U.S. patent application number 14/615873 was filed with the patent office on 2015-06-04 for pyrazolopyrimidine jak inhibitor compounds and methods.
This patent application is currently assigned to Genentech, Inc.. The applicant listed for this patent is Genentech, Inc.. Invention is credited to Paul Gibbons, Emily Hanan, Wendy Liu, Joseph P. Lyssikatos, Steven R. Magnuson, Rohan Mendonca, Richard Pastor, Thomas E. Rawson, Michael Siu, Mark E. Zak, Aihe Zhou, Bing-Yan Zhu.
Application Number | 20150152117 14/615873 |
Document ID | / |
Family ID | 43411778 |
Filed Date | 2015-06-04 |
United States Patent
Application |
20150152117 |
Kind Code |
A1 |
Gibbons; Paul ; et
al. |
June 4, 2015 |
PYRAZOLOPYRIMIDINE 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 and R.sup.3 are defined herein, are useful as inhibitors of
one or more Janus kinases. 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 a Janus kinase activity in a patient are disclosed.
##STR00001##
Inventors: |
Gibbons; Paul; (San
Francisco, CA) ; Hanan; Emily; (Redwood City, CA)
; Liu; Wendy; (Foster City, CA) ; Lyssikatos;
Joseph P.; (Piedmont, CA) ; Magnuson; Steven R.;
(Dublin, CA) ; Mendonca; Rohan; (Pleasanton,
CA) ; Pastor; Richard; (San Francisco, CA) ;
Rawson; Thomas E.; (Mountain View, CA) ; Siu;
Michael; (Burlingame, CA) ; Zak; Mark E.; (San
Mateo, CA) ; Zhou; Aihe; (San Jose, CA) ; Zhu;
Bing-Yan; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
43411778 |
Appl. No.: |
14/615873 |
Filed: |
February 6, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13382145 |
Apr 10, 2012 |
8999998 |
|
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PCT/US10/40906 |
Jul 2, 2010 |
|
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14615873 |
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61222918 |
Jul 2, 2009 |
|
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Current U.S.
Class: |
514/210.18 ;
514/210.21; 514/233.2; 514/252.16; 514/259.3; 544/117; 544/281 |
Current CPC
Class: |
A61K 31/519 20130101;
C07D 487/04 20130101; A61P 29/00 20180101; A61P 17/06 20180101;
A61P 35/02 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A compound of Formula I: ##STR00757## enantiomers, diastereomers
or pharmaceutically acceptable salts thereof, wherein: R.sup.1 is
hydrogen, C.sub.1-C.sub.6 alkyl, --OR.sup.6, --NR.sup.6R.sup.7 or
halogen; R.sup.2 is 5- or 6-membered heteroaryl, wherein R.sup.2 is
optionally substituted with 1-3 R.sup.4; R.sup.3 is phenyl, 5-6
membered heteroaryl, C.sub.3-C.sub.6 cycloalkyl or 3-10 membered
heterocyclyl, wherein R.sup.3 is optionally substituted by 1-5
R.sup.5; R.sup.4 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
--(C.sub.0-C.sub.6 alkyl)CN, --(C.sub.0-C.sub.6 alkyl)OR.sup.6,
--(C.sub.0-C.sub.6 alkyl)SR.sup.6, --(C.sub.0-C.sub.6
alkyl)NR.sup.6R.sup.7, --(C.sub.0-C.sub.6 alkyl)CF.sub.3,
--(C.sub.0-C.sub.6 alkyl)C(O)R.sup.6, --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.6 alkyl)NR.sup.6C(O)R.sup.7, --(C.sub.0-C.sub.6
alkyl)C(O)3-6 membered heterocyclyl, --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.6
alkyl)phenyl, --(C.sub.0-C.sub.6 alkyl)5-6 membered heteroaryl or
--(C.sub.0-C.sub.6 alkyl)(3-6-membered heterocyclyl), wherein
R.sup.4 is independently optionally substituted by R.sup.15;
R.sup.5 is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, oxo, halogen, --(C.sub.0-C.sub.3
alkyl)CN, --(C.sub.0-C.sub.3 alkyl)OR.sup.11, --(C.sub.0-C.sub.3
alkyl)SR.sup.11, --(C.sub.0-C.sub.3 alkyl)NR.sup.11R.sup.12,
--(C.sub.0-C.sub.3 alkyl)OCF.sub.3, --(C.sub.0-C.sub.3
alkyl)CF.sub.3, --(C.sub.0-C.sub.3 alkyl)NO.sub.2,
--(C.sub.0-C.sub.3 alkyl)C(O)R.sup.11, --(C.sub.0-C.sub.3
alkyl)C(O)OR.sup.11, --(C.sub.0-C.sub.3
alkyl)C(O)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)NR.sup.11C(O)R.sup.12, --(C.sub.0-C.sub.3
alkyl)S(O).sub.1-2R.sup.11, --(C.sub.0-C.sub.3
alkyl)NR.sup.11S(O).sub.1-2R.sup.12, --(C.sub.0-C.sub.3
alkyl)S(O).sub.1-2NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.3
alkyl)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)C(O)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)(5-6-membered heteroaryl) or --(C.sub.0-C.sub.3 alkyl)phenyl,
wherein R.sup.5 is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --CF.sub.3, --(C.sub.0-C.sub.3
