrogen and heated to 80.degree. C. for 16 h at
which point LCMS indicated complete conversion of
2,3-dichloropyrazine (6). The reaction mixture was transferred to
brine (8 L) in 50 L 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
obtain 536 g of pure tert-butyl
3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7) 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
(7).
[0379] Total: 617 g, Yield: 40%.
##STR00500##
STEP 2: 2-(AZETIDIN-3-YL)-3-CHLOROPYRAZINE HYDROCHLORIDE (8)
[0380] To a solution of tert-butyl
3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7) (300 g, 1.112
mol, 1 eq.) in methanol (6 L) was added concentrated HCl (400 mL,
4.8 mol, 4.3 eq.) and the resulting mixture was stirred at RT for
112 h. The mixture was concentrated and dried on rotavapor to
obtain 230 g of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride
(8).
##STR00501##
STEP 3: 2-(3-(3-CHLOROPYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE (9)
[0381] A mixture of 2-(azetidin-3-yl)-3-chloropyrazine
hydrochloride (8) (163 g, 0.79 mol), 2-bromoquinoline (164 g, 0.79
mol, 1 eq., Combi-Blocks) and cesium carbonate (772 g, 2.37 mol, 3
eq., Aldrich) in anhydrous DMF (6.5 L) was heated to 110.degree. C.
and stirred for 19 h. After cooling to RT, the mixture was
transferred to 50 L separatory funnel and diluted with water (13
L). Then it was extracted with ethyl acetate (20 L.times.2) and the
organic extracts were combined, washed with water (8 L), brine (8
L), dried and concentrated. The resulting residue was purified by
column chromatography (eluting with hexanes/ethyl acetate=9:1 to
3:1). All fractions containing desired compound were combined and
concentrated. The obtained solid was triturated with MTBE (250 mL),
washed with MTBE (100 mL.times.2) and dried to obtain 100 g of
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99%
purity. The mother liquor was concentrated and purified by column
chromatography and trituration with MTBE again to give 4.5 g of
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99%
purity. Yield: 45% for two steps.
[0382] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.ppm 8.67 (d,
J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.04 (d, J=9.6 Hz, 1H), 7.72
(d, J=8.4 Hz, 1H), 7.65-7.50 (m, 2H), 7.23 (t, J=7.35 Hz, 2H), 6.79
(d, J=9.0 Hz, 1H), 4.60-4.30 (m, 5H). HPLC purity: >99% (215 nm
and 254 nm) LCMS: m/z: 297.1 (M+1), Calcd. for
C.sub.16H.sub.13ClN.sub.4: 296.08.
##STR00502##
2-(3-(3-CHLOROPYRAZIN-2-YL)AZETIDIN-1-YL)QUINAZOLINE (10)
[0383] 2-(Azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (1.50
g, 7.28 mmol), 2-chloroquinazoline (1.20 g, 7.28 mmol, Parkway
Scientific), and cesium carbonate (5.22 g, 16.0 mmol, Fluka) were
mixed in DMF (30 mL) in a round bottom flask under a nitrogen
atmosphere. The mixture was stirred at 110.degree. C. for 17 h. The
reaction mixture was cooled to RT, diluted with water, and
extracted with EtOAc (2.times.). The combined organic extracts were
washed with saturated sodium chloride, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The resulting crude
mixture was purified via silica gel flash column chromatography
eluting with 0% to 100% EtOAc in hexanes to give 1.02 g (47%) of a
yellow amorphous solid.
[0384] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 4.41-4.50
(m, 1H) 4.58-4.63 (m, 2H) 4.65-4.72 (m, 2H) 7.22-7.28 (m, 1H)
7.61-7.72 (m, 3H) 8.28 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H)
9.04 (s, 1H). ESI (M+1) 298.1; calc for C.sub.15H.sub.12ClN.sub.5
297.
##STR00503##
STEP 1. 3-(3-MORPHOLIN-4-YL-PYRAZIN-2-YL)-AZETIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER (11)
[0385] A mixture of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (269 mg, 1.0 mmol) in morpholine was heated by microwave
at 160.degree. C. for 2 h. The mixture was concentrated to give the
crude compound and which was purified by column chromatography to
afford pure product (11) (300 mg, yield 94%) as solid. ESI-MS
(M+1): 321 calc. for C.sub.16H.sub.24N.sub.4O.sub.3 320.
##STR00504##
STEP 2. 4-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-MORPHOLINE HYDROCHLORIDE
(12)
[0386] To a solution of 4 N HCl/MeOH (10 mL) was added compound
(11) (300 mg, 0.90 mmol) at 0.degree. C. and the resulting mixture
was stirred at RT for 1 h. The mixture was concentrated under
reduced pressure to give (12) (200 mg, yield 100%), which was used
directly for the next step without further purification. ESI-MS
(M+1): 221 calc. for C.sub.11H.sub.16N.sub.4O 220.
[0387] The following Table 1 lists compounds of Preparation P4.1 to
P4.4, which were made analogous to Preparation 4 by using the
appropriate materials.
TABLE-US-00002 TABLE 1 PREPARATION P4.1 TO P4.4 ESI-MS Prep. #
Structure Chemical Name (M + 1) P4.1 ##STR00505## tert-butyl 3-(3-
morpholinopyrazin-2- yl)azetidine-1- carboxylate 321 P4.2
##STR00506## tert-butyl 3-(3-(4- hydroxypiperidin-1-
yl)pyrazin-2-yl)- azetidine-1- carboxylate 335 P4.3 ##STR00507##
4-(3-azetidin-3-yl- pyrazin-2-yl)- morpholine hydrochloride 221
P4.4 ##STR00508## 1-(3-(azetidin-3-yl)- pyrazin-2-
yl)piperidin-4-ol hydrochloride 235
##STR00509##
STEP 1.
3-[3-(2-METHOXY-PHENOXY)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (13)
[0388] A mixture of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (100 mg, 0.37 mmol), 2-methoxy-phenol (47 mg, 0.37 mmol)
and Cs.sub.2CO.sub.3 (242 mg, 0.74 mmol) in DMSO (10 mL) was
stirred at 90.degree. C. overnight. The mixture was diluted with
water and extracted with EtOAc. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated to give the
crude compound, which was purified by column chromatography to
afford pure product (13) (80 mg, 0.22 mmol, yield 61%) as solid.
ESI-MS (M+1): 358 calc. for C.sub.19H.sub.23N.sub.3O.sub.4 357.
##STR00510##
STEP 2. 2-AZETIDIN-3-YL-3-(2-METHOXY-PHENOXY)-PYRAZINE
HYDROCHLORIDE (14)
[0389] To a solution of 4 N HCl/MeOH (10 mL) was added compound
(13) (80 mg, 0.22 mmol) at 0.degree. C. The resulting mixture was
stirred at RT for 1 h. The mixture was concentrated under reduced
pressure to give (14) (65 mg, yield 100%), which was used for the
next step without further purification. ESI-MS (M+1): 258 calc. for
C.sub.14H.sub.15N.sub.3O.sub.2 257.
[0390] The following Table 2 lists compounds of Preparation P5.1 to
P5.8, which were made analogous to Preparation 5 by using the
appropriate materials.
TABLE-US-00003 TABLE 2 PREPARATION P5.1 TO P5.8 ESI-MS Ex. #
Structure Chemical Name (M + 1) P5.1 ##STR00511## 3-[3-(2-methoxy-
phenoxy)-pyrazin- 2-yl]-azetidine-1-carboxylic acid tert-butyl
ester 358 P5.2 ##STR00512## tert-butyl 3-(3-(3-
methoxyphenoxy)pyrazin-2- yl)azetidine-1-carboxylate 358 P5.3
##STR00513## tert-butyl 3-(3-(4- methoxyphenoxy)pyrazin-2-
yl)azetidine-1-carboxylate 358 P5.4 ##STR00514## tert-butyl 3-(3-
phenoxypyrazin-2- yl)azetidine-1-carboxylate 328 P5.5 ##STR00515##
2-azetidin-3-yl-3- (2-methoxy- phenoxy)-pyrazine hydrochloride 258
P5.6 ##STR00516## 2-(azetidin-3-yl)-3-(3- methoxyphenoxy)pyrazine
hydrochloride 258 P5.7 ##STR00517## 2-(azetidin-3-yl)-3-(4-
methoxyphenoxy)pyrazine hydrochloride 258 P5.8 ##STR00518##
2-(azetidin-3-yl)-3- phenoxypyrazine hydrochloride 228
##STR00519##
STEP 1. 2-TRICHLOROMETHYL-1H-BENZOIMIDAZOLE (17)
[0391] 2,2,2-trichloro-acetimidic acid benzyl ester (16) (2.3 g,
9.22 mmol, Alfa Aesar) was added to a solution of
Benzene-1,2-diamine (15) (1.0 g, 9.2 mmol) in acetic acid (30 mL),
the solution was stirred at RT for 1 h. H.sub.2O (20 mL) was added
to the mixture and the suspension was filtered. The filter cake was
washed with water and dried under vacuum to afford compound (17)
(1.90 g yield 88%) which was used directly for the next step
without further purification. ESI-MS (M+1): 235 calc. for
C.sub.8H.sub.5Cl.sub.3N.sub.2 234.
##STR00520##
STEP 2. 1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID METHYL ESTER (18)
[0392] Na.sub.2CO.sub.3 (0.64 g, 6.07 mmol) was added to a solution
of (17) (1.9 g, 6.07 mmol) in 20 mL MeOH. The reaction mixture was
heated to reflux for 14 h and then cooled to RT. 1N HCl was added
to the solution and the reaction mixture was stirred for 0.5 hour.
The mixture was extracted with EA. The organic phase was washed
with brine, dried over Na.sub.2SO.sub.4 and evaporated to give the
title compound (0.89 g, yield 83%). ESI-MS (M+1): 177 calc. for
C.sub.9H.sub.8N.sub.2O.sub.2 176.
##STR00521##
STEP 3. 1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID (19)
[0393] A mixture of 1H-benzoimidazole-2-carboxylic acid methyl
ester (18) (0.89 g, 5.1 mmol) in 2 N aq. NaOH (10 mL) and MeOH (10
mL) was stirred at RT for 18 h. The mixture was acidified to pH=4
with 1 N aqueous HCl. The mixture was extracted with EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and evaporated to obtain compound (19) as a brown solid (0.67 g,
yield 80%). ESI-MS (M+1): 163 calc. for
C.sub.8H.sub.6N.sub.2O.sub.2 162.
[0394] The following Table 3 lists compounds of Preparation P6.1 to
P6.18, which were made analogous to Preparation 6 by using the
appropriate materials.
TABLE-US-00004 TABLE 3 PREPARATION P6.1 TO P6.18 ESI-MS Ex. #
Structure Chemical Name (M + 1) P6.1 ##STR00522## 4-chloro-2-
(trichloromethyl)-1H- benzo[d]imidazole 268 P6.2 ##STR00523##
5-chloro-2- (trichloromethyl)-1H- benzo[d]imidazole 268 P6.3
##STR00524## 4-fluoro-2- (trichloromethyl)-1H- benzo[d]imidazole
252 P6.4 ##STR00525## 5-fluoro-2- (trichloromethyl)-1H-
benzo[d]imidazole 252 P6.5 ##STR00526## 4-methyl-2-
(trichloromethyl)-1H- benzo[d]imidazole 249 P6.6 ##STR00527##
5-methyl-2- (trichloromethyl)-1H- benzo[d]imidazole 249 P6.7
##STR00528## methyl 4-chloro-1H- benzo[d]imidazole-2- carboxylate
211 P6.8 ##STR00529## methyl 5-chloro-1H- benzo[d]imidazole-2-
carboxylate 211 P6.9 ##STR00530## methyl 4-fluoro-1H-
benzo[d]imidazole-2- carboxylate 195 P6.10 ##STR00531## methyl
5-fluoro-1H- benzo[d]imidazole- 2-carboxylate 195 P6.11
##STR00532## methyl 4-methyl-1H- benzo[d]imidazole- 2-carboxylate
191 P6.12 ##STR00533## methyl 5-methyl-1H- benzo[d]imidazole-
2-carboxylate 191 P6.13 ##STR00534## 4-chloro-1H-benzo[d]-
imidazole-2- carboxylic acid 197 P6.14 ##STR00535##
5-chloro-1H-benzo[d]- imidazole-2- carboxylic acid 197 P6.15
##STR00536## 4-fluoro-1H-benzo[d]- imidazole-2- carboxylic acid 181
P6.16 ##STR00537## 5-fluoro-1H-benzo[d]- imidazole-2- carboxylic
acid 181 P6.17 ##STR00538## 4-methyl-1H-benzo[d]- imidazole-2-
carboxylic acid 177 P6.18 ##STR00539## 5-methyl-1H-benzo[d]-
imidazole-2- carboxylic acid 177
##STR00540##
STEP 1.
3-[3-(4-METHOXY-PHENYL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (21)
[0395] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (100 mg, 0.37 mmol, as prepared in the above Preparation
2) in dioxane (8 mL) was added a solution of Na.sub.2CO.sub.3 (78
mg, 0.64 mmol) in 0.5 mL water, followed by additional of
4-methoxybenzeneboronic acid (20) (49 mg 0.40 mmol) and
Pd(dppf)Cl.sub.2 (8 mg). The resulting mixture was heated to reflux
overnight under N.sub.2 atmosphere. TLC showed that the starting
material was consumed completely. The solution was filtered and the
filtrate was concentrated to give the residue which was purified by
column chromatography on silica gel to give the product compound
(21) (120 mg, yield 96%) as solid. ESI-MS (M+1): 342 calc. for
C.sub.19H.sub.23N.sub.3O.sub.3 341.
##STR00541##
STEP 2. 2-AZETIDIN-3-YL-3-(4-METHOXY-PHENYL)-PYRAZINE HYDROCHLORIDE
(22)
[0396] To a solution of 4 N HCl in MeOH (10 mL) was added (21) (120
mg, 0.35 mmol) at 0.degree. C. and the resulting mixture was
stirred at RT for 1 h. The mixture was concentrated under reduced
pressure to give 2-azetidin-3-yl-3-(4-methoxy-phenyl)-pyrazine (22)
(95 mg, yield 100%) which was used for the next step without
further purification. ESI-MS (M+1): 242 calc. for
C.sub.14H.sub.15N.sub.3O 241.
[0397] The following Table 4 lists compounds of Preparation P7.1 to
P7.6, which were made analogous to Preparation 7 by using the
appropriate materials.
TABLE-US-00005 TABLE 4 PREPARATION P7.1 TO P7.6 ESI-MS Ex. #
Structure Chemical Name (M + 1) P7.1 ##STR00542## tert-butyl
3-(3-(4- methoxyphenyl)pyrazin-2- yl)azetidine-1-carboxylate 342
P7.2 ##STR00543## tert-butyl 3-(3-(2- methoxyphenyl)pyrazin-2-
yl)azetidine-1-carboxylate 342 P7.3 ##STR00544## tert-butyl 3-(3-
phenylpyrazin-2- yl)azetidine-1-carboxylate 312 P7.4 ##STR00545##
2-(azetidin-3-yl)-3-(4- methoxyphenyl)pyrazine hydrochloride 242
P7.5 ##STR00546## 2-(azetidin-3-yl)-3-(2- methoxyphenyl)pyrazine
hydrochloride 242 P7.6 ##STR00547## 2-(azetidin-3-yl)-3-
phenylpyrazine hydrochloride 212
##STR00548##
STEP 1. TERT-BUTYL 3-(2-FLUOROPYRIDIN-3-YL)AZETIDINE-1-CARBOXYLATE
(25)
[0398] To a 2 L 3 necked round bottomed flask fitted with a
mechanical stirrer, under nitrogen atmosphere was placed Zinc dust,
which was preactivated according to above Preparation 2, (51.2 g,
0.78 mol, 1.94 eq) and dimethyl acetamide (162 mL). To the above
suspension, 1,2-dibromoethane (12.14 g, 0.0646 mol, 0.16 eq) was
added dropwise at RT (exotherm and bubbling were observed),
followed by dropwise addition of TMSCl (6.99 g, 0.0646 mol, 0.16
eq). A vigorous reaction (exotherm to 55.degree. C.) was observed.
To this, a solution of N-Boc-3-iodoazetidine (2) (182.88 g, 0.646
mol, 1.6 eq) in dimethyl acetamide (378 mL) was added dropwise
using an addition funnel (exotherm to 50.degree. C. was observed).
The suspension was stirred for 1.5 h at RT and was then degassed
with nitrogen for 15 min. Stirring was stopped and suspension was
allowed to stand under nitrogen. To a 5 L 3 necked round bottomed
flask, fitted with mechanical stirrer, flushed with nitrogen were
placed 3-iodo-2-fluoropyridine (24) (90 g, 0.404 mol, 1.0 eq),
PdCl.sub.2dppf.CH.sub.2Cl.sub.2 (9.88 g, 0.012 mol, 0.03 eq), CuI
(4.76 g, 0.025 mol, 0.062 eq) and dimethyl acetamide (396 mL). The
red colored suspension was degassed with nitrogen for 15 min.
[0399] The Zinc reagent solution in 2 L flask was cannulated into 5
L round bottomed flask. The resulting reaction mixture was degassed
again with nitrogen for 15 min with stirring and heated to
80.degree. C. for overnight under nitrogen. LCMS indicates
completion of reaction. The reaction was cooled to RT and quenched
by addition of brine solution (1 L). To this EtOAc (1 L) and water
(1 L) were added and layers were separated. The aqueous layer was
extracted with EtOAc (2.times.2 L). The combined EtOAc layers were
washed with water (2 L), brine (1 L), dried (Na.sub.2SO.sub.4),
filtered, and evaporated. The crude was purified by column
chromatography to give 52 g of tert-butyl
3-(2-fluoropyridin-3-yl)azetidine-1-carboxylate (25) (yield: 51%)
as an oil, which solidified on standing.
[0400] .sup.1H NMR (300 MHz CDCl.sub.3): 8.13 (doublet, J=4.8 Hz,
1H), 7.83-7.76 (dt, 1H), 7.28-7.20 (dt, 1H), 4.35 (t, J=8.7 Hz,
2H), 4.05-3.88 (m, 3H), 1.46 (s, 9H). LC-MS: 253 (M+1); calcd for
C.sub.13H.sub.17FN.sub.2O.sub.2: 252.28
##STR00549##
STEP 2. 3-(2-PHENYL-PYRIDIN-3-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (27)
[0401] To a solution of
3-(2-fluoro-pyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl
ester (25) (200 mg, 0.80 mmol), Ni(acac).sub.2 (20 mg, 0.08 mmol),
DPPF (32 mg, 0.08 mmol) in THF (10 mL) was added PhMgBr (1 M, 0.8
mL, 0.80 mmol). The resulting mixture was heated to reflux
overnight under N.sub.2 atmosphere. TLC showed that the staring
material was consumed completely. The solution was filtered and the
filtrate was concentrated to give the residue, The crude compound
was purified by column chromatography on silica gel to give the
product 3 compound (27) (180 mg, yield 78%) as solid. ESI-MS (M+1):
311 calc. for C.sub.19H.sub.22N.sub.2O.sub.2 310.
##STR00550##
STEP 3. 3-AZETIDIN-3-YL-2-PHENYL-PYRIDINE HYDROCHLORIDE (28)
[0402] To a solution of 4 M HCl in MeOH (10 mL) was added
3-(2-phenyl-pyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl
ester (27) (180 mg, 0.58 mmol) at 0.degree. C. and the resulting
mixture was stirred at RT for 1 h. The mixture was concentrated
under reduced pressure to give 3-azetidin-3-yl-2-phenyl-pyridine
hydrochloride (28) (120 mg, yield 94%) which was used for the next
step without further purification. ESI-MS (M+1): 211 calc. for
C.sub.14H.sub.14N.sub.2 210.
##STR00551##
STEP 1. 3-(3-M-TOLYL-PYRAZIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (30)
[0403] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (540 mg, 2.0 mmol, Preparation 2), 3-methyl-phenylboronic
acid (78) (299.2 mg, 2.2 mmol), K.sub.3PO.sub.4 (818 mg, 4.0 mmol),
in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl.sub.2
(73.2 mg, 0.1 mmol) then the reaction mixture was stirred at
90.degree. C. under nitrogen atmosphere overnight. The reaction
mixture was filtered through CELITE.RTM. and washed with EtOAc (50
mL). The filtrate was concentrated and the crude product was
purified by silica gel column to give
3-(3-m-tolyl-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (30) (597 mg, 1.84 mmol, yield 91.85%).
[0404] ESI-MS (M+1): 326 calc. for C.sub.19H.sub.23N.sub.3O.sub.2
325.
##STR00552##
STEP 2. 2-AZETIDIN-3-YL-3-M-TOLYL-PYRAZINE HYDROCHLORIDE (31)
[0405] A solution of
3-(3-m-tolyl-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (30) (325 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL) was stirred at
RT for 30 min. The reaction mixture was concentrated to give (31)
(260 mg, 0.99 mmol, yield 99.24%). ESI-MS (M+1): 226 calc. for
C.sub.14H.sub.15N.sub.3 225.
##STR00553##
STEP 1.
3-[3-(3-METHOXY-PHENYL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (33)
[0406] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (540 mg, 2.0 mmol, Preparation 2),
3-methoxy-phenylboronic acid (29) (334.4 mg, 2.2 mmol),
K.sub.3PO.sub.4 (818 mg, 4.0 mmol), in dioxane (20 mL) and water (4
mL) was added Pd(dppf)Cl.sub.2 (73.2 mg, 0.1 mmol) then the
reaction mixture was stirred at 90.degree. C. under nitrogen
atmosphere overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with EtOAc (50 mL). The filtrate was
concentrated and the crude product was purified by silica gel
column to give compound (33) (627.4 mg, 1.84 mmol, yield
91.85%).
[0407] ESI-MS (M+1): 342 calc. for C.sub.19H.sub.23N.sub.3O.sub.3
341.
##STR00554##
STEP 2. 2-AZETIDIN-3-YL-3-(3-METHOXY-PHENYL)-PYRAZINE HYDROCHLORIDE
(34)
[0408] A solution of (33) (341 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL)
was stirred at RT for 30 min. The reaction mixture was concentrated
to give (34) (260 mg, 0.99 mmol, yield 99.24%).
[0409] ESI-MS (M+1): 242 calc. for C.sub.14H.sub.15N.sub.3O
241.
##STR00555##
STEP 1.
3-[3-(4-HYDROXYMETHYL-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDINE-1
CARBOXYLIC ACID TERT-BUTYL ESTER (36)
[0410] To a solution of compound (7) (540 mg, 2 mmol, Preparation
2) and 4-amino-2-methyl-butan-1-ol (230 mg, 2 mmol) in DMSO (20 mL)
was added Et.sub.3N (404 mg, 4 mmol). The reaction mixture was
stirred at 110.degree. C. overnight. The reaction mixture was
diluted with water, extracted with EtOAc (50 mL.times.3). 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 (EtOAc:Petrol ether=3:1) on silica gel to give (36).
(557 mg, 1.6 mmol, yield 80%).
[0411] ESI-MS (M+1): 349 calc. for C.sub.18H.sub.28N.sub.4O.sub.3
348.
##STR00556##
STEP 2. [1-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-PIPERIDIN-4-YL]-METHANOL
HYDROCHLORIDE (37)
[0412] A solution of (36) (557 mg, 1.6 mmol) in 4N HCl/MeOH (20 mL)
was stirred at RT for 30 min. The reaction mixture was concentrated
to give (37) (450 mg, 1.58 mmol, yield 98%).
[0413] ESI-MS (M+1): 249 calc. for C.sub.13H.sub.20N.sub.4O
248.
##STR00557##
STEP 1. 4-(3-CHLORO-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (39)
[0414] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol,
2.0 eq.) and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg,
1.27 mmol, 0.2 eq) was added slowly, followed by TMSCl (137 mg,
1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of 4-iodo-piperidine-1-carboxylic acid tert-butyl ester
(38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added
dropwise. The suspension was stirred for 1 h at RT.
[0415] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dichloro-pyrazine (6) (0.95 g, 6.4
mmol, 1.0 eq), Pd(dppf)Cl.sub.2 (446 mg, 0.64 mmol, 0.1 eq),
cuprous iodide (121 mg, 0.64 mmol, 0.1 eq), and DMA (20 mL,
anhydrous). The dark solution was degassed for 15 min. The clear
zinc reagent solution above the residual solid zinc was transferred
to the above 100 mL flask by cannulation. The dark solution was
degassed and heated to 80.degree. C. for 16 h. The reaction was
diluted with brine and extracted with EtOAc (3.times.100 mL). The
combined organics were washed with water (2.times.100 mL) and brine
(100 mL), followed by drying over sodium sulfate. The solution was
concentrated and the residue was purified by flash column
chromatography on silica gel (PE:EAOAc=2:1) to give the title
compound (39) (0.95 g, 3.2 mmol, 50% yield) as a light yellow
solid.
[0416] ESI-MS (M+1): 298 calc. for C.sub.14H.sub.20ClN.sub.3O.sub.2
297.
##STR00558##
STEP 2.
4-[3-(4-HYDROXYMETHYL-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-PIPERIDINE-1--
CARBOXYLIC ACID TERT-BUTYL ESTER (40)
[0417] To a solution of
4-(3-chloro-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl
ester (39) (297 mg, 1 mmol) and piperidin-4-yl-methanol (35) (126.5
mg, 1.1 mmol) in DMSO (6 mL) was added Et.sub.3N (202 mg, 2 mmol).
The reaction mixture was stirred at 100.degree. C. overnight. The
reaction mixture was diluted with water, extracted with EtOAc (30
mL.times.3). 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
compound (40) (302 mg, 0.8 mmol, yield 80.32%).
[0418] ESI-MS (M+1): 377 calc. for C.sub.20H.sub.32N.sub.4O.sub.3
376.
##STR00559##
STEP 3. [1-(3-PIPERIDIN-4-YL-PYRAZIN-2-YL)-PIPERIDIN-4-YL]-METHANOL
HYDROCHLORIDE (41)
[0419] A solution of
4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-piperidine-1-carboxyl-
ic acid tert-butyl ester (40) (376 mg, 1 mmol) in 4N HCl/MeOH (20
mL) was stirred at RT for 30 min. The reaction mixture was
concentrated to give (41) (308 mg, 0.98 mmol, yield 98.72%).
[0420] ESI-MS (M+1): 277 calc. for C.sub.15H.sub.24N.sub.4O
276.
##STR00560##
STEP 1. 3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDINE-1
CARBOXYLIC ACID TERT-BUTYL ESTER (43)
[0421] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (200 mg, 0.74 mmol, Preparation 2) and
3-methyl-pyrrolidine (42) (69.2 mg, 0.84 mmol) in DMSO (5 mL) was
added Et.sub.3N (149.5 mg, 1.48 mmol). The reaction mixture was
stirred at 10.degree. C. overnight. The reaction mixture was
diluted with water, extracted with EtOAc (30 mL.times.3). 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
3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidine-1-carboxylic
acid tert-butyl ester (43) (194 mg, 0.56 mmol, yield 75.99%).
[0422] ESI-MS (M+1): 319 calc. for C.sub.17H.sub.26N.sub.4O.sub.2
318
##STR00561##
STEP 2. 2-AZETIDIN-3-YL-3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZINE
HYDROCHLORIDE (44)
[0423] A solution of
3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidine-1-carboxylic
acid tert-butyl ester (43) (191 mg, 0.6 mmol) in 4N HCl/MeOH (13
mL) was stirred at RT for 30 min. The reaction mixture was
concentrated to give
2-azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride
(44)
[0424] (150 mg, 0.59 mmol, yield 99%).
[0425] ESI-MS (M+1): 219 calc. for C.sub.12H.sub.18N.sub.4 218
##STR00562##
3-(3-CHLORO-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYL
ESTER (46)
[0426] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (1.3
g, preactivated according to the above Preparation 1, 20 mmol, 2.0
eq.) and DMA (10 mL, anhydrous). 1,2-Dibromoethane (400 mg, 2.0
mmol, 0.2 eq) was added slowly, followed by TMSCl (240 mg, 2.0
mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of N-Boc-3-iodoazetidine (2) (4 g, 16 mmol, 1.6 eq) in DMA
(10 mL, anhydrous) was added dropwise. The suspension was stirred
for 1 h at RT.
[0427] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dichloro-quinoxaline (44) (2 g, 10
mmol, 1.0 eq), Pd(dppf)Cl.sub.2 (800 mg, 1.0 mmol, 0.1 eq), cuprous
iodide (200 mg, 1.0 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The
dark solution was degassed for 15 min. The clear zinc reagent
solution above the residual solid zinc was transferred to the above
100 mL flask by cannulation. The dark solution was degassed and
heated to 80.degree. C. for 16 h. The reaction was diluted with
brine and extracted with EtOAc (3.times.100 mL). The combined
organics were washed with water (2.times.100 mL) and brine (100
mL), followed by drying over sodium sulfate. The solution was
concentrated and the residue was purified by flash column
chromatography (PE:EAOAc=2:1) provides
3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (46) (1.43 g, 4.5 mmol, 45% yield) as a light yellow
solid.
[0428] ESI-MS (M+1): 320 calc. for C.sub.16H.sub.18ClN.sub.3O.sub.2
319.
##STR00563##
STEP 1.
3-[3-(4-HYDROXYMETHYL-PIPERIDIN-1-YL)-QUINOXALIN-2-YL]-AZETIDINE--
1-CARBOXYLIC ACID TERT-BUTYL ESTER (47)
[0429] To a solution of
3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (46) (638 mg, 2 mmol, Preparation 14) and
piperidin-4-yl-methanol (253 mg, 2.2 mmol) in DMSO (10 mL) was
added Et.sub.3N (404 mg, 4 mmol). The reaction mixture was stirred
at 140.degree. C. in microwave heating for 4 h. The reaction
mixture was diluted with water, extracted with EtOAc (30
mL.times.3). 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 (47)
(670 mg, 1.68 mmol, yield 84.15%). ESI-MS (M+1): 399 calc. for
C.sub.17H.sub.22N.sub.4O 398.
##STR00564##
STEP 2.
[1-(3-AZETIDIN-3-YL-QUINOXALIN-2-YL)-PIPERIDIN-4-YL]-METHANOL
HYDROCHLORIDE (48)
[0430] A solution of (47) (670 mg, 1.68 mmol) in 4N HCl/MeOH (25
mL) was stirred at RT for 30 min. The reaction mixture was
concentrated to give
[1-(3-azetidin-3-yl-quinoxalin-2-yl)-piperidin-4-yl]-methanol
hydrochloride (48) (560 mg, 1.67 mmol, yield 99%).
[0431] ESI-MS (M+1): 299 calc. for C.sub.17H.sub.22N.sub.4O
298.
##STR00565## ##STR00566##
STEP 1. 2-AZETIDIN-3-YL-3-CHLORO-PYRAZINE HYDROCHLORIDE (8)
[0432] A solution of compound (7) (540 mg, 2.0 mmol) in 2N HCl/MeOH
(20 mL) was stirred at RT for 30 min according to Preparation 2.
The reaction mixture was concentrated to give compound (8) (440 mg,
1.99 mmol, yield 99.7%).
[0433] ESI-MS (M+1): 170 calc. for C.sub.7HClN.sub.3 169.
##STR00567##
STEP 2.
4-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-3,6-DIHYDRO-2H-PYRIDINE-1-CARBOX-
YLIC ACID TERT-BUTYL ESTER (50)
[0434] To a solution of (8) (442 mg, 2.0 mmol), 4-phenylboronic
acid-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
(49) (679.8 mg, 2.2 mmol), K.sub.3PO.sub.4 (818 mg, 4.0 mmol) in
dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl.sub.2 (73.2
mg, 0.1 mmol) then the reaction mixture was stirred at 90.degree.
C. under nitrogen atmosphere overnight. The reaction mixture was
filtered through CELITE.RTM. and washed with EtOAc (50 mL). The
filtrate was concentrated and the crude product was purified by
silica gel column to give (50) (540 mg, 1.7 mmol, yield 85%).
[0435] ESI-MS (M+1): 317 calc. for C.sub.17H.sub.24N.sub.4O.sub.2
316.
##STR00568##
STEP 3. 4-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER (51)
[0436] To a solution of
4-(3-azetidin-3-yl-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (50) (540 mg, 1.7 mmol) in MeOH was added
Pd/C (10%, 0.5 g) under nitrogen. The reaction was stirred under
hydrogen (30 psi) at RT for 6 h. Filtered to remove Pd/C and
concentrated to dryness to give
4-(3-azetidin-3-yl-pyrazin-2-yl)-piperidine-1-carboxylic acid
tert-butyl ester (51) (502 mg, 1.58 mmol yield 92.9%).
[0437] ESI-MS (M+1): 319 calc. for C.sub.17H.sub.26N.sub.4O.sub.2
318.
##STR00569##
STEP 4.
4-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDINE-1-C-
ARBOXYLIC ACID TERT-BUTYL ESTER (53)
[0438] To a solution of (51) (318 mg, 1 mmol) and
2-chloro-quinoline (52) (163 mg, 1 mmol) in DMF was added
Cs.sub.2CO.sub.3 (650 mg, 2 mmol). The reaction mixture was stirred
at 100.degree. C. overnight. The reaction mixture was diluted with
water, extracted with EtOAc (3.times.20 mL). The combined organic
extracts were washed with water (20 mL) and brine (20 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 (53) (346 mg, 0.78 mmol, yield 77.8%).
[0439] ESI-MS (M+1): 446 calc. for C.sub.26H.sub.31N.sub.5O.sub.2
445.
##STR00570##
STEP 5.
2-[3-(3-PIPERIDIN-4-YL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-QUINOLINE
HYDROCHLORIDE (54)
[0440] A solution of
4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-1-carboxyli-
c acid tert-butyl ester (53) (346 mg, 0.78 mmol) in 4N HCl/MeOH (20
mL) was stirred at RT for 30 min. The reaction mixture was
concentrated to give the product (54) (294 mg, 0.77 mmol, yield
98.9%).
[0441] ESI-MS (M+1): 346 calc. for C.sub.21H.sub.23N.sub.5 345.
##STR00571##
STEP 1. 3-BROMO-5-FLUORO-PYRIDIN-2-YLAMINE (56)
[0442] NBS (10 g, 56.2 mmol) was added slowly to a solution of
5-fluoro-pyridin-2-ylamine (55) (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 obtain a residue, which was purified by silica gel
chromatography (10% to 20% EtOAc in petroleum ether) to give
3-bromo-5-fluoro-pyridin-2-ylamine (56) (5.2 g, 27.2 mmol, 31%
yield) as a yellow solid.
[0443] ESI-MS (M+1): 191 calc. for C.sub.5H.sub.4BrFN.sub.2
190.
##STR00572##
STEP 2. 2,3-DIBROMO-5-FLUORO-PYRIDINE (57)
[0444] At 60.degree. C., 3-bromo-5-fluoro-pyridin-2-ylamine (56)
(1.91 g, 0.01 mol) was dissolved in 48% hydrobromic acid (30 mL).
After cooling to -5.degree. C., bromine (3.24 g, 0.02 mol) was
added dropwise over 5 min. A solution of sodium nitrite (1.01 g,
0.02 mol) in water (3 mL) was then added at a rate to keep the
temperature of the reaction mixture between -5.degree. C. and
0.degree. C. When finished, the temperature was allowed to reach
25.degree. C. The bromine was reduced with an excess of solid
sodium sulfite, and the reaction mixture was extracted with EtOAc
(3.times.50 mL). The combined organic extracts were washed with
water (30 mL), 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 (10% to 20%
EtOAc in petroleum ether) to give 2,3-dibromo-5-fluoro-pyridine
(57) (1.27 g, 5.0 mmol, 50% yield) as a yellow solid.
[0445] ESI-MS (M+1): 254 calc. for C.sub.5H.sub.2Br.sub.2FN
253.
##STR00573##
STEP 3. 3-(3-BROMO-5-FLUORO-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER (58)
[0446] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol)
and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol)
was added slowly, followed by TMSCl (137 mg, 1.27 mmol). The
reaction was stirred for 15 min at RT. A solution of
N-Boc-3-iodoazetidine (2) (2.7 g, 9.5 mmol) in DMA (10 mL,
anhydrous) was added dropwise. The suspension was stirred for 1 h
at RT.
[0447] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dibromo-pyridine (57) (1.62 g, 6.4
mmol), Pd(dppf)Cl.sub.2 (446 mg, 0.64 mmol, 0.1 eq), cuprous iodide
(121 mg, 0.64 mmol), and DMA (20 mL, anhydrous). The dark solution
was degassed for 15 min. The clear zinc reagent solution above the
residual solid zinc was transferred to the above 100 mL flask by
cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography (PE:EtOAc=2:1)
provided the title compound (58) (860 mg, 2.6 mmol, 40% yield) as a
light yellow solid.
[0448] ESI-MS (M+1): 331 calc. for
C.sub.13H.sub.16BrFN.sub.2O.sub.2 330.
##STR00574## ##STR00575##
STEP 1. [1-(3,6-DICHLORO-PYRIDAZIN-4-YL)-PIPERIDIN-4-YL]-METHANOL
(60)
[0449] To a solution of 3,4,6-trichloro-pyridazine (59) (364 mg, 2
mmol) and piperidin-4-yl-methanol (35) (253 mg, 2.2 mmol) in DMSO
(5 mL) was added Et.sub.3N (404 mg, 4 mmol). The reaction mixture
was stirred at 100.degree. C. overnight. The reaction mixture was
diluted with water, extracted with EtOAc (30 mL.times.3). 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
[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-methanol (60)
(292.3 mg, 1.12 mmol, yield 75.99%).
[0450] ESI-MS (M+1): 262 calc. for C.sub.10H.sub.13Cl.sub.2N.sub.3O
261.
##STR00576##
STEP 2.
4-[4-(TERT-BUTYL-DIMETHYL-SILANYLOXYMETHYL)-PIPERIDIN-1-YL]-3,6-D-
ICHLORO-PYRIDAZINE (61)
[0451] [1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-methanol
(60) (1.83 g, 7 mol) upon treatment with TBSCl (2.1 g, 14 mmol) and
imidazole (2.38 g, 35 mmol) in DMF (15 mL) stirred at RT for 3 h,
The reaction mixture was diluted with water, extracted with EtOAc
(40 mL.times.3). The combined organic extracts were washed with
water (20 mL) and brine (20 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
4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-3,6-dichloro--
pyridazine (61) (2.55 g, 6.8 mmol, 99% yield)
[0452] ESI-MS (M+1): 376 calc. for
C.sub.16H.sub.27Cl.sub.2N.sub.3OSi 375.
##STR00577##
STEP 3.
3-{4-[4-(TERT-BUTYL-DIMETHYL-SILANYLOXYMETHYL)-PIPERIDIN-1-YL]-6--
CHLORO-PYRIDAZIN-3-YL}-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER
(62)
[0453] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol)
and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol)
was added slowly, followed by TMSCl (137 mg, 1.27 mmol). The
reaction was stirred for 15 min at RT. A solution of
N-Boc-3-iodoazetidine (2) (2.7 g, 9.5 mmol) in DMA (10 mL,
anhydrous) was added dropwise. The suspension was stirred for 1 h
at RT.
[0454] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with
4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-3,6-dichloro--
pyridazine (61) (2.4 g, 6.4 mmol), Pd(dppf)Cl.sub.2 (446 mg, 0.64
mmol), cuprous iodide (121 mg, 0.64 mmol), and DMA (20 mL,
anhydrous). The dark solution was degassed for 15 min. The clear
zinc reagent solution above the residual solid zinc was transferred
to the above 100 mL flask by cannulation. The dark solution was
degassed and heated to 80.degree. C. for 16 h. The reaction was
diluted with brine and extracted with EtOAc (3.times.100 mL). The
combined organics were washed with water (2.times.100 mL) and brine
(100 mL), followed by drying over sodium sulfate. The solution was
concentrated and the residue was purified by flash column
chromatography (PE:EAOAc=2:1) provides the title compound (62)
(1.25 g, 2.5 mmol, 39% yield) as a light yellow solid.
[0455] ESI-MS (M+1): 497 calc. for
C.sub.24H.sub.41ClN.sub.4O.sub.3Si 496.
##STR00578##
STEP 4.
3-{4-[4-(TERT-BUTYL-DIMETHYL-SILANYLOXYMETHYL)-PIPERIDIN-1-YL]-PY-
RIDAZIN-3-YL}-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER (63)
[0456] To a solution of
3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-6-chloro-p-
yridazin-3-yl}-azetidine-1-carboxylic acid tert-butyl ester (62)
(843 mg, 1.7 mmol) in MeOH was added Pd/C (10%, 0.5 g) under
nitrogen. The reaction was stirred under hydrogen at RT for 6 h,
filtered to remove Pd/C and concentrated to dryness to give
3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-pyridazin--
3-yl}-azetidine-1-carboxylic acid tert-butyl ester (63) (730 mg,
1.58 mmol yield 92.9%).
[0457] ESI-MS (M+1): 463 calc. for C.sub.24H.sub.42N.sub.4O.sub.3Si
462.
##STR00579##
STEP 5.
[1-(3-AZETIDIN-3-YL-PYRIDAZIN-4-YL)-PIPERIDIN-4-YL]-METHANOL
HYDROCHLORIDE (64)
[0458] A mixture of
3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-pyridazin--
3-yl}-azetidine-1-carboxylic acid tert-butyl ester (63) (730 mg,
1.58 mmol) in 4 M HCl/MeOH solution (20 mL) was stirred at RT for
30 min. Then the solvent was evaporated at 40.degree. C. to give
[1-(3-azetidin-3-yl-pyridazin-4-yl)-piperidin-4-yl]-methanol
hydrochloride (64) (387 mg, 1.56 mmol, 98% yield) as a yellow
solid.
[0459] ESI-MS (M+1): 249 calc. for C.sub.13H.sub.20N.sub.4O
248.
##STR00580##
STEP 1. 4-DIMETHYLCARBAMOYL-PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL
ESTER (66)
[0460] To a mixture of piperidine-1,4-dicarboxylic acid
mono-tert-butyl ester (65) (229 mg, 1 mmol, AalenChem) in DCM (5
mL) was added TEA (202 mg, 2 mmol) and HATU (414 mg, 1.2 mmol). The
reaction mixture was stirred for 5 min and dimethylamine
hydrochloride (81 mg, 1 mmol) was added. The reaction mixture was
stirred at RT overnight. The mixture was diluted with water (10
mL), and extracted with EtOAc (2.times.20 mL). The combined organic
extracts were washed with water (5 mL) and brine (5 mL), dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated in
vacuo and the residue was purified by column chromatography to give
4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester
(66) (220 mg, 0.85 mmol, 85% yield) as a light yellow oil.
##STR00581##
STEP 2. PIPERIDINE-4-CARBOXYLIC ACID DIMETHYLAMIDE HYDROCHLORIDE
(67)
[0461] A solution of 4-dimethylcarbamoyl-piperidine-1-carboxylic
acid tert-butyl ester (66) (220 mg, 0.85 mmol) in 4N HCl/MeOH (20
mL) was stirred at RT for 30 min. The reaction mixture was
concentrated to give the product piperidine-4-carboxylic acid
dimethylamide hydrochloride (67) (163 mg, 0.85 mmol, yield
99.9%).
[0462] ELSD-MS (M+1): 157 calc. for C.sub.8H.sub.16N.sub.2O
156.
[0463] The following Table 5 lists compounds of Preparation P19.1
to P19.4, which were made analogous to Preparation 19 by using the
appropriate materials.
TABLE-US-00006 TABLE 5 PREPARATION P19.1 TO P19.4 ESI-MS Ex. #
Chemical Structure Chemical Name (M + 1) P19.1 ##STR00582##
4-Dimethylcarbamoyl- piperidine-1-carboxylic acid tert-butyl ester
257 P19.2 ##STR00583## 4-methylcarbamoyl- piperidine-1-carboxylic
acid tert-butyl ester 243 P19.3 ##STR00584##
Piperidine-4-carboxylic acid dimethylamide hydrochloride 157 P19.4
##STR00585## Piperidine-4-carboxylic acid methylamide hydrochloride
143
##STR00586##
STEP 1. 3-(3-M-TOLYL-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER
[0464] To a solution of
3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (46) (639 mg, 2.0 mmol, as prepared in the above Preparation
14), 3-methyl-phenylboronic acid (68) (299.2 mg, 2.2 mmol),
K.sub.3PO.sub.4 (818 mg, 4.0 mmol) in dioxane (20 mL) and water (4
mL) was added Pd(dppf)Cl.sub.2 (73.2 mg, 0.1 mmol) then the
reaction mixture was stirred at 90.degree. C. under nitrogen
atmosphere overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with EtOAc (50 mL). The filtrate was
concentrated and the crude product was purified by silica gel
column to give 3-(3-m-tolyl-quinoxalin-2-yl)-azetidine-1-carboxylic
acid tert-butyl ester (69) (637 mg, 1.7 mmol, yield 85%).
[0465] ESI-MS (M+1): 376 calc. for C.sub.23H.sub.25N.sub.3O.sub.2
375
##STR00587##
STEP 2. 2-AZETIDIN-3-YL-3-M-TOLYL-QUINOXALINE HYDROCHLORIDE
(70)
[0466] A solution of
3-(3-m-tolyl-quinoxalin-2-yl)-azetidine-1-carboxylic acid
tert-butyl ester (69) (637 mg, 1.7 mmol) in 4N HCl/MeOH (25 mL) was
stirred at RT for 30 min. The reaction mixture was concentrated to
give 2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride (70) (523
mg, 1.68 mmol, yield 98.8%).
[0467] ESI-MS (M+1): 276 calc. for C.sub.18H.sub.17N.sub.3 275.
[0468] The following Table 6 lists compounds of Preparation P20.1
to P20.10, which were made analogous to Preparation 20 by using the
appropriate materials.
TABLE-US-00007 TABLE 6 PREPARATION P20.1 TO P20.10 Ex. # Chemical
Structure Chemical Name ESI-MS (M + 1) P20.1 ##STR00588##
3-(3-m-Tolyl-quinoxalin-2-yl)- azetidine-1-carboxylic acid tert-
butyl ester 376 P20.2 ##STR00589## tert-butyl 3-(3-(4-
aminophenyl)quinoxalin-2- yl)azetidine-1-carboxylate 376 P20.3
##STR00590## tert-butyl 3-(3-(3- hydroxyphenyl)quinoxalin-2-
yl)azetidine-1-carboxylate 378 P20.4 ##STR00591## tert-butyl
3-(3-(3- methoxyphenyl)quinoxalin-2- yl)azetidine-1-carboxylate 392
P20.5 ##STR00592## tert-butyl 3-(3- phenylquinoxalin-2-
yl)azetidine-1-carboxylate 362 P20.6 ##STR00593##
2-Azetidin-3-yl-3-m-tolyl- quinoxaline hydrochloride 276 P20.7
##STR00594## 4-(3-(azetidin-3-yl)quinoxalin- 2-yl)aniline
hydrochloride 277 P20.8 ##STR00595##
3-(3-(azetidin-3-yl)quinoxalin- 2-yl)phenol hydrochloride 278 P20.9
##STR00596## 2-(azetidin-3-yl)-3-(3- methoxyphenyl)quinoxaline
hydrochloride 292 P20.10 ##STR00597## 2-(azetidin-3-yl)-3-
phenylquinoxaline hydrochloride 262
##STR00598##
STEP 1,3-[3-(2-HYDROXY-PHENYL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER (72)
[0469] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (540 mg, 2.0 mmol, see Preparation 2),
2-hydroxy-phenylboronic acid (71) (303.6 mg, 2.2 mmol),
K.sub.3PO.sub.4 (818 mg, 4.0 mmol), in dioxane (20 mL) and water (4
mL) was added Pd(dppf)Cl.sub.2 (73.2 mg, 0.1 mmol) then the
reaction mixture was stirred at 90.degree. C. under nitrogen
atmosphere overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with EtOAc (50 mL). The filtrate was
concentrated and the crude product was purified by silica gel
column to give (72) (601.7 mg, 1.84 mmol, yield 91.85%).
[0470] ESI-MS (M+1): 328 calc. for C.sub.18H.sub.21N.sub.3O.sub.3
327.
##STR00599##
STEP 2. 2-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-PHENOL HYDROCHLORIDE
(73)
[0471] A solution of
3-[3-(2-hydroxy-phenyl)-pyrazin-2-yl]-azetidine-1-carboxylic acid
tert-butyl ester (72) (325 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL) was
stirred at RT for 30 min. The reaction mixture was concentrated to
give (74) (274.3 mg, 0.99 mmol, yield 99.24%).
[0472] ESI-MS (M+1): 228 calc. for C.sub.13H.sub.13N.sub.3O
227.
[0473] The following Table 7 lists compounds of Preparation P21.1
to P21.8, which were made analogous to Preparation 21 by using the
appropriate materials.
TABLE-US-00008 TABLE 7 PREPARATION P21.1 TO P21.8 Ex. # Chemical
Structure Chemical Name ESI-MS (M + 1) P21.1 ##STR00600##
2-(3-(azetidin-3-yl)pyrazin-2- yl)phenol hydrochloride 228 P21.2
##STR00601## 3-(3-(azetidin-3-yl)pyrazin-2- yl)phenol hydrochloride
228 P21.3 ##STR00602## 4-(3-(azetidin-3-yl)pyrazin-2- yl)phenol
hydrochloride 228 P21.4 ##STR00603## 2-(3-(azetidin-3-yl)pyrazin-2-
yl)aniline hydrochloride 226 P21.5 ##STR00604##
3-(3-(azetidin-3-yl)pyrazin-2- yl)aniline hydrochloride 226 P21.6
##STR00605## 4-(3-(azetidin-3-yl)pyrazin-2- yl)aniline
hydrochloride 226 P21.7 ##STR00606##
2-(azetidin-3-yl)-3-(4-fluoro-3- methoxyphenyl)pyrazine
hydrochloride 260 P21.8 ##STR00607## 4-(3-(azetidin-3-yl)pyrazin-2-
yl)-2-fluoroaniline hydrochloride 245
##STR00608##
STEP 1. TERT-BUTYL 3-(3-(PIPERIDIN-1-YL)PYRAZIN-2-YL)AZETIDINE-1
CARBOXYLATE (74)
[0474] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (200 mg, 0.74 mmol, see Preparation 2) and piperidine
(69.2 mg, 0.84 mmol) in DMSO (5 mL) was added Et.sub.3N (149.5 mg,
1.48 mmol). The reaction mixture was stirred at 100.degree. C.
overnight. The reaction mixture was diluted with water, extracted
with EtOAc (30 mL.times.3). 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 tert-butyl
3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidine-1-carboxylate (74).
(194 mg, 0.56 mmol, yield 75.99%).
##STR00609##
STEP 2. 2-AZETIDIN-3-YL-3-PIPERIDIN-1-YL-PYRAZINE HYDROCHLORIDE
(75)
[0475] A solution of
3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidine-1-carboxylic acid
tert-butyl ester (74) (191 mg, 0.6 mmol) in 4N HCl/MeOH (13 mL) was
stirred at RT for 30 min. The reaction mixture was concentrated to
give (75) (150 mg, 0.59 mmol, yield 99%). ESI-MS (M+1): 219 calc.
for C.sub.12H.sub.18N.sub.4 218
[0476] The following Table 8 lists compounds of Preparation P22.1
to P22.12, which were made analogous to Preparation 22 by using the
appropriate materials.
TABLE-US-00009 TABLE 8 PREPARATION P22.1 TO P22.12 Ex. # Chemical
Structure Chemical Name ESI-MS (M + 1) P22.1 ##STR00610##
tert-butyl 3-(3-(piperidin-1- yl)pyrazin-2-yl)azetidine-1-
carboxylate 319 P22.2 ##STR00611## tert-butyl 3-(3-(4-
methylpiperidin-1-yl)pyrazin- 2-yl)azetidine-1-carboxylate 333
P22.3 ##STR00612## tert-butyl 3-(3-(4- carbamoylpiperidin-1-
yl)pyrazin-2-yl)azetidine-1- carboxylate 362 P22.4 ##STR00613##
tert-butyl 3-(3-(4- (dimethylcarbamoyl)piperidin-
1-yl)pyrazin-2-yl)azetidine-1- carboxylate 390 P22.5 ##STR00614##
tert-butyl 3-(3-(4- (methylcarbamoyl)piperidin-1-
yl)pyrazin-2-yl)azetidine-1- carboxylate 376 P22.6 ##STR00615##
tert-butyl 3-(3-(4- acetylpiperazin-1-yl)pyrazin-2-
yl)azetidine-1-carboxylate 362 P22.7 ##STR00616##
2-(azetidin-3-yl)-3-(piperidin- 1-yl)pyrazine hydrochloride 219
P22.8 ##STR00617## 2-(azetidin-3-yl)-3-(4-
methylpiperidin-1-yl)pyrazine hydrochloride 233 P22.9 ##STR00618##
1-(3-(azetidin-3-yl)pyrazin-2- yl)piperidine-4-carboxamide
hydrochloride 262 P22.10 ##STR00619##
1-(3-(azetidin-3-yl)pyrazin-2- yl)-N,N-dimethylpiperidine-4-
carboxamide hydrochloride 290 P22.11 ##STR00620##
1-(3-(azetidin-3-yl)pyrazin-2- yl)-N-methylpiperidine-4-
carboxamide hydrochloride 276 P22.12 ##STR00621##
1-(4-(3-(azetidin-3-yl)pyrazin- 2-yl)piperazin-1-yl)ethanone
hydrochloride 262
##STR00622##
STEP 1.
3-(5'-FLUORO-4-HYDROXYMETHYL-3,4,5,6-TETRAHYDRO-2H-[1,3']BIPYRIDI-
NYL-2'-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER (76)
[0477] To a solution of
3-(3-bromo-5-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid
tert-butyl ester (58) (660 mg, 2 mmol, Preparation 17) and
piperidin-4-yl-methanol (35) (230 mg, 2 mmol) in DMSO (20 mL) was
added Et.sub.3N (404 mg, 4 mmol). The reaction mixture was stirred
at 100.degree. C. overnight. The reaction mixture was diluted with
water, extracted with EtOAc (50 mL.times.3). 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
(EtOAc:PE=3:1) on silica gel to give (76) (490 mg, 1.34 mmol, yield
67%), ESI-MS (M+1): 366 calc. for C.sub.19H.sub.28FN.sub.3O.sub.3
365.
##STR00623##
STEP 2.
(2'-AZETIDIN-3-YL-5'-FLUORO-3,4,5,6-TETRAHYDRO-2H-[1,3']BIPYRIDIN-
YL-4-YL)-METHANOL HYDROCHLORIDE (77)
[0478] A mixture of
3-(5'-fluoro-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-2'-y-
l)-azetidine-1-carboxylic acid tert-butyl ester (76) (490 mg, 1.34
mmol) in 4 M HCl/MeOH solution (10 mL) was stirred at RT for 30
min. Then the solvent was evaporated at 40.degree. C. to give (77)
(392 mg, 1.3 mmol, 98% yield) as a yellow solid. ESI-MS (M+1): 266
calc. for C.sub.14H.sub.20FN.sub.3O 265.
##STR00624##
STEP 1. 3-(3-BROMO-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (3)
[0479] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol,
2.0 eq.) and DMA (10 mL, anhydrous). 1,2-Dibromoethane (236 mg,
1.27 mmol, 0.2 eq) was added slowly, followed by TMSCl (137 mg,
1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of N-Boc-3-iodoazetidine (2) (2.7 g, 9.5 mmol, 1.5 eq) in
DMA (10 mL, anhydrous) was added dropwise. The suspension was
stirred for 1 h at RT.
[0480] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dibromo-pyridine (1) (1.5 g, 6.4 mmol,
1.0 eq), PdCl.sub.2(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI (121 mg,
0.64 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark solution
was degassed for 15 min. The clear zinc reagent solution above the
residual solid zinc was transferred to the above 100 mL flask by
cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography (PE:EtOAc=2:1)
provides the title compound (3) (600 mg, 31% yield) as a light
yellow solid.
[0481] ESI-MS (M+1): 313 calc. for C.sub.13H.sub.17BrN.sub.2O.sub.2
312.
##STR00625##
STEP 2. 3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (79)
[0482] To a stirred solution of
3-(3-bromo-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (3) (150 mg, 0.48 mmol) in dioxane (10 mL) was added
phenylboronic acid (78) (87 mg, 0.71 mmol), Na.sub.2CO.sub.3 (152
mg, 1.4 mmol) and H.sub.2O (2 mL). The reaction mixture was
degassed with N.sub.2 and then PdCl.sub.2(dppf) (35 mg, 0.05 mmol)
was added. The reaction mixture was stirred at 80.degree. C. for 12
h. The reaction mixture was left to reach RT and filtered through a
pad of CELITE.RTM. and the filter cake was washed with
CH.sub.2Cl.sub.2 (20 mL.times.3). The combined filtrates were
evaporated in vacuo and the residue was purified by column
chromatography ((EtOAc:Petrol ether=3:1) to give the desired
compound (79) (130 mg, 87% yield). ESI-MS (M+1): 311 calc. for
C.sub.19H.sub.22N.sub.2O.sub.2 310.
##STR00626##
STEP 3. 2-AZETIDIN-3-YL-3-PHENYL-PYRIDINE HYDROCHLORIDE
[0483] A mixture of
3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (79) (130 mg, 0.60 mmol) in HCl/MeOH solution (5 mL) was
stirred at RT for 30 min. Then the solvent was evaporated at
40.degree. C. to give 2-Azetidin-3-yl-3-phenyl-pyridine
hydrochloride (80) (100 mg, 100% yield) as a yellow solid.
[0484] ESI-MS (M+1): 211 calc. for C.sub.14H.sub.14N.sub.2 210.
##STR00627##
STEP 1. 1-METHYL-1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID METHYL ESTER
(81)
[0485] To a solution of 1H-benzoimidazole-2-carboxylic acid methyl
ester (18) (177 mg, 1.0 mmol) in dry DMF (5 mL) was added sodium
hydride (applied as 60% dispersion in oil, 62 mg, 1.5 mmol)) at
0.degree. C. under N.sub.2 atmosphere. After 0.5 h, iodomethane
(284 mg, 2.0 mmol) was added slowly. The reaction mixture was
stirred at RT for 4 h. The reaction was diluted with brine at
0.degree. C. and extracted with EtOAc (3.times.20 mL). The combined
organics were washed with water (2.times.15 mL), brine (20 mL),
dried over sodium sulfate and filtered. The filtrate was
concentrated and purified by flash column chromatography to provide
the title compound (81) (180 mg, 90% yield) as a light yellow
solid.
[0486] ESI-MS (M+1): 191 calc. for C10H10N2O2 190.
##STR00628##
STEP 2. 1-METHYL-1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID (82)
[0487] A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid
methyl ester (81) (190 mg, 1.0 mmol) and NaOH (80 mg, 2.0 mmol) in
MeOH/H.sub.2O (1:1, 20 mL) was stirred at 50.degree. C. for 1 h.
The mixture was concentrated, then diluted with water (15 mL),
adjusted pH=2 with concentrated HCl. Then the precipitate was
formed and filtered, washed with water and dried to give
1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg, 1.0
mmol, yield 100%)
[0488] ESI-MS (M+1): 177 calc. for C.sub.9H.sub.8N.sub.2O.sub.2
176.
##STR00629##
STEP 3.
[3-(3-CHLORO-PYRAZIN-2-YL)-AZETIDIN-1-YL]-(1-METHYL-1H-BENZOIMIDA-
ZOL-2-YL)-METHANONE (83)
[0489] A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid
(82) (176 mg, 1.0 mmol), 2-Azetidin-3-yl-3-chloro-pyrazine
hydrochloride (8) (169 mg, 1.0 mmol), HOBt (151 mg, 1.2 mmol), EDCI
(231 mg, 1.2 mmol) and N-methyl-morpholine (NMM) (300 mg, 3.0 mmol)
in DMF (5 mL) was stirred at RT for 24 h. The mixture was diluted
with water (20 mL), and filtered. The filter cake was washed with
water and dried in vacuo to provide
[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl-
)-methanone (83) (300 mg, yield 90%).
[0490] ESI-MS (M+1): 328 calc. for C.sub.16H.sub.14ClN.sub.5O
327.
##STR00630##
[3-(3-CHLORO-PYRAZIN-2-YL)-AZETIDIN-1-YL]-[1-(2,2,2-TRIFLUORO-ETHYL)-1H-B-
ENZOIMIDAZOL-2-YL]-METHANONE (85)
[0491] To a solution of
(1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methano-
ne (84), as prepared in Preparation 36 below, (314 mg, 1.0 mmol) in
dry DMF (10 mL) was added sodium hydride (applied as 60% dispersion
in oil, 62 mg, 1.5 mmol)) at 0.degree. C. under N.sub.2 atmosphere.
After 0.5 h, 1,1,1-Trifluoro-2-iodo-ethane (418 mg, 2.0 mmol) was
added slowly. The reaction mixture was stirred at RT for 4 h. The
reaction was quenched with water (10 mL) at 0.degree. C. and
extracted with EtOAc (3.times.20 mL). The combined organics were
washed with water (2.times.15 mL), brine (20 mL), dried over sodium
sulfate and filtered. The filtrate was concentrated and the residue
was purified by flash column chromatography to provide (85) (355
mg, 0.90 mmol, 90% yield) as white solid.
[0492] ESI-MS (M+1): 396 calc. for
C.sub.17H.sub.13ClF.sub.3N.sub.5O 395.
##STR00631##
STEP 1. 3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (86)
[0493] To a stirred solution of
3-(3-bromo-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (3) (158 mg, 0.48 mmol) in dioxane (10 mL) was added
phenylboronic acid (78) (87 mg, 0.71 mmol), Na.sub.2CO.sub.3 (152
mg, 1.4 mmol) and H.sub.2O (2 mL). The reaction mixture was
degassed with N.sub.2 and then PdCl.sub.2(dppf) (35 mg, 0.05 mmol)
was added. The reaction mixture was stirred at 80.degree. C. for 12
h. The reaction mixture was left to reach RT and filtered through a
pad of CELITE.RTM. and the filter cake was washed with
CH.sub.2Cl.sub.2 (20 mL.times.3). The combined filtrates were
evaporated in vacuo and the residue was purified by column
chromatography ((EtOAc:Petrol ether=3:1) to give
3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (125 mg, 0.38 mmol, 80% yield).
[0494] ESI-MS (M+1): 329 calc. for C.sub.19H.sub.21FN.sub.2O.sub.2
328.
##STR00632##
STEP 2. 2-AZETIDIN-3-YL-5-FLUORO-3-PHENYL-PYRIDINE HYDROCHLORIDE
(87)
[0495] A mixture of
3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (86) (125 mg, 0.38 mmol) in 4 M HCl/MeOH solution (10 mL) was
stirred at RT for 30 min. Then the solvent was evaporated at
40.degree. C. to give 2-azetidin-3-yl-5-fluoro-3-phenyl-pyridine
hydrochloride (87) (100 mg, 0.38 mmol, 100% yield) as a yellow
solid.
[0496] ESI-MS (M+1): 229 calc. for C.sub.14H.sub.13FN.sub.2
228.
##STR00633##
STEP 1. 4-(3-CHLORO-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (88)
[0497] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol,
2.0 eq.) and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg,
1.27 mmol, 0.2 eq) was added slowly, followed by TMSCl (137 mg,
1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of 4-iodo-piperidine-1-carboxylic acid tert-butyl ester
(38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added
dropwise. The suspension was stirred for 1 h at RT.
[0498] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dichloro-pyrazine (6) (0.95 g, 6.4
mmol, 1.0 eq), PdCl.sub.2(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI
(121 mg, 0.64 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark
solution was degassed for 15 min. The clear zinc reagent solution
above the residual solid zinc was transferred to the above 100 mL
flask by cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography (PE:EA=2:1)
provides the title compound (88) (0.95 g, 3.2 mmol, 50% yield) as a
light yellow solid.
[0499] ESI-MS (M+1): 298 calc. for C.sub.14H.sub.20ClN.sub.3O.sub.2
297.
##STR00634##
STEP 4. 4-(3-PHENYL-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (89)
[0500] To a stirred solution of (88) (142 mg, 0.48 mmol) in dioxane
(10 mL) was added phenylboronic acid (78) (87 mg, 0.71 mmol),
Na.sub.2CO.sub.3 (152 mg, 1.4 mmol) and H.sub.2O (2 mL). The
reaction mixture was degassed with N.sub.2 and then
PdCl.sub.2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture
was stirred at 80.degree. C. for 12 h. The reaction mixture was
left to reach RT and filtered through a pad of CELITE.RTM. and the
filter cake was washed with CH.sub.2Cl.sub.2 (20 mL.times.3). The
combined filtrates were evaporated in vacuo and the residue was
purified by column chromatography ((EtOAc:Petrol ether=1:1) to give
4-(3-Phenyl-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl
ester (89) (128 mg, 0.38 mmol, 80% yield).
[0501] ESI-MS (M+1): 340 calc. for C.sub.20H.sub.25N.sub.3O.sub.2
339.
##STR00635##
STEP 4. 2-PHENYL-3-PIPERIDIN-4-YL-PYRAZINE HYDROCHLORIDE (90)
[0502] A mixture of
4-(3-Phenyl-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl
ester (89) (128 mg, 0.38 mmol) in 4 M HCl/MeOH solution (10 mL) was
stirred at RT. for 30 min. Then the solvent was evaporated at
40.degree. C. to give 2-phenyl-3-piperidin-4-yl-pyrazine
hydrochloride (90) (105 mg, 0.38 mmol, 100% yield) as a yellow
solid.
