U.S. patent application number 12/488312 was filed with the patent office on 2010-02-25 for triazolopyridine jak inhibitor compounds and methods.
Invention is credited to He HAIYING, Zheng JIFU, Zhao JUNPING, Steven R. MAGNUSON, Richard PASTOR, Michael SIU, Xu XING, Xiao YISONG, Bing-Yan ZHU.
Application Number | 20100048557 12/488312 |
Document ID | / |
Family ID | 41434469 |
Filed Date | 2010-02-25 |
United States Patent
Application |
20100048557 |
Kind Code |
A1 |
ZHU; Bing-Yan ; et
al. |
February 25, 2010 |
Triazolopyridine JAK Inhibitor Compounds and Methods
Abstract
A compound of Formula I, enantiomers, diasteriomers, tautomers
or pharmaceutically acceptable salts thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are defined herein, are
useful as JAK kinase inhibitors. A pharmaceutical composition that
includes a compound of Formula I and a pharmaceutically acceptable
carrier, adjuvant or vehicle, and methods of treating or lessening
the severity of a disease or condition responsive to the inhibition
of JAK kinase activity in a patient are disclosed. ##STR00001##
Inventors: |
ZHU; Bing-Yan; (Palo Alto,
CA) ; SIU; Michael; (Burlingame, CA) ;
MAGNUSON; Steven R.; (Dublin, CA) ; PASTOR;
Richard; (San Francisco, CA) ; HAIYING; He;
(Shanghai, CN) ; YISONG; Xiao; (Shanghai, CN)
; JIFU; Zheng; (Shanghai, CN) ; XING; Xu;
(Shanghai, CN) ; JUNPING; Zhao; (Yan'an,
CN) |
Correspondence
Address: |
BRINKS, HOFER, GILSON & LIONE
P.O. BOX 1340
MORRISVILLE
NC
27560
US
|
Family ID: |
41434469 |
Appl. No.: |
12/488312 |
Filed: |
June 19, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61074506 |
Jun 20, 2008 |
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Current U.S.
Class: |
514/233.2 ;
514/253.04; 514/303; 544/127; 544/362; 546/119 |
Current CPC
Class: |
A61P 37/02 20180101;
A61P 25/00 20180101; A61P 29/00 20180101; A61P 35/04 20180101; A61P
25/14 20180101; A61P 37/08 20180101; C07D 471/04 20130101; A61P
9/00 20180101; C07D 487/04 20130101; A61P 19/08 20180101; A61K
31/5377 20130101; A61P 35/02 20180101; A61P 9/10 20180101; A61P
25/28 20180101; A61P 35/00 20180101; A61P 21/00 20180101; A61P
43/00 20180101; A61P 1/16 20180101; A61P 3/10 20180101; A61P 17/04
20180101; A61K 31/437 20130101; A61P 37/04 20180101; A61P 17/00
20180101; A61K 31/496 20130101; A61P 31/12 20180101; A61P 7/00
20180101; A61P 5/00 20180101; A61P 25/16 20180101; A61P 7/02
20180101; A61P 37/00 20180101; A61P 37/06 20180101; A61P 19/02
20180101; A61P 31/00 20180101; A61P 17/06 20180101 |
Class at
Publication: |
514/233.2 ;
546/119; 544/127; 544/362; 514/303; 514/253.04 |
International
Class: |
A61K 31/437 20060101
A61K031/437; C07D 471/04 20060101 C07D471/04; A61K 31/496 20060101
A61K031/496; A61K 31/5377 20060101 A61K031/5377; A61P 35/00
20060101 A61P035/00; A61P 3/10 20060101 A61P003/10; A61P 9/00
20060101 A61P009/00; A61P 31/12 20060101 A61P031/12; A61P 37/00
20060101 A61P037/00; A61P 29/00 20060101 A61P029/00; A61P 25/00
20060101 A61P025/00 |
Claims
1. A compound of Formula I ##STR00376## enantiomers, diasteriomers,
tautomers or pharmaceutically acceptable salts thereof, wherein:
R.sup.1 is H, C(O)OR.sup.a, phenyl, C.sub.1-C.sub.9 heterocyclyl or
C.sub.1-C.sub.9 heteroaryl, wherein said phenyl and heteroaryl are
optionally substituted by 1 to 5 R.sup.6; R.sup.2 is phenyl,
C.sub.1-C.sub.9 heteroaryl or C.sub.1-C.sub.9 heterocyclyl, wherein
the phenyl, heteroaryl and heterocyclyl are optionally substituted
by 1 to 5 R.sup.7; R.sup.3, R.sup.4 and R.sup.5 are independently
H, CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, CF.sub.3, F or Cl;
R.sup.6 is independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, CN, CF.sub.3,
S(O).sub.1-2NR.sup.aR.sup.b, C(O)R.sup.a, NR.sup.aC(O)OR.sup.b,
NR.sup.aS(O).sub.1-2NR.sup.b, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heteroaryl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl, (C.sub.0-C.sub.6
alkyl)C.sub.3-C.sub.6 cycloalkyl, (C.sub.0-C.sub.6
alkyl)C.sub.6-C.sub.9 aryl, (C.sub.0-C.sub.6 alkyl)C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b or C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)(C.sub.6 aryl), wherein said alkyl, alkenyl and alkynyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl and
C(O)(C.sub.1-C.sub.4 alkyl); R.sup.7 is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a, (C.sub.0-C.sub.6
alkyl)NR.sup.aR.sup.b, (C.sub.0-C.sub.6 alkyl)(C.sub.6-C.sub.9
aryl), halo, C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.b,
SO.sub.2(C.sub.1-C.sub.6 alkyl), SO.sub.2NR.sup.aR.sup.b, CN,
CF.sub.3, CH.sub.2CF.sub.3, nitro, S(O)(C.sub.1-C.sub.6 alkyl),
S(O)NR.sup.aR.sup.b, NR.sup.aS(O).sub.1-2R.sup.b, C(O)R.sup.a,
C(O)OR.sup.a, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heteroaryl,
(C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl or
(C.sub.0-C.sub.6 alkyl)C.sub.3-C.sub.6 cycloalkyl, wherein said
alkyl, alkenyl and alkynyl are optionally substituted by 1 to 5
substituents independently selected from oxo, NR.sup.aR.sup.b,
OR.sup.a, and halo, and said aryl, heteroaryl, heterocyclyl and
cycloalkyl are optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, halo, CF.sub.3,
NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl; R.sup.a and R.sup.b are
independently H, OR.sup.c, C(O)O(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, C.sub.6 aryl or C.sub.3-C.sub.6 cycloalkyl,
wherein said alkyl, aryl and cycloalkyl are optionally substituted
by 1 to 5 substituents independently selected from C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.3 alkyl)OR.sup.c, oxo, halo, NR.sup.cR.sup.d
and C.sub.4-C.sub.5 heterocyclyl; or R.sup.a and R.sup.b together
with the atom to which they are attached form a C.sub.1-C.sub.5
heterocyclyl; and R.sup.c and R.sup.d are independently H,
C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 cycloalkyl or phenyl,
wherein said alkyl, cycloalkyl and phenyl are optionally
substituted by 1 to 5 substituents independently selected from
halo, CH.sub.3, OH or NH.sub.2, C(O)O(C.sub.1-C.sub.6 alkyl) and
C(O)NH(C.sub.1-C.sub.6 alkyl).
2. The compound of claim 1, selected from Formula I: ##STR00377##
enantiomers, diasteriomers, tautomers or pharmaceutically
acceptable salts thereof, wherein: R.sup.1 is H, C(O)OR.sup.a,
phenyl or C.sub.1-C.sub.9 heteroaryl, wherein said phenyl and
heteroaryl are optionally substituted by 1 to 5 R.sup.6; R.sup.2 is
phenyl, C.sub.1-C.sub.9 heteroaryl or C.sub.1-C.sub.9 heterocyclyl,
wherein the phenyl, heteroaryl and heterocyclyl are optionally
substituted by 1 to 5 R.sup.7; R.sup.3, R.sup.4 and R.sup.5 are
independently H, CH.sub.3, CH.sub.2CH.sub.3, CF.sub.3, F or Cl;
R.sup.6 is independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, CN, C.sub.1-C.sub.5
heteroaryl, C.sub.1-C.sub.5 heterocyclyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.6-C.sub.9 aryl, C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b or C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)(C.sub.6 aryl), wherein said alkyl, alkenyl and alkynyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl and C(O)(C.sub.1-C.sub.4 alkyl); R.sup.7 is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a, (C.sub.0-C.sub.6
alkyl)NR(C.sub.0-C.sub.6 alkyl)(C.sub.6-C.sub.9 aryl), halo,
C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.b, SO.sub.2(C.sub.1-C.sub.6
alkyl), SO.sub.2NR.sup.aR.sup.b, CN or nitro, wherein said alkyl,
alkenyl and alkynyl are optionally substituted by 1 to 5
substituents independently selected from oxo and halo, and said
aryl is optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, halo, CF.sub.3, NR.sup.cR.sup.d and
C.sub.1-C.sub.4 alkyl; R.sup.a and R.sup.b are independently H,
OR.sup.c, C(O)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.6 aryl or C.sub.3-C.sub.6 cycloalkyl, wherein said alkyl,
aryl and cycloalkyl are optionally substituted by 1 to 5
substituents independently selected from C.sub.1-C.sub.4 alkyl,
(C.sub.0-C.sub.3 alkyl)OR.sup.c, oxo, halo, NR.sup.cR.sup.d and
C.sub.4-C.sub.5 heterocyclyl; or R.sup.a and R.sup.b together with
the atom to which they are attached form a C.sub.1-C.sub.5
heterocyclyl; and R.sup.c and R.sup.d are independently H,
C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 cycloalkyl or phenyl,
wherein said alkyl, cycloalkyl and phenyl are optionally
substituted by 1 to 5 substituents independently selected from
halo, CH.sub.3 OH or NH.sub.2, C(O)O(C.sub.1-C.sub.6 alkyl) and
C(O)NH(C.sub.1-C.sub.6 alkyl).
3. The compound of claim 1, wherein R.sup.1 is phenyl or
C.sub.1-C.sub.9 heteroaryl, wherein said phenyl and heteroaryl are
optionally substituted by 1 to 5 R.sup.6.
4. The compound of claim 3, wherein R.sup.1 is phenyl optionally
substituted by 1 to 5 R.sup.6.
5. The compound of claim 3, wherein R.sup.1 is C.sub.1-C.sub.9
heteroaryl optionally substituted by 1 to 5 R.sup.6.
6. The compound of claim 5, wherein said C.sub.1-C.sub.9 heteroaryl
is pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,
triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,
thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,
isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,
indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,
isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,
thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl or furopyridinyl, each of which is
optionally substituted by 1 to 5 R.sup.6.
7. The compound of claim 6, wherein said C.sub.1-C.sub.9 heteroaryl
is pyridinyl optionally substituted by 1 to 4 R.sup.6.
8. The compound of claim 3, wherein R.sup.6 is independently
C.sub.1-C.sub.6 alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, CN, C.sub.1-C.sub.5
heteroaryl, C.sub.4-C.sub.5 heterocyclyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.6 aryl, C(O)OR.sup.a, C(O)(C.sub.0-C.sub.5
alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5
heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5
heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.3-C.sub.6
cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5
heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)(C.sub.6 aryl), wherein said
alkyl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4 alkyl).
9. The compound of claim 8, wherein R.sup.6 is C.sub.4-C.sub.5
heterocyclyl optionally substituted by 1 to 5 substituents
independently selected from OH, oxo, halo, CF.sub.3,
NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4
alkyl).
10. The compound of claim 9, wherein said heterocyclyl is
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
1,1-dioxotetrahydrothiophenyl, piperidinyl, piperizinyl,
tetrahydropyranyl, thianyl, morpholinyl, pyridizinyl or
hexahydropyrimidinyl.
11. The compound of claim 9, wherein said heterocyclyl is
piperidinyl, piperizinyl or morpholinyl.
12. The compound of claim 8, wherein R.sup.6 is (C.sub.0-C.sub.6
alkyl)OR.sup.a or (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b.
13. The compound of claim 12, wherein R.sup.6 is (C.sub.0-C.sub.3
alkyl)OR.sup.a or (C.sub.0-C.sub.3 alkyl)NR.sup.aR.sup.b.
14. The compound of claim 8, wherein R.sup.6 is halo.
15. The compound of claim 14, wherein R.sup.6 is F or Cl.
16. The compound of claim 8, wherein R.sup.6 is
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heterocyclyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.3-C.sub.6 cycloalkyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heteroaryl),
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)(C.sub.6 aryl), wherein said
alkyl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4 alkyl).
17. The compound of claim 8, wherein R.sup.6 is C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b or C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), wherein said alkyl is
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl and C(O)(C.sub.1-C.sub.4 alkyl).
18. The compound of claim 1, wherein R.sup.1 is H.
19. The compound of claim 1, wherein R.sup.1 is C(O)OR.sup.a,
wherein R.sup.a is independently H, OR.sup.c, C(O)O(C.sub.1-C.sub.6
alkyl), C.sub.1-C.sub.6 alkyl, C.sub.6 aryl or C.sub.3-C.sub.6
cycloalkyl, wherein said alkyl, aryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.3 alkyl)OR.sup.c, oxo, halo,
NR.sup.cR.sup.d and C.sub.4-C.sub.5 heterocyclyl.
20. The compound of claim 1, wherein R.sup.3, R.sup.4 and R.sup.5
are independently H, CH.sub.3, CF.sub.3, or F.
21. The compound of claim 1, wherein R.sup.3, R.sup.4 and R.sup.5
are independently H or F.
22. The compound of claim 1, wherein R.sup.3, R.sup.4 and R.sup.5
are H.
23. The compound of claim 1, wherein R.sup.2 is phenyl,
C.sub.1-C.sub.9 heteroaryl or C.sub.3-C.sub.5 heterocyclyl, wherein
the phenyl, heteroaryl and heterocyclyl are optionally substituted
by 1 to 5 R.sup.7.
24. The compound of claim 23, wherein R.sup.2 is phenyl optionally
substituted by 1 to 5 R.sup.7.
25. The compound of claim 24, wherein R.sup.7 is independently
C.sub.1-C.sub.6 alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, (C.sub.0-C.sub.6
alkyl)(C.sub.6-C.sub.9 aryl), halo, C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.b, SO.sub.2(C.sub.1-C.sub.6 alkyl),
SO.sub.2NR.sup.aR.sup.b, CN or nitro, wherein said alkyl is
optionally substituted by 1 to 5 substituents independently
selected from oxo and halo, and said aryl is optionally substituted
by 1 to 5 substituents independently selected from OR.sup.a, halo,
CF.sub.3, NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl.
26. The compound of claim 25, wherein R.sup.7 is independently
C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, NR.sup.aC(O)R.sup.b,
SO.sub.2(C.sub.1-C.sub.6 alkyl) SO.sub.2NR.sup.aR.sup.b, CN or
nitro.
27. The compound of claim 26, wherein R.sup.7 is independently
NH.sub.2, OCH.sub.3, CH.sub.3, CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, NO.sub.2, OCF.sub.3,
S(O).sub.2N(CH.sub.3).sub.2, S(O).sub.2NH(CH(CH.sub.3).sub.2),
S(O).sub.2NH(C(CH.sub.3).sub.3), CN, CF.sub.3, F, Cl,
NHC(O)CH.sub.3 or S(O).sub.2CH.sub.3.
28. The compound of claim 23, wherein R.sup.2 is C.sub.1-C.sub.9
heteroaryl optionally substituted by 1 to 5 R.sup.7.
29. The compound of claim 28, wherein said C.sub.1-C.sub.9
heteroaryl is pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl,
pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl,
isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,
triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,
thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl or furopyridinyl, each of which is
optionally substituted by 1 to 5 R.sup.7.
30. The compound of claim 29, wherein said C.sub.1-C.sub.9
heteroaryl is pyridinyl or pyrazolyl optionally substituted by 1 to
5 R.sup.7.
31. The compound of claim 30, wherein R.sup.7 is independently
CH.sub.3, CH.sub.2(phenyl), CH.sub.2CH(CH.sub.3).sub.2, or
CF.sub.3.
32. The compound of claim 23, wherein said R.sup.2 is
C.sub.3-C.sub.5 heterocyclyl optionally substituted by 1 to 5
R.sup.7.
33. The compound of claim 32, wherein R.sup.2 is piperidinyl,
morpholinyl or piperizinyl optionally substituted by 1 to 5
R.sup.7.
34. The compound of claim 33, wherein R.sup.7 is independently
CH.sub.3, CH.sub.2CH.sub.3, OH or OCH.sub.3.
35. The compound of claim 1, wherein R.sup.1 is phenyl, optionally
substituted by 1 to 5 R.sup.6; and R.sup.2 is phenyl, optionally
substituted by 1 to 5 R.sup.7.
36. The compound of claim 1, wherein R.sup.1 is phenyl, optionally
substituted by 1 to 5 R.sup.6; and R.sup.2 is heterocyclyl,
optionally substituted by 1 to 5 R.sup.7.
37. The compound of claim 36, wherein said heterocyclyl is
piperidinyl, morpholinyl or piperizinyl.
38. The compound of claim 1, wherein R.sup.1 is pyridyl, optionally
substituted by 1 to 5 R.sup.6; and R.sup.2 is phenyl, optionally
substituted by 1 to 5 R.sup.7.
39. The compound of claim 1, wherein R.sup.1 is pyridyl, optionally
substituted by 1 to 4 R.sup.6; and R.sup.2 is heterocyclyl,
optionally substituted by 1 to 5 R.sup.7.
40. The compound of claim 39, wherein said heterocyclyl is
piperidinyl, morpholinyl or piperizinyl.
41. The compound of claim 1, wherein R.sup.1 is phenyl, optionally
substituted by 1 to 5 R.sup.6; and R.sup.2 is pyridyl, optionally
substituted by 1 to 4 R.sup.7.
42. The compound of claim 1, wherein R.sup.1 is pyridyl, optionally
substituted by 1 to 4 R.sup.6; and R.sup.2 is pyridyl, optionally
substituted by 1 to 4 R.sup.7.
43. A compound selected from: ##STR00378## ##STR00379##
##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384##
##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389##
##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394##
##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399##
##STR00400## ##STR00401## ##STR00402##
44. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier, adjuvant or vehicle.
45. The composition of claim 44, further comprising an additional
therapeutic agent selected from an anti-proliferative agent, an
anti-inflammatory agent, an immunomodulatory agent, a neurotropic
factor, an agent for treating cardiovascular disease, an agent for
treating liver disease, an anti-viral agent, an agent for treating
blood disorders, an agent for treating diabetes, or an agent for
treating immunodeficiency disorders.
46. A pharmaceutical composition comprising a compound of claim 1
in an amount to detectably inhibit JAK2 kinase activity and a
pharmaceutically acceptable carrier, adjuvant or vehicle.
47. A method of treating or lessening the severity of a disease or
condition responsive to the inhibition of JAK2 kinase activity in a
patient, comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
48. The method of claim 47, wherein said disease or condition is
cancer, stroke, diabetes, hepatomegaly, cardiovascular disease,
multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral
disease, autoimmune diseases, atherosclerosis, restenosis,
psoriasis, allergic disorders, inflammation, inflammatory diseases,
neurological disorders, a neurodegenerative disease, a
hormone-related disease, conditions associated with organ
transplantation, immunodeficiency disorders, destructive bone
disorders, proliferative disorders, infectious diseases, conditions
associated with cell death, thrombin-induced platelet aggregation,
liver disease, pathologic immune conditions involving T cell
activation, CNS disorders or a myeloproliferative disorder.
49. The method of claim 48, wherein said disease or condition is
cancer.
50. The method of claim 48, wherein said disease is a
myeloproliferative disorder.
51. The method of claim 50, wherein said myeloproliferative
disorder is polycythemia vera, essential thrombocytosis,
myelofibrosis or chronic myelogenous leukemia (CML).
52. The method of claim 49, wherein said cancer is breast, ovary,
cervix, prostate, testis, penile, genitourinary tract, seminoma,
esophagus, larynx, gastric, stomach, gastrointestinal, skin,
keratoacanthoma, follicular carcinoma, melanoma, lung, small cell
lung carcinoma, non-small cell lung carcinoma (NSCLC), lung
adenocarcinoma, squamous carcinoma of the lung, colon, pancreas,
thyroid, papillary, bladder, liver, biliary passage, kidney, bone,
myeloid disorders, lymphoid disorders, hairy cells, buccal cavity
and pharynx (oral), lip, tongue, mouth, salivary gland, pharynx,
small intestine, colon, rectum, anal, renal, prostate, vulval,
thyroid, large intestine, endometrial, uterine, brain, central
nervous system, cancer of the peritoneum, hepatocellular cancer,
head cancer, neck cancer, Hodgkin's or leukemia.
53. The method of claim 48, wherein said cardiovascular disease is
restenosis, cardiomegaly, atherosclerosis, myocardial infarction or
congestive heart failure.
54. The method of claim 48, wherein said neurodegenerative disease
is Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, and cerebral ischemia, and
neurodegenerative disease caused by traumatic injury, glutamate
neurotoxicity or hypoxia.
55. The method of claim 48, wherein said inflammatory diseases is
rheumatoid arthritis, psoriasis, contact dermatitis or delayed
hypersensitivity reactions.
56. The method of claim 47, further comprising administering a
second chemotherapeutic agent.
57. A kit for treating a disease or disorder responsive to the
inhibition of a JAK kinase, comprising: (a) a first pharmaceutical
composition comprising a compound of claim 1; and (b) instructions
for use.
58. The kit of claim 57, further comprising: (c) a second
pharmaceutical composition, comprising a chemotherapeutic
agent.
59. The kit of claim 58, wherein said instructions comprise
instructions for the simultaneous, sequential or separate
administration of said first and second pharmaceutical compositions
to a patient in need thereof.
60. The kit of claim 58, wherein said first and second compositions
are contained in separate containers.
61. The kit of claim 58, wherein said first and second compositions
are contained in the same container.
62. A compound of claim 1, selected from a compound of Examples
1-312.
Description
FIELD OF THE INVENTION
[0001] Triazolopyridine compounds of Formula I, which are
inhibitors of Janus kinases, for example JAK2 kinase, as well as
compositions containing these compounds and methods of use
including, but not limited to, in vitro, in situ and in vivo
diagnosis or treatment of mammalian cells.
BACKGROUND OF INVENTION
[0002] Myeloproliferative disorders (MPD) originate in
hematopoietic stem cells and primarily manifest in elevated counts
of mostly normal cells of the myeloid lineage. A primary
distinction between Philadelphia-chromosome positive (Ph+) and
Philadelphia-chromosome negative (Ph-) can be made. Ph+ MPD results
in chronic myelogenous leukemia and is driven by a bcr-abl fusion
protein that drives hematopoietic cell proliferation. Ph- MPD can
be further subclassified into three distinct disorders by related
varieties, namely polycythemia vera (PV), essential thrombocythemia
(ET) and idiopathic myelofibrosis (IMF). Dameshek, W., Blood
6(4):372-375 (1951). Patients with PV suffer from high counts of
red blood cells, whereas patients with ET have high levels of
circulating platelets. If left untreated, both diseases can result
in life-threatening thrombotic events. Patients with IMF experience
fibrosis of the bone marrow with subsequent displacement of
hematopoiesis into the spleen and liver. This primarily leads to
splenomegaly, which is followed by anemia in later stages of the
disease as hematopoiesis becomes non-productive. These patients
have a poor prognosis, although under certain conditions they can
be cured by means of an allogeneic bone marrow transplant. There is
no known cure for Ph- MPD diseases.
[0003] An activating mutation in the tyrosine kinase JAK2 is
associated with PV, ET, IMF and other diseases. Virtually all
patients with PV and about 50% patients with ET and IMF harbor this
mutation. Morgan, K. J. and Gilliland, D. G., Ann. Rev. Med.
59:213-222 (2008). The mutation is an exchange from valine to
phenylalanine at position 617 in the mature human JAK2 protein
(V617F). Additional mutations in JAK2, commonly found in exon 12
and referred to as exon 12 mutations, also have an activating
effect and can lead to MPD. Furthermore, a T875N mutation was
associated with megakaryoblastic leukemia. Finally, JAK2 fusion
proteins have been identified in acute leukemias.