alkyl)OR.sup.13 or --(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14; or
two R.sup.5 are taken together to form --O(CH.sub.2).sub.1-3O--;
R.sup.6 and R.sup.7 are independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)OR.sup.8,
--C(O)NR.sup.8R.sup.9, --NR.sup.8C(O)R.sup.9,
--NR.sup.8C(O)OR.sup.9, --OC(O)NR.sup.8, --S(O).sub.1-2R.sup.8,
--NR.sup.8S(O).sub.1-2R.sup.9, --S(O).sub.1-2NR.sup.8R.sup.9,
C.sub.3-C.sub.6 cycloalkyl, phenyl, 3-6 membered heterocyclyl or
5-6 membered heteroaryl, wherein said R.sup.6 and R.sup.7 are
independently optionally substituted by R.sup.20, or R.sup.6 and
R.sup.7 are taken together with the atom to which they are attached
to form a 3-6-membered heterocyclyl, optionally substituted by
halogen, oxo, --CF.sub.3 or C.sub.1-C.sub.3 alkyl; R.sup.8 and
R.sup.9 are independently hydrogen or C.sub.1-C.sub.3 alkyl; or
R.sup.8 and R.sup.9 are taken together with the atom to which they
are attached to form a 3-6-membered heterocyclyl, optionally
substituted by halogen, oxo, --CF.sub.3 or C.sub.1-C.sub.3 alkyl;
R.sup.11 is independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, 3-6 membered heterocyclyl,
--C(O)R.sup.13, --C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
NR.sup.13C(O)R.sup.14, S(O).sub.1-2R.sup.13,
--NR.sup.13S(O).sub.1-2R.sup.14 or --S(O).sub.1-2NR.sup.13R.sup.14,
wherein said alkyl, cycloalkyl and heterocyclyl are independently
optionally substituted by oxo, C.sub.1-C.sub.3 alkyl, OR.sup.13,
NR.sup.13R.sup.14 or halogen; R.sup.12 is independently hydrogen or
C.sub.1-C.sub.3 alkyl, wherein said alkyl is independently
optionally substituted by halogen or oxo; or R.sup.11 and R.sup.12
are taken together with the atom to which they are attached to form
a 3-6-membered heterocyclyl, optionally substituted by halogen,
oxo, --CF.sub.3 or C.sub.1-C.sub.3 alkyl; R.sup.13 and R.sup.14 are
independently hydrogen or C.sub.1-C.sub.3 alkyl optionally
substituted by halogen or oxo; or R.sup.13 and R.sup.14 are taken
together with the atom to which they are attached to form a
3-6-membered heterocyclyl, optionally substituted by halogen, oxo,
--CF.sub.3 or C.sub.1-C.sub.3 alkyl; R.sup.15 is C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, oxo,
halogen, --CN, --OR.sup.16, --SR.sup.16, --NR.sup.16R.sup.17,
--OCF.sub.3, --CF.sub.3, --C(O)R.sup.16, --C(O)OR.sup.16,
--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)R.sup.17,
--NR.sup.16C(O)OR.sup.17, --OC(O)NR.sup.16, C.sub.3-C.sub.6
cycloalkyl, 3-6-membered heterocyclyl, --C(O)(3-6-membered
heterocyclyl, 5-6-membered heteroaryl or phenyl, wherein R.sup.15
is independently optionally substituted by halogen, C.sub.1-C.sub.3
alkyl, oxo, --CN, --CF.sub.3, --OR.sup.18, --NR.sup.18R.sup.19;
R.sup.16 and R.sup.17 are independently hydrogen or C.sub.1-C.sub.6
alkyl optionally substituted by oxo or halogen; or R.sup.16 and
R.sup.17 are taken together with the atom to which they are
attached to form a 3-6 membered heterocyclyl optionally substituted
by oxo, halogen or C.sub.1-C.sub.3 alkyl; R.sup.18 and R.sup.19 are
independently hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo or halogen; or R.sup.18 and R.sup.19 are taken
together with the atom to which they are attached to form a 3-6
membered heterocyclyl optionally substituted by oxo, halogen or
C.sub.1-C.sub.3 alkyl; R.sup.20 is C.sub.1-C.sub.6 alkyl, oxo,
halogen, --OR.sup.21, --NR.sup.21R.sup.22, --CN, C.sub.3-C.sub.6
cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered
heteroaryl, wherein R.sup.20 is optionally substituted by oxo,
halogen or C.sub.1-C.sub.3 alkyl; and R.sup.20 and R.sup.21 are
independently hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo or halogen; or R.sup.20 and R.sup.21 are taken
together with the atom to which they are attached to form a 3-6
membered heterocyclyl optionally substituted by oxo, halogen or
C.sub.1-C.sub.3 alkyl. with the proviso that said compound is other
than
N-(5-methyl-4-(4-propylphenyl)thiazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide;
N-(4-(4-chlorophenyl)thiazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide; or
N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide.
2. The compound of claim 1, wherein R.sup.1 is hydrogen or
--NH.sub.2.