[0503] ESI-MS (M+1): 240 calc. for C.sub.15H.sub.17N.sub.3 239.
##STR00636##
STEP 1. 3-(3-CHLORO-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (91)
[0504] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (1.3
g, preactivated according to the above Preparation 1, 20 mmol, 2.0
eq.) and DMA (10 mL, anhydrous). 1,2-dibromoethane (400 mg, 2.0
mmol, 0.2 eq) was added slowly, followed by TMSCl (240 mg, 2.0
mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of N-Boc-3-iodoazetidine (2) (4 g, 16 mmol, 1.6 eq) in DMA
(10 mL, anhydrous) was added dropwise. The suspension was stirred
for 1 h at RT.
[0505] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-Dichloro-quinoxaline (44) (2 g, 10
mmol, 1.0 eq), PdCl.sub.2(dppf) (800 mg, 1.0 mmol, 0.1 eq), CuI
(200 mg, 1.0 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark
solution was degassed for 15 min. The clear zinc reagent solution
above the residual solid zinc was transferred to the above 100 mL
flask by cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography (PE:EA=2:1)
provides 3-(3-Chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid
tert-butyl ester (91) (1.43 g, 4.5 mmol, 45% yield) as a light
yellow solid.
[0506] ESI-MS (M+1): 320 calc. for C.sub.16H.sub.18ClN.sub.3O.sub.2
319.
##STR00637##
STEP 2. 3-(3-PIPERIDIN-1-YL-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER (92)
[0507] To a mixture of
3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (91) (0.16 g, 0.50 mmol) and piperidine (0.085 g, 1.0 mmol)
was added triethylamine (0.10 g, 1.0 mmol) and DMSO (3 mL). The
solution was heated to 160.degree. C. in microwave for 2 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 flash column chromatography on silica gel (20% to 50%
EtOAc in petroleum ether) to give
3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylic acid
tert-butyl ester (92) (0.16 g, 0.90 mmol, 90% yield) as a white
solid. ESI-MS (M+1): 369 calc. for C.sub.21H.sub.28N.sub.4O.sub.2
368.
##STR00638##
STEP 3. 2-AZETIDIN-3-YL-3-PIPERIDIN-1-YL-QUINOXALINE HYDROCHLORIDE
(93)
[0508] A mixture of
3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylic acid
tert-butyl ester (92) (139 mg, 0.38 mmol) in 4 M HCl/MeOH solution
(10 mL) was stirred at RT for 30 min. Then the solvent was
evaporated at 40.degree. C. to give
2-azetidin-3-yl-3-piperidin-1-yl-quinoxaline hydrochloride (93)
(115 mg, 0.38 mmol, 100% yield) as a yellow solid. ESI-MS (M+1):
269 calc. for C.sub.16H.sub.20N.sub.4 269
[0509] The following Table 9 lists compounds of Preparation P29.1
to P29.4, which were made analogous to Preparation 29 by using the
appropriate materials.
TABLE-US-00010 TABLE 9 PREPARATION P29.1 TO P29.4 Ex. # Structure
Chemical Name ESI-MS (M + 1) P29.1 ##STR00639##
3-(3-Piperidin-1-yl-quinoxalin-2-yl)- azetidine-1-carboxylic acid
tert-butyl ester 369 P29.2 ##STR00640## tert-butyl
3-(3-(4-hydroxypiperidin-1- yl)quinoxalin-2-yl)azetidine-1-
carboxylate 385 P29.3 ##STR00641##
2-Azetidin-3-yl-3-piperidin-1-yl- quinoxaline hydrochloride 269
P29.4 ##STR00642## 1-(3-(azetidin-3-yl)quinoxalin-2-
yl)piperidin-4-ol hydrochloride 285
##STR00643##
STEP 1.
3-(2,3-DIHYDRO-INDOL-1-YL)-3',4',5',6'-TETRAHYDRO-2'H-[2,4']BIPYR-
IDINYL 1'-CARBOXYLIC ACID TERT-BUTYL ESTER (95)
[0510] A mixture of
3-bromo-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic
acid tert-butyl ester (94) (280 mg, 0.82 mmol),
2,3-dihydro-1H-indole (97 mg, 0.82 mmol), Pd.sub.2(dba).sub.3 (37
mg, 0.04 mmol), BINAP (24 mg, 0.04 mmol) and t-BuONa (173 mg, 1.64
mmol) in toluene (20 mL) was stirred at 100.degree. C. for 12 h.
The mixture was left to reach RT and filtered through a pad of
Celite and the filter cake was washed with CH.sub.2Cl.sub.2 (30
mL). The combine filtrate was evaporated in vacuo and the residue
was purified by flash column chromatography (20% to 40% EtOAc in
petroleum ether) to afford
3-(2,3-dihydro-indol-1-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1-
'-carboxylic acid tert-butyl ester (95) (100 mg, 0.29 mmol, yield
32%).
[0511] ESI-MS (M+1): 380 calc. for C.sub.23H.sub.29N.sub.3O.sub.2
379.
##STR00644##
STEP 2.
3-(2,3-DIHYDRO-INDOL-1-YL)-1',2',3',4',5',6'-HEXAHYDRO-[2,4']BIPY-
RIDINYL HYDROCHLORIDE (96)
[0512] To
3-(2,3-dihydro-indol-1-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipy-
ridinyl-1'-carboxylic acid tert-butyl ester (95) (100 mg, 0.29
mmol) was added 4 M HCl in MeOH (20 mL). The reaction mixture was
stirred at RT for 1 h. Then it was concentrated to give
3-(2,3-dihydro-indol-1-yl)-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl
hydrochloride (96) (0.083 g, 0.29 mmol, 100% yield) which was used
in the next step without further purification.
[0513] ESI-MS (M+1): 280 calc. for C.sub.18H.sub.21N.sub.3 279.
##STR00645##
STEP 1. 3-(3-BROMO-QUINOLIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (98)
[0514] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol,
2.0 eq.) and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg,
1.27 mmol, 0.2 eq) was added slowly, followed by TMSCl (137 mg,
1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of N-Boc-3-iodoazetidine (2) (2.7 g, 9.5 mmol, 1.5 eq) in
DMA (10 mL, anhydrous) was added dropwise. The suspension was
stirred for 1 h at RT.
[0515] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dibromo-quinoline (97) (1.82 g, 6.4
mmol, 1.0 eq), PdCl.sub.2(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI
(121 mg, 0.64 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark
solution was degassed for 15 min. The clear zinc reagent solution
above the residual solid zinc was transferred to the above 100 mL
flask by cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography (EtOAc:Petro
ether=4:1) provides the title compound (98) (1.2 g, 3.30 mmol, 52%
yield) as a light yellow solid.
[0516] ESI-MS (M+1): 363 calc. for C.sub.17H.sub.19BrN.sub.2O.sub.2
362.
##STR00646##
STEP 2. 3-(3-PHENYL-QUINOLIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID
TERT-BUTYL ESTER (99)
[0517] To a stirred solution of
3-(3-bromo-quinolin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (98) (174 mg, 0.48 mmol) in dioxane (10 mL) was added
phenylboronic acid (78) (87 mg, 0.71 mmol), Na.sub.2CO.sub.3 (152
mg, 1.4 mmol) and H.sub.2O (2 mL). The reaction mixture was
degassed with N.sub.2 and then PdCl.sub.2(dppf) (35 mg, 0.05 mmol)
was added. The reaction mixture was stirred at 80.degree. C. for 12
h. The reaction mixture was left to reach RT and filtered through a
pad of CELITE.RTM. and the filter cake was washed with
CH.sub.2Cl.sub.2 (20 mL.times.3). The combined filtrates were
evaporated in vacuo and the residue was purified by column
chromatography ((EtOAc:Petrol ether=3:1) to give the desired
compound (95) (154 mg, 0.42 mmol, 87% yield).
[0518] ESI-MS (M+1): 361 calc. for C.sub.23H.sub.24N.sub.2O.sub.2
360.
##STR00647##
STEP 3. 2-AZETIDIN-3-YL-3-PHENYL-QUINOLINE HYDROCHLORIDE (100)
[0519] A mixture of
3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (99) (216 mg, 0.60 mmol) in 4 M HCl/MeOH solution (10 mL) was
stirred at RT. for 30 min. Then the solvent was evaporated at
40.degree. C. to give 2-azetidin-3-yl-3-phenyl-pyridine (100) (177
mg, 100% yield) as a yellow solid.
[0520] ESI-MS (M+1): 261 calc. for C.sub.18H.sub.16N.sub.2 260.
##STR00648##
STEP 1.
3-BROMO-3',4',5',6'-TETRAHYDRO-2'H-[2,4']BIPYRIDINYL-1'-CARBOXYLI-
C ACID TERT-BUTYL ESTER (101)
[0521] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol,
2.0 eq.) and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg,
1.27 mmol, 0.2 eq) was added slowly, followed by TMSCl (137 mg,
1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A
solution of 4-Iodo-piperidine-1-carboxylic acid tert-butyl ester
(38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added
dropwise. The suspension was stirred for 1 h at RT.
[0522] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 2,3-dibromo-pyridine (1) (1.5 g, 6.4 mmol,
1.0 eq), PdCl.sub.2(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI (121 mg,
0.64 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark solution
was degassed for 15 min. The clear zinc reagent solution above the
residual solid zinc was transferred to the above 100 mL flask by
cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography (PE:EtOAc=2:1)
provides the title compound (101) (761 mg, 2.3 mmol, 35% yield) as
a light yellow solid.
[0523] ESI-MS (M+1): 341 calc. for C.sub.15H.sub.21BrN.sub.2O.sub.2
340.
##STR00649##
STEP 2.
3-PHENYL-3',4',5',6'-TETRAHYDRO-2'H-[2,4']BIPYRIDINYL-1'-CARBOXYL-
IC ACID TERT-BUTYL ESTER (102)
[0524] To a stirred solution of
3-bromo-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic
acid tert-butyl ester (101) (163 mg, 0.48 mmol) in dioxane (10 mL)
was added phenylboronic acid (78) (87 mg, 0.71 mmol),
Na.sub.2CO.sub.3 (152 mg, 1.4 mmol) and H.sub.2O (2 mL). The
reaction mixture was degassed with N.sub.2 and then
PdCl.sub.2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture
was stirred at 80.degree. C. for 12 h. The reaction mixture was
left to reach RT and filtered through a pad of CELITE.RTM. and the
filter cake was washed with CH.sub.2Cl.sub.2 (20 mL.times.3). The
combined filtrates were evaporated in vacuo and the residue was
purified by column chromatography ((EtOAc:Petrol ether=4:1) to give
the desired compound (102) (138 mg, 0.41 mmol, 85% yield).
[0525] ESI-MS (M+1): 339 calc. for C.sub.21H.sub.26N.sub.2O.sub.2
338.
##STR00650##
STEP 3. 3-PHENYL-11',2',3',4',5',6'-HEXAHYDRO-[2,4']BIPYRIDINYL
HYDROCHLORIDE (103)
[0526] A mixture of
3-phenyl-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic
acid tert-butyl ester (102) (202 mg, 0.60 mmol) in HCl/MeOH
solution (5 mL) was stirred at RT. for 30 min. Then the solvent was
evaporated at 40.degree. C. to give
3-phenyl-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl
hydrochloride (103) (162 mg, 0.60 mmol, 100% yield) as a yellow
solid.
[0527] ESI-MS (M+1): 239 calc. for C.sub.16H.sub.18N.sub.2 238.
##STR00651##
STEP 1. 3-PHENYL-N--O-TOLYL-ACRYLAMIDE (106)
[0528] A solution of o-tolylamine (104) (5.3 g, 50.0 mmol) in DCM
(50 mL) was added to a stirring mixture of pyridine (5 mL) and DMAP
(0.61 g, 5.0 mmol) in DCM (20 mL) at 0.degree. C. under N.sub.2.
The mixture was stirred for 15 min before a solution of cinnamoyl
chloride (105) (8.3 g, 50.0 mmol) in DCM (50 mL) was added over 10
min. After being stirred for further 15 min, the mixture was
allowed to warm to RT. The precipitate formed was collected, washed
with cold DCM and dried to afford the title compound (106) (9.9 g,
42.0 mmol, 84% yield).
##STR00652##
STEP 2. 8-METHYL-1H-QUINOLIN-2-ONE (107)
[0529] An intimate mixture of the 3-phenyl-n-o-tolyl-acrylamide
(106) (5 g, 2.1 mmol) and aluminum chloride (0.83 g, 6.3 mmol) was
heated rapidly to melting then heated at 100.degree. C. for 1 h.
After cooling to RT, iced water was added and the resultant
precipitate was washed with water and 5% aqueous hydrochloric acid
to give (107) (2.9 g, 1.8 mmol, 87% yield). ESI-MS (M+1): 160 calc.
for C.sub.10H.sub.9NO 159.
##STR00653##
STEP 3. 2-CHLORO-8-METHYL-QUINOLINE (108)
[0530] A mixture of 8-methyl-1H-quinolin-2-one (107) (580 mg, 3.6
mmol) and phosphorus oxychloride (5 mL) was stirred at 60.degree.
C. overnight. The mixture was then poured onto ice water and
extracted with DCM (3.times.50 mL). The combined extracts were
washed with water (2.times.100 mL) and dried with Na.sub.2SO.sub.4,
and the solvent was removed. The residue was chromatographed on
silica gel using 5% to 20% EtOAc in petroleum ether to give product
(108) as small colorless crystals (400 mg, 2.3 mmol, 63%
yield).
[0531] The following Table 10 lists compounds of Preparation P33.1
to P33.12, which were made analogous to Preparation 33 by using the
appropriate materials.
TABLE-US-00011 TABLE 10 PREPARATION P33.1 TO P33.12 Ex. # Structure
Chemical Name ESI-MS (M + 1) P33.1 ##STR00654##
N-(o-tolyl)cinnamamide 238 P33.2 ##STR00655## N-(4-
fluorophenyl)cinnamamide 242 P33.3 ##STR00656## N-(3-
fluorophenyl)cinnamamide 242 P33.4 ##STR00657## N-(2-
chlorophenyl)cinnamamide 258 P33.5 ##STR00658##
8-Methyl-1H-quinolin-2-one 160 P33.6 ##STR00659##
6-Fluoro-1H-quinolin-2-one 164 P33.7 ##STR00660##
7-Fluoro-1H-quinolin-2-one 164 P33.8 ##STR00661##
8-Chloro-1H-quinolin-2-one 180 P33.9 ##STR00662##
2-chloro-8-methylquinoline 178 P33.10 ##STR00663##
2-chloro-6-fluoroquinoline 182 P33.11 ##STR00664##
2-chloro-7-fluoroquinoline 182 P33.12 ##STR00665##
2,8-dichloroquinoline 198
##STR00666##
STEP 1. 6-CHLOROQUINAZOLIN-2-AMINE (110)
[0532] A mixture of 5-chloro-2-fluoro-benzaldehyde (109) (5 g, 31.6
mmol) and guanidine carbonate (7.5 g, 41.1 mmol) was heated at
140.degree. C. in DMA (50 mL) for 3 h. 100 ml water was added and
after refrigeration, a solid was isolated by filtration, and dried
under vacuum to give the product (110) (2.8 g, 15.8 mmol, 50%
yield). ESI-MS (M+1): 180 calc. for C.sub.8H.sub.6ClN.sub.3
179.
##STR00667##
STEP 2. 2,6-DICHLORO-QUINAZOLINE (111)
[0533] To a suspension of 6-chloro-quinazolin-2-ylamine (110) (2.8
g, 15.8 mmol) and SbCl.sub.3 (7.2 g, 32 mmol) in 1,2-dichloroethane
(100 mL) was added tert-butylnitrate (6.2 ml, 52 mmol) and heated
at 60.degree. C. for 3 h under nitrogen atmosphere. To the mixture
was added aqueous saturated NaHCO.sub.3 and the mixture was
filtered off and filtrate was extracted with CHCl.sub.3. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and evaporated. The residue was purified by silica gel column
chromatography, using CHCl.sub.3/EtOAc (9:1, v/v) as eluent to give
2,6-dichloro-quinazoline (111) (0.65 g, 3.12 mmol, 20% yield).
[0534] The following Table 11 lists compounds of Preparation P34.1
to P34.8, which were made analogous to Preparation 34 by using the
appropriate materials.
TABLE-US-00012 TABLE 11 PREPARATION P34.1 TO P34.8 Ex. # Structure
Chemical Name ESI-MS (M + 1) P34.1 ##STR00668##
6-chloroquinazolin-2-amine 180 P34.2 ##STR00669##
8-chloroquinazolin-2-amine 180 P34.3 ##STR00670##
7-chloroquinazolin-2-amine 180 P34.4 ##STR00671##
5-chloroquinazolin-2-amine 180 P34.5 ##STR00672##
2,6-dichloroquinazoline 199 P34.6 ##STR00673##
2,8-dichloroquinazoline 199 P34.7 ##STR00674##
2,7-dichloroquinazoline 199 P34.8 ##STR00675##
2,5-dichloroquinazoline 199
##STR00676##
2-CHLORO-1,6-NAPHTHYRIDINE (113)
[0535] A mixture of phosphoryl trichloride (5.17 ml, 56.5 mmol) and
1,6-naphthyridin-2(1H)-one (112) (1.65 g, 11.29 mmol, Alfa Aesar)
was stirred at 70.degree. C. for 16 h. The reaction mixture was
cooled to RT and was poured onto 150 g of ice carefully. EtOAc (50
mL) was added and the mixture was treated carefully with about 30
mL of 5 M NaOH until the final pH is persistently >10. The
mixture was vigorously mixed, then transferred into a separatory
funnel. The EtOAc layer was then separated and dried and
re-suspended in 30 mL of DCM, the insoluble solids were filtered
off. The filtrate was loaded onto a silica gel pad and flushed with
30% EtOAc in hexanes to give a solid after drying. The solid was
initially white but changed color to yellow after drying on the
high vacuum line over night. Yield; 1.19 g, 64%. The material (113)
was used directly in the next step without any further
purification.
##STR00677##
(1H-BENZOIMIDAZOL-2-YL)-[3-(3-CHLORO-PYRAZIN-2-YL)-AZETIDIN-1-YL]-METHANO-
NE (84)
[0536] A mixture of 1H-benzoimidazole-2-carboxylic acid (19) (100
mg, 0.47 mmol), 2-azetidin-3-yl-3-chloro-pyrazine hydrochloride (8)
(96 mg, 0.47 mmol), HATU (540 mg, 1.3 mmol) and Et.sub.3N (101 mg,
1 mmol) in dry DCM (10 mL) was stirred at RT overnight. Then the
mixture reaction was poured into saturated aqueous Na.sub.2CO.sub.3
and extracted with DCM (50 mL.times.3), the organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
give the crude compound which was purified by ISCO silica gel
column (10% to 80% EtOAc in petroleum ether) and followed by
reverse phase prep. HPLC (10% to 80% water/MeCN) to afford pure
(1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methano-
ne (84) (50 mg, 0.16 mmol, yield 34%).
[0537] .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta. (ppm) 8.67 (d,
J=2.8 Hz, 1H); 8.43 (d, J=6.4 Hz, 1H); 7.63 (br, 2H); 7.25 (s, 2H);
5.10-5.08 (m, 1H); 4.97-4.93 (m, 1H); 4.51-4.39 (m, 3H).
[0538] ESI-MS (M+1): 314 calc. for C.sub.15H.sub.12ClN.sub.5O
313.
[0539] The following Table 12 lists compound of Preparation P36.1,
which was made analogous to Preparation 36 by using the appropriate
materials.
TABLE-US-00013 TABLE 12 PREPARATION P36.1 Ex. # Structure Chemical
Name ESI-MS (M + 1) P36.1 ##STR00678##
(7-chloro-1H-benzo[d]imidazol-2-yl)(3-
(3-chloropyrazin-2-yl)azetidin-1- yl)methanone 348
##STR00679##
STEP 1. 3-[3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-PYRAZIN-2-YL]-AZETIDINE-1
CARBOXYLIC ACID TERT-BUTYL ESTER (115)
[0540] To a solution of
3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl
ester (7) (1.0 g, 3.7 mmol) in dioxane (16 mL) was added a solution
of Na.sub.2CO.sub.3 (780 mg, 6.4 mmol) in 5 mL water, followed by
additional of
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran
(114) (purchased from WUXI APPTEC) (840 mg 4.0 mmol) and
Pd(dppf)Cl.sub.2 (80 mg). The resulting mixture was heated to
reflux overnight under N.sub.2 atmosphere. TLC showed that the
staring material was consumed completely. The solution was filtered
and the filtrate was concentrated to give the residue which was
purified by ISCO silica gel column (10% to 80% EtOAc in petroleum
ether) to give the product
3-[3-(3,6-dihydro-2H-pyran-4-yl)-pyrazin-2-yl]-azetidine-1-carboxylic
acid tert-butyl ester (115) (938 mg, 2.96 mmol, yield 80%) as
solid. ESI-MS (M+1): 318 calc. for C.sub.17H.sub.23N.sub.3O.sub.3
317.
##STR00680##
STEP 2:
3-[3-(TETRAHYDRO-PYRAN-4-YL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER (116)
[0541] A mixture of (115) (938 mg, 2.96 mmol) and wet Pd--C (50%,
400 mg) in MeOH (30 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 the desired compound (116) (897 mg, 2.81 mmol,
yield 95%). ESI-MS (M+1): 320 calc. for
C.sub.17H.sub.25N.sub.3O.sub.3 319.
##STR00681##
STEP 3. 2-AZETIDIN-3-YL-3-(TETRAHYDRO-PYRAN-4-YL)-PYRAZINE
HYDROCHLORIDE (117)
[0542] To a solution of 4 N HCl in MeOH (10 mL) was added
3-[3-(Tetrahydro-pyran-4-yl)-pyrazin-2-yl]-azetidine-1-carboxylic
acid tert-butyl ester (116) (897 mg, 2.81 mmol) at 0.degree. C. and
the resulting mixture was stirred at RT for 1 h. The mixture was
concentrated under reduced pressure to give
2-azetidin-3-yl-3-(tetrahydro-pyran-4-yl)-pyrazine hydrochloride
(117) (716 mg, yield 100%) which was used for the next step without
further purification. ESI-MS (M+1): 220 calc. for
C.sub.12H.sub.17N.sub.3O 219.
##STR00682##
STEP 1. OXETAN-3-YLIDENE-ACETIC ACID ETHYL ESTER (120)
[0543] To a solution of oxetan-3-one (118) (5 g, 69.4 mmol) in
CH.sub.2Cl.sub.2 (50 mL) at 0.degree. C. was added ethyl
2-triphenylphosphoranylideneacetate (119) (26.6 g, 76.3 mmol). The
solution was allowed to warm to RT and stirred for 15 min. The
reaction mixture was then filtered through a pad of silica (washing
with 30 percent EtOAc:Petrol ether), and the solvent removed under
reduced pressure to give ethyl 2-(oxetan-3-ylidene)acetate (120) as
a colourless viscous oil (8.15 g, 57.4 mmol, yield: 79%). ESI-MS
(M+1): 142 calc. for C.sub.7H.sub.10O.sub.3 142.
##STR00683##
STEP 2. 2-(3-ETHOXYCARBONYL-OXETAN-3-YL)-MALONIC ACID DIMETHYL
ESTER (121)
[0544] To a solution of oxetan-3-ylidene-acetic acid ethyl ester
(120) (5.0 g, 35.2 mmol) in DMF (30 mL) at RT was added sodium
hydride (60% wt in mineral oil) (4.2 g, 106 mmol). The mixture was
stirred at RT for 60 min and malonic acid dimethyl ester (4.7 g,
35.2 mmol) was added. The reaction mixture was stirred at RT for 4
h. Then the reaction mixture was neutralized with saturated
NH.sub.4Cl (10 mL), diluted with EtOAc (30 mL) and water (30 mL).
The aqueous phase was extracted with EtOAc (3.times.80 mL) and the
combined organic extracts were washed with brine (100 mL), dried
over MgSO.sub.4, filtered, and concentrated to give the product
(121) (8.0 g, 30.8 mmol, yield: 87%). ESI-MS (M+1): 261 calc. for
C.sub.11H.sub.16O.sub.7 260.
##STR00684##
STEP 3. (3-ETHOXYCARBONYLMETHYL-OXETAN-3-YL)-ACETIC ACID ETHYL
ESTER (122)
[0545] To a solution of 2-(3-Ethoxycarbonyl-oxetan-3-yl)-malonic
acid dimethyl ester (121) (5.0 g, 21.7 mmol) in DMSO (25 mL) was
added NaCl (3.8 g, 65.1 mmol). The solution was heated at
160.degree. C. for 3 h. The reaction mixture was diluted with EtOAc
(30 mL) and water (30 mL). The aqueous phase was extracted with
EtOAc (3.times.100 mL) and the combined organic extracts were
washed with brine (100 mL), dried over MgSO.sub.4, filtered, and
concentrated to give the product (122) (2.3 g, 10 mmol, yield:
46%). ESI-MS (M+1): 231 calc. for C.sub.11H.sub.18O.sub.5 230.
##STR00685##
STEP 4. 2-[3-(2-HYDROXY-ETHYL)-OXETAN-3-YL]-ETHANOL (123)
[0546] (3-Ethoxycarbonylmethyl-oxetan-3-yl)-acetic acid ethyl ester
(122) (2.3 g, 10 mmol) was dissolved in 20 ml of THF. This solution
was cooled down to 0.degree. C. using an ice bath and AlLiH.sub.4
(1.1 g, 30 mmol) was added by portions. The reaction mixture was
stirred for 4 h at ambient temperature, and then saturated aqueous
solution of ammonium chloride (20 mL) was added. THF was evaporated
off under reduced pressure, then the reaction mixture was taken up
in ethyl acetate. The organic phase was separated from the aqueous
phase. This extraction was repeated one more time and then the
organic phases were combined and washed with brine (100 mL), dried
over MgSO.sub.4, filtered, and concentrated to give the product
(123) (1.3 g, 8.9 mmol, yield: 89%). ESI-MS (M+1): 147 calc. for
C.sub.7H.sub.14O.sub.3 146.
##STR00686##
STEP 5. METHANESULFONIC ACID
2-[3-(2-METHANESULFONYLOXY-ETHYL)-OXETAN-3-YL]-ETHYL ESTER
(124)
[0547] To a solution of 2-[3-(2-Hydroxy-ethyl)-oxetan-3-yl]-ethanol
(123) (1.3 g, 8.9 mmol) in CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C.
was added Et.sub.3N (2.7 g, 26.7 mmol) and methanesulfonyl chloride
(2.0 g, 17.8 mmol). The solution was allowed to warm to RT and
stirred for 15 min. The reaction mixture was diluted with water (80
mL). The aqueous phase was extracted with CH.sub.2Cl.sub.2
(3.times.50 mL) and the combined organic extracts were washed with
brine (100 mL), dried over MgSO.sub.4, filtered, and concentrated
to give the product (124) (2.0 g, 6.6 mmol, yield: 74%). ESI-MS
(M+1): 303 calc. for C.sub.9H.sub.18O.sub.7S.sub.2 302.
##STR00687##
STEP 6. 7-(2,4-DIMETHOXY-BENZYL)-2-OXA-7-AZA-SPIRO[3.5]NONANE
(125)
[0548] To a solution of (124) (2.0 g, 6.6 mmol) in MeCN (20 mL)
were added 2,4-dimethoxy-benzylamine (1.2 g, 7.3 mmol) and
Et.sub.3N (2.0 g, 19.8 mmol). The solution was allowed to heat at
reflux for 12 h. The reaction mixture was then filtered through a
pad of silica (washing with 30 percent EtOAc:Petrol ether), and the
solvent removed under reduced pressure to give the product (125)
(1.2 g, 4.3 mmol, yield: 65%). ESI-MS (M+1): 278 calc. for
C.sub.16H.sub.23NO.sub.3 277.
##STR00688##
STEP 7. 2-OXA-7-AZA-SPIRO[3.5]NONANE (126)
[0549] To a solution of
7-(2,4-Dimethoxy-benzyl)-2-oxa-7-aza-spiro[3.5]nonane (125) (300
mg, 1.1 mmol) in MeOH (10 mL) was added Pd(OH).sub.2 (300 mg). The
reaction solution was stirred at RT overnight under H.sub.2
atmosphere. LCMS showed that most of the staring material was
consumed. The mixture was filtered and concentrated to give the
product (126) (112 mg, 0.88 mmol, yield: 80%). ESI-MS (M+1): 128
calc. for C.sub.7H.sub.13NO 127.
##STR00689##
STEP 1. 6-ETHYL-2-OXA-6-AZA-SPIRO[3.3]HEPTANES (128)
[0550] To a solution of 3-bromo-2,2-bis(bromomethyl)propanol (127)
(3.25 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol, in 10
mL water) in EtOH (20 mL) were added toluene-4-sulfonamide (3.76 g,
22 mmol). The reaction mixture was refluxed for 2 h, evaporated to
remove EtOH then diluted with EAOAc (20 mL), washed with H.sub.2O
(20 mL). The organic layer was washed with brine (20 mL), dried
over Na.sub.2SO.sub.4, and filtered, evaporated to give the product
to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128)
(1.6 g, 6.3 mmol, yield: 63%).
[0551] ESI-MS (M+1): 128 calc. for C.sub.7H.sub.13NO 127.
##STR00690##
STEP 2. 2-OXA-6-AZA-SPIRO[3.3]HEPTANE OXALATE SALT (129)
[0552] A mixture of
6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.27 g,
5 mmol) in MeOH (10 mL) was added magnesium chips. The mixture was
reacted using ultrasound at RT for 20 mins. Oxalic acid was added
and the mixture was stirred for 15 min, then concentrated to give
oxalate salt (129) (1.06 g, 3.68 mmol, yield: 73.6%).
[0553] .sup.1H NMR: (D.sub.2O, 400 MHz): .delta. (ppm) 4.76 (s,
4H), 4.23 (s, 4H). ESI-MS (M+1): 101 calc. for C.sub.5H.sub.9NO
100.
##STR00691##
STEP 1. 6-ACETYL-2,6-DIAZA-SPIRO[3.3]HEPTANE-2-CARBOXYLIC ACID
TERT-BUTYL ESTER (131)
[0554] To a solution of 2,6-diaza-spiro[3.3]heptane-2-carboxylic
acid tert-butyl ester (130) (purchased from WUXI APPTEC.RTM.) ((500
mg, 2.73 mmol) in CH.sub.2Cl.sub.2 (10 mL) were added KOH (459 mg,
8.19 mmol) and Ac.sub.2O (279 mg, 2.73 mmol). The reaction mixture
was stirred at RT for 1 h, then diluted with CH.sub.2Cl.sub.2 (20
mL), washed with H.sub.2O (20 mL). The organic layer was washed
with brine (20 mL), dried over Na.sub.2SO.sub.4, and filtered,
evaporated to give the product (131) (510 mg, 2.13 mmol, yield:
78%). ESI-MS (M+1): 241 calc. for C.sub.12H.sub.20N.sub.2O.sub.3
240.
##STR00692##
STEP 2. 1-(2,6-DIAZA-SPIRO[3.3]HEPT-2-YL)-ETHANONE HYDROCHLORIDE
(132)
[0555] To a solution of
6-Acetyl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl
ester (131) (300 mg, 1.33 mmol) in CH.sub.2Cl.sub.2 (10 mL) were
added TFA (388 mg, 4.0 mmol). The reaction mixture was stirred at
RT for 1 h, then diluted with CH.sub.2Cl.sub.2 (20 mL), washed with
H.sub.2O (20 mL). The organic layer was washed with brine (20 mL),
dried over Na.sub.2SO.sub.4, and filtered, evaporated to give the
product (132) (176 mg, 1.0 mmol, yield: 75%). ESI-MS (M+1): 141
calc. for C.sub.7H.sub.12N.sub.2O 140.
##STR00693##
STEP 1. 2,2-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL
TRIFLUOROMETHANESULFONATE AND
6,6-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL TRIFLUOROMETHANESULFONATE
(134)
[0556] A solution of 2,2-dimethyltetrahydropyran-4-one (133) (115
g, 0.9 mol, 1.0 eq.) in anhydrous THF (600 mL) was cooled to
-78.degree. C. and to it was added LDA (2.0 M, 538 mL, 1.08 mol,
1.2 eq.) drop wise under N.sub.2 keeping the internal temperature
below -65.degree. C. The resulting solution was stirred at
-78.degree. C. for 20 min. A solution of
N-phenyl-bis(trifluoromethanesulfonimide) (353 g, 0.99 mol, 1.1
eq.) in anhydrous THF (1900 mL) was added to the above solution
slowly keeping the internal temperature below -65.degree. C. The
reaction mixture was warmed to room temperature slowly and stirred
overnight. The reaction was quenched with saturated aqueous sodium
bicarbonate solution, and extracted with MTBE (2 L.times.2). The
combined organic layers was washed with 10% aqueous NaOH solution
(1 L.times.2), brine (500 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered and concentrated to give crude title triflate product
mixture as dark brown oil. The crude product was extracted with
hexanes (2 L.times.5) and the combined hexanes extracts was
purified by column chromatography (directly loaded onto silica gel,
Hexanes.fwdarw.15% ethyl acetate in hexanes, R.sub.f=0.6,
visualized with KMnO.sub.4 stain) to give 200 g of the triflate
product mixture (134) (a mixture of
2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate
and 6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl
trifluoromethanesulfonate ratio=80.6:19.4 by GCMS) as a light
yellow liquid (.about.90% purity by GC-MS and .sup.1H NMR). This
was taken to the next step without further purification.
##STR00694##
STEP 2.
2-(2,2-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL)-4,4,5,5-TETRAMETHYL-1,-
3,2-DIOXABOROLANE AND
2-(6,6-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOX-
ABOROLANE (136)
[0557] A mixture of compound 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl
trifluoromethanesulfonate and
6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate
(134) (200 g, 0.77 mol, 1.0 eq.), bis(pinacolato)diboron (135) (195
g, 0.77 mol, 1.0 eq.), and potassium acetate (151 g, 1.54 mol, 2.0
eq.) in dioxane (2 L) was degassed for 15 min, to it was added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (19 g, 0.023 mol, 0.03 eq.) and the
reaction mixture was degassed again for 15 min. The reaction
mixture was heated to 80.degree. C. overnight, cooled, filtered
through a medium fritted funnel, and washed with MTBE (300
mL.times.4). The organic extracts were combined and concentrated
under reduced pressure. The crude product mixture (136) was cooled
using an ice bath, stirred with an overhead stirrer and to it was
added aqueous 2M NaOH solution (2 L) keeping the internal
temperature below 15.degree. C. The basic aqueous solution was
extracted with MTBE (250 mL.times.3), and the organic extracts were
discarded. The aqueous phase was cooled using an ice bath and the
pH was adjusted to 3 to 5 with concentrated HCl keeping the
internal temperature below 10.degree. C. The heterogeneous solution
(off-white solid precipitated out at pH 3-5) was extracted with
EtOAc (3 L and 1.5 L). The combined organic layer was washed with
water (1 L), brine (1 L), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product mixture (136) was purified by
column chromatography (Hexanes.fwdarw.15% ethyl acetate in hexanes,
R.sub.f=0.5, visualized on KMnO.sub.4) to give 125 g of
2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1-
,3,2-dioxaborolane and
2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane mixture (136) as a white solid (58% overall yield,
>97% purity by GCMS and .sup.1H NMR, The ratio of regioisomers
was found to be 80.4:19.6).
[0558] GCMS: >97%
[0559] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.46-6.43 (m, 1H),
4.06 (q, 2H, J=3.0 Hz), 1.96-1.94 (m, 2H), 1.20 (s, 12H), 1.09 (s,
6H)
[0560] GCMS: 239 (M+1); calcd for C.sub.13H.sub.23BO.sub.3:
238.13
##STR00695##
Example 1.1
(1H-BENZOIMIDAZOL-2-YL)-[3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDIN-1-YL]-METHANON-
E
[0561] To a mixture of 1H-benzoimidazole-2-carboxylic acid (124 mg,
0.76 mmol) in DMF (5 mL) was added TEA (152 mg, 1.5 mmol) and HATU
(347 mg, 0.92 mmol). The reaction mixture was stirred for 5 min and
2-azetidin-3-yl-3-phenyl-pyridine hydrochloride (100 mg, 0.76 mmol)
was added. The reaction mixture was stirred at RT overnight. The
mixture was diluted with water (10 mL), and extracted with EtOAc
(2.times.20 mL). The combined organic extracts were washed with
water (5 mL) and brine (5 mL), dried over Na.sub.2SO.sub.4, and
filtered. The filtrate was evaporated in vacuo and the residue was
purified by column chromatography to give
(1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methano-
ne (100 mg, 0.28 mmol, 59% yield) as a light yellow solid.
[0562] The following Table 13A lists compounds of Examples 1.1 to
1.17, which were made analogous to Scheme 1 by using the
appropriate materials and reaction conditions, which are listed in
Table 13B. The NMR of the Examples are listed in Table 13C.
TABLE-US-00014 TABLE 13A EXAMPLES 1.1 TO 1.17 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (uM) 1.1 ##STR00696##
(1H-Benzoimidazol-2-yl)-[3- (3-phenyl-pyridin-2-yl)-
azetidin-1-yl]-methanone 355 0.0219 1.2 ##STR00697##
(1H-Benzoimidazol-2-yl)-[3- (5-fluoro-3-phenyl-pyridin-
2-yl)-azetidin-1-yl]- methanone 373 0.843 1.3 ##STR00698##
(1H-benzoimidazol-2-yl)-[4- (3-phenyl-pyrazin-2-yl)-
piperidin-1-yl]-methanone 384 0.092 1.4 ##STR00699##
Benzothiazol-2-yl-[3-(3- phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 373 0.446 1.5 ##STR00700##
(1H-Benzoimidazol-2-yl)-[3- (3-piperidin-1-yl-quinoxalin-
2-yl)-azetidin-1-yl]- methanone 413 0.0271 1.6 ##STR00701##
(1H-Benzoimidazol-2-yl)- {3-[3-(4-hydroxy-piperidin-
1-yl)-quinoxalin-2-yl]- azetidin-1-yl}-methanone 429 0.0115 1.7
##STR00702## (1H-Benzoimidazol-2-yl)-[3- (2,3-dihydro-indol-1-yl)-
3',4',5',6'-tetrahydro-2'H- [2,4']bipyridinyl-1'-yl]- methanone 424
0.92 1.8 ##STR00703## (1H-Benzoimidazol-2-yl)-[3-
(3-phenyl-quinolin-2-yl)- azetidin-1-yl]-methanone 405 0.0834 1.9
##STR00704## (1H-Benzoimidazol-2-yl)-(3-
phenyl-3',4',5',6'-tetrahydro- 2'H-[2,4']bipyridinyl-1'-yl)-
methanone 383 0.0217 1.10 ##STR00705## (1H-Benzoimidazol-2-yl)-
{4-[3-(4-hydroxymethyl- piperidin-1-yl)-pyrazin-2-
yl]-piperidin-1-yl}- methanone 421 0.0098 1.11 ##STR00706##
(3-(3-phenylpyrazin-2- yl)azetidin-1-yl)(pyridin-2- yl)methanone
317 0.828 1.12 ##STR00707## (6-methylpyridin-2-yl)(3-(3-
phenylpyrazin-2-yl)azetidin- 1-yl)methanone 331 3.67 1.13
##STR00708## (3-methylpyridin-2-yl)(3-(3-
phenylpyrazin-2-yl)azetidin- 1-yl)methanone 331 11.9 1.14
##STR00709## (5-methylpyridin-2-yl)(3-(3-
phenylpyrazin-2-yl)azetidin- 1-yl)methanone 331 2.03 1.15
##STR00710## (4-methylpyridin-2-yl)(3-(3-
phenylpyrazin-2-yl)azetidin- 1-yl)methanone 331 4.71 1.16
##STR00711## (1H-Benzoimidazol-2-yl)-[3-
(3-phenyl-quinoxalin-2-yl)- azetidin-1-yl]-methanone 406 0.0335
1.17 ##STR00712## (1H-Benzoimidazol-2-yl)-[3-
(3-morpholin-4-yl-pyrazin-2- yl)-azetidin-1-yl]-methanone 365
0.14
TABLE-US-00015 TABLE 13B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 1.1 TO 1.17 Ex. # Starting Material 1
Starting Material 2 Reaction Condition 1.1 ##STR00713##
##STR00714## HATU, TEA, DMF 1.2 ##STR00715## ##STR00716## HATU,
TEA, DMF 1.3 ##STR00717## ##STR00718## HATU, TEA, DMF 1.4
##STR00719## ##STR00720## HATU, TEA, DMF 1.5 ##STR00721##
##STR00722## HATU, TEA, DMF 1.6 ##STR00723## ##STR00724## HATU,
TEA, DMF 1.7 ##STR00725## ##STR00726## HATU, TEA, DMF 1.8
##STR00727## ##STR00728## HATU, TEA, DMF 1.9 ##STR00729##
##STR00730## HATU, TEA, DMF 1.10 ##STR00731## ##STR00732## HATU,
TEA, DMF 1.11 ##STR00733## ##STR00734## HATU, TEA, THF 1.12
##STR00735## ##STR00736## HATU, TEA, THF 1.13 ##STR00737##
##STR00738## HATU, TEA, THF 1.14 ##STR00739## ##STR00740## HATU,
TEA, THF 1.15 ##STR00741## ##STR00742## HATU, TEA, THF 1.16
##STR00743## ##STR00744## HATU, TEA, DMF 1.17 ##STR00745##
##STR00746## HATU, TEA, DCM
TABLE-US-00016 TABLE 13C 1H NMR .delta. (PPM) DATA FOR EXAMPLES 1.1
TO 1.17 Ex. # Structure NMR 1.1 ##STR00747## (DMSO, 400 MHz): 8.61
(s, 1 H); 7.72-7.70 (m, 2 H); 7.66-7.20 (m, 10 H); 4.88-4.86 (m, 2
H); 4.20- 4.13 (m, 3 H). 1.2 ##STR00748## (CDCl.sub.3, 400 MHz):
8.49 (d, J = 2.4 Hz, 1H); 8.13- 8.10 (m, 1H); 7.67-7.66 (m, 2H);
7.55-7.50 (m, 3H); 7.45-7.43 (m, 2H); 7.37-7.35 (m, 2H); 4.99- 4.95
(m, 1H); 4.78-4.74 (m, 1H); 4.39-4.37 (m, 1 H); 3.34-4.25 (m, 1H);
4.17-4.13 (m, 1H). 1.3 ##STR00749## (CDCl.sub.3, 400 MHz): 8.50 (s,
2H); 7.70-7.67 (m, 2H); 7.56-7.51 (m, 5H); 7.37-7.26 (m, 2H); 6.06-
6.03 (m, 1H); 4.91-4.88 (m, 1H); 3.39-3.28 (m, 2H), 2.90-2.84 (m,
1H); 2.17-2.11 (m, 2H); 2.01- 1.90 (m, 2H). 1.4 ##STR00750##
(CDCl.sub.3, 400 MHz): 8.60 (dd, J = 2.4, 17.2 Hz, 2H); 8.06 (d, J
= 7.6 Hz, 1H); 7.96 (d, J = 7.2 Hz, 1H); 7.56-7.45 (m, 7H);
5.15-5.06 (m, 2H); 4.53- 4.42 (m, 2H); 4.39-4.32 (m, 1H). 1.5
##STR00751## (DMSO, 400 MHz): 7.93-7.91 (m, 1H); 7.77-7.70 (m, 2H);
7.63-7.61 (m, 1H); 7.55-7.49 (m, 2H); 7.28-7.22 (m, 2H); 5.13-5.11
(m, 1H); 5.01-5.00 (m, 1H); 4.54-4.53 (m, 1H); 4.42-4.40 (m, 2H);
3.18-3.16 (m, 4H); 1.71-1.68 (m, 4H); 1.61-1.59 (m, 2H). 1.6
##STR00752## (DMSO, 400 MHz): 7.92 (d, J = 7.6 Hz, 1H); 7.77- 7.71
(m, 2H); 7.65-7.63 (m, 1H); 7.55-7.50 (m, 2H); 7.30-7.20 (m, 2H);
5.13-5.10 (m, 1H); 4.73 (d, J = 4.0 Hz, 1H); 4.54-4.48 (m, 1H);
4.46-4.41 (m, 2H); 3.70-3.69 (m, 3H); 3.49-3.44 (m, 2H); 2.99-2.95
(m, 2H); 1.95-1.91 (m, 2H); 1.63-1.58 (m, 2H). 1.7 ##STR00753##
(CDCl.sub.3, 400 MHz): 8.53 (d, J = 4.8 Hz, 1H); 8.30 (d, J = 8.4,
1H); 7.78-7.68 (m, 3H); 7.52-7.45 (m, 2H); 7.37-7.31 (m, 1H);
7.10-7.03 (m, 1H); 6.91- 6.87 (m, 1H); 6.34 (d, J = 7.6 Hz, 1H);
4.89-4.86 (m, 1H); 4.30-4.27 (m, 1H); 3.82-3.73 (m, 3H); 3.50-3.38
(m, 1H); 3.34-3.25 (m, 2H); 2.95-2.89 (m, 1H); 2.53-2.43 (m, 1H);
2.33-2.29 (m, 1H); 1.96-1.94 (m, 1H); 1.89-1.85 (m, 1H). 1.8
##STR00754## (DMSO, 400 MHz): 8.22 (s, 1); 8.06 (d, J = 8.8 Hz,
1H); 7.99 (d, J = 8.0 Hz, 1H); 7.74-7.69 (m, 2H); 7.60-7.45 (m,
8H); 7.27-7.21 (m, 2H); 5.08- 5.06 (m, 1H); 4.88-4.86 (m, 1H);
4.35-4.33 (m, 2H); 4.14-4.13 (m, 1H). 1.9 ##STR00755## (CD.sub.3OD,
400 MHz): 8.73-8.71 (m, 1H); 8.35-8.33 (m, 1H); 7.91-7.88 (m, 1H);
7.68-7.88 (m, 1H); 7.58-7.54 (m, 3H); 7.45-7.43 (m, 2H); 7.40-7.37
(m, 2H); 5.07-5.02 (m, 1H); 4.80-4.71 (m, 1H); 3.48-3.45 (m, 1H);
3.28-3.25 (m, 1H); 2.90-2.80 (m, 1H); 2.15-2.00 (m, 4H). 1.10
##STR00756## (CD.sub.3OD, 400 MHz): 8.14-8.12 (m, 1H); 8.10-8.08
(m, 1H); 7.76-7.74 (m, 2H); 7.50-7.48 (m, 2H); 4.35 (d, J = 6.8 Hz,
1H); 3.50 (d, J = 6.4 Hz, 2H); 3.46-3.43 (m, 4H); 3.31-3.30 (m,
2H); 3.15 (s, 1H); 2.92-2.89 (m, 2H); 1.99-1.98 (m, 3H); 1.89 (d, J
= 12.8 Hz, 3H); 1.71-1.48 (m, 2H). 1.11 ##STR00757## (CD.sub.3OD,
400 MHz): 8.65 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 2H),
7.98-7.89 (m, 2H), 7.52-7.47 (m, 6H), 4.90-4.86 (m, 2H), 4.39-4.26
(m, 3H). 1.12 ##STR00758## (CD.sub.3OD, 400 MHz): 8.64 (d, J = 2.4
Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.80 (d, J =
8 Hz, 1H), 7.51-7.46 (m, 6H), 4.85-4.83 (m, 2H), 4.37-4.31 (m, 3H),
2.54 (s, 3H). 1.13 ##STR00759## (CD.sub.3OD, 400 MHz): 8.53 (d, J =
2.4 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.91-7.89 (m,
1H), 7.51-7.43 (m, 6H), 4.39-4.29 (m, 5H), 2.45 (s, 3H). 1.14
##STR00760## (CD.sub.3OD, 400 MHz): 8.63 (d, J = 2.4 Hz, 1H), 8.52
(d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H),
7.76-7.73 (m, 1H), 7.50-7.46 (m, 5H), 4.85-4.84 (m, 2H), 4.37-4.26
(m, 3H), 2.36 (s, 3H). 1.15 ##STR00761## (CD.sub.3OD, 400 MHz):
9.48 (d, J = 2.4 Hz, 1H), 9.42 (d, J = 2.8 Hz, 1H), 9.22 (d, J =
5.2 Hz, 1H), 8.58- 8.57 (m, 1H), 8.31 (s, 5H), 8.14-8.12 (m, 1H),
5.61-5.52 (m, 2H), 5.04-4.97 (m, 3H), 3.15 (s, 3H). 1.16
##STR00762## (d-DMSO, 400 MHz): 8.17-8.11 (m, 2H); 7.86-7.85 (m,
2H); 7.67-7.48 (m, 7H); 7.27-7.26 (m, 2H); 5.11-5.07 (m, 1H);
4.98-4.94 (m, 1H); 4.51-4.49 (m, 1H); 4.39-4.35 (m, 1H); 4.27-4.22
(m, 1H). 1.17 ##STR00763## (CDCl.sub.3, 400 MHz): 8.23-8.22 (m,
1H); 8.16-8.15 (m, 1H); 7.71-7.69 (m, 2H); 7.36-7.34 (m, 2H); 5.33
(t, J = 10.0 Hz, 1H); 5.10-5.06 (m, 1H); 4.65- 4.59 (m, 2H);
4.35-4.25 (m, 1H); 3.88-3.89 (m, 4H); 3.17-3.14 (m, 4H)
##STR00764##
Example 2.1
(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-[3-(3-PHENYL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-
-METHANONE
[0563] To a stirred solution of
[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl-
)-methanone (100 mg, 0.30 mmol) in dioxane (10 mL) was added
phenylboronic acid (87 mg, 0.71 mmol), Na.sub.2CO.sub.3 (152 mg,
1.4 mmol) and H.sub.2O (2 mL). The reaction mixture was degassed
with N.sub.2 and then PdCl.sub.2(dppf) (35 mg, 0.05 mmol) was
added. The reaction mixture was stirred at 80.degree. C. for 12 h.
The reaction mixture was left to reach RT and filtered through a
pad of CELITE.RTM. and the filter cake was washed with
CH.sub.2Cl.sub.2 (20 mL.times.3). The combined filtrates were
evaporated in vacuo and the residue was purified by column
chromatography to give the desired compound (60 mg, 0.17 mmol,
yield 70%)
[0564] The following Table 14A lists compounds of Examples 2.1 to
2.30, which were made analogous to Scheme 2 by using the
appropriate materials and reaction conditions, which are listed in
Table 14B. The NMR data of the Examples are listed in Table
14C.
TABLE-US-00017 TABLE 14A EXAMPLES 2.1 TO 2.30 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (uM) 2.1 ##STR00765##
(1-Methyl-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 370 0.181 2.2 ##STR00766##
[3-(3-Phenyl-pyrazin-2-yl)- azetidin-1-yl]-[1-(2,2,2-trifluoro-
ethyl)-1H-benzoimidazol-2-yl]- methanone 438 0.893 2.3 ##STR00767##
(1H-Benzoimidazol-2-yl)-[3-(3- phenyl-pyrazin-2-yl)-azetidin-1-
yl]-methanone 356 0.0248 2.4 ##STR00768##
(1H-Benzoimidazol-2-yl)-{3-[3- (3,4-dimethoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 416 0.0188 2.5 ##STR00769##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-isopropyl-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 398 0.049 2.6 ##STR00770##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-trifluoromethoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 440 0.0357 2.7 ##STR00771##
1H-Benzoimidazol-2-yl)-{3-[3- (3,5-dimethoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 416 0.056 2.8 ##STR00772##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-ethoxy-phenyl)-pyrazin-2-yl]-
azetidin-1-yl}-methanone 400 0.0299 2.9 ##STR00773##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-isopropoxy-phenyl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 414 0.0352 2.10 ##STR00774##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-fluoro-5-methoxy-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 404 0.0424 2.11
##STR00775## (1H-Benzoimidazol-2-yl)-{3-[3-
(2-methoxy-pyridin-4-yl)-pyrazin- 2-yl]-azetidin-1-yl}-methanone
387 0.093 2.12 ##STR00776## (1H-Benzoimidazol-2-yl)-{3-[3-
(5-methoxy-pyridin-3-yl)-pyrazin- 2-yl]-azetidin-1-yl}-methanone
387 0.640 2.13 ##STR00777## (1H-benzo[d]imidazol-2-yl)(3-(3-
(4-fluoro-3-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)methanone 388
0.013 2.14 ##STR00778## (1H-Benzoimidazol-2-yl)-{3-[3-
(4-methoxy-3-methyl-phenyl)- pyrazin-2-yl]-azetidin-1-yl}-
methanone 400 0.0201 2.15 ##STR00779##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-fluoro-5-methyl-phenyl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 388 0.0393 2.16
##STR00780## (1H-Benzoimidazol-2-yl)-{3-[3-
(5-methyl-pyridin-3-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 371
0.195 2.17 ##STR00781## (1H-Benzoimidazol-2-yl)-{3-[3-
(4-methyl-thiophen-2-yl)-pyrazin- 2-yl]-azetidin-1-yl}-methanone
376 0.013 2.18 ##STR00782## (1H-Benzoimidazol-2-yl)-{3-[3-
(1-methyl-1H-pyrazol-4-yl)- pyrazin-2-yl]-azetidin-1-yl}- methanone
360 0.216 2.19 ##STR00783## (1H-Benzoimidazol-2-yl)-{3-[3-
(3-hydroxymethyl-phenyl)- pyrazin-2-yl]-azetidin-1-yl}- methanone
386 0.0336 2.20 ##STR00784## (1H-Benzoimidazol-2-yl)-{3-[3-
(4-hydroxymethyl-phenyl)- pyrazin-2-yl]-azetidin-1-yl}- methanone
386 0.0398 2.21 ##STR00785## 1-(4-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2- yl}-phenyl)-ethanone 398 0.0247
2.22 ##STR00786## 1-(3-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2- yl}-phenyl)-ethanone 398 0.0151
2.23 ##STR00787## (1H-Benzoimidazol-2-yl)-{3-[3-
(3-methoxymethyl-phenyl)- pyrazin-2-yl]-azetidin-1-yl}- methanone
400 0.0449 2.24 ##STR00788## 4-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2- yl}-N,N-dimethyl-benzamide 427
0.026 2.25 ##STR00789## 3-{3-[1-(1H-Benzoimidazole-2-
carbonyl)-azetidin-3-yl]-pyrazin-2- yl}-N,N-dimethyl-benzamide 427
0.537 2.26 ##STR00790## (1H-benzo[d]imidazol-2-yl)(3-(3-
(pyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)methanone 357 0.25 2.27
##STR00791## (7-chloro-1H-benzo[d]imidazol-2-
yl)(3-(3-(pyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)methanone 391
0.587 2.28 ##STR00792## (1H-benzo[d]imidazol-2-yl)(3-(3-
(2-methylpyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)methanone 371
0.037 2.29 ##STR00793## (1H-benzo[d]imidazol-2-yl)(3-(3-
(m-tolyl)pyrazin-2-yl)azetidin-1- yl)methanone 370 0.0148 2.30
##STR00794## 3-(3-(1-(1H-benzo[d]imidazole-2-
carbonyl)azetidin-3-yl)pyrazin-2- yl)benzonitrile 381 0.226
TABLE-US-00018 TABLE 14B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 2.1 TO 2.30 Ex.# Structure NMR 2.1
##STR00795## (CD.sub.3OD, 400 MHz): 8.65 (d, J = 2.4 Hz, 1 H); 8.53
(d, J = 2.4, 1 H); 7.70-7.67 (m, 1 H); 7.59-7.58 (m, 1 H);
7.53-7.40 (m, 5 H); 7.38-7.35 (m, 1 H); 7.34-7.31 (m, 1 H);
4.81-4.80 (m, 2 H); 4.41-4.32 (m, 1 H); 4.07 (s, 3 H) 2.2
##STR00796## (CD.sub.3OD, 400 MHz): 8.67-8.66 (m, 1 H); 8.53-8.52
(m, 1 H); 7.74-7.72 (m, 1 H); 7.63-7.61 (m, 1 H); 7.53-7.48 (m, 5
H); 7.45-7.41 (m, 1 H); 7.37-7.33 (m, 1 H); 5.60- 5.56 (m, 2 H);
4.94-4.92 (m, 2 H); 4.41-4.34 (m, 3 H). 2.3 ##STR00797##
(CDCl.sub.3, 400 MHz): 8.62-8.60 (m, 2H); 7.69-7.68 (m, 2H);
7.58-7.44 (m, 5H); 7.43-7.32 (m, 2H); 5.22-5.12 (m, 2H); 4.64-4.62
(m, 1H); 4.52-4.34 (m, 1H). 2.4 ##STR00798## (CDCl.sub.3, 400 MHz):
8.51-8.48 (m, 2 H); 7.72 (br, 1H); 7.47 (br, 1H); 7.24 (brs, 2H);
7.05 (s, 1 H); 6.93 (s, 2 H); 5.15-5.16 (m, 2H); 4.58-4.54 (m, 1
H); 4.46-4.44 (m, 1H); 4.38-4.30 (m, 1 H); 3.90 (s, 6 H) 2.5
##STR00799## (CDCl.sub.3, 400 MHz): 8.60-8.57 (m, 2 H); 7.67 (brs,
2H); 7.46-7.44 (m, 1H); 7.38-7.37 (m, 2 H); 7.31-7.26 (m, 3 H);
5.17-5.16 (m, 2H); 4.63-4.62 (m, 1H); 4.51-4.50 (m, 1 H); 4.36-4.33
(m, 1 H); 3.05-2.99 (m, 2H); 1.33 (d, J = 6.8 Hz, 6H). 2.6
##STR00800## (DMSO, 400 MHz): 8.75-8.74 (m, 1 H); 8.67-8.66 (m,
1H); 7.69-7.54 (m, 6H); 7.27-7.25 (m, 2H); 4.95-4.92 (m, 2H);
4.31-4.25 (m, 3H). 2.7 ##STR00801## (CDCl.sub.3, 400 MHz): 8.60 (d,
J = 2.4 Hz, 1H); 8.56 (d, J = 2.4 Hz, 1H); 7.67 (br, 2H); 7.43-7.40
(m, 1H); 7.32- 7.30 (m, 2H); 7.02-6.98 (m, 3H); 5.17-5.16 (m, 2H);
4.66-4.60 (m, 2H); 4.54-4.49 (m, 1H); 4.40-4.36 (m, 1H); 1.38 (d, J
= 6.0 Hz, 6H). 2.8 ##STR00802## (CDCl.sub.3, 400 MHz): 8.63-8.59
(m, 2 H); 7.70 (br, 2 H); 7.44-7.28 (m, 3 H); 7.06-7.01 (m, 3 H);
5.20-5.18 (m, 2 H); 4.63-4.53 (m, 2 H); 4.41-4.40 (m, 1 H);
4.15-4.10 (m, 2 H); 1.49-1.45 (m, 3 H). 2.9 ##STR00803## (DMSO, 400
MHz): 8.70 (d, J = 2.4 Hz, 1H); 8.64 (d, J = 2.4 Hz, 1H); 7.71
(brs, 1H); 7.50-7.41 (m, 5 H); 7.26 (brs, 2H); 5.32-5.29 (m, 1H);
4.98-4.93 (m, 2H); 4.61- 4.59 (m, 2H); 4.34-4.28 (m, 2H); 4.24-4.21
(m, 1H). 2.10 ##STR00804## (CDCl.sub.3, 400 MHz): 8.62 (d, J = 2.4
Hz, 1H); 8.57 (d, J = 2.4 Hz, 1H); 7.69-7.67 (m, 2H); 7.34-7.32 (m,
2H); 7.26-7.15 (m, 2H); 6.96-6.92 (m, 1H); 5.19-5.14 (m, 2H); 4.62
(t, J = 6.0 Hz, 1H); 4.51 (t, J = 9.2 Hz, 1H); 4.37-4.34 (m, 1H);
3.97 (s, 3H) 2.11 ##STR00805## (CDCl.sub.3, 400 MHz): 8.70-8.69 (m,
1H); 8.63-8.62 (m, 1 H); 8.43-8.42 (m, 1 H); 7.74-7.72 (m, 2 H);
7.43-7.41 (m, 2H); 7.12-7.11 (m, 1 H); 7.01 (s, 1 H); 5.15-5.11 (m,
2 H); 4.56-4.52 (m, 2 H); 4.32-4.31 (m, 1 H); 4.06 (s, 3 H). 2.12
##STR00806## (CDCl.sub.3, 400 MHz): 8.66-8.65 (m, 1H); 8.57-8.56
(m, 2H); 8.50 (s, 1H); 7.96 (s, 1H); 7.66-7.64 (m, 2H); 7.36- 7.34
(m, 2H); 5.09-5.00 (m, 2H); 4.59-4.46 (m, 2H); 4.29-4.27 (m, 1H);
4.00 (s, 3H) 2.13 ##STR00807## (CDCl.sub.3, 400 MHz): 8.54 (d, J =
1.6 Hz, 1H); 8.49 (d, J = 2.4 Hz, 1H); 7.62 (s, 2H); 7.33-7.26 (m,
3H); 7.19 (s, 1H); 7.09 (t, J = 8.8 Hz, 1H); 5.13-5.10 (m, 2H);
4.29- 4.18 (m, 1H); 2.62 (s, 3H). 2.14 ##STR00808## (CDCl.sub.3,
400 MHz): 8.56 (s, 2H); 7.69 (brs, 2H); 7.34- 7.24 (m, 4 H);
6.96-6.94 (m, 1H); 5.21-5.15 (m, 2H); 4.60-4.40 (m, 3H); 3.90 (s,
3H); 2.30 (s, 3H). 2.15 ##STR00809## (CDCl.sub.3, 400 MHz):
8.62-8.57 (m, 2H); 7.67-7.67 (m, 2H); 7.30 (brs, 2 H); 7.05-7.03
(m, 3 H); 5.17-5.15 (m, 2H); 4.62-4.48 (m, 2H); 4.35-4.33 (m, 1 H);
2.46 (s, 3 H). 2.16 ##STR00810## (CDCl.sub.3, 400 MHz): 8.83 (s,
1H); 8.67 (s, 1H); 8.65 (d, J = 2.0 Hz, 1H); 8.56 (d, J = 2.0 Hz,
1H); 8.31 (s, 1H); 7.65-7.62 (m, 2H); 7.33-7.31 (m, 2H); 5.11-5.07
(m, 1H); 5.03-5.00 (m, 1H); 4.29-4.25 (m, 1H); 2.57 (s, 3H). 2.17
##STR00811## (CDCl.sub.3, 400 MHz): 8.58-8.54 (m, 2 H); 7.61 (br, 2
H); 7.40-7.38 (m, 2 H); 7.27-7.25 (m, 2 H); 5.15-5.13 (m, 1 H);
4.96-4.92 (m, 1 H); 4.58-4.53 (m, 2 H); 4.38-4.36 (m, 1H); 2.29 (s,
3H). 2.18 ##STR00812## (CDCl.sub.3, 400 MHz): 8.50-8.49 (m, 2 H);
7.87 (brs, 2H); 7.72 (br, 2 H); 7.41-7.40 (m, 2H); 5.30-5.29 (m,
1H); 5.08-5.07(m, 1 H); 4.65-4.61 (m, 2H); 4.49-4.48 (m, 1H); 4.03
(s, 3H). 2.19 ##STR00813## (DMSO, 400 MHz): 8.70 (d, J = 2.4 Hz,
1H); 8.64 (d, J = 2.4 Hz, 1H); 7.71 (brs, 1H); 7.50-7.41 (m, 5 H);
7.26 (brs, 2H); 5.32-5.29 (m, 1H); 4.98-4.93 (m, 2H); 4.61- 4.59
(m, 2H); 4.34-4.28 (m, 2H); 4.24-4.21 (m, 1H). 2.20 ##STR00814##
(DMSO, 400 MHz): 8.69 (d, J = 2.4 Hz, 1H); 8.63 (d, J = 2.4 Hz,
1H); 7.53-7.47 (m, 5 H); 7.71 (br, 2H); 4.97- 4.88 (m, 2H); 4.59
(s, 2 H); 4.33-4.21 (m, 3H). 2.21 ##STR00815## (CDCl.sub.3, 400
MHz): 8.65-8.61 (m, 2 H); 8.12-8.10 (m, 2 H); 7.70-7.68 (m, 2 H);
7.59-7.57 (m, 2 H); 7.36-7.34 (m, 2 H); 5.21-5.10 (m, 2 H);
4.64-4.61 (m, 1 H);; 4.51- 4.50 (m, 1 H); 4.32-4.29 (m, 1 H); 2.68
(s, 3 H). 2.22 ##STR00816## (CDCl.sub.3, 400 MHz): 8.63-8.59 (m, 2
H); 8.09-8.07 (m, 2H); 7.64-7.62 (m, 4H); 7.34-7.31 (m, 2H);
5.15-5.14 (m, 2H); 4.60-4.58 (m, 1H); 4.51-4.49 (m, 1H); 4.32- 4.30
(m, 1H); 2.66 (s, 3H). 2.23 ##STR00817## (CDCl.sub.3, 400 MHz):
8.63-8.59 (m, 2 H); 7.70-7.68 (m, 2H); 7.54-7.47 (m, 3H); 7.38-7.34
(m, 3H); 7.02-7.00 (m, 4H); 5.16-5.12 (m, 2H); 4.61-4.60 (m, 1H);
4.58- 4.51 (m, 2H); 4.48-4.46 (m, 1H); 4.39-4.33 (m, 1H); 3.44 (s,
3H). 2.24 ##STR00818## (CDCl.sub.3, 400 MHz): 8.58-8.54 (m, 2 H);
7.67-7.66 (m, 2 H); 7.57-7.54 (m, 2 H); 7.49-7.47 (m, 2H);
7.34-7.32 (m, 2 H); 5.10-5.00 (m, 2H); 4.52-4.51 (m, 1H); 4.41-
4.40 (m, 1H); 4.27-4.21 (m, 1H); 3.15 (s, 3 H); 3.02 (s, 3 H). 2.25
##STR00819## (CDCl.sub.3, 400 MHz): 8.60-8.55 (m, 2 H); 7.66 (brs,
2H); 7.57-7.50 (m, 4H); 7.30-7.29 (m, 2H); 5.10 (brs, 2H);
4.56-4.55 (m, 1H); 4.45-4.44 (m, 2H); 4.29-4.27 (m, 1H); 3.15 (s,
3H); 3.04 (s, 3H). 2.26 ##STR00820## (CDCl.sub.3, 400 MHz):
8.90-8.80 (m, 2H); 8.70 (s, 1H); 8.60 (s, 1H); 7.85-7.72 (m, 2H);
7.67-7.62 (m, 2H); 7.46-7.45 (m, 2H); 5.24-5.13 (m, 2H); 4.66-4.62
(m, 1H); 4.54-4.49 (m, 1H); 4.30 (brs, 1H). 2.27 ##STR00821##
(CDCl.sub.3, 400 MHz): 8.75-8.72 (m, 2H); 8.59 (s, 1H); 8.54 (s,
1H); 7.84-7.83 (m, 1H); 7.45-7.36 (m, 2H); 7.24-7.11 (m, 2H);
5.19-5.08 (m, 2H); 4.58-4.45 (m, 2H); 4.29-4.22 (m, 1H). 2.28
##STR00822## (CDCl.sub.3, 400 MHz): .delta. (ppm) 8.69-8.60 (m,
3H); 7.80 (d, J = 8.0 Hz, 1H); 7.55 (d, J = 8.0 Hz, 1H); 7.32-7.26
(m, 3H); 7.22-7.20 (m, 1H); 5.20-5.16 (m, 2H); 4.68-4.64 (m, 1H);
4.55-4.51 (m, 1H); 4.32-4.28 (m, 1H); 2.69 (s, 3H). 2.29
##STR00823## (CDCl.sub.3, 400 MHz): 8.60-8.57 (m, 2H); 7.81-7.79
(m, 1H); 7.55-7.40 (m, 1H); 7.34-7.26 (m, 6H); 5.18-5.17 (m, 2H);
4.66-4.62 (m, 1H); 4.52-4.48 (m, 1H); 4.38- 4.34 (m, 1H); 2.46 (s,
3H). 2.30 ##STR00824## (CDCl.sub.3, 400 MHz): .delta. (ppm)
8.69-8.68 (m, 1H); 8.61- 8.60 (m, 1H); 7.89 (s, 1H); 7.87-7.65 (m,
5H); 7.32-7.26 (m, 2H); 5.25-5.13 (m, 2H); 4.68-4.64 (m, 1H); 4.55-
4.51 (m, 1H); 4.29-4.26 (m, 1H).