[0004] The V617F mutation functions to activate JAK2, which leads
to MPD. In non-mutated form, JAK2 is linked to cytokine receptors
(i.e. EPO-R, TPO-R and others) and only gets activated if the
receptor itself is activated by stimulation with the cognate
cytokine ligand. Hematopoiesis as a whole is then regulated through
the availability of ligands. For example, the cytokine
erythropoietin (EPO) stimulates hematopoietic progenitor cells to
give rise to red blood cells. A mutation that uncouples JAK2
activation from EPO, therefore, leads to elevated levels of red
blood cells. By analogy, thrombopoietin (TPO) regulates platelet
growth by binding to the TPO-R, which in turn also signals through
JAK2. Thus, elevated levels of platelets can also result from
aberrant JAK2 activation.
[0005] Compounds are needed that inhibit JAK2, which would be
beneficial to patients with JAK2 driven myeloproliferative
disorders, as well as, other diseases that are responsive to the
inhibition of JAK2. Such diseases include both diseases in which
JAK2 is activated by mutation or amplification, as well as,
diseases in which JAK2 activation is a part of the oncogenic
cascade. Numerous tumor cell lines and tumor samples have high
levels of phospho-STAT3, which is a JAK2 target gene.
[0006] JAK1 was initially identified in a screen for novel kinases
(Wilks A. F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607).
Genetic and biochemical studies have shown that JAK1 is
functionally and physically associated with the type I interferon
(e.g., IFNalpha), type II interferon (e.g., IFNgamma), IL-2 and
IL-6 cytokine receptor complexes (Kisseleva et al., 2002, gene
285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol. 3:651-662;
O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). JAK1 knockout
mice die perinatally due to defects in LIF receptor signaling
(Kisseleva et al., 2002, gene 285:1-24; O'Shea et al., 2002, Cell,
109 (suppl.): S121-S131). Characterization of tissues derived from
JAK1 knockout mice demonstrated critical roles for this kinase in
the IFN, IL-10, IL-2/IL-4, and IL-6 pathways. A humanized
monoclonal antibody targeting the IL-6 pathway (Tocilizumab) was
recently approved by the European Commission for the treatment of
moderate-to-severe rheumatoid arthritis (Scheinecker et al., 2009,
Nat. Rev. Drug Discov. 8:273-274).
[0007] JAK3 associates exclusively with the gamma common cytokine
receptor chain, which is present in the IL-2, IL-4, IL-7, IL-9,
IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for
lymphoid cell development and proliferation and mutations in JAK3
result in severe combined immunodeficiency (SCID) (O'Shea et al.,
2002, Cell, 109 (suppl.): S121-S131). Based on its role in
regulating lymphocytes, JAK3 and JAK3-mediated pathways have been
targeted for immunosuppressive indications (e.g., transplantation
rejection and rheumatoid arthritis) (Baslund et al., 2005,
Arthritis & Rheumatism 52:2686-2692; Changelian et al., 2003,
Science 302: 875-878).
[0008] TYK2 associates with the type I interferon (e.g., IFNalpha),
IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva
et al., 2002, gene 285:1-24; Watford, W. T. & O'Shea, J. J.,
2006, Immunity 25:695-697). Consistent with this, primary cells
derived from a TYK2 deficient human are defective in type I
interferon, IL-6, IL-10, IL-12 and IL-23 signaling. A fully human
monoclonal antibody targeting the shared p40 subunit of the IL-12
and 11-23 cytokines (Ustekinumab) was recently approved by the
European Commission for the treatment of moderate-to-severe plaque
psoriasis (Krueger et al., 2007, N. Engl. J. Med. 356:580-92; Reich
et al., 2009, Nat. Rev. Drug Discov. 8:355-356). In addition, an
antibody targeting the IL-12 and IL-23 pathways underwent clinical
trials for treating Crohn's Disease (Mannon et al., 2004, N. Engl.
J. Med. 351:2069-79).
SUMMARY OF INVENTION
[0009] One embodiment includes a compound of Formula I:
##STR00002##
enantiomers, diasteriomers, tautomers or pharmaceutically
acceptable salts thereof, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are defined herein.
[0010] Another embodiment includes a pharmaceutical composition
that includes a compound of Formula I and a pharmaceutically
acceptable carrier, adjuvant or vehicle.
[0011] Another embodiment includes a method of treating or
lessening the severity of a disease or condition responsive to the
inhibition of one or more Janus kinase activity, selected from
JAK1, JAK2, JAK3 and TYK2, in a patient. The method includes
administering to the patient a therapeutically effective amount of
a compound of Formula I.
[0012] Another embodiment includes a method of treating or
lessening the severity of a disease or condition responsive to the
inhibition of JAK2 kinase activity in a patient. The method
includes administering to the patient a therapeutically effective
amount of a compound of Formula I.
[0013] Another embodiment includes a kit for treating a disease or
disorder responsive to the inhibition of a JAK kinase. The kit
includes a first pharmaceutical composition comprising a compound
of Formula I and instructions for use
DETAILED DESCRIPTION OF THE INVENTION
[0014] Reference will now be made in detail to certain embodiments,
examples of which are illustrated in the accompanying structures
and formulas. While the invention will be described in conjunction
with the enumerated embodiments, it will be understood that they
are not intended to limit the invention to those embodiments. On
the contrary, the invention is intended to cover all alternatives,
modifications, and equivalents, which may be included within the
scope of the present invention as defined by the claims. One
skilled in the art will recognize many methods and materials
similar or equivalent to those described herein, which could be
used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described. In the event that one or more of the incorporated
literature, patents, and similar materials differs from or
contradicts this application, including but not limited to defined
terms, term usage, described techniques, or the like, this
application controls.
[0015] The term "alkyl" refers to a saturated linear or
branched-chain monovalent hydrocarbon radical, wherein the alkyl
radical may be optionally substituted independently with one or
more substituents described herein. In one example, the alkyl
radical is one to eighteen carbon atoms (C.sub.1-C.sub.18). In
other examples, the alkyl radical is C.sub.0-C.sub.6,
C.sub.0-C.sub.5, C.sub.0-C.sub.3, C.sub.1-C.sub.12,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6,
C.sub.1-C.sub.5, C.sub.1-C.sub.4, or C.sub.1-C.sub.3. Examples of
alkyl groups include C.sub.1-C.sub.8 hydrocarbon moieties such as
methyl (Me, --CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3), 1-propyl
(n-Pr, n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr,
i-propyl, --CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (1-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, 1-heptyl and
1-octyl.
[0016] The term "alkenyl" refers to linear or branched-chain
monovalent hydrocarbon radical with at least one site of
unsaturation, i.e., a carbon-carbon double bond, wherein the
alkenyl radical may be optionally substituted independently with
one or more substituents described herein, and includes radicals
having "cis" and "trans" orientations, or alternatively, "E" and
"Z" orientations. In one example, the alkenyl radical is two to
eighteen carbon atoms (C.sub.2-C.sub.18). In other examples, the
alkenyl radical is C.sub.2-C.sub.12, C.sub.2-C.sub.10,
C.sub.2-C.sub.8, C.sub.2-C.sub.6 or C.sub.2-C.sub.3. Examples
include, but are not limited to, ethenyl or vinyl
(--CH.dbd.CH.sub.2), prop-1-enyl (--CH.dbd.CHCH.sub.3), prop-2-enyl
(--CH.sub.2CH.dbd.CH.sub.2), 2-methylprop-1-enyl, but-1-enyl,
but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,
hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,
hexa-1,3-dienyl.
[0017] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical with at least one site of unsaturation, i.e., a
carbon-carbon, triple bond, wherein the alkynyl radical may be
optionally substituted independently with one or more substituents
described herein. In one example, the alkynyl radical is two to
eighteen carbon atoms (C.sub.2-C.sub.18). In other examples, the
alkynyl radical is C.sub.2-C.sub.12, C.sub.2-C.sub.10,
C.sub.2-C.sub.8, C.sub.2-C.sub.6 or C.sub.2-C.sub.3. Examples
include, but are not limited to, ethynyl (--C.ident.CH),
prop-1-ynyl (--C.ident.CCH.sub.3), prop-2-ynyl (propargyl,
--CH.sub.2C.ident.CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
[0018] "Cycloalkyl" refers to a non-aromatic, saturated or
partially unsaturated hydrocarbon ring group wherein the cycloalkyl
group may be optionally substituted independently with one or more
substituents described herein. In one example, the cycloalkyl group
is 3 to 12 carbon atoms (C.sub.3-C.sub.12). In other examples,
cycloalkyl is C.sub.3-C.sub.10 or C.sub.5-C.sub.10. In other
examples, the cycloalkyl group, as a monocycle, is C.sub.3-C.sub.6
or C.sub.5-C.sub.6. In another example, the cycloalkyl group, as a
bicycle, is C.sub.7-C.sub.12. Examples of monocyclic cycloalkyl
include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,
1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,
1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,
cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic
cycloalkyls having 7 to 12 ring atoms include, but are not limited
to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary
bridged bicyclic cycloalkyls include, but are not limited to,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and
bicyclo[3.2.2]nonane.
[0019] "Aryl" refers to a cyclic aromatic hydrocarbon group
optionally substituted independently with one or more substituents
described herein. In one example, the aryl group is 6-20 carbon
atoms (C.sub.6-C.sub.20). In another example, the aryl group is
C.sub.6-C.sub.9. In another example, the aryl group is a C.sub.6
aryl group. Aryl groups may be represented in the exemplary
structures as "Ar". Aryl includes a bicyclic group comprising an
aromatic ring with a fused non-aromatic or partially saturated
ring. Example aryl groups include, but are not limited to, phenyl,
naphthalenyl, anthracenyl, indenyl, indanyl,
1,2-dihydronapthalenyl, 1,2,3,4-tetrahydronapthyl, and the
like.
[0020] "Halo" refers to F, Cl, Br or I.
[0021] "Heterocyclyl" refers to a saturated or a partially
unsaturated (i.e., having one or more double and/or triple bonds
within the ring) cyclic group in which at least one ring atom is a
heteroatom independently selected from nitrogen, oxygen, phosphorus
and sulfur, the remaining ring atoms being carbon. The heterocyclyl
group may be optionally substituted with one or more substituents
described below. In one embodiment, heterocyclyl includes
monocycles or bicycles having 1 to 9 carbon ring members
(C.sub.1-C.sub.9). In other examples, heterocyclyl includes
monocycles or bicycles having C.sub.1-C.sub.5, C.sub.3-C.sub.5 or
C.sub.4-C.sub.5. Examples of bicycle systems include, but are not
limited to, [3,5], [4,5], [5,5], [3,6], [4,6], [5,6], or [6,6]
systems. In another embodiment, heterocyclyl includes bridged ring
systems having [2.2.1], [2.2.2], [3.2.2] and [4.1.0] arrangements,
and having 1 to 3 heteroatoms selected from N, O, S and P. In
another embodiment, heterocyclyl includes spiro groups having 1 to
3 heteroatoms selected from N, O, S and P. The heterocyclyl group
may be a carbon-linked group or heteroatom-linked group.
"Heterocyclyl" includes a heterocyclyl group fused to a cycloalkyl
group.
[0022] Exemplary heterocyclyl groups include, but are not limited
to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl,
thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl,
homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,
diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl,
dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl,
2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl,
dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl,
dithiolanyl, pyrazolidinylimidazolinyl, imidazolidinyl,
3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and
azabicyclo[2.2.2]hexanyl. Examples of a heterocyclyl group wherein
a ring atom is substituted with oxo (.dbd.O) are indolinonyl,
pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclyl
groups herein are optionally substituted independently with one or
more substituents described herein. Heterocycles are described in
Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.
A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7,
and 9; "The Chemistry of Heterocyclic Compounds, A series of
Monographs" (John Wiley & Sons, New York, 1950 to present), in
particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.
(1960) 82:5566.
[0023] The term "heteroaryl" refers to an aromatic carbocyclic
radical in which at least one ring atom is a heteroatom
independently selected from nitrogen, oxygen and sulfur, the
remaining ring atoms being carbon. Heteroaryl groups may be
optionally substituted with one or more substituents described
herein. In one example, the heteroaryl group contains 1 to 9 carbon
ring atoms (C.sub.1-C.sub.9). In other examples, the heteroaryl
group is C.sub.1-C.sub.5, C.sub.3-C.sub.5 or C.sub.5-C.sub.10. In
one embodiment, exemplary heteroaryl groups include monocyclic
aromatic 5-, 6- and 7-membered rings containing one or more
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In another embodiment, exemplary heteroaryl groups include
fused ring systems of 8 to 20 atoms wherein at least one aromatic
ring contains one or more heteroatoms independently selected from
nitrogen, oxygen, and sulfur. "Heteroaryl" includes heteroaryl
groups fused with an aryl, cycloalkyl or heterocyclyl group.
Examples of heteroaryl groups include, but are not limited to,
pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,
triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,
thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,
isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,
indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,
isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,
thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, and furopyridinyl.
[0024] In certain embodiments, the heterocyclyl or heteroaryl group
is C-attached. By way of example and not limitation, carbon bonded
heterocyclyls include bonding arrangements at position 2, 3, 4, 5,
or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine,
position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a
pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,
thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4,
or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of
an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an
aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4,
5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of
an isoquinoline. (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl,
6-pyridyl).
[0025] In certain embodiments, the heterocyclyl or heteroaryl group
is N-attached. By way of example and not limitation, the nitrogen
bonded heterocyclyl or heteroaryl group include bonding
arrangements at position 1 of an aziridine, azetidine, pyrrole,
pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,
2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,
3-pyrazoline, piperidine, piperazine, indole, indoline,
1H-indazole, position 2 of a isoindole, or isoindoline, position 4
of a morpholine, and position 9 of a carbazole, or
.beta.-carboline.
[0026] In an embodiment, for Formula I, alkyl, alkenyl and alkynyl
are optionally substituted by 1 to 5 substituents independently
selected from by one or more OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and aryl, heterocyclyl, heteroaryl and cycloalkyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4 alkyl), wherein
R.sup.a, R.sup.c and R.sup.d are defined below for Formula I. In
another embodiment, for Formula I, alkyl, alkenyl and alkynyl are
optionally substituted by 1 to 3 substituents independently
selected from by one or more OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and aryl, heterocyclyl, heteroaryl and cycloalkyl are
optionally substituted by 1 to 3 substituents independently
selected from OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4 alkyl), wherein
R.sup.a, R.sup.c and R.sup.d are defined below for Formula I.
[0027] In an embodiment, for Formula I, alkyl, alkenyl and alkynyl
are optionally substituted by 1 to 5 substituents independently
selected from oxo and halo, and aryl is optionally substituted by 1
to 5 substituents independently selected from OR.sup.a, halo,
CF.sub.3, NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl, wherein
R.sup.a, R.sup.c and R.sup.d are defined below for Formula I. In
another embodiment, for Formula I, alkyl, alkenyl and alkynyl are
optionally substituted by 1 to 3 substituents independently
selected from oxo and halo, and aryl is optionally substituted by 1
to 3 substituents independently selected from OR.sup.a, halo,
CF.sub.3, NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl, wherein
R.sup.a, R.sup.c and R.sup.d are defined below for Formula I.
[0028] In an embodiment, for Formula I, alkyl, aryl and cycloalkyl
are optionally substituted by 1 to 5 substituents independently
selected from C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.3
alkyl)OR.sup.c, oxo, halo, NR.sup.cR.sup.d and C.sub.4-C.sub.5
heterocyclyl, wherein R.sup.c and R.sup.d are defined below for
Formula I. In another embodiment, for Formula I, alkyl, aryl and
cycloalkyl are optionally substituted by 1 to 3 substituents
independently selected from C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.3
alkyl)OR.sup.c, oxo, halo, NR.sup.cR.sup.d and C.sub.4-C.sub.5
heterocyclyl, wherein R.sup.c and R.sup.d are defined below for
Formula I.
[0029] In an embodiment, for Formula I, alkyl, cycloalkyl and
phenyl are optionally substituted by 1 to 5 substituents
independently selected from halo, CH.sub.3 OH, NH.sub.2,
C(O)O(C.sub.1-C.sub.6 alkyl) and C(O)NH(C.sub.1-C.sub.6 alkyl). In
another embodiment, for Formula I, alkyl, cycloalkyl and phenyl are
optionally substituted by 1 to 3 substituents independently
selected from halo, CH.sub.3 OH, NH.sub.2, C(O)O(C.sub.1-C.sub.6
alkyl) and C(O)NH(C.sub.1-C.sub.6 alkyl).
[0030] "Treat" and "treatment" includes both therapeutic treatment
and prophylactic or preventative measures, wherein the object is to
prevent or slow down (lessen) an undesired physiological change or
disorder, such as the development or spread of cancer. For purposes
of this invention, beneficial or desired clinical results include,
but are not limited to, alleviation of symptoms, diminishment of
extent of disease, stabilized (i.e., not worsening) state of
disease, delay or slowing of disease progression, amelioration or
palliation of the disease state, and remission (whether partial or
total), whether detectable or undetectable. "Treatment" can also
mean prolonging survival as compared to expected survival if not
receiving treatment. Those in need of treatment include those
already with the condition or disorder as well as those prone to
have the condition or disorder, (for example, through a genetic
mutation) or those in which the condition or disorder is to be
prevented.
[0031] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent
growth and/or kill existing cancer cells, it may be cytostatic
and/or cytotoxic. For cancer therapy, efficacy can, for example, be
measured by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
[0032] The term "bioavailability" refers to the systemic
availability (i.e., blood/plasma levels) of a given amount of drug
administered to a patient. Bioavailability is an absolute term that
indicates measurement of both the time (rate) and total amount
(extent) of drug that reaches the general circulation from an
administered dosage form.
[0033] The terms "cancer" and "cancerous" refer to or describe the
physiological condition in mammals that is typically characterized
by unregulated cell growth. A "tumor" comprises one or more
cancerous cells. Examples of cancer include, but are not limited
to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or
lymphoid malignancies. More particular examples of such cancers
include squamous cell cancer (e.g., epithelial squamous cell
cancer), lung cancer including small-cell lung cancer, non-small
cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous
carcinoma of the lung, cancer of the peritoneum, hepatocellular
cancer, gastric or stomach cancer including gastrointestinal
cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian
cancer, liver cancer, bladder cancer, hepatoma, breast cancer,
colon cancer, rectal cancer, colorectal cancer, endometrial or
uterine carcinoma, salivary gland carcinoma, kidney or renal
cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic
carcinoma, anal carcinoma, penile carcinoma, as well as head and
neck cancer.
[0034] A "chemotherapeutic agent" is a chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include Erlotinib (TARCEVA.RTM., Genentech, Inc./OSI Pharm.),
Trastuzumab (HERCEPTIN.RTM., Genentech, Inc.); bevacizumab
(AVASTIN.RTM., Genentech, Inc.); Rituximab (RITUXAN.RTM.,
Genentech, Inc./Biogen Idec, Inc.), Bortezomib (VELCADE.RTM.,
Millennium Pharm.), Fulvestrant (FASLODEX.RTM., AstraZeneca),
Sutent (SU11248, Pfizer), Letrozole (FEMARA.RTM., Novartis),
Imatinib mesylate (GLEEVEC.RTM., Novartis), PTK787/ZK 222584
(Novartis), Oxaliplatin (Eloxatin.RTM., Sanofi), 5-FU.
(5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE.RTM.,
Wyeth), Lapatinib (GSK572016, Glaxo Smith Kline), Lonafarnib (SCH
66336), Sorafenib (BAY43-9006, Bayer Labs), and Gelitinib
(IRESSA.RTM., AstraZeneca), AG1478, AG1571 (SU 5271; Sugen),
alkylating agents such as thiotepa and CYTOXAN.RTM.
cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan
and piposulfan; aziridines such as benzodopa, carboquone,
meturedopa, and uredopa; ethylenimines and methylamelamines
including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and
trimethylomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including the synthetic analog
topotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogs);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
dolastatin; duocarmycin (including the synthetic analogs, KW-2189
and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil,
chlornaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, and ranimnustine; antibiotics
such as the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin gamma1I and calicheamicin omegaI1 (Angew Chem. Intl.
Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A;
bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and related chromoprotein enediyne
antibiotic chromophores), aclacinomysins, actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, carabicin, caminomycin,
carzinophilin, chromomycinis, dactinomycin, daunorubicin,
detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN.RTM.
(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin
C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogs such as denopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogs such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine; androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformithine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; lonidainine; maytansinoids such as maytansine and
ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine;
pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic
acid; 2-ethylhydrazide; procarbazine; PSK.RTM. polysaccharide
complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;
sizofuran; spirogermanium; tenuazonic acid; triaziquone;
2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2
toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa;
taxoids, e.g., TAXOL.RTM. (paclitaxel; Bristol-Myers Squibb
Oncology, Princeton, N.J.), ABRAXANE.RTM. (Cremophor-free),
albumin-engineered nanoparticle formulations of paclitaxel
(American Pharmaceutical Partners, Schaumberg, Ill.), and
TAXOTERE.RTM. (doxetaxel; Rhone-Poulenc Rorer, Antony, France);
chloranbucil; GEMZAR.RTM. (gemcitabine); 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; etoposide (VP-16); ifosfamide;
mitoxantrone; vincristine; NAVELBINE.RTM. (vinorelbine);
novantrone; teniposide; edatrexate; daunomycin; aminopterin;
xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difluoromethylornithine (DMFO); retinoids such as retinoic acid;
capecitabine; and pharmaceutically acceptable salts, acids and
derivatives of any of the above.
[0035] Also included in the definition of "chemotherapeutic agent"
are: (i) anti-hormonal agents that act to regulate or inhibit
hormone action on tumors such as anti-estrogens and selective
estrogen receptor modulators (SERMs), including, for example,
tamoxifen (including NOLVADEX.RTM.; tamoxifen citrate), raloxifene,
droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and FARESTON.RTM. (toremifine citrate); (ii) aromatase
inhibitors that inhibit the enzyme aromatase, which regulates
estrogen production in the adrenal glands, such as, for example,
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca); (iii)
anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; as well as troxacitabine (a
1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase
inhibitors; (v) lipid kinase inhibitors; (vi) antisense
oligonucleotides, particularly those which inhibit expression of
genes in signaling pathways implicated in aberrant cell
proliferation, such as, for example, PKC-alpha, Ralf and H-Ras;
(vii) ribozymes such as VEGF inhibitors (e.g., ANGIOZYME.RTM.) and
(viii) vaccines such as gene therapy vaccines, for example,
ALLOVECTIN.RTM., LEUVECTIN.RTM., and VAXID.RTM.; PROLEUKIN.RTM.
rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN.RTM.;
ABARELIX.RTM. rmRH; (ix) anti-angiogenic agents; and (x)
pharmaceutically acceptable salts, acids and derivatives of any of
the above.
[0036] Humanized monoclonal antibodies with therapeutic potential
as agents in combination with the Janus kinase inhibitors of the
invention include: alemtuzumab, apolizumab, aselizumab, atlizumab,
bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab
mertansine, cedelizumab, certolizumab pegol, cidfusituzumab,
cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab,
erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin,
inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab,
matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab,
nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab,
palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab,
pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab,
resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab,
sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab,
tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab
celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab,
visilizumab, adalimumab, etanercept, infliximab and the
anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott
Laboratories) which is a recombinant exclusively human-sequence,
full-length IgG.sub.1.lamda. antibody genetically modified to
recognize interleukin-12 p40 protein.
[0037] The term "prodrug" as used in this application refers to a
precursor or derivative form of a pharmaceutically active substance
that is less efficacious to the patient or cytotoxic to tumor cells
compared to the parent drug and is capable of being enzymatically
or hydrolytically activated or converted into the more active
parent form. See, e.g., Wilman, "Prodrugs in Cancer Chemotherapy"
Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting
Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to
Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al.,
(ed.), pp. 247-267, Humana Press (1985). The prodrugs of this
invention include, but are not limited to, phosphate-containing
prodrugs, thiophosphate-containing prodrugs, sulfate-containing
prodrugs, peptide-containing prodrugs, D-amino acid-modified
prodrugs, glycosylated prodrugs, .beta.-lactam-containing prodrugs,
optionally substituted phenoxyacetamide-containing prodrugs or
optionally substituted phenylacetamide-containing prodrugs,
5-fluorocytosine and other 5-fluorouridine prodrugs which can be
converted into the more active cytotoxic free drug. Examples of
cytotoxic drugs that can be derivatized into a prodrug form for use
in this invention include, but are not limited to, those
chemotherapeutic agents described above.
[0038] A "liposome" is a small vesicle composed of various types of
lipids, phospholipids and/or surfactant which is useful for
delivery of a drug (such as a compound of Formula I and,
optionally, a chemotherapeutic agent) to a mammal. The components
of the liposome are commonly arranged in a bilayer formation,
similar to the lipid arrangement of biological membranes.
[0039] The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic
products, that contain information about the indications, usage,
dosage, administration, contraindications and/or warnings
concerning the use of such therapeutic products.