3. The compound of claim 1, wherein R.sup.2 is selected from
pyrazolyl or thiazolyl optionally substituted with 1-3 R.sup.4.
4. The compound of claim 1, wherein R.sup.2 is: ##STR00758##
wherein R.sup.10 is hydrogen or R.sup.4.
5. The compound of claim 1, wherein R.sup.4 is independently
--(C.sub.0-C.sub.6 alkyl)OR.sup.6, --(C.sub.0-C.sub.6
alkyl)SR.sup.6, halogen, --(C.sub.0-C.sub.6 alkyl)CN,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6
alkynyl, --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.6, --(C.sub.0-C.sub.6
alkyl)C(O)NR.sup.6NR.sup.7, --(C.sub.0-C.sub.6 alkyl)OC(O)NR.sup.6,
--(C.sub.0-C.sub.6 alkyl)NR.sup.6C(O)OR.sup.7, --(C.sub.0-C.sub.6
alkyl)NR.sup.6C(O)NR.sup.7 or --(C.sub.0-C.sub.6
alkyl)NR.sup.6C(O)R.sup.7, --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.6
alkyl)C(O)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.6
alkyl)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.6
alkyl)NR.sup.6R.sup.7 or --(C.sub.0-C.sub.6 alkyl)CF.sub.3, wherein
R.sup.4 is independently optionally substituted by R.sup.15.
6. The compound of claim 5, wherein R.sup.4 is independently
selected from: F, Cl, Br, I, --CH.sub.2CN, --CH.sub.2CH.sub.2CN,
--CH(CH.sub.3)CN, ##STR00759## ##STR00760## ##STR00761##
##STR00762## ##STR00763## ##STR00764## ##STR00765## ##STR00766##
##STR00767## ##STR00768## wherein the wavy line represents the
point of attachment to R.sup.2.
7. The compound of claim 1, wherein R.sup.3 is phenyl, pyridinyl or
4-6 membered hererocyclyl, wherein R.sup.3 is optionally
substituted by R.sup.5.
8. The compound of claim 1, wherein R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, oxo, --CN, --(C.sub.0-C.sub.3
alkyl)OR.sup.11, --(C.sub.0-C.sub.3 alkyl)SR.sup.11,
--(C.sub.0-C.sub.3 alkyl)NR.sup.11R.sup.12, (C.sub.0-C.sub.3
alkyl)OCF.sub.3 or --CF.sub.3, wherein said alkyl is independently
optionally substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo,
--CF.sub.3, --(C.sub.0-C.sub.3 alkyl)OR.sup.13 or
--(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14.
9. The compound of claim 7, wherein R.sup.3 is selected from:
##STR00769## ##STR00770## ##STR00771## wherein the wavy line
represents the point of attachment to R.sup.2.
10. The compound of claim 1, wherein R.sup.3 is phenyl optionally
substituted by 1-2 R.sup.5.
11. The compound of claim 1, wherein --R.sup.2-R.sup.3 is:
##STR00772## wherein n is 0, 1, 2 or 3.
12. A compound of claim 1, enantiomers, diastereomers or
pharmaceutically acceptable salts thereof, wherein: R.sup.1 is
hydrogen, C.sub.1-C.sub.6 alkyl, --OR.sup.6, --NR.sup.6R.sup.7 or
halogen; R.sup.2 is 5- or 6-membered heteroaryl, wherein R.sup.2 is
optionally substituted with 1-3 R.sup.4; R.sup.3 is phenyl, 5- or
6-membered heteroaryl, wherein R.sup.3 is optionally substituted by
1-5 R.sup.5; R.sup.4 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
--(C.sub.0-C.sub.6 alkyl)OR.sup.6, --(C.sub.0-C.sub.6
alkyl)SR.sup.6, --(C.sub.0-C.sub.6 alkyl)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.6 alkyl)CF.sub.3, --(C.sub.0-C.sub.6
alkyl)C(O)R.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.6,
--(C.sub.0-C.sub.6alkyl)C(O)NR.sup.6R.sup.7, --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl) or --(C.sub.0-C.sub.6
alkyl)(3-6-membered heterocyclyl), wherein R.sup.4 is independently
optionally substituted by C.sub.1-C.sub.3 alkyl, oxo, halogen,
--CF.sub.3, --OR.sup.8 or --NR.sup.8R.sup.9; R.sup.5 is
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, halogen, --(C.sub.0-C.sub.3 alkyl)CN,
--(C.sub.0-C.sub.3 alkyl)OR.sup.11, --(C.sub.0-C.sub.3
alkyl)SR.sup.11, --(C.sub.0-C.sub.3 alkyl)NR.sup.11R.sup.12,
--(C.sub.0-C.sub.3 alkyl)OCF.sub.3, --(C.sub.0-C.sub.3
alkyl)CF.sub.3, --(C.sub.0-C.sub.3 alkyl)NO.sub.2,
--(C.sub.0-C.sub.3 alkyl)C(O)R.sup.11, --(C.sub.0-C.sub.3
alkyl)C(O)OR.sup.11, --(C.sub.0-C.sub.3
alkyl)C(O)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)NR.sup.11C(O)R.sup.12, --(C.sub.0-C.sub.3
alkyl)S(O).sub.1-2R.sup.11, --(C.sub.0-C.sub.3
alkyl)NR.sup.11S(O).sub.1-2R.sup.12, --(C.sub.0-C.sub.3
alkyl)S(O).sub.1-2NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.3
alkyl)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)C(O)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)(5-6-membered heteroaryl) or --(C.sub.0-C.sub.3 alkyl)phenyl,
wherein R.sup.5 is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --CF.sub.3, --(C.sub.0-C.sub.3
alkyl)OR.sup.13 or --(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14; or
two R.sup.5 are taken together to form --O(CH.sub.2).sub.1-3O--;
R.sup.6 is independently hydrogen, C.sub.1-C.sub.3 alkyl,
--C(O)R.sup.8, --C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9,
--NR.sup.8C(O)R.sup.9, --S(O).sub.1-2R.sup.8,