TABLE-US-00019 TABLE 14C STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 2.1 TO 2.30. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 2.1 ##STR00825## ##STR00826## PdCl.sub.2(dppf),
Na.sub.2CO.sub.3, dioxane/H.sub.2O 80.degree. C. 2.2 ##STR00827##
##STR00828## PdCl.sub.2(dppf), Na.sub.2CO.sub.3, dioxane/H.sub.2O
80.degree. C. 2.3 ##STR00829## ##STR00830## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.4 ##STR00831##
##STR00832## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.5 ##STR00833## ##STR00834## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.6 ##STR00835##
##STR00836## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.7 ##STR00837## ##STR00838## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.8 ##STR00839##
##STR00840## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.9 ##STR00841## ##STR00842## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.10 ##STR00843##
##STR00844## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.11 ##STR00845## ##STR00846## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.12 ##STR00847##
##STR00848## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.13 ##STR00849## ##STR00850## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.14 ##STR00851##
##STR00852## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.15 ##STR00853## ##STR00854## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.16 ##STR00855##
##STR00856## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.17 ##STR00857## ##STR00858## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.18 ##STR00859##
##STR00860## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.19 ##STR00861## ##STR00862## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.20 ##STR00863##
##STR00864## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.21 ##STR00865## ##STR00866## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.22 ##STR00867##
##STR00868## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.23 ##STR00869## ##STR00870## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.24 ##STR00871##
##STR00872## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
80.degree. C. 2.25 ##STR00873## ##STR00874## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O 80.degree. C. 2.26 ##STR00875##
##STR00876## PdCl.sub.2(dppf), K.sub.3PO.sub.4, dioxane/H.sub.2O
reflux 2.27 ##STR00877## ##STR00878## PdCl.sub.2(dppf),
K.sub.3PO.sub.4, dioxane/H.sub.2O reflux 2.28 ##STR00879##
##STR00880## PdCl.sub.2(dppf), K.sub.2CO.sub.3, dioxane/H.sub.2O
reflux 2.29 ##STR00881## ##STR00882## PdCl.sub.2(dppf),
K.sub.2CO.sub.3, dioxane/H.sub.2O reflux 2.30 ##STR00883##
##STR00884## PdCl.sub.2(dppf), K.sub.2CO.sub.3, dioxane/H.sub.2O
reflux
##STR00885##
Example 3.1
(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-[3-(3-PIPERIDIN-1-YL-PYRAZIN-2-YL)-AZETID-
IN-1-YL]-METHANONE
[0565] To a mixture of
[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl-
)-methanone (0.10 g, 0.30 mmol), piperidine (0.052 g, 0.60 mmol)
and triethylamine (0.091 g, 0.90 mmol) was added DMSO (4 mL). The
solution was heated to 120.degree. C. for 5 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),
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 50% EtOAc in
petroleum ether) to give
(1-methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azeti-
din-1-yl]-methanone (0.072 g, 0.19 mmol, 63% yield) as white
solid.
[0566] The following Table 15A lists compounds of Examples 3.1 to
3.54, which were made analogous to Scheme 3 by using the
appropriate materials and reaction conditions, which are listed in
Table 15B. The NMR data of the Examples are listed in Table
15C.
TABLE-US-00020 TABLE 15A EXAMPLES 3.1 TO 3.54 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (uM) 3.1 ##STR00886##
(1-Methyl-1H- benzoimidazol-2-yl)-[3-(3-
piperidin-1-yl-pyrazin-2-yl)- azetidin-1-yl]-methanone 377 0.136
3.2 ##STR00887## {3-[3-(4-Hydroxy-piperidin-
1-yl)-pyrazin-2-yl]-azetidin- 1-yl}-(1-methyl-1H-
benzoimidazol-2-yl)- methanone 393 0.351 3.3 ##STR00888##
[3-(3-Piperidin-1-yl-pyrazin- 2-yl)-azetidin-1-yl]-[1-(2,2,2-
trifluoro-ethyl)-1H- benzoimidazol-2-yl]- methanone 445 0.575 3.4
##STR00889## {3-[3-(4-Hydroxy-piperidin-
1-yl)-pyrazin-2-yl]-azetidin- 1-yl}-[1-(2,2,2-trifluoro-
ethyl)-1H-benzoimidazol-2- yl]-methanone 461 0.963 3.5 ##STR00890##
(1H-Benzoimidazol-2-yl)-[3- (3-pyrrolidin-1-yl-pyrazin-2-
yl)-azetidin-1-yl]-methanone 349 0.0217 3.6 ##STR00891##
(1H-Benzoimidazol-2-yl)-{3- [3-(4-trifluoromethyl-
piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 431 0.0205
3.7 ##STR00892## (R & S)-(1H-Benzoimidazol-
2-yl)-{3-[3-(2-methyl- piperidin-1-yl)-pyrazin-2-yl]-
azetidin-1-yl}-methanone 377 0.0636 3.8 ##STR00893##
(1H-Benzoimidazol-2-yl)-{3- [3-(3-methyl-piperidin-1-yl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 377 0.016 3.9 ##STR00894##
(1H-Benzoimidazol-2-yl)-{3- [3-(4-methyl-piperidin-1-yl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 377 0.0272 3.10
##STR00895## (1H-Benzoimidazol-2-yl)-{3-
[3-(4,4-dimethyl-piperidin-1- yl)-pyrazin-2-yl]-azetidin-1-
yl}-methanone 391 0.0481 3.11 ##STR00896##
(1H-Benzoimidazol-2-yl)-{3- [3-(4-hydroxymethyl-
piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 393 0.0072
3.12 ##STR00897## (1H-Benzoimidazol-2-yl)-(3-
{3-[4-(1-hydroxy-1-methyl- ethyl)-piperidin-1-yl]-
pyrazin-2-yl}-azetidin-1-yl)- methanone 421 0.0563 3.13
##STR00898## (1H-Benzoimidazol-2-yl)-(3- {3-[4-(1-hydroxy-1-methyl-
ethyl)-piperidin-1-yl]- pyrazin-2-yl}-azetidin-1-yl)- methanone 393
0.0381 3.14 ##STR00899## 1-{3-[1-(1H- Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}- piperidine-4-carbonitrile 388 0.00529
3.15 ##STR00900## (1H-Benzoimidazol-2-yl)-{3- [3-(4-methoxymethyl-
piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 407 0.0185
3.16 ##STR00901## (R & S)-(1H-Benzoimidazol-
2-yl)-{3-[3-(3-methyl- pyrrolidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 363 0.00892 3.17 ##STR00902## (R &
S)-(1H- Benzoimidazol-2-yl)-{3-[3- (2-methyl-pyrrolidin-1-yl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 363 0.0149 3.18
##STR00903## (1H-Benzoimidazol-2-yl)-{3- [3-(3,4-dihydro-1H-
isoquinolin-2-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 411
0.00676 3.19 ##STR00904## (1H-Benzoimidazol-2-yl)-{3-
[3-(1,3-dihydro-isoindol-2- yl)-pyrazin-2-yl]-azetidin-1-
yl}-methanone 397 0.043 3.20 ##STR00905## (R &
S)-(1H-Benzoimidazol- 2-yl)-{3-[3-(3-phenyl-
pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 425 0.0468
3.21 ##STR00906## (R & S)-(1H-Benzoimidazol-
2-yl)-{3-[3-(2-phenyl- pyrrolidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 425 0.163 3.22 ##STR00907##
(1H-Benzoimidazol-2-yl)-[3- (3-cyclopentylamino-pyrazin-
2-yl)-azetidin-1-yl]- methanone 363 0.0363 3.23 ##STR00908##
(1H-Benzoimidazol-2-yl)-[3- (3-cyclohexylamino-pyrazin-
2-yl)-azetidin-1-yl]- methanone 377 0.0389 3.24 ##STR00909##
(1H-Benzoimidazol-2-yl)-[3- (3-benzylamino-pyrazin-2-
yl)-azetidin-1-yl]-methanone 385 0.171 3.25 ##STR00910##
(1H-Benzoimidazol-2-yl)-{3- [3-(2-hydroxy-ethylamino)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 339 0.74 3.26 ##STR00911##
(1H-benzo[d]imidazol-2- yl)(3-(3-((2- methoxyethyl)amino)pyrazin-
2-yl)azetidin-1-yl)methanone 353 0.0586 3.27 ##STR00912##
1-{3-[1-(1H- Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}- piperidine-4-carboxylic acid amide
406 0.00312 3.28 ##STR00913## (R & S)-(1H-Benzoimidazol-
2-yl)-{3-[3-(3- hydroxymethyl-piperidin-1-
yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone 393 0.0206 3.29
##STR00914## (1H-Benzoimidazol-2-yl)-{3- [3-(3-hydroxy-piperidin-1-
yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone 379 0.0352 3.30
##STR00915## [3-(3-Azepan-1-yl-pyrazin-2- yl)-azetidin-1-yl]-(1H-
benzoimidazol-2-yl)- methanone 379 0.0342 3.31 ##STR00916##
[3-(3-Azetidin-1-yl-pyrazin- 2-yl)-azetidin-1-yl]-(1H-
benzoimidazol-2-yl)- methanone 335 0.0882 3.32 ##STR00917##
(R)-(1H-Benzoimidazol-2- yl)-{3-[3-(2-hydroxymethyl-
pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 379 0.104
3.33 ##STR00918## (1H-Benzoimidazol-2-yl)-[3-
(3-isopropylamino-pyrazin-2- yl)-azetidin-1-yl]-methanone 337 0.133
3.34 ##STR00919## (S)-(1H-Benzoimidazol-2-
yl)-{3-[3-(2-hydroxymethyl- pyrrolidin-1-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 379 0.917 3.35 ##STR00920##
(1H-Benzoimidazol-2-yl)-(3- {3-[4-(2-hydroxy-ethyl)-
piperidin-1-yl]-pyrazin-2-yl}- azetidin-1-yl)-methanone 407 0.0094
3.36 ##STR00921## (1H-Benzoimidazol-2-yl)-[3-
(3-[1,4]oxazepan-4-yl- pyrazin-2-yl)-azetidin-1-yl]- methanone 379
0.0627 3.37 ##STR00922## (1H-Benzoimidazol-2-yl)-{3-
[3-(4-methyl-[1,4]diazepan- 1-yl)-pyrazin-2-yl]-azetidin-
1-yl}-methanone 392 4.28 3.38 ##STR00923## 1-(4-{3-[1-(1H-
Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-
[1,4]diazepan-1-yl)-ethanone 420 0.0859 3.39 ##STR00924##
(1H-Benzoimidazol-2-yl)-{3- [3-(4-hydroxy-azepan-1-yl)-
pyrazin-2-yl]-azetidin-1-yl}- methanone 393 0.0368 3.40
##STR00925## (R & S)-(1H- Benzoimidazol-2-yl)-{3-[3-
(3-hydroxymethyl-pyrrolidin- 1-yl)-pyrazin-2-yl]-azetidin-
1-yl}-methanone 379 0.0665 3.41 ##STR00926##
(R)-(1H-Benzoimidazol-2- yl)-{3-[3-(3-hydroxy-
piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 379 0.0709
3.42 ##STR00927## (S)-(1H-Benzoimidazol-2- yl)-{3-[3-(3-hydroxy-
piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 379 0.170
3.43 ##STR00928## (R & S)-1-{3-[1-(1H-
Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-
piperidine-3-carbonitrile 388 0.0868 3.44 ##STR00929## 1-{3-[1-(1H-
Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-
piperidine-4-carboxylic acid methylamide 420 0.016 3.45
##STR00930## 1-{3-[1-(1H- Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}- piperidine-4-carboxylic acid
dimethylamide 434 0.0166 3.46 ##STR00931## 1-(1-(3-(1-(1H-
benzo[d]imidazole-2- carbonyl)azetidin-3-
yl)pyrazin-2-yl)piperidin-4- yl)ethanone 405 0.0119 3.47
##STR00932## 1-(4-(3-(1-(1H- benzo[d]imidazole-2-
carbonyl)azetidin-3- yl)pyrazin-2-yl)piperazin-1- yl)ethanone 406
0.192 3.48 ##STR00933## (R)-(1H-benzo[d]imidazol-2- yl)(3-(3-(3-
hydroxypyrrolidin-1- yl)pyrazin-2-yl)azetidin-1- yl)methanone 365
0.0718 3.49 ##STR00934## (S)-(1H-benzo[d]imidazol-2- yl)(3-(3-(3-
hydroxypyrrolidin-1- yl)pyrazin-2-yl)azetidin-1- yl)methanone 365
0.0632 3.50 ##STR00935## (1H-benzo[d]imidazol-2-
yl)(3-(3-(piperidin-1- yl)pyrazin-2-yl)azetidin-1- yl)methanone 363
0.0107 3.51 ##STR00936## (1H-benzo[d]imidazol-2-
yl)(3-(3-(4-hydroxypiperidin- 1-yl)pyrazin-2-yl)azetidin-1-
yl)methanone 379 0.0233 3.52 ##STR00937##
(1H-Benzoimidazol-2-yl)-{3- [3-(2-oxa-7-aza-
spiro[3.5]non-7-yl)-pyrazin- 2-yl]-azetidin-1-yl}- methanone 405
0.0276 3.53 ##STR00938## (1H-Benzoimidazol-2-yl)-{3-
[3-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-pyrazin-
2-yl]-azetidin-1-yl}- methanone 377 0.1320 3.54 ##STR00939##
1-(6-{3-[1-(1H- Benzoimidazole-2-carbonyl)-
azetidin-3-yl]-pyrazin-2-yl}- 2,6-diaza-spiro[3.3]hept-2-
yl)-ethanone 418 0.4900
TABLE-US-00021 TABLE 15B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 3.1 TO 3.54. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 3.1 ##STR00940## ##STR00941## TEA, DMSO 120.degree. C.
3.2 ##STR00942## ##STR00943## TEA, DMSO 120.degree. C. 3.3
##STR00944## ##STR00945## TEA, DMSO 120.degree. C. 3.4 ##STR00946##
##STR00947## TEA, DMSO 120.degree. C. 3.5 ##STR00948## ##STR00949##
TEA, DMSO 120.degree. C. 3.6 ##STR00950## ##STR00951## TEA, DMSO
120.degree. C. 3.7 ##STR00952## ##STR00953## TEA, DMSO 120.degree.
C. 3.8 ##STR00954## ##STR00955## TEA, DMSO 120.degree. C. 3.9
##STR00956## ##STR00957## TEA, DMSO 120.degree. C. 3.10
##STR00958## ##STR00959## TEA, DMSO 120.degree. C. 3.11
##STR00960## ##STR00961## TEA, DMSO 120.degree. C. 3.12
##STR00962## ##STR00963## TEA, DMSO 120.degree. C. 3.13
##STR00964## ##STR00965## TEA, DMSO 120.degree. C. 3.14
##STR00966## ##STR00967## TEA, DMSO 120.degree. C. 3.15
##STR00968## ##STR00969## TEA, DMSO 120.degree. C. 3.16
##STR00970## ##STR00971## TEA, DMSO 120.degree. C. 3.17
##STR00972## ##STR00973## TEA, DMSO 120.degree. C. 3.18
##STR00974## ##STR00975## TEA, DMSO 120.degree. C. 3.19
##STR00976## ##STR00977## TEA, DMSO 120.degree. C. 3.20
##STR00978## ##STR00979## TEA, DMSO 120.degree. C. 3.21
##STR00980## ##STR00981## TEA, DMSO 120.degree. C. 3.22
##STR00982## ##STR00983## TEA, DMSO 120.degree. C. 3.23
##STR00984## ##STR00985## TEA, DMSO 120.degree. C. 3.24
##STR00986## ##STR00987## TEA, DMSO 120.degree. C. 3.25
##STR00988## ##STR00989## TEA, DMSO 120.degree. C. 3.26
##STR00990## ##STR00991## TEA, DMSO 120.degree. C. 3.27
##STR00992## ##STR00993## TEA, DMSO 120.degree. C. 3.28
##STR00994## ##STR00995## TEA, DMSO 120.degree. C. 3.29
##STR00996## ##STR00997## TEA, DMSO 120.degree. C. 3.30
##STR00998## ##STR00999## TEA, DMSO 120.degree. C. 3.31
##STR01000## ##STR01001## TEA, DMSO 120.degree. C. 3.32
##STR01002## ##STR01003## TEA, DMSO 120.degree. C. 3.33
##STR01004## ##STR01005## TEA, DMSO 120.degree. C. 3.34
##STR01006## ##STR01007## TEA, DMSO 120.degree. C. 3.35
##STR01008## ##STR01009## TEA, DMSO 120.degree. C. 3.36
##STR01010## ##STR01011## TEA, DMSO 120.degree. C. 3.37
##STR01012## ##STR01013## TEA, DMSO 120.degree. C. 3.38
##STR01014## ##STR01015## TEA, DMSO 120.degree. C. 3.39
##STR01016## ##STR01017## TEA, DMSO 120.degree. C. 3.40
##STR01018## ##STR01019## TEA, DMSO 120.degree. C. 3.41
##STR01020## ##STR01021## TEA, DMSO 120.degree. C. 3.42
##STR01022## ##STR01023## TEA, DMSO 120.degree. C. 3.43
##STR01024## ##STR01025## TEA, DMSO 120.degree. C. 3.44
##STR01026## ##STR01027## TEA, DMSO 120.degree. C. 3.45
##STR01028## ##STR01029## TEA, DMSO 120.degree. C. 3.46
##STR01030## ##STR01031## TEA, DMSO 120.degree. C. 3.47
##STR01032## ##STR01033## 36.1 .mu.W, 145.degree. C. 36.2
Et.sub.3N, Ac.sub.2O, DCM 3.48 ##STR01034## ##STR01035##
K.sub.2CO.sub.3, iPrOH, H.sub.2O, 160.degree. C. .mu.W 3.49
##STR01036## ##STR01037## K.sub.2CO.sub.3, iPrOH, H.sub.2O,
160.degree. C. .mu.W 3.50 ##STR01038## ##STR01039##
K.sub.2CO.sub.3, i-PrOH, H.sub.2O, .mu.W, 160.degree. C. 3.51
##STR01040## ##STR01041## K.sub.2CO.sub.3, i-PrOH, H.sub.2O, .mu.W,
160.degree. C. 3.52 ##STR01042## ##STR01043## TEA, DMSO 120.degree.
C. 3.53 ##STR01044## ##STR01045## TEA, DMSO 120.degree. C. 3.54
##STR01046## ##STR01047## TEA, DMSO 120.degree. C.
TABLE-US-00022 TABLE 15C 1H NMR (PPM) DATA FOR EXAMPLES 3.1 TO 3.54
Ex. # Structure NMR 3.1 ##STR01048## (CD.sub.3OD, 400 MHz): 8.11
(d, J = 2.4 Hz, 1 H); 8.30 (d, J = 2.4 Hz, 1 H); 7.68-7.66 (m, 1
H); 7.51- 7.49 (m, 1 H); 7.37-7.33 (m, 1 H); 7.29-7.25 (m, 1 H);
5.03-4.98 (m, 1 H); 4.79-4.76 (m, 1 H); 4.53- 4.49 (m, 1 H);
4.41-4.39 (m, 1 H); 4.26-4.23 (m, 1 H); 4.05 (s, 3 H); 3.03-3.00
(m, 4 H); 1.72- 1.67(m, 4 H); 1.61-1.57 (m, 2 H). 3.2 ##STR01049##
(CD.sub.3OD, 400 MHz): 8.17-8.16 (m, 1 H); 8.10- 8.09 (m, 1 H);
7.71-7.69 (m, 1 H); 7.58-7.55 (m, 1 H); 7.41-7.39 (m, 1 H);
7.37-7.29 (m, 1H); 5.04- 5.01 (m, 1 H); 4.79-4.76 (m, 1 H);
4.57-4.54 (m, 1 H); 4.46-4.45 (m, 1 H); 4.31-4.26 (m, 1 H); 4.09
(s, 3 H); 3.38-3.34 (m, 1 H); 2.95-2.89 (m, 2 H); 1.99-1.97 (m, 2
H); 1.69-1.67 (m, 2 H). 3.3 ##STR01050## (CD.sub.3OD, 400 MHz):
8.14 (d, J = 2.4 Hz, 1 H); 8.08 (d, J = 2.4 Hz, 1 H); 7.75-7.73 (m,
1 H); 7.63- 7.61 (m, 1 H); 7.44-7.40 (m, 1 H); 7.36-7.33 (m, 1 H);
5.63-5.58 (m, 2 H); 5.12-5.07 (m, 1 H); 4.92- 4.90 (m, 1 H);
4.54-4.52 (m, 1 H); 4.44-4.40 (m, 1 H); 4.31-4.28 (m, 1 H);
3.06-3.03 (m, 4 H); 1.75- 1.69 (m, 4 H); 1.64-1.59 (m, 2 H). 3.4
##STR01051## (CD.sub.3OD, 400 MHz): 8.16 (d, J = 2.8 Hz, 1 H); 8.09
(d, J = 2.8 Hz, 1 H); 7.76-7.74 (m, 1 H); 7.64- 7.62 (m, 1 H);
7.45-7.43 (m, 1 H); 7.37-7.33 (m, 1 H); 5.64-5.58 (m, 2 H);
5.10-5.08 (m, 1 H); 4.93- 4.89 (m, 1 H); 4.56-4.53 (m, 1 H);
4.45-4.41 (m, 1 H); 4.38-4.31 (m, 1 H); 3.78-3.76 (m, 4 H); 3.38-
3.36 (m, 2 H); 2.95-2.90 (m, 2 H); 2.00-1.96 (m, 2 H); 1.70-1.67
(m, 2 H) 3.5 ##STR01052## (CDCl.sub.3, 400 MHz): 7.98-7.96 (m, 2
H); 7.74-7.64 (m, 2 H); 7.31-7.26 (m, 2 H); 5.25-5.12 (m, 2 H);
4.80-4.76 (m, 1 H); 4.60-4.55 (m, 1 H); 4.35-4.29 (m, 1 H);
3.51-3.49 (m, 4 H); 2.04-1.99 (m, 4 H). 3.6 ##STR01053##
(CDCl.sub.3, 400 MHz): 8.21 (d, J = 2.4 Hz, 1H); 8.12 (d, J = 2.4,
1H); 7.67 (br, 2H); 7.33-7.31 (m, 2H); 5.32-5.27 (m, 1H); 5.10-5.06
(m, 1H); 4.63-4.61 (m, 2H); 4.30-4.26 (m, 1H); 3.45 (s, 2H); 2.93-
2.81 (m, 2H); 2.26-2.19 (m, 1H); 1.99-1.98 (m, 2H); 1.87-1.74 (m,
2H). 3.7 ##STR01054## (CDCl.sub.3, 400 MHz): 8.26-8.23 (m, 2H);
7.73-7.71 (m, 2H); 7.38-7.35 (m, 2H); 5.32-5.23 (m, 1H); 5.07-5.00
(m, 1H); 4.60-4.45 (m, 2H); 4.49-4.47 (m, 3H); 3.51-3.48 (m, 1H);
3.12-3.08 (m, 1H); 3.03-2.91 (m, 1H); 1.88-1.73 (m, 4H); 1.57-1.55
(m, 2H); 1.01-0.99 (m, 1H); 1.51-1.47 (m, 3H) 3.8 ##STR01055##
(CDCl.sub.3, 400 MHz): 8.10-8.04 (m, 2H); 7.75-7.74 (m, 1H);
7.51-7.50 (m, 1H); 7.29-7.19 (m, 1H); 5.24-5.18 (m, 1H); 5.07-5.04
(m, 1H); 4.57-4.56 (m, 2H); 4.25-4.21 (m, 1H); 3.25-3.22 (m, 2 H);
2.75-2.70 (m, 1H); 2.48-2.39 (m, 1H); 1.83-1.65 (m, 4H); 1.07-1.03
(m, 1H); 0.91 (d, J = 6.4 Hz, 3 H). 3.9 ##STR01056## (CDCl.sub.3,
400 MHz): 8.11-8.05 (m, 2H); 7.75-7.74 (m, 1H); 7.51-7.50 (m, 1H);
7.25-7.19 (m, 2H); 5.26-5.21 (m, 1H); 5.07-5.04 (m, 1H); 4.57-4.56
(m, 2H); 4.26-4.23 (m, 1H); 3.34-3.29 (m, 2 H); 2.78-2.74 (m, 2H);
1.75-1.72 (m, 2H); 1.55-1.53 (m, 1H); 1.38-1.31 (m, 2 H); 0.97 (d,
J = 6.4 Hz, 3 H). 3.10 ##STR01057## (CDCl.sub.3, 400 MHz):
8.14-8.10 (m, 2H); 7.70-7.68 (m, 2H); 7.32-7.24 (m, 2H); 5.30-5.26
(m, 1H); 5.08-5.03 (m, 1H); 4.62-4.60 (m, 2H); 4.29-4.25 (m, 1H);
3.10-3.08 (m, 4H); 1.55-1.53(m, 4H); 1.01 (s, 6H). 3.11
##STR01058## (CDCl.sub.3, 400 MHz): 8.14-8.13 (m, 1H); 8.08-8.07
(m, 1H); 7.77-7.75 (m, 1H); 7.55-7.52 (m, 1H); 7.30-7.22 (m, 2H);
5.27-5.21 (m, 1H); 5.07-5.04 (m, 1H); 4.60-4.58 (m, 2H); 4.25-4.21
(m, 1H); 3.58-3.55 (m, 2H); 3.40-3.34(m, 2H); 2.89-2.77 (m, 2H);
2.41 (br, 1H); 1.87-1.84 (m, 1H); 1.69- 1.68 (m, 1H); 1.49-1.40 (m,
2H). 3.12 ##STR01059## (CD.sub.3OD, 400 MHz): 8.16 (d, J = 2.4 Hz,
1H); 8.09 (d, J = 2.4 Hz, 1H); 7.63 (brs, 2H); 7.30-7.28 (m, 2H);
5.20-5.16 (m, 1H); 4.98-4.93 (m, 1H); 4.60-4.56 (m, 1H); 4.47-4.43
(m, 1H); 4.37-4.35 (m, 1H); 3.46 (d, J = 12.4 Hz, 2H); 2.83-2.78
(m, 2H); 1.89-1.86 (m, 2H); 1.56-1.46 (m, 3H); 1.19 (s, 6H) 3.13
##STR01060## (CDCl.sub.3, 400 MHz): 8.12 (d, J = 2.4 Hz, 1H); 8.04
(d, J = 2.4 Hz, 1H); 7.79 (br, 1H); 7.51 (br, 1H); 7.19 (br, 2H);
5.25-5.20 (m, 1H); 5.04-5.00 (m, 1H); 4.58-4.56 (m, 2H); 4.24-4.21
(m, 1H); 3.38- 3.35 (m, 1H); 3.31 (s, 3H); 3.30-3.27 (m, 2H);
2.94-2.89 (m, 2H); 2.02-1.98 (m, 2H); 1.73-1.68 (m, 2H). 3.14
##STR01061## (CDCl.sub.3, 400 MHz): 8.20 (d, J = 42.4 Hz, 1H); 8.13
(d, J = 2.4 Hz, 1H); 7.70-7.68 (m, 2H); 7.35- 7.32 (m, 2H);
5.32-5.27 (m, 1H); 5.03-4.99 (m, 1H); 4.64-4.56 (m, 2H); 4.29-4.23
(m, 1H); 3.34- 3.29 (m, 2H); 3.09-3.02 (m, 2H); 2.86-2.82 (m, 1H);
2.12-1.97 (m, 4H). 3.15 ##STR01062## (CDCl.sub.3, 400 MHz):
8.15-8.06 (m, 2H); 7.376-7.74 (m, 1H); 7.52-7.50 (m, 1H); 7.28-7.24
(m, 2H); 5.27-5.22 (m, 1H); 5.07-5.04 (m, 1H); 4.61-4.58 (m, 2H);
4.27-4.24 (m, 1H); 3.36-3.27 (m, 7H); 2.89-2.78 (m, 2H); 1.92-1.78
(m, 3H); 1.49-1.40 (m, 2H). 3.16 ##STR01063## (CDCl.sub.3, 400
MHz): 7.95-7.93 (m, 2H); 7.67 (brs, 2H); 7.32-7.24 (m, 2H);
5.25-5.12 (m, 2H); 4.72- 4.70 (m, 1H); 4.62-4.48 (m, 1H); 4.31-4.27
(m, 1H); 3.63-3.48 (m, 3H); 3.19-3.12 (m, 1H); 2.34- 2.32 (m, 1H);
2.12-2.09 (m, 1H); 1.61-1.58 (m, 1H); 1.14-1.12 (m, 3H). 3.17
##STR01064## (CDCl.sub.3, 400 MHz): 7.98-7.96 (m, 2H); 7.75-7.59
(m, 2H); 7.26-7.24 (m, 2H); 5.31-5.08 (m, 2H); 4.69-4.47 (m, 2H);
4.21-4.19 (m, 2H); 3.70-3.68 (m, 1H); 3.13-3.11 (m, 1H); 2.16-2.15
(m, 1H); 1.95-1.94 (m, 1H); 1.77-1.76 (m, 1H); 1.63-1.62 (m, 1H);
1.18 (s, 3H) 3.18 ##STR01065## (CDCl.sub.3, 400 MHz): 8.20-8.13 (m,
2H); 7.68 (brs, 2H); 7.33-7.32 (m, 2H); 7.24-7.16 (m, 4H); 5.34-
5.29 (m, 1H); 5.15-5.11 (m, 1H); 4.68-4.59 (m, 2H); 4.46-4.31 (m,
3H); 3.42-3.40 (m, 2H); 3.16- 3.05 (m, 2H). 3.19 ##STR01066##
(CDCl.sub.3, 400 MHz): 8.07-8.06 (m, 1H); 8.00-7.99 (m, 1H);
7.70-7.48 (m, 1H); 7.39-7.37 (m, 2H); 7.29-7.17 (m, 4H); 5.07-5.05
(m, 1H); 5.00-4.90 (m, 6H); 4.52-4.46 (m, 2H). 3.20 ##STR01067##
(CDCl.sub.3, 400 MHz): 7.98-7.96 (m, 2H); 7.69-7.68 (m, 2H);
7.35-7.30 (m, 4H); 7.28-7.15 (m, 3H); 5.27-5.23 (m, 1H); 5.13-5.07
(m, 1H); 4.67-4.63 (m, 1H); 4.55-4.43 (m, 1H); 4.34-4.32 (m, 1H);
3.83-3.75 (m, 2H); 3.70-3.65 (m, 2H); 3.48-3.46 (m, 1H); 2.41-2.39
(m, 1H); 2.14-2.12 (m, 1H). 3.21 ##STR01068## (CDCl.sub.3, 400
MHz): 7.93-7.89 (m, 2H); 7.67 (brs, 2H); 7.50-7.24 (m, 6H);
7.17-7.15 (m, 1H); 5.23- 5.05 (m, 3H); 4.65-4.63 (m, 1H); 4.53-4.51
(m, 1H); 4.27-4.26 (m, 1H); 3.97-3.95 (m, 1H); 3.42- 3.40 (m, 1H);
2.42-2.41 (m, 1H); 2.07-2.06 (m, 1H); 2.00-1.84 (m, 2H). 3.22
##STR01069## (CDCl.sub.3, 400 MHz): 7.98 (d, J = 2.8 Hz, 1H); 7.80
(d, J = 2.8 Hz, 1H); 7.69 (brs, 2H); 7.34-7.30 (m, 2H); 5.31-5.26
(m, 1H); 5.16-5.12 (m, 1H); 4.78- 4.74 (m, 1H); 4.65-4.60 (m, 1H);
4.35-4.33 (m, 1H); 4.11-4.10 (m, 1H); 3.95-3.88 (m, 1H); 2.17- 2.09
(m, 2H); 1.79-1.66 (m, 4H); 1.51-1.43 (m, 2H). 3.23 ##STR01070##
(CDCl.sub.3, 400 MHz): 7.89-7.72 (m, 2H); 7.62 (brs, 2H); 7.30-7.26
(m, 2H); 5.25-5.20 (m, 1H); 5.11- 5.08 (m, 1H); 4.66-4.53 (m, 2H);
3.95-3.84 (m, 2H); 2.02-1.99 (m, 1H); 1.73-1.35 (m, 6H); 1.21- 1.16
(m, 3H). 3.24 ##STR01071## (CD.sub.3OD, 400 MHz): 7.83-7.81 (m,
2H); 7.70-7.68 (m, 2H); 7.39-7.21 (m, 7H); 5.19-5.13 (m, 1H);
5.10-5.06 (m, 1H); 4.67 (s, 2H); 4.63-4.54 (m, 2H); 4.25-4.21 (m,
1H). 3.25 ##STR01072## (CD.sub.3OD, 400 MHz): 7.89-7.88 (m, 1 H);
7.80- 7.79 (m, 1 H); 7.69-7.66 (m, 2 H); 7.37-7.35 (m, 2 H);
5.19-5.18 (m, 1 H); 5.06-5.08 (m, 1 H); 4.62- 4.55 (m, 2 H);
4.24-4.20 (m, 1H); 3.80-3.79 (m, 2 H); 3.63-3.61 (m, 2 H). 3.26
##STR01073## (CDCl.sub.3, 400 MHz): 7.94 (d, J = 2.4 Hz, 1H); 7.82
(d, J = 2.4 Hz, 1H); 7.78-7.60 (m, 2H); 7.32-7.31 (m, 2H);
5.29-5.28 (m, 1H); 5.16-5.14 (m, 1H); 4.76-4.73 (m, 2H); 4.65-4.63
(m, 1H); 4.00-3.95 (m, 1H); 3.71-3.61 (m, 4H); 3.43 (s, 3H). 3.27
##STR01074## (CDCl.sub.3, 400 MHz): 8.22-8.16 (m, 2 H); 7.65 (br, 2
H); 7.62-7.54 (m, 4H); 5.11-5.07 (m, 1 H); 4.89- 4.85 (m, 1H);
4.51-4.49 (m, 1H); 4.29-4.25 (m, 2H); 3.45-3.43 (m, 2 H); 2.83-2.73
(m, 1H); 2.52- 2.51 (m, 1 H); 1.82-1.71 (m, 4 H). 3.28 ##STR01075##
(CD.sub.3OD, 400 MHz): 8.18 (d, J = 2.4 Hz, 1H); 8.11 (d, J = 2.4
Hz, 1H); 7.68-7.65 (m, 2H); 7.35- 7.32 (m, 2H); 5.21-5.17 (m, 1H);
5.02-4.95 (m, 1H); 4.65-4.59 (m, 1H); 4.47-4.36 (m, 2H); 3.57- 3.53
(m, 1H); 3.48-3.34 (m, 3H); 2.86-2.84 (m, 1H); 2.64-2.58 (m, 1H);
1.96-1.94 (m, 1H); 1.85- 1.76 (m, 3H); 1.21-1.18 (m, 1H). 3.29
##STR01076## (CD.sub.3OD, 400 MHz): 8.17 (d, J = 2.4 Hz, 1H); 8.10
(d, J = 2.4 Hz, 1H); 7.63 (brs, 2H); 7.28-7.20 (m, 2H); 5.20-5.14
(m, 1H); 4.97-4.92 (m, 1H); 4.58-4.53 (m, 1H); 4.47-4.42 (m, 1H);
4.38-4.32 (m, 1H); 3.89-3.85 (m, 1H); 3.41-3.37 (m, 1H); 3.34-3.20
(m, 1H); 2.88-2.77 (m, 2H); 2.02-1.98 (m, 1H); 1.91-1.88 (m, 1H);
1.71-1.67 (m, 1H); 1.49-1.46 (m, 1H). 3.30 ##STR01077##
(CDCl.sub.3, 400 MHz): 8.04-8.00 (m, 2H); 7.73-7.70 (m, 2H);
7.38-7.36 (m, 2H); 5.27-5.22 (m, 1H); 5.03-4.99 (m, 1H); 4.60-4.53
(m, 2H); 4.27-4.23 (m, 1H); 3.45-3.42 (m, 4H); 1.83 (brs, 4H)1.65-
1.63 (m, 6H). 3.31 ##STR01078## (CD.sub.3OD, 400 MHz): 7.97-7.92
(m, 2H); 7.76-7.74 (m, 1 H); 7.59-7.58 (m, 1 H); 7.32 (br, 2 H);
5.15- 5.13 (m, 1H); 5.04-5.01 (m, 1H); 4.57-4.50 (m, 2 H);
4.20-4.14 (m, 5H); 2.45-2.37 (m, 1H). 3.32 ##STR01079##
(CDCl.sub.3, 400 MHz): 7.97-7.94 (m, 1 H); 7.84-7.81 (m, 1 H);
7.71-7.65 (m, 2H); 7.22 (brs, 2H); 5.27- 5.23 (m, 1H); 5.01-5.02
(m, 1H); 4.62-4.56 (m, 2 H); 4.39-4.36 (m, 1H); 4.20-4.15 (m, 1H);
3.77- 3.60 (m, 3H); 3.20-3.15 (m, 1H); 2.09 (s, 3 H); 1.95-1.92 (m,
1H); 1.77-1.75 (m, 2 H). 3.33 ##STR01080## (CD.sub.3OD, 400 MHz):
7.88-7.81 (m, 2H); 7.68-7.66 (m, 2H); 7.35-7.33 (m, 2H); 5.20-5.15
(m, 1H); 5.03-4.99 (m, 1H); 4.62-4.50 (m, 2H); 4.28-4.17 (m, 1H);
4.15-4.10 (m, 1H); 1.33-1.30 (m, 6H). 3.34 ##STR01081##
(CDCl.sub.3, 400 MHz): 7.96-7.94 (m, 1 H); 7.83-7.81 (m, 1 H);
7.70-7.60 (m, 2H); 7.22 (brs, 2H); 5.26- 5.24 (m, 1H); 5.011-5.02
(m, 1H); 4.61-4.56 (m, 2H); 4.38-4.36 (m, 1H); 4.18-4.16 (m, 1H);
3.76- 3.59 (m, 3H); 3.15-3.13 (m, 1H); 2.08 (s, 3H); 1.94-1.92 (m,
1H); 1.76-1.73 (m, 2 H). 3.35 ##STR01082## (CDCl.sub.3, 400 MHz):
8.20-8.17 (m, 2H); 7.75-7.72 (m, 2 H); 7.43-7.40 (m, 2H); 5.33-5.32
(m, 1H); 505-5.02 (m, 1H); 4.63-4.61 (m, 2H); 4.57-4.55 (m, 1H);
4.36-4.34 (m, 1H); 3.79-3.77 (m, 1H); 3.42-3.36 (m, 2H); 2.95-2.90
(m, 2 H); 1.89-1.79 (m, 3 H); 1.65-1.67 (m, 2 H); 1.47-1.45 (m,
2H). 3.36 ##STR01083## (CD.sub.3OD, 400 MHz): 8.11-8.06 (m, 2 H);
7.72- 7.70 (m, 2 H); 7.43-7.40 (m, 2 H); 5.16-5.11 (m, 1 H);
5.00-4.98 (m, 1 H); 4.59-4.52 (m, 2 H); 4.34- 4.33 (m, 1 H);
3.89-3.82 (m, 4 H); 2.06-2.03 (m, 2 H). 3.37 ##STR01084##
(CD.sub.3OD, 400 MHz): 8.17-8.16 (m, 1 H); 8.08- 8.07 (m, 1 H);
7.68-7.66 (m, 2 H); 7.36-7.34 (m, 2 H); 5.17-5.14 (m, 1 H);
4.95-4.94 (m, 1 H); 4.59- 4.52 (m, 2 H); 4.35-4.27 (m, 1 H);
3.76-3.57 (m, 6 H); 3.37-3.31 (m, 2 H); 3.30 (s, 3 H); 2.26-2.24
(m, 2 H). 3.38 ##STR01085## (CDCl.sub.3, 400 MHz): 8.13-8.07 (m,
2H); 7.73-7.70 (m, 2H); 7.44-7.41 (m, 2 H); 5.12-5.09 (m, 1 H);
4.95-4.94 (m, 1 H); 4.62-4.51 (m, 2 H); 4.33-4.30 (m, 1H);
3.79-3.76 (m, 2 H); 3.66-3.60 (m, 3 H); 3.48-3.45 (m, 2 H);
3.42-3.40 (m, 1 H); 2.11 (s, 3 H); 2.05-2.02 (m, 1 H); 1.94-1.88
(m, 1 H). 3.39 ##STR01086## (CD.sub.3OD, 400 MHz): 8.05-8.00 (m, 2
H); 7.70- 7.68 (m, 2 H); 7.39-7.36 (m, 2 H); 5.15-5.13 (m, 1H);
4.99-4.98 (m, 1 H); 4.56-4.50 (m, 2H); 4.33- 4.30 (m, 1 H);
3.92-3.90 (m, 1 H); 3.57-3.54 (m, 1 H); 3.47-3.41 (m, 3 H);
2.14-2.11 (m, 1 H); 1.99- 1.69 (m, 5 H). 3.40 ##STR01087##
(CD.sub.3OD, 400 MHz): 7.98-7.97 (m, 1 H); 7.88- 7.87 (m, 1 H);
7.69-7.66 (m, 2 H); 7.37-7.34 (m, 2H); 5.15-5.07 (m, 1 H);
4.58-4.44 (m, 2H); 3.66- 3.60 (m, 5 H); 3.45-3.43 (m, 1 H); 3.65
(s, 2 H); 2.55-2.51 (m, 1 H); 2.16-2.11 (m, 1 H); 1.85-1.80 (m, 1
H). 3.41 ##STR01088## (CDCl.sub.3, 400 MHz): 8.19 (d, J = 2.8 Hz,
1H); 8.11 (d, J = 2.8, 1H); 7.67-7.64 (m, 2H); 7.33-7.30 (m, 2H);
5.20-5.18 (m, 1H); 4.98-4.96 (m, 1H); 4.58- 4.56 (m, 1H); 4.48-4.45
(m, 1H); 4.40-4.38 (m, 1H); 3.89-3.86 (m, 1H); 3.42-3.39 (m, 1H);
3.22- 3.18 (m, 1H); 2.90-2.89 (m, 1H); 2.84-2.80 (m, 1H); 2.02-2.00
(m, 1H); 1.93-1.90 (m, 1H); 1.74- 1.70 (m, 1H); 1.50-1.48 (m, 1H).
3.42 ##STR01089## (CDCl.sub.3, 400 MHz): 8.20 (d, J = 2.8 Hz, 1H);
8.12 (d, J = 2.8, 1H); 7.66 (br, 2H); 7.34-7.31 (m, 2H); 5.21-5.19
(m, 1H); 4.97-4.96 (m, 1H); 4.61-4.54 (m, 1H); 4.48-4.38 (m, 2H);
3.89-3.85 (m, 1H); 3.42-3.41 (m, 1H); 3.23-3.20 (m, 1H); 2.91-2.88
(m, 1H); 2.84-2.79 (m, 1H); 2.04-2.00 (m, 1H); 1.95-1.90 (m, 1H);
1.74-1.70 (m, 1H); 1.51-1.47 (m, 1H). 3.43 ##STR01090##
(CDCl.sub.3, 400 MHz): 8.22(m, 1H); 8.11 (m, 1H); 7.68-7.65 (m,
2H); 7.35-7.31 (m, 2H); 5.30 (m, 1H); 5.02 (m, 1H); 4.60 (d, J =
6.4 Hz, 2H); 4.37- 4.34 (m, 1H); 3.34-3.28 (m, 2H); 3.08-2.93 (m,
3H); 1.98-1.90 (m, 3H); 1.74-1.72 (m, 1H). 3.44 ##STR01091##
(CDCl.sub.3, 400 MHz): 8.18 (d, J = 2.0 Hz, 1H); 8.12 (d, J = 2.4
Hz, 1H); 7.74-7.71 (m, 2H); 7.40-7.38 (m, 2H); 5.31 (t, J = 9.6 Hz,
1H); 5.04-5.00 (m, 1H); 4.62-4.58 (m, 2H); 4.34-4.27 (m, 1H); 3.40
(t, J = 12.0 Hz, 2H); 2.91 (d, J = 12.8 Hz, 1H); 2.86 (d, J = 4.4
Hz, 4H); 2.37-2.31 (m, 1H); 2.07- 1.87 (m, 4H).
3.45 ##STR01092## (CDCl.sub.3, 400 MHz): 8.14 (d, J = 2.4 Hz, 1H);
8.07 (d, J = 2.8 Hz, 1H); 7.67-7.65 (m, 2H); 5.22 (t, J = 10.0 Hz,
1H); 5.03-4.99 (m, 1H); 4.54 (d, J = 7.2 Hz, 2H); 4.28-4.24 (m,
1H); 3.37 (t, J = 12.8 Hz, 2H); 3.07 (s, 3H); 2.94 (s, 3H);
2.92-2.80 (m, 2H); 2.71-2.65 (m, 1H); 2.02-1.93 (m, 2H); 1.80 (d, J
= 8.4 Hz, 2H). 3.46 ##STR01093## (CDCl.sub.3, 400 MHz): 8.15-8.14
(m, 1H); 8.06-8.05 (m, 1H); 7.07-7.06 (m, 1H); 7.47-7.46 (m, 1H);
7.28-7.18 (m, 2H); 5.23-5.21 (m, 1H); 5.04-5.02 (m, 1H); 4.56-5.54
(m, 2H); 4.23-4.21 (m, 1H); 3.38-3.36 (m, 2H); 2.89-2.80 (m, 2H);
2.48-2.45 (m, 1H); 2.16 (s, 3H); 1.98-1.96 (m, 2H); 1.82- 1.79 (m,
2H). 3.47 ##STR01094## (CDCl.sub.3, 400 MHz): 8.20 (d, J = 2.4 Hz,
1H); 8.10 (d, J = 2.4 Hz, 1H); 7.66-7.64 (m, 2H); 7.32-7.29 (m,
2H); 5.26 (t, J = 8.0 Hz, 1H); 5.03-5.00 (m, 1H); 4.60-4.54 (m,
2H); 4.28-4.25 (m, 1H); 3.81- 3.71 (m, 2H); 3.63-3.61 (m, 2H);
3.15-3.14 (m, 2H); 3.07-3.05 (m, 2H); 2.14 (s, 3H). 3.48
##STR01095## (MeOD, 400 MHz): 8.00-7.97 (m, 1H); 7.92-7.88 (m, 1H);
7.68 (brs, 2H); 7.36-7.35 (m, 2H); 5.18- 5.05 (m, 2H); 4.61-4.46
(m, 4H); 3.87-3.79 (m, 2H); 3.56-3.52 (m, 1H); 3.41-3.39 (m, 1H);
2.13- 1.93 (m, 2H). 3.49 ##STR01096## (MeOD, 400 MHz): 7.96-7.92
(m, 1H); 7.91-7.89 (m, 1H); 7.68 (brs, 2H); 7.35-7.33 (m, 2H);
5.21- 4.88 (m, 2H); 4.63-4.41 (m, 4H); 3.86-3.80 (m, 2H); 3.55-3.50
(m, 1H); 3.37-3.40 (m, 1H); 2.13- 2.00 (m, 2H). 3.50 ##STR01097##
(CDCl.sub.3, 400 MHz): 8.16 (d, J = 2.4 Hz, 1H); 8.11 (d, J = 2.4
Hz, 1H); 7.71-7.69 (m, 2H); 7.32-7.30 (m, 2H); 5.33-5.28 (m, 1H);
5.11-5.07 (m, 1H); 4.67-4.65 (m, 2H); 4.32-4.29 (m, 1H); 3.11-3.08
(m, 4H); 1.78-1.74 (m, 4H); 1.68-1.64 (m, 2H). 3.51 ##STR01098##
(MeOD, 400 MHz): 8.17 (d, J = 2.8 Hz, 1H); 8.10 (d, J = 2.8 Hz,
1H); 7.71-7.68 (m, 2H); 7.42- 7.39 (m, 2H); 5.13-5.15 (m, 1H);
4.94-4.93 (m, 1H); 4.61-4.59 (m, 1H); 4.46-4.50 (m, 1H); 4.39- 4.35
(m, 1H); 3.80-3.76 (m, 1H); 3.39-3.35 (m, 2H); 2.98-2.92 (m, 2H);
2.01-1.97 (m, 2H); 1.71- 1.68 (m, 2H). 3.52 ##STR01099##
(CDCl.sub.3, 400 MHz): 8.19 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 2.4
Hz, 1H), 7.81-7.65 (m, 1H), 7.56-7.50 (m, 1H), 7.32 (s, 2H),
5.30-5.24 (m, 1H), 5.09- 5.05 (m, 1H), 4.61 (d, J = 16 Hz, 2H),
4.49 (s, 4H), 4.32-4.24 (m, 1H), 3.04-3.01 (m, 4H), 2.07- 2.03 (m,
4H). 3.53 ##STR01100## (CDCl.sub.3, 400 MHz): 8.00 (d, J = 4.0 Hz,
2H), 7.76-7.59 (m, 2H), 7.31-7.29 (m, 2H), 5.24-5.19 (m, 1H),
5.12-5.08 (m, 1H), 4.87 (s, 4H), 4.81- 7.76 (m, 1H), 4.61-4.54 (m,
1H), 4.27 (s, 4H), 4.04-4.00 (m, 1H) 3.54 ##STR01101## (MeOD, 400
MHz): 7.99 (dd, J = 2.8 Hz, 7.6 Hz, 2H), 7.66-7.62 (m, 2H),
7.33-7.30 (m, 2H), 5.17- 5.12 (m, 1H), 5.02-4.98 (m, 1H), 4.61-4.50
(m, 2H), 4.41 (s, 2H), 4.28 (s, 4H), 4.19-4.12 (m, 3H), 1.88 (s,
3H).
##STR01102##
Example 4.1
2-(3-(3-(2-METHOXYPYRIDIN-3-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE
[0567] A glass microwave reaction vessel was charged with
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.160 g, 0.539
mmol), sodium carbonate (0.300 g, 2.83 mmol, JT Baker),
2-methoxy-3-pyridineboronic acid (0.150 g, 0.981 mmol, Aldrich) and
trans-dichlorobis(triphenylphosphine)palladium (ii) (0.030 g, 0.043
mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and the
reaction mixture was sealed under argon and heated in an Initiator
microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala,
Sweden) at 145.degree. C. for 15 min. The reaction mixture was
partitioned between EtOAc/water and the aqueous layer was extracted
with EtOAc (3.times.). The combined organic layers were evaporated
to dryness and the residue was dissolved in MeOH and purified by
reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA,
100.times.50 mm column) eluting with 0.1% TFA-H.sub.2O:0.1% TFA
CH.sub.3CN (9:1.fwdarw.1:9). The fractions containing the desired
product were combined and concentrated in vacuo. The residue was
dissolved in MeOH and loaded onto an SCX II cartridge eluting with
MeOH then 2M NH.sub.3 in MeOH to give 145 mg (73%) of an off-white
amorphous solid.
[0568] The following Table 16A lists compounds of Examples 4.1 to
4.45, which were made analogous to Scheme 4 by using the
appropriate materials and reaction conditions, which are listed in
Table 16B. The NMR data of the Examples are listed in Table
16C.
TABLE-US-00023 TABLE 16A EXAMPLES 4.1 TO 4.45 Ex. ESI-MS IC.sub.50
# Structure Chemical Name (M + 1) (nM) 4.1 ##STR01103##
2-(3-(3-(2-methoxypyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 370.0 0.00234 4.2 ##STR01104##
2-(3-(3-(6-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 354 0.00279 4.3 ##STR01105##
2-(3-(3-(2-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 354.20 0.00648 4.4 ##STR01106##
2-(3-(3-(6-fluoropyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 358.0 0.00418 4.5 ##STR01107## 2-(3-(3-(6-
(trifluoromethyl)pyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 408.0 0.0142 4.6 ##STR01108##
2-(3-(3-(2,6-dimethoxypyridin- 3-yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 400.20 0.00135 4.7 ##STR01109##
2-(3-(3-(5-fluoropyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 358.20 0.0123 4.8 ##STR01110##
2-(3-(3-(6-methoxypyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 2,2,2- trifluoroacetate 370.2 0.00787 4.9 ##STR01111##
2-(3-(3-(6-fluoro-5- methylpyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate 372.20 0.0122
4.10 ##STR01112## 2-(3-(3-(pyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate 340.20 0.00787
4.11 ##STR01113## 2-(3-(3-(4- (methylsulfonyl)phenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate 417.2 0.00262
4.12 ##STR01114## 5-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)pyridin-2- amine 355.20 0.00278 4.13 ##STR01115##
5-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)pyridin-3- amine
355.0 0.00376 4.14 ##STR01116## 2-(3-(3-(6-methoxypyridin-2-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 370.20 0.0012 4.15
##STR01117## 2-(3-(3-(2- (trifluoromethyl)pyridin-3-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 2,2,2- trifluoroacetate
408.0 0.12360 4.16 ##STR01118## N,N-dimethyl-5-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)pyrimidin-2-amine 2,2,2-
trifluoroacetate 384.0 0.02279 4.17 ##STR01119##
2-(3-(3-(4-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 2,2,2- trifluoroacetate 354.0 0.02626 4.18
##STR01120## 2-(3-(3-(5- (methylsulfonyl)pyridin-3-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 2,2,2- trifluoroacetate
418.0 4.19 ##STR01121## 2-(3-(3-(5-methylpyridin-3-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 2,2,2- trifluoroacetate
354.0 0.01625 4.20 ##STR01122## 2-(3-(3-(5-methoxypyridin-3-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 2,2,2- trifluoroacetate
370.1 0.02472 4.21 ##STR01123## 2-(3-(3-(4-chloro-3-
methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 387.1 0.0023
4.22 ##STR01124## 2-(3-(3-(3-fluoro-4- methylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 371.2 0.0042 4.23 ##STR01125##
2-chloro-4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenol
389.0 0.0023 4.24 ##STR01126## 2-(3-(3-(3-methoxy-5-
(trifluoromethyl)phenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline 437.2
0.0149 4.25 ##STR01127## 2-(3-(3-(4-ethoxy-3-
fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 401.2 0.0062
4.26 ##STR01128## 2-(3-(3-(3-chloro-4- ethoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 417.00 0.0106 4.27 ##STR01129##
2-(3-(3-(3-chloro-4- propoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 432.2 0.0171 4.28 ##STR01130##
2-(3-(3-(3-fluoro-5- (trifluoromethyl)phenyl)pyrazin-
2-yl)azetidin-1-yl)quinoline 425.20 0.0122 4.29 ##STR01131##
2-(3-(3-(4-methoxy-3- methylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 383.20 0.0035 4.30 ##STR01132##
2-(3-(3-(3-fluoro-5- isopropoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 415.20 0.0110 4.31 ##STR01133##
2-(3-(3-(3-fluoro-5- methylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 371.20 0.0051 4.32 ##STR01134##
2-(3-(3-(3-chloro-4- fluorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 392.20 0.0041 4.33 ##STR01135##
2-(3-(3-(3,4- difluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline
375.20 0.0099 4.34 ##STR01136## 2-(3-(3-(3,4-
dichlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 407.0 0.0084
4.35 ##STR01137## 2-(3-(3-(3,4- dimethylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 367.20 0.0055 4.36 ##STR01138##
2-(3-(3-(3-chloro-4- methylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 388.2 0.0067 4.37 ##STR01139##
2-(3-(3-(3-chloro-5- methylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 387.0 0.0072 4.38 ##STR01140##
2-(3-(3-(4-fluoro-3- methylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 371.0 0.0064 4.39 ##STR01141##
2-(3-(3-(pyrimidin-5-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline
341.20 0.0887 4.40 ##STR01142## 2-(3-(3-(4-chloro-3-
(trifluoromethyl)phenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline 441.0
0.0091 4.41 ##STR01143## 2-(3-(3-(3,6-dihydro-2H-pyran-
4-yl)pyrazin-2-yl)azetidin-1- yl)quinoline 345 0.0011 4.42
##STR01144## 2-(3-(3-(2,2-dimethyl-3,6-
dihydro-2H-pyran-4-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline and
2-(3-(3-(6,6-dimethyl-3,6- dihydro-2H-pyran-4-yl)pyrazin-
2-yl)azetidin-1-yl)quinoline 373 0.001 4.43 ##STR01145##
2-(3-(3-(1H-pyrazol-4- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 329
0.007 4.44 ##STR01146## 2-(3-(3-(3-fluoro-5-
(trifluoromethyl)phenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline
425.20 0.0122 4.45 ##STR01147## 2-(3-(3-(6-methoxypyridin-2-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 370.20 0.0012
TABLE-US-00024 TABLE 16B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 4.1 TO 4.45. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Reaction Purification Ex. # Key Starting Material(s) Key
Starting Material(s) Condition Method* 4.1 ##STR01148##
##STR01149## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W A 4.2 ##STR01150##
##STR01151## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W A 4.3 ##STR01152##
##STR01153## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W B 4.4 ##STR01154##
##STR01155## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W B 4.5 ##STR01156##
##STR01157## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W B 4.6 ##STR01158##
##STR01159## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W B 4.7 ##STR01160##
##STR01161## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W B 4.8 ##STR01162##
##STR01163## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W E 4.9 ##STR01164##
##STR01165## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W E 4.10 ##STR01166##
##STR01167## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W E 4.11 ##STR01168##
##STR01169## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W E 4.12 ##STR01170##
##STR01171## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.13 ##STR01172##
##STR01173## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.14 ##STR01174##
##STR01175## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.15 ##STR01176##
##STR01177## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W C 4.16 ##STR01178##
##STR01179## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W C 4.17 ##STR01180##
##STR01181## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W C 4.18 ##STR01182##
##STR01183## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W C 4.19 ##STR01184##
##STR01185## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W C 4.20 ##STR01186##
##STR01187## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W C 4.21 ##STR01188##
##STR01189## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.22 ##STR01190##
##STR01191## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.23 ##STR01192##
##STR01193## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.24 ##STR01194##
##STR01195## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.25 ##STR01196##
##STR01197## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.26 ##STR01198##
##STR01199## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.27 ##STR01200##
##STR01201## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.28 ##STR01202##
##STR01203## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.29 ##STR01204##
##STR01205## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.30 ##STR01206##
##STR01207## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.31 ##STR01208##
##STR01209## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.32 ##STR01210##
##STR01211## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.33 ##STR01212##
##STR01213## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.34 ##STR01214##
##STR01215## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.35 ##STR01216##
##STR01217## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.36 ##STR01218##
##STR01219## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.37 ##STR01220##
##STR01221## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.38 ##STR01222##
##STR01223## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.39 ##STR01224##
##STR01225## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.40 ##STR01226##
##STR01227## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.41 ##STR01228##
##STR01229## Pd(tBu.sub.3P).sub.2, KOAc Dioxane/water 125.degree.
C./.mu.W, 30 min E 4.42 ##STR01230## ##STR01231##
Pd(tBu.sub.3P).sub.2, KOAc Dioxane/water 135.degree. C./.mu.W, 30
min E 4.43 ##STR01232## ##STR01233## Pd(tBu.sub.3P).sub.2, KOAc
Dioxane/water 135.degree. C./.mu.W, 30 min F 4.44 ##STR01234##
##STR01235## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D 4.45 ##STR01236##
##STR01237## PdCl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3
Dioxane/water, 145.degree. C., .mu.W D Purification Methods: Method
A-reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA, 100
.times. 50 mm column) eluting with 0.1% TFA-H.sub.2O:0.1% TFA
CH.sub.3CN (9:1 .fwdarw. 1:9). The fractions containing the desired
product were combined and concentrated in vacuo. The residue was
dissolved in MeOH and loaded onto an SCX II cartridge eluting with
MeOH then 2M NH.sub.3 in MeOH. Method B-reverse phase HPLC
(Instrumentation: MS--Waters SQ; UV--Waters 2487 or Waters PD;
Solvents: A: Water w/0.1% NH.sub.4OH B: Acetonitrile w/0.1%
NH.sub.4OH; Column: Phenomenex Gemini-NX C18 110A 5 um 21 .times.
100; Flow Rate 44 mL/min. 10 min Method, variable gradient over 8
mins. Method C-reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A
AXIA 100 .times. 50 mm column) eluting with 0.1% TFA-H.sub.2O:0.1%
TFA CH.sub.3CN (9:1 .fwdarw. 1:9). The fractions containing the
desired product were combined and concentrated in vacuo. Method
D-reverse-phase HPLC (Instrument: Waters Autopurificaton system;
Column: Xbridge 19 .times. 100 mm, 10 um; Flow rate; 40 ml/min;
Mobile phase: 0.1% NH.sub.4OH in acetonitrile (B) and water (A)).
Method E-reverse-phase HPLC (Instrument: Waters Autopurificaton
system; Column Xbridge 19 .times. 100 mm, 10 um; Flow rate: 40
ml/min; Mobile phase: 0.1% TFA in acetonitrile (B) and water (A)).
Method E-purification by silica gel chromatography eluting with a
gradient of EtOAc in hexane. Method F-purification by silica gel
chromatography eluting with a gradient of MeOH in DCM.