[0040] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0041] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0042] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0043] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0044] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. Many organic compounds
exist in optically active forms, i.e., they have the ability to
rotate the plane of plane-polarized light. In describing an
optically active compound, the prefixes D and L, or R and S, are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and l or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or l meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory. For a given
chemical structure, these stereoisomers are identical except that
they are mirror images of one another. A specific stereoisomer may
also be referred to as an enantiomer, and a mixture of such isomers
is often called an enantiomeric mixture. A 50:50 mixture of
enantiomers is referred to as a racemic mixture or a racemate,
which may occur where there has been no stereoselection or
stereospecificity in a chemical reaction or process. The terms
"racemic mixture" and "racemate" refer to an equimolar mixture of
two enantiomeric species, devoid of optical activity.
[0045] The phrase "pharmaceutically acceptable salt," as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound of Formula I. Exemplary salts include, but are
not limited, to sulfate, citrate, acetate, oxalate, chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion.
[0046] A "solvate" refers to an association or complex of one or
more solvent molecules and a compound of Formula I. Examples of
solvents that form solvates include, but are not limited to, water,
isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,
and ethanolamine. The term "hydrate" refers to the complex where
the solvent molecule is water.
[0047] The term "protecting group" or "Pg" refers to a substituent
that is commonly employed to block or protect a particular
functionality while reacting other functional groups on the
compound. For example, an "amino-protecting group" is a substituent
attached to an amino group that blocks or protects the amino
functionality in the compound. Suitable amino-protecting groups
include acetyl, trifluoroacetyl, phthalimido, t-butoxycarbonyl
(BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl
(Fmoc). Similarly, a "hydroxy-protecting group" refers to a
substituent of a hydroxy group that blocks or protects the hydroxy
functionality. Suitable hydroxy-protecting groups include acetyl,
trialkylsilyl, dialkylphenylsilyl, benzoyl, benzyl,
benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, and
tetrahydropyranyl. A "carboxy-protecting group" refers to a
substituent of the carboxy group that blocks or protects the
carboxy functionality. Common carboxy-protecting groups include
--CH.sub.2CH.sub.2SO.sub.2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,
2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl,
nitroethyl and the like. For a general description of protecting
groups and their use, see T. W. Greene and P. Wuts, Protective
Groups in Organic Synthesis, Third Ed., John Wiley & Sons, New
York, 1999; and P. Kocienski, Protecting Groups, Third Ed., Verlag,
2003.
[0048] The term "patient" includes human patients and animal
patients. The term "animal" includes companion animals (e.g., dogs,
cats and horses), food-source animals, zoo animals, marine animals,
birds and other similar animal species.
[0049] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0050] The terms "compound of this invention," and "compounds of
the present invention", and "compounds of Formula I", unless
otherwise indicated, include compounds of Formula I and
stereoisomers, tautomers, solvates, metabolites, salts (e.g.,
pharmaceutically acceptable salts) and prodrugs thereof. Unless
otherwise stated, structures depicted herein are also meant to
include compounds that differ only in the presence of one or more
isotopically enriched atoms. For example, compounds of Formula I,
wherein one or more hydrogen atoms are replaced deuterium or
tritium, or one or more carbon atoms are replaced by a .sup.13C- or
.sup.14C-enriched carbon are within the scope of this
invention.
[0051] "Inflammatory disorder" as used herein can refer to any
disease, disorder, or syndrome in which an excessive or unregulated
inflammatory response leads to excessive inflammatory symptoms,
host tissue damage, or loss of tissue function. "Inflammatory
disorder" also refers to a pathological state mediated by influx of
leukocytes and/or neutrophil chemotaxis.
[0052] "Inflammation" as used herein refers to a localized,
protective response elicited by injury or destruction of tissues,
which serves to destroy, dilute, or wall off (sequester) both the
injurious agent and the injured tissue. Inflammation is notably
associated with influx of leukocytes and/or neutrophil chemotaxis.
Inflammation can result from infection with pathogenic organisms
and viruses and from noninfectious means such as trauma or
reperfusion following myocardial infarction or stroke, immune
response to foreign antigen, and autoimmune responses. Accordingly,
inflammatory disorders amenable to treatment with Formula I
compounds encompass disorders associated with reactions of the
specific defense system as well as with reactions of the
nonspecific defense system.
[0053] "Specific defense system" refers to the component of the
immune system that reacts to the presence of specific antigens.
Examples of inflammation resulting from a response of the specific
defense system include the classical response to foreign antigens,
autoimmune diseases, and delayed type hypersensitivity response
mediated by T-cells. Chronic inflammatory diseases, the rejection
of solid transplanted tissue and organs, e.g., kidney and bone
marrow transplants, and graft versus host disease (GVHD), are
further examples of inflammatory reactions of the specific defense
system.
[0054] The term "nonspecific defense system" as used herein refers
to inflammatory disorders that are mediated by leukocytes that are
incapable of immunological memory (e.g., granulocytes, and
macrophages). Examples of inflammation that result, at least in
part, from a reaction of the nonspecific defense system include
inflammation associated with conditions such as adult (acute)
respiratory distress syndrome (ARDS) or multiple organ injury
syndromes; reperfusion injury; acute glomerulonephritis; reactive
arthritis; dermatoses with acute inflammatory components; acute
purulent meningitis or other central nervous system inflammatory
disorders such as stroke; thermal injury; inflammatory bowel
disease; granulocyte transfusion associated syndromes; and
cytokine-induced toxicity.
[0055] "Autoimmune disease" as used herein refers to any group of
disorders in which tissue injury is associated with humoral or
cell-mediated responses to the body's own constituents.
[0056] "Allergic disease" as used herein refers to any symptoms,
tissue damage, or loss of tissue function resulting from allergy.
"Arthritic disease" as used herein refers to any disease that is
characterized by inflammatory lesions of the joints attributable to
a variety of etiologies. "Dermatitis" as used herein refers to any
of a large family of diseases of the skin that are characterized by
inflammation of the skin attributable to a variety of etiologies.
"Transplant rejection" as used herein refers to any immune reaction
directed against grafted tissue, such as organs or cells (e.g.,
bone marrow), characterized by a loss of function of the grafted
and surrounding tissues, pain, swelling, leukocytosis, and
thrombocytopenia. The therapeutic methods of the present invention
include methods for the treatment of disorders associated with
inflammatory cell activation.
[0057] "Inflammatory cell activation" refers to the induction by a
stimulus (including, but not limited to, cytokines, antigens or
auto-antibodies) of a proliferative cellular response, the
production of soluble mediators (including but not limited to
cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive
amines), or cell surface expression of new or increased numbers of
mediators (including, but not limited to, major histocompatability
antigens or cell adhesion molecules) in inflammatory cells
(including but not limited to monocytes, macrophages, T
lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear
leukocytes such as neutrophils, basophils, and eosinophils), mast
cells, dendritic cells, Langerhans cells, and endothelial cells).
It will be appreciated by persons skilled in the art that the
activation of one or a combination of these phenotypes in these
cells can contribute to the initiation, perpetuation, or
exacerbation of an inflammatory disorder.
[0058] The term "NSAID" is an acronym for "non-steroidal
anti-inflammatory drug" and is a therapeutic agent with analgesic,
antipyretic (lowering an elevated body temperature and relieving
pain without impairing consciousness) and, in higher doses, with
anti-inflammatory effects (reducing inflammation). The term
"non-steroidal" is used to distinguish these drugs from steroids,
which (among a broad range of other effects) have a similar
eicosanoid-depressing, anti-inflammatory action. As analgesics,
NSAIDs are unusual in that they are non-narcotic. NSAIDs include
aspirin, ibuprofen, and naproxen. NSAIDs are usually indicated for
the treatment of acute or chronic conditions where pain and
inflammation are present. NSAIDs are generally indicated for the
symptomatic relief of the following conditions: rheumatoid
arthritis, osteoarthritis, inflammatory arthropathies (e.g.
ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome,
acute gout, dysmenorrhoea, metastatic bone pain, headache and
migraine, postoperative pain, mild-to-moderate pain due to
inflammation and tissue injury, pyrexia, ileus, and renal colic.
Most NSAIDs act as non-selective inhibitors of the enzyme
cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the
formation of prostaglandins and thromboxane from arachidonic acid
(itself derived from the cellular phospholipid bilayer by
phospholipase A.sub.2). Prostaglandins act (among other things) as
messenger molecules in the process of inflammation. COX-2
inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib,
rofecoxib, rofecoxib, and valdecoxib.
[0059] "JAK kinase," and "Janus kinase" refer to the JAK1, JAK2,
JAK3 and TYK2 protein kinases.
Triazolopyridine JAK Inhibitor Compounds
[0060] In one embodiment, a compound of Formula I, and
pharmaceutical formulations thereof, are provided that are useful
in the treatment of diseases, conditions and/or disorders
responsive to the inhibition of JAK kinases.
[0061] Another embodiment includes compounds of Formula I
##STR00003##
enantiomers, diasteriomers, tautomers or pharmaceutically
acceptable salts thereof, wherein:
[0062] R.sup.1 is H, C(O)OR.sup.a, phenyl, C.sub.1-C.sub.9
heterocyclyl or C.sub.1-C.sub.9 heteroaryl, wherein said phenyl and
heteroaryl are optionally substituted by 1 to 5 R.sup.6;
[0063] R.sup.2 is phenyl, C.sub.1-C.sub.9 heteroaryl or
C.sub.1-C.sub.9 heterocyclyl, wherein the phenyl, heteroaryl and
heterocyclyl are optionally substituted by 1 to 5 R.sup.7;
[0064] R.sup.3, R.sup.4 and R.sup.5 are independently H, CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, CF.sub.3, F or Cl;
[0065] R.sup.6 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6
alkyl)OR.sup.a, (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, CN,
CF.sub.3, S(O).sub.1-2NR.sup.aR.sup.b, C(O)R.sup.a,
NR.sup.aC(O)OR.sup.b, NR.sup.aS(O).sub.1-2NR.sup.b,
(C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heteroaryl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl, (C.sub.0-C.sub.6
alkyl)C.sub.3-C.sub.6 cycloalkyl, (C.sub.0-C.sub.6
alkyl)C.sub.6-C.sub.9 aryl, (C.sub.0-C.sub.6 alkyl)C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b or C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.6 aryl), wherein said alkyl, alkenyl and alkynyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl and
C(O)(C.sub.1-C.sub.4 alkyl);
[0066] R.sup.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6
alkyl)OR.sup.a, (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b,
(C.sub.0-C.sub.6 alkyl)(C.sub.6-C.sub.9 aryl), halo,
C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.b, SO.sub.2(C.sub.1-C.sub.6
alkyl), SO.sub.2NR.sup.aR.sup.b, CN, CF.sub.3, CH.sub.2CF.sub.3,
nitro, S(O)(C.sub.1-C.sub.6 alkyl), S(O)NR.sup.aR.sup.b,
NR.sup.aS(O).sub.1-2R.sup.b, C(O)R.sup.a, C(O)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heteroaryl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl or (C.sub.0-C.sub.6
alkyl)C.sub.3-C.sub.6 cycloalkyl, wherein said alkyl, alkenyl and
alkynyl are optionally substituted by 1 to 5 substituents
independently selected from oxo, NR.sup.aR.sup.b, OR.sup.a, and
halo, and said aryl, heteroaryl, heterocyclyl and cycloalkyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, halo, CF.sub.3, NR.sup.cR.sup.d and
C.sub.1-C.sub.4 alkyl;
[0067] R.sup.a and R.sup.b are independently H, OR.sup.c,
C(O)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.6 aryl
or C.sub.3-C.sub.6 cycloalkyl, wherein said alkyl, aryl and
cycloalkyl are optionally substituted by 1 to 5 substituents
independently selected from C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.3
alkyl)OR.sup.c, oxo, halo, NR.sup.cR.sup.d and C.sub.4-C.sub.5
heterocyclyl; or
[0068] R.sup.a and R.sup.b together with the atom to which they are
attached form a C.sub.1-C.sub.5 heterocyclyl; and
[0069] R.sup.c and R.sup.d are independently H, C.sub.1-C.sub.3
alkyl, C.sub.3-C.sub.6 cycloalkyl or phenyl, wherein said alkyl,
cycloalkyl and phenyl are optionally substituted by 1 to 5
substituents independently selected from halo, CH.sub.3 OH or
NH.sub.2, C(O)O(C.sub.1-C.sub.6 alkyl) and C(O)NH(C.sub.1-C.sub.6
alkyl).
[0070] Another embodiment includes compounds of Formula I:
##STR00004##
enantiomers, diasteriomers, tautomers or pharmaceutically
acceptable salts thereof, wherein:
[0071] R.sup.1 is H, C(O)OR.sup.a, phenyl or C.sub.1-C.sub.9
heteroaryl, wherein said phenyl and heteroaryl are optionally
substituted by 1 to 6 R.sup.6
[0072] R.sup.2 is phenyl, C.sub.1-C.sub.9 heteroaryl or
C.sub.1-C.sub.9 heterocyclyl, wherein the phenyl, heteroaryl and
heterocyclyl are optionally substituted by 1 to 6 R.sup.7;
[0073] R.sup.3, R.sup.4 and R.sup.5 are independently H, CH.sub.3,
CH.sub.2CH.sub.3, CF.sub.3, F or Cl;
[0074] R.sup.6 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6
alkyl)OR.sup.a, (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, CN,
C.sub.1-C.sub.5 heteroaryl, C.sub.1-C.sub.5 heterocyclyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.9 aryl, C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b, C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)(C.sub.6
aryl), wherein said alkyl, alkenyl and alkynyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said aryl,
heterocyclyl, heteroaryl and cycloalkyl are optionally substituted
by 1 to 5 substituents independently selected from OR.sup.a, oxo,
halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl and
C(O)(C.sub.1-C.sub.4 alkyl);
[0075] R.sup.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6
alkyl)OR.sup.a, (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b,
(C.sub.0-C.sub.6 alkyl)(C.sub.6-C.sub.9 aryl), halo,
C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.b, SO.sub.2(C.sub.1-C.sub.6
alkyl), SO.sub.2NR.sup.aR.sup.b, CN, nitro, wherein said alkyl,
alkenyl and alkynyl are optionally substituted by 1 to 5
substituents independently selected from oxo and halo, and said and
said aryl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, halo, CF.sub.3,
NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl;
[0076] R.sup.a and R.sup.b are independently H, OR.sup.c,
C(O)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.6 aryl
or C.sub.3-C.sub.6 cycloalkyl, wherein said alkyl, aryl and
cycloalkyl are optionally substituted by 1 to 5 substituents
independently selected from C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.3
alkyl)OR.sup.c, oxo, halo, NR.sup.cR.sup.d and C.sub.4-C.sub.5
heterocyclyl; or
[0077] R.sup.a and R.sup.b together with the atom to which they are
attached form a C.sub.1-C.sub.5 heterocyclyl; and
[0078] R.sup.c and R.sup.d are independently H, C.sub.1-C.sub.3
alkyl, C.sub.3-C.sub.6 cycloalkyl or phenyl, wherein said alkyl,
cycloalkyl and phenyl are optionally substituted by 1 to 5
substituents independently selected from halo, CH.sub.3 OH,
NH.sub.2, C(O)O(C.sub.1-C.sub.6 alkyl) and C(O)NH(C.sub.1-C.sub.6
alkyl).
[0079] In one embodiment, R.sup.1 is phenyl or C.sub.1-C.sub.9
heteroaryl, wherein said phenyl and heteroaryl are optionally
substituted by 1 to 5 R.sup.6.
[0080] In one embodiment, R.sup.1 is phenyl optionally substituted
by 1 to 5 R.sup.6.
[0081] In one embodiment, R.sup.1 is phenyl optionally substituted
by 1 to 3 R.sup.6.
[0082] In one embodiment, R.sup.1 is phenyl optionally substituted
by 2 R.sup.6.
[0083] In one embodiment, R.sup.1 is phenyl optionally substituted
by 1 R.sup.6.
[0084] In one embodiment, R.sup.1 is C.sub.1-C.sub.9 heteroaryl
optionally substituted by 1 to 5 R.sup.6.
[0085] In one embodiment, C.sub.1-C.sub.9 heteroaryl is pyridinyl,
imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl or furopyridinyl, each of which is optionally
substituted by 1 to 5 R.sup.6.
[0086] In one embodiment, R.sup.1 is pyridinyl optionally
substituted by 1 to 4 R.sup.6.
[0087] In one embodiment, R.sup.1 is pyridinyl optionally
substituted by 2 R.sup.6.
[0088] In one embodiment, R.sup.1 is pyridinyl optionally
substituted by 1 R.sup.6.
[0089] In one embodiment, R.sup.1 is H.
[0090] In one embodiment, R.sup.1 is C(O)OR.sup.a, wherein R.sup.a
is independently H, OR.sup.c, C(O)O(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, C.sub.6 aryl or C.sub.3-C.sub.6 cycloalkyl,
wherein said alkyl, aryl and cycloalkyl are optionally substituted
by 1 to 5 substituents independently selected from C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.3 alkyl)OR.sup.c, Oxo, halo, NR.sup.cR.sup.d
and C.sub.4-C.sub.5 heterocyclyl.
[0091] In one embodiment, R.sup.1 is phenyl or C.sub.1-C.sub.9
heteroaryl, optionally substituted by 1 to 3 R.sup.6. In one
example, R.sup.1 is phenyl, pyrazolyl, benzimidazolyl or pyridyl,
optionally substituted by 1 to 3 R.sup.6. In one example, In one
example, R.sup.1 is phenyl, pyrazolyl or pyridyl, optionally
substituted by 1 to 3 R.sup.6, wherein R.sup.6 is independently
C.sub.1-C.sub.6 alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo, CF.sub.3,
C(O)OR.sup.a, C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heterocyclyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heterocyclyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.3-C.sub.6 cycloalkyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heteroaryl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)(C.sub.6 aryl), wherein said
alkyl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5
heterocyclyl and C(O)(C.sub.1-C.sub.4 alkyl). In one example,
R.sup.1 is phenyl, pyrazolyl or pyridyl, optionally substituted by
1 R.sup.6, wherein R.sup.6 is independently C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b, C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.6
aryl), wherein said alkyl is optionally substituted by 1 to 5
substituents independently selected from OR.sup.a, NR.sup.cR.sup.d,
oxo and halo, and said aryl, heterocyclyl, heteroaryl and
cycloalkyl are optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, oxo, halo, CF.sub.3,
NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl and C(O)(C.sub.1-C.sub.4
alkyl).
[0092] In one embodiment, R.sup.1 is phenyl or pyridinyl,
optionally substituted by 1 to 3 R.sup.6, wherein R.sup.6 is
independently C.sub.1-C.sub.3 alkyl, (C.sub.0-C.sub.6
alkyl)OR.sup.a, (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, halo,
CF.sub.3, S(O).sub.2R.sup.a, S(O).sub.1-2NR.sup.aR.sup.b,
NR.sup.aS(O).sub.1-2R.sup.b, (C.sub.0-C.sub.5 alkyl)C.sub.1-C.sub.5
heterocyclyl or C(O)OR.sup.a, wherein said alkyl is optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, NR.sup.cR.sup.d, OXO, S(O), 2R.sup.a,
S(O).sub.1-2NR.sup.aR.sup.b and halo, and said heterocyclyl is
optionally substituted by 1 to 3 substituents independently
selected from (C.sub.0-C.sub.5 alkyl)OR.sup.a, oxo, halo, CF.sub.3,
(C.sub.0-C.sub.5 alkyl)NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl and
C(O)R.sup.c. In one example, R.sup.1 is selected from the
following:
##STR00005## ##STR00006## ##STR00007##
wherein the wavy line represents the point of attachment to Formula
I.
[0093] In one embodiment, R.sup.1 is phenyl or pyridinyl,
optionally substituted by 1 R.sup.6, wherein R.sup.6 is
independently C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heterocyclyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.3-C.sub.6 cycloalkyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heteroaryl),
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.6 aryl), wherein said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl and
C(O)(C.sub.1-C.sub.4 alkyl). In one example, R.sup.1 is selected
from the following:
##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013## ##STR00014##
wherein the wavy line represents the point of attachment to Formula
I.
[0094] In one embodiment, R.sup.1 is C.sub.1-C.sub.5 heteroaryl,
optionally substituted by 1 to 3 R.sup.6. In one example, R.sup.1
is pyrazolyl or thiazolyl, optionally substituted by 1 or 2
R.sup.6, wherein R.sup.6 is C.sub.1-C.sub.6 alkyl or
(C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl, wherein said
alkyl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and said heterocyclyl is optionally substituted by 1 to 5
substituents independently selected from OR.sup.a, oxo, halo,
CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl and C(O)(C.sub.1-C.sub.4 alkyl).
In one example, said heterocyclyl is pyrrolidinyl,
tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or
morpholinyl. In one example, R.sup.1 is selected from the
following:
##STR00015## ##STR00016##
wherein the wavy line represents the point of attachment to Formula
I.
[0095] In one embodiment, R.sup.1 is C.sub.8-C.sub.9 bicyclic
heterocyclyl, optionally substituted by 1 to 5 R.sup.6. In one
example, R.sup.1 is indolinyl or isoindolinyl, optionally
substituted by 1 to 3 R.sup.6. In one example, R.sup.1 is
3,3-dimethylindolin-2-only or 3,3-dimethylisoindolin-1-onyl.
[0096] In one embodiment, R.sup.1 is C.sub.1-C.sub.5 heterocyclyl,
optionally substituted by 1 to 5 R.sup.6. In one example, R.sup.1
is oxetanyl, optionally substituted by 1 to 3 R.sup.6.
[0097] In one embodiment, R.sup.6 is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a, (C.sub.0-C.sub.6
alkyl)NR.sup.aR.sup.b, halo, CN, CF.sub.3,
S(O).sub.1-2NR.sup.aR.sup.b, C(O)R.sup.a, NR.sup.aC(O)OR.sup.b,
NR.sup.aS(O).sub.1-2NR.sup.b, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heteroaryl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl, (C.sub.0-C.sub.6
alkyl)C.sub.3-C.sub.6 cycloalkyl, (C.sub.0-C.sub.6
alkyl)C.sub.6-C.sub.9 aryl, (C.sub.0-C.sub.6 alkyl)C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b, C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b or C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)(C.sub.6 aryl), wherein said alkyl, alkenyl and alkynyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl and
C(O)(C.sub.1-C.sub.4 alkyl).
[0098] In one embodiment, R.sup.6 is independently C.sub.1-C.sub.6
alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a, (C.sub.0-C.sub.6
alkyl)NR.sup.aR.sup.b, halo, CN, C.sub.1-C.sub.5 heteroaryl,
C.sub.4-C.sub.5 heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6
aryl, C(O)OR.sup.a, C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heterocyclyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heterocyclyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.3-C.sub.6 cycloalkyl),
C(O)NR.sup.a(C.sub.0-C.sub.5 alkyl)(C.sub.1-C.sub.5 heteroaryl),
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)NR.sup.aR.sup.b,
C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)(C.sub.6 aryl), wherein said
alkyl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, NR.sup.cR.sup.d, oxo and
halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl are
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4 alkyl).
[0099] In one embodiment, R.sup.6 is C.sub.4-C.sub.5 heterocyclyl
optionally substituted by 1 to 5 substituents independently
selected from OH, oxo, halo, CF.sub.3, NR.sup.cR.sup.d,
C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4 alkyl).
[0100] In one embodiment, heterocyclyl is pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothiophenyl,
1,1-dioxotetrahydrothiophenyl, piperidinyl, piperizinyl,
tetrahydropyranyl, thianyl, morpholinyl, pyridizinyl or
hexahydropyrimidinyl.
[0101] In one embodiment, heterocyclyl is piperidinyl, piperizinyl
or morpholinyl.
[0102] In one embodiment, R.sup.6 is (C.sub.0-C.sub.6
alkyl)OR.sup.a or (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b.
[0103] In one embodiment, R.sup.6 is (C.sub.0-C.sub.3
alkyl)OR.sup.a or (C.sub.0-C.sub.3 alkyl)NR.sup.aR.sup.b.
[0104] In one embodiment, R.sup.6 is halo.
[0105] In one embodiment, R.sup.6 is F or Cl.
[0106] In one embodiment, R.sup.6 is S(O).sub.1-2NR.sup.aR.sup.b.
In one example, R.sup.6 is S(O).sub.2NH.sub.2.
[0107] In one embodiment, R.sup.6 is NR.sup.aC(O)R.sup.b. In one
example, R.sup.6 is NHCOCH.sub.3.