--NR.sup.8S(O).sub.1-2R.sup.9 or --S(O).sub.1-2NR.sup.8R.sup.9,
wherein said alkyl is independently optionally substituted by oxo,
OH or halogen; R.sup.7 is independently hydrogen or C.sub.1-C.sub.3
alkyl, wherein said alkyl is independently optionally substituted
by halogen; or R.sup.6 and R.sup.7 are taken together with the atom
to which they are attached to form a 5- or 6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl; R.sup.8 and R.sup.9 are independently
hydrogen or C.sub.1-C.sub.3 alkyl; or R.sup.8 and R.sup.9 are taken
together with the atom to which they are attached to form a 5- or
6-membered heterocyclyl, optionally substituted by halogen, oxo,
--CF.sub.3 or C.sub.1-C.sub.3 alkyl; R.sup.11 is independently
hydrogen, C.sub.1-C.sub.3 alkyl, --C(O)R.sup.13, --C(O)OR.sup.13,
--C(O)NR.sup.13R.sup.14, --NR.sup.13C(O)R.sup.14,
--S(O).sub.1-2R.sup.13, --NR.sup.13S(O).sub.1-2R.sup.14 or
--S(O).sub.1-2NR.sup.13R.sup.14, wherein said alkyl is
independently optionally substituted by oxo, OH or halogen;
R.sup.12 is independently hydrogen or C.sub.1-C.sub.3 alkyl,
wherein said alkyl is independently optionally substituted by
halogen; or R.sup.11 and R.sup.12 are taken together with the atom
to which they are attached to form a 5- or 6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl; and R.sup.13 and R.sup.14 are independently
hydrogen or C.sub.1-C.sub.3 alkyl; or R.sup.13 and R.sup.14 are
taken together with the atom to which they are attached to form a
5- or 6-membered heterocyclyl, optionally substituted by halogen,
oxo, --CF.sub.3 or C.sub.1-C.sub.3 alkyl; with the proviso that
said compound is other than
N-(5-methyl-4-(4-propylphenyl)thiazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide;
N-(4-(4-chlorophenyl)thiazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide; or
N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide.
13. The compound of claim 1, selected from Examples 1-508.
14. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier, adjuvant or vehicle.
15. A method of preventing, treating or lessening the severity of a
disease or condition responsive to the inhibition of a Janus kinase
activity in a patient, comprising administering to said patient a
therapeutically effective amount of a compound of claim 1.
16. The method of claim 15, wherein said disease or condition is
cancer, polycythemia vera, essential thrombocytosis, myelofibrosis,
chronic myelogenous leukemia (CML), rheumatoid arthritis,
inflammatory bowel syndrome, Chron's disease, psoriasis, contact
dermatitis or delayed hypersensitivity reactions.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/382,145, filed Apr. 10, 2012, which is a national stage
entry of International Application No. PCT/US2010/040906, filed
Jul. 2, 2010, which claims the benefit of U.S. Provisional
Application Ser. No. 61/222,918, filed Jul. 2, 2009, each of which
is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] Pyrazolopyrimidine compounds of Formula I, which are
inhibitors of one or more Janus kinases, 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
[0003] Cytokine pathways mediate a broad range of biological
functions, including many aspects of inflammation and immunity.
Janus kinases (JAK), including JAK1, JAK2, JAK3 and TYK2 are
cytoplasmic protein kinases that associate with type I and type II
cytokine receptors and regulate cytokine signal transduction.
Cytokine engagement with cognate receptors triggers activation of
receptor associated JAKs and this leads to JAK-mediated tyrosine
phosphorylation of signal transducer and activator of transcription
(STAT) proteins and ultimately transcriptional activation of
specific gene sets (Schindler et al., 2007, J Biol. Chem. 282:
20059-63). JAK1, JAK2 and TYK2 exhibit broad patterns of gene
expression, while JAK3 expression is limited to leukocytes.
Cytokine receptors are typically functional as heterodimers, and as
a result, more than one type of JAK kinase is usually associated
with cytokine receptor complexes. The specific JAKs associated with
different cytokine receptor complexes have been determined in many
cases through genetic studies and corroborated by other
experimental evidence.
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).
[0004] Biochemical and genetic studies have shown an association
between JAK2 and single-chain (e.g., EPO), IL-3 and interferon
gamma cytokine receptor families (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). Consistent
with this, JAK2 knockout mice die of anemia (O'Shea et al., 2002,
Cell, 109 (suppl.): S121-S131). Kinase activating mutations in JAK2
(e.g., JAK2 V617F) are associated with myeloproliferative disorders
(MPDs) in humans.