TABLE-US-00025 TABLE 16C 1H NMR .delta. (PPM) DATA FOR EXAMPLES 4.1
TO 4.45 Ex. # Structure NMR 4.1 ##STR01238## (300 MHz,
DMSO-d.sub.6) 2.59 (s, 3 H) 4.21-4.50 (m, 5 H) 6.75 (d, J = 8.77
Hz, 1 H) 7.21 (ddd, J = 8.00, 6.47, 1.61 Hz, 1 H) 7.45 (d, J = 8.04
Hz, 1 H) 7.48-7.60 (m, 2 H) 7.70 (d, J = 7.60 Hz, 1 H) 7.93 (dd, J
= 7.97, 2.41 Hz, 1 H) 8.02 (d, J = 8.77 Hz, 1 H) 8.63-8.74 (m, 3
H). 4.2 ##STR01239## (300 MHz, DMSO-d.sub.6) 2.59 (s, 3 H)
4.21-4.50 (m, 5 H) 6.75 (d, J = 8.77 Hz, 1 H) 7.21 (ddd, J = 8.00,
6.47, 1.61 Hz, 1 H) 7.45 (d, J = 8.04 Hz, 1 H) 7.48-7.60 (m, 2 H)
7.70 (d, J = 7.60 Hz, 1 H) 7.93 (dd, J = 7.97, 2.41 Hz, 1 H) 8.02
(d, J = 8.77 Hz, 1 H) 8.63-8.74 (m, 3 H). 4.3 ##STR01240## (400
MHz, DMSO-d.sub.6) 8.74 (d, J = 2.35 Hz, 1 H) 8.67 (d, J = 2.35 Hz,
1 H) 8.61 (dd, J = 4.69, 1.56 Hz, 1 H) 8.02 (d, J = 9.00 Hz, 1 H)
7.66-7.78 (m, 2 H) 7.47-7.58 (m, 2 H) 7.41 (dd, J = 7.63, 4.89 Hz,
1 H) 7.21 (t, J = 7.24 Hz, 1 H) 6.74 (d, J = 8.61 Hz, 1 H)
4.24-4.31 (m, 2 H) 4.17-4.24 (m, 2 H) 3.93-4.07 (m, 1 H) 2.28 (s, 3
H). 4.4 ##STR01241## (400 MHz, DMSO-d.sub.6) 8.74 (d, J = 2.35 Hz,
1 H) 8.68 (d, J = 2.35 Hz, 1 H) 8.49 (d, J = 2.35 Hz, 1 H) 8.25
(td, J = 8.12, 2.54 Hz, 1 H) 8.02 (d, J = 8.61 Hz, 1 H) 7.70 (d, J
= 7.43 Hz, 1 H) 7.46-7.61 (m, 2 H) 7.40 (dd, J = 8.61, 2.74 Hz, 1
H) 7.14-7.27 (m, 1 H) 6.75 (d, J = 8.61 Hz, 1 H) 4.37-4.49 (m, 1 H)
4.23-4.37 (m, 4H). 4.5 ##STR01242## (400 MHz, DMSO-d.sub.6) 8.74
(d, J = 2.35 Hz, 1 H) 8.68 (d, J = 2.35 Hz, 1 H) 8.49 (d, J = 2.35
Hz, 1 H) 8.25 (td, J = 8.12, 2.54 Hz, 1 H) 8.02 (d, J = 8.61 Hz, 1
H) 7.70 (d, J = 7.43 Hz, 1 H) 7.46-7.61 (m, 2 H) 7.40 (dd, J =
8.61, 2.74 Hz, 1 H) 7.14-7.27 (m, 1 H) 6.75 (d, J = 8.61 Hz, 1 H)
4.37-4.49 (m, 1 H) 4.23-4.37 (m, 4H). 4.6 ##STR01243## (400 MHz,
DMSO-d.sub.6) 8.64 (d, J = 2.35 Hz, 1 H) 8.60 (d, J = 1.96 Hz, 1 H)
8.02 (d, J = 9.00 Hz, 1 H) 7.78 (d, J = 8.22 Hz, 1 H) 7.70 (d, J =
7.82 Hz, 1 H) 7.43-7.62 (m, 2 H) 7.21 (t, J = 7.04 Hz, 1 H) 6.76
(d, J = 9.00 Hz, 1 H) 6.59 (d, J = 8.22 Hz, 1 H) 4.31 (br. s., 1 H)
4.23 (t, J = 6.65 Hz, 2 H) 4.00-4.14 (m, 2 H) 3.97 (s, 3 H) 3.94
(s, 3 H). 4.7 ##STR01244## (400 MHz ,DMSO-d.sub.6) 8.77 (d, J = 2.3
Hz, 2 H), 8.70 (d, J = 2.3 Hz, 1 H), 8.69 (s, 1 H), 8.07-7.97 (m, 2
H), 7.70 (d, J = 8.2 Hz, 1 H), 7.59- 7.47 (m, 2 H), 7.26-7.16 (m, 1
H), 6.76 (d, J = 9.0 Hz, 1 H), 4.50-4.40 (m, 1 H), 4.37-4.23 (m, 4
H) 4.8 ##STR01245## (500 MHz, DMSO-d.sub.6) 8.68-8.79 (m, 2 H) 8.43
(d, J = 2.29 Hz, 1 H) 8.38 (d, J = 9.28 Hz, 1 H) 8.00 (dd, J =
8.59, 2.41 Hz, 1 H) 7.93 (d, J = 7.90 Hz, 1 H) 7.77 (d, J = 3.55
Hz, 2 H) 7.49 (dd, J = 8.08, 4.07 Hz, 1 H) 7.03 (d, J = 8.59 Hz, 1
H) 7.05 (d, J = 9.74 Hz, 1 H) 4.66 (br. s., 2 H) 4.45-4.64 (m, 2 H)
3.96 (s, 3 H). 4.9 ##STR01246## (500 MHz, DMSO-d.sub.6) 8.78 (d, J
= 2.41 Hz, 1 H) 8.71-8.76 (m, 1 H) 8.39 (d, J = 9.51 Hz, 1 H) 8.30
(s, 1 H) 8.11 (d, J = 9.51 Hz, 1 H) 7.93 (d, J = 7.90 Hz, 1 H) 7.78
(d, J = 3.55 Hz, 2 H) 7.44-7.52 (m, 1 H) 7.05 (d, J = 9.28 Hz, 1 H)
4.52-4.72 (m, 5 H) 2.37 (s, 3 H). 4.10 ##STR01247## (500 MHz,
DMSO-d.sub.6) 8.83 (s, 1 H) 8.79 (d, J = 2.29 Hz, 1 H) 8.76 (s, 2
H) 8.39 (d, J = 9.39 Hz, 1 H) 8.09 (d, J = 7.90 Hz, 1 H) 7.93 (d, J
= 7.90 Hz, 1 H) 7.77 (br. s., 2 H) 7.64 (dd, J = 7.73, 4.75 Hz, 1
H) 7.50 (d, J = 8.02 Hz, 1 H) 7.05 (d, J = 9.39 Hz, 1 H) 4.67 (br.
s., 2 H) 4.60 (br. s., 3 H). 4.11 ##STR01248## (600 MHz
,DMSO-d.sub.6) 8.80 (s, 1 H), 8.77-8.71 (m, 1 H), 8.37 (d, J = 9.3
Hz, 1 H), 8.18-8.08 (m, J = 8.1 Hz, 2 H), 7.92 (d, J = 7.9 Hz, 1
H), 7.91- 7.87 (m, J = 8.1 Hz, 2 H), 7.78 (br. s., 2 H), 7.48 (t, J
= 5.7 Hz, 1 H), 7.02 (d, J = 9.3 Hz, 1 H), 4.70-4.54 (m, 6 H) 4.12
##STR01249## (500 MHz, DMSO-d.sub.6) 8.57 (s, 2 H) 8.17 (s, 1 H)
8.03 (d, J = 9.05 Hz, 1 H) 7.70 (d, J = 7.90 Hz, 1 H) 7.65 (dd, J =
8.59, 2.29 Hz, 1 H) 7.57 (d, J = 8.36 Hz, 1 H) 7.52 (t, J = 7.56
Hz, 1 H) 7.21 (t, J = 7.33 Hz, 1 H) 6.76 (d, J = 8.94 Hz, 1 H) 6.60
(d, J = 8.59 Hz, 1 H) 6.35 (s, 2 H) 4.47 (q, J = 7.48 Hz, 1 H) 4.37
(t, J = 8.08 Hz, 2 H) 4.22-4.30 (m, 2 H). 4.13 ##STR01250## (500
MHz, DMSO-d.sub.6) 8.67 (d, J = 2.29 Hz, 1 H) 8.63 (d, J = 2.29 Hz,
1 H) 8.08 (d, J = 2.52 Hz, 1 H) 8.02 (d, J = 8.94 Hz, 1 H)
7.89-7.96 (m, 1 H) 7.70 (d, J = 8.02 Hz, 1 H) 7.54- 7.63 (m, 1 H)
7.45-7.54 (m, 1 H) 7.21 (t, J = 7.33 Hz, 1H) 7.11 (d, J = 1.95 Hz,
1 H) 6.75 (d, J = 8.94 Hz, 1 H) 5.57 (br. s., 1 H) 4.31-4.45 (m,
3H) 4.20-4.31 (m, 2 H). 4.14 ##STR01251## (500 MHz, DMSO-d.sub.6)
8.72 (d, J = 2.29 Hz, 1 H) 8.65 (d, J = 2.29 Hz, 1 H) 8.01 (d, J =
8.94 Hz, 1 H) 7.93 (t, J = 7.85 Hz, 1 H) 7.69 (d, J = 7.90 Hz, 1 H)
7.63 (d, J = 7.33 Hz, 1 H) 7.55 (d, J = 8.48 Hz, 1 H) 7.51 (t, J =
7.56 Hz, 1 H) 7.20 (t, J = 7.27 Hz, 1 H) 6.98 (d, J = 8.25 Hz, 1 H)
6.76 (d, J = 8.94 Hz, 1 H) 4.81-4.95 (m, 1 H) 4.40 (t, J = 8.25 Hz,
2 H) 4.21- 4.33 (m, 2 H) 4.00 (s, 3 H). 4.15 ##STR01252## (400 MHz,
CD.sub.3OD) 8.94 (d, J = 4.69 Hz, 1 H) 8.88 (d, J = 2.35 Hz, 1 H)
8.72 (d, J = 2.35 Hz, 1 H) 8.38 (d, J = 9.39 Hz, 1 H) 8.06 (d, J =
7.04 Hz, 1 H) 7.94 (d, J = 7.82 Hz, 1 H) 7.90 (dd, J = 7.92, 4.79
Hz, 1 H) 7.75- 7.87 (m, 2 H) 7.49-7.65 (m, 1 H) 7.00 (d, J = 9.39
Hz, 1 H) 4.62-4.84 (m, 4 H) 4.14 (quin, J = 7.34 Hz, 1 H). 4.16
##STR01253## (400 MHz, CD.sub.3OD) 8.67-8.70 (m, 1 H) 8.65-8.67 (m,
1 H) 8.63 (s, 2 H) 8.38 (d, J = 9.39 Hz, 1 H) 7.94 (d, J = 7.63 Hz,
1 H) 7.75-7.88 (m, 2 H) 7.51-7.61 (m, 1 H) 7.02 (d, J = 9.59 Hz, 1
H) 4.67-4.85 (m, 5 H) 3.32 (s, 6 H). 4.17 ##STR01254## (400 MHz,
CD.sub.3OD) 8.86 (d, J = 2.35 Hz, 1 H) 8.76 (d, J = 2.54 Hz, 1 H)
8.68 (d, J = 5.28 Hz, 1 H) 8.55 (s, 1 H) 8.38 (d, J = 9.59 Hz, 1 H)
7.94 (d, J = 8.02 Hz, 1 H) 7.75-7.89 (m, 2 H) 7.70 (d, J = 5.48 Hz,
1 H) 7.56 (td, J = 7.48, 1.27 Hz, 1 H) 7.00 (d, J = 9.39 Hz, 1 H)
4.75-4.83 (m, 2 H) 4.63-4.75 (m, 2 H) 4.19-4.37 (m, 1 H) 2.34 (s, 3
H). 4.18 ##STR01255## (300 MHz, CD.sub.3OD) 9.31 (d, J = 2.19 Hz, 1
H) 9.16 (d, J = 2.05 Hz, 1 H) 8.85 (d, J = 2.34 Hz, 1 H) 8.78 (d, J
= 2.34 Hz, 1 H) 8.62 (t, J = 2.12 Hz, 1 H) 8.38 (d, J = 9.50 Hz, 1
H) 7.94 (d, J = 8.04 Hz, 1 H) 7.73-7.89 (m, 2 H) 7.56 (td, J =
7.38, 1.46 Hz, 1 H) 7.02 (d, J = 9.35 Hz, 1 H) 4.76-4.84 (m, 4 H)
4.56-4.73 (m, 1 H) 3.36 (s, 3 H). 4.19 ##STR01256## (300 MHz,
CD.sub.3OD) 8.80 (d, J = 2.48 Hz, 1 H) 8.73 (d, J = 2.48 Hz, 1 H)
8.60-8.69 (m, 2 H) 8.37 (d, J = 9.35 Hz, 1 H) 8.01-8.11 (m, 1 H)
7.93 (d, J = 7.89 Hz, 1 H) 7.72-7.89 (m, 2 H) 7.48-7.62 (m, 1 H)
7.00 (d, J = 9.50 Hz, 1 H) 4.73-4.83 (m, 4 H) 4.58-4.72 (m, 1 H)
2.56 (s, 3 H). 4.20 ##STR01257## (300 MHz, CD.sub.3OD) 8.80 (d, J =
2.34 Hz, 1 H) 8.73 (d, J = 2.48 Hz, 1 H) 8.48 (d, J = 2.78 Hz, 1 H)
8.31-8.43 (m, 2 H) 7.93 (d, J = 7.89 Hz, 1 H) 7.74-7.88 (m, 2 H)
7.71 (dd, J = 2.78, 1.75 Hz, 1 H) 7.55 (ddd, J = 8.00, 6.76, 1.46
Hz, 1 H) 7.00 (d, J = 9.50 Hz, 1 H) 4.73-4.82 (m, 4 H) 4.60-4.73
(m, 1 H) 4.03 (s, 3 H). 4.21 ##STR01258## (500 MHz, DMSO-d.sub.6)
8.68 (d, J = 2.41 Hz, 1 H) 8.63 (d, J = 2.41 Hz, 1 H) 8.01 (d, J =
8.82 Hz, 1 H) 7.69 (d, J = 7.67 Hz, 1 H) 7.53-7.63 (m, 3 H)
7.47-7.53 (m, 1 H) 7.43 (dd, J = 8.19, 2.00 Hz, 1 H) 7.14-7.26 (m,
1 H) 6.74 (d, J = 8.94 Hz, 1 H) 4.36-4.46 (m, 1 H) 4.32 (t, J =
7.96 Hz, 2 H) 4.20-4.29 (m, 2 H) 2.45 (s, 3 H). 4.22 ##STR01259##
(500 MHz, DMSO-d.sub.6) 8.68 (d, J = 2.41 Hz, 1 H) 8.63 (d, J =
2.41 Hz, 1 H) 8.04 (d, J = 8.82 Hz, 1 H) 7.71 (d, J = 7.68 Hz, 1 H)
7.50-7.62 (m, 2 H) 7.48 (t, J = 7.85 Hz, 1 H) 7.39 (d, J = 10.65
Hz, 1 H) 7.33 (dd, J = 7.73, 1.55 Hz, 1 H) 7.22 (t, J = 7.39 Hz, 1
H) 6.76 (d, J = 9.05 Hz, 1 H) 4.39- 4.51 (m, 1 H) 4.21-4.39 (m, 4H)
2.35 (s, 3 H). 4.23 ##STR01260## (500 MHz, DMSO-d.sub.6) 8.62 (d, J
= 2.41 Hz, 1 H) 8.59 (d, J = 2.29 Hz, 1 H) 8.01 (d, J = 8.82 Hz, 1
H) 7.70 (d, J = 7.22 Hz, 1 H) 7.59 (d, J = 2.06 Hz, 1 H) 7.54-7.58
(m, 1 H) 7.47- 7.54 (m, 1 H) 7.39 (dd, J = 8.42, 2.12 Hz, 1 H)
7.17-7.25 (m, 1 H) 7.14 (d, J = 8.36 Hz, 1 H) 6.75 (d, J = 8.82 Hz,
1 H) 4.40-4.51 (m, 1 H) 4.33 (t, J = 8.13 Hz, 2 H) 4.19-4.29 (m, 2
H). 4.24 ##STR01261## (500 MHz, DMSO-d.sub.6) 8.73 (d, J = 2.41 Hz,
1 H) 8.66 (d, J = 2.41 Hz, 1 H) 8.02 (d, J = 8.94 Hz, 1 H) 7.70 (d,
J = 7.79 Hz, 1 H) 7.54-7.60 (m, 1 H) 7.46-7.54 (m, 2 H) 7.43 (d, J
= 9.39 Hz, 2 H) 7.14-7.28 (m, 1 H) 6.75 (d, J = 8.82 Hz, 1 H)
4.36-4.47 (m, 1 H) 4.24-4.36 (m, 4 H) 3.94 (s, 3 H). 4.25
##STR01262## (500 MHz, DMSO-d.sub.6) 8.64 (d, J = 2.41 Hz, 1 H)
8.60 (d, J = 2.41 Hz, 1 H) 8.01 (d, J = 8.82 Hz, 1 H) 7.69 (d, J =
7.33 Hz, 1 H) 7.53-7.58 (m, 1 H) 7.45-7.53 (m, 2 H) 7.37 (dd, J =
8.53, 1.78 Hz, 1 H) 7.31 (t, J = 8.53 Hz, 1 H) 7.15-7.25 (m, 1 H)
6.74 (d, J = 8.94 Hz, 1 H) 4.41-4.55 (m, 1 H) 4.32 (t, J = 8.13 Hz,
2 H) 4.13- 4.28 (m, 4 H) 1.41 (t, J = 6.99 Hz, 3 H). 4.26
##STR01263## (500 MHz, DMSO-d.sub.6) 8.65 (d, J = 2.41 Hz, 1 H)
8.61 (d, J = 2.41 Hz, 1 H) 8.02 (d, J = 8.93 Hz, 1 H) 7.70 (d, J =
7.56 Hz, 1 H) 7.68 (d, J = 2.18 Hz, 1 H) 7.44-7.62 (m, 3 H) 7.30
(d, J = 8.59 Hz, 1 H) 7.14-7.25 (m, 1 H) 6.75 (d, J = 8.94 Hz, 1 H)
4.39- 4.56 (m, 1 H) 4.32 (t, J = 8.13 Hz, 2 H) 4.06-4.29 (m, 4 H)
1.42 (t, J = 6.93 Hz, 3 H). 4.27 ##STR01264## (500 MHz,
DMSO-d.sub.6) 8.65 (d, J = 2.41 Hz, 1 H) 8.61 (d, J = 2.41 Hz, 1 H)
8.02 (d, J = 8.94 Hz, 1 H) 7.70 (d, J = 7.45 Hz, 1 H) 7.67 (d, J =
2.18 Hz, 1 H) 7.46-7.61 (m, 3 H) 7.30 (d, J = 8.59 Hz, 1 H)
7.16-7.25 (m, 1 H) 6.75 (d, J = 8.82 Hz, 1 H) 4.40- 4.52 (m, 1 H)
4.32 (t, J = 8.13 Hz, 2 H) 4.21-4.29 (m, 2 H) 4.13 (t, J = 6.42 Hz,
2 H) 1.82 (sxt, J = 6.99 Hz, 2 H) 1.05 (t, J = 7.39 Hz, 3 H). 4.28
##STR01265## (500 MHz, DMSO-d.sub.6) 8.76 (d, J = 2.41 Hz, 1 H)
8.68 (d, J = 2.29 Hz, 1 H) 8.02 (d, J = 8.82 Hz, 1 H) 7.88 (d, J =
8.59 Hz, 1 H) 7.77-7.85 (m, 2 H) 7.70 (d, J = 7.90 Hz, 1 H) 7.54-
7.61 (m, 1 H) 7.44-7.54 (m, 1 H) 7.12-7.29 (m, 1 H) 6.75 (d, J =
8.82 Hz, 1 H) 4.42 (quin, J = 7.25 Hz, 1 H) 4.30 (d, J = 7.22 Hz, 4
H). 4.29 ##STR01266## (500 MHz, DMSO-d.sub.6) 8.59-8.63 (m, 1 H)
8.54-8.59 (m, 1 H) 8.01 (d, J = 8.93 Hz, 1 H) 7.69 (d, J = 7.68 Hz,
1 H) 7.53-7.59 (m, 1 H) 7.47- 7.53 (m, 1 H) 7.33-7.46 (m, 2 H)
7.14-7.28 (m, 1 H) 7.10 (d, J = 8.36 Hz, 1 H) 6.74 (d, J = 8.94 Hz,
1 H) 4.39-4.52 (m, 1 H) 4.33 (t, J = 8.13 Hz, 2 H) 4.18-4.29 (m, 2
H) 3.88 (s, 3 H) 2.26 (s, 3 H). 4.30 ##STR01267## (500 MHz,
DMSO-d.sub.6) 8.70 (d, J = 2.41 Hz, 1 H) 8.63 (d, J = 2.41 Hz, 1 H)
8.02 (d, J = 8.93 Hz, 1 H) 7.70 (d, J = 7.67 Hz, 1 H) 7.48-7.60 (m,
2 H) 7.10-7.31 (m, 1 H) 6.85-7.06 (m, 3 H) 6.75 (d, J = 8.82 Hz, 1
H) 4.75 (dt, J = 12.03, 6.01 Hz, 1 H) 4.36- 4.50 (m, 1 H) 4.18-4.35
(m, 4 H) 1.32 (d, J = 5.96 Hz, 6H). 4.31 ##STR01268## (500 MHz,
DMSO-d.sub.6) 8.69 (d, J = 2.41 Hz, 1 H) 8.63 (d, J = 2.41 Hz, 1 H)
8.02 (d, J = 8.94 Hz, 1 H) 7.70 (d, J = 7.56 Hz, 1 H) 7.54-7.58 (m,
1 H) 7.48-7.54 (m, 1 H) 7.14-7.31 (m, 4 H) 6.75 (d, J = 8.82 Hz, 1
H) 4.37-4.50 (m, 1 H) 4.20-4.36 (m, 4 H) 2.44 (s, 3 H). 4.32
##STR01269## (500 MHz, DMSO-d.sub.6) 8.71 (d, J = 2.41 Hz, 1 H)
8.64 (d, J = 2.41 Hz, 1 H) 8.02 (d, J = 8.93 Hz, 1 H) 7.80- 7.87
(m, 1 H) 7.70 (d, J = 7.67 Hz, 1 H) 7.54-7.65 (m, 3 H) 7.48-7.54
(m, 1 H) 7.17-7.24 (m, 1 H) 6.75 (d, J = 8.94 Hz, 1 H) 4.37-4.47
(m, 1 H) 4.22-4.36 (m, 4 H). 4.33 ##STR01270## (500 MHz,
DMSO-d.sub.6) 8.70 (d, J = 2.41 Hz, 1 H) 8.64 (d, J = 2.41 Hz, 1 H)
8.01 (d, J = 8.82 Hz, 1 H) 7.66- 7.74 (m, 2 H) 7.58-7.66 (m, 1 H)
7.53-7.58 (m, 1 H) 7.48-7.53 (m, 1 H) 7.41-7.48 (m, 1 H) 7.12-7.26
(m, 1 H) 6.74 (d, J = 8.94 Hz, 1 H) 4.38-4.48 (m, 1 H) 4.31 (t, J =
8.08 Hz, 2 H) 4.21-4.29 (m, 2 H). 4.34 ##STR01271## (500 MHz,
DMSO-d.sub.6) 8.72 (d, J = 2.41 Hz, 1 H) 8.65 (d, J = 2.41 Hz, 1 H)
8.02 (d, J = 8.93 Hz, 1 H) 7.87 (d, J = 1.95 Hz, 1 H) 7.82 (d, J =
8.25 Hz, 1 H) 7.70 (d, J = 7.45 Hz, 1 H) 7.60 (dd, J = 8.31, 2.00
Hz, 1 H) 7.54- 7.58 (m, 1 H) 7.48-7.54 (m, 1 H) 7.16-7.27 (m, 1 H)
6.76 (d, J = 8.82 Hz, 1 H) 4.37-4.47 (m, 1 H) 4.32 (t, J = 8.02 Hz,
2 H) 4.24-4.30 (m, 2 H). 4.35 ##STR01272## (500 MHz, DMSO-d.sub.6)
8.63 (d, J = 2.41 Hz, 1 H) 8.60 (d, J = 2.41 Hz, 1 H) 8.02 (d, J =
8.82 Hz, 1 H) 7.70 (d, J = 7.56 Hz, 1 H) 7.53-7.58 (m, 1 H)
7.48-7.53 (m, 1 H) 7.36 (s, 1 H) 7.26-7.34 (m, 2 H) 7.17-7.24 (m, 1
H) 6.75 (d, J = 8.94 Hz, 1 H) 4.36- 4.47 (m, 1 H) 4.32 (t, J = 8.02
Hz, 2 H) 4.21-4.29 (m, 2 H) 2.34 (s, 3 H) 2.33 (s, 3 H). 4.36
##STR01273## (500 MHz, DMSO-d.sub.6) 8.68 (d, J = 2.29 Hz, 1 H)
8.63 (d, J = 2.41 Hz, 1 H) 8.01 (d, J = 8.82 Hz, 1 H) 7.69 (d, J =
7.56 Hz, 1 H) 7.64 (d, J = 1.49 Hz, 1 H) 7.48-7.59 (m, 3 H) 7.46
(dd, J = 7.79, 1.60 Hz, 1 H) 7.13- 7.28 (m, 1 H) 6.75 (d, J = 8.82
Hz, 1 H) 4.37-4.48 (m, 1 H) 4.19-4.36 (m, 4 H) 2.44 (s, 3 H). 4.37
##STR01274## (500 MHz, DMSO-d.sub.6) 8.70 (d, J = 2.41 Hz, 1 H)
8.63 (d, J = 2.41 Hz, 1 H) 8.02 (d, J = 8.82 Hz, 1 H) 7.70 (d, J =
7.67 Hz, 1 H) 7.54-7.59 (m, 1 H) 7.49-7.54 (m, 1 H) 7.45 (s, 2 H)
7.35 (s, 1 H) 7.12-7.27 (m, 1 H) 6.76 (d, J = 8.82 Hz, 1 H)
4.36-4.47 (m, 1 H) 4.20-4.36 (m, 4 H) 2.44 (s, 3 H). 4.38
##STR01275## (500 MHz, DMSO-d.sub.6) 8.66 (d, J = 2.41 Hz, 1 H)
8.61 (d, J = 2.41 Hz, 1 H) 8.01 (d, J = 8.94 Hz, 1 H) 7.70 (d, J =
7.56 Hz, 1 H) 7.54-7.58 (m, 1 H) 7.48-7.54 (m, 2 H) 7.41-7.47 (m, 1
H) 7.31 (t, J = 9.11 Hz, 1 H) 7.17-7.25 (m, 1 H) 6.74 (d, J = 8.82
Hz, 1 H) 4.37-4.45 (m, 1 H) 4.32 (t, J = 8.02 Hz, 2 H) 4.21-4.29
(m, 2 H) 2.26-2.42 (m, 3 H). 4.39 ##STR01276## (500 MHz,
DMSO-d.sub.6) 9.36 (s, 1 H) 9.08 (s, 2 H) 8.78 (d, J = 2.41 Hz, 1
H) 8.73 (d, J = 2.29 Hz, 1 H) 8.03 (d, J = 8.82 Hz, 1 H) 7.71 (d, J
= 8.02 Hz, 1 H) 7.48-7.60 (m, 2 H) 7.22 (t, J = 7.33 Hz, 1 H) 6.76
(d, J = 8.82 Hz, 1 H) 4.41-4.52 (m, 1 H) 4.23-4.39 (m, 4 H).
4.40 ##STR01277## (500 MHz, DMSO-d.sub.6) 8.74 (d, J = 2.41 Hz, 1
H) 8.67 (d, J = 2.41 Hz, 1 H) 8.06 (s, 1 H) 8.02 (d, J = 8.94 Hz, 1
H) 7.93 (s, 2 H) 7.70 (d, J = 7.67 Hz, 1 H) 7.54-7.60 (m, 1 H)
7.48-7.54 (m, 1 H) 7.16-7.27 (m, 1 H) 6.76 (d, J = 8.94 Hz, 1 H)
4.36- 4.45 (m, 1 H) 4.26-4.36 (m, 4 H). 4.41 ##STR01278## (300 MHz,
MeOH) 8.57 (1 H, d, J = 2.5 Hz), 8.48 (1 H, d, J = 2.3 Hz), 8.03 (1
H, d, J = 9.1 Hz), 7.70 (2 H, m), 7.54 (1 H, m), 7.23-7.30 (1 H,
m), 6.78 (1 H, d, J = 8.9 Hz), 5.99 (1 H, br. s.), 4.38-4.66 (3 H,
m), 4.02 (4 H, m), 3.32-3.37 (2 H, m), 2.61 (2 H, m) 4.42
##STR01279## (300 MHz, MeOH) 8.57 (1 H, d, J = 2.3 Hz), 8.48 (1 H,
d, J = 2.5 Hz), 8.04 (1 H, d, J = 8.9 Hz), 7.71 (2 H, d, J = 7.7
Hz), 7.58 (1 H, t, J = 7.7 Hz), 7.22-7.34 (1 H, m), 6.79 (1 H, d, J
= 8.9 Hz), 5.99 (1 H, s), 4.50-4.70 (3 H, m), 4.39-4.50 (3 H, m),
2.46- 2.58 (2 H, m), 1.45 (1 H, s), 1.39 (6 H, s) ##STR01280## 4.43
##STR01281## (300 MHz, DMSO-d.sub.6) 13.31 (1 H, br. s.), 8.50 (1
H, d, J = 2.2 Hz), 8.54 (1 H, d, J = 2.3 Hz), 8.29 (1 H, s),
7.97-8.08 (2 H, m), 7.71 (1 H, d, J = 7.9 Hz), 7.47-7.61 (2 H, m),
7.22 (1 H, t, J = 6.7 Hz), 6.79 (1 H, d, J = 8.9 Hz), 4.42-4.71 (3
H, m), 4.21- 4.42 (2 H, m) 4.44 ##STR01282## (500 MHz,
DMSO-d.sub.6) 8.76 (d, J = 2.41 Hz, 1 H) 8.68 (d, J = 2.29 Hz, 1 H)
8.02 (d, J = 8.82 Hz, 1 H) 7.88 (d, J = 8.59 Hz, 1 H) 7.77-7.85 (m,
2 H) 7.70 (d, J = 7.90 Hz, 1 H) 7.54- 7.61 (m, 1 H) 7.44-7.54 (m, 1
H) 7.12-7.29 (m, 1 H) 6.75 (d, J = 8.82 Hz, 1 H) 4.42 (quin, J =
7.25 Hz, 1 H) 4.30 (d, J = 7.22 Hz, 4 H). 4.45 ##STR01283## (500
MHz, DMSO-d.sub.6) 8.72 (d, J = 2.29 Hz, 1 H) 8.65 (d, J = 2.29 Hz,
1 H) 8.01 (d, J = 8.94 Hz, 1 H) 7.93 (t, J = 7.85 Hz, 1 H) 7.69 (d,
J = 7.90 Hz, 1 H) 7.63 (d, J = 7.33 Hz, 1 H) 7.55 (d, J = 8.48 Hz,
1 H) 7.51 (t, J = 7.56 Hz, 1 H) 7.20 (t, J = 7.27 Hz, 1 H) 6.98 (d,
J = 8.25 Hz, 1 H) 6.76 (d, J = 8.94 Hz, 1 H) 4.81-4.95 (m, 1 H)
4.40 (t, J = 8.25 Hz, 2 H) 4.21- 4.33 (m, 2 H) 4.00 (s, 3 H).
##STR01284##
Example 5.1
2-(3-(3-PHENYLPYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE
[0569] A glass microwave reaction vessel was charged with
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.085 g, 0.286
mmol), phenylboronic acid (0.070 g, 0.573 mmol, Aldrich), potassium
phosphate (0.152 g, 0.716 mmol, Alfa Aesar),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium
(II) (0.020 g, 0.029 mmol, Aldrich), water (0.400 mL) and dioxane
(1.6 mL). The mixture was purged with Argon gas and heated in an
Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.,
Upssala, Sweden) at 100.degree. C. for 30 min. LCMS showed the
product. The mixture was diluted with EtOAc and washed with
Na.sub.2CO.sub.3 and brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was purified
by silica gel chromatography (12 g, 10%-100% EtOAc-Hexane). The
product was obtained as a white solid (85 mg, 88%).
[0570] The following Table 17A lists compounds of Examples 5.1 to
5.43, which were made analogous to Scheme 5 by using the
appropriate materials and reaction conditions, which are listed in
Table 17B. The NMR data of the Examples are listed in Table
17C.
TABLE-US-00026 TABLE 17A EXAMPLES 5.1 TO 5.43 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (.mu.M) 5.1 ##STR01285##
2-(3-(3-phenylpyrazin-2- yl)azetidin-1-yl)quinoline 339 0.0012 5.2
##STR01286## 2-(3-(3-(4- methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 369 0.002 5.3 ##STR01287## 2-(3-(3-(4-
fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 357 0.002 5.4
##STR01288## 2-(3-(3-(2- fluorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 357 0.01 5.5 ##STR01289## 2-(3-(3-(3-
fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 357 0.004 5.6
##STR01290## 2-(3-(3-(pyridin-4- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 340 0.004 5.7 ##STR01291## 3-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)benzonitrile 364 0.003 5.8
##STR01292## 4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)benzonitrile 364 0.003 5.9 ##STR01293## methyl
3-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin- 2-yl)benzoate 397
0.0002 5.10 ##STR01294## ethyl 4-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)benzoate 411 0.002 5.11 ##STR01295##
2-(3-(3-(2- methoxypyridin-4- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 370 0.002 5.12 ##STR01296## 2-(3-(3-(2-fluoropyridin-
4-yl)pyrazin-2-yl)azetidin- 1-yl)quinoline 358 0.01 5.13
##STR01297## 2-(3-(3-(3- (methylthio)phenyl)pyrazin-
2-yl)azetidin-1- yl)quinoline 385 0.004 5.14 ##STR01298##
1-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)ethanone 381 0.003 5.15 ##STR01299## 2-(3-(3-(4-
phenoxyphenyl)pyrazin-2- yl)azctidin-1-yl)quinoline 431 0.034 5.16
##STR01300## 2-(3-(3-(4- (trifluoromethyl)phenyl)
pyrazin-2-yl)azetidin-1- yl)quinoline 407 0.027 5.17 ##STR01301##
2-(3-(3-(3-fluoro-4- methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 387 0.003 5.18 ##STR01302##
N,N-dimethyl-3-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)aniline 382 0.002 5.19 ##STR01303##
N-methyl-3-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzamide 396 0.0007 5.20 ##STR01304## tert-butyl
4-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-5,6-
dihydropyridine-1(2H)- carboxylate 444 0.0007 5.21 ##STR01305##
2-(3-(3-([1,1'-biphenyl]-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 415 0.002 5.22 ##STR01306## 2-fluoro-4-(3-(1-
(quinolin-2-yl)azetidin-3- yl)pyrazin-2- yl)benzonitrile 382 0.006
5.23 ##STR01307## 2-fluoro-5-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2- yl)benzonitrile 382 0.007 5.24 ##STR01308##
N,N-dimethyl-3-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzamide 410 0.018 5.25 ##STR01309## 2-(3-(3-(2-
methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 369 0.002 5.26
##STR01310## 2-(3-(3-(3- (trifluoromethyl)phenyl)
pyrazin-2-yl)azetidin-1- yl)quinoline 407 0.01344 5.27 ##STR01311##
2-(3-(3-(3- ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 383
0.00388 5.28 ##STR01312## 1-(3-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)phenyl)ethanone 381 0.00124 5.29
##STR01313## (3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)methanol 369 0.00676 5.30 ##STR01314## 2-(3-(3-(3-
(trifluoromethoxy)phenyl) pyrazin-2-yl)azctidin-1- yl)quinoline 423
0.00665 5.31 ##STR01315## 2-(3-(3-(3- (benzyloxy)phenyl)pyrazin-
2-yl)azetidin-1- yl)quinoline 445 0.01077 5.32 ##STR01316##
N-cyclopropyl-3-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzamide 422 0.00337 5.33 ##STR01317##
N,N-dimethyl-3-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-
yl)benzenesulfonamide 446 0.01703 5.34 ##STR01318## 2-(3-(3-(4-
ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 383 0.01717 5.35
##STR01319## (4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)methanol 369 0.00519 5.36 ##STR01320## 2-(3-(3-(4-
propylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 381 0.00995 5.37
##STR01321## 2-(3-(3-(4- ethylphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 367 0.00609 5.38 ##STR01322##
N,N-dimethyl-4-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)aniline 382 0.0127 5.39 ##STR01323## 2-(3-(3-(4-
(trifluoromethoxy)phenyl) pyrazin-2-yl)azetidin-1- yl)quinoline 423
0.01747 5.40 ##STR01324## 2-(3-(3-(4- isopropoxyphenyl)pyrazin-
2-yl)azetidin-1- yl)quinoline 397 0.00723 5.41 ##STR01325##
2-methyl-2-(4-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-
yl)phenyl)propanenitrile 406 0.00737 5.42 ##STR01326##
4-((4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)sulfonyl) morpholine 488 0.03337 5.43 ##STR01327##
2-(3-(3-(4-(piperidin-1- ylsulfonyl)phenyl)pyrazin-
2-yl)azetidin-1- yl)quinoline 486 0.02119
TABLE-US-00027 TABLE 17B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 5.1 TO 5.43. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Reaction Purification EX # Key Starting Material(s) Key
Starting Material(s) Condition Method* 5.1 ##STR01328##
##STR01329## PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W A
Aldrich 5.2 ##STR01330## ##STR01331## PREPA- RATION 2
Dioxane/water, 100.degree. C., .mu.W A Aldrich 5.3 ##STR01332##
##STR01333## PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W A
Aldrich 5.4 ##STR01334## ##STR01335## PREPA- RATION 2
Dioxane/water, 100.degree. C., .mu.W A Aldrich 5.5 ##STR01336##
##STR01337## PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W A
Alfa Aesar 5.6 ##STR01338## ##STR01339## PREPA- RATION 2
Dioxane/water, 100.degree. C., .mu.W B Combi-blocks 5.7
##STR01340## ##STR01341## PREPA- RATION 2 Dioxane/water,
100.degree. C., .mu.W A Boron Molecular Ltd 5.8 ##STR01342##
##STR01343## PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W A
Aldrich 5.9 ##STR01344## ##STR01345## PREPA- RATION 2
Dioxane/water, 100.degree. C., .mu.W A Combi-blocks 5.10
##STR01346## ##STR01347## PREPA- RATION 2 Dioxane/water,
100.degree. C., .mu.W A Aldrich 5.11 ##STR01348## ##STR01349##
PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W C Combi-blocks
5.12 ##STR01350## ##STR01351## PREPA- RATION 2 Dioxane/water,
100.degree. C., .mu.W C Frontier 5.13 ##STR01352## ##STR01353##
PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W A ASDI 5.14
##STR01354## ##STR01355## PREPA- RATION 2 Dioxane/water,
100.degree. C., .mu.W A Alfa Aesar 5.15 ##STR01356## ##STR01357##
PREPA- RATION 2 Dioxane/water, 100.degree. C., .mu.W A Frontier
5.16 ##STR01358## ##STR01359## PREPA- RATION 2 Dioxane/water,
100.degree. C. A Aldrich 5.17 ##STR01360## ##STR01361## PREPA-
RATION 2 Dioxane/water, 100.degree. C. A Aldrich 5.18 ##STR01362##
##STR01363## PREPA- RATION 2 Dioxane/water, 100.degree. C. A
Frontier 5.19 ##STR01364## ##STR01365## PREPA- RATION 2
Dioxane/water, 100.degree. C. A Combi-blocks 5.20 ##STR01366##
##STR01367## PREPA- RATION 2 Dioxane/water, 100.degree. C. A Boron
Molecular 5.21 ##STR01368## ##STR01369## PREPA- RATION 2
Dioxane/water, 100.degree. C. A Aldrich 5.22 ##STR01370##
##STR01371## PREPA- RATION 2 Dioxane/water, 100.degree. C. A Alfa
Aesar 5.23 ##STR01372## ##STR01373## PREPA- RATION 2 Dioxane/water,
100.degree. C. A Combi-blocks 5.24 ##STR01374## ##STR01375## PREPA-
RATION 2 Dioxane/water, 100.degree. C. C Boron Molecules 5.25
##STR01376## ##STR01377## PREPA- RATION 2 Dioxane/water,
100.degree. C. A Aldrich 5.26 ##STR01378## ##STR01379## PREPA-
RATION 2 Dioxane/water, 100.degree. C. D ASDI 5.27 ##STR01380##
##STR01381## PREPA- RATION 2 Dioxane/water, 100.degree. C. D ASDI
5.28 ##STR01382## ##STR01383## PREPA- RATION 2 Dioxane/water,
100.degree. C. D ASDI 5.29 ##STR01384## ##STR01385## PREPA- RATION
2 Dioxane/water, 100.degree. C. D ASDI 5.30 ##STR01386##
##STR01387## PREPA- RATION 2 Dioxane/water, 100.degree. C. D ASDI
5.31 ##STR01388## ##STR01389## PREPA- RATION 2 Dioxane/water,
100.degree. C. D ASDI 5.32 ##STR01390## ##STR01391## PREPA- RATION
2 Dioxane/water, 100.degree. C. D ASDI 5.33 ##STR01392##
##STR01393## PREPA- RATION 2 Dioxane/water, 100.degree. C. D ASDI
5.34 ##STR01394## ##STR01395## PREPA- RATION 2 Dioxane/water,
100.degree. C. D ASDI 5.35 ##STR01396## ##STR01397## PREPA- RATION
2 Dioxane/water, 100.degree. C. D ASDI 5.36 ##STR01398##
##STR01399## PREPA- RATION 2 Dioxane/water, 100.degree. C. D ASDI
5.37 ##STR01400## ##STR01401## PREPA- RATION 2 Dioxane/water,
100.degree. C. D ASDI 5.38 ##STR01402## ##STR01403## PREPA- RATION
2 Dioxane/water, 100.degree. C. D ASDI 5.39 ##STR01404##
##STR01405## PREPA- RATION 2 Dioxane/water, 100.degree. C. D ASDI
5.40 ##STR01406## ##STR01407## PREPA- RATION 2 Dioxane/water,
100.degree. C. D ASDI 5.41 ##STR01408## ##STR01409## PREPA- RATION
2 Dioxane/water, 100.degree. C. D ASDI 5.42 ##STR01410##
##STR01411## PREPA- RATION 2 Dioxane/water, 100.degree. C. D ASDI
5.43 ##STR01412## ##STR01413## PREPA- RATION 2 Dioxane/water,
100.degree. C. D ASDI *PURIFICATION CONDITIONS: METHOD A
purification by silica gel chromatography: (ISCO 12 g
RediSep-silica column, eluting with a gradient of 10% to 100% EtOAc
in hexane). METHOD B purification by silica gel chromatography:
(ISCO 12 g RediSep-silica column, eluting with a gradient of 0% to
10% Me0H in CH.sub.2Cl.sub.2). METHOD C reverse-phase HPLC
(Shimazu; Gemini 10 .mu.M C18 110A AXIA, 100 x 50 mm column)
eluting with 0.1% TFA- H.sub.2O:0.1% TFA CH.sub.3CN (10% .fwdarw.
55%). The fractions containing the desired product were combined,
neutralized with Na.sub.2CO.sub.3, and extracted with a mixed
solvent of CHCl.sub.3: i-PrOH (3:1) three times. The organic phase
was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. METHOD D
reverse phase purification using the following conditions:
(Instrumentation: MS - Waters SQ; UV - Waters 2487 or Waters PD;
Solvents: A: Water w/ 0.1% NH.sub.4OH B: Acetonitrile w/ 0.1%
NH.sub.4OH; Column: Phenomenex Gemini-NX C18 110A Sum 21x100; Flow
Rate: 44 mL/min. 10 min Method, variable gradient over 8 min).
TABLE-US-00028 TABLE 17C 1H NMR .delta. (PPM) DATA FOR EXAMPLES 5.1
TO 5.43 Ex. # Structure NMR 5.1 ##STR01414## (400 MHz,
CHLOROFORM-d) 4.32-4.53 (m, 5 H) 6.61 (d, J = 9.00 Hz, 1 H)
7.18-7.23 (m, 1 H) 7.46- 7.55 (m, 6 H) 7.59 (d, J = 8.02 Hz, 1 H)
7.72 (d, J = 8.41 Hz, 1 H) 7.85 (d, J = 9.00 Hz, 1 H) 8.55 (dd, J =
15.16, 2.45 Hz, 2 H). 5.2 ##STR01415## (400 MHz, CHLOROFORM-d) 3.90
(s, 3 H) 4.38- 4.52 (m, 5 H) 6.62 (d, J = 8.80 Hz, 1 H) 7.04 (d, J
= 8.61 Hz, 2 H) 7.21 (t, J = 7.43 Hz, 1 H) 7.44-7.55 (m, 3 H) 7.60
(d, J = 7.83 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.86 (d, J = 8.80
Hz, 1 H) 8.49-8.55 (m, 2 H). 5.3 ##STR01416## (400 MHz,
CHLOROFORM-d) 4.30-4.53 (m, 5 H) 6.63 (d, J = 8.80 Hz, 1 H)
7.18-7.25 (m, 3 H) 7.49- 7.56 (m, 3 H) 7.60 (d, J = 8.02 Hz, 1 H)
7.72 (d, J = 8.41 Hz, 1 H) 7.87 (d, J = 8.80 Hz, 1 H) 8.47-8.63 (m,
2 H). 5.4 ##STR01417## (400 MHz, CHLOROFORM-d) 4.12-4.25 (m, 1 H)
4.34-4.49 (m, 4 H) 6.62 (d, J = 8.80 Hz, 1 H) 7.16- 7.25 (m, 2 H)
7.30-7.38 (m, 1 H) 7.45-7.56 (m, 3 H) 7.59 (d, J = 8.02 Hz, 1 H)
7.72 (d, J = 8.41 Hz, 1 H) 7.86 (d, J = 8.80 Hz, 1 H) 8.57 (d, J =
2.54 Hz, 1 H) 8.64 (d, J = 2.54 Hz, 1 H). 5.5 ##STR01418## (400
MHz, CHLOROFORM-d) 4.32-4.54 (m, 5 H) 6.63 (d, J = 9.00 Hz, 1 H)
7.16-7.33 (m, 4 H) 7.45-7.57 (m, 2 H) 7.60 (d, J = 7.82 Hz, 1 H)
7.72 (d, J = 8.41 Hz, 1 H) 7.87 (d, J = 9.00 Hz, 1 H) 8.54 (d, J =
2.35 Hz, 1 H) 8.61 (d, J = 2.35 Hz, 1 H). 5.6 ##STR01419## (400
MHz, CHLOROFORM-d) 4.30-4.39 (m, 1 H) 4.41-4.52 (m, 4 H) 6.63 (d, J
= 8.80 Hz, 1 H) 7.23 (t, J = 7.53 Hz, 1 H) 7.44-7.49 (m, 2 H)
7.51-7.57 (m, 1 H) 7.61 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz,
1 H) 7.88 (d, J = 8.80 Hz, 1 H) 8.58 (d, J = 2.35 Hz, 1 H) 8.66 (d,
J = 2.35 Hz, 1 H) 8.78-8.83 (m, 2 H). 5.7 ##STR01420## (400 MHz,
CHLOROFORM-d) 4.28-4.38 (m, 1 H) 4.40-4.51 (m, 4 H) 6.64 (d, J =
8.80 Hz, 1 H) 7.20- 7.25 (m, 1 H) 7.50-7.57 (m, 1 H) 7.59-7.84 (m,
5 H) 7.85-7.92 (m, 2 H) 8.57 (d, J = 2.35 Hz, 1 H) 8.65 (d, J =
2.35 Hz, 1 H). 5.8 ##STR01421## (400 MHz, CHLOROFORM-d) 4.28-4.37
(m, 1 H) 4.39-4.50 (m, 4 H) 6.63 (d, J = 8.80 Hz, 1 H) 7.19-7.25
(m, 1 H) 7.50-7.57 (m, 1 H) 7.61 (d, J = 7.82 Hz, 1 H) 7.66 (d, J =
8.41 Hz, 2 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.84 (d, J = 8.41 Hz, 2 H)
7.89 (d, J = 8.80 Hz, 1 H) 8.57 (d, J = 2.54 Hz, 1 H) 8.65 (d, J =
2.35 Hz, 1 H). 5.9 ##STR01422## (400 MHz, CHLOROFORM-d) 3.97 (s, 3
H) 4.34- 4.60 (m, 5 H) 6.63 (d, J = 8.80 Hz, 1 H) 7.18-7.25 (m, 1
H) 7.49-7.57 (m, 1 H) 7.58-7.68 (m, 2 H) 7.69-7.80 (m, 2 H) 7.87
(d, J = 9.00 Hz, 1 H) 8.17- 8.24 (m, 2 H) 8.54-8.58 (m, 1 H) 8.61
(d, J = 2.35 Hz, 1 H). 5.10 ##STR01423## .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.45 (t, J = 7.14 Hz, 3 H) 4.27-4.55 (m,
7 H) 6.62 (d, J = 8.80 Hz, 1 H) 7.17-7.24 (m, 1 H) 7.49-7.64 (m, 4
H) 7.72 (d, J = 8.22 Hz, 1 H) 7.87 (d, J = 9.00 Hz, 1 H) 8.21 (d, J
= 8.41 Hz, 2 H) 8.56 (d, J = 2.35 Hz, 1 H) 8.62 (d, J = 2.35 Hz, 1
H). 5.11 ##STR01424## (400 MHz, CHLOROFORM-d) 4.02 (s, 3 H) 4.29-
4.53 (m, 5 H) 6.63 (d, J = 9.00 Hz, 1 H) 6.87 (s, 1 H) 7.03 (dd, J
= 5.28, 1.37 Hz, 1 H) 7.19-7.25 (m, 1 H) 7.50-7.56 (m, 1 H) 7.61
(d, J = 8.02 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.88 (d, J = 8.80
Hz, 1 H) 8.33 (d, J = 5.28 Hz, 1 H) 8.56 (d, J = 2.35 Hz, 1 H) 8.64
(d, J = 2.35 Hz, 1 H). 5.12 ##STR01425## (400 MHz, CHLOROFORM-d)
4.28-4.39 (m, 1 H) 4.41-4.53 (m, 4 H) 6.64 (d, J = 8.80 Hz, 1 H)
7.14 (s, 1 H) 7.20-7.26 (m, 1 H) 7.35 (d, J = 5.09 Hz, 1 H)
7.51-7.57 (m, 1 H) 7.61 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz,
1 H) 7.90 (d, J = 8.80 Hz, 1 H) 8.41 (d, J = 5.28 Hz, 1 H) 8.59 (d,
J = 2.35 Hz, 1 H) 8.69 (d, J = 2.35 Hz, 1 H). 5.13 ##STR01426##
(400 MHz, CHLOROFORM-d) 2.55 (s, 3 H) 4.34- 4.52 (m, 5 H) 6.63 (d,
J = 8.80 Hz, 1 H) 7.18-7.25 (m, 2 H) 7.35-7.47 (m, 3 H) 7.50-7.56
(m, 1 H) 7.60 (d, J = 7.82 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.87
(d, J = 9.00 Hz, 1 H) 8.54 (d, J = 2.35 Hz, 1 H) 8.59 (d, J = 2.35
Hz, 1 H). 5.14 ##STR01427## (400 MHz, CHLOROFORM-d) 2.69 (s, 3 H)
4.30- 4.54 (m, 5 H) 6.62 (d, J = 8.80 Hz, 1 H) 7.22 (t, J = 7.43
Hz, 1 H) 7.50-7.56 (m, 1 H) 7.60 (d, J = 8.02 Hz, 1 H) 7.64 (d, J =
8.41 Hz, 2 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.87 (d, J = 8.80 Hz, 1 H)
8.12 (d, J = 8.41 Hz, 2 H) 8.57 (d, J = 2.35 Hz, 1 H) 8.62 (d, J =
2.35 Hz, 1 H). 5.15 ##STR01428## (400 MHz, CHLOROFORM-d) 4.38-4.54
(m, 5 H) 6.63 (d, J = 8.80 Hz, 1 H) 7.08-7.24 (m, 6 H) 7.36- 7.44
(m, 2 H) 7.46-7.56 (m, 3 H) 7.60 (d, J = 8.02 Hz, 1 H) 7.72 (d, J =
8.41 Hz, 1 H) 7.87 (d, J = 8.80 Hz, 1 H) 8.52 (d, J = 2.35 Hz, 1 H)
8.56 (d, J = 2.35 Hz, 1 H). 5.16 ##STR01429## (400 MHz,
CHLOROFORM-d) 4.28-4.56 (m, 5 H) 6.63 (d, J = 9.00 Hz, 1 H)
7.19-7.25 (m, 1 H) 7.54 (t, J = 7.63 Hz, 1 H) 7.61 (d, J = 8.02 Hz,
1 H) 7.66 (d, J = 8.02 Hz, 2 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.80 (d,
J = 8.22 Hz, 2 H) 7.88 (d, J = 8.80 Hz, 1 H) 8.57 (d, J = 2.35 Hz,
1 H) 8.64 (d, J = 2.35 Hz, 1 H). 5.17 ##STR01430## (400 MHz,
CHLOROFORM-d) 3.99 (s, 3 H) 4.38- 4.51 (m, 5 H) 6.63 (d, J = 8.80
Hz, 1 H) 7.05-7.14 (m, 1 H) 7.18-7.25 (m, 2 H) 7.33 (dd, J = 11.74,
1.96 Hz, 1 H) 7.53 (t, J = 7.63 Hz, 1 H) 7.60 (d, J = 8.02 Hz, 1 H)
7.72 (d, J = 8.41 Hz, 1 H) 7.88 (d, J = 8.80 Hz, 1 H) 8.52 (d, J =
2.15 Hz, 1 H) 8.56 (d, J = 2.35 Hz, 1 H). 5.18 ##STR01431## (400
MHz, CHLOROFORM-d) 3.03 (s, 6 H) 4.34- 4.55 (m, 5 H) 6.63 (d, J =
8.80 Hz, 1 H) 6.76-6.88 (m, 3 H) 7.18-7.24 (m, 1 H) 7.36 (t, J =
7.92 Hz, 1 H) 7.49-7.56 (m, 1 H) 7.60 (d, J = 7.82 Hz, 1 H) 7.72
(d, J = 8.41 Hz, 1 H) 7.86 (d, J = 9.00 Hz, 1 H) 8.52 (d, J = 2.35
Hz, 1 H) 8.56 (d, J = 2.35 Hz, 1 H). 5.19 ##STR01432## (400 MHz,
CHLOROFORM-d) 3.06 (d, J = 4.89 Hz, 3 H) 4.32-4.53 (m, 5 H) 6.27
(br. s., 1 H) 6.62 (d, J = 9.00 Hz, 1 H) 7.22 (t, J = 7.43 Hz, 1 H)
7.48-7.78 (m, 5 H) 7.83-8.06 (m, 3 H) 8.55 (d, J = 2.35 Hz, 1 H)
8.61 (d, J = 2.35 Hz, 1 H). 5.20 ##STR01433## (400 MHz,
DMSO-d.sub.6) 1.46 (s, 9 H) 3.31 (br. s., 2 H) 3.59 (t, J = 5.28
Hz, 2 H) 4.08 (br. s., 2 H) 4.20-4.32 (m, 2 H) 4.38-4.59 (m, 3 H)
5.92 (br. s., 1 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 6.75 Hz,
1 H) 7.46- 7.61 (m, 2 H) 7.71 (d, J = 7.82 Hz, 1 H) 8.04 (d, J =
8.80 Hz, 1 H) 8.52 (d, J = 2.35 Hz, 1 H) 8.56 (d, J = 2.35 Hz, 1
H). 5.21 ##STR01434## (400 MHz, CHLOROFORM-d) 4.38-4.54 (m, 5 H)
6.63 (d, J = 9.00 Hz, 1 H) 7.19-7.24 (m, 1 H) 7.36- 7.42 (m, 1 H)
7.44-7.55 (m, 4 H) 7.57-7.63 (m, 2 H) 7.66 (d, J = 7.63 Hz, 2 H)
7.69-7.77 (m, 3 H) 7.87 (d, J = 8.80 Hz, 1 H) 8.56 (d, J = 2.54 Hz,
1 H) 8.60 (d, J = 2.35 Hz, 1 H). 5.22 ##STR01435## (400 MHz,
CHLOROFORM-d) 4.26-4.38 (m, 1 H) 4.41-4.54 (m, 4 H) 6.64 (d, J =
9.00 Hz, 1 H) 7.20- 7.25 (m, 1 H) 7.41-7.49 (m, 2 H) 7.51-7.58 (m,
1 H) 7.62 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.80 (t,
J = 7.34 Hz, 1 H) 7.90 (d, J = 8.80 Hz, 1 H) 8.58 (d, J = 2.15 Hz,
1 H) 8.67 (d, J = 2.15 Hz, 1 H). 5.23 ##STR01436## (400 MHz,
CHLOROFORM-d) 4.26-4.37 (m, 1 H) 4.40-4.53 (m, 4 H) 6.65 (s, 1 H)
7.20-7.25 (m, 1 H) 7.40 (t, J = 8.51 Hz, 1 H) 7.51-7.58 (m, 1 H)
7.62 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.75- 7.81
(m, 1 H) 7.86 (dd, J = 5.97, 2.25 Hz, 1 H) 7.90 (d, J = 8.80 Hz, 1
H) 8.56 (d, J = 2.35 Hz, 1 H) 8.65 (d, J = 2.15 Hz, 1 H). 5.24
##STR01437## (400 MHz, CHLOROFORM-d) 2.98-3.22 (m, 6 H) 4.30-4.54
(m, 5 H) 6.63 (d, J = 8.80 Hz, 1 H) 7.22 (t, J = 7.14 Hz, 1 H)
7.49-7.64 (m, 6 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.87 (d, J = 9.00 Hz,
1 H) 8.55 (d, J = 2.35 Hz, 1 H) 8.61 (d, J = 2.35 Hz, 1 H). 5.25
##STR01438## (400 MHz, CHLOROFORM-d) 3.82 (s, 3 H) 4.04- 4.56 (m, 5
H) 6.61 (d, J = 8.80 Hz, 1 H) 7.02 (d, J = 8.41 Hz, 1 H) 7.12 (t, J
= 7.43 Hz, 1 H) 7.21 (t, J = 7.43 Hz, 1 H) 7.37 (dd, J = 7.53, 1.47
Hz, 1 H) 7.43-7.55 (m, 2 H) 7.59 (d, J = 7.82 Hz, 1 H) 7.72 (d, J =
8.41 Hz, 1 H) 7.85 (d, J = 8.80 Hz, 1 H) 8.53 (d, J = 2.54 Hz, 1 H)
8.58 (d, J = 2.35 Hz, 1 H). 5.26 ##STR01439## (400 MHz,
DMSO-d.sub.6) 4.22-4.45 (m, 5 H) 6.76 (d, J = 8.61 Hz, 1 H) 7.22
(t, J = 6.85 Hz, 1 H) 7.46-7.60 (m, 2 H) 7.71 (d, J = 7.82 Hz, 1 H)
7.78-7.85 (m, 1 H) 7.89-7.98 (m, 3 H) 8.03 (d, J = 9.00 Hz, 1 H)
8.68 (d, J = 2.35 Hz, 1 H) 8.74 (d, J = 2.35 Hz, 1 H). 5.27
##STR01440## (400 MHz, DMSO-d.sub.6) 1.37 (t, J = 6.85 Hz, 3 H)
4.12 (q, J = 7.04 Hz, 2 H) 4.23-4.52 (m, 5 H) 6.77 (d, J = 9.00 Hz,
1 H) 7.06-7.15 (m, 3 H) 7.19-7.27 (m, 1 H) 7.42-7.61 (m, 3 H) 7.71
(d, J = 7.82 Hz, 1 H) 8.04 (d, J = 8.61 Hz, 1 H) 8.63 (d, J = 2.35
Hz, 1 H) 8.68 (d, J = 2.35 Hz, 1 H). 5.28 ##STR01441## (400 MHz,
DMSO-d.sub.6) 2.68 (s, 3 H) 4.23-4.47 (m, 5 H) 6.75 (d, J = 9.00
Hz, 1 H) 7.17-7.24 (m, 1 H) 7.47-7.59 (m, 2 H) 7.67-7.78 (m, 2 H)
7.87 (d, J = 7.43 Hz, 1 H) 8.02 (d, J = 9.00 Hz, 1 H) 8.09-8.16 (m,
2 H) 8.67 (d, J = 2.35 Hz, 1 H) 8.72 (d, J = 2.35 Hz, 1 H) 5.29
##STR01442## (400 MHz, DMSO-d.sub.6) 4.20-4.45 (m, 5 H) 4.62 (d, J
= 5.48 Hz, 2 H) 5.35 (t, J = 5.67 Hz, 1 H) 6.75 (d, J = 9.00 Hz, 1
H) 7.21 (t, J = 7.24 Hz, 1 H) 7.42-7.60 (m, 6 H) 7.70 (d, J = 8.22
Hz, 1 H) 8.03 (d, J = 8.61 Hz, 1 H) 8.63 (d, J = 2.35 Hz, 1 H) 8.67
(d, J = 2.35 Hz, 1 H). 5.30 ##STR01443## (400 MHz, DMSO-d.sub.6)
4.23-4.47 (m, 5 H) 6.76 (d, J = 9.00 Hz, 1 H) 7.23 (t, J = 7.24 Hz,
1 H) 7.48-7.66 (m, 5 H) 7.67-7.75 (m, 2 H) 8.01-8.09 (m, 1 H)
8.65-8.68 (m, 1 H) 8.71-8.75 (m, 1 H). 5.31 ##STR01444## (400 MHz,
DMSO-d.sub.6) 4.15-4.44 (m, 5 H) 5.21 (s, 2 H) 6.73 (d, J = 9.00
Hz, 1 H) 7.11-7.25 (m, 4 H) 7.28-7.34 (m, 1 H) 7.41 (t, J = 7.63
Hz, 2 H) 7.45- 7.59 (m, 5 H) 7.70 (d, J = 7.82 Hz, 1 H) 8.02 (d, J
= 9.00 Hz, 1 H) 8.63 (d, J = 2.35 Hz, 1 H) 8.67 (d, J = 2.35 Hz, 1
H) 5.32 ##STR01445## (400 MHz, DMSO-d.sub.6) 0.57-0.64 (m, 2 H)
0.69- 0.77 (m, 2 H) 2.89 (tq, J = 7.34, 3.98 Hz, 1 H) 4.22- 4.45
(m, 5 H) 6.75 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 7.43 Hz, 1 H)
7.47-7.59 (m, 2 H) 7.61-7.67 (m, 1 H) 7.72 (dd, J = 14.87, 7.82 Hz,
2 H) 7.93-8.08 (m, 3 H) 8.57 (d, J = 3.91 Hz, 1 H) 8.66 (d, J =
2.35 Hz, 1 H) 8.71 (d, J = 2.35 Hz, 1 H) 5.33 ##STR01446## (400
MHz, DMSO-d.sub.6) 2.70 (s, 6 H) 4.25-4.43 (m, 5 H) 6.72-6.78 (m, 1
H) 7.17-7.25 (m, 1 H) 7.47- 7.59 (m, 2 H) 7.70 (d, J = 7.82 Hz, 1
H) 7.82-7.88 (m, 1 H) 7.90-7.98 (m, 3 H) 8.03 (d, J = 8.61 Hz, 1 H)
8.68 (d, J = 2.35 Hz, 1 H) 8.74 (d, J = 2.74 Hz, 1 H) 5.34
##STR01447## (400 MHz, DMSO-d.sub.6) 1.38 (t, J = 7.04 Hz, 3 H)
4.13 (q, J = 6.78 Hz, 2 H) 4.22-4.29 (m, 2 H) 4.35 (t, J = 8.02 Hz,
2 H) 4.41-4.51 (m, 1 H) 6.76 (d, J = 9.00 Hz, 1 H) 7.05-7.12 (m, 2
H) 7.19-7.25 (m, 1 H) 7.48-7.59 (m, 4 H) 7.71 (d, J = 7.82 Hz, 1 H)
8.04 (d, J = 9.00 Hz, 1 H) 8.59-8.61 (m, 1 H) 8.61-8.63 (m, 1 H)
5.35 ##STR01448## (400 MHz, DMSO-d.sub.6) 4.19-4.47 (m, 5 H) 4.62
(d, J = 5.87 Hz, 2 H) 5.33 (t, J = 5.67 Hz, 1 H) 6.75 (d, J = 9.00
Hz, 1 H) 7.21 (t, J = 7.04 Hz, 1 H) 7.47-7.59 (m, 6 H) 7.70 (d, J =
7.82 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1 H) 8.63 (d, J = 2.74 Hz, 1 H)
8.66 (d, J = 2.74 Hz, 1 H) 5.36 ##STR01449## (400 MHz,
DMSO-d.sub.6) 0.95 (t, J = 7.43 Hz, 3 H) 1.67 (sxt, J = 7.43 Hz, 2
H) 2.66 (t, J = 7.63 Hz, 2 H) 4.23- 4.47 (m, 5 H) 6.76 (d, J = 9.00
Hz, 1 H) 7.20-7.26 (m, 1 H) 7.38 (d, J = 7.82 Hz, 2 H) 7.47-7.61
(m, 4 H) 7.72 (d, J = 7.43 Hz, 1 H) 8.05 (d, J = 9.00 Hz, 1 H) 8.62
(d, J = 2.35 Hz, 1 H) 8.65 (d, J = 2.35 Hz, 1 H) 5.37 ##STR01450##
(400 MHz, DMSO-d.sub.6) 1.26 (t, J = 7.43 Hz, 3 H) 2.72 (q, J =
7.56 Hz, 2 H) 4.22-4.50 (m, 5 H) 6.76 (d, J = 9.00 Hz, 1 H)
7.18-7.27 (m, 1 H) 7.40 (d, J = 8.22 Hz, 2 H) 7.47-7.61 (m, 4 H)
7.71 (d, J = 7.82 Hz, 1 H) 8.04 (d, J = 9.00 Hz, 1 H) 8.62 (d, J =
2.35 Hz, 1 H) 8.65 (d, J = 2.74 Hz, 1 H) 5.38 ##STR01451## (400
MHz, DMSO-d.sub.6) 3.01 (s, 6 H) 4.17-4.55 (m, 5 H) 6.76 (d, J =
9.00 Hz, 1 H) 6.86 (d, J = 9.00 Hz, 2 H) 7.16-7.25 (m, 1 H)
7.42-7.61 (m, 4 H) 7.70 (d, J = 7.43 Hz, 1 H) 8.02 (d, J = 9.00 Hz,
1 H) 8.51-8.58 (m, 2 H) 5.39 ##STR01452## (400 MHz, DMSO-d.sub.6)
4.28-4.48 (m, 5 H) 6.80 (d, J = 9.00 Hz, 1 H) 7.22-7.30 (m, 1 H)
7.52-7.62 (m, 4 H) 7.74 (d, J = 9.00 Hz, 3 H) 8.09 (d, J = 8.61 Hz,
1 H) 8.66 (d, J = 2.35 Hz, 1 H) 8.72 (d, J = 2.35 Hz, 1 H) 5.40
##STR01453## (400 MHz, DMSO-d.sub.6) 1.33 (d, J = 6.26 Hz, 6 H)
4.20-4.52 (m, 5 H) 4.73 (dt, J = 12.03, 5.92 Hz, 1 H) 6.78 (d, J =
9.00 Hz, 1 H) 7.08 (d, J = 8.61 Hz, 2 H) 7.24 (t, J = 6.85 Hz, 1 H)
7.46-7.62 (m, 4 H) 7.72 (d, J = 8.22 Hz, 1 H) 8.06 (d, J = 9.00 Hz,
1 H) 8.59-8.61 (m, 1H) 8.61-8.63 (m, 1 H) 5.41 ##STR01454## (400
MHz, DMSO-d.sub.6) 1.77 (s, 6 H) 4.23-4.46 (m, 5 H) 6.75 (d, J =
9.00 Hz, 1 H) 7.21 (t, J = 7.24 Hz, 1 H) 7.48-7.59 (m, 2 H)
7.62-7.76 (m, 5 H) 8.03 (d, J = 8.61 Hz, 1 H) 8.65 (d, J = 2.35 Hz,
1 H) 8.69 (d, J = 2.35 Hz, 1 H) 5.42 ##STR01455## (400 MHz,
DMSO-d.sub.6) 2.89-3.02 (m, 4 H) 3.61- 3.75 (m, 4 H) 4.22-4.48 (m,
5 H) 6.74 (d, J = 8.61 Hz, 1 H) 7.17-7.24 (m, 1 H) 7.47-7.61 (m, 2
H) 7.70 (d, J = 7.82 Hz, 1 H) 7.84-7.97 (m, 4 H) 8.02 (d, J = 9.00
Hz, 1 H) 8.69 (d, J = 2.35 Hz, 1 H) 8.75 (d, J = 2.35 Hz, 1 H) 5.43
##STR01456## (400 MHz, DMSO-d.sub.6) 1.41 (d, J = 3.91 Hz, 2 H)
1.57 (d, J = 4.69 Hz, 4 H) 2.99 (t, J = 5.28 Hz, 4 H) 4.20-4.47 (m,
5 H) 6.74 (d, J = 9.00 Hz, 1 H) 7.18- 7.25 (m, 1 H) 7.48-7.58 (m, 2
H) 7.70 (d, J = 7.82 Hz, 1 H) 7.81-7.88 (m, 2 H) 7.88-7.95 (m, 2 H)
8.02 (d, J = 9.00 Hz, 1 H) 8.68 (d, J = 2.35 Hz, 1 H) 8.74 (d, J =
2.35 Hz, 1 H)
##STR01457##
Example 6.1
(R--&
S--)-2-(3-(3-(3-(PYRIDIN-3-YL)PYRROLIDIN-1-YL)PYRAZIN-2-YL)AZETIDIN--
1-YL)QUINOLINE
[0571] To a 3 mL vial was added
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.04000 g,
0.135 mmol), 3-(pyrrolidin-3-yl)pyridine (commerically available at
Array Biopharma, 0.040 g, 0.270 mmol), and triethylamine
(commerically available at Sigma Aldrich, 0.038 ml, 0.270 mmol) in
DMSO (Solvent Volume: 0.449 ml) and the reaction was stirred at
110.degree. C. overnight. Upon completion, the reaction was
filtered into a 24 well plate and purified by reverse phase
purification using the following conditions: (Instrumentation:
MS--Waters SQ; UV--Waters 2487 or Waters PD; Solvents: A: Water
w/0.1% NH.sub.4OH B: Acetonitrile w/0.1% NH.sub.4OH; Column:
Phenomenex Gemini-NX C18 110A 5 um 21.times.100; Flow Rate: 44
mL/min. 10 min Method, variable gradient over 8 mins.)