[0108] In one embodiment, R.sup.6 is C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.3-C.sub.6 cycloalkyl), C(O)NR.sup.a(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heteroaryl), C(O)NR.sup.a(C.sub.1-C.sub.5
alkyl)NR.sup.aR.sup.b, C(O)NR.sup.a(C.sub.1-C.sub.5 alkyl)(C.sub.6
aryl), wherein said alkyl is optionally substituted by 1 to 5
substituents independently selected from OR.sup.a, NR.sup.cR.sup.d,
oxo and halo, and said aryl, heterocyclyl, heteroaryl and
cycloalkyl are optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, oxo, halo, CF.sub.3,
NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl and C(O)(C.sub.1-C.sub.4
alkyl).
[0109] In one embodiment, R.sup.6 is C(O)OR.sup.a,
C(O)(C.sub.0-C.sub.5 alkyl)NR.sup.aR.sup.b or C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), wherein said alkyl is
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally
substituted by 1 to 5 substituents independently selected from
OR.sup.a, oxo, halo, CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4
alkyl and C(O)(C.sub.1-C.sub.4 alkyl).
[0110] In one embodiment, R.sup.6 is independently C.sub.1-C.sub.6
alkyl, (C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl, (C.sub.0-C.sub.6
alkyl)C.sub.3-C.sub.6 cycloalkyl, or C(O)(C.sub.0-C.sub.5
alkyl)(C.sub.1-C.sub.5 heterocyclyl), wherein said alkyl is
optionally substituted by 1 to 5 substituents independently
selected from OR.sup.a, NR.sup.cR.sup.d, oxo and halo, and said
heterocyclyl and cycloalkyl are optionally substituted by 1 to 5
substituents independently selected from OR.sup.a, oxo, halo,
CF.sub.3, NR.sup.cR.sup.d, C.sub.1-C.sub.4 alkyl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl and C(O)(C.sub.1-C.sub.4 alkyl).
In one example, R.sup.6 is selected from the following:
##STR00017##
wherein the wavy line represents the point of attachment in Formula
I.
[0111] In one embodiment, R.sup.6 is (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heteroaryl, optionally substituted by 1 to 5
substituents independently selected from OR.sup.a, halo, CF.sub.3,
NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl. In one example, R.sup.7
is pyridinyl, optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, halo, CF.sub.3,
NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl.
[0112] In one embodiment, R.sup.6 is selected from the
following:
##STR00018##
wherein the wavy line represents the point of attachment in Formula
I.
[0113] In one embodiment, R.sup.3, R.sup.4 and R.sup.5 are
independently H, CH.sub.3, CF.sub.3, or F.
[0114] In one embodiment, R.sup.3, R.sup.4 and R.sup.5 are
independently H or F.
[0115] In one embodiment, R.sup.3, R.sup.4 and R.sup.5 are H.
[0116] In one embodiment, R.sup.3 is OCH.sub.3.
[0117] In one embodiment, R.sup.2 is phenyl, C.sub.1-C.sub.9
heteroaryl or C.sub.3-C.sub.5 heterocyclyl,
[0118] wherein the phenyl, heteroaryl and heterocyclyl are
optionally substituted by 1 to 5 R.sup.7.
[0119] In one embodiment, R.sup.2 is phenyl optionally substituted
by 1 to 5 R.sup.7.
[0120] In one embodiment, R.sup.2 is phenyl optionally substituted
by 1 to 3 R.sup.7.
[0121] In one embodiment, R.sup.2 is phenyl optionally substituted
by 2 R.sup.7.
[0122] In one embodiment, R.sup.2 is phenyl or pyridinyl,
optionally substituted by 2 R.sup.7, wherein R.sup.7 is
independently C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCH.sub.3,
NH.sub.2, NO.sub.2, CH.sub.2NH.sub.2, F, Cl, C(O)NR.sup.aR.sup.b,
NR AC(O)R.sup.b, SO.sub.2(C.sub.1-C.sub.3 alkyl),
SO.sub.2NR.sup.aR.sup.b, CN, CF.sub.3, OCF.sub.3, C(O)R.sup.a,
C(O)OR.sup.a, (C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl,
C(O)(C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl or
C(O)NR.sup.a(C.sub.0-C.sub.6 alkyl)C.sub.1-C.sub.5 heterocyclyl,
wherein said heterocyclyl is optionally substituted by
C.sub.1-C.sub.4 alkyl. In one example, R.sup.2 is selected
from:
##STR00019## ##STR00020## ##STR00021##
wherein the wavy line represents the point of attachment in Formula
I.
[0123] In one embodiment, R.sup.2 is pyrazolyl, optionally
substituted by 1 or 2 R.sup.7,
[0124] wherein R.sup.7 is independently R.sup.7 is independently
C.sub.1-C.sub.6 alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a,
(C.sub.0-C.sub.6 alkyl)NR.sup.aR.sup.b, (C.sub.0-C.sub.6
alkyl)(C.sub.6-C.sub.9 aryl), halo, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heteroaryl, (C.sub.0-C.sub.6
alkyl)C.sub.1-C.sub.5 heterocyclyl or (C.sub.0-C.sub.6
alkyl)C.sub.3-C.sub.6 cycloalkyl, wherein said alkyl, is optionally
substituted by 1 to 5 substituents independently selected from oxo,
NR.sup.aR.sup.b, OR.sup.a, and halo, and said aryl, heteroaryl,
heterocyclyl and cycloalkyl are optionally substituted by 1 to 5
substituents independently selected from OR.sup.a, halo, CF.sub.3,
NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl. In one example, R.sup.2
is selected from
##STR00022##
wherein the wavy line represents the point of attachment in Formula
I.
[0125] In one embodiment, R.sup.2 is phenyl optionally substituted
by 1 R.sup.7.
[0126] In one embodiment, R.sup.7 is independently C.sub.1-C.sub.6
alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a, (C.sub.0-C.sub.6
alkyl)NR.sup.aR.sup.b, (C.sub.0-C.sub.6 alkyl)(C.sub.6-C.sub.9
aryl), halo, C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.b,
SO.sub.2(C.sub.1-C.sub.6 alkyl), SO.sub.2NR.sup.aR.sup.b, CN,
nitro, wherein said alkyl is optionally substituted by 1 to 5
substituents independently selected from oxo and halo, and said and
said aryl is optionally substituted by 1 to 5 substituents
independently selected from OR.sup.a, halo, CF.sub.3,
NR.sup.cR.sup.d and C.sub.1-C.sub.4 alkyl.
[0127] In one embodiment, R.sup.7 is independently C.sub.1-C.sub.4
alkyl, (C.sub.0-C.sub.6 alkyl)OR.sup.a, (C.sub.0-C.sub.6
alkyl)NR.sup.aR.sup.b, halo, NR.sup.aC(O)R.sup.b,
SO.sub.2(C.sub.1-C.sub.6 alkyl), SO.sub.2NR.sup.aR.sup.b, CN or
nitro.
[0128] In one embodiment, R.sup.7 is independently C.sub.3-C.sub.6
cycloalkyl.
[0129] In one embodiment, R.sup.7 is independently NH.sub.2,
OCH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
NO.sub.2, OCF.sub.3, S(O).sub.2N(CH.sub.3).sub.2,
S(O).sub.2NH(CH(CH.sub.3).sub.2), S(O).sub.2NH(C(CH.sub.3).sub.3),
CN, CF.sub.3, F, Cl, NHC(O)CH.sub.3 or S(O).sub.2CH.sub.3.
[0130] In one embodiment, R.sup.7 is independently NH.sub.2,
OCH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
NO.sub.2, OCF.sub.3, S(O).sub.2N(CH.sub.3).sub.2,
S(O).sub.2NH(CH(CH.sub.3).sub.2), S(O).sub.2NH(C(CH.sub.3).sub.3),
CN, CF.sub.3, F, Cl, NHC(O)CH.sub.3, S(O).sub.2CH.sub.3, CO.sub.2H,
S(O)CH.sub.3, cyclopentyl, 1-hydroxyethyl, 1-aminoethyl or
CH.sub.2CF.sub.3.
[0131] In one embodiment, R.sup.2 is C.sub.1-C.sub.9 heteroaryl
optionally substituted by 1 to 5 R.sup.7.
[0132] In one embodiment, C.sub.1-C.sub.9 heteroaryl is pyridinyl,
imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl or furopyridinyl, each of which is optionally
substituted by 1 to 5 R.sup.7.
[0133] In one embodiment, R.sup.2 is pyridinyl or pyrazolyl
optionally substituted by 1 to 5 R.sup.7.
[0134] In one embodiment, R.sup.2 is pyridinyl or pyrazolyl
optionally substituted by 1 to 3 R.sup.7.
[0135] In one embodiment, R.sup.2 is pyridinyl or pyrazolyl
optionally substituted by 1 R.sup.7.
[0136] In one embodiment, R.sup.7 is independently CH.sub.3,
CH.sub.2(phenyl), CH.sub.2CH(CH.sub.3).sub.2, or CF.sub.3.
[0137] In one embodiment, R.sup.2 is C.sub.3-C.sub.5 heterocyclyl
optionally substituted by 1 to 5 R.sup.7.
[0138] In one embodiment, R.sup.2 is piperidinyl, morpholinyl or
piperizinyl optionally substituted by 1 to 5 R.sup.7.
[0139] In one embodiment, R.sup.2 is piperidinyl, morpholinyl or
piperizinyl optionally substituted by 1 to 3 R.sup.7.
[0140] In one embodiment, R.sup.2 is piperidinyl, morpholinyl or
piperizinyl optionally substituted by 2 R.sup.7.
[0141] In one embodiment, R.sup.2 is piperidinyl, morpholinyl or
piperizinyl optionally substituted by 1 R.sup.7.
[0142] In one embodiment, R.sup.7 is independently CH.sub.3,
CH.sub.2CH.sub.3, OH or OCH.sub.3.
[0143] In one embodiment, R.sup.1 is phenyl, optionally substituted
by 1 to 5 R.sup.6; and R.sup.2 is phenyl, optionally substituted by
1 to 5 R.sup.7.
[0144] In one embodiment, R.sup.1 is phenyl, optionally substituted
by 1 to 5 R.sup.6; and
[0145] R.sup.2 is heterocyclyl, optionally substituted by 1 to 5
R.sup.7.
[0146] In one embodiment, heterocyclyl is piperidinyl, morpholinyl
or piperizinyl.
[0147] In one embodiment, R.sup.1 is pyridyl, optionally
substituted by 1 to 4 R.sup.6; and R.sup.2 is phenyl, optionally
substituted by 1 to 5 R.sup.7.
[0148] In one embodiment, R.sup.1 is pyridyl, optionally
substituted by 1 to 4 R.sup.6; and R.sup.2 is heterocyclyl,
optionally substituted by 1 to 5 R.sup.7.
[0149] In one embodiment, heterocyclyl is piperidinyl, morpholinyl
or piperizinyl.
[0150] In one embodiment, R.sup.1 is phenyl, optionally substituted
by 1 to 5 R.sup.6; and
[0151] R.sup.2 is pyridyl, optionally substituted by 1 to 4
R.sup.7.
[0152] In one embodiment, R.sup.1 is pyridyl, optionally
substituted by 1 to 4 R.sup.6; and R.sup.2 is pyridyl, optionally
substituted by 1 to 4 R.sup.7.
[0153] In one embodiment, R.sup.1 is phenyl or pyridinyl,
optionally substituted by 1 to 3 R.sup.6, wherein R.sup.6 is
independently C.sub.1-C.sub.3 alkyl, halo, CF.sub.3 or
C(O)OR.sup.a; and R.sup.2 is phenyl or pyridinyl, optionally
substituted by 2 R.sup.7, wherein R.sup.7 is independently
C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCH.sub.3, NH.sub.2,
CH.sub.2NH.sub.2, F, Cl, C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.b,
SO.sub.2(C.sub.1-C.sub.3 alkyl), SO.sub.2NR.sup.a b, CN, CF.sub.3,
OCF.sub.3, C(O)R.sup.a, C(O)OR.sup.a.
[0154] Another embodiment includes a compound selected from:
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047##
[0155] Another embodiment includes compounds of Formula I, selected
from the compounds of Examples 1-312.
[0156] Another embodiment includes a compound of Formula I that has
K.sub.i and/or EC.sub.50 that is at least 15 fold, alternatively 10
fold, or 5 fold or more selective in inhibiting one Janus kinase
activity over inhibiting each of the other Janus kinase
activities.
[0157] The compounds of Formula I may contain asymmetric or chiral
centers, and, therefore, exist in different stereoisomeric forms.
It is intended that all stereoisomeric forms of the compounds of
Formula I, including but not limited to: diastereomers,
enantiomers, and atropisomers as well as mixtures thereof such as
racemic mixtures, form part of the present invention. In addition,
the present invention embraces all geometric and positional
isomers. For example, if a compound of Formula I incorporates a
double bond or a fused ring, both the cis- and trans-forms, as well
as mixtures, are embraced within the scope of the invention. Both
the single positional isomers and mixture of positional isomers,
e.g., resulting from the N-oxidation of the pyrimidinyl and
pyrrozolyl rings, or the E and Z forms of compounds of Formula I
(for example oxime moieties), are also within the scope of the
present invention.
[0158] In the structures shown herein, where the stereochemistry of
any particular chiral atom is not specified, then all stereoisomers
are contemplated and included as the compounds of the invention.
Where stereochemistry is specified by a solid wedge or dashed line
representing a particular configuration, then that stereoisomer is
so specified and defined.
[0159] The compounds of the present invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like, and it is
intended that the invention, as defined by the claims, embrace both
solvated and unsolvated forms.
[0160] In an embodiment, compounds of Formula I may exist in
different tautomeric forms, and all such forms are embraced within
the scope of the invention, as defined by the claims. The term
"tautomer" or "tautomeric form" refers to structural isomers of
different energies which are interconvertible via a low energy
barrier. For example, proton tautomers (also known as prototropic
tautomers) include interconversions via migration of a proton, such
as keto-enol and imine-enamine isomerizations. Valence tautomers
include interconversions by reorganization of some of the bonding
electrons.
[0161] The present invention also embraces isotopically-labeled
compounds of Formula I, which are identical to those recited
herein, but for the fact that one or more atoms are replaced by an
atom having an atomic mass or mass number different from the atomic
mass or mass number usually found in nature. All isotopes of any
particular atom or element as specified are contemplated within the
scope of the invention. Exemplary isotopes that can be incorporated
into compounds of Formula I include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and
iodine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.32P,
.sup.33P, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I, and .sup.125I,
respectively. Certain isotopically-labeled compounds of Formula I
(e.g., those labeled with .sup.3H and .sup.14C) are useful in
compound and/or substrate tissue distribution assays. Tritiated
(i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are useful
for their ease of preparation and detectability. Further,
substitution with heavier isotopes such as deuterium (i.e.,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability (e.g., increased in vivo half-life or
reduced dosage requirements) and hence may be preferred in some
circumstances. Positron emitting isotopes such as .sup.15O,
.sup.13N, .sup.11C, and .sup.18F are useful for positron emission
tomography (PET) studies to examine substrate receptor occupancy.
Isotopically labeled compounds of Formula I can generally be
prepared by following procedures analogous to those disclosed in
the Schemes and/or in the Examples herein below, by substituting an
isotopically labeled reagent for a non-isotopically labeled
reagent.
Synthesis of Triazolopyridine JAK Inhibitor Compounds
[0162] Compounds of Formula I may be synthesized by synthetic
routes described herein. In certain embodiments, processes
well-known in the chemical arts can be used, in addition to, or in
light of, the description contained herein. The starting materials
are generally available from commercial sources such as Aldrich
Chemicals (Milwaukee, Wis.) or are readily prepared using methods
well known to those skilled in the art (e.g., prepared by methods
generally described in Louis F. Fieser and Mary Fieser, Reagents
for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.),
Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.
Springer-Verlag, Berlin, including supplements (also available via
the Beilstein online database)), or Comprehensive Heterocyclic
Chemistry, Editors Katrizky and Rees, Pergamon Press, 1984. Methods
for triazolopyridine synthesis are also disclosed in: WO 02/38572
and WO 2006/038116.
[0163] Compounds of Formula I may be prepared singly or as compound
libraries comprising at least 2, for example 5 to 1,000 compounds,
or 10 to 100 compounds of Formula I. Libraries of compounds of
Formula I may be prepared by a combinatorial `split and mix`
approach or by multiple parallel syntheses using either solution
phase or solid phase chemistry, by procedures known to those
skilled in the art. Thus according to a further aspect of the
invention there is provided a compound library comprising at least
2 compounds of Formula I, enantiomers, diasteriomers, tautomers or
pharmaceutically acceptable salts thereof.
[0164] For illustrative purposes, reaction schemes 1-6 depicted
below provide routes for synthesizing the compounds of the present
invention as well as key intermediates. For a more detailed
description of the individual reaction steps, see the Examples
section below. Those skilled in the art will appreciate that other
synthetic routes may be used to synthesize the inventive compounds.
Although specific starting materials and reagents are depicted in
the Schemes and discussed below, other starting materials and
reagents can be easily substituted to provide a variety of
derivatives and/or reaction conditions. In addition, many of the
compounds prepared by the methods described below can be further
modified in light of this disclosure using conventional chemistry
well known to those skilled in the art.
[0165] In the preparation of compounds of the present invention,
protection of remote functionality (e.g., primary or secondary
amine) of intermediates may be necessary. The need for such
protection will vary depending on the nature of the remote
functionality and the conditions of the preparation methods.
Suitable amino-protecting groups (NH-Pg) include acetyl,
trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)
and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such
protection is readily determined by one skilled in the art. For a
general description of protecting groups and their use, see T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York, 1991.
[0166] Compounds of the invention may be prepared from readily
available starting materials using the general methods illustrated
herein.
##STR00048##
[0167] For example, compounds of Formula I can be synthesized as
shown in Reaction Scheme 1. A common protected intermediate 5,
which is available from 2-amino-3-bromopyridine (2), can be
subjected to palladium-catalyzed coupling reactions such as the
Suzuki reaction with boronic acids or boronate esters to form
compounds of Formula 6 after protective group removal.
Palladium-catalyzed amination of aryl or heteroaryl halides with
triazolopyridinamine 6 provides compounds of Formula 1a.
Palladium-catalyzed amination of methoxycarbonyl substituted phenyl
halides or methoxycarbonyl substituted heteroaryl halides 7 with
triazolopyridinamine 6 provides compounds of Formula 1b. Hydrolysis
of the corresponding methyl esters 1b affords carboxylic acids 1c,
which can be subjected to standard amide formation methods to yield
amides 1d.
[0168] It will be appreciated that where appropriate functional
groups exist, compounds of various formulae or any intermediates
used in their preparation may be further derivatised by one or more
standard synthetic methods employing condensation, substitution,
oxidation, reduction, or cleavage reactions. Particular
substitution approaches include conventional alkylation, arylation,
heteroarylation, acylation, sulfonylation, halogenation, nitration,
formylation and coupling procedures.
[0169] In a further example, primary amine or secondary amine
groups may be converted into amide groups (--NHCOR' or --NRCOR') by
acylation. Acylation may be achieved by reaction with an
appropriate acid chloride in the presence of a base, such as
triethylamine, in a suitable solvent, such as dichloromethane, or
by reaction with an appropriate carboxylic acid in the presence of
a suitable coupling agent such HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) in a suitable solvent such as dichloromethane.
Similarly, amine groups may be converted into sulphonamide groups
(--NHSO.sub.2R' or --NR''SO.sub.2R') groups by reaction with an
appropriate sulphonyl chloride in the presence of a suitable base,
such as triethylamine, in a suitable solvent such as
dichloromethane. Primary or secondary amine groups can be converted
into urea groups (--NHCONR'R'' or --NRCONR'R'') by reaction with an
appropriate isocyanate in the presence of a suitable base such as
triethylamine, in a suitable solvent, such as dichloromethane.
[0170] An amine (--NH.sub.2) may be obtained by reduction of a
nitro (--NO.sub.2) group, for example by catalytic hydrogenation,
using for example hydrogen in the presence of a metal catalyst, for
example palladium on a support such as carbon in a solvent such as
ethyl acetate or an alcohol e.g. methanol. Alternatively, the
transformation may be carried out by chemical reduction using for
example a metal, e.g. tin or iron, in the presence of an acid such
as hydrochloric acid.
[0171] In a further example, amine (--CH.sub.2NH.sub.2) groups may
be obtained by reduction of nitriles (--CN), for example by
catalytic hydrogenation using for example hydrogen in the presence
of a metal catalyst, for example palladium on a support such as
carbon, or Raney nickel, in a solvent such as an ether e.g. a
cyclic ether such as tetrahydrofuran, at an appropriate
temperature, for example from about -78.degree. C. to the reflux
temperature of the solvent.
[0172] In a further example, amine (--NH.sub.2) groups may be
obtained from carboxylic acid groups (--CO.sub.2H) by conversion to
the corresponding acyl azide (--CON.sub.3), Curtius rearrangement
and hydrolysis of the resultant isocyanate (--N.dbd.C.dbd.O).
[0173] Aldehyde groups (--CHO) may be converted to amine groups
(--CH.sub.2NR'R'')) by reductive amination employing an amine and a
borohydride, for example sodium triacetoxyborohydride or sodium
cyanoborohydride, in a solvent such as a halogenated hydrocarbon,
for example dichloromethane, or an alcohol such as ethanol, where
necessary in the presence of an acid such as acetic acid at around
ambient temperature.
[0174] In a further example, aldehyde groups may be converted into
alkenyl groups (--CH.dbd.CHR') by the use of a Wittig or
Wadsworth-Emmons reaction using an appropriate phosphorane or
phosphonate under standard conditions known to those skilled in the
art.
[0175] Aldehyde groups may be obtained by reduction of ester groups
(such as --CO.sub.2Et) or nitriles (--CN) using diisobutylaluminium
hydride in a suitable solvent such as toluene. Alternatively,
aldehyde groups may be obtained by the oxidation of alcohol groups
using any suitable oxidising agent known to those skilled in the
art.
[0176] Ester groups (--CO.sub.2R') may be converted into the
corresponding acid group (--CO.sub.2H) by acid- or base-catalysed
hydrolysis, depending on the nature of R. If R is t-butyl,
acid-catalysed hydrolysis can be achieved for example by treatment
with an organic acid such as trifluoroacetic acid in an aqueous
solvent, or by treatment with an inorganic acid such as
hydrochloric acid in an aqueous solvent.
[0177] Carboxylic acid groups (--CO.sub.2H) may be converted into
amides (CONHR' or --CONR'R'') by reaction with an appropriate amine
in the presence of a suitable coupling agent, such as HATU, in a
suitable solvent such as dichloromethane.
[0178] In a further example, carboxylic acids may be homologated by
one carbon (i.e --CO.sub.2H to --CH.sub.2CO.sub.2H) by conversion
to the corresponding acid chloride (--COCl) followed by
Arndt-Eistert synthesis.
[0179] In a further example, --OH groups may be generated from the
corresponding ester (e.g. --CO.sub.2R'), or aldehyde (--CHO) by
reduction, using for example a complex metal hydride such as
lithium aluminium hydride in diethyl ether or tetrahydrofuran, or
sodium borohydride in a solvent such as methanol. Alternatively, an
alcohol may be prepared by reduction of the corresponding acid
(--CO.sub.2H), using for example lithium aluminium hydride in a
solvent such as tetrahydrofuran, or by using borane in a solvent
such as tetrahydrofuran.
[0180] Alcohol groups may be converted into leaving groups, such as
halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy,
e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g.
p-toluenesulfonyloxy group using conditions known to those skilled
in the art. For example, an alcohol may be reacted with thioyl
chloride in a halogenated hydrocarbon (e.g. dichloromethane) to
yield the corresponding chloride. A base (e.g. triethylamine) may
also be used in the reaction.
[0181] In another example, alcohol, phenol or amide groups may be
alkylated by coupling a phenol or amide with an alcohol in a
solvent such as tetrahydrofuran in the presence of a phosphine,
e.g. triphenylphosphine and an activator such as diethyl-,
diisopropyl, or dimethylazodicarboxylate. Alternatively alkylation
may be achieved by deprotonation using a suitable base e.g. sodium
hydride followed by subsequent addition of an alkylating agent,
such as an alkyl halide.
[0182] Aromatic halogen substituents in the compounds may be
subjected to halogen-metal exchange by treatment with a base, for
example a lithium base such as n-butyl or t-butyl lithium,
optionally at a low temperature, e.g. around -78.degree. C., in a
solvent such as tetrahydrofuran, and then quenched with an
electrophile to introduce a desired substituent. Thus, for example,
a formyl group may be introduced by using N,N-dimethylformamide as
the electrophile. Aromatic halogen substituents may alternatively
be subjected to metal (e.g. palladium or copper) catalysed
reactions, to introduce, for example, acid, ester, cyano, amide,
aryl, heteraryl, alkenyl, alkynyl, thio- or amino substituents.