[0005] 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).
[0006] 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
[0007] One embodiment includes a compound of Formula I:
##STR00002##
[0008] enantiomers, diasteriomers, tautomers or pharmaceutically
acceptable salts thereof, wherein R.sup.1, R.sup.2 and R.sup.3 are
defined herein.
[0009] Another embodiment includes a pharmaceutical composition
that includes a compound of Formula I and a pharmaceutically
acceptable carrier, adjuvant or vehicle.
[0010] 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.
[0011] Another embodiment includes the use of a compound of Formula
I for therapy.
[0012] Another embodiment includes the use of a compound of Formula
I for preventing, treating or lessening the severity of a disease.
In one embodiment, the disease is an autoimmune disease.
[0013] Another embodiment includes the use of a compound of Formula
I in the manufacture of a medicament for preventing, treating or
lessening the severity of a disease. In one embodiment, the disease
is an autoimmune disease.
[0014] Another embodiment includes a kit for treating a disease or
disorder responsive to the inhibition of a Janus kinase. The kit
includes a first pharmaceutical composition comprising a compound
of Formula I and instructions for use.
DETAILED DESCRIPTION OF THE INVENTION
[0015] 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, 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 methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention.
DEFINITIONS
[0016] 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. C.sub.0 alkyl
refers to a bond. Examples of alkyl groups include 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 (i-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.
[0017] Groups of the type (C.sub.0-C.sub.n alkyl)R, includes alkyl
groups substituted by the R group at any of the atoms in the group
available for substitution (in an exemplary embodiment, n is a
number from 1-6 and R is --OH, --OCH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, --CN, halogen, C.sub.3-C.sub.6 cycloalkyl,
phenyl or 3- to 9-membered heterocyclyl), For example, the group
(C.sub.0-C.sub.3 alkyl)CN includes the groups --CN, --CH.sub.2CN,
--CH.sub.2CH.sub.2CN, --CH(CN)CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CN, --CH(CN)CH.sub.2CH.sub.3,
--CH.sub.2CH(CN)CH.sub.3, --C(CH.sub.3).sub.2CN,
--C(CH.sub.2CN)CH.sub.3. For example, the group (C.sub.0-C.sub.2
alkyl)C.sub.3 cycloalkyl includes the groups:
##STR00003##
[0018] 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 and
hexa-1,3-dienyl.
[0019] 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.
[0020] "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.8, 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.8, 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.
[0021] "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 includes bicyclic groups 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 and
1,2,3,4-tetrahydronapthyl. In one example, aryl includes
phenyl.
[0022] "Halogen" or "halogen" refer to F, Cl, Br or I.
[0023] The terms "heterocycle," "heterocyclyl" and "heterocyclic
ring" are used interchangeably herein and refer to: (i) a saturated
or partially unsaturated cyclic group (i.e., having one or more
double and/or triple bonds within the ring) ("heterocycloalkyl"),
or (ii) an aromatic cyclic group ("heteroaryl"), and in each case,
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) with the remaining ring
atoms being heteroatoms selected from N, O, S and P. 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, with the
remaining ring atoms being heteroatoms selected from N, O, S and P.
In another embodiment, heterocyclyl includes 3-7-membered rings or
3-6 membered rings, containing one or more heteroatoms
independently selected from N, O, S and P. In other examples,
heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered
rings, containing one or more heteroatoms independently selected
from N, O, S and P. In another embodiment, heterocyclyl includes
bi- or polycyclic or bridged 4-, 5-, 6-, 7-, 8- and 9-membered ring
systems, containing one or more heteroatoms independently selected
from N, O, S and P. 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. Examples of bridged ring systems include, but are not
limited to [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 4
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.
[0024] 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,
oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl,
thiazepanyl, 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, 3,6-diazabicyclo[3.1.1]heptanyl,
6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl,
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 dihydropyridinonyl, pyridinonyl, piperidinonyl,
pyrrolidinonyl, pyrimidinonyl, dihydropyrimidinonyl, piperazinonyl,
pyrazinonyl, pyridazinonyl, dihydropyridazinonyl,
dihydropyrrolonyl, pyrrolonyl, oxazolidinonyl, thiazolidinonyl,
imidazolidinonyl, 1-oxothienyl, 1,1-dioxothienyl,
1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl 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,
N.Y., 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.
[0025] 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.4-C.sub.5. 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 up to 9 carbon atoms wherein at least one
aromatic ring contains one or more heteroatoms independently
selected from nitrogen, oxygen, and sulfur. Fused systems can be
fused at one or more points on the rings. "Heteroaryl" includes
heteroaryl groups fused with an aryl, cycloalkyl or other
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, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl and furopyridinyl.
[0026] 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).
[0027] 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.
[0028] "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.
[0029] 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).
[0030] 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.
[0031] "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. "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.
[0032] "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.
[0033] 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.
[0034] "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.
[0035] "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.
[0036] "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.
[0037] 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 A2). 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.
[0038] 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.