[0572] The following Table 18A lists compounds of Examples 6.1 to
6.60, which were made analogous to Scheme 6 by using the
appropriate materials and reaction conditions, which are listed in
Table 18B. The NMR data of the Examples are listed in Table
18C.
TABLE-US-00029 TABLE 18A EXAMPLES 6.1 TO 6.60 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (.mu.M) 6.1 ##STR01458##
(R- & S-)-2-(3-(3-(3-(pyridin- 3-yl)pyrrolidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 409.0 0.001 6.2 ##STR01459## (R- &
S-)-2-(3-(3-(3- phenethylpyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 436 0.010 6.3 ##STR01460## (R- & S-)-2-(3-(3-(3-
benzylpyrrolidin-1-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline 422
0.005 6.4 ##STR01461## (R)-N,N-dimethyl-1-(3-(1-
(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyrrolidin-3- amine 375
0.097 6.5 ##STR01462## (R- & S-)-tert-butyl methyl(1-
(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyrrolidin-3-
yl)carbamate 461 0.002 6.6 ##STR01463## (R- &
S-)-N,N-dimethyl-1-(3- (1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3- amine 375 0.061 6.7 ##STR01464##
2-(3-(3-(3- azabicyclo[3.1.0]hexan-3- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 344 0.003 6.8 ##STR01465## (R- & S-)-2-(3-(3-(3-
(phenylsulfonyl)pyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 472 0.008 6.9 ##STR01466## (R- &
S-)-3-methyl-5-(1-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3- yl)-1,2,4-oxadiazole 414 0.001 6.10
##STR01467## (R)-1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)pyrrolidin-3-ol 348 0.007 6.11 ##STR01468## (R- &
S-)-2-(3-(3-(3-(pyridin- 4-yl)pyrrolidin-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 409 0.001 6.12 ##STR01469##
2-(3-(3-(pyrrolidin-1- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 332
0.003 6.13 ##STR01470## (3aR,6aS)-tert-butyl 5-(3-(1-
(quinolin-2-yl)azetidin-3- yl)pyrazin-2- yl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate 473 0.001 6.14 ##STR01471## tert-butyl
5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate 473 0.003 6.15
##STR01472## tert-butyl 4-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)- 1,4-diazepane-1-carboxylate 461.1
0.225 6.16 ##STR01473## (R)-(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)pyrrolidin-3-yl)methanol 362 0.006
6.17 ##STR01474## (R- & S-)-2-(3-(3-(3-
(methylsulfonyl)pyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 410 0.033 6.18 ##STR01475## (S)-(1-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)pyrrolidin-3-yl)methanol 362 0.006
6.19 ##STR01476## (R)-tert-butyl 1-(3-(1-
(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyrrolidin-3-
ylcarbamate 447.0 0.021 6.20 ##STR01477##
(S)-2-(3-(3-(3-fluoropyrrolidin- 1-yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 350.0 0.023 6.21 ##STR01478##
2-(3-(3-(3,3-difluoropyrrolidin- 1-yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 368 0.01575 6.22 ##STR01479##
2-(3-(3-(4-isopropyl-1,4- diazepan-1-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 403 0.655 6.23 ##STR01480##
(1R,5R)-3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-
3-azabicyclo[3.2.2]nonane 386 0.035 6.24 ##STR01481##
2-(3-(3-(azepan-1-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline 360
0.003 6.25 ##STR01482## 2-(3-(3-(4-methyl-1,4-
diazepan-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline 375 0.233 6.26
##STR01483## 3-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)-3-
azabicyclo[3.2.2]nonane 386 0.035 6.27 ##STR01484##
1-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-
1,4-diazepan-1-yl)ethanone 403 0.01607 6.28 ##STR01485## (R- &
S-)-2-(3-(3-(3- phenylpyrrolidin-1-yl)pyrazin-
2-yl)azetidin-1-yl)quinoline 408 0.0050 6.29 ##STR01486##
(3S,4S)-1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)pyrrolidine-3,4-diol 364 0.085 6.30 ##STR01487##
N-(4-methoxybenzyl)-3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-amine 398 0.189 6.31 ##STR01488##
(1R,4R)-5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-
2-oxa-5- azabicyclo[2.2.1]heptane 360 0.01545 6.32 ##STR01489## (R-
& S-)-2-(1-(3-(1-(quinolin 2-yl)azetidin-3-yl)pyrazin-2-
yl)pyrrolidin-3-yl)thiazole 415 0.0871 6.33 ##STR01490##
(S)-(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)pyrrolidin-2-yl)methanol 362 0.01457 6.34 ##STR01491##
((2S,4S)-4-fluoro-1-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-2- yl)methanol 380 0.02989 6.35
##STR01492## (R)-2-(3-(3-(2- (methoxymethyl)pyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 362 0.81150 6.36
##STR01493## 2-(3-(3- (hexahydrocyclopenta[c]pyrrol-
2(1H)-yl)pyrazin-2-yl)azetidin- 1-yl)quinoline 372 0.00396 6.37
##STR01494## (R- & S-)-2-(3-(3-(3- isobutylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 388 0.02193 6.38
##STR01495## 2-(3-(3-(3,3- dimethylpyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 360 0.01275 6.39
##STR01496## (R- & S-)-2-(3-(3-(3- (methoxymethyl)pyrrolidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 376 0.00666 6.40
##STR01497## 2-(3-(3-(4- (trifluoromethyl)piperidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 414 0.0065 6.41
##STR01498## 1-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 371 0.00013 6.42
##STR01499## 2-(3-(3-(4,4-difluoropiperidin-
1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline 382 0.0086 6.43
##STR01500## 4-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)morpholine 348 0.0147 6.44 ##STR01501##
2-(3-(3-(4-fluoropiperidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 364 0.0014 6.45 ##STR01502##
2-(3-(3-(3-methoxyazetidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 348 0.021 6.46 ##STR01503##
2-(3-(3-(3,3-difluoroazetidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 354 0.027 6.47 ##STR01504##
4-methyl-1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidin-4-ol 376 0.0097 6.48 ##STR01505##
1-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)-1H-
pyrazole-4-carbonitrile 354 0.066 6.49 ##STR01506##
2-(3-(3-(4-methyl-1H-pyrazol- 1-yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 343 0.020 6.50 ##STR01507## tert-butyl
(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)azetidin-3-yl)carbamate 433 0.0056 6.51 ##STR01508##
2,2-dimethyl-4-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)morpholine 376 0.006 6.52 ##STR01509## 2-(3-(3-(4-methyl-1H-
imidazol-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline 343 0.005 6.53
##STR01510## 1-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 372 0.0015 6.54 ##STR01511##
(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-
1H-pyrazol-4-yl)methanol 359 0.091 6.55 ##STR01512##
(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-
1H-imidazol-4-yl)methanol 359 0.270 6.56 ##STR01513##
1-methyl-4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperazin-2-one 375 0.0022 6.57 ##STR01514##
N-(2,6-dimethylphenyl)-1-(3- (1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-3- carboxamide 493 0.010 6.58
##STR01515## (S)-tert-butyl (1-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidin-3- yl)carbamate 461 0.013 6.59
##STR01516## (4-(cyclopropylmethyl)-1-(3-
(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)piperidin-4-
yl)methanol 430 0.004 6.60 ##STR01517##
2-(3-(3-((1R,5S)-8-methyl-3,8- diazabicyclo[3.2.1]octan-3-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline 387 >10
TABLE-US-00030 TABLE 18B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 6.1 TO 6.60. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Key Starting Purification Ex. # Material(s) Key Starting
Material(s) Reaction Condition Condition* 6.1 ##STR01518##
##STR01519## TEA, DMSO, 110.degree. C. A 6.2 ##STR01520##
##STR01521## TEA, DMSO, 110.degree. C. A 6.3 ##STR01522##
##STR01523## TEA, DMSO, 110.degree. C. A 6.4 ##STR01524##
##STR01525## TEA, DMSO, 110.degree. C. A 6.5 ##STR01526##
##STR01527## TEA, DMSO, 110.degree. C. A 6.6 ##STR01528##
##STR01529## TEA, DMSO, 110.degree. C. A 6.7 ##STR01530##
##STR01531## TEA, DMSO, 110.degree. C. A 6.8 ##STR01532##
##STR01533## TEA, DMSO, 110.degree. C. A 6.9 ##STR01534##
##STR01535## TEA, DMSO, 110.degree. C. A 6.10 ##STR01536##
##STR01537## TEA, DMSO, 110.degree. C. A 6.11 ##STR01538##
##STR01539## TEA, DMSO, 110.degree. C. A 6.12 ##STR01540##
##STR01541## TEA, DMSO, 110.degree. C. A 6.13 ##STR01542##
##STR01543## TEA, DMSO, 110.degree. C. A 6.14 ##STR01544##
##STR01545## TEA, DMSO, 110.degree. C. A 6.15 ##STR01546##
##STR01547## TEA, DMSO, 110.degree. C. A 6.16 ##STR01548##
##STR01549## TEA, DMSO, 110.degree. C. D 6.17 ##STR01550##
##STR01551## TEA, DMSO, 110.degree. C. A 6.18 ##STR01552##
##STR01553## TEA, DMSO, 110.degree. C. A 6.19 ##STR01554##
##STR01555## TEA, DMSO, 110.degree. C. A 6.20 ##STR01556##
##STR01557## K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.21
##STR01558## ##STR01559## K.sub.2CO.sub.3, DMSO, 110.degree. C. B
6.22 ##STR01560## ##STR01561## K.sub.2CO.sub.3, DMSO, 110.degree.
C. A 6.23 ##STR01562## ##STR01563## K.sub.2CO.sub.3, DMSO,
110.degree. C. A 6.24 ##STR01564## ##STR01565## K.sub.2CO.sub.3,
DMSO, 110.degree. C. A 6.25 ##STR01566## ##STR01567##
K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.26 ##STR01568##
##STR01569## K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.27
##STR01570## ##STR01571## K.sub.2CO.sub.3, DMSO, 110.degree. C. A
6.28 ##STR01572## ##STR01573## K.sub.2CO.sub.3, DMSO, 110.degree.
C. A 6.29 ##STR01574## ##STR01575## K.sub.2CO.sub.3, DMSO,
110.degree. C. A 6.30 ##STR01576## ##STR01577## K.sub.2CO.sub.3,
DMSO, 110.degree. C. C 6.31 ##STR01578## ##STR01579##
K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.32 ##STR01580##
##STR01581## K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.33
##STR01582## ##STR01583## K.sub.2CO.sub.3, DMSO, 110.degree. C. A
6.34 ##STR01584## ##STR01585## K.sub.2CO.sub.3, DMSO, 110.degree.
C. A 6.35 ##STR01586## ##STR01587## K.sub.2CO.sub.3, DMSO,
110.degree. C. A 6.36 ##STR01588## ##STR01589## K.sub.2CO.sub.3,
DMSO, 110.degree. C. A 6.37 ##STR01590## ##STR01591##
K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.38 ##STR01592##
##STR01593## K.sub.2CO.sub.3, DMSO, 110.degree. C. A 6.39
##STR01594## ##STR01595## K.sub.2CO.sub.3, DMSO, 110.degree. C. A
6.40 ##STR01596## ##STR01597## TEA, DMSO, 110.degree. C. B 6.41
##STR01598## ##STR01599## TEA, DMSO, 110.degree. C. B 6.42
##STR01600## ##STR01601## TEA, DMSO, 110.degree. C. B 6.43
##STR01602## ##STR01603## TEA, DMSO, 110.degree. C. B 6.44
##STR01604## ##STR01605## TEA, DMSO, 110.degree. C. B 6.45
##STR01606## ##STR01607## TEA, DMSO, 110.degree. C. B 6.46
##STR01608## ##STR01609## TEA, DMSO, 110.degree. C. B 6.47
##STR01610## ##STR01611## 1. HCl 2. Et.sub.3N, DMSO, 110.degree. C.
B 6.48 ##STR01612## ##STR01613## Cs.sub.2CO.sub.3, DMSO,
110.degree. C. B 6.49 ##STR01614## ##STR01615## Cs.sub.2CO.sub.3,
DMSO, 110.degree. C. B 6.50 ##STR01616## ##STR01617## TEA, DMSO,
110.degree. C. B 6.51 ##STR01618## ##STR01619## TEA, DMSO,
110.degree. C. B 6.52 ##STR01620## ##STR01621## Cs.sub.2CO.sub.3,
DMSO, 110.degree. C. B 6.53 ##STR01622## ##STR01623## TEA, DMSO,
110.degree. C. B 6.54 ##STR01624## ##STR01625## allylchloro[1,3-
bis(2,6-di-i- propylphenyl)-4,5- dihydroimidazol-2-
ylidene]palladium(II), Cs.sub.2CO.sub.3, Dioxane, 135.degree. C.,
.mu.W, 30 min E 6.55 ##STR01626## ##STR01627## TEA, DMSO,
110.degree. C. B 6.56 ##STR01628## ##STR01629## TEA, DMSO,
110.degree. C. B 6.57 ##STR01630## ##STR01631## TEA, DMSO,
110.degree. C. B 6.58 ##STR01632## ##STR01633## TEA, DMSO,
110.degree. C. B 6.59 ##STR01634## ##STR01635## TEA, DMSO,
110.degree. C. B 6.60 ##STR01636## ##STR01637## K.sub.2CO.sub.3,
DMSO, 110.degree. C. C *Purification Conditions: Method A--reverse
phase purification using the following conditions:
(Instrumentation: MS--Waters SQ; UV--Waters 2487 or Waters PD;
Solvents: A: Water w/ 0.1% NH.sub.4OH B: Acetonitrile w/ 0.1%
NH.sub.4OH; Column. Phenomenex Gemini-NX C18 110A 5 um 21 .times.
100; Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8
mins). Method B--purification by silica gel chromatography:
(Biotage 50 g SNAP HP-silica column, eluting with a gradient of
EtOAc in hexane). Method C--reverse-phase HPLC (Gilson; Gemini-NX
10 m C18 110A AXIA, 100 .times. 50 mm column) eluting with 0.1%
TFA-H.sub.2O:0.1% TFA CH.sub.3CN (9:1 .fwdarw. 1:9). The fractions
containing the desired product were combined and concentrated in
vacuo. The residue was dissolved in DCM and loaded onto a
Si-Carbonate cartridge (Silicycle) eluting with DCM. Method
D--Product precipitated out of solution. Method E--purification by
silica gel chromatography eluting with a gradient of MeOH in
DCM.
TABLE-US-00031 TABLE 18C 1H NMR .delta. (PPM) DATA FOR EXAMPLES 6.1
TO 6.60 Ex. # Structure NMR 6.1 ##STR01638## (400 MHz,
DMSO-d.sub.6) 2.09 (quin, J = 9.88 Hz, 1 H) 2.38 (td, J = 5.87,
2.35 Hz, 1 H) 3.44-3.56 (m, 1 H) 3.55-3.66 (m, 2 H) 3.76 (td, J =
9.78, 6.65 Hz, 1 H) 3.85 (dd, J = 9.78, 7.43 Hz, 1 H) 4.27-4.49 (m,
5 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.16-7.25 (m, 1 H) 7.39 (dd, J =
7.82, 4.69 Hz, 1 H) 7.46-7.59 (m, 2 H) 7.70 (d, J = 7.82 Hz, 1 H)
7.77-7.85 (m, 1 H) 7.93-8.06 (m, 3 H) 8.48 (dd, J = 4.69, 1.56 Hz,
1 H) 8.60 (d, J = 2.35 Hz, 1 H) 6.2 ##STR01639## (400 MHz,
DMSO-d.sub.6) 1.54-1.68 (m, 1 H) 1.76 (q, J = 6.91 Hz, 2 H)
2.02-2.24 (m, 2 H) 2.68 (t, J = 7.63 Hz, 2 H) 3.24 (t, J = 9.19 Hz,
1 H) 3.42-3.60 (m, 3 H) 4.34 (s, 4 H) 4.45 (s, 1 H) 6.78 (d, J =
9.00 Hz, 1 H) 7.13-7.34 (m, 6 H) 7.47-7.59 (m, 2 H) 7.71 (d, J =
8.22 Hz, 1 H) 7.91 (d, J = 2.74 Hz, 1 H) 7.97 (d, J = 2.74 Hz, 1 H)
8.03 (d, J = 9.00 Hz, 1 H) 6.3 ##STR01640## (400 MHz, DMSO-d.sub.6)
1.60-1.72 (m, 1 H) 1.99 (dd, J = 10.56, 5.48 Hz, 1 H) 2.75 (dd, J =
7.24, 2.54 Hz, 2 H) 3.23-3.30 (m, 1 H) 3.45 (dd, J = 10.17, 7.04
Hz, 1 H) 3.50-3.59 (m, 2 H) 4.25-4.44 (m, 5 H) 6.77 (d, J = 8.61
Hz, 1 H) 7.15-7.25 (m, 2 H) 7.24-7.29 (m, 2 H) 7.29- 7.36 (m, 2 H)
7.47-7.60 (m, 2 H) 7.70 (d, J = 7.82 Hz, 1 H) 7.90 (d, J = 2.35 Hz,
1 H) 7.96 (d, J = 2.74 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1 H) 6.4
##STR01641## (400 MHz, DMSO-d.sub.6) 2.02-2.18 (m, 1 H) 2.38 (qd, J
= 6.00, 3.91 Hz, 1 H) 2.45-2.54 (m, 3 H) 3.45-3.58 (m, 1 H)
3.57-3.67 (m, 2 H) 3.76 (td, J = 9.78, 6.65 Hz, 1 H) 3.86 (dd, J =
9.78, 7.43 Hz, 1 H) 4.30-4.50 (m, 5 H) 6.78 (d, J = 9.00 Hz, 1 H)
7.16-7.25 (m, 1 H) 7.39 (dd, J = 7.82, 4.69 Hz, 1 H) 7.47-7.59 (m,
2 H) 7.70 (d, J = 7.82 Hz, 1 H) 7.82 (d, J = 7.82 Hz, 1 H)
7.95-8.06 (m, 3 H) 8.48 (dd, J = 4.69, 1.56 Hz, 1 H) 8.61 (d, J =
2.35 Hz, 1 H) 6.5 ##STR01642## (400 MHz, DMSO-d.sub.6) 1.43 (s, 8
H) 2.01-2.13 (m, 2 H) 2.47-2.54 (m, 3 H) 2.81 (s, 3 H) 3.46-3.60
(m, 4 H) 4.29-4.40 (m, 4 H) 4.40-4.49 (m, 1 H) 6.79 (d, J = 8.61
Hz, 1 H) 7.16-7.25 (m, 1 H) 7.47-7.60 (m, 2 H) 7.71 (d, J = 7.82
Hz, 1 H) 7.95-8.06 (m, 2 H) 6.6 ##STR01643## (400 MHz,
DMSO-d.sub.6) 1.76 (quin, J = 10.07 Hz, 1 H) 2.07-2.17 (m, 1 H)
2.22 (s, 5 H) 2.64-2.77 (m, 1 H) 3.17 (br. s., 1 H) 3.41 (s, 1 H)
3.44-3.67 (m, 3 H) 4.35 (dt, J = 8.70, 4.45 Hz, 3 H) 4.41-4.51 (m,
1 H) 6.79 (d, J = 9.00 Hz, 1 H) 7.17-7.25 (m, 1 H) 7.47-7.60 (m, 2
H) 7.71 (d, J = 7.43 Hz, 1 H) 7.96 (dd, J = 18.78, 2.74 Hz, 2 H)
8.03 (d, J = 9.00 Hz, 1 H) 6.7 ##STR01644## (400 MHz, DMSO-d.sub.6)
0.30 (q, J = 4.30 Hz, 1 H) 0.66 (td, J = 7.63, 4.69 Hz, 1 H)
1.59-1.70 (m, 2 H) 3.46 (d, J = 10.17 Hz, 2 H) 3.73 (d, J = 10.17
Hz, 2 H) 4.23-4.35 (m, 3 H) 4.36-4.46 (m, 2 H) 6.78 (d, J = 9.00
Hz, 1 H) 7.17-7.26 (m, 1 H) 7.48-7.60 (m, 2 H) 7.71 (d, J = 7.43
Hz, 1 H) 7.97 (d, J = 2.35 Hz, 1 H) 8.00 (d, J = 2.35 Hz, 1 H) 8.03
(d, J = 9.00 Hz, 1 H) 6.8 ##STR01645## (400 MHz, DMSO-d.sub.6)
2.21-2.37 (m, 2 H) 3.46-3.61 (m, 2 H) 3.63-3.72 (m, 1 H) 3.80 (dd,
J = 11.74, 5.87 Hz, 1H) 4.18-4.40 (m, 6 H) 6.77 (d, J = 9.00 Hz, 1
H) 7.18- 7.26 (m, 1 H) 7.48-7.56 (m, 1 H) 7.55-7.61 (m, 1 H)
7.67-7.75 (m, 3 H) 7.77-7.86 (m, 1 H) 7.93-7.99 (m, 2 H) 8.00-8.07
(m, 3 H) 6.9 ##STR01646## (400 MHz, DMSO-d.sub.6) 2.23-2.35 (m, 1
H) 2.38 (s, 3 H) 2.43-2.51 (m, 1 H) 3.61-3.74 (m, 2 H) 3.79-3.88
(m, 1 H) 3.88-3.99 (m, 2 H) 4.33-4.48 (m, 5 H) 6.81 (d, J = 9.00
Hz, 1 H) 7.24 (ddd, J = 7.92, 6.55, 1.56 Hz, 1 H) 7.51-7.63 (m, 2
H) 7.74 (d, J = 7.43 Hz, 1 H) 8.02- 8.04 (m, 1 H) 8.04-8.08 (m, 2
H) 6.10 ##STR01647## (400 MHz, DMSO-d.sub.6) 1.88 (d, J = 3.52 Hz,
1 H) 1.92- 2.04 (m, 1 H) 3.25 (d, J = 10.95 Hz, 1 H) 3.40-3.50 (m,
1 H) 3.64-3.76 (m, 2 H) 4.29-4.42 (m, 5 H) 4.42-4.51 (m, 1 H) 4.97
(d, J = 3.13 Hz, 1 H) 6.79 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 7.43
Hz, 1 H) 7.48-7.60 (m, 2 H) 7.71 (d, J = 7.43 Hz, 1 H) 7.91 (d, J =
2.74 Hz, 1 H) 7.97 (d, J = 2.35 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1 H)
6.11 ##STR01648## (400 MHz, DMSO-d.sub.6) 1.97-2.13 (m, 1 H) 2.38
(dq, J = 8.95, 6.15 Hz, 1 H) 3.44-3.56 (m, 1 H) 3.56-3.68 (m, 1 H)
3.74 (td, J = 9.59, 7.04 Hz, 1 H) 3.85 (dd, J = 9.98, 7.24 Hz, 1 H)
4.29-4.49 (m, 1 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.16-7.25 (m, 1 H)
7.36-7.44 (m, 1 H) 7.46-7.60 (m, 1 H) 7.70 (d, J = 7.04 Hz, 1 H)
7.97 (d, J = 2.74 Hz, 1 H) 7.99-8.06 (m, 1 H) 8.49-8.56 (m, 1 H)
6.12 ##STR01649## (400 MHz, DMSO-d.sub.6) 1.91 (dt, J = 6.16, 3.37
Hz, 1 H) 3.43-3.53 (m, 1 H) 4.31-4.44 (m, 1 H) 6.78 (d, J = 9.00
Hz, 1 H) 7.17-7.24 (m, 1 H) 7.48-7.59 (m, 1 H) 7.70 (d, J = 7.82
Hz, 1 H) 7.91 (d, J = 2.35 Hz, 1 H) 7.97 (d, J = 2.35 Hz, 1 H) 8.03
(d, J = 9.00 Hz, 1 H) 6.13 ##STR01650## (400 MHz, DMSO-d.sub.6)
1.41 (s, 9 H) 2.95 (br. s., 2 H) 3.17 (d, J = 5.09 Hz, 1 H) 3.40
(d, J = 3.91 Hz, 2 H) 3.52 (br. s., 2 H) 3.68 (dd, J = 10.37, 7.24
Hz, 2 H) 4.10 (q, J = 5.09 Hz, 1 H) 4.30-4.46 (m, 5 H) 6.77 (d, J =
9.00 Hz, 1 H) 7.16-7.26 (m, 1 H) 7.46-7.59 (m, 2 H) 7.70 (d, J =
7.82 Hz, 1 H) 7.93-8.06 (m, 3 H) 6.14 ##STR01651## (400 MHz,
DMSO-d.sub.6) 1.41 (s, 8 H) 2.95 (br. s., 2 H) 3.17 (d, J = 5.09
Hz, 1 H) 3.23 (d, J = 10.17 Hz, 2 H) 3.40 (d, J = 3.91 Hz, 1 H)
3.52 (br. s., 2 H) 3.68 (dd, J = 10.56, 7.43 Hz, 2 H) 4.10 (q, J =
4.96 Hz, 1 H) 4.31-4.47 (m, 5 H) 6.77 (d, J = 9.00 Hz, 1 H)
7.17-7.25 (m, 1 H) 7.47-7.59 (m, 2 H) 7.71 (d, J = 7.43 Hz, 1 H)
7.95-8.06 (m, 3 H) 6.15 ##STR01652## (400 MHz, DMSO-d.sub.6) 1.36
(d, J = 19.56 Hz, 9 H) 1.86-1.97 (m, 2 H) 3.42 (dd, J = 11.35, 5.67
Hz, 4 H) 3.53 (br. s., 4 H) 4.20-4.35 (m, 3 H) 4.42-4.50 (m, 2 H)
6.81 (d, J = 8.80 Hz, 1 H) 7.19-7.27 (m, 1 H) 7.55 (dd, J = 6.65,
1.37 Hz, 1 H) 7.58 (s, 1 H) 7.73 (d, J = 7.43 Hz, 1 H) 8.02-8.12
(m, 3 H) 6.16 ##STR01653## (400 MHz, DMSO-d.sub.6) 1.69 (dq, J =
12.18, 7.81 Hz, 1 H) 1.99 (dq, J = 12.10, 6.01 Hz, 1 H) 2.29-2.42
(m, 1H) 3.32-3.37 (m, 1 H) 3.38-3.56 (m, 5 H) 4.29- 4.38 (m, 4 H)
4.39-4.47 (m, 1 H) 4.70 (t, J = 5.38 Hz, 1 H) 6.78 (d, J = 8.80 Hz,
1 H) 7.16-7.25 (m, 1 H) 7.47-7.54 (m, 1 H) 7.54-7.59 (m, 1 H) 7.70
(d, J = 7.63 Hz, 1 H) 7.91 (d, J = 2.54 Hz, 1 H) 7.97 (d, J = 2.54
Hz, 1 H) 8.03 (d, J = 8.80 Hz, 1 H) 6.17 ##STR01654## (400 MHz,
DMSO-d.sub.6) 2.34-2.45 (m, 1 H) 2.95 (s, 3 H) 3.51-3.61 (m, 1 H)
3.63-3.73 (m, 1 H) 3.80- 3.92 (m, 2 H) 4.29-4.40 (m, 1 H) 4.40-4.53
(m, 3 H) 6.74 (d, J = 9.00 Hz, 1 H) 7.21-7.29 (m, 1 H) 7.52-7.59
(m, 1 H) 7.60-7.65 (m, 1 H) 7.66-7.72 (m, 1 H) 7.96-8.05 (m, 2 H)
6.18 ##STR01655## (400 MHz, ACETONITRILE-d.sub.3) 1.66-1.79 (m, 1
H) 1.96-2.09 (m, 1 H) 2.43 (dt, J = 14.23, 7.07 Hz, 1 H) 3.35 (dd,
J = 10.17, 7.04 Hz, 1 H) 3.48-3.61 (m, 3 H) 4.31-4.55 (m, 3 H) 6.74
(d, J = 9.00 Hz, 1 H) 7.21-7.30 (m, 1 H) 7.52-7.59 (m, 1 H)
7.60-7.66 (m, 1 H) 7.66-7.73 (m, 1 H) 7.89 (d, J = 2.54 Hz, 1 H)
7.93 (d, J = 2.54 Hz, 1 H) 7.99 (d, J = 9.00 Hz, 1 H) 6.19
##STR01656## (400 MHz, DMSO-d.sub.6) 1.41 (s, 9 H) 1.86 (dq, J =
12.47, 6.41 Hz, 1 H) 2.09 (dq, J = 12.62, 6.49 Hz, 1 H) 3.17 (d, J
= 5.09 Hz, 1 H) 3.45-3.55 (m, 1 H) 3.55-3.62 (m, 1 H) 3.62-3.71 (m,
1 H) 4.03-4.14 (m, 1 H) 4.28-4.45 (m, 5 H) 6.78 (d, J = 9.00 Hz, 1
H) 7.14-7.25 (m, 2 H) 7.48-7.60 (m, 2 H) 7.71 (d, J = 7.43 Hz, 1 H)
7.91-8.00 (m, 2 H) 8.04 (d, J = 9.00 Hz, 1 H) 6.20 ##STR01657##
(400 MHz, DMSO-d.sub.6) 1.99-2.30 (m, 2 H) 3.48- 3.64 (m, 2 H)
3.71-3.96 (m, 2 H) 4.30-4.42 (m, 4 H) 4.45-4.55 (m, 1 H) 5.32-5.52
(m, 1 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.17-7.25 (m, 1 H) 7.48-7.60
(m, 2 H) 7.70 (d, J = 7.43 Hz, 1 H) 7.95-8.06 (m, 3 H) 6.21
##STR01658## (400 MHz, ACETONITRILE-d.sub.3) (tt, J = 14.08, 7.24
Hz, 2 H) 3.75 (t, J = 7.24 Hz, 2 H) 3.89 (t, J = 13.20 Hz, 2 H)
4.27-4.38 (m, 1 H) 4.40- 4.54 (m, 4 H) 6.77 (d, J = 8.80 Hz, 1 H)
7.22-7.30 (m, 1 H) 7.53-7.60 (m, 1 H) 7.60-7.65 (m, 1 H) 7.67-7.74
(m, 1 H) 8.00 (d, J = 8.80 Hz, 1 H) 8.07 (dd, J = 16.63, 2.54 Hz, 2
H) 6.22 ##STR01659## (400 MHz, DMSO-d.sub.6) 0.96 (d, J = 6.65 Hz,
6 H) 1.79-1.91 (m, 2 H) 2.45-2.54 (m, 1 H) 2.58-2.65 (m, 2 H)
2.70-2.77 (m, 2 H) 2.86 (quin, J = 6.55 Hz, 1 H) 3.42- 3.50 (m, 4
H) 4.16-4.33 (m, 3 H) 4.37-4.47 (m, 2 H) 6.78 (d, J = 8.61 Hz, 1 H)
7.16-7.26 (m, 1 H) 7.46-7.60 (m, 2 H) 7.70 (d, J = 7.43 Hz, 1 H)
7.98-8.06 (m, 3 H) 6.23 ##STR01660## (400 MHz, DMSO-d.sub.6) 1.67
(d, J = 9.78 Hz, 1 H) 1.83 (d, J = 7.82 Hz, 1 H) 2.11 (br. s., 1 H)
3.31 (d, J = 4.69 Hz, 1 H) 4.26-4.33 (m, 1 H) 4.32-4.42 (m, 1 H)
4.43-4.51 (m, 1 H) 6.79 (d, J = 9.00 Hz, 1 H) 7.17-7.25 (m, 1 H)
7.48-7.60 (m, 1 H) 7.71 (d, J = 7.43 Hz, 1 H) 8.04 (d, J = 9.00 Hz,
1 H) 8.11 (d, J = 2.35 Hz, 1 H) 8.15 (d, J = 2.35 Hz, 1 H) 6.24
##STR01661## (400 MHz, DMSO-d.sub.6) 1.53-1.62 (m, 4 H) 1.79 (br.
s., 4 H) 3.42-3.48 (m, 5 H) 4.20-4.31 (m, 1 H) 4.39 (t, J = 7.04
Hz, 2 H) 4.46-4.55 (m, 2 H) 6.85 (d, J = 9.00 Hz, 1 H) 7.28 (t, J =
6.85 Hz, 1 H) 7.54-7.65 (m, 2 H) 7.76 (d, J = 7.82 Hz, 1 H) 8.03
(q, J = 2.35 Hz, 2 H) 8.12 (d, J = 9.00 Hz, 1 H) 6.25 ##STR01662##
(400 MHz, DMSO-d.sub.6) 1.89-2.01 (m, 1 H) 2.35 (s, 1 H) 2.60-2.69
(m, 1 H) 2.80 (d, J = 3.52 Hz, 1 H) 3.48 (br. s., 2 H) 3.50-3.56
(m, 1 H) 4.18-4.34 (m, 1 H) 4.37-4.47 (m, 1 H) 6.78 (d, J = 8.61
Hz, 1 H) 7.17-7.26 (m, 1 H) 7.47-7.60 (m, 1 H) 7.71 (d, J = 7.43
Hz, 1 H) 7.99-8.07 (m, 1 H) 6.26 ##STR01663## (400 MHz,
DMSO-d.sub.6) 1.66 (d, J = 9.78 Hz, 1 H) 1.83 (d, J = 7.43 Hz, 1 H)
2.11 (br. s., 1 H) 3.31 (d, J = 4.30 Hz, 1 H) 4.26-4.33 (m, 1 H)
4.33-4.42 (m, 1 H) 4.43-4.52 (m, 1 H) 6.79 (d, J = 9.00 Hz, 1 H)
7.18-7.26 (m, 1 H) 7.48-7.61 (m, 1 H) 7.71 (d, J = 7.82 Hz, 1 H)
8.04 (d, J = 9.00 Hz, 1 H) 8.11 (d, J = 2.35 Hz, 1 H) 8.15 (d, J =
2.35 Hz, 1 H) 6.27 ##STR01664## (400 MHz, DMSO-d.sub.6) 1.77-1.88
(m, 1 H) 1.96 (s, 2 H) 3.12-3.30 (m, 5 H) 3.40-3.61 (m, 6 H) 3.66
(br. s., 1 H) 4.18-4.36 (m, 2 H) 4.41-4.52 (m, 1 H) 6.76-6.84 (m, 1
H) 7.23 (t, J = 7.43 Hz, 1 H) 7.48-7.62 (m, 1 H) 7.72 (d, J = 7.82
Hz, 1 H) 8.01- 8.14 (m, 2 H) 6.28 ##STR01665## (400 MHz,
DMSO-d.sub.6) 2.05 (quin, J = 9.98 Hz, 1 H) 2.34 (qd, J = 5.93,
4.11 Hz, 1 H) 3.40-3.52 (m, 1 H) 3.53- 3.65 (m, 2 H) 3.68-3.86 (m,
2 H) 4.29-4.49 (m, 5 H) 6.77 (d, J = 8.61 Hz, 1 H) 7.16-7.29 (m, 2
H) 7.30-7.41 (m, 4 H) 7.47-7.59 (m, 2 H) 7.70 (d, J = 7.43 Hz, 1 H)
7.91-8.06 (m, 3 H) 6.29 ##STR01666## (400 MHz, DMSO-d.sub.6) 3.22
(d, J = 11.35 Hz, 2 H) 3.85 (dd, J = 11.15, 3.72 Hz, 2 H) 4.02 (br.
s., 2 H) 4.26- 4.42 (m, 4 H) 4.50 (t, J = 6.06 Hz, 1 H) .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 5.15 (d, J = 2.35 Hz, 2 H) 6.78 (d,
J = 9.00 Hz, 1 H) 7.16-7.25 (m, 1 H) 7.48-7.55 (m, 1 H) 7.55-7.60
(m, 1 H) 7.71 (d, J = 7.82 Hz, 1 H) 7.90 (d, J = 2.35 Hz, 1 H) 7.96
(d, J = 2.74 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1 H) 6.30 ##STR01667##
(400 MHz, DMSO-d.sub.6) 3.74 (s, 3 H) 4.18-4.27 (m, 1 H) 4.28-4.36
(m, 2 H) 4.47-4.57 (m, 3 H) 6.82 (d, J = 8.80 Hz, 1 H) 6.89 (d, J =
8.61 Hz, 2 H) 7.06 (t, J = 5.97 Hz, 1 H) 7.19-7.31 (m, 3 H)
7.50-7.57 (m, 1 H) 7.57-7.62 (m, 1 H) 7.69-7.76 (m, 2 H) 7.88 (d, J
= 2.74 Hz, 1 H) 8.05 (d, J = 8.80 Hz, 1 H) 6.31 ##STR01668## (400
MHz, DMSO-d.sub.6) 1.81-1.88 (m, 1 H) 1.88-1.94 (m, 1 H) 3.21 (d, J
= 9.39 Hz, 1 H) 3.73 (dd, J = 9.19, 1.37 Hz, 1 H) 3.80 (dd, J =
7.63, 1.37 Hz, 1 H) 3.86-.sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 3.92 (m, 1 H) 4.17- 4.27 (m, 1 H) 4.28-4.39 (m, 3 H)
4.43-4.51 (m, 1 H) 4.63 (s, 1 H) 4.69 (s, 1 H) 6.78 (d, J = 9.00
Hz, 1 H) 7.17- 7.25 (m, 1 H) 7.48-7.60 (m, 2 H) 7.70 (d, J = 7.43
Hz, 1 H) 7.98-8.06 (m, 3 H) 6.32 ##STR01669## (400 MHz,
DMSO-d.sub.6) 1.92-2.11 (m, 3 H) 3.40 (dd, J = 8.61, 3.52 Hz, 2 H)
3.94-4.04 (m, 1 H) 4.36- 4.48 (m, 4 H) 4.50-4.58 (m, 1 H) 5.68 (t,
J = 7.04 Hz, 1 H) 6.80 (d, J = 9.00 Hz, 1 H) 7.17-7.25 (m, 1 H)
7.48 (d, J = 3.13 Hz, 1 H) 7.50-7.56 (m, 1 H) 7.56-7.61 (m, 1 H)
7.68 (d, J = 3.13 Hz, 1 H) 7.71 (d, J = 7.04 Hz, 1 H) 7.98 (d, J =
2.74 Hz, 1 H) 8.02-8.08 (m, 2 H) 6.33 ##STR01670## (400 MHz,
DMSO-d.sub.6) 1.66-1.81 (m, 1 H) 1.88 (d, J = 7.43 Hz, 1 H) 1.94
(ddd, J = 13.89, 7.04, 3.33 Hz, 1 H) 2.00-2.10 (m, 1 H) 3.21 (t, J
= 7.24 Hz, 1 H) 3.47-3.56 (m, 1 H) 3.65-3.76 (m, 1 H) 4.25-4.37 (m,
5 H) 4.47-4.56 (m, 1 H) 4.62 (t, J = 5.67 Hz, 1 H) 6.77 (d, J =
9.00 Hz, 1 H) 7.16-7.24 (m, 1 H) 7.52 (dd, J = 6.85, 1.37 Hz, 1 H)
7.54-7.59 (m, 1 H) 7.70 (d, J = 7.43 Hz, 1 H) 7.94-7.97 (m, 1 H)
7.97- 8.00 (m, 1 H) 8.02 (d, J = 9.00 Hz, 1 H) 6.34 ##STR01671##
(400 MHz, DMSO-d.sub.6) 2.17-2.38 (m, 2 H) 3.33- 3.40 (m, 1 H)
3.47-3.63 (m, 2H) 3.95 (t, J = 13.11 Hz, 1 H) 4.26-4.41 (m, 3 H)
4.45-4.57 (m, 2 H) 4.77 (t, J = 5.48 Hz, 1 H) 5.27-5.48 (m, 1 H)
6.78 (d, J = 9.00 Hz, 1 H) 7.22 (t, J = 7.24 Hz, 1 H) 7.53 (d, J =
6.65 Hz, 1 H) 7.55-7.61 (m, 1 H) 7.71 (d, J = 7.82 Hz, 1 H)
8.00-8.09 (m, 2 H) 6.35 ##STR01672## (400 MHz, DMSO-d.sub.6) ppm
1.67-1.86 (m, 2 H) 1.90-2.00 (m, 1 H) 2.05-2.15 (m, 1 H) 3.15-3.26
(m, 4 H) 3.47 (dd, J = 9.39, 3.91 Hz, 1 H) 3.65-3.75 (m, 1 H)
4.22-4.36 (m, 4 H) 4.44 (dd, J = 6.85, 4.11 Hz, 1 H) 4.47-4.56 (m,
1 H) 6.76 (d, J = 9.00 Hz, 1 H) 7.17-7.24 (m, 1 H) 7.47-7.54 (m, 1
H) 7.55 (s, 1 H) 7.70 (d, J = 7.82 Hz, 1 H) 7.96-8.06 (m, 2 H) 6.36
##STR01673## (400 MHz, DMSO-d.sub.6) 1.45-1.62 (m, 1 H) 1.68-1.84
(m, 1 H) 2.72 (br. s., 1 H) 3.15 (dd, J = 10.17, 3.52 Hz, 1 H) 3.41
(br. s., 1 H) 3.55 (dd, J = 10.76, 7.63 Hz, 1 H) 4.33 (d, J = 2.35
Hz, 2 H) 4.44 (s, 1 H) 6.79 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 7.04
Hz, 1 H) 7.48-7.59 (m, 1 H) 7.71 (d, J = 7.82 Hz, 1 H) 7.97-8.06
(m, 2 H) 6.37 ##STR01674## (400 MHz, DMSO-d.sub.6) 0.92 (dd, J =
6.46, 2.93 Hz, 4 H) 1.33 (t, J = 6.94 Hz, 1 H) 1.52 (quin, J = 9.93
Hz, 1 H) 1.58-1.70 (m, 1 H) 2.01-2.12 (m, 1 H) 2.19- 2.31 (m, 1 H)
3.13-3.22 (m, 1 H) 3.40-3.49 (m, 1 H) 3.49-3.64 (m, 1 H) 4.29-4.39
(m, 3 H) 4.45 (s, 1 H) 6.78 (d, J = 8.80 Hz, 1 H) 7.21 (t, J = 6.75
Hz, 1 H) 7.47-7.60 (m, 1 H) 7.70 (d, J = 7.82 Hz, 1 H) 7.91 (d, J =
2.35 Hz, 1 H) 7.96 (d, J = 2.35 Hz, 1 H) 8.03 (d, J = 8.80 Hz, 1 H)
6.38 ##STR01675## (400 MHz, DMSO-d.sub.6) 1.11 (s, 5 H) 1.73 (t, J
= 7.04 Hz, 2 H) 3.24 (s, 2 H) 3.59 (t, J = 6.85 Hz, 2 H) 4.30-4.45
(m, 5 H)
6.78 (d, J = 9.00 Hz, 1 H) 7.17-7.25 (m, 1 H) 7.47-7.60 (m, 2 H)
7.70 (d, J = 7.82 Hz, 1 H) 7.90 (d, J = 2.74 Hz, 1 H) 7.96 (d, J =
2.35 Hz, 1 H) 8.03 (d, J = 8.61 Hz, 1 H) 6.39 ##STR01676## (400
MHz, DMSO-d.sub.6) 1.62-1.74 (m, 1 H) 2.02 (dd, J = 11.74, 5.09 Hz,
1 H) 3.25-3.32 (m, 4 H) 3.37-3.43 (m, 2 H) 3.46-3.59 (m, 3 H)
4.30-4.46 (m, 5 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.16-7.24 (m, 1 H)
7.48-7.60 (m, 2 H) 7.70 (d, J = 7.82 Hz, 1 H) 7.92 (d, J = 2.35 Hz,
1 H) 7.97 (d, J = 2.74 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1 H) 6.40
##STR01677## (300 MHz, MeOH) 8.22 (1 H, d, J = 2.6 Hz), 8.15 (1 H,
d, J = 2.5 Hz), 8.01 (1 H, d, J = 8.9 Hz), 7.64-7.74 (2 H, m), 7.55
(1 H, td, J = 7.7, 1.4 Hz), 7.18-7.30 (1 H, m), 6.77 (1 H, d, J =
8.9 Hz), 4.54-4.67 (2 H, m), 4.38-4.49 (3 H, m), 3.57 (2 H, d, J =
12.9 Hz), 2.76-3.03 (2 H, m), 2.42 (1 H, m), 1.96-2.13 (2 H, m),
1.66-1.96 (2 H, m). 6.41 ##STR01678## (300 MHz, MeOH) 8.22 (1 H, d,
J = 2.6 Hz), 8.15 (1 H, d, J = 2.5 Hz), 8.01 (1 H, d, J = 8.9 Hz),
7.64-7.74 (2 H, m), 7.55 (1 H, td, J = 7.7, 1.4 Hz), 7.18-7.30 (1
H, m), 6.77 (1 H, d, J = 8.9 Hz), 4.54-4.67 (2 H, m), 4.38-4.49 (3
H, m), 3.31-3-36 (2 H, m), 3.00- 3.16 (3 H, m), 1.99-2.22 (4H, m)
6.42 ##STR01679## (300 MHz, MeOH) 8.22 (1 H, d, J = 2.6 Hz), 8.15
(1 H, d, J = 2.5 Hz), 8.01 (1 H, d, J = 8.9 Hz), 7.64-7.74 (2 H,
m), 7.55 (1 H, td, J = 7.7, 1.4 Hz), 7.18-7.30 (1 H, m), 6.77 (1 H,
d, J = 8.9 Hz), 4.54-4.67 (2 H, m), 4.38-4.49 (3 H, m), 3.31-3-36
(4 H, m), 2.13- 2.27 (4H, m) 6.43 ##STR01680## (300 MHz, MeOH) 8.22
(1 H, d, J = 2.6 Hz), 8.15 (1 H, d, J = 2.5 Hz), 8.01 (1 H, d, J =
8.9 Hz), 7.64-7.74 (2 H, m), 7.55 (1 H, td, J = 7.7, 1.4 Hz),
7.18-7.30 (1 H, m), 6.77 (1 H, d, J = 8.9 Hz), 4.54-4.67 (2 H, m),
4.38-4.49 (3 H, m), 3.83-3.99 (4 H, m), 3.06- 3.27 (4H, m) 6.44
##STR01681## (300 MHz, MeOH) 8.20 (1 H, d, J = 2.5 Hz), 8.14 (1 H,
d, J = 2.6 Hz), 8.01 (1 H, d, J = 8.9 Hz), 7.64-7.74 (2 H, m),
7.49-7.60 (1 H, m), 7.20-7.30 (1 H, m), 6.77 (1 H, d, J = 8.9 Hz),
4.94 (1 H, dt, J = 6.6, 3.3 Hz), 4.78 (1 H, dt, J = 6.7, 3.3 Hz),
4.54-4.67 (2 H, m), 4.35-4.52 (3 H, m), 3.24-3.45 (1 H, m), 3.05-
3.22 (2 H, m), 1.90-2.25 (4 H, m) 6.45 ##STR01682## (300 MHz, MeOH)
7.93-8.04 (3 H, m), 7.64-7.73 (2 H, m), 7.55 (1 H, ddd, J = 8.4,
7.0, 1.4 Hz), 7.19- 7.30 (1 H, m), 6.76 (1 H, d, J = 8.9 Hz),
4.45-4.57 (4 H, m), 4.30-4.44 (3 H, m), 4.10-4.26 (1 H, m),
3.93-4.08 (2 H, m), 3.38 (3 H, s) 6.46 ##STR01683## (300 MHz, MeOH)
8.09 (2 H, q, J = 2.6 Hz), 8.01 (1 H, d, J = 8.9 Hz), 7.64-7.73 (2
H, m), 7.55 (1 H, ddd, J = 8.5, 6.9, 1.4 Hz), 7.25 (1 H, td, J =
7.5, 1.0 Hz), 6.77 (1 H, d, J = 9.1 Hz), 4.45-4.61 (8 H, m),
4.10-4.27 (1 H, m) 6.47 ##STR01684## (300 MHz, MeOH) 8.17 (1 H, d,
J = 2.5 Hz), 8.12 (1 H, d, J = 2.6 Hz), 8.01 (1 H, d, J = 8.9 Hz),
7.69 (2 H, dd, J = 8.0, 5.2 Hz), 7.55 (1 H, td, J = 7.7, 1.5 Hz),
7.20-7.30 (1 H, m), 6.77 (1 H, d, J = 8.9 Hz), 4.51- 4.65 (2 H, m),
4.36-4.49 (3 H, m), 3.09-3.38 (4 H, m), 1.69-1.93 (4 H, m), 1.32 (3
H, s) 6.48 ##STR01685## (300 MHz, MeOH) 9.08-9.13 (1 H, m), 8.77 (1
H, d, J = 2.5 Hz), 8.50 (1 H, d, J = 2.3 Hz), 8.28 (1 H, s), 8.01
(1 H, d, J = 9.1 Hz), 7.63-7.72 (2 H, m), 7.50- 7.59 (1 H, m), 7.24
(1 H, td, J = 7.5, 1.0 Hz), 6.75 (1 H, d, J = 8.9 Hz), 4.74 (1 H,
quin, J = 7.2 Hz), 4.46- 4.60 (4 H, m) 6.49 ##STR01686## (300 MHz,
MeOH) 8.60 (1 H, d, J = 2.5 Hz), 8.40 (1 H, d, J = 2.5 Hz), 8.24 (1
H, s), 7.99 (1 H, d, J = 8.9 Hz), 7.62-7.74 (3 H, m), 7.54 (1 H,
ddd, J = 8.5, 7.0, 1.5 Hz), 7.23 (1 H, td, J = 7.5, 1.0 Hz), 6.73
(1 H, d, J = 9.1 Hz), 4.74-4.84 (1 H, m), 4.38-4.59 (4 H, m), 2.22
(3 H, s) 6.50 ##STR01687## (300 MHz, DMSO-d.sub.6) 8.03 (2 H, dd, J
= 5.7, 3.1 Hz), 7.96 (1 H, d, J = 2.6 Hz), 7.71 (1 H, d, J = 7.6
Hz), 7.46-7.62 (3 H, m), 7.21 (1 H, ddd, J = 8.0, 6.5, 1.6 Hz),
6.78 (1 H, d, J = 8.8 Hz), 4.25-4.52 (7 H, m), 3.97-4.18 (1 H, m),
3.92 (2 H, dd, J = 8.1, 5.6 Hz), 1.40 (9 H, s) 6.51 ##STR01688##
(300 MHz, DMSO-d.sub.6) 8.25 (1 H, d, J = 2.5 Hz), 8.20 (1 H, d, J
= 2.5 Hz), 8.04 (1 H, d, J = 8.9 Hz), 7.71 (1 H, d, J = 8.2 Hz),
7.48-7.63 (2 H, m), 7.14- 7.28 (1 H, m), 6.80 (1 H, d, J = 8.9 Hz),
4.44-4.56 (2 H, m), 4.23-4.44 (3 H, m), 3.78-3.89 (2 H, m),
2.99-3.12 (2 H, m), 2.89 (2 H, s), 1.30 (6 H, s) 6.52 ##STR01689##
(300 MHz, DMSO-d.sub.6) 8.76 (1 H, d, J = 2.5 Hz), 8.56 (1 H, d, J
= 2.5 Hz), 7.96-8.07 (2 H, m), 7.71 (1 H, d, J = 7.6 Hz), 7.46-7.60
(2 H, m), 7.35 (1 H, s), 7.22 (1 H, ddd, J = 7.9, 6.5, 1.5 Hz),
6.76 (1 H, d, J = 8.9 Hz), 4.35-4.51 (2 H, m), 4.24-4.31 (3H, m),
2.20 (3 H, s). 6.53 ##STR01690## (400 MHz, MeOH) 9.03 (1 H, s),
8.12 (1 H, d, J = 2.5 Hz), 8.05 (1 H, d, J = 2.5 Hz), 7.73 (1 H, d,
J = 7.6 Hz), 7.60-7.69 (1 H, m), 7.51 (1 H, d, J = 8.6 Hz), 7.21 (1
H, t, J = 7.5 Hz), 4.50-4.58 (2 H, m), 4.24-4.42 (3 H, m),
3.22-3.32 (2 H, m), 2.86-3.06 (3 H, m), 2.00-2.12 (2 H, m),
1.87-2.00 (2 H, m) 6.54 ##STR01691## (400 MHz, MeOH) 8.52 (1 H, d,
J = 2.3 Hz), 8.32 (2 H, s), 7.88 (1 H, d, J = 8.8 Hz), 7.75 (1 H,
s), 7.56 (2 H, dd, J = 7.8, 4.1 Hz), 7.43 (1 H, t, J = 7.7 Hz),
7.12 (1 H, t, J = 7.5 Hz), 6.63 (1 H, d, J = 9.0 Hz), 4.65-4.73 (1
H, m), 4.54 (2 H, s), 4.33-4.46 (4 H, m) 6.55 ##STR01692## (300
MHz, DMSO-d.sub.6) 8.78 (2 H, d, J = 2.5 Hz), 8.57 (2 H, d, J = 2.3
Hz), 8.03 (3 H, dd, J = 5.1, 3.8 Hz), 7.71 (2 H, d, J = 7.6 Hz),
7.43-7.62 (5 H, m), 7.22 (2 H, ddd, J = 7.9, 6.6, 1.5 Hz), 6.76 (2
H, d, J = 8.9 Hz), 5.06 (2 H, t, J = 5.6 Hz), 4.48 (2H, m), 4.28-
4.31 (3H, m), 4.26 (2 H, d, J = 5.6 Hz). 6.56 ##STR01693## (400
MHz, MeOH) 8.17 (1 H, d, J = 2.5 Hz), 8.07 (1 H, d, J = 2.5 Hz),
7.90 (1 H, d, J = 8.8 Hz), 7.57 (2 H, dd, J = 8.0, 3.7 Hz),
7.40-7.48 (1 H, m), 7.13 (1 H, t, J = 7.1 Hz), 6.66 (1 H, d, J =
8.8 Hz), 4.41-4.56 (2 H, m), 4.28-4.41 (3 H, m), 3.81 (2 H, s),
3.41 (4 H, s), 2.92 (3 H, s) 6.57 ##STR01694## (400 MHz, MeOH) 8.11
(1 H, d, J = 2.5 Hz), 8.05 (1 H, d, J = 2.5 Hz), 7.91 (1 H, d, J =
9.0 Hz), 7.58 (2 H, dd, J = 7.7, 4.4 Hz), 7.40-7.47 (1 H, m), 7.14
(1 H, t, J = 7.5 Hz), 6.99 (3 H, s), 6.66 (1 H, d, J = 9.0 Hz),
4.43-4.57 (2 H, m), 4.27-4.43 (3 H, m), 3.58 (1 H, d, J = 11.0 Hz),
3.35 (1 H, d, J = 12.7 Hz), 3.05- 3.15 (1 H, m), 2.77-2.96 (2 H,
m), 2.02-2.31 (7 H, m), 1.70-1.94 (3 H, m) 6.58 ##STR01695## (400
MHz, MeOH) 8.21 (1 H, d, J = 2.5 Hz), 8.13 (1 H, d, J = 2.5 Hz),
8.02 (1 H, d, J = 8.8 Hz), 7.69 (2 H, dd, J = 7.6, 4.9 Hz), 7.56 (1
H, t, J = 7.6 Hz), 7.25 (1 H, t, J = 7.4 Hz), 6.77 (1 H, d, J = 8.8
Hz), 4.56-4.73 (2 H, m), 4.36-4.52 (3 H, m), 3.69-3.83 (1 H, m),
3.39 (1H, m), 2.97 (1H, t, J = 8.9 Hz), 2.76 (1 H, dd, J = 12.1,
8.6 Hz), 1.91-2.02 (2 H, m), 1.82 (1 H, m), 1.40-1.59 (10 H, m),
1.29-1.40(1 H, m) 6.59 ##STR01696## (300 MHz, MeOH) 8.56 (1 H, d, J
= 2.5 Hz), 8.44 (1 H, d, J = 2.5 Hz), 7.69 (2 H, dd, J = 7.7, 5.6
Hz), 7.56 (1 H, t, J = 7.7 Hz), 7.25 (1 H, t, J = 7.5 Hz), 6.78 (1
H, d, J = 8.8 Hz), 4.54-4.72 (2 H, m), 4.34-4.54 (3 H, m), 3.64 (2
H, s), 3.09-3.28 (4 H, m), 1.68- 1.86 (4 H, m), 1.31 (1 H, m),
0.84-1.01 (1 H, m), 0.77 (1 H, t, J = 6.8 Hz), 0.38-0.59 (2 H, m),
0.07- 0.19 (2 H, m) 6.60 ##STR01697## (400 MHz, DMSO-d.sub.6)
1.61-1.78 (m, 1 H) 1.89 (br. s., 1 H) 2.18 (s, 2 H) 2.98-3.16 (m, 3
H) 3.20 (d, J = 11.15 Hz, 1 H) 3.36-3.55 (m, 1 H) 3.67 (d, J =
13.30 Hz, 1 H) 4.06 (t, J = 11.05 Hz, 1 H) 4.33 (d, J = 11.74 Hz, 1
H) 6.58 (d, J = 9.39 Hz, 1 H) 7.17 (t, J = 7.34 Hz, 1 H) 7.37-7.44
(m, 1 H) 7.44-7.53 (m, 1 H) 7.56 (d, J = 7.43 Hz, 1 H) 8.21 (d, J =
2.54 Hz, 1 H) 8.24 (d, J = 2.54 Hz, 1 H)
##STR01698##
Examples 6.61 AND 6.62
Separated Stereoisomers of Example 6.1
[0573] Note: the absolute stereochemistry of each separated isomer
was not further determined.
2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quino-
line (SCHEME 6, Example 6.1) was chirally separated by using a
Chiralpak ASH (150.times.4.6 mm i.d.), mobile phase 85% liquid
CO.sub.2/15% methanol containing 0.2% DEA (Flow rate: 4 ml/min,
column temp: 40.degree. C., outlet pressure: 100 Bar, wavelength:
248 nm)
[0574] Separated isomer Example 6.61: ESI-MS (M+1): 409. PDE10
IC.sub.50 (uM): 0.0115.
[0575] .sup.1H NMR .delta. (ppm) (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.00-2.16 (m, 1H) 2.31-2.44 (m, 1H) 3.46-3.57 (m, 1H) 3.57-3.68
(m, 2H) 3.68-3.81 (m, 1H) 3.81-3.90 (m, 1H) 4.30-4.52 (m, 4H) 6.79
(d, J=9.00 Hz, 1H) 7.21 (t, J=7.24 Hz, 1H) 7.39 (dd, J=7.82, 4.69
Hz, 1H) 7.45-7.61 (m, 2H) 7.71 (d, J=8.02 Hz, 1H) 7.82 (d, J=7.83
Hz, 1H) 7.94-8.08 (m, 3H) 8.49 (d, J=4.50 Hz, 1H) 8.61 (s, 1H)
[0576] Separated isomer Example 6.62: ESI-MS (M+1): 409. PDE10
IC.sub.50 (uM): 0.0022.
[0577] .sup.1H NMR .delta. (ppm) (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.10 (quin, J=9.93 Hz, 1H) 2.30-2.44 (m, 1H) 3.46-3.58 (m, 1H)
3.58-3.68 (m, 2H) 3.70-3.81 (m, 1H) 3.86 (dd, J=9.59, 7.43 Hz, 1H)
4.30-4.51 (m, 5H) 6.79 (d, J=9.00 Hz, 1H) 7.22 (t, J=6.75 Hz, 1H)
7.39 (dd, J=7.82, 4.69 Hz, 1H) 7.47-7.61 (m, 2H) 7.71 (d, J=7.82
Hz, 1H) 7.82 (d, J=7.83 Hz, 1H) 7.95-8.07 (m, 3H) 8.49 (d, J=3.52
Hz, 1H) 8.61 (d, J=1.76 Hz, 1H)
##STR01699##
Example 7
METHYL
(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-YL)-
CARBAMATE
Step 1. tert-Butyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbam-
ate
[0578] To a round bottomed flask was added
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (1.0337 g, 3.48
mmol), tert-butyl pyrrolidin-3-ylcarbamate (commercially available
from TCI, 1.298 g, 6.97 mmol), and triethylamine (commercially
available from Aldrich, 0.971 ml, 6.97 mmol) in DMSO (11.61 ml) to
stir at 110.degree. C. overnight.
[0579] The reaction mixture was diluted with water and extracted
with CH.sub.2Cl.sub.2. The organic extract was washed with water,
saturated NaCl, dried over MgSO.sub.4, filtered and concentrated in
vacuo. The crude product was adsorbed onto a plug of silica gel and
chromatographed through a Biotage 50 g SNAP HP-silica column,
eluting with a gradient of 10% to 100% EtOAc in hexane, to provide
tert-butyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbam-
ate (1.3145 g, 2.94 mmol, 85% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.41 (s, 9H) 1.86 (dq, J=12.35, 6.32 Hz,
1H) 2.01-2.15 (m, 1H) 3.34 (d, J=4.89 Hz, 1H) 3.44-3.54 (m, 1H)
3.54-3.62 (m, 1H) 3.61-3.71 (m, 1H) 4.08 (d, J=5.67 Hz, 1H)
4.27-4.45 (m, 3H) 6.78 (d, J=8.80 Hz, 1H) 7.15-7.26 (m, 1H)
7.47-7.60 (m, 1H) 7.71 (d, J=7.82 Hz, 1H) 7.93 (d, J=2.54 Hz, 1H)
7.98 (d, J=2.35 Hz, 1H) 8.03 (d, J=8.80 Hz, 1H) ESI (M+1) 447.0;
calc for C.sub.25H.sub.30N.sub.6O.sub.2 446.