Suitable procedures which may be employed include those described
by Heck, Suzuki, Stille, Buchwald or Hartwig.
[0183] Aromatic halogen substituents may also undergo nucleophilic
displacement following reaction with an appropriate nucleophile
such as an amine or an alcohol. Advantageously, such a reaction may
be carried out at elevated temperature in the presence of microwave
irradiation.
Methods of Separation
[0184] In each of the exemplary Schemes it may be advantageous to
separate reaction products from one another and/or from starting
materials. The desired products of each step or series of steps is
separated and/or purified (hereinafter separated) to the desired
degree of homogeneity by the techniques common in the art.
Typically such separations involve multiphase extraction,
crystallization from a solvent or solvent mixture, distillation,
sublimation, or chromatography. Chromatography can involve any
number of methods including, for example: reverse-phase and normal
phase; size exclusion; ion exchange; high, medium, and low pressure
liquid chromatography methods and apparatus; small scale
analytical; simulated moving bed (SMB) and preparative thin or
thick layer chromatography, as well as techniques of small scale
thin layer and flash chromatography.
[0185] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like.
[0186] Selection of appropriate methods of separation depends on
the nature of the materials involved. For example, boiling point,
and molecular weight in distillation and sublimation, presence or
absence of polar functional groups in chromatography, stability of
materials in acidic and basic media in multiphase extraction, and
the like. One skilled in the art will apply techniques most likely
to achieve the desired separation.
[0187] Diastereomeric mixtures can be separated into their
individual diastereoisomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography and/or fractional crystallization. Enantiomers
can be separated by converting the enantiomeric mixture into a
diastereomeric mixture by reaction with an appropriate optically
active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's acid chloride), separating the diastereoisomers and
converting (e.g., hydrolyzing) the individual diastereoisomers to
the corresponding pure enantiomers. Also, some of the compounds of
the present invention may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of a chiral HPLC column.
[0188] A single stereoisomer, e.g. an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents (Eliel, E. and Wilen, S.,
Stereochemistry of Organic Compounds, John Wiley & Sons, Inc.,
New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302
(1975)). Racemic mixtures of chiral compounds of the invention can
be separated and isolated by any suitable method, including: (1)
formation of ionic, diastereomeric salts with chiral compounds and
separation by fractional crystallization or other methods, (2)
formation of diastereomeric compounds with chiral derivatizing
reagents, separation of the diastereomers, and conversion to the
pure stereoisomers, and (3) separation of the substantially pure or
enriched stereoisomers directly under chiral conditions. See: Drug
Stereochemistry, Analytical Methods and Pharmacology, Irving W.
Wainer, Ed., Marcel Dekker, Inc., New York (1993).
[0189] Diastereomeric salts can be formed by reaction of
enantiomerically pure chiral bases such as brucine, quinine,
ephedrine, strychnine, .alpha.-methyl-.beta.-phenylethylamine
(amphetamine), and the like with asymmetric compounds bearing
acidic functionality, such as carboxylic acid and sulfonic acid.
The diastereomeric salts may be induced to separate by fractional
crystallization or ionic chromatography. For separation of the
optical isomers of amino compounds, addition of chiral carboxylic
or sulfonic acids, such as camphorsulfonic acid, tartaric acid,
mandelic acid, or lactic acid can result in formation of the
diastereomeric salts.
[0190] Alternatively, the substrate to be resolved is reacted with
one enantiomer of a chiral compound to form a diastereomeric pair
(Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds,
John Wiley & Sons, Inc., New York, 1994, p. 322).
Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents,
such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the pure or enriched
enantiomer. A method of determining optical purity involves making
chiral esters, such as a menthyl ester, e.g. (-) menthyl
chloroformate in the presence of base, or Mosher ester,
.alpha.-methoxy-.alpha.-(trifluoromethyl)phenyl acetate (Jacob, J.
Org. Chem. 47:4165 (1982)), of the racemic mixture, and analyzing
the NMR spectrum for the presence of the two atropisomeric
enantiomers or diastereomers. Stable diastereomers of atropisomeric
compounds can be separated and isolated by normal- and
reverse-phase chromatography following methods for separation of
atropisomeric naphthyl-isoquinolines (WO 96/15111). By method (3),
a racemic mixture of two enantiomers can be separated by
chromatography using a chiral stationary phase (Chiral Liquid
Chromatography W. J. Lough, Ed., Chapman and Hall, New York,
(1989); Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or
purified enantiomers can be distinguished by methods used to
distinguish other chiral molecules with asymmetric carbon atoms,
such as optical rotation and circular dichroism.
[0191] Positional isomers, for example E and Z forms, of compounds
of Formula I, and intermediates for their synthesis, may be
observed by characterization methods such as NMR and analytical
HPLC. For certain compounds where the energy barrier for
interconversion is sufficiently high, the E and Z isomers may be
separated, for example by preparatory HPLC.
Biological Evaluation
[0192] Previous studies have shown that the isolated kinase domains
of human JAK1, JAK2, JAK3 or TYK2 phosphorylate peptide substrates
in in vitro kinase assays (Saltzman et al., Biochem. Biophys. Res.
Commun. 246:627-633 (2004)). The catalytically active kinase domain
of human JAK1, JAK2, JAK3 or TYK2 was purified from extracts of SF9
insect cells infected with a recombinant baculovirus expression
vector encoding the human JAK1, JAK2, JAK3 or TYK2 kinase domains
(JAK1 amino acid residues N852-D1154 according to the numbering of
GenBank sequence accession number P23458, JAK2 amino acid residues
D812-G1132 according to the numbering of GenBank sequence accession
number NP.sub.--004963.1; JAK3 amino acid residues S783-S1124
according to the numbering of GenBank sequence accession number
P52333, and TYK2 amino acid residues N873-C1187 according to the
numbering of GenBank sequence accession number P29597). The
activity of the JAK1, JAK2, JAK3 or TYK2 kinase domains can be
measured by a number of direct and indirect methods, including
quantification of phosphorylation of peptide substrates derived
from the human JAK3 protein (Saltzman et al., Biochem. Biophys.
Res. Commun. 246:627-633 (2004)). The activity of the JAK1, JAK2,
JAK3 or TYK2 kinase domains was measured in vitro by monitoring
phosphorylation of JAK3 derived peptides using the Caliper LabChip
technology (see Examples).
[0193] The compounds of the present invention are tested for their
capacity to inhibit a Janus kinase activity and activation (primary
assays) and for their biological effects on growing cells
(secondary assays) as described herein. The compounds having
IC.sub.50 of less than 10 .mu.M (preferably less than 5 .mu.M, more
preferably less than 1 .mu.M, most preferably less than 0.5 .mu.M)
in the appropriate Janus kinase activity and activation assay (see
Examples A and B), and EC.sub.50 of less than 20 .mu.M (preferably
less than 10 .mu.M, more preferably less than 5 .mu.M, most
preferably less than 1 .mu.M) in the appropriate cellular assays
(see Example C) are useful as Janus kinase inhibitors.
Administration of Triazolopyridine Compounds
[0194] Another embodiment includes a method of treating or
lessening the severity of a disease or condition responsive to the
inhibition of one or more Janus kinase activity, selected from
JAK1, JAK2, JAK3 and TYK2, in a patient. The method includes
administering to the patient a therapeutically effective amount of
a compound of Formula I.
[0195] Another embodiment includes a method of treating or
lessening the severity of a disease or condition responsive to the
inhibition of JAK2 kinase activity in a patient. The method
includes the step of administering to a patient a therapeutically
effective amount of a compound of Formula I.
[0196] In one embodiment, the disease or condition is cancer,
stroke, diabetes, hepatomegaly, cardiovascular disease, multiple
sclerosis, Alzheimer's disease, cystic fibrosis, viral disease,
autoimmune diseases, atherosclerosis, restenosis, psoriasis,
allergic disorders, inflammation, neurological disorders, a
hormone-related disease, conditions associated with organ
transplantation, immunodeficiency disorders, destructive bone
disorders, proliferative disorders, infectious diseases, conditions
associated with cell death, thrombin-induced platelet aggregation,
liver disease, pathologic immune conditions involving T cell
activation, CNS disorders or a myeloproliferative disorder.
[0197] In one embodiment, the disease or condition is cancer.
[0198] In one embodiment, the disease is a myeloproliferative
disorder.
[0199] In one embodiment, the myeloproliferative disorder is
polycythemia vera, essential thrombocytosis, myelofibrosis or
chronic myelogenous leukemia (CML).
[0200] In one embodiment, the cancer is breast, ovary, cervix,
prostate, testis, penile, genitourinary tract, seminoma, esophagus,
larynx, gastric, stomach, gastrointestinal, skin, keratoacanthoma,
follicular carcinoma, melanoma, lung, small cell lung carcinoma,
non-small cell lung carcinoma (NSCLC), lung adenocarcinoma,
squamous carcinoma of the lung, colon, pancreas, thyroid,
papillary, bladder, liver, biliary passage, kidney, bone, myeloid
disorders, lymphoid disorders, hairy cells, buccal cavity and
pharynx (oral), lip, tongue, mouth, salivary gland, pharynx, small
intestine, colon, rectum, anal, renal, prostate, vulval, thyroid,
large intestine, endometrial, uterine, brain, central nervous
system, cancer of the peritoneum, hepatocellular cancer, head
cancer, neck cancer, Hodgkin's or leukemia.
[0201] In one embodiment, the cardiovascular disease is restenosis,
cardiomegaly, atherosclerosis, myocardial infarction or congestive
heart failure.
[0202] In one embodiment, the neurodegenerative disease is
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, and cerebral ischemia, and
neurodegenerative disease caused by traumatic injury, glutamate
neurotoxicity or hypoxia.
[0203] In one embodiment, the inflammatory diseases is rheumatoid
arthritis, psoriasis, contact dermatitis or delayed
hypersensitivity reactions.
[0204] In one embodiment, the inflammatory disease is inflammatory
bowel disease,
[0205] In one embodiment, the autoimmune disease is lupus or
multiple sclerosis.
[0206] Evaluation of drug-induced immunosuppression by the
compounds of the invention may be performed using in vivo
functional tests, such as rodent models of induced arthritis and
therapeutic or prophylactic treatment to assess disease score, T
cell-dependent antibody response (TDAR), and delayed-type
hypersensitivity (DTH). Other in vivo systems including murine
models of host defense against infections or tumor resistance
(Burleson G R, Dean J H, and Munson A E. Methods in
Immunotoxicology, Vol. 1. Wiley-Liss, New York, 1995) may be
considered to elucidate the nature or mechanisms of observed
immunosuppression. The in vivo test systems can be complemented by
well-established in vitro or ex vivo functional assays for the
assessment of immune competence. These assays may comprise B or T
cell proliferation in response to mitogens or specific antigens,
measurement of signaling through one or more of the Janus kinase
pathways in B or T cells or immortalized B or T cell lines,
measurement of cell surface markers in response to B or T cell
signaling, natural killer (NK) cell activity, mast cell activity,
mast cell degranulation, macrophage phagocytosis or kill activity,
and neutrophil oxidative burst and/or chemotaxis. In each of these
tests determination of cytokine production by particular effector
cells (e.g., lymphocytes, NK, monocytes/macrophages, neutrophils)
may be included. The in vitro and ex vivo assays can be applied in
both preclinical and clinical testing using lymphoid tissues and/or
peripheral blood (House R V. "Theory and practice of cytokine
assessment in immunotoxicology" (1999) Methods 19:17-27; Hubbard A
K. "Effects of xenobiotics on macrophage function: evaluation in
vitro" (1999) Methods; 19:8-16; Lebrec H, et al (2001) Toxicology
158:25-29).
[0207] Collagen-Induced Arthritis (CIA) 6-week detailed study using
an autoimmune mechanism to mimic human arthritis; rat and mouse
models (Example 68). Collagen-induced arthritis (CIA) is one of the
most commonly used animal models of human rheumatoid arthritis
(RA). Joint inflammation, which develops in animals with CIA,
strongly resembles inflammation observed in patients with RA.
Blocking tumor necrosis factor (TNF) is an efficacious treatment of
CIA, just as it is a highly efficacious therapy in treatment of RA
patients. CIA is mediated by both T-cells and antibodies (B-cells).
Macrophages are believed to play an important role in mediating
tissue damage during disease development. CIA is induced by
immunizing animals with collagen emulsified in Complete Freund's
Adjuvant (CFA). It is most commonly induced in the DBA/1 mouse
strain, but the disease can also be induced in Lewis rats.
[0208] There is good evidence that B-cells play a key role in the
pathogenesis of autoimmune and/or inflammatory disease.
Protein-based therapeutics that deplete B cells such as Rituxan are
effective against autoantibody-driven inflammatory diseases such as
rheumatoid arthritis (Rastetter et al. (2004) Annu Rev Med 55:477).
CD69 is the early activation marker in leukocytes including T
cells, thymocytes, B cells, NK cells, neutrophils, and eosinophils.
The CD69 human whole blood assay (Example 69) determines the
ability of compounds to inhibit the production of CD69 by B
lymphocytes in human whole blood activated by crosslinking surface
IgM with goat F(ab')2 anti-human IgM.
[0209] The T-cell Dependent Antibody Response (TDAR) is a
predictive assay for immune function testing when potential
immunotoxic effects of compounds need to be studied. The IgM-Plaque
Forming Cell (PFC) assay, using Sheep Red Blood Cells (SRBC) as the
antigen, is currently a widely accepted and validated standard
test. TDAR has proven to be a highly predictable assay for adult
exposure immunotoxicity detection in mice based on the US National
Toxicology Program (NTP) database (M. I. Luster et al (1992)
Fundam. Appl. Toxicol. 18:200-210). The utility of this assay stems
from the fact that it is a holistic measurement involving several
important components of an immune response. A TDAR is dependent on
functions of the following cellular compartments: (1)
antigen-presenting cells, such as macrophages or dendritic cells;
(2) T-helper cells, which are critical players in the genesis of
the response, as well as in isotype switching; and (3) B-cells,
which are the ultimate effector cells and are responsible for
antibody production. Chemically-induced changes in any one
compartment can cause significant changes in the overall TDAR (M.
P. Holsapple In: G. R. Burleson, J. H. Dean and A. E. Munson,
Editors, Modern Methods in Immunotoxicology, Volume 1, Wiley-Liss
Publishers, New York, N.Y. (1995), pp. 71-108). Usually, this assay
is performed either as an ELISA for measurement of soluble antibody
(R. J. Smialowizc et al (2001) Toxicol. Sci. 61:164-175) or as a
plaque (or antibody) forming cell assay (L. Guo et al (2002)
Toxicol. Appl. Pharmacol. 181:219-227) to detect plasma cells
secreting antigen specific antibodies. The antigen of choice is
either whole cells (e.g. sheep erythrocytes) or soluble protein
antigens (T. Miller et al (1998) Toxicol. Sci. 42:129-135).
[0210] A compound of Formula I may be administered by any route
appropriate to the disease or condition to be treated. Suitable
routes include oral, parenteral (including subcutaneous,
intramuscular, intravenous, intraarterial, intradermal, intrathecal
and epidural), transdermal, rectal, nasal, topical (including
buccal and sublingual), vaginal, intraperitoneal, intrapulmonary,
and intranasal. For local immunosuppressive treatment, the
compounds may be administered by intralesional administration,
including perfusing or otherwise contacting the graft with the
inhibitor before transplantation. It will be appreciated that the
preferred route may vary with for example the condition of the
recipient. Where the compound of Formula I is administered orally,
it may be formulated as a pill, capsule, tablet, etc. with a
pharmaceutically acceptable carrier or excipient. Where the
compound of Formula I is administered parenterally, it may be
formulated with a pharmaceutically acceptable parenteral vehicle
and in a unit dosage injectable form, as detailed below.
[0211] A dose to treat human patients may range from about 10 mg to
about 1000 mg of a compound of Formula I. A typical dose may be
about 100 mg to about 300 mg of a compound of Formula I. A dose may
be administered once a day (QD), twice per day (BID), or more
frequently, depending on the pharmacokinetic and pharmacodynamic
properties, including absorption, distribution, metabolism, and
excretion of the particular compound. In addition, toxicity factors
may influence the dosage and administration regimen. When
administered orally, the pill, capsule, or tablet may be ingested
daily or less frequently for a specified period of time. The
regimen may be repeated for a number of cycles of therapy.
[0212] Another embodiment of the invention aspect of this invention
provides a compound of this invention for use as a medicament in
the treatment of the diseases or conditions described herein in a
mammal, for example, a human, suffering from such disease or
condition. Also provided is the use of a compound of this invention
in the preparation of a medicament for the treatment of the
diseases and conditions described herein in a warm-blooded animal,
such as a mammal, for example a human, suffering from such
disorder.
Pharmaceutical Formulations of Triazolopyridine Compounds
[0213] Another embodiment includes a pharmaceutical composition
that includes a compound of Formula I and a pharmaceutically
acceptable carrier, adjuvant or vehicle.
[0214] In one embodiment, the pharmaceutical composition also
includes an additional therapeutic agent selected from an
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory agent, a neurotropic factor, an agent for treating
cardiovascular disease, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, or an agent for treating immunodeficiency
disorders.
[0215] In another embodiment, a compound of Formula I is present in
a pharmaceutical formulation in an amount to detectably inhibit one
or more of a Janus kinase activity, selected from JAK1, JAK2, JAK3
and TYK2, and a pharmaceutically acceptable carrier, adjuvant or
vehicle.
[0216] In one embodiment, a compound of Formula I is present in a
pharmaceutical formulation in an amount to detectably inhibit JAK2
kinase activity and a pharmaceutically acceptable carrier, adjuvant
or vehicle.
[0217] In one embodiment, a compound of Formula I is present in a
pharmaceutical formulation in an amount to detectably inhibit JAK2
kinase activity and is at least 10 fold or more selective in
inhibiting JAK2 kinase activity over inhibiting each of JAK1, JAK3
and Tyk-2 activity.
[0218] In one embodiment, a compound of Formula I is present in a
pharmaceutical formulation in an amount to detectably inhibit one
of a Janus kinase activity and is at least 15 fold, alternatively
10 fold, or 5 fold or more selective in inhibiting one such Janus
kinase activity over inhibiting each of the other Janus kinase
activity.
[0219] In one embodiment, a compound of Formula I is present in a
pharmaceutical formulation in an amount to detectably inhibit a
Janus kinase activity and is at least 15 fold, alternatively 10
fold, or 5 fold or more selective in inhibiting one Janus kinase
activity over inhibiting each of the other JAK1, JAK2, JAK3 and/or
Tyk-2 activity.
[0220] A typical formulation is prepared by mixing a compound of
the present invention and a carrier, diluent or excipient. Suitable
carriers, diluents and excipients are well known to those skilled
in the art and include materials such as carbohydrates, waxes,
water soluble and/or swellable polymers, hydrophilic or hydrophobic
materials, gelatin, oils, solvents, water, and the like. The
particular carrier, diluent or excipient used will depend upon the
means and purpose for which the compound of the present invention
is being applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be
administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents such as water and other non-toxic solvents that
are soluble or miscible in water. Suitable aqueous solvents include
water, ethanol, propylene glycol, polyethylene glycols (e.g.,
PEG400, PEG300), etc. and mixtures thereof. The formulations may
also include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0221] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the compound, such as a complex with a cyclodextrin
derivative or other known complexation agent) is dissolved in a
suitable solvent in the presence of one or more of the excipients
described above. The compound of the present invention is typically
formulated into pharmaceutical dosage forms to provide an easily
controllable dosage of the drug and to enable patient compliance
with the prescribed regimen.
[0222] The pharmaceutical composition (or formulation) for
application may be packaged in a variety of ways depending upon the
method used for administering the drug. Generally, an article for
distribution includes a container having deposited therein the
pharmaceutical formulation in an appropriate form. Suitable
containers are well-known to those skilled in the art and include
materials such as bottles (plastic and glass), sachets, ampoules,
plastic bags, metal cylinders, and the like. The container may also
include a tamper-proof assemblage to prevent indiscreet access to
the contents of the package. In addition, the container has
deposited thereon a label that describes the contents of the
container. The label may also include appropriate warnings.
[0223] Pharmaceutical, formulations of a compound of Formula I may
be prepared for various routes and types of administration. A
compound of Formula I having the desired degree of purity is
optionally mixed with pharmaceutically acceptable diluents,
carriers, excipients or stabilizers (Remington's Pharmaceutical
Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a
lyophilized formulation, milled powder, or an aqueous solution.
Formulation may be conducted by mixing at ambient temperature at
the appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed.
The pH of the formulation depends mainly on the particular use and
the concentration of compound, but may range from about 3 to about
8. Formulation in an acetate buffer at pH 5 is a suitable
embodiment.
[0224] The inhibitory compound for use herein is preferably
sterile. The compound ordinarily will be stored as a solid
composition, although lyophilized formulations or aqueous solutions
are acceptable.
[0225] The pharmaceutical compositions of the invention will be
formulated, dosed, and administered in a fashion, i.e. amounts,
concentrations, schedules, course, vehicles, and route of
administration, consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
site of delivery of the agent, the method of administration, the
scheduling of administration, and other factors known to medical
practitioners. The "therapeutically effective amount" of the
compound to be administered will be governed by such
considerations, and is the minimum amount necessary to prevent,
ameliorate, or treat the disorder. Such amount is preferably below
the amount that is toxic to the host.
[0226] As a general proposition, the initial pharmaceutically
effective amount of the inhibitor administered parenterally per
dose will be in the range of about 0.01-100 mg/kg, namely about 0.1
to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day.
[0227] Acceptable diluents, carriers, excipients, and stabilizers
are nontoxic to recipients at the dosages and concentrations
employed, and include buffers such as phosphate, citrate, and other
organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides, and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g. Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). The active pharmaceutical ingredients
may also be entrapped in microcapsules prepared, for example, by
coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin-microcapsules and
poly-(methylmethacylate) microcapsules, respectively, in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions. Such techniques are disclosed in Remington's
Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
[0228] Sustained-release preparations may be prepared. Suitable
examples of sustained-release preparations include semipermeable
matrices of solid hydrophobic polymers containing a compound of
Formula I, which matrices are in the form of shaped articles, e.g.
films, or microcapsules. Examples of sustained-release matrices
include polyesters, hydrogels (for example,
poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),
polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic
acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl
acetate, degradable lactic acid-glycolic acid copolymers such as
the LUPRON DEPOT.TM. (injectable microspheres composed of lactic
acid-glycolic acid copolymer and leuprolide acetate), and
poly-D-(-)-3-hydroxybutyric acid.
[0229] The formulations to be used for in vivo administration must
be sterile, which is readily accomplished by filtration through
sterile filtration membranes.
[0230] The formulations include those suitable for the
administration routes detailed herein. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any of the methods well known in the art of pharmacy. Techniques
and formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, Pa.). Such methods include
the step of bringing into association the active ingredient with
the carrier which constitutes one or more accessory ingredients. In
general the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both, and then, if
necessary, shaping the product.
[0231] Formulations of a compound of Formula I suitable for oral
administration may be prepared as discrete units such as pills,
capsules, cachets or tablets each containing a predetermined amount
of the compound of Formula I.
[0232] Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as a powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent. The tablets may optionally be coated or scored and
optionally are formulated so as to provide slow or controlled
release of the active ingredient therefrom.
[0233] Tablets, troches, lozenges, aqueous or oil suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
e.g. gelatin capsules, syrups or elixirs may be prepared for oral
use. Formulations of a compound of Formula I intended for oral use
may be prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents including sweetening agents,
flavoring agents, coloring agents and preserving agents, in order
to provide a palatable preparation. Tablets containing the active
ingredient in admixture with non-toxic pharmaceutically acceptable
excipient which are suitable for manufacture of tablets are
acceptable. These excipients may be, for example, inert diluents,
such as calcium or sodium carbonate, lactose, calcium or sodium
phosphate; granulating and disintegrating agents, such as maize
starch, or alginic acid; binding agents, such as starch, gelatin or
acacia; and lubricating agents, such as magnesium stearate, stearic
acid or talc. Tablets may be uncoated or may be coated by known
techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate alone
or with a wax may be employed.
[0234] For infections of the eye or other external tissues e.g.
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w. When formulated in an
ointment, the active ingredients may be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the
active ingredients may be formulated in a cream with an
oil-in-water cream base.