[0039] A "chemotherapeutic agent" is a chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include Erlotinib (TARCEVA.RTM., Genentech, IncJOSI 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 Gefitinib
(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 CBI-TMI); 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, carminomycin,
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, zomibicin;
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; elfornithine; 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;
sizofiran; 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.
[0040] 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.
[0041] Humanized monoclonal antibodies with therapeutic potential
as agents in combination with the Janus kinase inhibitors of the
invention include: adalimumab, etanercept, infliximab, 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, 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.
[0042] 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.
[0043] "Liposome" refers to a vesicle composed of one or more
lipids, phospholipids and/or surfactants, 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 can be in a bilayer formation, similar to the lipid
arrangement of biological membranes.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] "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.
[0048] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] The terms "JAK kinase," and "Janus kinase" refer to the
JAK1, JAK2, JAK3 and TYK2 protein kinases.
[0056] 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, formulas 1a-1n
and stereoisomers, tautomers, solvates, metabolites, salts (e.g.,
pharmaceutically acceptable salts) and prodrugs thereof. Unless
otherwise stated, strictures 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
and formulas 1a-1n, 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.
[0057] Pyrazolopyrimidine Janus Kinase Inhibitor Compounds
[0058] 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 one or more Janus kinases.
[0059] Another embodiment includes compounds of Formula I:
##STR00004##
[0060] enantiomers, diastereomers or pharmaceutically acceptable
salts thereof, wherein:
[0061] R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl, --OR.sup.6,
--NR.sup.6R.sup.7 or halogen;
[0062] R.sup.2 is 5- or 6-membered heteroaryl, wherein R.sup.2 is
optionally substituted with 1-3 R.sup.4;
[0063] R.sup.3 is phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.6
cycloalkyl or 3-10 membered heterocyclyl, wherein R.sup.3 is
optionally substituted by 1-5 R.sup.5;
[0064] R.sup.4 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
--(C.sub.0-C.sub.6 alkyl)CN, --(C.sub.0-C.sub.6 alkyl)OR.sup.6,
--(C.sub.0-C.sub.6 alkyl)SR.sup.6, --(C.sub.0-C.sub.6
alkyl)NR.sup.6R.sup.7, --(C.sub.0-C.sub.6 alkyl)CF.sub.3,
--(C.sub.0-C.sub.6 alkyl)C(O)R.sup.6, --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.6 alkyl)NR.sup.6C(O)R.sup.7, --(C.sub.0-C.sub.6
alkyl)C(O)3-6 membered heterocyclyl, --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.6
alkyl)phenyl, --(C.sub.0-C.sub.6 alkyl)5-6 membered heteroaryl or
--(C.sub.0-C.sub.6 alkyl)(3-6-membered heterocyclyl), wherein
R.sup.4 is independently optionally substituted by R.sup.15;
[0065] R.sup.5 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, oxo, halogen,
--(C.sub.0-C.sub.3 alkyl)CN, --(C.sub.0-C.sub.3 alkyl)OR.sup.11,
--(C.sub.0-C.sub.3 alkyl)SR.sup.11, --(C.sub.0-C.sub.3
alkyl)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3 alkyl)OCF.sub.3,
--(C.sub.0-C.sub.3 alkyl)CF.sub.3, --(C.sub.0-C.sub.3
alkyl)NO.sub.2, --(C.sub.0-C.sub.3 alkyl)C(O)R.sup.11,
--(C.sub.0-C.sub.3 alkyl)C(O)OR.sup.11, --(C.sub.0-C.sub.3
alkyl)C(O)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)NR.sup.11C(O)R.sup.12, --(C.sub.0-C.sub.3 alkyl)
S(O).sub.1-2R.sup.11, --(C.sub.0-C.sub.3
alkyl)NR.sup.11S(O).sub.1-2R.sup.12, --(C.sub.0-C.sub.3
alkyl)S(O).sub.1-2NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.3
alkyl)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)C(O)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)(5-6-membered heteroaryl) or --(C.sub.0-C.sub.3 alkyl)phenyl,
wherein R.sup.5 is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --CF.sub.3, --(C.sub.0-C.sub.3
alkyl)OR.sup.13 or --(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14;
or
[0066] two R.sup.5 are taken together to form
--O(CH.sub.2).sub.1-3O--;
[0067] R.sup.6 and R.sup.7 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, --CN, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8,
--C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9, --NR.sup.8C(O)R.sup.9,
--NR.sup.8C(O)OR.sup.9, --OC(O)NR.sup.8, --S(O).sub.1-2R.sup.8,