STEP 2.
1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-AMI-
NE
[0580] To a round bottomed flask was added tert-butyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbam-
ate (1.3145 g, 2.94 mmol) and hydrogen chloride, IM in diethyl
ether (0.089 ml, 2.94 mmol) to stir. Solvent was evaporated. The
reaction mixture was diluted with saturated sodium bicarbonate and
extracted with CH.sub.2Cl.sub.2. The organic extract was washed
with water, saturated Na.sub.2CO.sub.3, saturated NaCl, dried over
MgSO.sub.4, filtered and concentrated in vacuo to give
1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine
(0.696 g, 2.009 mmol, 68.2% yield).
STEP 3. METHYL
(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-YL)CARBAM-
ATE
[0581] To a round bottomed flask was added
1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine
(0.0974 g, 0.281 mmol), pyridine (commercially available through
Aldrich, 0.045 ml, 0.562 mmol), and 4-(pyrrolidin-1-yl)pyridine
(PPY) (commercially available through Alfa Aesar, 0.042 g, 0.281
mmol) to stir at RT in DCM (0.937 ml). Methyl carbonochloridate
(commercially available through Aldrich, 0.027 ml, 0.422 mmol) was
added and allowed to stir overnight. The crude product was adsorbed
onto a plug of silica gel and chromatographed through a Biotage 50
g SNAP HP-silica column, eluting with a gradient of 1% to 6% MeOH
in CH.sub.2Cl.sub.2, to provide methyl
(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbam-
ate.
[0582] The following Table 19A lists compounds of Examples 7.1 to
7.5, which were made analogous to Scheme 7, Steps 2 and 3, by using
the appropriate materials and reaction conditions, which are listed
in Table 19B. The NMR data of the Examples are listed in Table
19C.
TABLE-US-00032 TABLE 19A EXAMPLES 7.1 TO 7.5 ESI-MS IC.sub.50 Ex. #
Structure Chemical Name (M + 1) (.mu.M) 7.1 ##STR01700## (R- &
S-)-methyl (1-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate 405.1 0.002 7.2
##STR01701## 1-(3-(1-(quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)pyrrolidin-3- amine 347.1 0.038 7.3 ##STR01702##
(R- & S-)-N-(1-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide 425 0.011 7.4
##STR01703## (R- & S-)-ethyl (1-(3-(1-
(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyrrolidin-3-
yl)carbamate 419 0.001 7.5 ##STR01704## (R- &
S-)-2-methoxy-N-(1-(3- (1-(quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3- yl)acetamide 419 0.0044
TABLE-US-00033 TABLE 19B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 7.3 TO 7.5. Key Starting Purification
Ex. # Material(s) Key Starting Material(s) Reaction Condition
Condition* 7.3 ##STR01705## ##STR01706## 4-PPY, Py, DCM, RT A 7.4
##STR01707## ##STR01708## 4-PPY, Py, DCM, RT A 7.5 ##STR01709##
##STR01710## 4-PPY, Py, DCM, RT A *Purification Method A:
purification by silica gel chromatography: (Biotage 50 g SNAP
HP-silica column, eluting with a gradient of 1% to 6% MeOH in
CH.sub.2Cl.sub.2). Examples 7.1 to 7.2 are prepared as described in
Scheme 7. Unless otherwise stated, all starting materials are
commercially available from common vendors
TABLE-US-00034 TABLE 19C 1H NMR .delta. (PPM) DATA FOR EXAMPLES 7.1
TO 7.5 Ex. # Structure NMR 7.1 ##STR01711## (400 MHz, DMSO-d.sub.6)
0.83-0.94 (m, 1 H) 1.20-1.40 (m, 1 H) 1.70 (dq, J = 12.37, 6.31 Hz,
1 H) 1.86 (br. s., 1 H) 1.96-2.09 (m, 1 H) 3.17 (dd, J = 9.98, 4.69
Hz, 1 H) 3.44-3.59 (m, 2 H) 3.59-3.71 (m, 2 H) 4.30-4.48 (m, 4 H)
6.80 (d, J = 9.00 Hz, 1 H) 7.23 (t, J = 6.85 Hz, 1 H) 7.48-7.62 (m,
2 H) 7.72 (d, J = 7.82 Hz, 1 H) 7.92 (d, J = 2.35 Hz, 1 H) 7.98 (d,
J = 2.35 Hz, 1 H) 8.05 (d, J = 9.00 Hz, 1 H) 7.2 ##STR01712## (400
MHz, DMSO-d.sub.6) 1.88 (dq, J = 12.52, 6.39 Hz, 1 H) 2.04-2.17 (m,
3 H) 3.35 (dd, J = 10.56, 4.89 Hz, 1 H) 3.47-3.65 (m, 4 H) 3.68
(dd, J = 10.56, 6.26 Hz, 1 H) 4.07-4.17 (m, 1 H) 4.29-4.44 (m, 4 H)
6.78 (d, J = 8.80 Hz, 1 H) 7.16-7.25 (m, 1 H) 7.45-7.59 (m, 2 H)
7.70 (d, J = 7.63 Hz, 1 H) 7.93 (d, J = 2.35 Hz, 1 H) 7.98 (d, J =
2.54 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1 H) 7.3 ##STR01713## (400 MHz,
DMSO-d.sub.6) 1.86-1.99 (m, 1 H) 2.12-2.26 (m, 1 H) 3.00 (s, 2 H)
3.41 (dd, J = 10.56, 5.67 Hz, 1 H) 3.49-3.65 (m, 1 H) 3.72 (dd, J =
10.37, 6.46 Hz, 1 H) 4.00 (br. s., 1 H) 4.28-4.46 (m, 3 H) 6.79 (d,
J = 8.80 Hz, 1 H) 7.21 (t, J = 7.24 Hz, 1 H) 7.42 (br. s., 1 H)
7.46-7.61 (m, 1 H) 7.71 (d, J = 8.02 Hz, 1 H) 7.96 (d, J = 2.35 Hz,
1 H) 8.00 (d, J = 2.54 Hz, 1 H) 8.04 (d, J = 8.80 Hz, 1 H) 7.4
##STR01714## (400 MHz, DMSO-d.sub.6) 1.19 (t, J = 7.04 Hz, 3 H)
1.90 (dq, J = 12.57, 6.57 Hz, 1 H) 2.06- 2.19 (m, 1 H) 3.36 (dd, J
= 10.56, 4.89 Hz, 1 H) 3.48-3.57 (m, 1 H) 3.58-3.67 (m, 1 H) 3.70
(dd, J = 10.47, 6.16 Hz, 1 H) 4.03 (q, J = 7.04 Hz, 2 H) 4.08-4.20
(m, 1 H) 4.32-4.52 (m, 4 H) 6.85 (d, J = 8.61 Hz, 1 H) 7.27 (t, J =
7.04 Hz, 1 H) 7.47 (d, J = 6.26 Hz, 1 H) 7.53-7.67 (m, 2 H) 7.76
(d, J = 7.82 Hz, 1 H) 7.96 (d, J = 2.54 Hz, 1 H) 8.01 (d, J = 2.54
Hz, 1H) 8.11 (d, J = 8.41 Hz, 1 H) 7.5 ##STR01715## (400 MHz,
DMSO-d.sub.6) 1.88-2.01 (m, 1 H) 2.04-2.19 (m, 1 H) 3.31 (s, 3 H)
3.44 (dd, J = 10.37, 5.48 Hz, 1 H) 3.48-3.63 (m, 2 H) 3.68 (dd, J =
10.27, 6.55 Hz, 1 H) 3.83 (s, 2 H) 4.29-4.44 (m, 5 H) 6.78 (d, J =
9.00 Hz, 1 H) 7.21 (t, J = 7.34 Hz, 1 H) 7.47-7.59 (m, 2 H) 7.70
(d, J = 8.02 Hz, 1 H) 7.94 (d, J = 2.54 Hz, 1 H) 7.99 (d, J = 2.54
Hz, 1 H) 8.03 (d, J = 8.80 Hz, 2 H)
##STR01716##
Examples 8.1 AND 8.2
Example 8.1
2-(3-(3-(1,4-DIAZEPAN-1-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE
[0583] To a round bottomed flask was added tert-butyl
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carbox-
ylate (0.5340 g, 1.159 mmol, SCHEME 6, Example 6.15) and HCl, (1.0
M solution in diethyl ether (1.159 ml, 1.159 mmol)) and the
reaction was allowed to stir at RT. After 1 h, the reaction mixture
was concentrated, then diluted with saturated Na.sub.2CO.sub.3 and
extracted with CH.sub.2Cl.sub.2. The organic extract was washed
with saturated Na.sub.2CO.sub.3, saturated NaCl, dried over
MgSO.sub.4, filtered and concentrated in vacuo to give
2-(3-(3-(1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline
(0.3627 g, 1.006 mmol, 87% yield).
[0584] ESI-MS (M+1): 361.1. PDE10 IC.sub.50 (.mu.M): 0.050.
Example 8.2
METHYL
4-(3-(1-(QUINOLN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)-1,4-DIAZEPANE-1-C-
ARBOXYLATE
[0585] To a round bottomed flask was added
2-(3-(3-(1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline
(0.0772 g, 0.214 mmol), pyridine (commercially available through
Aldrich, 0.035 m, 0.428 mmol), and 4-(pyrrolidin-1-yl)pyridine
(commercially available through Alfa Aesar, 0.032 g, 0.214 mmol)
and the reaction was allowed to stir at RT in DCM (0.714 ml).
Methyl carbonochloridate (commercially available through Aldrich,
0.021 ml, 0.321 mmol) was added and allowed to stir overnight. Upon
completion, the solvent was evaporated. The crude product was
adsorbed onto a plug of silica gel and chromatographed through a
Biotage 50 g SNAP HP-silica column, eluting with a gradient of 0.5%
to 5% MeOH in CH.sub.2CL.sub.2, to provide methyl
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carbox-
ylate (0.0632 g, 0.151 mmol, 70.5% yield). ESI-MS (M+1): 419.0.
PDE10 IC.sub.50 (.mu.M): 0.0046.
[0586] The following Table 20 lists NMR data of Examples 8.1 to
8.2, which were made as described in the above Scheme 8.
TABLE-US-00035 TABLE 20 1H NMR .delta. (PPM) DATA FOR EXAMPLES 8.1
TO 8.2 Ex. # Structure NMR 8.1 ##STR01717## (400 MHz, DMSO-d.sub.6)
1.86 (t, J = 5.58 Hz, 1 H) 2.85 (t, J = 5.77 Hz, 1 H) 2.93-3.03 (m,
1 H) 3.41-3.53 (m, 2 H) 4.19-4.34 (m, 2 H) 4.38-4.47 (m, 2 H) 6.79
(d, J = 8.80 Hz, 1 H) 7.21 (t, J = 7.34 Hz, 1 H) 7.46-7.61 (m, 1 H)
7.71 (d, J = 7.82 Hz, 1 H) 8.03 (d, J = 2.54 Hz, 2 H) 8.2
##STR01718## (400 MHz, DMSO-d.sub.6) 1.93 (br. s., 2 H) 3.42 (br.
s., 2 H) 3.48 (br. s., 2 H) 3.53 (d, J = 4.69 Hz, 2 H) 3.56-3.65
(m, 5 H) 4.21- 4.35 (m, 3 H) 4.41-4.51 (m, 2 H) 6.81 (d, J = 9.00
Hz, 1 H) 7.19-7.27 (m, 1 H) 7.49- 7.62 (m, 2 H) 7.73 (d, J = 7.82
Hz, 1 H) 8.05 (d, J = 8.80 Hz, 1 H) 8.11 (dd, J = 12.52, 2.54 Hz, 2
H)
##STR01719##
Example 9.1
N-METHYL-METHYL(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLID-
IN-3-YL)CARBAMATE
STEP 1.
N-METHYL-1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLI-
DIN-3-AMINE
[0587] To a round bottomed flask was added tert-butyl
methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)-
carbamate (3.0 g, 6.51 mmol) and hydrogen chloride, 5-6N in
isopropanol (0.237 g, 6.51 mmol) to stir overnight. Solvent was
evaporated and the reaction mixture was diluted with water and
extracted with EtOAc. The organic extract was washed with water,
saturated Na.sub.2CO.sub.3, saturated NaCl, and dried over MgSO4,
filtered and concentrated in vacuo to give
N-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrol-
idin-3-amine (1.0339 g, 2.87 mmol, 44.0% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.71-1.83 (m, 1H) 2.02 (dt, J=12.18,
5.94 Hz, 1H) 2.32 (s, 2H) 3.16-3.28 (m, 1H) 3.32 (br. s., 1H)
3.42-3.52 (m, 1H) 3.54-3.67 (m, 1H) 4.29-4.45 (m, 4H) 6.78 (d,
J=8.80 Hz, 1H) 7.17-7.25 (m, 1H) 7.48-7.59 (m, 2H) 7.71 (d, J=7.83
Hz, 1H) 7.91 (d, J=2.54 Hz, 1H) 7.97 (d, J=2.35 Hz, 1H) 8.03 (d,
J=8.80 Hz, 1H)
STEP 2.
N-METHYL-METHYL(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)-
PYRROLIDIN-3-YL)CARBAMATE
[0588] 14 Mar. 2011 To a round bottomed flask was added
N-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-a-
mine (0.0999 g, 0.277 mmol), pyridine (0.045 ml, 0.554 mmol), and
4-(pyrrolidin-1-yl)pyridine (0.041 g, 0.277 mmol) to stir at RT in
DCM (0.924 ml). Methyl carbonochloridate (0.027 ml, 0.416 mmol) was
added and allowed to stir for 2 h. Solvent was evaporated and the
crude product was adsorbed onto a plug of silica gel and
chromatographed through a Biotage 50 g SNAP HP-silica column,
eluting with a gradient of 1% to 4% MeOH in CH.sub.2Cl.sub.2, to
provide methyl
methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)-
carbamate (0.0307 g, 0.073 mmol, 26.5% yield).
[0589] The following Table 21A lists compounds of Examples 9.1 to
9.3, which were made analogous to Scheme 9 by using the appropriate
materials and reaction conditions, which are listed in Table 21B.
The NMR data of the Examples are listed in Table 21C.
TABLE-US-00036 TABLE 21A EXAMPLES 9.1 TO 9.3 ESI-MS IC.sub.50 Ex. #
Structure Chemical Name (M + 1) (uM) 9.1 ##STR01720##
N-methyl-methyl(1-(3-(1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate 419.0 0.00052 9.2
##STR01721## N-methyl-N-(1-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)pyrrolidin-3-
yl)methanesulfonamide 439.0 0.00568 9.3 ##STR01722## Ethyl
methyl(1-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)pyrrolidin-3-yl)carbamate 433.1 0.002
TABLE-US-00037 TABLE 21B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 9.1 TO 9.3. Reaction Purification Ex. #
Starting Material 1 Starting Material 2 Condition Condition* 9.1
##STR01723## ##STR01724## 4-PPY, Py, DCM A 9.2 ##STR01725##
##STR01726## 4-PPY, Py, DCM A 9.3 ##STR01727## ##STR01728## 4-PPY,
Py, DCM A *Purification condition: Method A: flash column
chromatography on silica gel using Biotage 50 g SNAP HP-silica
column, eluting with a gradient of 1% to 4% MeOH in
CH.sub.2Cl.sub.2 Unless otherwise stated, all starting materials
are commercially available from common vendors.
TABLE-US-00038 TABLE 21C 1H NMR .delta. (PPM) DATA FOR EXAMPLES 9.1
TO 9.3 Ex. # Structure NMR 9.1 ##STR01729## (400 MHz, DMSO-d.sub.6)
2.09 (q, J = 6.91 Hz, 2 H) 2.86 (s, 3 H) 3.49-3.61 (m, 4 H) 3.64
(s, 3 H) 4.31-4.41 (m, 4 H) 4.41-4.51 (m, 1 H) 6.79 (d, J = 8.80
Hz, 1 H) 7.22 (t, J = 6.85 Hz, 1 H) 7.48- 7.60 (m, 2 H) 7.71 (d, J
= 7.82 Hz, 1 H) 7.96- 8.07 (m, 3 H) 9.2 ##STR01730## (400 MHz,
DMSO-d.sub.6) 2.03-2.20 (m, 1 H) 2.83 (s, 2 H) 2.99 (s, 2 H)
3.49-3.61 (m, 2 H) 4.31- 4.51 (m, 3 H) 6.79 (d, J = 9.00 Hz, 1 H)
7.21 (t, J = 6.85 Hz, 1 H) 7.46-7.60 (m, 1 H) 7.71 (d, J = 7.82 Hz,
1 H) 7.96-8.06 (m, 2 H) 9.3 ##STR01731## (400 MHz, DMSO-d.sub.6)
1.21 (t, J = 7.14 Hz, 2 H) 2.08 (q, J = 7.50 Hz, 1 H) 2.85 (s, 2 H)
3.48- 3.61 (m, 2 H) 4.08 (q, J = 7.04 Hz, 1 H) 4.29- 4.40 (m, 2 H)
4.40-4.49 (m, 1 H) 4.72 (br. s., 1 H) 6.79 (d, J = 9.00 Hz, 1 H)
7.21 (t, J = 7.24 Hz, 1 H) 7.47-7.60 (m, 1 H) 7.70 (d, J = 7.82 Hz,
1 H) 7.95-8.06 (m, 2 H)
##STR01732##
Example 10.1
2-(3-(3-(4-CHLOROPHENYL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINAZOLINE
[0590] 2M aqueous sodium carbonate (0.378 mL, 0.756 mmol, J. T.
Baker) was added to a stirred mixture of
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.075 g,
0.252 mmol, Preparation 1),
trans-dichlorobis(triphenylphosphine)palladium (ii) (0.009 g, 0.013
mmol, Strem), and 4-chlorophenylboronic acid (0.047 g, 0.302 mmol,
ASDI) in 1,4-dioxane (1 mL) in a sealed tube under an argon
atmosphere. The reaction mixture was stirred at 80.degree. C. for
17 h. The reaction mixture was concentrated in vacuo and diluted
with DCM. The resulting suspension was filtered, and the filtrate
was concentrated in vacuo. The resulting crude material was
purified via reverse phase HPLC (Column: Xbridge 19.times.100 mm, 5
.mu.m, 1771302301) eluting with 0.1% NH.sub.4OH in
acetonitrile/water to give 0.060 g (64%) of a yellow amorphous
solid.
[0591] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 4.28-4.38
(m, 5H) 7.25-7.30 (m, 1H) 7.52 (d, J=8.48 Hz, 1H) 7.62 (s, 4H)
7.70-7.75 (m, 1H) 7.84 (br. d, J=7.80 Hz, 1H) 8.64 (d, J=2.41 Hz,
1H) 8.70 (d, J=2.41 Hz, 1H) 9.18 (s, 1H). ESI (M+1) 374.0; calc for
C.sub.21H.sub.16ClN.sub.5 373.
[0592] The following Table 22A lists compounds of Examples 10.1 to
10.20, which were made analogous to Scheme 10 by using the
appropriate materials and reaction conditions, which are listed in
Table 22B. The NMR data of the Examples are listed in Table
22C.
TABLE-US-00039 TABLE 22A EXAMPLES 10.1 TO 10.20 ESI-MS IC.sub.50
Ex. # Structure Chemical Name (M + 1) (.mu.M) 10.1 ##STR01733##
2-(3-(3-(4- chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline
374.0 0.00482 10.2 ##STR01734## 2-(3-(3-(3- chlorophenyl)pyrazin-2-
yl)azetidin-1-yl)quinazoline 374.0 0.00615 10.3 ##STR01735##
2-(3-(3-(2- chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline
374.0 0.0309 10.4 ##STR01736## 2-(3-(3-(o-tolyl)pyrazin-2-
yl)azetidin-1-yl)quinazoline 354.2 0.0178 10.5 ##STR01737##
1-(4-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)ethanone 382.2 0.00738 10.6 ##STR01738##
1-(3-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)ethanone 382.2 0.00136 10.7 ##STR01739##
N-(3-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)acetamide 397.2 0.000635 10.8 ##STR01740##
N-(4-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)methanesulfonamide 433.2 0.00336 10.9 ##STR01741##
N-(3-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)phenyl)methanesulfonamide 433.2 0.00959 10.10 ##STR01742##
2-(3-(3-(1H-indol-6-yl)pyrazin- 2-yl)azetidin-1-yl)quinazoline
379.2 0.00525 10.11 ##STR01743## 2-(3-(3-(1-methyl-1H-indol-5-
yl)pyrazin-2-yl)azetidin-1- yl)quinazoline 393.2 0.00595 10.12
##STR01744## 2-(3-(3-(1-methyl-1H-indol-6-
yl)pyrazin-2-yl)azetidin-1- yl)quinazoline 393.2 0.00298 10.13
##STR01745## 5-(3-(1-(quinazolin-2- azetidin-3-yl)pyrazin-2-
yl)indolin-2-one 395.2 0.00946 10.14 ##STR01746##
1-methyl-5-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)indolin-2-one 409.2 0.018 10.15 ##STR01747##
1-methyl-6-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-
1H-benzo[d]imidazol-2(3H)- one 410.2 0.0042 10.16 ##STR01748##
2-fluoro-4-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)aniline 373.1 0.00682 10.17 ##STR01749##
2-(3-(3-(p-tolyl)pyrazin-2- yl)azetidin-1-yl)quinazoline 354.2
0.00708 10.18 ##STR01750## 2-methyl-6-(3-(1-(quinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)isoquinolin-1(2H)-one 421.1 0.01739
10.19 ##STR01751## 2-(3-(3-(1H-indazol-5-
yl)pyrazin-2-yl)azetidin-1- yl)quinazoline 380.1 0.01216 10.20
##STR01752## 5-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)benzo[d]thiazole 397.1 0.0044
TABLE-US-00040 TABLE 22B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 10.1 TO 10.20. Reaction Purification
Ex. # Key Starting Material(s) Key Starting Material(s) Condition
Method* 10.1 ##STR01753## ##STR01754## Dioxane/water, 80.degree.
C., 17 h A 10.2 ##STR01755## ##STR01756## Dioxane/water, 80.degree.
C., 17 h A 10.3 ##STR01757## ##STR01758## Dioxane/water, 80.degree.
C., 17 h A 10.4 ##STR01759## ##STR01760## Dioxane/water, 80.degree.
C., 17 h A 10.5 ##STR01761## ##STR01762## Dioxane/water, 80.degree.
C., 17 h A 10.6 ##STR01763## ##STR01764## Dioxane/water, 80.degree.
C., 17 h A 10.7 ##STR01765## ##STR01766## Dioxane/water, 80.degree.
C., 17 h A 10.8 ##STR01767## ##STR01768## Dioxane/water, 80.degree.
C., 17 h A 10.9 ##STR01769## ##STR01770## Dioxane/water, 80.degree.
C., 17 h A 10.10 ##STR01771## ##STR01772## Dioxane/water,
80.degree. C., 17 h A 10.11 ##STR01773## ##STR01774##
Dioxane/water, 80.degree. C., 17 h A 10.12 ##STR01775##
##STR01776## Dioxane/water, 80.degree. C., 15 h A 10.13
##STR01777## ##STR01778## Dioxane/water, 80.degree. C., 15 h A
10.14 ##STR01779## ##STR01780## Dioxane/water, 80.degree. C., 15 h
A 10.15 ##STR01781## ##STR01782## Dioxane/water, 80.degree. C., 15
h A 10.16 ##STR01783## ##STR01784##
Pd.sub.2Cl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3 (4 equiv),
Dioxane/water, 80.degree. C., 17 h B 10.17 ##STR01785##
##STR01786## Pd.sub.2Cl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3,
Dioxane/water, 80.degree. C., 17 h B 10.18 ##STR01787##
##STR01788## Pd.sub.2Cl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3,
Dioxane/water, 80.degree. C., 17 h B 10.19 ##STR01789##
##STR01790## Pd.sub.2Cl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3,
Dioxane/water, 80.degree. C., 17 h B 10.20 ##STR01791##
##STR01792## Pd.sub.2Cl.sub.2(PPh.sub.3).sub.2, Na.sub.2CO.sub.3,
Dioxane/water, 80.degree. C., 17 h A, B *Purification Methods:
Method A--reverse phase HPLC (Column: Xbridge 19 .times. 100 mm, 5
.mu.m, 1771302301) eluting with 0.1% NH.sub.4OH in
acetonitrile/water. Method B--silica gel flash column
chromatography eluting with 0% to 75% EtOAc in hexanes Unless
otherwise stated, all starting materials are commercially available
from common vendors.
TABLE-US-00041 TABLE 22C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
10.1 TO 10.20 Ex. # Structure NMR 10.1 ##STR01793## (500 MHz,
DMSO-d.sub.6) 4.28-4.38 (m, 5 H) 7.25-7.30 (m, 1 H) 7.52 (d, J =
8.48 Hz, 1 H) 7.62 (s, 4 H) 7.70-7.75 (m, 1 H) 7.84 (br. d, J =
7.80 Hz, 1 H) 8.64 (d, J = 2.41 Hz, 1 H) 8.70 (d, J = 2.41 Hz, 1 H)
9.18 (s, 1 H) 10.2 ##STR01794## (500 MHz, DMSO-d.sub.6) 4.28-4.40
(m, 5 H) 7.28 (t, J = 7.40 Hz, 1 H) 7.50-7.62 (m, 4 H) 7.66 (s, 1
H) 7.70-7.75 (m, 1 H) 7.84 (d, J = 7.79 Hz, 1 H) 8.64 (d, J = 2.40
Hz, 1 H) 8.71 (d, J = 2.40 Hz, 1 H) 9.18 (s, 1 H) 10.3 ##STR01795##
(500 MHz, DMSO-d.sub.6) 3.96 (quin, J = 7.30 Hz, 1 H) 4.33 (m, 4 H)
7.28 (t, J = 7.39 Hz, 1 H) 7.50-7.59 (m, 4 H) 7.66 (br. d, J = 7.45
Hz, 1 H) 7.70-7.75 (m, 1 H) 7.84 (d, J = 7.56 Hz, 1 H) 8.67 (d, J =
2.41 Hz, 1 H) 8.76 (d, J = 2.52 Hz, 1 H) 9.18 (s, 1 H) 10.4
##STR01796## (500 MHz, DMSO-d.sub.6) 2.07 (s, 3 H) 3.94- 4.01 (m, 1
H) 4.22 (t, J = 8.36 Hz, 2 H) 4.28- 4.33 (m, 2 H) 7.23-7.30 (m, 2
H) 7.32-7.37 (m, 1 H) 7.37-7.44 (m, 2 H) 7.51 (d, J = 8.48 Hz, 1 H)
7.70-7.74 (m, 1 H) 7.84 (d, J = 7.56 Hz, 1 H) 8.63 (d, J = 2.52 Hz,
1 H) 8.70 (d, J = 2.41 Hz, 1 H) 9.17 (s, 1 H) 10.5 ##STR01797##
(500 MHz, DMSO-d.sub.6) 2.67 (s, 3 H) 4.29- 4.39 (m, 5 H) 7.28 (br.
t, J = 7.40, 7.40 Hz, 1 H) 7.51 (d, J = 8.25 Hz, 1 H) 7.71-7.77 (m,
3 H) 7.85 (br. d, J = 8.00 Hz, 1 H) 8.13 (d, J = 8.36 Hz, 2 H) 8.68
(d, J = 2.41 Hz, 1 H) 8.73 (d, J = 2.41 Hz, 1 H) 9.18 (s, 1 H) 10.6
##STR01798## (500 MHz, DMSO-d.sub.6) 2.67 (s, 3 H) 4.30- 4.40 (m, 5
H) 7.27 (t, J = 7.39 Hz, 1 H) 7.51 (d, J = 8.48 Hz, 1 H) 7.71 (t, J
= 7.68 Hz, 2 H) 7.83 (d, J = 8.02 Hz, 1 H) 7.86 (d, J = 7.68 Hz, 1
H) 8.10 (d, J = 7.79 Hz, 1 H) 8.13 (s, 1 H) 8.66 (d, J = 2.29 Hz, 1
H) 8.72 (d, J = 2.29 Hz, 1 H) 9.17 (s, 1 H) 10.7 ##STR01799## (500
MHz, DMSO-d.sub.6) 2.09 (s, 3 H) 4.29- 4.45 (m, 5 H) 7.26-7.30 (m,
2 H) 7.48 (t, J = 7.85 Hz, 1 H) 7.53 (d, J = 8.48 Hz, 1 H) 7.67
(br. d, J = 8.00 Hz, 1 H) 7.71-7.75 (m, 1 H) 7.83-.87 (m, 2 H) 8.63
(d, J = 2.41 Hz, 1 H) 8.68 (d, J = 2.41 Hz, 1 H) 9.19 (s, 1 H)
10.13 (s, 1H) 10.8 ##STR01800## (500 MHz, DMSO-d.sub.6) 3.10 (s, 3
H) 4.27- 4.32 (m, 2 H) 4.36-4.42 (m, 3 H) 7.28 (br. t, J = 7.40,
7.40 Hz, 1 H) 7.38 (d, J = 8.59 Hz, 2 H) 7.52 (d, J = 8.48 Hz, 1 H)
7.57 (d, J = 8.59 Hz, 2 H) 7.71-7.75 (m, 1 H) 7.85 (br. d, J = 8.00
Hz, 1 H) 8.61 (d, J = 2.40 Hz, 1 H) 8.65 (d, J = 2.41 Hz, 1 H) 9.18
(s, 1 H) 10.05 (s, 1 H) 10.9 ##STR01801## (500 MHz, DMSO-d.sub.6)
3.07 (s, 3 H) 4.30- 4.37 (m, 3 H) 4.38-4.44 (m, 2 H) 7.29 (br. t, J
= 7.50, 7.50 Hz, 1 H) 7.33-7.39 (m, 3 H) 7.51-7.55 (m, 2 H)
7.71-7.75 (m, 1 H) 7.86 (br. d, J = 8.10 Hz, 1 H) 8.64 (d, J = 2.41
Hz, 1 H) 8.70 (d, J = 2.41 Hz, 1 H) 9.19 (s, 1 H) 9.97 (s, 1 H)
10.10 ##STR01802## (500 MHz, DMSO-d.sub.6) 4.30-4.40 (m, 4 H)
4.42-4.49 (m, 1 H) 6.52-6.54 (m, 1 H) 7.24 (dd, J = 8.25, 1.49 Hz,
1 H) 7.27 (m, J = 7.80, 7.80 Hz, 1 H) 7.49 (t, J = 2.75 Hz, 1 H)
7.51 (d, J = 8.48 Hz, 1 H) 7.61 (s, 1 H) 7.68-7.74 (m, 2 H)
7.82-7.86 (m, 1 H) 8.62 (d, J = 2.40 Hz, 1 H) 8.63 (d, J = 2.40 Hz,
1 H) 9.17 (s, 1 H) 11.30 (br. s., 1 H) 10.11 ##STR01803## (500 MHz,
DMSO-d.sub.6) 3.87 (s, 3 H) 4.25- 4.36 (m, 4 H) 4.45-4.52 (m, 1 H)
6.57 (d, J = 2.86 Hz, 1 H) 7.27 (br. t, J = 7.40, 7.40 Hz, 1 H)
7.39 (dd, J = 8.42, 1.55 Hz, 1 H) 7.44 (d, J = 2.98 Hz, 1 H) 7.50
(d, J = 8.59 Hz, 1 H) 7.60 (d, J = 8.48 Hz, 1 H) 7.69-7.73 (m, 1 H)
7.77 (d, J = 1.26 Hz, 1 H) 7.83 (br. d, J = 7.10 Hz, 1 H) 8.60-8.63
(m, 2 H) 9.16 (s, 1 H) 10.12 ##STR01804## (500 MHz, DMSO-d.sub.6)
3.88 (s, 3 H) 4.28- 4.38 (m, 4 H) 4.47-4.54 (m, 1 H) 6.53 (d, J =
2.86 Hz, 1 H) 7.24-7.29 (m, 2 H) 7.47 (d, J = 3.09 Hz, 1 H) 7.51
(d, J = 8.48 Hz, 1 H) 7.64 (s, 1 H) 7.70 (m, J = 8.40 Hz, 2 H) 7.83
(br. d, J = 7.80 Hz, 1 H) 8.63 (d, J = 2.40 Hz, 1 H) 8.65 (d, J =
2.40 Hz, 1 H) 9.16 (s, 1 H) 10.13 ##STR01805## (500 MHz,
DMSO-d.sub.6) 3.60 (s, 2 H) 4.26- 4.31 (m, 2 H) 4.36-4.45 (m, 3 H)
6.98 (d, J = 8.02 Hz, 1 H) 7.26-7.30 (m, 1 H) 7.41 (d, J = 8.02 Hz,
1 H) 7.44 (s, 1 H) 7.51 (d, J = 8.48 Hz, 1 H) 7.70-7.75 (m, 1 H)
7.85 (br. d, J = 7.20 Hz, 1 H) 8.59 (d, J = 2.29 Hz, 1 H) 8.62 (d,
J = 2.41 Hz, 1 H) 9.18 (s, 1 H) 10.57 (s, 1 H) 10.14 ##STR01806##
(500 MHz, DMSO-d.sub.6) 3.20 (s, 3 H) 3.68 (s, 2 H) 4.27-4.32 (m, 2
H) 4.35-4.41 (m, 2 H) 4.41-4.48 (m, 1 H) 7.14 (d, J = 7.90 Hz, 1 H)
7.28 (br. t, J = 7.50, 7.50 Hz, 1 H) 7.49-7.53 (m, 3 H) 7.70-7.75
(m, 1 H) 7.85 (br. d, J = 7.20 Hz, 1 H) 8.60 (d, J = 2.41 Hz, 1 H)
8.63 (d, J = 2.41 Hz, 1 H) 9.18 (s, 1 H) 10.15 ##STR01807## (500
MHz, DMSO-d.sub.6) 3.35 (s, 3 H) 4.27- 4.32 (m, 2 H) 4.34-4.40 (m,
2 H) 4.43-4.50 (m, 1 H) 7.14 (d, J = 7.90 Hz, 1 H) 7.21 (dd, J =
8.00, 1.50 Hz, 1 H) 7.28 (t, J = 7.45 Hz, 1 H) 7.30 (s, 1 H) 7.51
(d, J = 8.48 Hz, 1 H) 7.70- 7.74 (m, 1 H) 7.84 (br. d, J = 7.90 Hz,
1 H) 8.61 (d, J = 2.41 Hz, 1 H) 8.64 (d, J = 2.40 Hz, 1 H) 9.18 (s,
1 H) 11.05 (s, 1 H) 10.16 ##STR01808## (500 MHz, d-CHLOROFORM) 3.98
(br. s., 2 H) 4.41 (quin, J = 7.20 Hz, 1 H) 4.53 (d, J = 7.20 Hz, 4
H) 6.88 (t, J = 8.61 Hz, 1 H) 7.11 (br. d, J = 8.00 Hz, 1 H)
7.20-7.27 (m, 2 H) 7.60- 7.70 (m, 3 H) 8.49 (d, J = 2.15 Hz, 1 H)
8.52 (d, J = 2.15 Hz, 1 H) 9.02 (s, 1 H) 10.17 ##STR01809## (500
MHz, d-CHLOROFORM) 2.45 (s, 3 H) 4.37 (quin, J = 7.20 Hz, 1 H)
4.45-4.57 (m, 4 H) 7.23 (t, J = 7.34 Hz, 1 H) 7.32 (d, .sup.1H NMR
(500 MHz, d-CHLOROFORM) .delta. J = 8.02 Hz, 2 H) 7.41 (d, J = 8.00
Hz, 2 H) 7.60-7.70 (m, 3 H) 8.52 (d, J = 2.20 Hz, 1 H) 8.56 (d, J =
2.15 Hz, 1 H) 9.01 (s, 1 H) 10.18 ##STR01810## (500 MHz,
d-CHLOROFORM) 3.66 (s, 3 H) 4.36 (quin, J = 7.40 Hz, 1 H) 4.46-4.59
(m, 4 H) 6.55 (d, J = 7.43 Hz, 1 H) 7.16 (d, J = 7.43 Hz, 1 H) 7.24
(t, J = 7.40 Hz, 1 H) 7.59-7.71 (m, 5 H) 8.56-8.60 (m, 2 H) 8.65
(d, J = 2.15 Hz, 1 H) 9.01 (s, 1 H) 10.19 ##STR01811## (500 MHz,
d-CHLOROFORM) 4.40-4.59 (m, 5 H) 7.21-7.25 (m, 1 H) 7.54-7.70 (m, 5
H) 7.90 (s, 1 H) 8.17 (s, 1 H) 8.56 (d, J = 2.30 Hz, 1 H) 8.60 (d,
J = 2.35 Hz, 1 H) 9.01 (s, 1 H) 10.53 (br. s, 1 H) 10.20
##STR01812## (400 MHz, d-CHLOROFORM) 4.42-4.59 (m, 5 H) 7.23 (t, J
= 7.43 Hz, 1 H) 7.59-7.71 (m, 4 H) 8.13 (d, J = 8.41 Hz, 1 H) 8.29
(d, J = 0.78 Hz, 1 H) 8.59 (d, J = 2.35 Hz, 1 H) 8.64 (d, J = 2.35
Hz, 1 H) 9.01 (s, 1 H) 9.11 (s, 1 H)
##STR01813##
Example 11.1
(1H-BENZOIMIDAZOL-2-YL)-(3-{3-[4-(1-HYDROXY-ETHYL)-PHENYL]-PYRAZIN-2-YL}-A-
ZETIDIN-1-YL)-METHANONE
[0593]
1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2--
yl}-phenyl)-ethanone (100 mg, 0.25 mmol, Scheme 2, Example 2.21)
was dissolved in 10 ml of methanol. This solution was cooled down
to 0.degree. C. using an ice bath and sodium tetraborohydride (19
mg, 0.50 mmol) was added by portions. The reaction mixture was
stirred for 4 h at ambient temperature, then saturated aqueous
solution of ammonium chloride (5 mL) was added. The methanol was
evaporated off under reduced pressure then the reaction mixture was
taken up in ethyl acetate. The organic phase was separated from the
aqueous phase. This extraction was repeated one more time and then
the organic phases were combined and dried over magnesium sulphate,
followed by concentrating under reduced pressure. The residue was
purified by column chromatography to give the title compound (75
mg, 0.19 mmol, 75% yield).
[0594] The following Table 23A lists compounds of Examples 11.1 to
11.3, which were made analogous to Scheme 11 by using the
appropriate materials and reaction conditions, which are listed in
Table 23B. The NMR data of the Examples are listed in Table
23C.
TABLE-US-00042 TABLE 23A EXAMPLES 11.1 TO 11.3 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (uM) 11.1 ##STR01814## (R &
S)-(1H-Benzoimidazol-2- yl)-(3-{3-[4-(1-hydroxy-ethyl)-
phenyl]-pyrazin-2-yl}-azetidin- 1-yl)-methanone 400 0.0288 11.2
##STR01815## (R & S)-(1H-Benzoimidazol-2-
yl)-(3-{3-[3-(1-hydroxy-ethyl)- phenyl]-pyrazin-2-yl}-azetidin-
1-yl)-methanone 400 0.0778 11.3 ##STR01816## (R &
S)-(1H-Benzoimidazol-2- yl)-(3-{3-[4-(1-hydroxy-ethyl)-
piperidin-1-yl]-pyrazin-2-yl}- azetidin-1-yl)-methanone 407
0.056
TABLE-US-00043 TABLE 23B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 11.1 TO 11.3. Reaction Ex. # Starting
Material 1 Condition 11.1 ##STR01817## NaBH.sub.4, MeOH 0.degree.
C. 11.2 ##STR01818## NaBH.sub.4, MeOH 0.degree. C. 11.3
##STR01819## NaBH.sub.4, MeOH 0.degree. C. Unless otherwise stated,
all starting materials are commercially available from common
vendors.
TABLE-US-00044 TABLE 23C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
11.1 TO 11.3 Ex. # Structure NMR 11.1 ##STR01820## (DMSO, 400 MHz):
8.65 (d, J = 2.4 Hz, 1H); 8.54 (d, J = 2.4 Hz, 1H); 7.67-7.65 (m, 2
H); 7.56-7.54 (m, 2H); 7.49-7.47 (m, 2H); 7.37-7.34 (m, 2H);
4.99-4.98 (m, 2H); 4.91-4.90 (m, 1H); 4.42-4.39 (m, 3H); 1.49 (d, J
= 6.4 Hz, 3H). 11.2 ##STR01821## (CDCl.sub.3, 400 MHz): 8.44 (s, 2
H); 7.51 (brs, 2H); 7.36-7.35 (m, 3H); 7.23-7.19 (m, 3H); 4.91-4.90
(m, 3H); 4.39-4.13 (m, 3H); 1.43 (d, J = 6.0 Hz, 3H). 11.3
##STR01822## (CD.sub.3OD, 400 MHz): 8.17 (d, J = 2.4 Hz, 1H); 8.11
(d, J = 2.4 Hz, 1H); 7.67 (m, 2H), 7.26 (m, 2H); 5.18 (t, J = 7.6,
1H); 4.96 (m, 1H); 4.62 (t, J = 8.0 Hz, 1H); 4.46-4.40 (m, 1H);
4.42-4.36 (m, 1H); 3.61-3.53 (m, 1H); 3.45 (d, J = 8.4 Hz, 2H);
2.2.89-2.79 (m, 1H); 2.01-1.75 (m, 2H); 1.61-1.42 (m, 2H) 1.38 (d,
J = 6.4 Hz, 1H); 1.19 (d, J = 6.4 Hz, 3H).
##STR01823##
Example 12.1
1-(4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-PIP-
ERIDIN-1-YL)-ETHANONE
STEP 1.
4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL-
}-3,6-DIHYDRO-2H-PYRIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER
[0595] To a mixture of
(1H-Benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methano-
ne (188 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 purified by
ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to
give
4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-d-
ihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (221 mg, 0.48
mmol, yield 80%). ESI-MS (M+1): 461 calc. for
C.sub.25H.sub.28N.sub.6O.sub.3 460.
STEP 2.
(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(1,2,3,6-TETRAHYDRO-PYRIDIN-4-YL)-PY-
RAZIN-2-YL]-AZETIDIN-1-YL}-METHANONE HYDROCHLORIDE
[0596] To
4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2--
yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (217
mg, 0.47 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
(1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-
-yl]-azetidin-1-yl}-methanone hydrochloride (187 mg, 0.47 mmol,
yield 100%). ESI-MS (M+1): 361 calc. for C.sub.20H.sub.20N.sub.6O
360.
STEP 3.
1-(4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-
-YL}-3,6-DIHYDRO-2H-PYRIDIN-1-YL)-ETHANONE
[0597] To a solution of
(1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-
-yl]-azetidin-1-yl}-methanone hydrochloride (187 mg, 0.47 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 (39 mg, 0.50 mmol) was added dropwise. After 1 h,
the reaction mixture was warmed to RT, 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 (170 mg, 0.42 mmol, 90% yield). ESI-MS (M+1): 403
calc. for C.sub.22H.sub.22N.sub.6O.sub.2 402.
STEP 4.
1-(4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-
-YL}-PIPERIDIN-1-YL)-ETHANONE
[0598] A mixture of
1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,-
6-dihydro-2H-pyridin-1-yl)-ethanone (170 mg, 0.42 mmol) and wet
Pd--C (50%, 50 mg) in MeOH (30 mL) was stirred under H.sub.2 (30
psi) at RT for 2 h then the reaction mixture was filtered through
CELITE.RTM. and washed with MeOH. The filtrate was concentrated in
vacuo and the residue was purified by ISCO silica gel column (10%
to 50% EtOAc in petroleum ether) to give
1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin--
2-yl}-piperidin-1-yl)-ethanone (101 mg, 0.25 mmol, 60% yield).
[0599] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. (ppm) 8.44 (dd,
J=2.4, 4.0 Hz, 2H); 7.23-7.22 (m, 2H); 7.39-7.37 (m, 2H); 5.36-5.34
(m, 1H); 5.08-5.05 (m, 1H); 4.81-4.62 (m, 3H); 4.41-4.38 (m, 1H);
4.01 (d, J=13.2 Hz, 1H); 3.28-3.26 (m, 1H); 3.06-3.01 (m, 1H);
2.79-2.77 (m, 1H); 2.20 (s, 3H); 2.04-2.01 (m, 1H); 1.88-1.75 (m,
3H).
[0600] ESI-MS (M+1): 405. PDE10 IC.sub.50 (uM): 0.427.
##STR01824##
Examples 13.1 and 13.2
##STR01825##
[0601] STEP 1.
(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(4-HYDROXY-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-AZ-
ETIDIN-1-YL}-METHANONE
[0602] To a mixture of
(1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methano-
ne (0.170 g, 0.50 mmol) and piperidin-4-ol (0.101 g, 1.0 mmol) was
added triethylamine (0.10 g, 1.0 mmol) and DMSO (4 mL). The
solution was heated to 120.degree. C. for 4 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
flash column chromatography on silica gel (20% to 50% EtOAc in
petroleum ether) to give
(1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-az-
etidin-1-yl}-methanone (0.16 g, 0.42 mmol, 85% yield) as a white
solid.
[0603] ESI-MS (M+1): 379 calc. for C.sub.20H.sub.22N.sub.6O.sub.2
378.
##STR01826##
STEP 2.
1-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-Y-
L}-PIPERIDIN-4-ONE
[0604]
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2--
yl]-azetidin-1-yl}-methanone (0.16 g, 0.42 mmol) was dissolved in
anhydrous CH.sub.2Cl.sub.2 (20 mL), treated with Dess-Martin
Periodinane (DMP) (195 mg, 0.46 mmol, 1.1 equiv) and stirred at RT
until complete conversion controlled by TLC (Petro
ether:EtOAc=1:1). The organic layer was washed with an aqueous
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 flash chromatography (20% to 40% EtOAc in
petroleum ether) to give
1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idin-4-one (0.134 g, 0.36 mmol, 85% yield) as a white solid.
[0605] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. (ppm) 8.24-8.14
(m, 2H); 7.71-7.68 (m, 2H); 7.35-7.24 (m, 2H); 5.34-5.30 (m, 1H);
5.08-5.04 (m, 1H); 4.69-4.60 (m, 2H); 4.39-4.31 (m, 1H); 3.55-3.44
(m, 4H); 2.67-2.57 (m, 4H).
[0606] ESI-MS (M+1): 377 calc. for C.sub.20H.sub.20N.sub.6O.sub.2
376.
##STR01827##
STEP 3.
(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(4,4-DIFLUORO-PIPERIDIN-1-YL)-PYRAZ-
IN-2-YL]-AZETIDIN-1-YL}-METHANONE
[0607] In a 50 mL flask,
1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idin-4-one (0.134 g, 0.36 mmol) was dissolved in anhydrous
CH.sub.2Cl.sub.2 (15 mL). The solution was cooled to -10.degree. C.
under nitrogen atmosphere and DAST (0.12 g, 0.72 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
CH.sub.2Cl.sub.2 (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 via flash chromatography
on silica gel (20% to 45% EtOAc in petroleum ether) to give
(1H-benzoimidazol-2-yl)-{3-[3-(4,4-difluoro-piperidin-1-yl)-pyrazin--
2-yl]-azetidin-1-yl}-methanone (0.114 g, 0.29 mmol, 80% yield) as a
white solid.
[0608] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. (ppm) 8.15 (d,
J=1.6 Hz, 1H); 8.07 (d, J=2.4, 1H); 7.64-7.62 (m, 2H); 7.29-7.26
(m, 2H); 5.26-5.22 (m, 1H); 5.00-4.96 (m, 1H); 4.56-4.54 (m, 2H);
4.23-4.19 (m, 1H); 3.23-3.20 (m, 4H); 2.12-2.04 (m, 4H).
ESI-MS (M+1): 399 calc. for C.sub.20H.sub.20F.sub.2N.sub.6O
398.
[0609] PDE10 IC.sub.50 (uM): 0.0765.
##STR01828##
Example 14.1
(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(4-HYDROXY-4-METHYL-PIPERIDIN-1-YL)-PYRAZIN--
2-YL]-AZETIDIN-1-YL}-METHANONE
[0610] To a solution of
1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piper-
idin-4-one (150 mg, 0.40 mol, SCHEME 13, Ex. 13.1) in 20 mL of THF
was added CH.sub.3MgBr (0.60 mol, 3 M in ether) dropwise at
0.degree. C. The mixture was stirred for 1 h at RT and then
quenched with saturated aqueous NH.sub.4Cl. The resulting mixture
was extracted with EtOAc (2.times.20 mL) and the combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give crude product which was purified by prep. TLC
(EtOAc:Petrol ether=1:1) to give
(1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin-
-2-yl]-azetidin-1-yl}-methanone (0.109 g, 0.28 mmol, 70% yield) as
a white solid.
[0611] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. (ppm) 8.12 (d,
J=2.8 Hz, 1H); 8.05 (d, J=2.8 Hz, 1H); 7.63-7.56 (m, 2H); 7.29-7.26
(m, 2H); 5.21-5.16 (m, 1H); 4.57-4.54 (m, 2H); 3.28-3.20 (m, 2H);
3.11-3.08 (m, 2H); 1.81-1.70 (m, 4H); 1.27 (s, 3H).
[0612] ESI-MS (M+1): 393. PDE10 IC.sub.50 (uM): 0.131.
##STR01829##
Example 15.1
(1H-BENZOIMIDAZOL-2-YL)-[3-(5-PHENYL-PYRIMIDIN-4-YL)-AZETIDIN-1-YL]-METHAN-
ONE
STEP 1. 3-(5-BROMO-2-CHLORO-PYRIMIDIN-4-YL)-AZETIDINE-1-CARBOXYLIC
ACID TERT-BUTYL ESTER
[0613] A 100 mL 3-neck round bottom flask fitted with a magnetic
stirrer and flushed with nitrogen was charged with zinc dust (813
mg, preactivated according to the above Preparation 1, 12.7 mmol)
and DMA (10 mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol)
was added slowly, followed by TMSCl (137 mg, 1.27 mmol). The
reaction was stirred for 15 minutes at RT. A solution of
N-Boc-3-iodoazetidine (2.7 g, 9.5 mmol) in DMA (10 mL, anhydrous)
was added dropwise. The suspension was stirred for 1 h at RT.
[0614] A 100 mL 3-neck round bottom flask fitted with a mechanical
stirrer was charged with 5-bromo-2,4-dichloro-pyrimidine (2 g, 4.42
mmol), Pd(dppf)Cl.sub.2 (324 mg, 0.442 mmol), CuI (84 mg, 0.442
mmol), and DMA (20 mL, anhydrous). The dark solution was degassed
for 15 minutes. The clear zinc reagent solution above the residual
solid zinc was transferred to the above 100 mL flask by
cannulation. The dark solution was degassed and heated to
80.degree. C. for 16 h. The reaction was diluted with brine and
extracted with EtOAc (3.times.100 mL). The combined organics were
washed with water (2.times.100 mL) and brine (100 mL), followed by
drying over sodium sulfate. The solution was concentrated and the
residue was purified by flash column chromatography provides the
title compound (0.7 g, 2.0 mmol, yield: 46%). ESI-MS (M+1): 348
calc. for C.sub.12H.sub.15BrClN.sub.3O.sub.2 347.
STEP 2. 4-AZETIDIN-3-YL-5-BROMO-2-CHLORO-PYRIMIDINE
HYDROCHLORIDE
[0615] The mixture of
3-(5-bromo-2-chloro-pyrimidin-4-yl)-azetidine-1-carboxylic acid
tert-butyl ester (0.7 g, 2.0 mmol) in HCl/MeOH (10 mL) was stirred
at RT for 1 h. Then it was concentrated to give
4-azetidin-3-yl-5-bromo-2-chloro-pyrimidine hydrochloride (0.57 g,
2.0 mmol, yield 100%) which was used in the next step without
further purification. ESI-MS (M+1): 248 calc. for
C.sub.7H.sub.7BrClN.sub.3 247.
STEP 3.
(1H-BENZOIMIDAZOL-2-YL)-[3-(5-BROMO-2-CHLORO-PYRIMIDIN-4-YL)-AZETI-
DIN-1-YL]-METHANONE
[0616] To a solution of 4-azetidin-3-yl-5-bromo-2-chloro-pyrimidine
hydrochloride (0.57 mg, 2.0 mmol) in DCM (20 mL) were added HATU
(1.5 g, 4.0 mmol), TEA (404 mg, 4 mmol) and
1H-benzoimidazole-2-carboxylic acid (398 mg, 2.4 mmol). The
reaction mixture was stirred at RT for 12 h. TLC showed that most
of starting materials were consumed completely. Then the solution
was washed with aqueous HCl (1 mol/L) (50 mL.times.3), saturated
aqueous NaHCO.sub.3 (50 mL.times.3) and brine, dried over
MgSO.sub.4. The solution was evaporated, the residue was purified
by column chromatography to give the product (206 mg, 0.53 mmol,
yield: 27%). ESI-MS (M+1): 392 calc. for
C.sub.15H.sub.11BrClN.sub.5O 391
STEP 4.
(1H-BENZOIMIDAZOL-2-YL)-[3-(2-CHLORO-5-PHENYL-PYRIMIDIN-4-YL)-AZET-
IDIN-1-YL]-METHANONE
[0617] A solution of
(1H-benzoimidazol-2-yl)-[3-(5-bromo-2-chloro-pyrimidin-4-yl)-azetidin-1-y-
l]-methanone (206 mg, 0.53 mmol) in dioxane (15 mL) was treated
with Na.sub.2CO.sub.3 (112 mg, 1.1 mmol dissolved 1 mL of
H.sub.2O), followed by additional of phenylboronic acid (78 mg 0.64
mmol) and Pd(dppf)Cl.sub.2 (37 mg, 0.05 mmol). 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 (102 mg, 0.28 mmol, yield:
53%).
[0618] ESI-MS (M+1): 362 calc. for C.sub.21H.sub.16ClN.sub.5O
361.
STEP 5.
(1H-BENZOIMIDAZOL-2-YL)-[3-(5-PHENYL-PYRIMIDIN-4-YL)-AZETIDIN-1-YL-
]-METHANONE
[0619] To a solution of
(1H-Benzoimidazol-2-yl)-[3-(2-chloro-5-phenyl-pyrimidin-4-yl)-azetidin-1--
yl]-methanone (102 mg, 0.28 mmol) in MeOH (10 mL) was added Pd/C
(100 mg). The reaction solution was stirred at RT overnight under
H.sub.2 atmosphere. The mixture was filtered and concentrated to
give the product (51 mg, 0.16 mmol, yield: 55%).
[0620] .sup.1H NMR: (CDCl.sub.3, 400 MHz): .delta. (ppm) 9.19 (s,
1H), 8.61 (s, 1H), 7.61-7.57 (m, 2H), 7.49-7.41 (m, 5H), 7.31-7.18
(m, 2H), 5.07 (d, J=6.8 Hz, 2H), 4.59-4.57 (m, 1H), 4.39-4.34 (m,
1H), 4.18-4.14 (m, 1H).
[0621] ESI-MS (M+1): 328.
[0622] PDE10 IC.sub.50 (uM): 0.0291.
##STR01830##
Example 16.1
2-(3-(3-(PROP-1-YN-1-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE
[0623] A mixture of
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.200 g, 0.674
mmol), tributyl(prop-1-yn-1-yl)stannane (0.266 g, 0.809 mmol), and
bis(tri-t-butylphosphine) palladium (o) (0.017 g, 0.034 mmol) in
p-dioxane (4 mL) was heated at 100.degree. C. in 16 h. The reaction
mixture was cooled, concentrated, and purified by ISCO (0-60%
EtOAc/Hexanes) to give the title compound (128 mg, 68%).
[0624] .sup.1H NMR (300 MHz, MeOH) 8.56 (1H, d, J=2.5 Hz), 8.44
(1H, d, J=2.5 Hz), 8.04 (1H, d, J=9.1 Hz), 7.71 (2H, dd, J=7.8, 5.6
Hz), 7.58 (1H, td, J=7.7, 1.3 Hz), 7.27 (1H, t, J=7.5 Hz), 6.80
(1H, d, J=8.9 Hz), 4.51-4.66 (5H, m), 2.21 (3H, s).
[0625] ESI-MS (M+1): 601. PDE10 IC.sub.50 (.mu.M): 0.077.
##STR01831##
Example 17.1
2-[3-(3-M-TOLYL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-QUINOLINE
[0626] To a solution of 2-azetidin-3-yl-3-m-tolyl-pyrazine
hydrochloride (131 mg, 0.05 mmol) and 2-chloro-quinoline (82 mg,
0.05 mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (325 mg, 1.0
mmol). The reaction mixture was stirred at 100.degree. C.
overnight. The reaction mixture was diluted with water, extracted
with EtOAc (30 mL.times.2). 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 (20% to 40% EtOAc in petroleum ether) to give
2-[3-(3-m-tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (44 mg, 0.13
mmol, 25%).
[0627] The following Table 24A lists compounds of Examples 17.1 to
17.6, which were made analogous to Scheme 17 by using the
appropriate materials and reaction conditions, which are listed in
Table 24B. The NMR data of the Examples are listed in Table
24C.
TABLE-US-00045 TABLE 24A EXAMPLES 17.1 TO 17.6 Ex. # Structure
Chemical Name ESI-MS (M + 1) IC.sub.50 (uM) 17.1 ##STR01832##
2-[3-(3-m-Tolyl- pyrazin-2-yl)-azetidin-1- yl]-quinoline 353
0.00178 17.2 ##STR01833## 2-[3-(3-m-Tolyl-
pyrazin-2-yl)-azetidin-1- yl]-quinazoline 354 0.012 17.3
##STR01834## 2-[3-(3-m-Tolyl- pyrazin-2-yl)-azetidin-1-
yl]-quinoxaline 354 0.0209 17.4 ##STR01835## 2-[3-(3-m-Tolyl-
pyrazin-2-yl)-azetidin-1- yl]-benzothiazole 359 0.0319 17.5
##STR01836## 2-{3-[3-(3-Methoxy- phenyl)-pyrazin-2-yl]-
azetidin-1-yl}-quinoline 369 0.00299 17.6 ##STR01837##
2-{3-[3-(3-Methoxy- phenyl)-pyrazin-2-yl]- azetidin-1-yl}-
quinazoline 370 0.00929
TABLE-US-00046 TABLE 24B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 17.1 TO 17.6. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 17.1 ##STR01838## ##STR01839## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 17.2 31 PREPARATION 9 ##STR01840## Cs.sub.2CO.sub.3,
DMF, 100.degree. C. 17.3 31 PREPARATION 9 ##STR01841##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 17.4 31 PREPARATION 9
##STR01842## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 17.5
##STR01843## ##STR01844## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
17.6 34 PREPARATION 10 ##STR01845## Cs.sub.2CO.sub.3, DMF,
100.degree. C.
TABLE-US-00047 TABLE 24C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
17.1 TO 17.6 Ex. # Structure NMR 17.1 ##STR01846## (CDCl.sub.3, 400
MHz): 8.53-8.49 (m, 2H); 7.99 (d, J = 8.4 Hz, 1H); 7.92 (d, J = 8.4
Hz, 1H); 7.60 (t, J = 6.4 Hz, 2H); 7.33 (dd, J = 2.4, 7.6 Hz, 2H);
7.24 (d, J = 7.6 Hz, 1H); 7.19 (s, 1H); 7.12 (d, J = 7.6 Hz, 1H);
6.53 (d, J = 9.2 Hz, 1H); 4.89 (br s, 1H); 4.72-4.68 (m, 2H);
4.48-4.42 (m, 2H); 2.37 (s, 3H) 17.2 ##STR01847## CD.sub.3OD, 400
MHz): 9.04 (s, 1H); 8.12 (d, J = 1.2 Hz, 1H); 8.49 (d, J = 1.2 Hz,
1H); 7.71-7.67 (m, 2H); 7.54-7.52 (m, 1H); 7.41 (t, J = 7.6 Hz,
1H); 7.33-7.26 (m, 2H); 7.285-7.23 (m, 2H); 4.38-4.36 (m, 5H); 2.43
(s, 3H) 17.3 ##STR01848## (CD.sub.3OD, 400 MHz): 8.62 (d, J = 2.4
Hz, 1H); 8.52 (d, J = 2.4 Hz, 1H); 8.17 (s, 1H), 7.79-7.76 (m, 1H);
7.61 (dd, J = 1.6, 8.8 Hz, 1H); 7.57-7.52 (m, 1H); 7.43 (t, J = 7.6
Hz, 1H); 7.37-7.33 (m, 3H); 7.29 (d, J = 7.6 Hz, 1H); 4.44-4.39 (m,
5H); 2.45(s, 3H). 17.4 ##STR01849## (CD.sub.3OD, 400 MHz): 8.63 (d,
J = 1.2 Hz, 1H); 8.51 (d, J = 1.6 Hz, 1H); 7.60 (d, J = 8.0 Hz,
1H); 7.44- 7.39 (m, 2H); 7.34-7.30 (m, 2H); 7.27-7.22 (m, 2H);
7.06-7.02 (m, 1H); 4.44-4.40 (m, 1H); 4.35- 4.25 (m, 4H); 2.43 (s,
3H). 17.5 ##STR01850## (CD.sub.3OD, 400 MHz): 8.54 (s,1H); 8.50 (d,
J = 0.8 Hz, 1H); 7.83 (d, J = 8.8 Hz, 1H); 7.71 (d, J = 8.4 Hz,
1H); 7.57 (d, J = 8.0 Hz, 1H); 7.50 (t, J = 7.2 Hz, 1H); 7.40 (t, J
= 8.0 Hz, 1H); 7.18 (t, J = 7.2 Hz, 1H); 7.05-7.00 (m, 3H); 6.60
(d, J = 8.8 Hz, 1H); 4.47-4.38 (m, 5H); 3.86 (s, 3H). 17.6
##STR01851## (CDCl3, 400 MHz): 8.96 (s, 1H); 8.53 (d, J = 2.8 Hz,
1H); 8.46 (d, J = 2.4 Hz, 1H); 7.62-7.55 (m, 3H); 7.38-7.33 (m,
1H); 7.16-7.13 (m, 1H); 7.01- 6.95 (m, 3H); 4.51-4.41 (m, 4H);
4.35-4.29 (m, 1H); 3.80 (s, 3H).
##STR01852##
Example 18.1
2-{3-[3-(3-METHOXY-PHENYL)-PYRIDIN-2-YL]-AZETIDIN-1-YL}-QUINOLINE
[0628] To a solution of
2-[3-(3-bromo-pyridin-2-yl)-azetidin-1-yl]-quinoline (339 mg, 1
mmol), 3-methoxy-phenylboronic acid (167.2 mg, 1.1 mmol),
K.sub.3PO.sub.4 (414 mg, 2.0 mmol) in dioxane (20 mL) and water (2
mL) was added Pd(dppf)Cl.sub.2 (36.6 mg, 0.05 mmol) then the
reaction mixture was stirred at 90.degree. C. under nitrogen
atmosphere overnight. The reaction mixture was filtered through
CELITE.RTM. and washed with EtOAc (50 mL). The filtrate was
concentrated and the crude product was purified by ISCO silica gel
column (10% to 80% EtOAc in petroleum ether) to give
2-{3-[3-(3-methoxy-phenyl)-pyridin-2-yl]-azetidin-1-yl}-quinoline
(132 mg, 0.36 mmol, yield 36%).
[0629] The following Table 25A lists compounds of Examples 18.1 to
18.2, which were made analogous to Scheme 18 by using the
appropriate materials and reaction conditions, which are listed in
Table 25B. The NMR data of the Examples are listed in Table
25C.
TABLE-US-00048 TABLE 25A EXAMPLES 18.1 TO 18.2 ESI- MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 18.1 ##STR01853##
2-{3-[3-(3-Methoxy- phenyl)-pyridin-2-yl]- azetidin-1-yl}-quinoline
368 0.00493 18.2 ##STR01854## 2-[3-(3-m-Tolyl-pyridin-2-
yl)-azetidin-1-yl]-quinoline 352 0.00609
TABLE-US-00049 TABLE 25B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 18.1 TO 18.2. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 18.1 ##STR01855## ##STR01856## Pd(dppf)Cl.sub.2,
K.sub.3PO.sub.4, Dioxane/water 18.2 ##STR01857## ##STR01858##
Pd(dppf)Cl.sub.2, K.sub.3PO.sub.4, Dioxane/water
TABLE-US-00050 TABLE 25C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
18.1 TO 18.2 Ex. # Structure NMR 18.1 ##STR01859## (CDCl.sub.3, 400
MHz): 8.79 (s, 1H); 8.03 (d, J = 9.2 Hz, 1H); 7.93 (d, J = 8.0 Hz,
1H); 7.78 (d, J = 8.8 Hz, 1H); 7.66-7.62 (m, 2H); 7.59-7.56 (m,
1H); 7.40-7.35 (m, 2H); 6.99-6.97 (m, 1H); 6.75 (t, J = 8.4 Hz,
2H); 6.57 (d, J = 9.2 Hz, 1H); 4.75 (s, 3H); 4.54-4.52 (m,2H); 3.79
(s, 3H). 18.2 ##STR01860## (CDCl.sub.3, 400 MHz): 8.65 (s, 1H);
7.99 (d, J = 9.2 Hz, 1H); 7.88 (d, J = 8.4 Hz, 1H); 7.67-7.59 (m,
3H); 7.35-7.30 (m, 3H); 7.22-7.19 (m, 1H); 6.95 (d, J = 11.6 Hz,
2H); 6.54 (d, J = 5.2 Hz, 1H); 4.74 (s, 3H); 4.33 (s, 2H); 2.37 (s,
3H).