[0235] If desired, the aqueous phase of the cream base may include
a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl
groups such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG 400) and
mixtures thereof. The topical formulations may desirably include a
compound which enhances absorption or penetration of the active
ingredient through the skin or other affected areas. Examples of
such dermal penetration enhancers include dimethyl sulfoxide and
related analogs.
[0236] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations. Emulgents and emulsion
stabilizers suitable for use in the formulation of the invention
include Tween.RTM. 60, Span.RTM. 80, cetostearyl alcohol, benzyl
alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl
sulfate.
[0237] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, croscarmellose, povidone,
methylcellulose, hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkyl oxide (e.g. ethylene
oxide, propylene oxide) with a fatty acid (e.g., polyoxyethylene
stearate), a condensation product of ethylene oxide with a long
chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a
condensation product of ethylene oxide with a partial ester derived
from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene
sorbitan monooleate). The aqueous suspension may also contain one
or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate,
one or more coloring agents, one or more flavoring agents and one
or more sweetening agents, such as sucrose or saccharin.
[0238] The pharmaceutical composition of a compound of Formula I
may be in the form of a sterile injectable preparation, such as a
sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0239] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0240] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0241] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10% particularly about 1.5% w/w.
[0242] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0243] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0244] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration may be prepared according to
conventional methods and may be delivered with other therapeutic
agents such as compounds heretofore used in the treatment or
prophylaxis of HIV infections as described below.
[0245] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0246] The formulations may be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
The invention further provides veterinary compositions comprising
at least one active ingredient as above defined together with a
veterinary carrier therefore. Veterinary carriers are materials
useful for the purpose of administering the composition and may be
solid, liquid or gaseous materials which are otherwise inert or
acceptable in the veterinary art and are compatible with the active
ingredient. These veterinary compositions may be administered
parenterally, orally or by any other desired route.
Combination Therapy
[0247] A compound of Formula I may be combined in a pharmaceutical
combination formulation, or dosing regimen as combination therapy,
with a second compound that has anti-hyperproliferative or
chemotherapeutic properties, that is useful for treating a disease
or disorder responsive to the inhibition of a JAK kinase, for
example a hyperproliferative disorder (e.g. cancer), or that is
useful in treating another disorder named herein. The second
compound of the pharmaceutical combination formulation or dosing
regimen preferably has complementary activities to a compound of
Formula I of the combination such that they do not adversely affect
each other. Such molecules are suitably present in combination in
amounts that are effective for the purpose intended.
[0248] In another embodiment, a compound of Formulas I may be
employed alone or in combination with other therapeutic agents for
the treatment of a disease or disorder described herein, such as an
immunologic disorder (e.g. psoriasis or inflammation). In certain
embodiments, a compound of Formula I is combined in a
pharmaceutical combination formulation, or dosing regimen as
combination therapy, with a second therapeutic compound that has
anti-inflammatory or that is useful for treating an inflammation,
immune-response disorder. The second therapeutic agent may be a
NSAID or other anti-inflammatory agent. In one embodiment, a
composition of this invention comprises a compound of Formula I, or
a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof, in combination
with a therapeutic agent such as an NSAID.
[0249] Another embodiment, therefore, includes a method of treating
or lessening the severity of a disease or condition responsive to
the inhibition of JAK2 kinase activity in a patient, comprising
administering to said patient a therapeutically effective amount of
a compound of Formula I, and further comprising, administering a
second chemotherapeutic agent.
[0250] The combination therapy may be administered as a
simultaneous or sequential regimen. When administered sequentially,
the combination may be administered in two or more administrations.
The combined administration includes coadministration, using
separate formulations or a single pharmaceutical formulation, and
consecutive administration in either order, wherein preferably
there is a time period while both (or all) active agents
simultaneously exert their biological activities.
[0251] Suitable dosages for any of the above coadministered agents
are those presently used and may be lowered due to the combined
action (synergy) of the newly identified agent and other
chemotherapeutic agents or treatments.
[0252] The combination therapy may provide "synergy" and prove
"synergistic", i.e. the effect achieved when the active ingredients
used together is greater than the sum of the effects that results
from using the compounds separately. A synergistic effect may be
attained when the active ingredients are: (1) co-formulated and
administered or delivered simultaneously in a combined, unit dosage
formulation; (2) delivered by alternation or in parallel as
separate formulations; or (3) by some other regimen. When delivered
in alternation therapy, a synergistic effect may be attained when
the compounds are administered or delivered sequentially, e.g. by
different injections in separate syringes. In general, during
alternation therapy, an effective dosage of each active ingredient
is administered sequentially, i.e. serially, whereas in combination
therapy, effective dosages of two or more active ingredients are
administered together.
Metabolites of the Triazolopyridine Compounds
[0253] Another embodiment includes in vivo metabolic products of an
administered compound of Formula I. Such products may result for
example from the oxidation, reduction, hydrolysis, amidation,
deamidation, esterification, deesterification, enzymatic cleavage,
and the like, of the administered compound.
[0254] Metabolite products typically are identified by preparing a
radiolabelled (e.g. .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it parenterally in a detectable dose
(e.g. greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g. by MS,
LC/MS or NMR analysis. In general, analysis of metabolites is done
in the same way as conventional drug metabolism studies well-known
to those skilled in the art. The conversion products, so long as
they are not otherwise found in vivo, are useful in diagnostic
assays for therapeutic dosing of a compound of Formula I.
Articles of Manufacture
[0255] Another embodiment includes a kit for treating a disease or
disorder responsive to the inhibition of a JAK kinase. The kit
includes:
[0256] (a) a first pharmaceutical composition comprising a compound
of Formula I; and
[0257] (b) instructions for use.
[0258] In another embodiment, the kit further includes:
[0259] (c) a second pharmaceutical composition, which includes a
chemotherapeutic agent.
[0260] In one embodiment, the instructions include instructions for
the simultaneous, sequential or separate administration of said
first and second pharmaceutical compositions to a patient in need
thereof.
[0261] In one embodiment, the first and second compositions are
contained in separate containers.
[0262] In one embodiment, the first and second compositions are
contained in the same container.
[0263] Containers for use include, for example, bottles, vials,
syringes, blister pack, etc. The containers may be formed from a
variety of materials such as glass or plastic. The container
includes a compound of Formula I or formulation thereof which is
effective for treating the condition and may have a sterile access
port (for example the container may be an intravenous solution bag
or a vial having a stopper pierceable by a hypodermic injection
needle). The container includes a composition comprising at least
one compound of Formula I. The label or package insert indicates
that the composition is used for treating the condition of choice,
such as cancer. In one embodiment, the label or package inserts
indicates that the composition comprising the compound of Formula I
can be used to treat a disorder. In addition, the label or package
insert may indicate that the patient to be treated is one having a
disorder characterized by overactive or irregular kinase activity.
The label or package insert may also indicate that the composition
can be used to treat other disorders.
[0264] The article of manufacture may comprise (a) a first
container with a compound of Formula I contained therein; and (b) a
second container with a second pharmaceutical formulation contained
therein, wherein the second pharmaceutical formulation comprises a
chemotherapeutic agent. The article of manufacture in this
embodiment of the invention may further comprise a package insert
indicating that the first and second compounds can be used to treat
patients at risk of stroke, thrombus or thrombosis disorder.
Alternatively, or additionally, the article of manufacture may
further comprise a second (or third) container comprising a
pharmaceutically-acceptable buffer, such as bacteriostatic water
for injection (BWFI), phosphate-buffered saline, Ringer's solution
and dextrose solution. It may further include other materials
desirable from a commercial and user standpoint, including other
buffers, diluents, filters, needles, and syringes.
[0265] In an embodiment, the compounds of Formula I can be used to
control JAK protein kinases, tyrosine kinases, additional
serine/threonine kinases, and/or dual specificity kinases. Thus,
they are useful as pharmacological standards for use in the
development of new biological tests, assays and in the search for
new pharmacological agents.
[0266] Compounds of Formula I may be assayed for the ability to
modulate the activity of JAK protein kinases, tyrosine kinases,
additional serine/threonine kinases, and/or dual specificity
kinases in vitro and in vivo. In vitro assays include biochemical
and cell-based assays that determine inhibition of the kinase
activity. Alternate in vitro assays quantify the ability of the
compound of Formula I to bind to kinases and may be measured either
by radiolabelling the compound of Formula I prior to binding,
isolating the compound of Formula I/kinase complex and determining
the amount of radiolabel bound, or by running a competition
experiment where a compound of Formula I is incubated with known
radiolabeled ligands. These and other useful in vitro assays are
well known to those of skill in the art.
[0267] In order to illustrate the invention, the following examples
are included. However, it is to be understood that these examples
do not limit the invention and are only meant to suggest a method
of practicing the invention. Persons skilled in the art will
recognize that the chemical reactions described may be readily
adapted to prepare other compounds of Formula I, and alternative
methods for preparing the compounds of Formula I are within the
scope of this invention. For example, the synthesis of
non-exemplified compounds according to the invention may be
successfully performed by modifications apparent to those skilled
in the art, e.g., by appropriately protecting interfering groups,
by utilizing other suitable reagents known in the art other than
those described, and/or by making routine modifications of reaction
conditions. Alternatively, other reactions disclosed herein or
known in the art will be recognized as having applicability for
preparing other compounds of the invention.
BIOLOGICAL EXAMPLES
[0268] Compounds of Formula I may be assayed for the ability to
modulate the activity of Janus protein kinases, tyrosine kinases,
additional serine/threonine kinases, and/or dual specificity
kinases in vitro and in vivo. In vitro assays include biochemical
and cell-based assays that determine inhibition of the kinase
activity. Alternate in vitro assays quantify the ability of the
compound of Formula I to bind to kinases and may be measured either
by radiolabelling the compound of Formula I prior to binding,
isolating the compound of Formula I/kinase complex and determining
the amount of radiolabel bound, or by running a competition
experiment where a compound of Formula I is incubated with known
radiolabeled ligands. These and other useful in vitro assays are
well known to those of skill in the art.
[0269] Previous studies have shown that the isolated kinase domains
of human JAK1, JAK2, JAK3 or TYK2 phosphorylate peptide substrates
in in vitro kinase assays (Saltzman et al., Biochem. Biophys. Res.
Commun. 246:627-633 (2004)). The catalytically active kinase domain
of human JAK1, JAK2, JAK3 or TYK2 was purified from extracts of SF9
insect cells infected with a recombinant baculovirus expression
vector encoding the human JAK1, JAK2, JAK3 or TYK2 kinase domains
(JAK1 amino acid residues N852-D1154 according to the numbering of
GenBank sequence accession number P23458, JAK2 amino acid residues
D812-G1132 according to the numbering of GenBank sequence accession
number NP.sub.--004963.1; JAK3 amino acid residues S783-S1124
according to the numbering of GenBank sequence accession number
P52333, and TYK2 amino acid residues N873-C1187 according to the
numbering of GenBank sequence accession number P29597). The
activity of the JAK1, JAK2, JAK3 or TYK2 kinase domains can be
measured by a number of direct and indirect methods, including
quantification of phosphorylation of peptide substrates derived
from the human JAK3 protein (Saltzman et al., Biochem. Biophys.
Res. Commun. 246:627-633 (2004)). The activity of the JAK1, JAK2,
JAK3 or TYK2 kinase domains was measured in vitro by monitoring
phosphorylation of JAK3 derived peptides using the Caliper LabChip
technology (see Examples).
Example A
JAK2 Inhibition Assay Protocol
[0270] The activity of the isolated JAK2 kinase domain was measured
by monitoring phosphorylation of a peptide derived from JAK3
(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently
labeled on the N-terminus with 5-carboxyfluorescein using the
Caliper LabChip technology (Caliper Life Sciences, Hopkinton,
Mass.). To determine the inhibition constants (Ki) of Examples
1-304, compounds were diluted serially in DMSO and added to 50
.mu.L kinase reactions containing 0.2 nM purified JAK2 enzyme, 100
mM Hepes pH7.2, 0.015% Brij-35, 1.5 .mu.M peptide substrate, 25
.mu.M ATP, 10 mM MgCl.sub.2, 4 mM DTT at a final DMSO concentration
of 2%. Reactions were incubated at 22.degree. C. in 384-well
polypropylene microtiter plates for 30 minutes and then stopped by
addition of 25 .mu.L an EDTA containing solution (100 mM Hepes pH
7.2, 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTA
concentration of 50 mM. After termination of the kinase reaction,
the proportion of phosphorylated product was determined as a
fraction of total peptide substrate using the Caliper LabChip 3000
according to the manufacturer's specifications. Ki values were then
determined using the Morrison tight binding model. Morrison, J. F.,
Biochim. Biophys. Acta. 185:269-296 (1969); William, J. W. and
Morrison, J. F., Meth. Enzymol., 63:437-467 (1979).
Example B
JAK1 and TYK2 Inhibition Assay Protocol
[0271] The activity of the isolated JAK1 or TYK2 kinase domain was
measured by monitoring phosphorylation of a peptide derived from
JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr)
fluorescently labeled on the N-terminus with 5-carboxyfluorescein
using the Caliper LabChip technology (Caliper Life Sciences,
Hopkinton, Mass.). To determine the inhibition constants (Ki) of
Examples 1-312, compounds were diluted serially in DMSO and added
to 50 uL kinase reactions containing 1.5 nM JAK1, 0.2 nM purified
JAK2 or 1 nM purified TYK2 enzyme, 100 mM Hepes pH7.2, 0.015%
Brij-35, 1.5 uM peptide substrate, 25 uM ATP, 10 mM MgCl.sub.2, 4
mM DTT at a final DMSO concentration of 2%. Reactions were
incubated at 22.degree. C. in 384-well polypropylene microtiter
plates for 30 minutes and then stopped by addition of 25 uL of an
EDTA containing solution (100 mM Hepes pH 7.2, 0.015% Brij-35, 150
mM EDTA), resulting in a final EDTA concentration of 50 mM. After
termination of the kinase reaction, the proportion of
phosphorylated product was determined as a fraction of total
peptide substrate using the Caliper LabChip 3000 according to the
manufacturer's specifications. Ki values were then determined using
the Morrison tight binding model. Morrison, J. F., Biochim.
Biophys. Acta. 185:269-296 (1969); William, J. W. and Morrison, J.
F., Meth. Enzymol., 63:437-467 (1979).
Example C
JAK3 Inhibition Assay Protocol
[0272] The activity of the isolated JAK3 kinase domain was measured
by monitoring phosphorylation of a peptide derived from JAK3
(Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg) fluorescently labeled
on the N-terminus with 5-carboxyfluorescein using the Caliper
LabChip technology (Caliper Life Sciences, Hopkinton, Mass.). To
determine the inhibition constants (Ki) of Examples 1-312,
compounds were diluted serially in DMSO and added to 50 uL kinase
reactions containing 5 nM purified JAK3 enzyme, 100 mM Hepes pH7.2,
0.015% Brij-35, 1.5 uM peptide substrate, 5 uM ATP, 10 mM
MgCl.sub.2, 4 mM DTT at a final DMSO concentration of 2%. Reactions
were incubated at 22.degree. C. in 384-well polypropylene
microtiter plates for 30 minutes and then stopped by addition of 25
uL of an EDTA containing solution (100 mM Hepes pH 7.2, 0.015%
Brij-35, 150 mM EDTA), resulting in a final EDTA concentration of
50 mM. After termination of the kinase reaction, the proportion of
phosphorylated product was determined as a fraction of total
peptide substrate using the Caliper LabChip 3000 according to the
manufacturer's specifications. Ki values were then determined using
the Morrison tight binding model. Morrison, J. F., Biochim.
Biophys. Acta. 185:269-296 (1969); William, J. W. and Morrison, J.
F., Meth. Enzymol., 63:437-467 (1979).
Example D
Cell-Based Pharmacology Assays
[0273] The activities of compounds 1-312 were determined in
cell-based assays that are designed to measure Janus kinase
dependent signaling. Compounds were serially diluted in DMSO and
incubated with Set-2 cells (German Collection of Microorganisms and
Cell Cultures (DSMZ); Braunschweig, Germany), which express the
JAK2V617F mutant protein, in 96-well microtiter plates for 1 hr at
37.degree. C. in RPMI medium at a final cell density of 10.sup.5
cells per well and a final DMSO concentration of 0.57%.
Compound-mediated effects on STAT5 phosphorylation were then
measured in the lysates of incubated cells using the Meso Scale
Discovery (MSD) technology (Gaithersburg, Md.) according to the
manufacturer's protocol and EC.sub.50 values were determined.
Alternatively, serially diluted compounds were added to NK92 cells
(American Type Culture Collection (ATCC); Manassas, Va.) in 96-well
microtiter plates in RPMI medium at a final cell density of
10.sup.5 cells per well and a final DMSO concentration of 0.57%.
Human recombinant IL-12 (R&D systems; Minneapolis, Minn.) was
then added at a final concentration of 10 ng/ml to the microtiter
plates containing the NK92 cells and compound and the plates were
incubated for 1 hr at 37.degree. C. Compound-mediated effects on
STAT4 phosphorylation were then measured in the lysates of
incubated cells using the Meso Scale Discovery (MSD) technology
(Gaithersburg, Md.) according to the manufacturer's protocol and
EC.sub.50 values were determined.
PREPARATIVE EXAMPLES
Abbreviations
CD.sub.3OD Deuterated Methanol
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMSO Dimethylsulfoxide
DMF Dimethylformamide
EtOAc Ethyl Acetate
EtOH Ethanol
[0274] HCl Hydrochloric acid HM-N Isolute.RTM. HM-N is a modified
form of diatomaceous earth IMS industrial methylated spirits
MeOH Methanol
[0275] Phosphorus oxychloride
NaH Sodium Hydride
Sodium Sulfate
[0276] Sodium bicarbonate NaOH Sodium hydroxide
Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0)
NEt.sub.3 Triethylamine
[0277] Pd.sub.2 dba.sub.3 Tris-(dibenzylideneacetone)dipalladium(0)
Si-SPE Pre-packed Isolute.RTM. silica flash chromatography
cartridge Si-ISCO Pre-packed ISCO.RTM. silica flash chromatography
cartridge
THF Tetrahydrofuran
General Experimental Conditions
[0278] .sup.1H NMR spectra were recorded at ambient temperature
using a Varian Unity Inova (400 MHz) spectrometer with a triple
resonance 5 mm probe. Chemical shifts are expressed in ppm relative
to tetramethylsilane. The following abbreviations have been used:
br=broad signal, s=singlet, d=doublet, dd=double doublet,
t=triplet, q=quartet, m=multiplet.
[0279] High Pressure Liquid Chromatography-Mass Spectrometry (LCMS)
experiments to determine retention times (R.sub.T) and associated
mass ions were performed using one of the following methods.
[0280] Method A: Experiments performed on a Waters Micromass ZQ
quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC
system with diode array detector. This system uses a Higgins
Clipeus 5 micron C18 100.times.3.0 mm column and a 1 ml/minute flow
rate. The initial solvent system was 95% water containing 0.1%
formic acid (solvent A) and 5% acetonitrile containing 0.1% formic
acid (solvent B) for the first minute followed by a gradient up to
5% solvent A and 95% solvent B over the next 14 minutes. The final
solvent system was held constant for a further 5 minutes.
[0281] Method B: Experiments performed on a Waters Platform LC
quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC
system with diode array detector and 100 position autosampler using
a Phenomenex Luna C18(2) 30.times.4.6 mm column and a 2 ml/minute
flow rate. The solvent system was 95% water containing 0.1% formic
acid (solvent A) and 5% acetonitrile containing 0.1% formic acid
(solvent B) for the first 0.50 minutes followed by a gradient up to
5% solvent A and 95% solvent B over the next 4 minutes. The final
solvent system was held constant for a further 0.50 minutes.
[0282] Microwave experiments were carried out using a Biotage
Initiator 60.TM. or CEM Explorer.RTM.. Temperatures from
40-250.degree. C. can be achieved, and pressures of up to 30 bar
can be reached.
[0283] In the examples described below, unless otherwise indicated
all temperatures are set forth in degrees Celsius. Reagents were
purchased from commercial suppliers such as Aldrich Chemical
Company, Lancaster, TCI or Maybridge, and were used without further
purification unless otherwise indicated.
[0284] The reactions set forth below were done generally under a
positive pressure of nitrogen or argon or with a drying tube
(unless otherwise stated) in anhydrous solvents, and the reaction
flasks were typically fitted with rubber septa for the introduction
of substrates and reagents via syringe. Glassware was oven dried
and/or heat dried.
[0285] Column chromatography was conducted on a Combiflash system
(Manufacturer: Teledyne Isco) having a silica gel column. .sup.1H
NMR spectra were recorded on a Varian instrument operating at 400
MHz. .sup.1H NMR spectra were obtained as CDCl.sub.3, d.sub.6-DMSO
or d.sub.4 MeOH solutions (reported in ppm), using chloroform as
the reference standard (7.25 ppm). When peak multiplicities are
reported, the following abbreviations are used: s (singlet), d
(doublet), t (triplet), m (multiplet), br (broadened), dd (doublet
of doublets), dt (doublet of triplets). Coupling constants, when
given, are reported in Hertz (Hz).
Example 1
##STR00049##
[0286]
N-Piperidin-4-yl-4-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,-
5-a]pyridin-2-ylamino]-benzamide
##STR00050##
[0287] Ethyl[(3-bromopyridin-2-yl)carbamothioyl]carbamate
[0288] To a solution of 2-amino-3-bromopyridine (50.0 g, 289 mmol,
1 equiv) in dichloromethane (500 mL) was added dropwise
ethoxycarbonyl isothiocyanate (39.0 g, 297 mmol, 1.03 equiv) at
room temperature. After 2 h, dichloromethane was removed in vacuo
to provide crude ethyl[(3-bromopyridin-2-yl)
carbamothioyl]carbamate (88 g).
##STR00051##
8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine
[0289] To a solution of hydroxylamine hydrochloride (0.10 kg, 1.4
mol, 5.0 equiv) and N,N-diisopropylethylamine (112 g, 0.867 mol,
3.00 eq) in 1:1 methanol/ethanol (1.5 L) was added
ethyl[(3-bromopyridin-2-yl)carbamothioyl]carbamate (88 g, 0.29
mmol, 1 equiv) in one portion at room temperature. After 2 h, the
reaction mixture was warmed to 60.degree. C. for overnight. The
reaction mixture was concentrated in vacuo, and water was added to
the resulting residue. The solids were filtered and rinsed
sequentially with 4:1 methanol/diethyl ether and diethyl ether to
provide product as an off-white solid (25 g, 40%). LCMS (ESI) m/z:
212.8; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.55 (m 1H),
7.70 (m, 1H), 6.75 (m, 1H), 6.20 (br s, 2H).
##STR00052##
Di-tert-butyl
(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)imidodicarbonate
[0290] A solution of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine
(10.6 g, 49.7 mmol, 1 equiv), di-tert-butyl dicarbonate (43.6 g,
0.200 mol, 4.01 equiv), and 4-dimethylaminopyridine (0.61 g, 5.0
mmol, 0.10 equiv) in pyridine (200 mL) was heated at 50.degree. C.
overnight. The reaction mixture was concentrated in vacuo. The
resulting residue was partitioned between water and diethyl ether.
The organic layer was separated and washed with water (3.times.).
Filtration of the organic through a plug of silica gel (4:1
petroleum ether/ethyl acetate) afforded crude product. (14.8 g,
72%). .sup.1H NMR (400 MHz), DMSO-d.sub.6) .delta.: 9.0 (m, 1H),
8.1 (m, 1H), 7.2 (m, 1H), 1.4 (s, 18H).
##STR00053##
8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
[0291] To a solution of di-tert-butyl
(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)imidodicarbonate (3.3 g,
8.0 mmol, 1 equiv),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.584
g, 0.798 mmol, 0.10 equiv), cesium carbonate (3.1 g, 9.5 mmol, 1.2
equiv), and 3-trifluoromethylphenyl boronic acid (1.8 g, 9.5 mmol,
1.2 equiv) in 10:1 1,2-dimethoxyethane/water (50 mL) was heated at
120.degree. C. overnight. The reaction mixture was concentrated in
vacuo, and the resulting residue was partitioned between ethyl
acetate and water. The collected organic was dried over anhydrous
sodium sulfate, filtered, and concentrated. Purification by the
flash column chromatography (4:1 petroleum ether/ethyl acetate)
afforded di-tert-butyl
(8-(3-trifluoromethylphenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)imido-dicar-
bonate (3.17 g, 83%).