--NR.sup.8S(O).sub.1-2R.sup.9, --S(O).sub.1-2NR.sup.8R.sup.9,
C.sub.3-C.sub.6 cycloalkyl, phenyl, 3-6 membered heterocyclyl or
5-6 membered heteroaryl, wherein said R.sup.6 and R.sup.7 are
independently optionally substituted by R.sup.20, or
[0068] R.sup.6 and R.sup.7 are taken together with the atom to
which they are attached to form a 3-6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl;
[0069] R.sup.8 and R.sup.9 are independently hydrogen or
C.sub.1-C.sub.3 alkyl; or
[0070] R.sup.8 and R.sup.9 are taken together with the atom to
which they are attached to form a 3-6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl;
[0071] R.sup.11 is independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, 3-6 membered heterocyclyl,
--C(O)R.sup.13, --C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--NR.sup.13C(O)R.sup.14, --S(O).sub.1-2R.sup.13,
--NR.sup.13S(O).sub.1-2R.sup.14 or --S(O).sub.1-2NR.sup.13R.sup.14,
wherein said alkyl, cycloalkyl and heterocyclyl are independently
optionally substituted by oxo, C.sub.1-C.sub.3 alkyl, OR.sup.13,
NR.sup.13R.sup.14 or halogen;
[0072] R.sup.12 is independently hydrogen or C.sub.1-C.sub.3 alkyl,
wherein said alkyl is independently optionally substituted by
halogen or oxo; or
[0073] R.sup.11 and R.sup.12 are taken together with the atom to
which they are attached to form a 3-6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl;
[0074] R.sup.13 and R.sup.14 are independently hydrogen or
C.sub.1-C.sub.3 alkyl optionally substituted by halogen or oxo;
or
[0075] R.sup.13 and R.sup.14 are taken together with the atom to
which they are attached to form a 3-6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl;
[0076] R.sup.15 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, oxo, halogen, --CN, OR.sup.16,
--SR.sup.16, --NR.sup.16R.sup.17, --OCF.sub.3, --CF.sub.3,
--C(O)R.sup.16, --C(O)OR.sup.16, --C(O)NR.sup.16R.sup.17,
--NR.sup.16C(O)R.sup.17, --NR.sup.16C(O)OR.sup.17,
--OC(O)NR.sup.16, C.sub.3-C.sub.6 cycloalkyl, 3-6-membered
heterocyclyl, --C(O)(3-6-membered heterocyclyl, 5-6-membered
heteroaryl or phenyl, wherein R.sup.15 is independently optionally
substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo, --CN,
--CF.sub.3, OR.sup.18, --NR.sup.18R.sup.19;
[0077] R.sup.16 and R.sup.17 are independently hydrogen or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo or halogen;
or
[0078] R.sup.16 and R.sup.17 are taken together with the atom to
which they are attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, halogen or C.sub.1-C.sub.3
alkyl;
[0079] R.sup.18 and R.sup.19 are independently hydrogen or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo or halogen;
or
[0080] R.sup.18 and R.sup.19 are taken together with the atom to
which they are attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, halogen or C.sub.1-C.sub.3 alkyl;
R.sup.20 is C.sub.1-C.sub.6 alkyl, oxo, halogen, --OR.sup.21,
--NR.sup.21R.sup.22, --CN, C.sub.3-C.sub.6 cycloalkyl, phenyl, 3-6
membered heterocyclyl or 5-6 membered heteroaryl, wherein R.sup.20
is optionally substituted by oxo, halogen or C.sub.1-C.sub.3 alkyl;
and
[0081] R.sup.20 and R.sup.21 are independently hydrogen or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo or halogen;
or
[0082] R.sup.20 and R.sup.21 are taken together with the atom to
which they are attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, halogen or C.sub.1-C.sub.3
alkyl.
[0083] Another embodiment includes compounds of Formula I:
##STR00005##
[0084] enantiomers, diastereomers or pharmaceutically acceptable
salts thereof, wherein:
[0085] R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl, --OR.sup.6,
--NR.sup.6R.sup.7 or halogen;
[0086] R.sup.2 is 5- or 6-membered heteroaryl, wherein R.sup.2 is
optionally substituted with 1-3 R.sup.4;
[0087] R.sup.3 is phenyl, 5- or 6-membered heteroaryl, wherein
R.sup.3 is optionally substituted by 1-5 R.sup.5;
[0088] R.sup.4 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
--(C.sub.0-C.sub.6 alkyl)OR.sup.6, --(C.sub.0-C.sub.6
alkyl)SR.sup.6, --(C.sub.0-C.sub.6 alkyl)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.6 alkyl)CF.sub.3, --(C.sub.0-C.sub.6
alkyl)C(O)R.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.6,
--(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.6R.sup.7, --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl) or --(C.sub.0-C.sub.6
alkyl)(3-6-membered heterocyclyl), wherein R.sup.4 is independently
optionally substituted by C.sub.1-C.sub.3 alkyl, oxo, halogen,
--CF.sub.3, --OR.sup.8 or --NR.sup.8R.sup.9;
[0089] R.sup.5 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
--(C.sub.0-C.sub.3 alkyl)CN, --(C.sub.0-C.sub.3 alkyl)OR.sup.11,
--(C.sub.0-C.sub.3 alkyl)SR.sup.11, --(C.sub.0-C.sub.3