##STR01861##
Example 19.1
(R &
S)-2-{3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRIDIN-2-YL]-AZETIDIN-1-YL}-QU-
INOLINE
[0630] To a solution of
2-[3-(3-bromo-pyridin-2-yl)-azetidin-1-yl]-quinoline (339 mg, 1
mmol), 3-methyl-pyrrolidine (93.5 mg, 1.1 mmol), BINAP (31.1 mg,
0.05 mmol), t-BuONa (196 mg, 2 mmol) in dioxane (25 mL) was added
Pd.sub.2(dba).sub.3 (45.75 mg, 0.05 mmol) then the reaction mixture
was stirred at 90.degree. C. under nitrogen atmosphere overnight.
The reaction mixture was filtered through CELITE.RTM. and washed
with EtOAc (50 mL). The filtrate was concentrated and the crude
product was purified by ISCO silica gel column (10% to 80% EtOAc in
petroleum ether) to give
2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinoline
(64 mg, 0.19 mmol, yield 19%).
[0631] The following Table 26A lists compounds of Examples 19.1 to
19.2, which were made analogous to Scheme 19 by using the
appropriate materials and reaction conditions, which are listed in
Table 26B. The NMR data of the Examples are listed in Table
26C.
TABLE-US-00051 TABLE 26A EXAMPLES 19.1 TO 19.2 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 19.1 ##STR01862## (R
& S)-2-{3-[3-(3-Methyl- pyrrolidin-1-yl)-pyridin-2-yl]-
azetidin-1-yl}-quinoline 345 0.864 19.2 ##STR01863##
4-Methyl-2'-(1-quinolin-2-yl- azetidin-3-yl)-3,4,5,6-
tetrahydro-2H- [1,3']bipyridinyl 345 0.00522
TABLE-US-00052 TABLE 26B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 19.1 TO 19.2. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 19.1 ##STR01864## ##STR01865## Pd.sub.2(dba).sub.3,
BINAP, t- BuONa, dioxane 19.2 ##STR01866## ##STR01867##
Pd.sub.2(dba).sub.3, BINAP, t- BuONa, dioxane
TABLE-US-00053 TABLE 26C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
19.1 TO 19.2 Ex. # Structure NMR 19.1 ##STR01868## (CDCl.sub.3, 400
MHz): 8.22 (s, 1H); 8.02 (d, J = 9.2 Hz, 1H); 7.96 (d, J = 8.4,
1H); 7.67-7.62 (m, 2H); 7.40-7.31 (m, 3H); 6.62 (d, J = 9.2 Hz,
1H); 5.04-4.74 (m, 3H); 4.60-4.57 (m, 1H); 3.42 (s, 1H); 3.41-3.32
(m, 1H); 3.27-3.18 (m, 1H); 2.91-2.86 (m, 1H); 2.39-2.33 (m, 1H);
2.14-2.09 (m, 1H); 1.62-1.57 (m, 1H); 1.19 (s, 1H); 1.09 (d, J =
2.4 Hz, 3H). 19.2 ##STR01869## (CDCl.sub.3, 400 MHz): 8.32-8.31 (m,
1H); 7.85 (d, J = 8.8 Hz, 1H); 7.73 (d, J = 8.4 Hz, 1H), 7.60-7.58
(m, 1H); 7.53-7.51 (m, 1H); 7.34-7.32 (m, 1H); 7.26-7.21 (m, 1H);
7.19-7.10 (m, 1H); 6.66 (d, J = 8.8 Hz, 1H); 4.59- 4.52 (m, 3H);
4.51-4.47 (m, 2H); 2.81 (m, 4H); 1.79- 1.68 (m, 4H); 1.62-1.56 (m,
2H).
##STR01870##
Example 20.1
{1-[3-(1-QUINOLIN-2-YL-PIPERIDIN-4-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}-METHA-
NOL
[0632] To a solution of
[1-(3-piperidin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol
hydrochloride (156 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg
0.5 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (325 mg, 1
mmol). The reaction mixture was stirred at 100.degree. C.
overnight. The reaction mixture was diluted with water, extracted
with EtOAc (2.times.20 mL). The combined organic extracts were
washed with water (15 mL) and brine (15 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
{1-[3-(1-quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-
-methanol (142 mg, 0.35 mmol, yield 70.47%).
[0633] The following Table 27A lists compounds of Examples 20.1 to
20.10, which were made analogous to Scheme 20 by using the
appropriate materials and reaction conditions, which are listed in
Table 27B. The NMR data of the Examples are listed in Table
27C.
TABLE-US-00054 TABLE 27A EXAMPLES 20.1 TO 20.10 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 20.1 ##STR01871##
{1-[3-(1-Quinolin-2-yl- piperidin-4-yl)-pyrazin-
2-yl]-piperidin-4-yl}- methanol 404 0.00172 20.2 ##STR01872##
{1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-
yl]-piperidin-4-yl}- methanol 376 0.00114 20.3 ##STR01873##
{1-[3-(1-Quinazolin-2- yl-azetidin-3-yl)- pyrazin-2-yl]-piperidin-
4-yl}-methanol 377 0.00256 20.4 ##STR01874## 4-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-phenylamine 377 >10 20.5
##STR01875## {1-[3-(1-Benzothiazol- 2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin- 4-yl}-methanol 382 0.0323 20.6
##STR01876## {1-[3-(1-Benzooxazol- 2-yl-azetidin-3-yl)-
pyrazin-2-yl]-piperidin- 4-yl}-methanol 366 2.170 20.7 ##STR01877##
(1-{3-[1-(5-Methyl- pyridin-2-yl)-azetidin-3- yl]-pyrazin-2-yl}-
piperidin-4-yl)-methanol 340 0.583 20.8 ##STR01878##
2-(4-benzylpiperidin-1- yl)-3-(1-(quinolin-2- yl)azetidin-3-
yl)quinoxaline 426 0.00243 20.9 ##STR01879## [5'-Fluoro-2'-(1-
quinolin-2-yl-azetidin-3- yl)-3,4,5,6-tetrahydro-
2H-[1,3']bipyridinyl-4- yl]-methanol 393 0.181 20.10 ##STR01880##
{1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyridazin-
4-yl]-piperidin-4-yl}- methanol 376 0.0322
TABLE-US-00055 TABLE 27B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 20.1 TO 20.10. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 20.1 ##STR01881## ##STR01882## Cs.sub.2CO.sub.3, DMF;
100.degree. C. 20.2 ##STR01883## ##STR01884## Cs.sub.2CO.sub.3,
DMF; 100.degree. C. 20.3 ##STR01885## ##STR01886##
Cs.sub.2CO.sub.3, DMF; 100.degree. C. 20.4 ##STR01887##
##STR01888## Cs.sub.2CO.sub.3, DMF; 100.degree. C. 20.5
##STR01889## ##STR01890## Cs.sub.2CO.sub.3, DMF; 100.degree. C.
20.6 ##STR01891## ##STR01892## Cs.sub.2CO.sub.3, DMF; 100.degree.
C. 20.7 ##STR01893## ##STR01894## Cs.sub.2CO.sub.3, DMF;
100.degree. C. 20.8 ##STR01895## ##STR01896## Cs.sub.2CO.sub.3,
DMF; 100.degree. C. 20.9 ##STR01897## ##STR01898##
Cs.sub.2CO.sub.3, DMF; 100.degree. C. 20.10 ##STR01899##
##STR01900## Cs.sub.2CO.sub.3, DMF; 100.degree. C.
TABLE-US-00056 TABLE 27C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
20.1 TO 20.10 Ex. # Structure NMR 20.1 ##STR01901## (CDCl.sub.3,
400 MHz): 8.28-8.15 (m, 4H); 7.80-7.69 (m, 2H); 7.52-7.44 (m, 1H);
7.14 (d, J = 8.0 Hz, 1H); 4.62 (s, 2H); 4.30 (d, J = 6.4 Hz, 1H);
3.64 (d, J = 29.4 Hz, 3H); 3.44 (d, J = 7.6 Hz, 3H); 2.97-2.91 (m,
2H); 2.10 (s, 4H); 1.90 (d, J = 6.4 Hz, 2H); 1.74 (s, 1H); 1.55 (d,
J = 9.6 Hz, 2H). 20.2 ##STR01902## (CDCl.sub.3, 400 MHz): 8.15 (d,
J = 2.4 Hz, 1H); 8.07 (d, J = 2.0 Hz, 1H); 7.87 (d, J = 8.4 Hz,
1H); 7.74 (d, J = 8.4 Hz, 1H); 7.60 (d, J = 7.6 Hz, 1H); 7.53 (t, J
= 7.2 Hz, 1H); 7.23-7.19(m, 1H); 6.65 (d, J = 8.8 Hz, 1H); 4.55 (t,
J = 8.0 Hz, 2H); 4.46 (t, J = 6.4 Hz, 2H); 4.34- 4.28 (m, 1H); 3.58
(d, J = 6.0 Hz, 2H); 3.44 (d, J = 12.8 Hz, 2H); 2.89-2.82 (m, 2H);
2.06 (s, 1H); 1.87 (d, J = 12.0 Hz, 1H); 1.74-1.68 (m, 1H);
1.52-1.41 (m, 2H). 20.3 ##STR01903## (CD.sub.3OD, 400 MHz): 9.01
(s, 1H); 8.06 (d, J = 2.8 Hz, 1H); 8.01 (d, J = 2.4 Hz, 1H); 7.71
(dd, J = 2.4, 8.0 Hz, 1H); 7.67-7.63 (m, 1H); 7.49 (d, J = 8.4 Hz,
1H); 7.22-7.18 (m, 1H); 4.52 (t, J = 8.0 Hz, 2H); 4.36- 4.30 (m,
2H); 4.28-4.26 (m, 1H); 3.40 (d, J = 6.4 Hz, 4H); 3.37 (s, 1H);
2.81-2.74 (m, 2H); 1.81-1.78 (m, 2H); 1.61-1.54(m, 1H); 1.43-1.39
(m, 2H). 20.4 ##STR01904## (CD.sub.3OD, 400 MHz): 8.91 (dd, J =
2.4, 7.2 Hz, 1H); 8.64 (dd, J = 0.8, 2.4 Hz, 1H); 8.31 (s, 1H);
7.82 (d, J = 8.4 Hz, 1H); 7.67 (m, 1H); 7.66-7.59 (m, 1H); 7.44-
7.40 (m, 1H); 4.73-4.72 (m, 1H); 4.31-4.25 (m, 4H); 4.17-4.16 (m,
1H); 4.08-4.05 (m, 1H); 3.83-3.75 (m, 3H); 3.52 (d, J = 6.4 Hz,
2H); 2.11-1.96 (m, 4H). 20.5 ##STR01905## (CD.sub.3OD, 400 MHz):
8.22-8.20 (m, 1H); 8.17-8.15 (dd, J = 2.4,8.4 Hz, 1H); 7.87 (d, J =
8.0 Hz, 1H); 7.62-7.58 (m, 2H); 7.49-7.44 (m, 1H); 4.62 (m, 1H);
4.54 (m, 1H); 4.32 (d, J = 6.8 Hz, 1H); 4.05-4.01 (m, 2H);
3.94-3.89 (m, 1H); 3.54-3.51 (m, 1H); 3.47 (d, J = 10.4 Hz, 2H);
3.02-2.90 (m, 2H); 1.93-1.86 (m, 2H); 1.58-1.45 (m, 3H). 20.6
##STR01906## (CD.sub.3OD, 400 MHz): 8.91 (d, J = 2.8 Hz, 1H); 8.66
(dd, J = 1.2,2.8 Hz, 1H); 7.33-7.30 (m, 2H); 7.20 (m, 1H); 7.10
(dd, J = 1.2,4.0 Hz, 1H); 4.25-4.10 (m, 5H); 3.96-3.91 (m, 1H);
3.83-3.74 (m, 3H); 3.65 (d, J = 1.6 Hz, 2H); 2.14-1.89 (m, 5H).
20.7 ##STR01907## (CD.sub.3OD, 400 MHz): 8.12 (d, J = 2.4 Hz, 1H);
8.07 (d, J = 2.4 Hz, 1H); 7.83 (s, 1H); 7.43-7.40 (m, 1H); 6.42 (d,
J = 8.8 Hz, 1H); 4.39-4.34 (m, 3H); 4.18-4.15 (m, 2H); 3.48-3.43
(m, 4H); 2.87-2.80 (m, 2H); 2.18 (s, 3H); 1.88-1.84 (m, 2H);
1.68-1.62 (m, 1H); 1.49-1.42 (m, 2H). 20.8 ##STR01908##
(CD.sub.3OD, 400 MHz): 8.34 (d, J = 8.0 Hz, 1H); 7.89 (s, 1H); 7.88
(t, J = 1.2 Hz, 1H); 7.86 (t, J = 1.2 Hz, 1H); 7.81-7.78 (m, 2H);
7.70-7.66 (m, 1H); 7.61-7.57 (m, 1H); 7.54-7.50 (m, 1H); 7.03 (d, J
= 9.2 Hz, 1H); 4.97-4.90 (m, 6H); 3.67 (d, J = 12.4 Hz, 2H); 3.54
(d, J = 6.0 Hz, 2H); 3.05-2.99 (m, 2H); 1.98-1.94 (m, 2H);
1.76-1.73 (m, 2H). 20.9 ##STR01909## (CD.sub.3OD, 400 MHz):
8.19-8.16 (m, 2H); 7.82 (d, J = 7.6 Hz, 1H); 7.77-7.71 (m, 2H);
7.45 (t, J = 7.6 Hz, 1H); 7.37 (d, J = 10.4 Hz, 1H); 7.04 (d, J =
9.2 Hz, 1H); 6.04 (s, 1H); 5.74 (s, 1H); 4.72 (s, 2H); 3.47-3.43
(m, 4H); 2.67 (t, J = 10.8 Hz, 2H); 1.83-1.80 (m, 2H); 1.60-1.57
(m, 1H); 1.43-1.31 (m, 3H). 20.10 ##STR01910## (CDCl.sub.3, 400
MHz): 8.77 (s, 1H); 7.82 (d, J = 8.8 Hz, 1H); 7.66 (s, 1H); 7.54
(d, J = 7.6 Hz, 1H); 7.46 (t, J = 7.6 Hz, 1H); 7.15 (t, J = 8.0 Hz,
1H); 6.81 (t, J = 2.0 Hz, 1H); 6.61 (d, J = 8.8 Hz, 1H); 4.60-4.58
(m, 4H); 4.41-4.16 (m, 1H); 3.55 (s, 2H); 3.23 (d, J = 12.4 Hz,
2H); 2.70-2.68 (m, 2H); 1.86 (d, J = 12.0 Hz, 2H); 1.64 (s, 2H);
1.51-1.37 (m, 1H)
##STR01911##
Examples 21.2, 21.2 and 21.3
Racemic Mixture and Separated Enantiomers, Wherein the Absolute
Stereospecificity were not Determined
##STR01912##
[0634] STEP 1. (R &
S)-2-{3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-QUINOL-
INE
[0635] To a solution of
2-Azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride
(44) (127 mg, 0.5 mmol, PREPARATION 13) and 2-chloro-quinoline
(81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (325
mg, 1 mmol). The reaction mixture was stirred at 100.degree. C.
overnight. The reaction mixture was diluted with water, extracted
with EtOAc (2.times.20 mL). The combined organic extracts were
washed with water (15 mL) and brine (15 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
(rac)-2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-qui-
noline (127.65 mg, 0.37 mmol, yield 74%).
[0636] ESI-MS (M+1): 346. PDE10 IC.sub.50 (uM): 0.00465.
[0637] (CDCl.sub.3, 400 MHz): 8.05 (d, J=8.4 Hz, 1H); 8.00 (d,
J=9.2 Hz, 1H); 7.93 (d, J=2.4 Hz, 1H); 7.84 (d, J=2.4 Hz, 1H);
7.66-7.60 (m, 2H); 7.35 (t, J=7.6 Hz, 1H); 6.58 (d, J=9.6 Hz, 1H);
4.94-4.51 (m, 4H); 4.48-4.34 (m, 1H); 3.45 (s, 3H); 3.08 (s, 1H);
2.31-2.25 (m, 1H); 2.09-2.02 (m, 1H); 1.58-1.51 (m, 1H); 1.07 (d,
J=6.8 Hz, 3H).
STEP 2. (R OR
S)-2-{3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-QUINOL-
INE
[0638] The racemic
2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline
obtained above (450 mg, 1.3 mmol) was separated by chiral prep.
HPLC (Column: Chiralcel OD-H 250*30 mm, 5 u; Mobile phase: 85%
hexane in EtOH (0.05% diethyl amine); Flow rate: 30 mL/minute) to
give their separated stereoisomers (187 mg, 0.54 mmol, 42% yield)
and (175 mg, 0.50 mmol, 38.5% yield). The absolute
stereospecificity was not determined.
[0639] Separated isomer Example 21.2: ESI-MS (M+1): 346. PDE10
IC.sub.50 (uM): 0.00367.
[0640] (CDCl.sub.3, 400 MHz): 7.97-7.93 (m, 2H); 7.87 (d, J=8.8 Hz,
1H); 7.73 (d, J=8.4 Hz, 1H); 7.60 (d, J=8.0 Hz, 1H); 7.53 (t, J=8.4
Hz, 1H); 7.22 (t, J=7.6 Hz, 1H); 6.66 (d, J=9.2 Hz, 1H); 4.59-4.53
(m, 3H); 4.43 (t, J=8.0 Hz, 1H); 4.33-4.26 (m, 1H); 3.66-3.48 (m,
3H); 3.18 (t, J=8.8 Hz, 1H); 2.37-2.30 (m, 1H); 2.13-2.09 (m, 1H);
1.65-1.55 (m, 1H); 1.22 (d, J=6.8 Hz, 3H).
[0641] Separated isomer Example 21.3: ESI-MS (M+1): 346. PDE10
IC.sub.50 (uM): 0.00367.
[0642] (CDCl.sub.3, 400 MHz): 7.86-7.83 (m, 2H); 7.76 (d, J=8.8 Hz,
1H); 7.64 (d, J=8.4 Hz, 1H); 7.50 (d, J=7.6 Hz, 1H); 7.45-7.42 (m,
1H); 7.12 (t, J=8.4 Hz, 1H); 6.55 (d, J=8.8 Hz, 1H); 4.48-4.43 (m,
3H); 4.18 (t, J=8.4 Hz, 1H); 4.20-4.17 (m, 1H); 3.55-3.38 (m, 3H);
3.10-3.06 (m, 1H); 2.25-2.24 (m, 1H); 2.03-1.99 (m, 1H); 1.52-1.47
(m, 1H); 1.05-1.04 (d, J=6.8 Hz, 3H).
##STR01913##
Example 22.1
2-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-3-M-TOLYL-QUINOXALINE
[0643] To a solution of 2-azetidin-3-yl-3-m-tolyl-quinoxaline
hydrochloride (311 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1.0
mmol) in DMF (6 mL) was added Cs.sub.2CO.sub.3 (650 mg, 2 mmol).
The reaction mixture was stirred at 100.degree. C. overnight. The
reaction mixture was diluted with water, extracted with EtOAc
(2.times.30 mL). The combined organic extracts were washed with
water (20 mL) and brine (20 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
2-(1-quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline (256 mg,
0.64 mmol yield 63.7%).
[0644] The following Table 28A lists compounds of Examples 22.1 to
22.4, which were made analogous to Scheme 22 by using the
appropriate materials and reaction conditions, which are listed in
Table 28B. The NMR data of the Examples are listed in Table
28C.
TABLE-US-00057 TABLE 28A EXAMPLES 22.1 TO 22.4 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 22.1 ##STR01914##
2-(1-Quinolin-2-yl-azetidin- 3-yl)-3-m-tolyl-quinoxaline 403
0.00399 22.2 ##STR01915## 4-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-quinoxalin-2- yl]-phenylamine 404 0.00156 22.3
##STR01916## 3-[3-(1-Quinolin-2-yl- azetidin-3-yl)-quinoxalin-2-
yl]-phenol 405 0.00099 22.4 ##STR01917## 2-(3-Methoxy-phenyl)-3-(1-
quinolin-2-yl-azetidin-3-yl)- quinoxaline 419 0.00222
TABLE-US-00058 TABLE 28B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 22.1 TO 22.4. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 22.1 ##STR01918## ##STR01919## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 22.2 ##STR01920## ##STR01921## Cs.sub.2CO.sub.3,
DMF, 100.degree. C. 22.3 ##STR01922## ##STR01923##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 22.4 ##STR01924##
##STR01925## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
TABLE-US-00059 TABLE 28C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
22.1 TO 22.4 Ex. # Structure NMR 22.1 ##STR01926## (DMSO, 400 MHz):
8.15-8.08 (m, 2H); 8.01 (d, J = 8.0 Hz, 1H); 7.84-7.82 (m, 2H);
7.68 (d, J = 7.6 Hz, 1H); 7.53-7.47 (m, 4H); 7.39- 7.31 (m, 2H);
7.21-7.17 (m, 1H); 6.75 (d, J = 8.8 Hz, 1H); 4.58-4.54 (m, 1H);
4.39 (t, J = 8.0 Hz, 2H); 4.26 (t, J = 8.4 Hz, 2H); 2.38 (s, 3H).
22.2 ##STR01927## (CD.sub.3OD, 400 MHz): 8.89 (d, J = 8.8 Hz, 1H);
8.11-8.08 (m, 2H); 7.86-7.82 (m, 3H); 7.75- 7.72 (m, 4H); 7.49-7.42
(m, 3H); 6.92 (d, J = 9.2 Hz, 1H); 4.85-4.68 (m, 5H). 22.3
##STR01928## (CD.sub.3OD, 400 MHz): 8.29 (d, J = 9.2 Hz, 1H);
8.15-8.09 (m, 2H); 7.87-7.83 (m, 3H); 7.78- 7.73 (m, 2H); 7.50-7.40
(m, 2H); 7.10-6.99 (m, 3H); 6.94 (d, J = 9.2 Hz, 1H); 4.81-4.67 (m,
5H). 22.4 ##STR01929## (CD.sub.3OD, 400 MHz): 8.27 (d, J = 8.0 Hz,
1H); 8.25-8.28 (m, 2H); 7.86-7.82 (m, 3H); 7.77- 7.71 (m, 2H);
7.53-7.46 (m, 2H); 7.21-7.13 (m, 3H); 6.93 (d, J = 9.2 Hz, 1H);
4.81-4.66 (m, 5H); 3.88 (s, 3H).
##STR01930##
Example 23.1
2-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PHENOL
[0645] To a solution of 2-(3-azetidin-3-yl-pyrazin-2-yl)-phenol
hydrochloride (275 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1
mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (650 mg, 2 mmol).
The reaction mixture was stirred at 100.degree. C. overnight. The
reaction mixture was diluted with water, extracted with EtOAc (30
mL.times.2). 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 ISCO silica gel column (10% to 80% EtOAc in petroleum
ether) to give
2-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (56 mg,
0.16 mmol, yield 16%).
[0646] The following Table 29A lists compounds of Examples 23.1 to
23.8, which were made analogous to Scheme 23 by using the
appropriate materials and reaction conditions, which are listed in
Table 29B. The NMR data of the Examples are listed in Table
29C.
TABLE-US-00060 TABLE 29A EXAMPLES 23.1 TO 23.8 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (uM) 23.1 ##STR01931##
2-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenol 355
0.0339 23.2 ##STR01932## 3-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-phenol 355 0.00465 23.3 ##STR01933##
4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenol 355
0.00442 23.4 ##STR01934## 2-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-phenylamine 354 0.133 23.5
##STR01935## 3-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-
yl]-phenylamine 354 0.0111 23.6 ##STR01936## 4-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-phenylamine 354 0.00522 23.7
##STR01937## 2-{3-[3-(4-Fluoro-3- methoxy-phenyl)-pyrazin-
2-yl]-azetidin-1-yl}- quinoline 387 0.00298 23.8 ##STR01938##
2-Fluoro-4-[3-(1-quinolin- 2-yl-azetidin-3-yl)-
pyrazin-2-yl]-phenylamine 372 0.00437
TABLE-US-00061 TABLE 29B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 23.1 TO 23.8. Unless otherwise stated,
all starting materials are commercially available from common
vendors Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 23.1 ##STR01939## ##STR01940## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 23.2 ##STR01941## ##STR01942## Cs.sub.2CO.sub.3,
DMF, 100.degree. C. 23.3 ##STR01943## ##STR01944##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 23.4 ##STR01945##
##STR01946## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 23.5
##STR01947## ##STR01948## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
23.6 ##STR01949## ##STR01950## Cs.sub.2CO.sub.3, DMF, 100.degree.
C. 23.7 ##STR01951## ##STR01952## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 23.8 ##STR01953## ##STR01954## Cs.sub.2CO.sub.3,
DMF, 100.degree. C.
TABLE-US-00062 TABLE 29C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
23.1 TO 23.8 Ex. # Structure NMR 23.1 ##STR01955## (CDCl.sub.3, 400
MHz): 8.57 (s, 2H); 8.06 (d, J = 9.6 Hz, 1H); 7.94 (d, J= 8.4 Hz,
1H); 7.73-7.68 (m, 2H); 7.45-7.41 (m, 1H); 7.35-7.31 (m, 1H);
7.29-7.28 (m, 1H); 7.06 (d, J = 8.4 Hz, 1H); 7.02-6.98 (m, 1H);
6.62 (d, J = 9.6 Hz, 1H); 5.07 (s, 1H); 4.88-4.72 (m, 3H); 4.55 (s,
1H); 4.33 (s, 1H) 23.2 ##STR01956## (CD.sub.3OD, 400 MHz): 8.68 (m,
1H); 8.52 (m, 1H); 8.49 (m, 1H); 8.28 (d, J = 7.2 Hz, 1H);
7.79-7.71 (m, 2H); 7.51-7.47 (m, 1H); 7.39-7.35 (m, 1H); 6.99-6.91
(m, 4H); 4.86-4.61 (m, 5H) 23.3 ##STR01957## (CDCl.sub.3, 400 MHz):
8.56-8.52 (m, 2H); 7.82 (d, J = 8.8 Hz, 1H); 7.95 (d, J = 8.4 Hz,
1H); 7.73- 7.67 (m, 2H); 7.42 (t, J = 8.0 Hz, 1H); 7.19 (d, J = 8.0
Hz, 2H); 6.88 (d, J = 8.8 Hz, 2H); 6.62 (d, J = 9.2 Hz, 1H); 4.73
(m, 2H); 4.36 (m, 1H); 4.19 (s, 2H). 23.4 ##STR01958## (CDCl.sub.3,
400 MHz): 8.49 (s, 1H); 8.41 (s, 1H); 7.65 (d, J = 8.8 Hz, 1H);
7.51 (d, J = 8.0 Hz, 1H); 7.46 (d, J = 1.2 Hz, 1H); 7.45-7.42 (m,
1H); 7.12-7.10 (m, 2H); 6.94 (dd, J = 7.6 Hz, 1H); 6.81-6.75 (m,
2H); 6.52 (d, J= 8.8 Hz, 1H); 4.37-4.21 (m, 5H); 4.13 (s, 2H) 23.5
##STR01959## (CDCl.sub.3, 400 MHz): 8.61-8.52 (m, 2H); 8.05 (d, J =
9.6 Hz, 1H); 8.00 (d, J = 8.4 Hz, 1H); 7.69- 7.69 (m, 2H);
7.41-7.26 (m, 2H); 7.02-6.98 (m, 2H); 6.91-6.90 (m, 1H); 6.62 (d, J
= 9.2 Hz, 1H); 4.85-4.31 (m, 5H). 23.6 ##STR01960## (CD.sub.3OD,
400 MHz): 8.63 (d, J = 2.4 Hz, 1H); 8.56 (d, J = 2.4 Hz, 1H); 8.31
(d, J = 9.2 Hz, 1H); 7.89 (d, J = 8.4 Hz, 1H); 7.78-7.75 (m, 2H);
7.50 (m, 1H); 7.45 (d, J = 8.4 Hz, 2H); 7.06 (d, J = 8.4 Hz, 2H);
6.94 (d, J = 9.6 Hz, 1H); 4.70 (s, 5H). 23.7 ##STR01961## (CDCl3,
400 MHz): 8.63 (d, J = 2.4 Hz, 1H); 8.57 (d, J = 2.0 Hz, 1H); 7.90
(d, J = 8.0 Hz, 1H); 7.76 (d, J = 9.2 Hz, 1H); 7.64 (dd, J = 1.2,
8.0 Hz, 1H); 7.59-7.55 (m, 1H); 7.28-7.20 (m, 3H); 7.06-7.03 (m,
1H); 6.67 (d, J = 8.8 Hz, 1H); 4.49-4.45 (m, 5H); 4.01 (s, 3H) 23.8
##STR01962## (CDCl3, 400 MHz): 8.43 (d, J = 2.0 Hz, 1H); 8.41 (d, J
= 2.0 Hz, 1H); 7.80 (d, J = 8.8 Hz, 1H); 7.66 (d, J = 8.4 Hz, 1H);
7.53 (dd, J = 1.2, 8.0 Hz, 1H); 7.48-7.44 (m, 1H); 7.17-7.13 (m,
2H); 7.06-7.03 (m, 1H); 6.81 (t, J = 8.8 Hz, 1H); 6.55 (d, J = 8.8
Hz, 1H); 4.38-4.35 (m, 5H); 4.01 (s, 2H)
##STR01963##
Example 24.1
2-[3-(3-PIPERIDIN-1-YL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-QUINOLINE
[0647] To a solution of 2-azetidin-3-yl-3-piperidin-1-yl-pyrazine
hydrochloride (127 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg
0.5 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (325 mg, 1
mmol). The reaction mixture was stirred at 100.degree. C.
overnight. The reaction mixture was diluted with water, extracted
with EtOAc (2.times.20 mL). The combined organic extracts were
washed with water (15 mL) and brine (15 mL), dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated in vacuo
and the residue was purified by ISCO silica gel column (10% to 80%
EtOAc in petroleum ether) to give
2-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (58
mg, 0.17 mmol yield 17%).
[0648] The following Table 30A lists compounds of Examples 24.1 to
24.7, which were made analogous to Scheme 24 by using the
appropriate materials and reaction conditions, which are listed in
Table 30B. The NMR data of the Examples are listed in Table
30C.
TABLE-US-00063 TABLE 30A EXAMPLES 24.1 TO 24.7 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 24.1 ##STR01964##
2-[3-(3-Piperidin-1-yl- pyrazin-2-yl)-azetidin-1- yl]-quinoline 346
0.00393 24.2 ##STR01965## 2-{3-[3-(4-Methyl-
piperidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-quinoline 368
0.000803 24.3 ##STR01966## 1-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-piperidine-4-carboxylic acid amide
389 0.00048 24.4 ##STR01967## 1-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-piperidine-4-carboxylic acid
dimethylamide 417 0.00355 24.5 ##STR01968## 1-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-piperidine-4-carboxylic acid
methylamide 403 0.00251 24.6 ##STR01969## 1-[3'-(1-Quinolin-2-yl-
azetidin-3-yl)-2,3,5,6- tetrahydro- [1,2']bipyrazinyl-4-yl]-
ethanone 389 0.029 24.7 ##STR01970## 1-[3-(1-Quinolin-2-yl-
azetidin-3-yl)-pyrazin-2- yl]-piperidin-4-ol 362 0.00497
TABLE-US-00064 TABLE 30B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 24.1 TO 24.7. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 24.1 ##STR01971## ##STR01972## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 24.2 ##STR01973## ##STR01974## Cs.sub.2CO.sub.3,
DMF, 100.degree. C. 24.3 ##STR01975## ##STR01976##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 24.4 ##STR01977##
##STR01978## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 24.5
##STR01979## ##STR01980## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
24.6 ##STR01981## ##STR01982## Cs.sub.2CO.sub.3, DMF, 100.degree.
C. 24.7 ##STR01983## ##STR01984## Cs.sub.2CO.sub.3, DMF,
100.degree. C.
TABLE-US-00065 TABLE 30C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
24.1 TO 24.7 Ex. # Structure NMR 24.1 ##STR01985## (CDCl.sub.3, 400
MHz): 8.12 (s, 2H); 8.05 (d, J = 20.8 Hz, 1H); 7.96 (d, J = 8.4 Hz,
1H); 7.67-7.63 (m, 2H); 7.40- 7.36 (m, 1H); 6.62 (d, J = 9.2 Hz,
1H); 5.07 (s, 1H); 4.75-4.71 (m, 3H); 4.39-4.36 (m, 1H); 3.06-3.04
(m, 4H); 1.75-1.69 (m, 4H); 1.64-1.62 (m, 2H). 24.2 ##STR01986##
(CDCl.sub.3, 400 MHz): 8.12 (d, J = 2.4 Hz, 1H); 8.06 (d, J = 2.4
Hz, 1H); 7.85 (d, J = 8.8 Hz, 1H); 7.74 (d, J = 8.4 Hz, 1H); 7.58
(d, J = 8.0 Hz, 1H); 7.50 (t, J = 2.8 Hz, 2H); 7.20-7.18 (m, 1H);
6.64 (d, J = 8.8 Hz, 1H); 4.56- 4.52 (m, 2H); 4.47-4.43 (m, 2H);
4.33-4.26 (m, 1H); 3.38 (d, J = 12.8 Hz, 2H); 2.83 (t, J = 12.0 Hz,
2H); 1.77 (d, J = 12.4 Hz, 2H); 1.57 (s, 1H); 1.44-1.35 (m, 2H);
1.01 (d, J = 6.4 Hz, 3H). 24.3 ##STR01987## (CDCl3, 400 MHz): 8.21
(m, 2H); 8.19 (dd, J = 2.4, 7.2 Hz, 2H); 8.09 (d, J = 9.2 Hz, 1H);
8.06 (d, J = 8.4 Hz, 1H); 7.75-7.69 (s, 1H); 6.68-6.66 (d, J = 9.2
Hz, 1H); 5.84 (s, 1H); 4.98 (s, 1H); 4.69 (m, 2H); 4.47-4.43 (m,
1H); 3.45 (d, J = 12.4 Hz, 2H); 2.89 (m, 2H); 2.42-2.41 (m, 1H);
2.06-2.04 (m, 4H) 24.4 ##STR01988## (CD.sub.3OD, 400 MHz): 8.31 (d,
J = 9.6 Hz, 1H); 8.20 (dd, J = 2.4, 15.6 Hz, 2H); 7.87 (d, J = 8.0
Hz, 1H); 7.80-7.74 (m, 2H); 7.51-7.47 (m, 1H); 6.98 (d, J = 9.6 Hz,
1H); 4.90 (t, J = 9.2 Hz, 2H); 4.73 (t, J = 7.8 Hz, 2H); 4.60- 4.57
(m, 1H); 3.49 (d, J = 12.8 Hz, 2H); 3.14 (s, 3H); 3.01-2.91 (m,
5H); 2.43-2.38 (m, 1H); 1.94-1.85 (m, 4H). 24.5 ##STR01989##
(CD.sub.3OD, 400 MHz): 8.33 (d, J = 9.6 Hz, 1H); 8.23 (d, J = 2.4
Hz, 1H); 8.19 (d, J = 2.4 Hz, 1H); 7.89 (d, J = 7.6 Hz, 1H);
7.79-7.76 (m, 2H); 7.53-7.49 (m, 1H); 7.00 (d, J= 9.6 Hz, 1H);
4.93-4.89 (m, 2H); 4.74 (t, J = 6.4 Hz, 2H); 4.60-4.56 (m, 1H);
3.50-3.47 (d, J = 12.8 Hz, 2H); 2.93-2.91 (m, 2H); 2.75 (s, 3H);
2.43-2.38 (m, 1H); 1.93- 1.98 (m, 4H). 24.6 ##STR01990## (MeOD, 400
MHz): 8.32 (d, J = 9.6 Hz, 1H); 8.28 (d, J = 2.4 Hz, 1H); 8.22 (d,
J = 2.4 Hz, 1H); 7.88 (d, J = 8.0 Hz, 1H); 7.80-7.74 (m, 2H);
7.52-7.48 (m, 1H); 6.99 (d, J = 9.6 Hz, 1H); 4.91 (d, J = 9.2 Hz,
2H); 4.75 (s, 2H); 4.63-4.59 (m, 1H); 3.79-3.73 (m, 4H); 3.23 (t, J
= 5.2 Hz, 2H); 3.14 (t, J = 5.2 Hz, 2H); 2.15 (s, 3H). 24.7
##STR01991## (MeOD, 400 MHz): 8.07-8.02 (m, 2H); 7.94 (d, J= 9.2
Hz, 1H); 7.59 (d, J = 8.8 Hz, 2H); 7.47 (t, J = 6.4 Hz, 1H); 7.16
(t, J = 6.0 Hz, 1H); 6.69 (d, J = 9.2 Hz, 1H); 4.52 (s, 2H);
4.35-3.34 (m, 3H); 3.75-3.68 (m, 1H); 3.37- 3.29 (m, 2H); 2.89 (m,
2H); 1.95-1.89 (m, 2H); 1.69- 1.65 (m, 2H).
##STR01992##
Example 25.1
2-METHOXY-1-{4-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN--
1-YL}-ETHANONE
[0649] A solution of 2-azetidin-3-yl-3-chloro-pyrazine
hydrochloride (190 mg, 0.5 mmol) and Et.sub.3N (101 mg, 1 mL,) in
DCM (15 mL) was added methoxy-acetyl chloride (purchased from
ALDRICH) (81 mg, 0.75 mmol). The reaction was stirred at RT for 2
h. The reaction mixture was concentrated and purified by ISCO
silica gel column (10% to 80% EtOAc in petroleum ether) give the
product
2-methoxy-1-{4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-
-1-yl}-ethanone (82 mg, 0.20 mmol, 39% yield).
[0650] The following Table 31A lists compounds of Examples 25.1 to
25.4, which were made analogous to Scheme 25 by using the
appropriate materials and reaction conditions, which are listed in
Table 31B. The NMR data of the Examples are listed in Table
31C.
TABLE-US-00066 TABLE 31A EXAMPLES 25.1 TO 25.4 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 25.1 ##STR01993##
2-Methoxy-1-{4-[3-(1- quinolin-2-yl-azetidin-3- yl)-pyrazin-2-yl]-
piperidin-1-yl}-ethanone 418 0.0636 25.2 ##STR01994##
1-{4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-
yl]-piperidin-1-yl}- ethanone 388 0.0342 25.3 ##STR01995##
N-{4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-
yl]-phenyl}-acetamide 396 0.00236 25.4 ##STR01996##
1-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-
2-yl)-5,6-dihydropyridin- 1(2H)-yl)ethanone 386 0.0006
TABLE-US-00067 TABLE 31B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 25.1 TO 25.4. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 25.1 ##STR01997## ##STR01998## Et.sub.3N, DCM 25.2 54
PREPARATION 16 ##STR01999## Et.sub.3N, DCM 25.3 ##STR02000##
##STR02001## Et.sub.3N, DCM 25.4 ##STR02002## ##STR02003##
Et.sub.3N, DCM
TABLE-US-00068 TABLE 31C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
25.1 TO 25.4 Ex. # Structure NMR 25.1 ##STR02004## (CD.sub.3OD, 400
MHz): 8.41-8.38 (m, 2H); 7.97 (t, J = 7.6 Hz, 1H); 7.64 (t, J = 8.8
Hz, 2H); 7.54-7.50 (m, 1H); 7.24-7.19 (m, 1H); 6.72 (t, J = 8.8 Hz,
1H); 4.64-4.44 (m, 6H); 4.22-4.11 (m, 2H); 3.97 (d, J = 13.2 Hz,
1H); 3.42 (s, 3H); 3.30-3.15 (m, 2H); 2.84-2.82 (m, 1H); 1.82- 1.78
(m, 4H) 25.2 ##STR02005## (CDCl.sub.3, 400 MHz): 8.35-8.33 (m, 2H);
7.85 (d, J = 8.8 Hz, 1H); 7.72 (d, J = 8.4 Hz, 1H); 7.55 (dd, J =
1.2, 8.0 Hz, 1H); 7.51-7.47 (m, 1H); 7.21-7.17 (m, 1H); 6.61 (d, J
= 8.8 Hz, 1H); 4.73 (d, J = 12.4 Hz, 1H); 4.60-4.47 (m, 4H);
4.36-4.32 (m, 1H); 3.94-3.91 (m, 1H), 3.19-3.13 (m, 1H); 2.95-2.88
(m, 1H); 2.64-3.63 (m, 1H); 2.07 (s, 3H); 2.03-2.00 (m, 1H);
1.77-1.71 (m, 3H). 25.3 ##STR02006## (CD.sub.3OD, 400 MHz):
8.53-8.44 (m, 2H); 7.94 (d, J = 9.2 Hz, 1H); 7.69 (d, J = 8.4 Hz,
2H); 7.60-7.56 (m, 2H); 7.47-7.42 (m, 3H); 7.18 (t, J = 7.6 Hz,
1H); 6.64 (d, J = 9.2 Hz, 1H); 4.39- 4.33 (m, 5H); 2.08 (s, 3H).
25.4 ##STR02007## (400 MHz, chloroform-d) 2.19 (d, J = 5.87 Hz, 3
H) 2.69 (br. S., 2 H) 3.72 (t, J = 5.58 Hz, 1 H) 3.89 (t, J = 5.58
Hz, 1 H) 4.19 (d, J = 2.54 Hz, 1 H) 4.31 (d, J = 2.54 Hz, 1 H)
4.36-4.56 (m, 5H), 5.77-5.88 (m, 1 H) 6.65 (dd, J = 8.90, 2.25 Hz,
1 H) 7.22 (t, J = 7.43 Hz, 1 H) 7.53 (t, J = 7.63 Hz, 1 H) 7.61 (d,
J = 8.02 Hz, 1 H) 7.74 (d, J = 8.41 Hz, 1 H) 7.89 (dd, J = 8.90,
3.03 Hz, 1 H) 8.42 (t, J = 2.93 Hz, 1 H) 8.49 (d, J = 2.54 Hz, 1
H).
##STR02008##
Examples 26.1, 26.2, and 26.3
Racemic Mixtures and Separated Enantiomers, Absolute
Stereochemistry not Further Determined
STEP 1.
1-{1-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-4--
YL}-ETHANONE
[0651] To a solution of
2-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-quinoline (80 mg, 0.27
mmol) and 1-piperidin-4-yl-ethanone (WUXI APPTEC) (34.3 mg, 0.27
mmol) in DMSO (5 mL) was added Et.sub.3N (54.5 mg, 0.54 mmol). The
reaction mixture was stirred at 100.degree. C. overnight. The
reaction mixture was diluted with water, extracted with EtOAc (20
mL.times.3). 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
1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl-
}-ethanone (65.8 mg, 0.17 mmol, yield 62.9%). ESI-MS (M+1): 388
calc. for C.sub.23H.sub.25N.sub.5O 387.
##STR02009##
STEP 2. (S &
R)-1-{1-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}--
ETHANOL
[0652] A solution of
1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-eth-
anone (96.75 mg, 0.25 mmol) in MeOH (10 mL) was added NaBH.sub.4
(37 mg, 1 mmol). The mixture was stirred at RT for 2 h. The
reaction mixture was concentrated to give the product
(racemic)-1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-
-4-yl}-ethanol (76 mg, 0.20 mmol, yield 78%).
[0653] ESI-MS (M+1): 390. PDE10 IC.sub.50 (uM): 0.00805.
[0654] (CD.sub.3OD, 400 MHz): 8.31 (d, J=9.2 Hz, 1H); 8.22-8.16 (m,
2H); 7.88 (d, J=7.6 Hz, 1H); 7.78-7.75 (m, 2H); 7.52-7.48 (m, 1H);
6.98 (d, J=9.6 Hz, 1H); 4.89 (d, J=7.2 Hz, 1H); 4.72 (t, J=7.2 Hz,
2H); 4.56-4.55 (m, 1H); 3.60-3.57 (m, 1H); 3.47 (d, J=12.8 Hz, 2H);
2.87-2.84 (m, 2H); 1.98-1.97 (m, 1H); 1.77-1.76 (m, 1H); 1.56-1.48
(m, 3H); 1.47 (d, J=3.2 Hz, 1H); 1.20 (d, J=6.4 Hz, 3H).
##STR02010##
STEP 3. SEPARATED R AND
S-1-{1-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}-E-
THANOL
[0655] The racemic mixture of
1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-eth-
anol (450 mg, 1.16 mmol) was separated by chiral prep. HPLC
(Column: Chiralpak AD-H 250*30 mm, 5 u; Mobile phase: 70% hexane in
EtOH (0.05% diethyl amine); Flow rate: 20 mL/minute) to give their
separated enantiomers (152 mg, 0.41 mmol, 34% yield) and 182 mg,
0.47 mmol, 41% yield).
[0656] Separated isomer Example 26.2: ESI-MS (M+1): 390. PDE10
IC.sub.50 (uM): 0.00237.
[0657] .sup.1H NMR .delta. (ppm) (CDCl.sub.3, 400 MHz): 8.16-8.08
(m, 2H); 7.88 (d, J=8.8 Hz, 1H); 7.73 (d, J=8.4 Hz, 1H); 7.62-7.59
(m, 1H); 7.55-7.51 (m, 1H); 7.24-7.20 (m, 1H); 6.66 (d, J=8.8 Hz,
1H); 4.57-4.53 (m, 2H); 4.48-4.45 (m, 2H); 4.34-4.32 (m, 1H);
3.70-3.68 (m, 1H); 3.50-3.46 (m, 2H); 2.88-2.81 (m, 2H); 2.02-1.99
(m, 1H); 1.79-1.76 (m, 1H); 1.58-1.49 (m, 3H); 1.25 (d, J=6.4 Hz,
3H).
[0658] Separated isomer Example 26.3: ESI-MS (M+1): 390. PDE10
IC.sub.50 (uM): 0.00262.
[0659] .sup.1H NMR .delta. (ppm) (CDCl.sub.3, 400 MHz): 8.15-8.08
(m, 2H); 7.88 (d, J=8.8 Hz, 1H); 7.73 (d, J=8.4 Hz, 1H); 7.61-7.55
(m, 1H); 7.53-7.51 (m, 1H); 7.23-7.19 (m, 1H); 6.66 (d, J=9.2 Hz,
1H); 4.57-4.53 (m, 2H); 4.48-4.44 (m, 2H); 4.35-4.29 (m, 1H);
3.69-3.67 (m, 1H); 3.49-3.46 (m, 2H); 2.87-2.81 (m, 2H); 2.02-1.99
(m, 1H); 1.79-1.76 (m, 1H); 1.57-1.51 (m, 3H); 1.25 (d, J=6.4 Hz,
3H).
##STR02011##
Example 27.1
2-FLUORO-5-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PHENOL
[0660] To a solution of
2-{3-[3-(4-fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinolin-
e (193 mg, 0.5 mmol) in 1,2-dichloro-ethane (5 mL) was added
BBr.sub.3 (250 mg, 1.0 mmol). The reaction mixture was stirred at
RT for 2 h. The reaction mixture was diluted with water, extracted
with DCM (2.times.30 mL). The combined organic extracts were washed
with water (20 mL) and brine (20 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
2-fluoro-5-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol
(111 mg, 0.31 mmol yield 62%).
[0661] ESI-MS (M+1): 373. PDE10 IC.sub.50 (uM): 0.00284.
[0662] .sup.1H NMR .delta. (ppm) (CD.sub.3OD, 400 MHz): 8.63-8.57
(m, 2H); 8.29 (d, J=8.0 Hz, 1H); 7.87 (d, J=8.0 Hz, 1H); 7.79-7.72
(m, 2H); 7.52-7.48 (m, 1H); 7.26-7.21 (m, 1H); 7.15-7.13 (m, 1H);
7.00-6.96 (m, 1H); 6.93 (d, J=9.2 Hz, 1H); 4.68-4.64 (m, 5H).
##STR02012##
Example 28.1
(1-{3-[1-(6-METHYL-QUINOLIN-2-YL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-PIPERIDIN-4-
-YL)-METHANOL
[0663] To a solution of
[1-(3-azetidin-3-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol
hydrochloride (284 mg, 1.0 mmol) and 2-chloro-6-methyl-quinoline
(purchased from ALDRICH) (177 mg, 1.0 mmol) in DMF (15 mL) was
added Cs.sub.2CO.sub.3 (650 mg, 2.0 mmol). The reaction mixture was
stirred at 100.degree. C. overnight. The reaction mixture was
diluted with water, extracted with EtOAc (2.times.30 mL). The
combined organic extracts were washed with water (20 mL) and brine
(20 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 (EtOAc:Petrol ether=5:1) on silica gel to give
(1-{3-[1-(6-methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin--
4-yl)-methanol (102 mg, 0.26 mmol 26%).
[0664] The following Table 32A lists compounds of Examples 28.1 to
28.18, which were made analogous to Scheme 28 by using the
appropriate materials and reaction conditions, which are listed in
Table 32B. The NMR data of the Examples are listed in Table
32C.
TABLE-US-00069 TABLE 32A EXAMPLES 28.1 TO 28.18 ESI-MS Ex. #
Structure Chemical Name (M+ 1) IC.sub.50 (uM) 28.1 ##STR02013##
(1-{3-[1-(6-Methyl-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-
2-yl}-piperidin-4-yl)- methanol 390 0.00117 28.2 ##STR02014##
(1-{3-[1-(7-Fluoro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-
2-yl}-piperidin-4-yl)- methanol 394 0.0001 28.3 ##STR02015##
(1-{3-[1-(6-Fluoro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-
2-yl}-piperidin-4-yl)- methanol 394 0.0037 28.4 ##STR02016##
{1-[3-(1-[1,8]Naphthyridin- 2-yl-azetidin-3-yl)-pyrazin-
2-yl]-piperidin-4-yl}- methanol 377 0.0419 28.5 ##STR02017##
(1-{3-[1-(6-Chloro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-
2-yl}-piperidin-4-yl)- methanol 410 0.00116 28.6 ##STR02018##
(1-{3-[1-(6-Chloro- quinoxalin-2-yl)-azetidin-3-
yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0144 28.7
##STR02019## (1-{3-[1-(6-Methyl-pyridin-
2-yl)-azetidin-3-yl]-pyrazin- 2-yl}-piperidin-4-yl)- methanol 340
0.217 28.8 ##STR02020## (1-{3-[1-(5-Chloro-pyridin-
2-yl)-azetidin-3-yl]-pyrazin- 2-yl}-piperidin-4-yl)- methanol 360
0.490 28.9 ##STR02021## (1-(3-(1-(5-bromopyridin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)methanol 404 0.466
28.10 ##STR02022## (1-(3-(1-(8-methylquinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)methanol 390 0.446
28.11 ##STR02023## (1-{3-[1-(8-Fluoro-quinolin-
2-yl)-azetidin-3-yl]-pyrazin- 2-yl}-piperidin-4-yl)- methanol 394
0.00228 28.12 ##STR02024## (1-(3-(1-(8-chloroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)methanol 410 0.0233
28.13 ##STR02025## (1-{3-[1-(8-Chloro- quinazolin-2-yl)-azetidin-3-
yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0117 28.14
##STR02026## (1-{3-[1-(7-Chloro- quinazolin-2-yl)-azetidin-3-
yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0001 28.15
##STR02027## (1-{3-[1-(6-Chloro- quinazolin-2-yl)-azetidin-3-
yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0068 28.16
##STR02028## (1-{3-[1-(5-Chloro- quinazolin-2-yl)-azetidin-3-
yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 28.17 ##STR02029##
(1-{3-[1-(7-Chloro- quinoxalin-2-yl)-azetidin-3-
yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0005 28.18
##STR02030## 2-[3-(3-Piperidin-1-yl- pyrazin-2-yl)-azetidin-1-yl]-
benzothiazole 352 >10
TABLE-US-00070 TABLE 32B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 28.1 TO 28.18. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 28.1 ##STR02031## ##STR02032## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 28.2 37 PREPARATION 11 ##STR02033##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.3 37 PREPARATION 11
##STR02034## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.4 37
PREPARATION 11 ##STR02035## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
28.5 37 PREPARATION 11 ##STR02036## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 28.6 37 PREPARATION 11 ##STR02037##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.7 37 PREPARATION 11
##STR02038## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.8 37
PREPARATION 11 ##STR02039## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
28.9 37 PREPARATION 11 ##STR02040## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 28.10 37 PREPARATION 11 ##STR02041##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.11 37 PREPARATION 11
##STR02042## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.12 37
PREPARATION 11 ##STR02043## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
28.13 37 PREPARATION 11 ##STR02044## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 28.14 37 PREPARATION 11 ##STR02045##
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.15 37 PREPARATION 11
##STR02046## Cs.sub.2CO.sub.3, DMF, 100.degree. C. 28.16 37
PREPARATION 11 ##STR02047## Cs.sub.2CO.sub.3, DMF, 100.degree. C.
28.17 37 PREPARATION 11 ##STR02048## Cs.sub.2CO.sub.3, DMF,
100.degree. C. 28.18 ##STR02049## ##STR02050## K.sub.2CO.sub.3,
iPrOH/H.sub.2O 160.degree. C., .mu.W
TABLE-US-00071 TABLE 32C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
28.1 TO 28.18 Ex. # Structure NMR 28.1 ##STR02051## (CDCl.sub.3,
400 MHz): 8.14-8.06 (m, 2H); 7.79 (d, J = 8.8 Hz, 1H); 7.64 (d, J =
9.2 Hz, 1H); 7.37-7.35 (m, 2H); 6.62 (d, J = 9.2 Hz, 1H); 4.54-4.50
(m, 2H); 4.45-4.41 (m, 2H); 4.33-4.25 (m, 1H); 3.58-3.56 (m, 2H);
3.45- 3.42 (m, 2H) ; 2.88-2.81 (m, 2H); 2.43 (s, 3H); 1.89- 1.85
(m, 2H); 1.75-1.65 (m, 1H); 1.50-1.46 (m, 2H). 28.2 ##STR02052##
(CDCl.sub.3, 400 MHz): 8.10-8.09 (m, 1H); 8.03-8.02 (m, 1H); 7.77
(d, J = 8.8 Hz, 1H); 7.51-7.47 (m, 1H); 7.30- 7.27 (m, 1H);
6.93-6.88 (m, 1H); 6.54-6.51 (m, 1H); 4.50-4.46 (m, 2H); 4.41-4.37
(m, 2H); 4.28-4.23 (m, 1H); 3.54-3.53 (m, 2H); 3.38 (d, J = 12.8
Hz, 2H); 1.85-1.82 (m, 2H); 1.69-1.64 (m, 1H); 1.53-1.37 (m, 1H)
28.3 ##STR02053## (CDCl.sub.3, 400 MHz): 8.16-8.09 (m, 2H); 7.82
(d, J = 8.8 Hz, 1H); 7.73-7.69 (m, 1H); 7.33-7.28 (m, 1H); 7.27-
7.23 (m, 1H); 6.69 (d, J = 8.8 Hz, 1H); 4.56-4.52 (m, 2H);
4.46-4.43 (m, 2H); 4.36-4.30 (m, 1H); 3.60 (d, J = 6.4 Hz, 2H);
3.47-3.44 (m, 2H); 2.91-2.84 (m, 2H); 1.92-1.88 (m, 2H); 1.75-1.69
(m, 1H); 1.53-1.43 (m, 2H). 28.4 ##STR02054## (CD3OD, 400 MHz):
8.07 (s, 1H); 8.16-8.14 (m, 2H); 8.10 (d, J = 2.4 Hz, 1H); 8.02 (d,
J = 9.2 Hz, 1H); 7.26- 7.23 (m, 1H); 6.83 1 (d, J = 9.2 Hz, 1H);
4.55 (m, 2H); 4.37 (m, 3H); 3.50-3.43 (m, 4H); 2.89-2.83 (m, 2H);
1.89-1.86 (m, 2H); 1.68-1.64 (m, 1H); 1.50-1.40 (m, 2H). 28.5
##STR02055## (CDCl.sub.3, 400 MHz): 8.18-8.10 (m, 2H); 7.80 (d, J =
4.8 Hz, 1H); 7.67 (d, J = 5.2 Hz, 1H); 7.59 (s, 1H); 7.49- 7.46 (m,
1H); 6.68 (d, J = 8.8 Hz, 1H); 4.58-4.54 (m, 2H); 4.49-4.46 (m,
2H); 4.37-4.30 (m, 1H); 3.62 (d, J = 6.4 Hz, 2H); 3.46 (d, J = 12.8
Hz, 2H); 2.92-2.86 (m, 2H); 1.93-1.90 (m, 2H); 1.76-1.69 (m, 1H);
1.54-1.44 (m, 2H). 28.6 ##STR02056## (CDCl.sub.3, 400 MHz):
8.20-8.13 (m, 2H); 8.13 (t, J = 2.4 Hz, 1H); 7.89 (d, J = 2.4 Hz,
1H); 7.65 (d, J = 8.8 Hz, 1H); 7.54-7.51 (m, 1H); 4.67-4.62 (m,
2H); 4.59-4.55 (m, 2H); 4.44-4.37 (m, 1H); 3.61 (d, J = 6.0 Hz,
2H); 3.46 (d, J = 12.8 Hz, 2H); 2.94-2.87 (m, 2H); 1.94-1.91 (m,
2H); 1.81-1.71 (m, 1H); 1.55-1.48 (m, 2H). 28.7 ##STR02057##
(CDCl.sub.3, 400 MHz): 8.09 (s, 1H); 8.00 (s, 1H); 7.30- 7.26 (m,
1H); 6.42-6.40 (m, 1H); 6.12-6.10 (m, 1H); 4.32 (s, 2H); 4.21-4.20
(m, 3H); 3.53-3.51 (m, 2H); 3.39-3.36 (m, 2H); 2.81-2.75 (m, 2H);
2.33 (s, 3H); 1.82-1.79 (m, 2H); 1.65-1.63 (m, 1H); 1.45-1.34 (m,
2H); 1.18-1.17 (m, 1H). 28.8 ##STR02058## (CDCl.sub.3, 400 MHz):
8.10-8.09 (m, 1H); 8.02-8.01 (m, 2H); 7.35-7.32 (m, 1H); 6.24 (d, J
= 8.8 Hz, 1H); 4.33- 4.29 (m, 2H); 4.25-4.19 (m, 3H); 3.51 (d, J =
6.0 Hz, 2H); 3.35 (d, J = 12.4 Hz, 2H); 2.81-2.75 (m, 2H);
1.83-1.80 (m, 2H); 1.70-1.59 (m, 1H); 1.43-1.36 (m, 2H). 28.9
##STR02059## (CDCl.sub.3, 400 MHz): 8.16 (s, 2H); 8.08 (d, J = 3.2
Hz, 1H); 6.27 (d, J = 8.8 Hz, 1H); 4.39-4.35 (m, 2H); 4.32- 4.27
(m, 3H); 3.58 (s, 2H); 3.43-3.40 (m, 3H); 2.88- 2.82 (m, 2H);
2.05-2.00 (m, 1H); 1.89-1.86 (m, 2H); 1.74-1.68 (m, 1H); 1.50-1.40
(m, 1H). 28.10 ##STR02060## (CDCl.sub.3, 400 MHz): 8.19-8.11 (m,
2H); 7.89 (d, J = 8.8 Hz, 1H); 7.49 (d, J = 8.0 Hz, 1H); 7.43 (d, J
= 6.8, 1H); 7.15 (t, J = 7.6 Hz, 1H); 6.69 (d, J = 8.8 Hz, 1H);
4.57-4.53 (m, 2H); 4.47-4.43 (m, 2H); 4.38-4.31 (m, 1H); 3.63-3.61
(m, 2H); 3.51-3.48 (m, 2H); 2.93-2.87 (m, 2H); 2.67 (s, 3H);
1.94-1.91 (m, 2H); 1.82-1.62 (m, 1H); 1.55-1.45 (m, 2H). 28.11
##STR02061## (CDCl.sub.3, 400 MHz): 8.09-8.02 (m, 2H); 7.82-7.83
(m, 1H); 7.32 (d, J = 8.0 Hz, 1H); 7.21-7.16 (m, 1H); 7.07- 7.02
(m, 1H); 6.63 (d, J = 8.8 Hz, 1H); 4.53-4.49 (m, 2H); 4.45-4.41 (m,
2H); 4.29-4.23 (m, 1H); 3.53 (d, J = 6.4 Hz, 2H); 3.39 (d, J = 12.8
Hz, 2H); 2.84-2.77 (m, 2H); 1.85-1.81 (m, 2H); 1.68-1.64 (m, 1H).
1.63-1.36 (m, 2H) 28.12 ##STR02062## (CDCl.sub.3, 400 MHz):
8.09-8.02 (m, 2H); 7.80 (d, J = 8.8 Hz, 1H); 7.60-7.58 (m, 1H);
7.44-7.43 (m, 1H); 7.04 (t, J = 7.6 Hz, 1H); 6.63 (d, J = 8.8 Hz,
1H); 4.53-4.49 (m, 2H); 4.45-4.41 (m, 2H); 4.28-4.23 (m, 1H); 3.54
(d, J = 6.4 Hz, 2H); 3.39 (d, J = 12.0 Hz, 2H); 2.81 (m, 2H);
1.86-1.83 (m, 2H); 1.71-1.63 (m, 1H); 1.46-1.36 (m, 2H). 28.13
##STR02063## (CDCl.sub.3, 400 MHz): 8.99 (s, 1H); 8.16-8.15 (m,
1H); 8.08-8.07 (m, 1H); 7.76-7.74 (m, 1H); 7.58-7.56 (m, 1H);
7.13-7.09 (m, 1H); 4.64-4.57 (m, 4H); 4.31-4.27 (m, 1H); 3.58-3.55
(m, 2H); 3.45-3.41 (m, 2H); 2.88- 2.82 (m, 2H); 2.33 (s, 1H);
1.89-1.86 (m, 2H); 1.73- 1.66 (m, 1H); 1.50-1.40 (m, 2H) 28.14
##STR02064## (CDCl.sub.3, 400 MHz): 8.91 (s, 1H); 8.10 (d, J = 2.8
Hz, 1H); 8.03 (d, J = 2.8 Hz, 1H); 7.56-7.51 (m, 2H); 7.11- 7.09
(m, 1H); 4.57-4.52 (m, 2H); 4.49-4.45 (m, 2H); 4.27-4.19 (m, 1H);
3.53 (d, J = 6.4 Hz, 2H); 3.38 (d, J = 12.4 Hz, 2H); 2.84-2.78 (m,
2H); 1.84-1.81 (m, 2H); 1.71-1.62 (m, 1H); 1.47-1.43 (m, 2H) 28.15
##STR02065## (CDCl.sub.3, 400 MHz): 8.96 (s, 1H); 8.18-8.09 (m,
2H); 7.66-7.58 (m, 3H); 4.61-4.54 (m, 4H); 4.35-4.25 (m, 1H);
3.61-3.59 (m, 2H); 3.46-3.43 (m, 2H); 2.92-2.85 (m, 2H); 1.91-1.89
(m, 2H); 1.75-1.71 (m, 1H); 1.52- 1.47 (m, 2H). 28.16 ##STR02066##
(CDCl.sub.3, 400 MHz): 9.42 (s, 1H); 8.20 (d, J = 2.8 Hz, 1H); 8.12
(d, J = 2.4 Hz, 1H); 7.57-7.54 (m, 2H); 7.25- 7.23 (m, 1H);
4.67-4.63 (m, 2H); 4.59-4.55 (m, 2H); 4.35-4.31 (m, 1H); 3.64-3.62
(m, 2H); 3.48-3.45 (m, 2H); 2.93-2.86 (m, 2H); 193-1.90 (m, 2H);
1.78-1.72 (m, 1H); 1.56-1.42 (m, 3H). 28.17 ##STR02067##
(CDCl.sub.3, 400 MHz): 8.14 (s, 1H); 8.12-8.11 (m, 1H); 8.06-8.05
(m, 1H); 7.73 (d, J = 8.8 Hz, 1H); 7.63-7.62 (m, 1H); 7.26-7.24 (m,
1H); 4.58-4.51 (m, 2H); 4.49- 4.47 (m, 2H); 4.36-4.28 (m, 1H); 3.54
(d, J = 4.4 Hz, 2H); 3.38-3.35 (m, 2H); 2.86-2.79 (m, 2H);
1.85-1.83 m, 2H); 1.73-1.62 (m, 1H); 1.47-1.37 (m, 2H) 28.18
##STR02068## (CDCl.sub.3, 400 MHz): 8.70-8.69 (m, 1 H); 8.42-8.41
(m, 1 H); 7.57-7.55 (m, 1H); 7.47-7.45 (m, 1 H); 7.38-7.34 (m, 1
H); 7.26-7.22 (m, 1 H); 5.21-5.18 (m, 1H); 4.72- 4.70 (m, 1 H)(;
4.30-4.16 (m, 2 H); 4.06-3.95 (m, 3 H); 3.83-3.80 (m, 1 H);
3.46-3.41 (m, 1 H); 2.27-2.12 (m, 1 H); 2.08-1.94 (m, 4 H);
1.61-1.58 (m, 1 H).
##STR02069##
Example 29.1
2-{3-[3-(3-METHOXY-PHENYL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-8-METHYL-QUINOLINE
[0665] To a solution of
2-azetidin-3-yl-3-(3-methoxy-phenyl)-pyrazine hydrochloride (138
mg, 0.50 mmol) and 2-chloro-quinoline (84 mg, 0.50 mmol) in DMF (6
mL) was added Cs.sub.2CO.sub.3 (325 mg, 1.0 mmol). The reaction
mixture was stirred at 110.degree. C. overnight. The reaction
mixture was diluted with water, extracted with EtOAc (30
mL.times.2). 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 (20% to 40%
EtOAc in petroleum ether) to give
2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-8-methyl-qui-
noline (118 mg, 0.31 mmol, 63.35%).