[0292] Di-tert-butyl
(8-(3-trifluoromethylphenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)imido-dicar-
bonate (3.15 g, 6.58 mmol, 1 equiv) was dissolved in a solution of
hydrogen chloride in dioxane (50 mL). The reaction mixture was
maintained at room temperature overnight. Dioxane was removed in
vacuo, and the resulting residue was dissolved in dichloromethane
(100 mL). The organic was washed sequentially with saturated
aqueous sodium bicarbonate solution and saturated aqueous sodium
chloride solution. The organic was dried over anhydrous sodium
sulfate, filtered, and concentrated to yield product (1.41 g, 77%).
LCMS (ESI) m/z: 279.1.
##STR00054##
Methyl
4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-y-
lamino) benzoate
[0293] A suspension of
8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
(1.0 g, 3.6 mmol, 1 equiv), methyl 4-iodobenzoate (0.95 g, 3.6
mmol, 1.0 equiv), palladium (II) acetate (0.080 g, 0.36 mmol, 0.10
equiv), cesium carbonate (2.34 g, 7.18 mmol, 2.0 equiv), and
Xantphos (0.10 g, 0.17 mmol, 0.047 equiv) in 1,4-dioxane (20 mL)
was heated to 80.degree. C. After 16 h, the reaction mixture was
concentrated in vacuo, and the resulting residue was diluted with
methanol and water. The solid was collected by filtration and
rinsed sequentially with water, isopropanol, and hexanes to afford
crude methyl
4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-
benzoate (1.07 g, 72%). LCMS (ESI) m/z: 413.0; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 10.29 (s, 1H), 8.88 (m, 1H), 8.63 (s,
1H), 8.40 (m, 1H), 8.02 (m, 1H), 7.78-7.90 (m, 6H), 7.20 (m, 1H),
3.80 (s, 3H).
##STR00055##
4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-
benzoic acid
[0294] A solution of methyl
4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino-
)benzoate (1.03 g, 2.50 mmol, 1 equiv) in 2M aqueous sodium
hydroxide (10 mL) and 1,4-dioxane (5 mL) was heated at
80-90.degree. C. After 3 h, the solution was cooled to 0.degree. C.
and neutralized by the addition of 6M HCl until pH=4-5. The
resulting solid was collected by filtration and rinsed sequentially
with water, isopropanol, and hexanes to afford crude
4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-
benzoic acid (1.0 g, HPLC purity: 89%). LCMS (ESI) m/z: 398.9;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.45 (br s, 1H),
10.22 (s, 1H), 8.89 (d, J=6.8 Hz, 1H), 8.65 (s, 1H), 8.42 (d, J=6.9
Hz, 1H), 8.03 (m, 1H), 7.77-7.84 (m, 6H), 7.21 (t, J=7.0 Hz,
1H).
N-Piperidin-4-yl-4-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyr-
idin-2-ylamino]-benzamide
[0295] To a solution of
4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-
benzoic acid (1.0 g, 2.5 mmol, 1 equiv),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (1.14 g, 3.00 mmol, 1.2 equiv),
N,N-diisopropylethylamine (484 mg, 3.74 mmol, 1.5 equiv) in 2:1
tetrahydrofuran/dichloromethane (50 mL) was added tert-butyl
4-amino-1-piperidinecarboxylate (0.60 g, 3.0 mmol, 1.2 equiv) at
room temperature. After 16 h, the reaction mixture was filtered,
and the filtrate was concentrate. The resulting residue was
dissolved in 1:1 trifluoroacetic acid/tetrahydrofuran (50 mL) at
room temperature. After 2 h, the reaction mixture was concentrated
in vacuo. Purification by preparative HPLC provided product (508
mg, 42%). LCMS (ESI) m/z: 481.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.06 (s, 1H), 8.85 (d, J=7.6 Hz, 1H), 8.60
(s, 1H), 8.38 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.84 (br
s, 2H), 7.72-7.79 (m, 3H), 7.32 (d, J=7.6 Hz, 2H), 7.15 (m, 1H),
4.02 (m, 1H), 3.27-3.32 (m, 2H), 2.95-3.05 (m, 2H), 1.87-1.94 (m,
2H), 1.41-1.48 (m, 2H).
Example 2
##STR00056##
[0296]
[8-(3-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methyl-
-pyridin-4-yl)-amine
##STR00057##
[0297]
8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
[0298] Made by following the procedure described for the
preparation of
8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
but substituting 3-methoxyphenyl boronic acid and making
non-critical variations.
[8-(3-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methyl-pyridi-
n-4-yl)-amine
[0299] A suspension of
8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.150 g,
0.625 mmol, 1 equiv), 4-bromo-2-methylpyridine (0.160 g, 0.935
mmol, 1.5 equiv), tris(dibenzylideneacetone)dipalladium (0) (27.5
mg, 0.03 mmol, 0.05 equiv), sodium tert-butoxide (0.90 g, 0.94
mmol, 1.5 equiv), and
2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl (38.9 mg, 0.625
mmol, 0.1 equiv) in toluene (2 mL) was purged with nitrogen for 15
min. The reaction mixture was heated at 110.degree. C. by microwave
for 10 min. The reaction mixture was diluted with ethyl acetate (50
mL) and filtered through celite. The filtrate was then washed with
brine (3.times.20 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated. Purification by preparative HPLC
afforded
8-(3-methoxyphenyl)-N-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi-
n-2-amine (80 mg, 39%). LCMS (ESI) m/z: 332.1; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 10.45 (br s, 1H), 8.81 (dd, J=6.4, 0.8
Hz, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.88 (dd, J=6.8, 0.8 Hz, 1H), 7.74
(s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.54 (dd, J=6.0, 2.0
Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.15 (t, J=6.8 Hz, 1H), 7.00 (dd,
J=8.0, 2.4 Hz, 1H), 3.83 (s, 3H), 2.42 (s, 3H).
[0300] Examples 3-126 shown in Table 1 were prepared according to
the above-described methods.
TABLE-US-00001 TABLE 1 LCMS (ESI) Ex # Structure Name m/z 3
##STR00058## (3,5-Difluoro-phenyl)-[8-(3- methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 353.1 4 ##STR00059##
[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-pyridin-4-yl-amine 318.0 5 ##STR00060##
(3-Fluoro-phenyl)-[8-(3- methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 335.0 6 ##STR00061##
[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-phenyl-amine 317.1 7 ##STR00062## (3,5-Difluoro-phenyl)-[8-(3-
trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-amine 406.9 8 ##STR00063## (2-Methyl-pyridin-4-yl)-[8-(3-
trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-amine 385.9 9 ##STR00064## (3-Fluoro-phenyl)-[8-(3-
trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-amine 388.9 10 ##STR00065## (4-Fluoro-phenyl)-[8-(3-
trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-amine 388.9 11 ##STR00066## Phenyl-[8-(3-trifluoromethoxy-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-amine 370.9 12
##STR00067## [8-(2-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
yl]-phenyl-amine 304.9 13 ##STR00068##
(3-Fluoro-phenyl)-(8-m-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-
yl)-amine 318.9 14 ##STR00069## (2-Methyl-pyridin-4-yl)-(8-m-
tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-yl)-amine 315.9 15
##STR00070## (4-Fluoro-phenyl)-(8-m-tolyl-
[1,2,4]triazolo[1,5-a]pyridin-2- yl)-amine 318.9 16 ##STR00071##
N,N-Dimethyl-4-(8-p-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino)-benzamide 371.9 17 ##STR00072## 4-[8-(4-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-cyclohexyl- benzamide
446.1 18 ##STR00073## N-(2-Piperazin-1-yl-ethyl)-4-[8-
(3-trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 526.1 19 ##STR00074##
N-(2-Morpholin-4-yl-ethyl)-4-(8- p-tolyl-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)-benzamide 457.0 20 ##STR00075##
N-Methyl-4-[8-(3- trifluoromethoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 427.9 21
##STR00076## 4-[8-(3-Trifluoromethoxy- phenyl)-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino]-benzamide 414.0 22 ##STR00077##
4-(8-m-Tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide
344.1 23 ##STR00078## N-(2-Morpholin-4-yl-ethyl)-4-(8-
m-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 457.2
24 ##STR00079## 4-[8-(4-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-yl)-benzamide 457.2 25 ##STR00080## 4-[8-(4-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-yl-
benzamide 443.1 26 ##STR00081## 4-[8-(4-Methoxy-phenyl)- [1
2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-ylmethyl-
benzamide 457.2 27 ##STR00082## 4-[8-(4-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-morpholin-4-yl-
ethyl)-benzamide 473.1 28 ##STR00083##
N-Cyclohexyl-4-[8-(4-methoxy- phenyl)-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino]-benzamide 442.1 29 ##STR00084##
N-(2-Amino-2-methyl-propyl)-4- [8-(4-methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 431.1 30
##STR00085## 4-[8-(4-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(3-morpholin-4-yl-
propyl)-benzamide 487.1 31 ##STR00086## 4-[8-(4-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-ylmethyl)-benzamide 471.2 32 ##STR00087##
4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-N,N-dimethyl- benzamide 388.1 33 ##STR00088##
4-[8-(4-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 461.1 34
##STR00089## 4-[8-(4-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-morpholin-4-yl-
ethyl)-benzamide 461.1 35 ##STR00090## N-Cyclohexyl-4-[8-(4-fluoro-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-benzamide 430.1
36 ##STR00091## 4-[8-(4-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(3-morpholin-4-yl-
propyl)-benzamide 475.1 37 ##STR00092## 4-[8-(4-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N,N-dimethyl- benzamide
376.1 38 ##STR00093## 4-[8-(4-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzoic acid 361.1 39
##STR00094## N-(2-Amino-2-methyl-propyl)-4- [8-(4-fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 419.1 40
##STR00095## 4-[8-(4-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzoic acid 348.9 41
##STR00096## 4-(8-p-Tolyl-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)-benzoic acid 344.9 42 ##STR00097##
4-[8-(4-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzoic acid 364.8 43 ##STR00098## 4-[8-(4-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-yl)-benzamide 461.2 44 ##STR00099## 4-[8-(4-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-morpholin-4-yl-
ethyl)-benzamide 477.2 45 ##STR00100## 4-[8-(4-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N,N-dimethyl- benzamide
392.1 46 ##STR00101## (2-{4-[8-(3-Trifluoromethoxy-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-
benzoylamino}-ethyl)-carbamic acid tert-butyl ester 557.0 47
##STR00102## (2-{4-[8-(3-Trifluoromethyl-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-
benzoylamino}-ethyl)-carbamic acid tert-butyl ester 541.1 48
##STR00103## {2-[4-(8-m-Tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino)-benzoylamino]-ethyl}- carbamic acid tert-butyl ester 487.1
49 ##STR00104## N-(2-Dimethylamino-ethyl)-4-(8-
p-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 415.0
50 ##STR00105## N-(1-Methyl-piperidin-4-yl)-4-(8-
p-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 441.1
51 ##STR00106## N-Piperidin-4-yl-4-(8-p-tolyl-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino)-benzamide 427.0 52
##STR00107## {2-[4-(8-p-Tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino)-benzoylamino]-ethyl}- carbamic acid tert-butyl ester 487.1
53 ##STR00108## N-Cyclohexyl-4-(8-p-tolyl-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino)-benzamide 426.1 54
##STR00109## N-Cyclohexyl-4-[8-(3-methoxy-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-benzamide 442.0
55 ##STR00110## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-yl)-benzamide 457.1 56 ##STR00111## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-ylmethyl-
benzamide 457.1 57 ##STR00112## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-morpholin-4-yl-
ethyl)-benzamide 473.1 58 ##STR00113##
N-(2-Amino-2-methyl-propyl)-4- [8-(3-methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 431.1 59
##STR00114## N-(2-Dimethylamino-ethyl)-4-[8- (3-methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 431.1 60
##STR00115## N-(2-Amino-ethyl)-4-[8-(3- methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 403.0 61
##STR00116## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-yl-
benzamide 443.0 62 ##STR00117## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N,N-dimethyl- benzamide
388.0 63 ##STR00118## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-methyl-benzamide 374.0
64 ##STR00119## N-Cyclohexyl-4-[8-(3-fluoro-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-benzamide 430.1
65 ##STR00120## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino-N-(3-morpholin-4-yl-
propyl)-benzamide 475.1 66 ##STR00121## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-yl)-benzamide 445.2 67 ##STR00122## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-ylmethyl-
benzamide 445.0 68 ##STR00123## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-morpholin-4-yl-
ethyl)-benzamide 461.2 69 ##STR00124##
N-(2-Amino-2-methyl-propyl)-4- [8-(3-fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 419.2 70
##STR00125## N-(2-Dimethylamino-ethyl)-4-[8- (3-fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 419.2 71
##STR00126## N-(2-Amino-ethyl)-4-[8-(3- fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 391.3 72
##STR00127## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-yl-
benzamide 431.0 73 ##STR00128## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-methyl-benzamide 362.1
74 ##STR00129## N-(3-Morpholin-4-yl-propyl)-4-
[8-(3-trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 541.1 75 ##STR00130##
N-(2-Amino-2-methyl-propyl)-4- [8-(3-trifluoromethoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 485.0 76
##STR00131## N-Cyclohexyl-4-[8-(3- trifluoromethoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 496.0 77
##STR00132## N-Piperidin-4-yl-4-[8-(3- trifluoromethoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 496.9 78
##STR00133## N-Piperidin-4-ylmethyl-4-[8-(3-
trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 511.0
79 ##STR00134## N-(1-Methyl-piperidin-4-yl)-4-[8-
(3-trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 511.0 80 ##STR00135##
N-(2-Morpholin-4-yl-ethyl)-4-[8- (3-trifiuoromethoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 527.0 81
##STR00136## N,N-Dimethyl-4-[8-(3- trifluoromethoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 441.9 82
##STR00137## N-(2-Dimethylamino-ethyl)-4-(8-
m-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 415.2
83 ##STR00138## N-(3-Morpholin-4-yl-propyl)-4-
(8-m-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide
471.3 84 ##STR00139## N-(2-Amino-2-methyl-propyl)-4-
(8-m-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide
415.3 85 ##STR00140## N-Cyclohexyl-4-(8-m-tolyl-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino)-benzamide 426.2 86
##STR00141## N-Piperidin-4-ylmethyl-4-(8-m-
tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 441.2 87
##STR00142## N-(1-Methyl-piperidin-4-yl)-4-(8-
m-tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 441.2
88 ##STR00143## N,N-Dimethyl-4-(8-m-tolyl-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino)-benzamide 372.1 89
##STR00144## N-Methyl-4-(8-m-tolyl-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino)-benzamide 358.1 90
##STR00145## N-(2-Dimethylamino-ethyl)-4-[8-
(3-trifluoromethoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 485.0 91 ##STR00146##
4-(8-m-Tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzoic acid
345.1 92 ##STR00147## 4-[8-(3-Trifluoromethoxy-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-benzoic acid
415.1 93 ##STR00148## 4-[8-(3-Trifluoromethyl-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 398.1 94
##STR00149## N-(2-Dimethylamino-ethyl)-4-[8-
(3-trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 469.0 95 ##STR00150##
N-(2-Amino-2-methyl-propyl)-4- [8-(3-trifluoromethyl-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 469.0 96
##STR00151## N-[3-(4-Methyl-piperazin-1-yl)-
propyl]-4-[8-(3-trifluoromethyl- phenyl)-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino]-benzamide 538.1 97 ##STR00152##
N-(1-Methyl-piperidin-4- ylmethyl)-4-[8-(3-
trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 509.1 98 ##STR00153##
N-(2-Piperazin-1-yl-ethyl)-4-[8- (3-trifluoromethyl-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 510.2 99
##STR00154## N,N-Dimethyl-4-[8-(3- trifluoromethyl-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 426.1 100
##STR00155## N-Piperidin-4-ylmethyl-4-[8-(3-
trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 495.0 101 ##STR00156## N-Methyl-4-[8-(3-
trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 412.1 102 ##STR00157## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-ylmethyl)-benzamide 475.2 103 ##STR00158##
N-(2-Amino-2-methyl-propyl)-4- [8-(3-chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 435.2 104
##STR00159## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-dimethylamino-
ethyl)-benzamide 435.2 105 ##STR00160## N-(2-Amino-ethyl)-4-[8-(3-
chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide
407.1 106 ##STR00161## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-methyl-benzamide 378.1
107 ##STR00162## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 363.9 108
##STR00163## 4-[8-(3-Fluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzoic acid 349.1 109
##STR00164## 4-[8-(3-Methoxy-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzoic acid 360.9 110
##STR00165## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-morpholin-4-yl-
ethyl)-benzamide 477.0 111 ##STR00166## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(3-morpholin-4-yl-
propyl)-benzamide 491.1 112 ##STR00167## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-ylmethyl-
benzamide 461.0 113 ##STR00168## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-[3-(4-methyl-
piperazin-1-yl)-propyl]- benzamide 504.1 114 ##STR00169##
4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-N-[2-(4-methyl- piperazin-1-yl)-ethyl]- benzamide 490.0
115 ##STR00170## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-piperidin-4-yl-
benzamide 447.2 116 ##STR00171## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(2-piperazin-1-yl-
ethyl)-benzamide 476.1 117 ##STR00172## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-(1-methyl-piperidin-
4-yl)-benzamide 461.2 118 ##STR00173## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N-cyclohexyl- benzamide
446.0 119 ##STR00174## N-Cyclohexyl-4-[8-(3-
trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 480.1 120 ##STR00175##
N-(1-Methyl-piperidin-4-yl)-4-[8- (3-trifluoromethyl-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 495.1 121
##STR00176## N-(2-Morpholin-4-yl-ethyl)-4-[8-
(3-trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-
ylamino]-benzamide 511.1 122 ##STR00177##
N-(3-Morpholin-4-yl-propyl)-4- [8-(3-trifluoromethyl-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 525.1 123
##STR00178## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzoic acid 365.0 124
##STR00179## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-N,N-dimethyl- benzamide
392.1 125 ##STR00180## 4-[8-(3-Chloro-phenyl)-
[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzoic acid methyl ester
379.0 126 ##STR00181## 4-[8-(3-Trifluoromethoxy-
phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-benzoic acid
methyl ester 429.0
Example 127
##STR00182##
[0301]
4-(8-(1-cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin--
2-ylamino)benzoic acid
##STR00183##
[0302] methyl
4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate
[0303] A suspension of
8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.8 g, 13.2 mmol, 1
equiv), methyl 4-iodobenzoate (3.4 g, 13 mmol, 1.0 equiv), cesium
carbonate (8.4 g, 26 mmol, 2.0 equiv),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (763 mg, 1.32 mmol,
0.10 equiv), and palladium (II) acetate (300 mg, 1.32 mmol, 0.10
equiv) in dioxane (100 mL) was heated at 80.degree. C. for 1 h. The
reaction mixture was cooled to room temperature and diluted with
dichloromethane (100 mL). The resulting solids were filtered and
sequentially rinsed with water (3.times.50 mL) and methanol
(2.times.20 mL). The solids were dried in vacuo to afford methyl
4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate (3.1
g). .sup.1H NMR (400 MHz, DMSO-d.sub.6), .delta.: 10.42 (s, 1H),
8.87 (m, 1H), 7.93 (m, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8
Hz, 2H), 7.00 (dd, J=7.4, 6.9 Hz, 1H), 3.81 (s, 3H).
##STR00184##
methyl
4-(8-(1-cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-
-2-ylamino)benzoate
[0304] A suspension of methyl
4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate (0.800
g, 2.30 mmol, 1 equiv),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (894
mg, 4.60 mmol, 2.00 equiv),
1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (376 mg,
0.461 mmol, 0.200 equiv) and cesium carbonate (1.50 g, 4.61 mmol,
2.00 equiv) in 5:1 1,2-dimethoxyethane/water (6 mL) was evacuated
and back-filled with nitrogen (3.times.). The reaction mixture was
heated at 140.degree. C. for 30 min in the microwave. LCMS of the
reaction mixture showed .about.60% conversion, and additional
bis(diphenylphosphino)ferrocenepalladium(II) chloride (95 mg, 0.12
mmol, 0.05 equiv) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (225
mg, 1.16 mmol, 0.500 equiv) were added. The reaction mixture was
then heated at 140.degree. C. for 30 min in the microwave. The
solids were collected by filtration and purified by flash column
chromatography (10% methanol, 1% ammonium hydroxide in
dichloromethane) to afford a gray solid (620 mg, 80% yield). LCMS
(ESI) m/z: 335.0.
##STR00185##
methyl
4-(8-(1-cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-
-2-ylamino)benzoate
[0305] A suspension of methyl
4-(8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate
(43 mg, 0.13 mmol, 1 equiv), cyclopentyl bromide (41 .mu.L, 0.38
mmol, 3.0 equiv) and cesium carbonate (126 mg, 0.383 mmol, 3.0
equiv) in N,N-dimethylformamide (1 mL) was heated at 100.degree. C.
After 2 h, the reaction mixture was diluted with ethyl acetate, and
the resulting solution was washed with saturated aqueous sodium
chloride solution. The collected organic was concentrated.
Purification of the resulting residue by flash column
chromatography (20% ethyl acetate in dichloromethane) afforded a
white solid (23.5 mg, 45% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.18 (s, 1H), 8.74-8.55 (m, 2H), 8.32 (s,
1H), 7.91 (dd, J=13.9, 8.1 Hz, 3H), 7.85 (d, J=8.9 Hz, 2H), 7.10
(t, J=7.0 Hz, 1H), 4.81 (s, 1H), 3.82 (s, 3H), 2.25-2.11 (m, 2),
2.11-1.93 (m, 2H), 1.85 (d, J=3.5 Hz, 2H), 1.77-1.63 (m, 2H).
4-(8-(1-Cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylami-
no)benzoic acid
[0306] Made by following the procedure described for the
preparation of
4-(8-(3-trifluoromethyl)phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)b-
enzoic acid and making non-critical variations. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.43 (s, 1H), 10.12 (s, 1H), 8.74-8.60
(m, 2H), 8.32 (s, 1H), 7.90 (t, J=6.8 Hz, 3H), 7.83 (d, J=8.8 Hz,
2H), 7.09 (s, 1H), 4.81 (d, J=7.0 Hz, 1H), 2.16 (m, 2H), 2.00 (m,
2H), 1.94-1.79 (m, 2H), 1.72 (dd, J=14.6, 8.1 Hz, 2H).
Example 128
##STR00186##
[0307]
(R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylam-
ino)-1H-pyrazol-1-yl)propan-2-ol
##STR00187##
[0308]
8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
[0309] Made by following the procedure described for the
preparation of
8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
with 4-methoxyphenyl boronic acid and making non-critical
variations.
##STR00188##
2-iodo-8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine
[0310] A solution of potassium iodide (5.4 g, 32 mmol, 3.9 equiv)
and sodium nitrite (1.73 g, 25.1 mmol, 3.00 equiv) in water (10 mL)
was added over 5 min to a solution of
8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.01 g,
8.36 mmol, 1 equiv) and p-toluenesulfonic acid (7.3 g, 38 mmol, 4.6
equiv) in acetonitrile at 24.degree. C. After 19 h, the reaction
mixture was diluted with ethyl acetate (250 mL), and the resulting
solution was washed sequentially with water (2.times.120 mL) and
saturated aqueous sodium chloride solution (120 mL). The collected
organic was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Purification by flash column chromatography
(20.fwdarw.30% ethyl acetate in heptane) provided product as a
light yellow solid (1.92 g, 65% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3), .delta.: 8.46 (dd, J=6.8, 1.0 Hz, 1H), 7.96 (m, 2H),
7.59 (dd, J=7.4, 1.1 Hz, 1H), 7.01-7.06 (m, 3H), 3.86 (s, 3H).
##STR00189##
Preparation of (R)-1-(4-amino-1H-pyrazol-1-yl)propan-2-ol
[0311] To a solution of 4-nitropyrazole (44.7 mg, 0.395 mmol, 1
equiv) in (R)-propylene oxide (1 mL) was added cesium carbonate (78
mg, 0.24 mmol, 0.61 equiv) at 24.degree. C. After 64 h, the
reaction mixture was partitioned between ethyl acetate (3 mL) and
half-saturated aqueous sodium chloride solution (3 mL). The organic
was separated, and the remaining aqueous phase was extracted with
ethyl acetate (2.times.3 mL). The collected organic was dried over
anhydrous sodium sulfate, filtered, and concentrated. The resulting
residue was dissolved in methanol (4 mL) and circulated through a
H-Cube.RTM. continuous-flow hydrogenation reactor (ThalesNano)
fitted with a palladium on carbon catalyst cartridge at 30.degree.
C. The resulting solution was concentrated in vacuo to provide
product as a pink oil, which was used without further purification.