[0666] The following Table 33A lists compounds of Examples 29.1 to
29.18, which were made analogous to Scheme 29 by using the
appropriate materials and reaction conditions, which are listed in
Table 33B. The NMR data of the Examples are listed in Table
33C.
TABLE-US-00072 TABLE 33A EXAMPLES 29.1 TO 29.18 ESI-MS Ex. #
Structure Chemical Name (M + 1) IC.sub.50 (uM) 29.1 ##STR02070##
2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)-8-
methylquinoline 383 0.997 29.2 ##STR02071##
6-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-
yl}-quinazoline 404 0.0750 29.3 ##STR02072##
8-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-
yl}-quinoline 403 0.111 29.4 ##STR02073##
7-Fluoro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-
yl}-quinoline 387 0.00122 29.5 ##STR02074##
2-{3-[3-(3-Methoxy-phenyl)- pyrazin-2-yl]-azetidin-1-yl}-6-
methyl-quinoline 383 0.0061- 29.6 ##STR02075##
2-{3-[3-(3-Methoxy-phenyl)- pyrazin-2-yl]-azetidin-1-yl}-
[1,8]naphthyridine 370 0.0794 29.7 ##STR02076##
8-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-
yl}-quinazoline 404 29.8 ##STR02077## 5-Chloro-2-{3-[3-(3-methoxy-
phenyl)-pyrazin-2-yl]-azetidin-1- yl}-quinazoline 404 29.9
##STR02078## 2-(3-(3-(3-methoxyphenyl)pyrazin-
2-yl)azetidin-1-yl)-4- phenylpyrimidine 396 4.3 29.10 ##STR02079##
2-(3-(3-(3-methoxyphenyl)pyrazin-
2-yl)azetidin-1-yl)benzo[d]thiazole 375 0.016 29.11 ##STR02080##
6-methoxy-2-(3-(3-(3- methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)benzo[d]thiazole 405 0.010 29.12 ##STR02081##
2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)-1,6-
naphthyridine 370 0.008 29.13 ##STR02082## 6-chloro-2-(3-(3-(3-
methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 403 0.0049
29.13 ##STR02083## 6-fluoro-2-(3-(3-(3- methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)benzo[d]thiazole 393 0.029 29.14 ##STR02084##
2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline-3-
carbonitrile 394 0.0062 29.15 ##STR02085##
1-[3-(3-Phenyl-pyrazin-2-yl)- azetidin-1-yl]-phthalazine 340 1.9100
29.16 ##STR02086## 6-chloro-2-(3-(3-phenylpyrazin-2-
yl)azetidin-1-yl)-1H- benzo[d]imidazole 362 0.0504 29.17
##STR02087## 2-(3-(3-phenylpyrazin-2-yl)azetidin-
1-yl)-1H-benzo[d]imidazole 327 0.191 29.18 ##STR02088##
2-((3-(3-phenylpyrazin-2- yl)azetidin-1-yl)methyl)-1H-
benzo[d]imidazole 342 1.07
TABLE-US-00073 TABLE 33B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 29.1 TO 29.18. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 29.1 ##STR02089## 34 PREPARATION 10 ##STR02090##
PREPARATION 33 Cs.sub.2CO.sub.3, DMF, 100.degree. C. 29.2 34
PREPARATION 10 ##STR02091## PREPARATION 34 Cs.sub.2CO.sub.3, DMF,
100.degree. C. 29.3 34 PREPARATION 10 ##STR02092## PREPARATION 33
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 29.4 34 PREPARATION 10
##STR02093## PREPARATION 33 Cs.sub.2CO.sub.3, DMF, 100.degree. C.
29.5 34 PREPARATION 10 ##STR02094## ALDRICH Cs.sub.2CO.sub.3, DMF,
100.degree. C. 29.6 34 PREPARATION 10 ##STR02095## ANICHEM
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 29.7 34 PREPARATION 10
##STR02096## PREPARATION 34 Cs.sub.2CO.sub.3, DMF, 100.degree. C.
29.8 34 PREPARATION 10 ##STR02097## PREPARATION 34
Cs.sub.2CO.sub.3, DMF, 100.degree. C. 29.9 34 PREPARATION 10
##STR02098## Combi-Blocks DMSO, 130-145.degree. C., .mu.W 29.10 34
PREPARATION 10 ##STR02099## Alfa Aesar DMSO, 130-145.degree. C.,
.mu.W 29.11 34 PREPARATION 10 ##STR02100## TCI America DMSO,
130-145.degree. C., .mu.W 29.12 34 PREPARATION 10 ##STR02101##
PREPARATION 35 DMSO, 145-155.degree. C., .mu.W 29.13 34 PREPARATION
10 ##STR02102## Aldrich DMSO, 145-155.degree. C., .mu.W 29.13 34
PREPARATION 10 ##STR02103## Aldrich DMSO, 145-155.degree. C., .mu.W
29.14 34 PREPARATION 10 ##STR02104## Aldrich DMSO, 100.degree. C.,
.mu.W 29.15 ##STR02105## PREPARATION 7 ##STR02106##
Cs.sub.2CO.sub.3, DMF, 120.degree. C. 29.16 ##STR02107##
PREPARATION 7 ##STR02108## WUXI APPTEC K.sub.2CO.sub.3, i-PrOH,
H.sub.2O, MW, 160.degree. C. 29.17 ##STR02109## PREPARATION 7
##STR02110## WUXI APPTEC K.sub.2CO.sub.3, i-PrOH, H.sub.2O, MW,
160.degree. C. 29.18 ##STR02111## PREPARATION 7 ##STR02112## WUXI
APPTEC K.sub.2CO.sub.3, i-PrOH, H.sub.2O, MW, 160.degree. C.
TABLE-US-00074 TABLE 33C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
29.1 TO 29.18 Ex. # Structure NMR 29.1 ##STR02113## (CDCl.sub.3,
400 MHz): 8.59-8.53 (m, 2H); 7.85 (d, J = 8.8 Hz, 1H); 7.47-7.40
(m, 3H); 7.14- 7.10 (m, 1H); 7.08-7.03 (m, 3H); 6.62 (d, J = 8.8
Hz, 1H); 4.44-4.37 (m, 5H); 3.90 (s, 3H); 2.64 (s, 3H). 29.2
##STR02114## (CDCl.sub.3, 400 MHz): 9.07 (s, 1H); 8.60-8.59 (m,
2H); 7.88-7.86 (m, 1H); 7.78-7.74 (m, 2H); 7.43-7.41 (m, 1H);
7.05-6.98 (m, 3H); 4.75-4.74 (m, 4H); 4.45-4.43 (m, 1H); 3.87 (s,
3H). 29.3 ##STR02115## (CDCl.sub.3, 400 MHz): 8.61 (s, 1H); 8.56
(s, 1H); 7.87 (d, J = 8.8 Hz, 1H); 7.67 (d, J = 7.6 Hz, 1H); 7.53
(d, J = 8.0 Hz, 1H); 7.48-7.44 (m, 1H); 7.15-7.11 (m, 1H);
7.09-7.06 (m, 3H) 6.68 (d, J = 8.8 Hz, 1H); 4.55-4.42 (m, 5H); 3.92
(s, 3H) 29.4 ##STR02116## (CDCl.sub.3, 400 MHz): 8.61-8.56 (m, 2H);
7.86- 7.83 (m, 1H); 7.59-7.55 (m, 1H); 7.47-7.43 (m, 1H); 7.38-7.35
(m, 1H); 7.09-7.05 (m, 3H); 7.01-6.91 (m, 1H); 6.58-6.65 (m, 1H);
4.48- 4.43 (m, 5H); 3.91 (s, 3H). 29.5 ##STR02117## (CDCl.sub.3,
400 MHz): 8.60-8.55 (m, 2H); 7.82 (d, J = 8.8 Hz, 1H); 7.71-7.69
(m, 1H); 7.47- 7.43 (m, 1H); 7.41-7.39 (m, 2H); 7.09-7.04 (m, 3H);
6.62 (d, J = 8.8 Hz, 1H); 4.49-4.43 (m, 5H); 3.91 (s, 3H); 2.46 (s,
3H). 29.6 ##STR02118## (CDCl.sub.3, 400 MHz): 8.59-8.54 (m, 2H);
7.77 (d, J = 8.8 Hz, 1H); 7.64 (d, J = 9.2 Hz, 1H); 7.57-7.56 (m,
1H); 7.47-7.41 (m, 2H); 7.07- 7.03 (m, 3H); 6.62 (d, J = 8.8 Hz,
1H); 4.46- 4.40 (m, 5H); 3.89 (s, 3H). 29.7 ##STR02119##
(CDCl.sub.3, 400 MHz): 9.00-8.99 (m, 1H); 8.61- 8.50 (m, 2H);
7.77-7.74 (m, 1H); 7.59-7.56 (m, 1H); 7.43-7.40 (m, 1H); 7.14-7.10
(m, 1H); 7.07-7.01 (m, 3H); 4.58-4.50 (m, 4H); 4.39- 4.36 (m, 1H);
3.87 (s, 3H). 29.8 ##STR02120## (CDCl.sub.3, 400 MHz): 9.54 (s,
1H); 8.65-8.63 (m, 2H); 7.83-7.80 (m, 2H); 7.48-7.44 (m, 2H);
7.08-6.99 (m, 3H); 4.82-4.81 (m, 4H); 4.50-4.47 (m, 1H); 3.89 (s,
3H). 29.9 ##STR02121## (400 MHz, DMSO-d.sub.6) 3.78-3.92 (m, 3H)
4.16-4.50 (m, 5H) 7.06-7.17 (m, 3H) 7.26 (d, J = 5.09 Hz, 1H)
7.42-7.56 (m, 4H) 8.06- 8.16 (m, 2H) 8.42 (d, J = 5.09 Hz, 1H) 8.64
(d, J = 2.15 Hz, 1H) 8.70 (d, J = 2.35 Hz, 1H). 29.10 ##STR02122##
(400 MHz, DMSO-d.sub.6) 3.84 (s, 3H) 4.24- 4.41 (m, 4H) 4.44-4.57
(m, 1H) 7.01-7.17 (m, 4H) 7.24-7.33 (m, 1H) 7.42-7.52 (m, 2H) 7.78
(d, J = 7.82 Hz, 1H) 8.66 (d, J = 2.35 Hz, 1H) 8.72 (d, J = 2.35
Hz, 1H) 29.11 ##STR02123## (400 MHz, DMSO-d.sub.6) 3.71-3.79 (m,
3H) 3.84 (s, 3H) 4.21-4.35 (m, 4H) 4.43-4.55 (m, 1H) 6.89 (dd, J =
8.80, 2.54 Hz, 1H) 7.04-7.15 (m, 3H) 7.34-7.43 (m, 2H) 7.44- 7.51
(m, 1H) 8.65 (d, J = 2.35 Hz, 1H) 8.71 (d, J = 2.35 Hz, 1H) 29.12
##STR02124## (400 MHz, DMSO-d.sub.6) 3.87 (s, 3H) 4.28-4.49 (m, 5H)
6.83 (d, J = 9.00 Hz, 1H) 7.06-7.19 (m, 3H) 7.38 (d, J = 5.87 Hz,
1H) 7.49 (t, J = 8.02 Hz, 1H) 8.13 (d, J = 9.00 Hz, 1H) 8.42 (d, J
= 5.67 Hz, 1H) 8.66 (d, J = 2.35 Hz, 1H) 8.71 (d, J = 2.15 Hz, 1H)
8.93 (s, 1H) 29.13 ##STR02125## (400 MHz, DMSO-d.sub.6) 8.69 (d, J
= 2.35 Hz, 1H), 8.64 (d, J = 2.35 Hz, 1H), 8.01 (d, J = 9.00 Hz,
1H), 7.82 (d, J = 2.15 Hz, 1H), 7.42- 7.60 (m, 3H), 7.06-7.19 (m,
3H), 6.81 (d, J = 9.00 Hz, 1H), 4.36-4.47 (m, 1H), 4.20-4.36 (m,
4H), 3.85 (s, 3H) 29.13 ##STR02126## (400 MHz, DMSO-d.sub.6) 8.71
(d, J = 2.54 Hz, 1H), 8.65 (d, J = 2.35 Hz, 1H), 7.71 (dd, J =
2.74, 8.80 Hz, 1H), 7.41-7.49 (m, 2H), 7.05- 7.17 (m, 4H), 4.49 (s,
1H), 4.23-4.38 (m, 4H), 3.83 (s, 3H) 29.14 ##STR02127## (400 MHz,
DMSO-d.sub.6) 8.73 (s, 1H), 8.67 (d, J = 2.35 Hz, 1H), 8.61 (d, J =
2.35 Hz, 1H), 7.77 (d, J = 8.02 Hz, 1H), 7.63-7.69 (m, 1H),
7.54-7.59 (m, 1H), 7.41-7.47 (m, 1H), 7.30 (t, J = 7.43 Hz, 1H),
7.04-7.13 (m, 3H), 4.43- 4.55 (m, 4H), 4.33-4.42 (m, 1H), 3.81 (s,
3H) 29.15 ##STR02128## (CD.sub.3OD, 400 MHz): 8.84 (S, 1h); 8.65
(d, J = 2.4 Hz, 1H); 8.53 (d, J = 2.4 Hz, 1H); 8.03- 8.00 (m, 1H);
7.92-7.80 (m, 3H); 7.57-7.50 (m, 5H); 4.77-4.71 (m, 4H); 4.49-4.46
(m, 1H). 29.16 ##STR02129## (CDCl.sub.3, 400 MHz): 8.54-8.53 (m,
1H); 8.42 (s, 1H); 7.54-7.53 (m, 3H); 7.35-7.32 (m, 2H); 7.26-7.20
(m, 1H); 7.11-7.09 (m, 1H); 6.97- 6.95 (m, 1H); 4.46-4.42 (m, 2H);
4.18-4.15 (m, 2H); 4.03-4.00 (m, 1H). 29.17 ##STR02130## (MeOD, 400
MHz): 8.66-8.65 (m, 1H); 8.55- 8.54 (m, 1H); 7.58-7.52 (m, 5H);
7.22-7.19 (m, 2H); 7.01-6.98 (m, 2H); 4.51-4.45 (m, 1H), 4.38-4.30
(m, 4H). 29.18 ##STR02131## (MeOD, 400 MHz): 8.67-8.65 (m, 1H);
8.60- 8.58 (m, 1H); 7.67-7.63 (m, 2H); 7.55-7.47 (m, 5H); 7.39-7.36
(m, 2H); 4.81 (s, 2H); 4.55- 4.48 (m, 5H).
##STR02132##
Example 30.1
3-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)BENZAMIDE
[0667] A mixture of
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile
(0.072 g, 0.198 mmol), potassium hydroxide (0.111 g, 1.981 mmol,
v/w) and t-BuOH (2 mL, Acros) was heated at 80.degree. C.
overnight. LCMS showed the product. The mixture was diluted with
water and extracted with a mixture of CHCl.sub.3:i-PrOH (3:1) three
times. The combined organic layers were dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The product was obtained as a white
solid (75 mg, 99%).
[0668] The following Table 34A lists compounds of Examples 30.1 to
30.4, which were made analogous to Scheme 30 by using the
appropriate materials and reaction conditions, which are listed in
Table 34B. The NMR data of the Examples are listed in Table
34C.
TABLE-US-00075 TABLE 34A EXAMPLES 30.1 TO 30.4 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (.mu.M) 30.1 ##STR02133##
3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin- 2-yl)benzamide 382
0.0008 30.2 ##STR02134## 4-(3-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin- 2-yl)benzamide 382 0.0013 30.3
##STR02135## 2-fluoro-5-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin- 2-yl)benzamide 400 0.0006 30.4
##STR02136## 2-fluoro-4-(3-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazin- 2-yl)benzamide 400 0.002
TABLE-US-00076 TABLE 34B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 30.1 TO 30.4. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Reaction Ex. # Key starting Material(s)/Source Condition
30.1 ##STR02137## SCHEME 5 KOH, t-BuOH, 80.degree. C. 30.2
##STR02138## SCHEME 5 KOH, t-BuOH, 80.degree. C. 30.3 ##STR02139##
SCHEME 5 EtOH/DMSO NaOH/H.sub.2O.sub.2 30.4 ##STR02140## SCHEME 5
EtOH/DMSO NaOH/H.sub.2O.sub.2
TABLE-US-00077 TABLE 34C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
30.1 TO 30.4 Ex. # Structure .sup.1H NMR 30.1 ##STR02141## (400
MHz, DMSO-d.sub.6) 4.24-4.35 (m, 4H) 4.37-4.46 (m, 1H) 6.75 (d, J =
8.80 Hz, 1H) 7.21 (t, J = 7.34 Hz, 1H) 7.45-7.59 (m, 3H) 7.62-7.81
(m, 3H) 7.99-8.17 (m, 4H) 8.67 (d, J = 2.35 Hz, 1H) 8.71 (d, J =
2.35 Hz, 1H) 30.2 ##STR02142## (400 MHz, DMSO-d.sub.6) 4.20-4.35
(m, 4H) 4.38-4.49 (m, 1H) 6.75 (d, J = 9.00 Hz, 1H) 7.16-7.28 (m,
1H) 7.45-7.59 (m, 3H) 7.64- 7.74 (m, 3H) 7.98-8.20 (m, 4H) 8.66 (d,
J = 2.35 Hz, 1H) 8.71 (d, J = 2.35 Hz, 1H) 30.3 ##STR02143## (400
MHz, chloroform-d) 4.34-4.51 (m, 5H) 5.94 (br. s., 1H) 6.64 (d, J =
9.00 Hz, 1H) 6.77 (d, J = 10.17 Hz, 1H) 7.19-7.25 (m, 1H) 7.34 (dd,
J = 11.35, 8.61 Hz, 1H) 7.49-7.56 (m, 1H) 7.60 (d, J = 7.82 Hz, 1H)
7.72 (d, J = 8.41 Hz, 1H) 7.77 (ddd, J = 8.17, 5.14, 2.54 Hz, 1H)
7.88 (d, J = 8.80 Hz, 1H) 8.30 (dd, J = 7.43, 2.54 Hz, 1H) 8.55 (d,
J = 2.35 Hz, 1H) 8.62 (d, J = 2.35 Hz, 1H). 30.4 ##STR02144## (400
MHz, chloroform-d) 4.33-4.52 (m, 5H) 5.89 (br. s., 1H) 6.64 (d, J =
9.00 Hz, 1H) 6.76 (d, J = 11.35 Hz, 1H) 7.20-7.26 (m, 1H) 7.36-7.47
(m, 2H) 7.54 (t, J = 7.73 Hz, 1H) 7.61 (d, J = 8.02 Hz, 1H) 7.73
(d, J = 8.41 Hz, 1H) 7.89 (d, J = 9.00 Hz, 1H) 8.30 (t, J = 8.02
Hz, 1H) 8.58 (d, J = 2.35 Hz, 1H) 8.65 (d, J = 2.35 Hz, 1H).
##STR02145##
Example 31.1
2-(3-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PHENYL)PROPAN-2-OL
[0669] To a mixture of methyl
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate (0.044
g, 0.110 mmol) and THF (1 mL) was added methylmagnesium bromide
(0.110 mL, 0.331 mmol). The mixture was stirred at RT for 2 h. LCMS
showed the product. The mixture was diluted with saturated
NH.sub.4Cl and extracted with EtOAc. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was
purified by silica gel chromatography (12 g, 10%-100%
EtOAc-Hexane). The product was obtained as a white solid (44 mg,
100%). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 1.66 (s, 6H)
1.88 (br. s., 1H) 4.29-4.63 (m, 5H) 6.62 (d, J=8.80 Hz, 1H) 7.22
(t, J=7.43 Hz, 1H) 7.39 (d, J=7.63 Hz, 1H) 7.51 (dt, J=11.79, 7.70
Hz, 2H) 7.57-7.65 (m, 2H) 7.66-7.76 (m, 2H) 7.87 (d, J=8.80 Hz, 1H)
8.54 (d, J=2.35 Hz, 1H) 8.58 (d, J=2.15 Hz, 1H). ESI (M+1) 397;
calc for C.sub.25H.sub.24N.sub.4 396.
[0670] The following Table 35A lists compounds of Examples 31.1 to
31.2, which were made analogous to Scheme 31 by using the
appropriate materials and reaction conditions, which are listed in
Table 35B. The NMR data of the Examples are listed in Table
35C.
TABLE-US-00078 TABLE 35A EXAMPLES 31.1 TO 31.2 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (.mu.M) 31.1 ##STR02146##
2-(3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-
2-yl)phenyl)propan-2-ol 397 0.0034 31.2 ##STR02147##
2-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-
2-yl)phenyl)propan-2-ol 397 0.0042
TABLE-US-00079 TABLE 35B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 31.1 TO 31.2. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Key Starting Material(s)/Source Reaction Condition
31.1 ##STR02148## SCHEME 5 CH.sub.3MgBr, THF, RT 31.2 ##STR02149##
SCHEME 5 CH.sub.3MgBr, THF, RT
TABLE-US-00080 TABLE 35C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
31.1 TO 31.2 Ex. # Structure NMR 31.1 ##STR02150## (400 MHz,
chloroform-d) 1.66 (s, 6H) 1.88 (br. s., 1H) 4.29-4.63 (m, 5H) 6.62
(d, J = 8.80 Hz, 1H) 7.22 (t, J = 7.43 Hz, 1H) 7.39 (d, J = 7.63
Hz, 1H) 7.51 (dt, J = 11.79, 7.70 Hz, 2H) 7.57-7.65 (m, 2H)
7.66-7.76 (m, 2H) 7.87 (d, J = 8.80 Hz, 1H) 8.54 (d, J = 2.35 Hz,
1H) 8.58 (d, J = 2.15 Hz, 1H). 31.2 ##STR02151## (400 MHz,
chloroform-d) 1.65 (s, 6H) 1.80 (s, 1H) 4.38-4.53 (m, 5H) 6.63 (d,
J = 8.80 Hz, 1H) 7.22 (t, J = 7.43 Hz, 1H) 7.47-7.56 (m, 3H) 7.60
(d, J = 7.63 Hz, 1H) 7.65 (d, J = 8.41 Hz, 2H) 7.72 (d, J = 8.41
Hz, 1H) 7.87 (d, J = 9.00 Hz, 1H) 8.53 (d, J = 2.35 Hz, 1H) 8.57
(d, J = 2.54 Hz, 1H).
##STR02152##
Example 32.1
2-(3-(3-(1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLI-
NE
[0671] A mixture of tert-butyl
4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(-
2H)-carboxylate (0.100 g, 0.225 mmol, SCHEME 5), CH.sub.2Cl.sub.2
(1 mL) and TFA (0.174 mL, 2.255 mmol) was stirred at RT for 1 h.
LCMS showed the product and no more starting material was present.
The mixture was concentrated in vacuo and neutralized with
Na.sub.2CO.sub.3. The mixture was extracted with a mixture of
CHCl.sub.3:i-PrOH (3:1) three times. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. The product was
obtained as a white solid (77 mg, 99%).
[0672] ESI-MS (M+1): 344. PDE10 IC.sub.50 (.mu.M): 0.013.
[0673] .sup.1H NMR .delta. (ppm): (400 MHz, chloroform-d) 2.53 (d,
J=1.76 Hz, 2H) 3.18 (t, J=5.67 Hz, 2H) 3.61 (d, J=2.74 Hz, 2H)
4.38-4.59 (m, 5H) 5.86 (br. s., 1H) 6.66 (d, J=8.80 Hz, 1H) 7.22
(t, J=7.43 Hz, 1H) 7.49-7.57 (m, 1H) 7.61 (d, J=7.83 Hz, 1H) 7.74
(d, J=8.41 Hz, 1H) 7.89 (d, J=9.00 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H)
8.47 (d, J=2.35 Hz, 1H).
##STR02153##
Example 33.1
LITHIUM
3-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)BENZOATE
[0674] A mixture of methyl
3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate (0.079
g, 0.198 mmol, SCHEME 5), lithium hydroxide hydrate (0.017 g, 0.397
mmol), water (0.4 mL) and THF (1.2 mL) was stirred at RT overnight.
The mixture was concentrated in vacuo. The product was obtained as
an off-white solid (83 mg, 108%).
[0675] ESI-MS (M+1): 383. PDE10 IC.sub.50 (.mu.M): 0.0016.
[0676] .sup.1H NMR .delta. (ppm): (400 MHz, DMSO-d.sub.6) 4.20-4.45
(m, 5H) 6.76 (d, J=9.00 Hz, 1H) 7.21 (t, J=7.04 Hz, 1H) 7.42-7.61
(m, 4H) 7.70 (d, J=7.82 Hz, 1H) 7.97-8.04 (m, 2H) 8.08 (s, 1H) 8.64
(dd, J=9.39, 2.35 Hz, 2H).
##STR02154##
Example 34.1
(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(2-METHOXY-PHENOXY)-PYRAZIN-2-YL]-AZETIDIN-1-
-YL}-METHANONE
[0677] The mixture of
2-azetidin-3-yl-3-(2-methoxy-phenoxy)-pyrazine hydrochloride (108
mg, 0.37 mmol), HATU (280 mg, 0.74 mmol) and TEA (130 mg, 1.3 mmol)
in dry DCM (10 mL) was stirred at RT for 30 min, then
1H-benzoimidazole-2-carboxylic acid was added to the solution. The
solution was heated to 80.degree. C. overnight. The mixture was
poured into saturated aqueous Na.sub.2CO.sub.3 and extracted with
DCM (50 mL.times.2). The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated to give the crude compound,
which was purified by ISCO silica gel column (10% to 80% EtOAc in
petroleum ether) and followed by reverse phase prep. HPLC (10% to
80% water/MeCN) to give
(1H-benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenoxy)-pyrazin-2-yl]-azetidin--
1-yl}-methanone (40 mg, 0.11 mmol, yield 27%).
[0678] The following Table 36A lists compounds of Examples 34.1 to
34.2, which were made analogous to Scheme 34 by using the
appropriate materials and reaction conditions, which are listed in
Table 36B. The NMR data of the Examples are listed in Table
36C.
TABLE-US-00081 TABLE 36A EXAMPLES 34.1 TO 34.2 ESI-MS IC.sub.50 Ex.
# Structure Chemical Name (M + 1) (uM) 34.1 ##STR02155##
(1H-Benzoimidazol-2-yl)-{3-[3- (2-methoxy-phenoxy)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 402 1.74 34.2 ##STR02156##
(1H-Benzoimidazol-2-yl)-{3-[3- (3-methoxy-phenoxy)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 402 0.78 34.3 ##STR02157##
(1H-benzoimidazol-2-yl)-{3-[3-(4- methoxy-phenoxy)-pyrazin-2-yl]-
azetidin-1-yl}-methanone 402 2.04 34.4 ##STR02158##
(1H-Benzoimidazol-2-yl)-[3-(3- phenoxy-pyrazin-2-yl)-azetidin-1-
yl]-methanone 372 0.73 34.5 ##STR02159##
(1H-benzoimidazol-2-yl)-{3-[3- (tetrahydro-pyran-4-yl)-pyrazin-2-
yl]-azetidin-1-yl}-methanone 364 0.124 34.6 ##STR02160##
(7-Chloro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 390 0.131 34.7 ##STR02161##
(6-Chloro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 390 0.0692 34.8 ##STR02162##
(7-Fluoro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 374 0.0438 34.9 ##STR02163##
(6-Fluoro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 374 0.0373 34.10 ##STR02164##
(6-methyl-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 370 0.0687 34.11 ##STR02165##
(6-methyl-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-
azetidin-1-yl]-methanone 370 0.0219 34.12 ##STR02166##
(1H-benzoimidazol-2-yl)-{3-[3-(2- methoxy-phenyl)-pyrazin-2-yl]-
azetidin-1-yl}-methanone 386 0.0978 34.13 ##STR02167##
(1H-benzoimidazol-2-yl)-{3-[3-(3- methoxy-phenyl)-pyrazin-2-yl]-
azetidin-1-yl}-methanone 386 0.087 34.14 ##STR02168##
(1H-Benzoimidazol-2-yl)-{3-[3- (4-methoxy-phenyl)-pyrazin-2-yl]-
azetidin-1-yl}-methanone 386 0.0322 34.14 ##STR02169##
(1H-benzoimidazol-2-yl)-[3-(2- phenyl-pyridin-3-yl)-azetidin-1-
yl]-methanone 355 0.515
TABLE-US-00082 TABLE 36B STARTING MATERIALS AND REACTION CONDITION
FOR PREPARATION OF EXAMPLES 34.1 TO 34.2. Unless otherwise stated,
all starting materials are commercially available from common
vendors. Ex. # Starting Material 1 Starting Material 2 Reaction
Condition 34.1 ##STR02170## PREPARATION 5 ##STR02171## PREPARATION
6 HATU, TEA, DCM, 80.degree. C. 34.2 ##STR02172## PREPARATION 5
##STR02173## PREPARATION 6 HATU, TEA, DCM, 80.degree. C. 34.3
##STR02174## PREPARATION 5 ##STR02175## PREPARATION 6 HATU, TEA,
DCM, 80.degree. C. 34.4 ##STR02176## PREPARATION 5 ##STR02177##
PREPARATION 6 HATU, TEA, DCM, 80.degree. C. 34.5 ##STR02178##
PREPARATION 37 ##STR02179## PREPARATION 6 HATU, TEA, THF 34.6
##STR02180## PREPARATION 7 ##STR02181## PREPARATION 6 HATU, TEA,
DCM, 0.degree. C. to RT 34.7 ##STR02182## PREPARATION 7
##STR02183## PREPARATION 6 HATU, TEA, DCM, 0.degree. C. to RT 34.8
##STR02184## PREPARATION 7 ##STR02185## PREPARATION 6 HATU, TEA,
DCM, 0.degree. C. to RT 34.9 ##STR02186## PREPARATION 7
##STR02187## PREPARATION 6 HATU, TEA, DCM, 0.degree. C. to RT 34.10
##STR02188## PREPARATION 7 ##STR02189## PREPARATION 6 HATU, TEA,
DCM, 0.degree. C. to RT 34.11 ##STR02190## PREPARATION 7
##STR02191## PREPARATION 6 HATU, TEA, DCM, 0.degree. C. to RT 34.12
##STR02192## PREPARATION 7 ##STR02193## PREPARATION 6 HATU, TEA,
DCM, RT 34.13 ##STR02194## PREPARATION 10 ##STR02195## PREPARATION
6 HATU, TEA, DCM, RT 34.14 ##STR02196## PREPARATION 7 ##STR02197##
PREPARATION 6 HATU, TEA, DCM, RT 34.14 ##STR02198## PREPARATION 8
##STR02199## PREPARATION 6 HATU, TEA, DCM, RT
TABLE-US-00083 TABLE 36C 1H NMR .delta. (PPM) DATA FOR EXAMPLES
34.1 TO 34.2 Ex. # Structure NMR 34.1 ##STR02200## (CD.sub.3OD, 400
MHz): 8.19 (d, J = 2.4 Hz, 1H); 7.93 (d, J = 2.8 Hz, 1H); 7.74-7.70
(m, 2H); 7.37-7.33 (m, 2H); 7.26-7.15 (m, 1H); 7.02-6.97 (m, 3H);
5.38- 5.29 (m, 2H); 4.85-4.71 (m, 2H); 4.53-4.10 (m, 1H); 3.69 (s,
3H). 34.2 ##STR02201## (CD.sub.3OD, 400 MHz): 8.18 (d, J = 2.4 Hz,
1H); 7.95 (d, J = 2.8 Hz, 1H); 7.70-7.68 (m, 2H); 7.35-7.33 (m,
2H); 7.28-7.24 (m, 1H); 6.76-6.73 (m, 1H); 6.66- 6.64 (m, 2H);
5.32-5.27 (m, 1H); 5.21-5.17 (m, 1H); 4.36-4.63 (m, 2H); 4.49-4.43
(m, 1H); 3.74 (s, 3H). 34.3 ##STR02202## (CD.sub.3OD, 400 MHz):
8.27-8.26 (m, 1H); 7.99-7.98 (m, 1H); 7.85-7.83 (m, 2H); 7.67-7.64
(m, 2H); 7.08-7.06 (m, 2H); 6.96-6.94 (m, 2H); 5.15-5.13 (m, 2H);
4.76-7.74 (m, 2H); 4.56-4.53 (m, 1H); 3.79 (s, 3H). 34.4
##STR02203## (CD.sub.3OD, 400 MHz): 8.29 (d, J = 2.8 Hz, 1H); 8.00-
7.99 (m, 1H); 7.75-7.73 (m, 2H); 7.49-7.47 (m, 2H); 7.43-7.39 (m,
2H); 7.25-7.23 (m, 1H); 7.17-7.14 (m, 2H); 5.22-5.13 (m, 2H);
4.73-4.68 (m, 2H); 4.58- 4.51 (m, 1H) 34.5 ##STR02204##
(CD.sub.3OD, 400 MHz): 8.48-8.45 (m, 2H); 7.74-7.72 (m, 2H);
7.47-7.44 (m, 2H); 5.15-5.12 (m, 1H); 5.03-5.01 (m, 1H); 4.64-4.56
(m, 3H); 4.09-4.02 (m, 2H); 3.65-3.59 (m, 2H); 3.17-3.13 (m, 1H);
2.05-2.03 (m, 2H); 1.66-1.63 (m, 2H) 34.6 ##STR02205## (CDCl.sub.3,
400 MHz) 8.62-8.58 (m, 2H); 7.54-7.49 (m, 6H); 7.31-7.20 (m, 2H);
5.16 (br, 2H); 4.63-4.59 (m, 1H); 4.50-4.46 (m, 1H); 4.40-4.33 (m,
1H). 34.7 ##STR02206## (CDCl.sub.3, 400 MHz): 8.55-8.51 (m, 2H);
7.47-7.41 (m, 7H); 7.24 (s, 1H); 5.06 (m, 2H); 4.53-4.50 (m, 1H);
4.42-4.37 (m, 1H); 4.30-4.28 (m, 1H). 34.8 ##STR02207##
(CDCl.sub.3, 400 MHz): 8.68-8.59 (m, 2H); 7.62-7.49 (m, 5H);
7.45-7.41 (m, 1H); 7.38-7.20 (m, 1H); 7.05-6.96 (m, 1H); 5.25-5.14
(m, 2H); 4.64-4.60 (m, 1H); 4.52-4.49 (m, 1H); 4.47-4.33 (m, 1H).
34.9 ##STR02208## (MeOD, 400 MHz): 8.62-8.61 (m, 1H); 8.55-8.54 (m,
1H); 7.68-7.52 (m, 6H); 7.35-7.31 (m, 1H); 7.11-7.08 (m, 1H);
5.06-5.00 (m, 2H); 4.46-4.36 (m, 3H). 34.10 ##STR02209##
(CDCl.sub.3, 400 MHz): 8.64-8.63 (m, 1H); 8.61-8.60 (m, 1H);
7.56-7.52 (m, 4H); 7.47-7.45 (m, 2H); 7.28-7.26 (m, 1H); 7.17-7.15
(m, 1H); 5.17-5.10 (m, 2H); 4.56-4.54 (m, 1H); 4.41-4.36 (m, 2H);
2.59 (s, 3H). 34.11 ##STR02210## (CDCl.sub.3, 400 MHz): 8.54-8.53
(m, 1H); 8.51-8.50 (m, 1H); 7.45-7.43 (m, 6H); 7.18 (brs, 1H);
7.06- 7.04 (m, 1H); 5.10-5.06 (m, 2H); 4.55-4.53 (m, 1H); 4.43-4.38
(m, 1H); 4.29-4.27 (m, 1H); 2.14 (s, 3H). 34.12 ##STR02211##
(CDCl.sub.3, 400 MHz): 8.69-8.68 (m, 1H); 8.56-8.55 (m, 1H);
7.74-7.72 (m, 2H); 7.53-7.45 (m, 3H); 7.36-7.34 (m, 1H); 7.17-7.12
(m, 2H); 5.01-4.95 (m, 2H); 4.50-4.91 (m, 2H); 4.15-4.09 (m, 1H);
3.81 (s, 3H). 34.13 ##STR02212## (CDCl.sub.3, 400 MHz): 8.62-8.57
(m, 2H); 7.69-7.67 (m, 2H); 7.46-7.42 (m, 1H); 7.34-7.32 (m, 2H);
7.06-7.01 (m, 3H); 5.19-5.15 (m, 2H); 4.68-4.31 (m, 3H); 3.88 (s,
3H). 34.14 ##STR02213## (CDCl.sub.3, 400 MHz): 8.86 (d, J = 2.8 Hz,
2H); 7.73- 7.71 (m, 2H); 7.45-7.43 (m, 2H); 7.40-7.37 (m, 2H);
7.07-7.05 (m, 2H); 5.24-5.22 (m, 1H); 5.13-5.12 (m, 1H); 4.59-4.57
(m, 1H); 4.48-4.40 (m, 2H); 3.89 (s, 3H). 34.14 ##STR02214##
(CDCl.sub.3, 400 MHz): 8.87-8.86 (m, 1H); 8.58-8.56 (m, 1H);
7.86-7.81 (m, 1H); 7.70-7.68 (m, 2H); 7.58-7.56 (m, 3H); 7.45-7.38
(m, 4H); 5.17-5.15 (m, 1H); 4.98-4.96 (m, 1H); 4.51-4.47 (m, 1H);
4.28-4.15 (m, 2H).
##STR02215##
Example 35.1
2-(3-(3-(1H-INDOL-5-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINAZOLINE
[0679] The above example was run in four different flasks under
four different sets of reaction conditions. All four flasks were
then combined before work up and purified to give the product.
[0680] Reaction condition (1): 2M aqueous sodium carbonate (0.252
mL, 0.504 mmol, J. T. Baker) was added to a stirred mixture of
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g,
0.168 mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202
mmol, Frontier Scientific), and
trans-dichlorobis(triphenylphosphine)palladium (ii) (0.006 mg,
0.008 mmol, Strem) in 1,4-dioxane (0.7 mL) in a sealed tube under
an argon atmosphere. The reaction mixture was stirred at 80.degree.
C. for 17 h before being cooled to RT and combined with the other
three crude reactions.
[0681] Reaction condition (2) 2M aqueous sodium carbonate (0.252
mL, 0.504 mmol, J. T. Baker) was added to a stirred mixture of
2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g,
0.168 mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202
mmol, Frontier), and tetrakis(triphenylphosphine)palladium (0.010
g, 0.008 mmol, Strem) in 1,4-dioxane (0.7 mL) in a sealed tube
under an argon atmosphere. The reaction mixture was stirred at
80.degree. C. for 17 h before being cooled to RT and combined with
the other three crude reactions.
[0682] Reaction condition (3)
2-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g,
0.168 mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202
mmol, Frontier Scientific), dichloro 1,1'-bis(diphenylphosphino)
ferrocene palladium (ii) (0.007 g, 0.008 mmol, Strem), and
potassium phosphate (0.035 mL, 0.420 mmol, Aldrich) were mixed in
1,4-dioxane (1.5 mL) and water (0.3 mL) in a sealed tube under an
argon atmosphere. The reaction mixture was stirred at 80.degree. C.
for 17 h before being cooled to RT and combined with the other
three crude reactions
[0683] Reaction condition (4)
2-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g,
0.168 mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202
mmol, Frontier Scientific),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium
(ii) (0.006 g, 0.008 mmol, Strem), and potassium phosphate (0.089
g, 0.420 mmol, Aldrich) were mixed in 1,4-dioxane (0.8 mL) and
water (0.2 mL) in a sealed tube under an argon atmosphere. The
reaction mixture was stirred at 80.degree. C. for 17 h before being
cooled to RT and combined with the other three crude reactions.
[0684] The combined reaction mixtures were diluted with water and
extracted with DCM (1.times.). The organic extract was dried over
magnesium sulfate, filtered, and concentrated in vacuo. The
resulting crude material was purified via silica gel flash column
chromatography eluting with 0% to 100% EtOAc in hexanes to give
0.217 g (85%) of a yellow amorphous solid.
[0685] ESI-MS (M+1): 379.1. PDE10 IC.sub.50 (.mu.M): 0.009.
[0686] .sup.1H NMR .delta. (ppm): (400 MHz, d-chloroform) 4.44-4.60
(m, 5H) 6.63 (s, 1H) 7.22 (t, J=7.20 Hz, 1H) 7.30 (d, J=2.00 Hz,
1H) 7.35 (d, J=8.41 Hz, 1H) 7.50 (d, J=8.41 Hz, 1H) 7.59-7.70 (m,
3H) 7.77 (s, 1H) 8.47-8.57 (m, 3H) 9.01 (s, 1H).
[0687] The following Table 37 lists compounds of Examples 36.1 to
36.190, which can be made according to the above schemes and
preparations.
TABLE-US-00084 TABLE 37 Examples 36.1 to 36.190 Ex. # Structure
Chemical Name 36.1 ##STR02216## 2-(3-(5-(2-methoxypyridin-3-
yl)pyrimidin-4-yl)azetidin-1- yl)quinazoline 36.2 ##STR02217##
2-(3-(6-(2-methoxypyridin-3-yl)-1H-
imidazo[4,5-b]pyrazin-5-yl)azetidin- 1-yl)quinazoline 36.3
##STR02218## 2-(2-methoxypyridin-3-yl)-3-(1-
(quinazolin-2-yl)azetidin-3- yl)pyrido[2,3-b]pyrazine 36.4
##STR02219## 3-(2-methoxypyridin-3-yl)-2-(1-
(quinazolin-2-yl)azetidin-3- yl)pyrido[2,3-b]pyrazine 36.5
##STR02220## 2-(3-(3-(2-methoxypyridin-3-
yl)quinoxalin-2-yl)azetidin-1- yl)quinazoline 36.6 ##STR02221##
methyl 3-(3-(3-hydroxy-1- (quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzoate 36.7 ##STR02222## methyl
3-(3-(3-hydroxy-1- (quinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)benzoate 36.8 ##STR02223##
3-(3-(4-(methylsulfonyl)piperidin-1-
yl)pyrazin-2-yl)-1-(quinazolin-2- yl)azetidin-3-ol 36.9
##STR02224## 3-(3-(4-(hydroxymethyl)piperidin-1-
yl)pyrazin-2-yl)-1-(quinolin-2- yl)azetidin-3-ol 36.10 ##STR02225##
1-(3-(3-hydroxy-1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.11 ##STR02226##
3-(3-(4-(methylsulfonyl)piperidin-
1-yl)pyrazin-2-yl)-1-(quinolin-2- yl)azetidin-3-ol 36.12
##STR02227## methyl 3-(3-(3-fluoro-1-(quinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)benzoate 36.13 ##STR02228## methyl
3-(3-(3-fluoro-1-(quinazolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)benzoate 36.14 ##STR02229## 2-(3-fluoro-3-(3-(4-
(methylsulfonyl)piperidin-1- yl)pyrazin-2-yl)azetidin-1-
yl)quinoline 36.15 ##STR02230## (1-(3-(3-fluoro-1-(quinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)methanol 36.16
##STR02231## 1-(3-(3-fluoro-1-(quinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.17
##STR02232## 2-(3-fluoro-3-(3-(4- (methylsulfonyl)piperidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinazoline 36.18 ##STR02233##
3-(3-(4-(hydroxymethyl)piperidin-
1-yl)pyrazin-2-yl)-1-(quinazolin-2- yl)azetidin-3-ol 36.19
##STR02234## 1-(3-(1-hydroxy-3-(quinazolin-2-
yl)cyclobutyl)pyrazin-2- yl)piperidine-4-carbonitrile 36.20
##STR02235## 2-(3-(6-(3- methoxyphenyl)pyrazolo[1,5-
a]pyridin-7-yl)azetidin-1- yl)quinoline 36.21 ##STR02236##
2-(3-(7-(3- methoxyphenyl)imidazo[1,5- a]pyridin-8-yl)azetidin-1-
yl)quinoline 36.22 ##STR02237## 2-(3-(6-(3-
methoxyphenyl)pyrazolo[1,5- a]pyrazin-7-yl)azetidin-1- yl)quinoline
36.23 ##STR02238## 2-(3-(6-(1H-imidazol-4-yl)-3-(3-
methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 36.24
##STR02239## 2-(3-(3-(3- methoxyphenyl)pyrrolo[1,2-
a]pyrazin-4-yl)azetidin-1- yl)quinoline 36.25 ##STR02240##
2-(3-(6-(3- methoxyphenyl)imidazo[1,2- a]pyrazin-5-yl)azetidin-1-
yl)quinoline 36.26 ##STR02241## 2-(3-(6-(3-
methoxyphenyl)imidazo[1,5- a]pyrazin-5-yl)azetidin-1- yl)quinoline
36.27 ##STR02242## 2-(3-(3-(3-methoxyphenyl)-6-
(oxetan-3-yl)pyrazin-2-yl)azetidin- 1-yl)quinoline 36.28
##STR02243## 2-(3-(6-(azetidin-3-yl)-3-(3- methoxyphenyl)pyrazin-2-
yl)azetidin-1-yl)quinoline 36.29 ##STR02244##
4-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-
2-yl)oxazole 36.30 ##STR02245## 3-(5-(3-methoxyphenyl)-6-(1-
(quinolin-2-yl)azetidin-3-yl)pyrazin- 2-yl)-1,2,4-oxadiazole 36.31
##STR02246## 1,1,1-trifluoro-2-(5-(3-
methoxyphenyl)-6-(1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)propan- 2-ol 36.32 ##STR02247##
N-((5-(3-methoxyphenyl)-6-(1- (quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)methyl)acetamide 36.33 ##STR02248##
2-(3-(3-(3-methoxyphenyl)-6- (tetrahydrofuran-2-yl)pyrazin-2-
yl)azetidin-1-yl)quinazoline 36.34 ##STR02249##
2-(3-(3-(3-methoxyphenyl)-6- (oxetan-2-yl)pyrazin-2-yl)azetidin-
1-yl)quinazoline 36.35 ##STR02250##
6-(3-methoxyphenyl)-5-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazine-2-
carbonitrile 36.36 ##STR02251## 2-(3-methoxyphenyl)-3-(1-(quinolin-
2-yl)azetidin-3-yl)-6,7-dihydro-5H- cyclopenta[b]pyrazin-5-one
36.37 ##STR02252## 3-(3-methoxyphenyl)-2-(1-
(quinazolin-2-yl)azetidin-3-yl)-6,7-
dihydro-5H-cyclopenta[b]pyrazin- 5-one 36.38 ##STR02253##
2-(3-methoxyphenyl)-3-(1- (quinazolin-2-yl)azetidin-3-yl)-5H-
pyrrolo[2,3-b]pyrazin-6(7H)-one 36.39 ##STR02254##
1-(6-(3-methoxyphenyl)-5-(1- (quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)ethanol 36.40 ##STR02255##
(6-(3-methoxyphenyl)-5-(1- (quinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)methanol 36.41 ##STR02256##
5-(3-methoxyphenyl)-6-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazine-2-
carboxamide 36.42 ##STR02257## 5-(3-methoxyphenyl)-6-(1-(quinolin-
2-yl)azetidin-3-yl)pyrazine-2- carbonitrile 36.43 ##STR02258##
1-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-
2-yl)ethanone 36.44 ##STR02259## 1-(5-(3-methoxyphenyl)-6-(1-
(quinolin-2-yl)azetidin-3-yl)pyrazin- 2-yl)ethanol 36.45
##STR02260## 2-(5-(3-methoxyphenyl)-6-(1-
(quinolin-2-yl)azetidin-3-yl)pyrazin- 2-yl)propan-2-ol 36.46
##STR02261## (5-(3-methoxyphenyl)-6-(1-
(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)methanol 36.47
##STR02262## 1-(6-(3-methoxyphenyl)-5-(1-
(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)ethanone 36.48
##STR02263## (S)-1-(3-(3-(1-(6-chloroquinazolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)-3- (trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.49 ##STR02264## (S)-1-(3-(3-(1-(6-chloroquinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)- 3-(trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.50 ##STR02265## (S)-1-(3-(3-(1-(6-fluoroquinazolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)-3- (trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.51 ##STR02266## (S)-1-(3-(3-(1-(6-fluoroquinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)-3- (trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.52 ##STR02267## (R)-1-(3-(3-(1-(6-chloroquinazolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)-3- (trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.53 ##STR02268## (R)-1-(3-(3-(1-(6-chloroquinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)- 3-(trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.54 ##STR02269## (R)-1-(3-(3-(1-(6-fluoroquinazolin-
2-yl)azetidin-3-yl)pyrazin-2-yl)-3- (trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.55 ##STR02270## (R)-1-(3-(3-(1-(6-fluoroquinolin-2-
yl)azetidin-3-yl)pyrazin-2-yl)- 3-(trifluoromethyl)pyrrolidin-1-
yl)ethanone 36.56 ##STR02271## 6-(3-(3-(4-cyanopiperidin-1-
yl)pyrazin-2-yl)azetidin-1-yl)-N- phenylnicotinamide 36.57
##STR02272## 1-(3-(1-(4-methylquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.58
##STR02273## 1-(3-(1-(4-chloroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.59
##STR02274## 1-(3-(1-(6-methoxy-4- methylquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.60 ##STR02275##
1-(3-(1-(4-methoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.61 ##STR02276##
1-(3-(1-(3-methylquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.62 ##STR02277##
1-(3-(1-(4,7-dimethylquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.63 ##STR02278##
1-(3-(1-(8-hydroxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.64 ##STR02279##
1-(3-(1-(3-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.65 ##STR02280##
1-(3-(1-(6-methylquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.66 ##STR02281##
1-(3-(1-(7-methoxy-4- methylquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.67 ##STR02282##
1-(3-(1-(4,8-dimethylquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.68 ##STR02283##
1-(3-(1-(5-(trifluoromethyl)quinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.69 ##STR02284##
1-(3-(1-(6-methoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.70 ##STR02285##
1-(3-(1-(7-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.71 ##STR02286##
1-(3-(1-(5-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.72 ##STR02287##
1-(3-(1-(8-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.73 ##STR02288##
1-(3-(1-(6-chloro-4-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.74 ##STR02289##
1-(3-(1-(5-methyl-1,6-naphthyridin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.75 ##STR02290##
1-(3-(1-(8-methyl-4- (trifluoromethyl)quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.76
##STR02291## 1-(3-(1-(7-chloro-4-methylquinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.77
##STR02292## 2-(3-(3-(4-cyanopiperidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline-4-carbonitrile 36.78
##STR02293## 1-(3-(1-(3-methyl-6- (trifluoromethyl)quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.79
##STR02294## 1-(3-(1-(3,7-dimethylquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.80
##STR02295## 1-(3-(1-(4-chloro-6-methylquinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.81
##STR02296## 1-(3-(1-(4-methyl-7,8-dihydro-6H-
cyclopenta[g]quinolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.82 ##STR02297##
1-(3-(1-(8-methoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.83 ##STR02298##
1-(3-(1-(6-fluoro-4-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.84 ##STR02299##
1-(3-(1-(4-chloro-6- methoxyquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.85 ##STR02300##
1-(3-(1-(4- (trifluoromethyl)quinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.86
##STR02301## 1-(3-(1-(6-chloroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.87
##STR02302## 1-(3-(1-(6-chloro-1,5-naphthyridin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.88
##STR02303## 1-(3-(1-(6-bromoquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.89
##STR02304## 1-(3-(1-(7-fluoro-4-methylquinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.90
##STR02305## 1-(3-(1-(6,7-dimethoxyquinazolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.91
##STR02306## 1-(3-(1-(4-fluoroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.92
##STR02307## 1-(3-(1-(7-bromoquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.93
##STR02308## 1-(3-(1-(6,8-dimethyl-1,5-
naphthyridin-2-yl)azetidin-3- yl)pyrazin-2-yl)piperidine-4-
carbonitrile 36.94 ##STR02309## 1-(3-(1-(3-methyl-8-
(trifluoromethyl)quinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.95 ##STR02310##
1-(3-(1-(3-methyl-6- (trifluoromethoxy)quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.96
##STR02311## 1-(3-(1-(3-methyl-8- (trifluoromethoxy)quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.97
##STR02312## 1-(3-(1-(6-chloro-3-methylquinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.98
##STR02313## 1-(3-(1-(6-fluoroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.99
##STR02314## 1-(3-(1-(6- (trifluoromethyl)quinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.100
##STR02315## 2-(3-(3-(4-cyanopiperidin-1-
yl)pyrazin-2-yl)azetidin-1- yl)quinoline-6-carbonitrile 36.101
##STR02316## 1-(3-(1-(6-bromoquinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.102
##STR02317## 1-(3-(1-(7-fluoroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.103
##STR02318## 1-(3-(1-(4-chloro-6-fluoroquinolin-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.104
##STR02319## 1-(3-(1-(pyrido[4,3-d]pyrimidin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.105
##STR02320## 1-(3-(1-(8-methoxyquinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.106
##STR02321## 1-(3-(1-(7-methoxyquinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.107
##STR02322## 1-(3-(1-(4-chloro-6- (trifluoromethyl)quinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.108
##STR02323## 1-(3-(1-(4-chloro-7- (trifluoromethyl)quinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.109
##STR02324## 1-(3-(1-(4-chloro-6- methoxyquinazolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.110 ##STR02325##
1-(3-(1-(4-chloro-7- methoxyquinazolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.111 ##STR02326##
1-(3-(1-(4-chloro-8- methoxyquinazolin-2-yl)azetidin-
3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.112 ##STR02327##
1-(3-(1-(4-chloro-5- fluoroquinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.113 ##STR02328##
1-(3-(1-(4-chloro-6- fluoroquinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.114 ##STR02329##
1-(3-(1-(4-chloro-7- fluoroquinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.115 ##STR02330##
1-(3-(1-(4-chloro-8- fluoroquinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.116 ##STR02331##
1-(3-(1-(4,7-dichloroquinazolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.117 ##STR02332##
1-(3-(1-(4-methylquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.118 ##STR02333##
1-(3-(1-(6-fluoro-4- methoxyquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.119 ##STR02334##
1-(3-(1-(6-chloro-4- methoxyquinolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.120 ##STR02335##
1-(3-(1-(4,6-dimethoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.121 ##STR02336##
1-(3-(1-(4,6-dimethoxyquinazolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.122 ##STR02337##
1-(3-(1-(4-methyl-6- (trifluoromethoxy)quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.123
##STR02338## 1-(3-(1-(5-fluoroquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.124
##STR02339## 1-(3-(1-(8-chloro-[1,3]dioxolo[4,5-
g]quinazolin-6-yl)azetidin-3- yl)pyrazin-2-yl)piperidine-4-
carbonitrile 36.125 ##STR02340##
1-(3-(1-(7-chloro-6-mcthylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.126 ##STR02341##
1-(3-(1-(7-bromoquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.127 ##STR02342##
1-(3-(1-(5-bromoquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.128 ##STR02343##
1-(3-(1-(6-chloro-1,7-naphthyridin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.129 ##STR02344##
1-(3-(1-(1,6-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.130 ##STR02345##
1-(3-(1-(4-chloropyrido[3,2- d]pyrimidin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.131 ##STR02346##
1-(3-(1-(1,7-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.132 ##STR02347##
1-(3-(1-(6-fluoroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.133 ##STR02348##
1-(3-(1-(7-fluoroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.134 ##STR02349##
1-(3-(1-(6-methoxy-1,7- naphthyridin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.135 ##STR02350##
1-(3-(1-(7-(trifluoromethyl)quinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.136 ##STR02351##
1-(3-(1-(pyrido[3,2-d]pyrimidin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.137 ##STR02352## 1-(3-(1-(6-
chloropyrido[3,2-d]pyrimidin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.138 ##STR02353##
1-(3-(1-(1,5-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.139 ##STR02354##
1-(3-(1-(7-methoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.140 ##STR02355##
1-(3-(1-(3-bromo-5-methyl-1,6- naphthyridin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.141 ##STR02356##
1-(3-(1-(6-bromopyrido[3,2- d]pyrimidin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.142 ##STR02357##
1-(3-(1-(2-bromopyrido[3,2- d]pyrimidin-6-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.143 ##STR02358##
1-(3-(1-(7-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.144 ##STR02359##
1-(3-(1-(6-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.145 ##STR02360##
1-(3-(1-(6-methylquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.146 ##STR02361##
1-(3-(1-(8-methylquinazolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.147 ##STR02362##
1-(3-(1-(8-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.148 ##STR02363##
1-(3-(1-(pyrido[3,4-d]pyrimidin-2- yl)azetidin-3-yl)pyrazin-2-
yl)piperidine-4-carbonitrile 36.149 ##STR02364##
1-(3-(1-(6-bromo-7- methoxyquinazolin-2-yl)azetidin-3-
yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.150 ##STR02365##
1-(3-(1-(7- bromopyrido[3,2-d]pyrimidin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.151
##STR02366## 1-(3-(1-(5-methoxyquinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.152
##STR02367## 1-(3-(1-(6-methoxyquinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.153
##STR02368## 1-(3-(1-(5-chloroquinazolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.154
##STR02369## 1-(3-(1-(5,7-dimethyl-6-
nitroquinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)piperidine-4-
carbonitrile 36.155 ##STR02370## 1-(3-(1-(6-(cyclopentyloxy)-7-
methoxyquinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)piperidine-4-
carbonitrile 36.156 ##STR02371## 1-(3-(1-(6,7-dimethoxyquinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.157
##STR02372## 1-(3-(1-(4,6-dichlorobenzo[d]thiazol-
2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.158
##STR02373## 1-(3-(1- ([1,3]dioxolo[4',5':4,5]benzo[1,2-
d]thiazol-6-yl)azetidin-3-yl)pyrazin-
2-yl)piperidine-4-carbonitrile
36.159 ##STR02374## 1-(3-(1-(4,6- difluorobenzo[d]thiazol-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.160
##STR02375## (1-(3-(3-methyl-1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)methanol 36.161
##STR02376## (1-(3-(3-(hydroxymethyl)-1-
(quinolin-2-yl)azetidin-3-yl)pyrazin- 2-yl)piperidin-4-yl)methanol
36.162 ##STR02377## (1-(3-(3-chloro-1-(quinolin-2-
yl)azetidin-3-yl)pyrazin-2- yl)piperidin-4-yl)methanol 36.163
##STR02378## 3-(3-(4-(hydroxymethyl)piperidin-1-
yl)pyrazin-2-yl)-1-(quinolin-2- yl)azetidine-3-carbonitrile 36.164
##STR02379## (1-(4-(1-(quinolin-2-yl)azetidin-3-
yl)pyrimidin-5-yl)piperidin-4- yl)methanol 36.165 ##STR02380##
(1-(5-(1-(quinolin-2-yl)azetidin-3- yl)pyrimidin-4-yl)piperidin-4-
yl)methanol 36.166 ##STR02381## (1-(4-(1-(quinolin-2-yl)azetidin-3-
yl)pyridin-3-yl)piperidin-4- yl)methanol 36.167 ##STR02382##
(1-(5-(1-(quinolin-2-yl)azetidin-3- yl)pyridazin-4-yl)piperidin-4-
yl)methanol 36.168 ##STR02383## (1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyridin-2-yl)piperidin-4- yl)methanol 36.169 ##STR02384##
(1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyridazin-4-yl)piperidin-4-
yl)methanol 36.170 ##STR02385## (1-(3-(1-(quinolin-2-yl)azetidin-3-
yl)pyridin-4-yl)piperidin-4- yl)methanol 36.171 ##STR02386##
(1-(3-(1-(7-chloro-8-fluoroquinolin- 2-yl)azetidin-3-yl)pyrazin-2-
yl)piperidin-4-yl)methanol 36.172 ##STR02387##
7-chloro-8-fluoro-2-(3-(3-(2- methoxypyridin-3-yl)pyrazin-2-
yl)azetidin-1-yl)quinoline 36.173 ##STR02388##
7-chloro-2-(4-(3-(4-fluoro-3- methoxyphenyl)pyrazin-2-yl)-5,6-
dihydropyridin-1(2H)-yl)quinoline 36.174 ##STR02389##
1-(7-chloroquinolin-2-yl)-4-(3-(4-
fluoro-3-methoxyphenyl)pyrazin-2- yl)piperidin-2-one 36.175
##STR02390## 1-(7-chloroquinolin-2-yl)-4-(3-(3,6-
dihydro-2H-pyran-4-yl)pyrazin-2- yl)piperidin-2-one 36.176
##STR02391## 7-chloro-2-(4-(3-(3,6-dihydro-2H-
pyran-4-yl)pyrazin-2-yl)-5,6- dihydropyridin-1(2H)-yl)quinoline
36.177 ##STR02392## 1-(3-(1-(7-chloroquinolin-2-yl)-
1,2,3,6-tetrahydropyridin-4- yl)pyrazin-2-yl)piperidine-4-
carbonitrile 36.178 ##STR02393## 1-(3-(1-(7-chloroquinolin-2-yl)-2-
oxopiperidin-4-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.179
##STR02394## 1-(3 -(1-(7-chloro-6- fluoroquinazolin-2-yl)-1,2,3,6-
tetrahydropyridin-4- yl)pyrazin-2-yl)piperidin-4-ol 36.180
##STR02395## 1-(7-chloro-6-fluoroquinazolin-2-
yl)-4-(3-(4-hydroxypiperidin-1- yl)pyrazin-2-yl)piperidin-2-one
36.181 ##STR02396## 3-(3-(1-(7-chloro-6-fluoroquinazolin-
2-yl)-1,2,3,6-tetrahydropyridin-4- yl)pyrazin-2-yl)benzamide 36.182
##STR02397## 3-(3-(1-(7-chloro-6-fluoroquinazolin-
2-yl)-2-oxopiperidin-4-yl)pyrazin-2- yl)benzamide 36.183
##STR02398## 4-(3-(1-acetyl-1,2,3,6-
tetrahydropyridin-4-yl)pyrazin-2-
yl)-1-(7-chloro-6-fluoroquinazolin- 2-yl)piperidin-2-one 36.184
##STR02399## 1-(4-(3-(1-(7-chloro-6-
fluoroquinazolin-2-yl)-1,2,3,6- tetrahydropyridin-4-yl)pyrazin-2-
yl)-5,6-dihydropyridin-1(2H)- yl)ethanone 36.185 ##STR02400##
2-(4-(3-(5,6-dihydro-2H-pyran-3-
yl)pyrazin-2-yl)-5,6-dihydropyridin- 1(2H)-yl)-7-fluoroquinoxaline
36.186 ##STR02401## 4-(3-(5,6-dihydro-2H-pyran-3-
yl)pyrazin-2-yl)-1-(7- fluoroquinoxalin-2-yl)piperidin-2- one
36.187 ##STR02402## N-(3-(3-(1-(7-fluoroquinoxalin-2-yl)-
2-oxopiperidin-4-yl)pyrazin-2- yl)phenyl)acetamide 36.188
##STR02403## N-(3-(3-(1-(7-fluoroquinoxalin-2-
yl)-1,2,3,6-tetrahydropyridin-4- yl)pyrazin-2-yl)phenyl)acetamide
36.189 ##STR02404## (1-(3-(1-(7-fluoroquinoxalin-2-yl)-
1,2,3,6-tetrahydropyridin-4- yl)pyrazin-2-yl)piperidin-4-
yl)methanol 36.190 ##STR02405##
1-(7-fluoroquinoxalin-2-yl)-4-(3-(4- (hydroxymethyl)piperidin-1-
yl)pyrazin-2-yl)piperidin-2-one
Biological Examples
[0688] The above PDE10 IC.sub.50 data were obtained by using the
following assays.
Example A
MPDE100A7 Enzyme Activity and Inhibition
[0689] Enzyme Activity. An IMAP TR-FRET assay was used to analyze
the enzyme activity (Molecular Devices Corp., Sunnyvale Calif.). 5
.mu.L of serial diluted PDE100A (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, Mass.) for time resolved fluorescence resonance energy
transfer. The data were analyzed with GraphPad Prism (La Jolla,
Calif.).
[0690] Enzyme Inhibition. To check the inhibition profile, 5 .mu.L
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 (Corning, 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 .mu.L of diluted binding reagents and plates were read
on an Envision (Perkin Elmer, Waltham, Mass.) 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, an In Vivo Test for Antipsychotic Activity
[0691] 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%.
[0692] 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, an In Vivo Test for
Antipsychotic Activity
[0693] 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.
[0694] 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.
[0695] 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, 263/8
gauge needle) or per os (p.o.) (18 gauge feeding needle) with
either control or compound solutions. Compounds can be injected at
1.0 ml/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)
[0696] 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:
[0697] Multiphase experiment
[0698] 300 sec/interval (5 min)
[0699] 12 intervals (1 h)
[0700] Individual on screen switches.
[0701] Start recording after first beam break.
[0702] End session after end of interval.
Cage Preparation:
[0703] Techniplast.TM. rat cage with filter top, but no wire lid.
Place .about.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:
[0704] Mark rats and record their weights. Bring rats to testing
room.
Phase I: Habituation
[0705] 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
[0706] 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.
[0707] During phase II, prepare pcp: Dissolve pcp in saline to a
concentration of 5 mg/mL.
[0708] Fill syringes (1 mL syringes with 26 g3/8 needle) with pcp
solution (1 mL/kg).
Phase III: Pcp Administration.
[0709] 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:
[0710] End-session to terminate experiment and so that computer
will compile data. Export raw data to spreadsheet file for data
analysis. Euthanize rats and take necessary tissue/sample for
PK.
Data Generation:
[0711] Export raw data to spreadsheet 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.
[0712] 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.
* * * * *