.sup.1H NMR (500 MHz, CDCl.sub.3), .delta.: 7.17 (s, 1H), 7.01 (s,
1H), 4.13 (m, 1H), 4.00 (dd, J=13.8, 2.7 Hz, 1H), 3.84 (dd, J=13.8,
7.9 Hz, 1H), 3.47 (s, 1H), 3.15 (br s, 2H), 1.18 (d, J=6.3 Hz,
3H).
(R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H--
pyrazol-1-yl)propan-2-ol
[0312] A suspension of
2-iodo-8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (53.6 mg,
0.153 mmol, 1 equiv), (R)-1-(4-amino-1H-pyrazol-1-yl)propan-2-ol
(27 mg, 0.19 mmol, 1.2 equiv), sodium tert-butoxide (43.1 mg, 0.448
mmol, 2.94 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(15.2 mg, 0.0263 mmol, 0.172 equiv) and
tris(dibenzylideneacetone)dipalladium (0) (10.5 mg, 0.0115 mmol,
0.0751 equiv) in dioxane (2 mL) was heated at 170.degree. C. in the
microwave for 15 min. The reaction mixture was partitioned between
saturated aqueous sodium chloride solution (5 mL) and ethyl acetate
(5 mL). The organic was separated, and the aqueous layer was
extracted with ethyl acetate (2.times.5 mL). The collected organic
was dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. Purification by flash column chromatography (5% methanol
in dichloromethane) afforded product as a white solid (42.4 mg, 73%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6), .delta.: 9.32 (s, 1H,
NH), 8.64 (dd, J=6.6, 0.9 Hz, 1H), 8.13 (dd, J=8.8 Hz, 2H), 7.81
(s, 1H), 7.74 (dd, J=7.5, 0.9 Hz, 1H), 7.47 (s, 1H), 7.08 (d, J=8.9
Hz, 2H), 7.03 (t, J=7.0 Hz, 1H), 4.92 (d, J=4.7 Hz, 1H, OH), 3.96
(m, 3H), 3.83 (s, 3H), 1.04 (d, J=5.8 Hz, 3H).
Example 129
##STR00190##
[0313]
8-(4-Methoxyphenyl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl-
)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
##STR00191##
[0314] 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole
[0315] Procedure adapted from Zabierek, A. A.; Konrad, K. M.;
Haidle, A. M. Tetrahedron Lett. 2008, 49, 2996.
[0316] To a solution of 4-nitro-1H-pyrazole (0.40 mg, 3.5 mmol, 1
equiv), 4-hydroxy-tetrahydropyran (0.36 g, 3.6 mmol, 1.0 equiv) and
triphenylphosphine (1.1 g, 4.2 mmol, 1.3 equiv) in tetrahydrofuran
(10 mL) at 20.degree. C. was added dibenzylazodicarboxylate (1.1 g,
4.6 mmol, 1.3 equiv) in tetrahydrofuran (2 mL) over 5 min. After 3
h the reaction mixture was concentrated in vacuo, and the resulting
residue was purified by flash column chromatography (40% ethyl
acetate in hexanes) to afford product as white solid (568 mg, 81%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.64 (s, 1H),
8.13 (s, 1H), 4.49 (s, 1H), 4.15-3.94 (m, 2H), 3.72-3.45 (m, 2H),
2.24-1.95 (m, 4H).
##STR00192##
1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine
[0317] A solution of
4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (568 mg, 2.88
mmol, 1 equiv) in methanol was circulated through a H-Cube.RTM.
Continuous-flow hydrogenation reactor (ThalesNano) fitted with a
palladium on carbon catalyst cartridge at 50.degree. C. The
collected solution was concentrated in vacuo to afford product as
pink solid (458 mg, 95% yield). LCMS (ESI) m/z: 168.0.
8-(4-Methoxyphenyl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-[1,2,-
4]triazolo[1,5-a]pyridin-2-amine
[0318] Made by following the procedure described for the
preparation of
(R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-
-pyrazol-1-yl)propan-2-ol with
1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine and making
non-critical variations. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.31 (s, 1H), 8.64 (dd, J=6.6, 0.9 Hz, 1H), 8.14 (d, J=8.9
Hz, 2H), 7.87 (s, 1H), 7.73 (m, 1H), 7.50 (s, 1H), 7.08 (d, J=8.9
Hz, 3H), 4.35 (m, 1H), 3.98 (dd, J=13.4, 10.9 Hz, 2H), 3.83 (s,
3H), 3.47 (m, 2H), 1.93 (m, 4H).
[0319] Examples 130-312 shown in Table 2 were prepared according to
the above-described methods.
TABLE-US-00002 TABLE 2 LCMS Ex Structure Name (ESI) m/z 130
##STR00193## methyl 4-(8-(1-cyclopentyl- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 403.2 131
##STR00194## N,N-dimethyl-4-(8-(3- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzamide 436.2 132
##STR00195## azetidin-1-yl(4-(8-(3- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)methanone 448.1 133
##STR00196## (3-methoxyazetidin-1-yl)(4- (8-(3-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)methanone 478.2 134 ##STR00197##
2-(4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-1H-pyrazol-1- yl)ethanol 351.2 135 ##STR00198##
5-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)picolinic acid 362.1 136 ##STR00199##
(3-hydroxyazetidin-1-yl)(4- (8-(3- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)methanone 464.0 137
##STR00200## (R)-(3-hydroxypyrrolidin-1- yl)(4-(8-(3-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)methanone 478.2 138 ##STR00201##
(R)-(3-hydroxypiperidin-1- yl)(4-(8-(3- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)methanone 492.1 139
##STR00202## (S)-(3-hydroxypyrrolidin-1- yl)(4-(8-(3-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)methanone 478.2 140 ##STR00203##
(S)-(3-hydroxypiperidin-1- yl)(4-(8-(3- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylaminophenyl)methanone 492.1 141
##STR00204## 5-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-N,N- dimethylpicolinamide 289.2 142 ##STR00205##
(3-aminoazetidin-1-yl)(4-(8- (3-(methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)methanone 463.1 143
##STR00206## (R)-2-(4-(8-(4- methoxyphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-1H-pyrazol-1-
yl)propan-1-ol 365.2 144 ##STR00207## (S)-2-(4-(8-(4-
methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-1H-pyrazol-1- yl)propan-1-ol 365.1 145 ##STR00208##
2-fluoro-4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 379.0 146 ##STR00209## 2,6-difluoro-4-(8-(4-
methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic
acid 397.1 147 ##STR00210## 8-(4-isocyanophenyl)-N-(1-
methyl-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
316.2 148 ##STR00211## N-(1-methyl-1H-pyrazol-4- yl)-8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
369.1 149 ##STR00212## 4-(2-(1-ethyl-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 330.1 150
##STR00213## N-(1-ethyl-1H-pyrazol-4-yl)- 8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
383.1 151 ##STR00214## (R)-1-(4-(8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-1H-pyrazol-1-
yl)propan-2-ol 413.2 152 ##STR00215## (R)-4-(2-(1-(2-
hydroxypropyl)-1H-pyrazol- 4-ylamino)-
[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.1 153
##STR00216## (R)-4-(2-(1-(1- hydroxypropan-2-yl)-1H-
pyrazol-4-ylamino)- [1,2,4]triazolo[1,5-a]pyridin-
8-yl)benzonitrile 360.1 154 ##STR00217## (S)-4-(2-(1-(1-
hydroxypropan-2-yl)-1H- pyrazol-4-ylamino)-
[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.2 155
##STR00218## 4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-2-methylbenzoic acid 375.1 156 ##STR00219##
(S)-1-(4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-1H-pyrazol-1- yl)propan-2-ol 365.1 157 ##STR00220##
(R)-2-(4-(8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-1H-pyrazol-1-
yl)propan-1-ol 413.1 158 ##STR00221## (S)-4-(2-(1-(2-
hydroxypropyl)-1H-pyrazol- 4-ylamino)-
[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.1 159
##STR00222## (S)-1-(4-(8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-1H-pyrazol-1-
yl)propan-2-ol 413.2 160 ##STR00223## (S)-2-(4-(8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-1H-pyrazol-1- yl)propan-1-ol 413.1 161 ##STR00224##
2-chloro-4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 395.1 162 ##STR00225## 2-chloro-4-(8-(4-
cyanophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid
390.0 163 ##STR00226## N,N-dimethyl-4-(8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzamide 436.4 164 ##STR00227## (4-(8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)(morpholino) methanone 478.1 165 ##STR00228##
8-(4-methoxyphenyl)-N-(1- (tetrahydrofuran-3-yl)-1H- pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 377.2 166 ##STR00229## 8-(4-
(methylsulfonyl)phenyl)-N- (1-(tetrahydrofuran-3-yl)-
1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 425.1 167
##STR00230## 8-(4-isocyanophenyl)-N-(1- (tetrahydrofuran-3-yl)-1H-
pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 372.1 168
##STR00231## (4-(8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)(pyrrolidin-
1-yl)methanone 462.1 169 ##STR00232## 4-(8-(4-cyanophenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-N,N- dimethylbenzamide
383.2 170 ##STR00233## 4-(8-(4-cyanophenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 356.3 171
##STR00234## 2-(4-(8-(4-methoxyphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-1H-pyrazol-1- yl)acetic
acid 365.1 172 ##STR00235## 8-(4-methoxyphenyl)-N-(1-
(1-methylpyrrolidin-3-yl)- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 390.2 173 ##STR00236##
4-(8-(4-cyanophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-2-
(trifluoromethyl)benzoic acid 424.0 174 ##STR00237##
4-(2-(1-(1-methylpyrrolidin- 3-yl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 385.2 175
##STR00238## N-(1-(1-methylpyrrolidin-3- yl)-1H-pyrazol-4-yl)-8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
438.1 176 ##STR00239## 4-(8-(4-methoxyphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-2-
(trifluoromethyl)benzoic acid 429.1 177 ##STR00240##
(S)-4-(2-(4-(3- hydroxypiperidine-1- carbonyl)phenylamino)-
[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 439.0 178
##STR00241## (R)-4-(2-(4-(3- hydroxypiperidine-1-
carbonyl)phenylamino)- [1,2,4]triazolo[1,5-a]pyridin-
8-yl)benzonitrile 439.0 179 ##STR00242## 8-(4-methoxyphenyl)-N-(1-
((tetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 391.1 180 ##STR00243## 8-(4-
(methylsulfonyl)phenyl)-N- 1-((tetrahydrofuran-3-
yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
439.1 181 ##STR00244## 4-(2-(1-((tetrahydrofuran-3-
yl)methyl)-1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-
a]pyridin-8-yl)benzonitrile 386.2 182 ##STR00245##
8-(4-methoxyphenyl)-N-(1- ((1-methylpyrrolidin-3-
yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
404.2 183 ##STR00246## N-(1-((1-methylpyrrolidin-3-
yl)methyl)-1H-pyrazol-4-yl)- 8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 452.1 184 ##STR00247##
4-(2-(1-((1-methylpyrrolidin- 3-yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 399.2 185
##STR00248## (S)-4-(2-(4-(3- hydroxypyrrolidine-1-
carbonyl)phenylamino)- [1,2,4]triazolo[1,5-a]pyridin-
8-yl)benzonitrile 424.9 186 ##STR00249## (R)-4-(2-(4-(3-
hydroxypyrrolidine-1- carbonyl)phenylamino)-
[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 425.0 187
##STR00250## 3-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 361.1 188 ##STR00251##
8-(4-methoxyphenyl)-N-(1- ((tetrahydro-2H-pyran-4-
yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
405.2 189 ##STR00252## 8-(4- (methylsulfonyl)phenyl)-N-
(1-((tetrahydro-2H-pyran-4- yl)methyl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 453.1 190 ##STR00253##
4-(2-(1-((tetrahydro-2H- pyran-4-yl)methyl)-1H- pyrazol-4-ylamino)-
[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 400.2 191
##STR00254## 4-(2-(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 386.2 192
##STR00255## 8-(4- (methylsulfonyl)phenyl)-N-
(1-(tetrahydro-2H-pyran-4- yl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 439.1 193 ##STR00256##
4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-2,6- dimethylbenzoic acid 389.1 194 ##STR00257##
8-(4-methoxyphenyl)-N-(1- ((1-methylpiperidin-4-
yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
418.2 195 ##STR00258## N-(1-((1-methylpiperidin-4-
yl)methyl)-1H-pyrazol-4-yl)- 8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 466.2 196 ##STR00259##
4-(2-(1-((1-methylpiperidin- 4-yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 413.2 197
##STR00260## 8-(4-methoxyphenyl)-N-(1- (1-methylpiperidin-4-yl)-1H-
pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 404.2 198
##STR00261## N-(1-(1-methylpiperidin-4- yl)-1H-pyrazol-4-yl)-8-(4-
(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine
452.1 199 ##STR00262## 4-(2-(1-(1-methylpiperidin-
4-yl)-1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-
a]pyridin-8-yl)benzonitrile 399.2
200 ##STR00263## N-ethyl-N-methyl-4-(8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzamide 450.1 201
##STR00264## 4-(8-(3-isopropylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 373.1 202
##STR00265## 3-(8-(3-isopropylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 373.1 203
##STR00266## (R)-4-(2-(1-((tetrahydro-2H- pyran-2-yl)methyl)-1H-
pyrazol-4-ylamino)- [1,2,4]triazolo[1,5-a]pyridin-
8-yl)benzonitrile 400.0 204 ##STR00267## (R)-4-(2-(1-((1-
methylpiperidin-2- yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 413.2 205
##STR00268## (S)-4-(2-(1-((tetrahydro-2H- pyran-2-yl)methyl)-1H-
pyrazol-4-ylamino)- [1,2,4]triazolo[1,5-a]pyridin-
8-yl)benzonitrile 400.0 206 ##STR00269## (S)-4-(2-(1-((1-
methylpiperidin-2- yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 413.2 207
##STR00270## 4-(8-(1-isobutyl-1H-pyrazol-
4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)benzoic acid 377.1
208 ##STR00271## 3-(8-(1-isobutyl-1H-pyrazol-
4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)benzoic acid 377.2
209 ##STR00272## N-(4-(1H-tetrazol-5- yl)phenyl)-8-(4-
methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 384.9 210
##STR00273## 4-(2-(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzoic acid 405.1 211
##STR00274## 4-(8-(3-fluorophenyl)-6- methyl-[1,2,4]triazolo[2,5-
a]pyridin-2-ylamino)benzoic acid 363.1 212 ##STR00275##
4-(6-chloro-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 383.0 213 ##STR00276## (R)-4-(2-(1-
((tetrahydrofuran-2- yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 386.3 214
##STR00277## (S)-4-(2-(1- ((tetrahydrofuran-2-
yl)methyl)-1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-
a]pyridin-8-yl)benzonitrile 386.3 215 ##STR00278##
4-(8-(3,4-difluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 367.1 216 ##STR00279##
4-(8-(3-fluorophenyl)-7- methyl-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)benzoic acid 363.1 217 ##STR00280##
4-(6-chloro-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-N,N- dimethylbenzamide 410.1 218 ##STR00281##
4-(8-(2-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 349.3 219 ##STR00282## 4-(8-o-tolyl-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 344.9 220
##STR00283## 4-(8-(3-fluorophenyl)-6- methyl-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)-N,N- dimethylbenzamide 390.1 221 ##STR00284##
4-(8-(3-fluorophenyl)-6- methyl-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)-N- methylbenzamide 376.1 222 ##STR00285##
4-(6-chloro-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-N- methylbenzamide 396.1 223 ##STR00286##
4-(8-(3-fluorophenyl)-7- methyl-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)-N,N- dimethylbenzamide 390.1 224 ##STR00287##
4-(8-(3-chloro-4- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 383.1 225 ##STR00288## 5-(2-(4-
carboxyphenylamino)- [1,2,4]triazolo[1,5-a]pyridin-
8-yl)-2-fluorobenzoic acid 393.1 226 ##STR00289## (R)-4-(2-(1-((1-
methylpyrrolidin-2- yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 399.1 227
##STR00290## (S)-4-(2-(1-((1- methylpyrrolidin-2-
yl)methyl)-1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-
a]pyridin-8-yl)benzonitrile 399.1 228 ##STR00291##
4-(2-(1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-
a]pyridin-8-yl)benzonitrile 302.1 229 ##STR00292##
4-(8-(3-fluorophenyl)-7- methoxy-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)benzoic acid 379.1 230 ##STR00293## methyl
4-(8-(1-isobutyl-1H- pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoate 391.1 231 ##STR00294## 4-(8-(3-
(hydroxymethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 361.0 232 ##STR00295## 4-(8-(3-
(dimethylcarbamoyl)phenyl)- [1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)benzoic acid 402.0 233 ##STR00296## methyl
4-(8-(4- (methylsulfinyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoate 407.1 234 ##STR00297## 4-(8-(4-
(methylsulfinyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 393.0 235 ##STR00298##
4-(8-(3-fluorophenyl)-7- methoxy-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)-N,N- dimethylbenzamide 406.1 236 ##STR00299##
(4-(8-(4- (methylsulfinyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)(morpholino) methanone 462.1 237 ##STR00300##
methyl 4-(8-(1-(pyridin-2- ylmethyl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 426.1 238
##STR00301## methyl 4-(8-(1-(pyridin-3- ylmethyl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 426.1 239
##STR00302## 4-(8-(1-(pyridin-2-ylmethyl)- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 412.1 240
##STR00303## 4-(8-(1-(pyridin-3-ylmethyl)- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 412.1 241
##STR00304## 4-(8-(1-(2-morpholinoethyl)- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 434.1 242
##STR00305## 3-chloro-5-(8-(4- methoxyphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)picolinic acid 395.9 243
##STR00306## 4-(8-(2-chlorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 364.7 244 ##STR00307## 4-(8-(3-(1-
hydroxyethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 375.0 245 ##STR00308##
4-(8-(3-acetylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 373.0 246 ##STR00309## 4-(8-(3-
(aminomethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 359.9 247 ##STR00310##
4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzonitrile 329.9 248 ##STR00311##
4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a] pyridin-2-
ylamino)benzene- sulfonamide 384.0 249 ##STR00312##
N-(4-(aminomethyl)phenyl)- 8-(3-fluorophenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 334.2 250 ##STR00313##
4-(6-fluoro-2-(1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-
4-ylamino)- [1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 404.1
251 ##STR00314## 6-fluoro-N-(1-((1- methylpyrrolidin-3-
yl)methyl)-1H-pyrazol-4-yl)- 8-(4- (methylsulfonyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 470.1 252 ##STR00315##
methyl 4-(2-(1-((1- methylpyrrolidin-3- yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzoate 432.1 253
##STR00316## 4-(8-(3-(1- aminoethyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 374.1 254
##STR00317## 4-(8-(3-carbamoylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 373.8 255
##STR00318## (4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)methanol 334.8 256 ##STR00319##
4-(2-(1-((1-methylpyrrolidin- 3-yl)methyl)-1H-pyrazol-4-
ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzoic acid 418.1 257
##STR00320## 4-(8-(1-((tetrahydro-2H- pyran-4-yl)methyl)-1H-
pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic
acid 419.1 258 ##STR00321## 4-(8-(1-(2,2,2-
trifluoroethyl)-1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)benzoic acid 403.0 259 ##STR00322##
4-(8-(2-isopropylpyridin-4- yl)-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)benzoic acid 374.1 260 ##STR00323##
N-(4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,2-a]pyridin-
2-ylamino)phenyl)acetamide 383.8 261 ##STR00324##
N-(4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)methane- sulfonamide 398.0 262 ##STR00325##
1-(4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)phenyl)ethanol 348.8 263 ##STR00326##
5-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-3,3- dimethylindolin-2-one 388.3 264 ##STR00327## methyl
4-(8-(1- ((tetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 419.1 265
##STR00328## methyl 4-(8-(1-((3- methyloxetan-3-yl)methyl)-
1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate
419.1 266 ##STR00329## methyl 4-(8-(1-(oxetan-3-
yl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoate 391.1 267 ##STR00330##
4-(8-(1-((tetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 405.1 268
##STR00331## 4-(8-(1-((3-methyloxetan-3-
yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 405.1 269 ##STR00332##
4-(8-(1-(oxetan-3-yl)-1H- pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 377.1 270
##STR00333## N-(4-(8-(3-fluorophenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenylsulfonyl) acetamide
447.7 M + Na 271 ##STR00334## N-(4-(4H-1,2,4-triazol-3-
yl)phenyl)-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-amine 372.2 272 ##STR00335## methyl 6-(8-(3- isopropylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)nicotinate 388.1 273
##STR00336## methyl 5-(8-(3- isopropylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)picolinate 388.1 274
##STR00337## methyl 4-(8-(1- (cyclopropylmethyl)-1H- pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 389.1 275
##STR00338## methyl 4-(8-(1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-
4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2- ylamino)benzoate 419.1 276
##STR00339## 4-(8-(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-
yl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)benzoic acid 405.1
277 ##STR00340## 5-(8-(3-isopropylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)picolinic acid 374.1 278
##STR00341## 4-(8-(3- (methylcarbamoyl)phenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 388.1 279
##STR00342## N-(4-(1-aminoethyl)phenyl)- 8-(3-fluorophenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 331 M - NH.sub.2 280
##STR00343## methyl 4-(8-(6- methoxypyridin-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 376.1 281
##STR00344## 4-(8-(6-methoxypyridin-3- yl)-[1,2,4]triazolo[1,5-
a]pyridin-2-ylamino)benzoic acid 362.1 282 ##STR00345## methyl
4-(8-(3,5- dimethoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoate 405.1 283 ##STR00346## 4-(8-(3,5-
dimethoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic
acid 391.1 284 ##STR00347## 6-(8-(3-isopropylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)nicotinic acid 374.2 285
##STR00348## methyl 4-(8-(3-tert-butyl-5- methylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 415.1 286
##STR00349## methyl 4-(8-(3-chloro-5- methylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 393.0 287
##STR00350## 4-(8-(3-tert-butyl-5- methylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 379.0 288
##STR00351## 4-(8-(3-chloro-5- methylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 379.0 289
##STR00352## methyl 4-(8-(1-isopropyl- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 377.1 290
##STR00353## methyl 4-(8-(1-cyclohexyl- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 417.1 291
##STR00354## 4-(8-(1-isopropyl-1H- pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 363.1 292
##STR00355## 4-(8-(1-cyclohexyl-1H- pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 403.1 293
##STR00356## N-(1H-benzo[d]imidazol-5- yl)-8-(3-fluorophenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 344.8 294 ##STR00357##
4-(8-(3-chloro-5- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 395.0 295 ##STR00358## methyl
4-(8-(5-chloro-6- methoxypyridin-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 410.1 296
##STR00359## methyl 4-(8-(5-fluoro-6- methoxypyridin-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 394.1 297
##STR00360## 4-(8-(5-chloro-6- methoxypyridin-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 396.2 298
##STR00361## methyl 4-(8-(pyridin-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 346.4 299
##STR00362## 4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-3-methylbenzoic acid 375.1 300 ##STR00363##
4-(8-(5-fluoro-6- methoxypyridin-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 380.3 301
##STR00364## 4-(8-(pyridin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 332.3 302 ##STR00365##
5-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)-3,3- dimethylisoindolin-1-one 388.2 303 ##STR00366##
methyl 4-(8-(2-chloro-4- methoxyphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 409.1 304
##STR00367## methyl 4-(8-(4-methoxy-2- methylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 389.1 305
##STR00368## 4-(8-(2-chloro-4- methoxyphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 395.1 306
##STR00369## 4-(8-(4-methoxy-2- methylphenyl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 375.1 307
##STR00370## 4-(8-phenyl- [1,2,4]triazolo[1,5-a]pyridin-
2-ylamino)benzoic acid 331.1 308 ##STR00371## methyl 4-(8-(1-((2,2-
difluorocyclopropyl)methyl)- 1H-pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 425.1 309
##STR00372## 4-(8-(1-((2,2- difluorocyclopropyl)methyl)-
1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic
acid 411.1 310 ##STR00373## 4-(8-(1-(2- (dimethylamino)ethyl)-1H-
pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic
acid 392.1 311 ##STR00374## methyl 4-(8-(1-(2-
(dimethylamino)ethyl)-1H- pyrazol-4-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 406.2 312
##STR00375## 8-(3,4-difluorophenyl)-N- (oxetan-3-yl)-
[1,2,4]triazolo[1,5-a]pyridin- 2-amine 303.0
[0320] Although the invention has been described and illustrated
with a certain degree of particularity, it is understood that the
present disclosure has been made only by way of example, and that
numerous changes in the combination and arrangement of parts can be
resorted to by those skilled in the art without departing from the
spirit and scope of the invention, as defined by the claims.
* * * * *