alkyl)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3 alkyl)OCF.sub.3,
--(C.sub.0-C.sub.3 alkyl)CF.sub.3, --(C.sub.0-C.sub.3
alkyl)NO.sub.2, --(C.sub.0-C.sub.3 alkyl)C(O)R.sup.11,
--(C.sub.0-C.sub.3 alkyl)C(O)OR.sup.11, --(C.sub.0-C.sub.3
alkyl)C(O)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)NR.sup.11C(O)R.sup.12, --(C.sub.0-C.sub.3 alkyl)
S(O).sub.1-2R.sup.11, --(C.sub.0-C.sub.3
alkyl)NR.sup.11S(O).sub.1-2R.sup.12, --(C.sub.0-C.sub.3
alkyl)S(O).sub.1-2NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.3
alkyl)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)C(O)(3-6-membered heterocyclyl), --(C.sub.0-C.sub.3
alkyl)(5-6-membered heteroaryl) or --(C.sub.0-C.sub.3 alkyl)phenyl,
wherein R.sup.5 is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --CF.sub.3, --(C.sub.0-C.sub.3
alkyl)OR.sup.13 or --(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14;
or
[0090] two R.sup.5 are taken together to form
--O(CH.sub.2).sub.1-3O--;
[0091] R.sup.6 is independently hydrogen, C.sub.1-C.sub.3 alkyl,
--C(O)R.sup.8, --C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9,
--NR.sup.8C(O)R.sup.9, --S(O).sub.1-2R.sup.8,
--NR.sup.8S(O).sub.1-2R.sup.9 or --S(O).sub.1-2NR.sup.8R.sup.9,
wherein said alkyl is independently optionally substituted by oxo,
OH or halogen;
[0092] R.sup.7 is independently hydrogen or C.sub.1-C.sub.3 alkyl,
wherein said alkyl is independently optionally substituted by
halogen; or
[0093] R.sup.6 and R.sup.7 are taken together with the atom to
which they are attached to form a 5- or 6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl;
[0094] R.sup.8 and R.sup.9 are independently hydrogen or
C.sub.1-C.sub.3 alkyl; or
[0095] R.sup.8 and R.sup.9 are taken together with the atom to
which they are attached to form a 5- or 6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl;
[0096] R.sup.11 is independently hydrogen, C.sub.1-C.sub.3 alkyl,
--C(O)R.sup.13, --C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--NR.sup.13C(O)R.sup.14, --S(O).sub.1-2R.sup.13,
--NR.sup.13S(O).sub.1-2R.sup.14 or --S(O).sub.1-2NR.sup.13R.sup.14,
wherein said alkyl is independently optionally substituted by oxo,
OH or halogen;
[0097] R.sup.12 is independently hydrogen or C.sub.1-C.sub.3 alkyl,
wherein said alkyl is independently optionally substituted by
halogen; or
[0098] R.sup.11 and R.sup.12 are taken together with the atom to
which they are attached to form a 5- or 6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl; and
[0099] R.sup.13 and R.sup.14 are independently hydrogen or
C.sub.1-C.sub.3 alkyl; or
[0100] R.sup.13 and R.sup.14 are taken together with the atom to
which they are attached to form a 5- or 6-membered heterocyclyl,
optionally substituted by halogen, oxo, --CF.sub.3 or
C.sub.1-C.sub.3 alkyl.
[0101] Another embodiment includes compounds of Formula I other
than: [0102]
N-(5-methyl-4-(4-propylphenyl)thiazol-2-yl)pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide; [0103]
N-(4-(4-chlorophenyl)thiazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide-
; or [0104]
N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide.
[0105] In certain embodiments, R.sup.2 is selected from pyridinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,
triazolyl, thiadiazolyl or furazanyl, and wherein R.sup.2 is
optionally substituted with 1-3 R.sup.4. In one embodiment, R.sup.2
is selected from pyridinyl or pyrazolyl, optionally substituted
with 1-3 R.sup.4.
[0106] In certain embodiments, R.sup.2 is selected from thiazolyl,
pyridinyl or pyrazolyl, optionally substituted with 1-3
R.sup.4.
[0107] In certain embodiments, R.sup.4 is independently
C.sub.1-C.sub.6 alkyl, --(C.sub.0-C.sub.6 alkyl)OR.sup.6,
--(C.sub.0-C.sub.6 alkyl)SR.sup.6, --(C.sub.0-C.sub.6
alkyl)NR.sup.6R.sup.7, --(C.sub.0-C.sub.6 alkyl)CF.sub.3,
--(C.sub.0-C.sub.6 alkyl)C(O)R.sup.6, --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.6 alkyl)(C.sub.3-C.sub.6 cycloalkyl) or
--(C.sub.0-C.sub.6 alkyl)(3-6-membered heterocyclyl), wherein
R.sup.4 is independently optionally substituted by C.sub.1-C.sub.3
alkyl, oxo, halogen, --CF.sub.3, --OR.sup.8 or
--NR.sup.8R.sup.9.
[0108] In certain embodiments, R.sup.4 is C.sub.1-C.sub.6 alkyl,
halogen, --(C.sub.0-C.sub.6 alkyl)CN, --(C.sub.0-C.sub.6
alkyl)OR.sup.6, --(C.sub.0-C.sub.6 alkyl)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.6 alkyl)CF.sub.3, --(C.sub.0-C.sub.6
alkyl)C(O)R.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.6,
--(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.6R.sup.7, --(C.sub.0-C.sub.6
alkyl)NR.sup.6C(O)R.sup.7, --(C.sub.0-C.sub.6 alkyl)C(O)3-6
membered heterocyclyl, --(C.sub.0-C.sub.6 alkyl)(C.sub.3-C.sub.6
cycloalkyl), --(C.sub.0-C.sub.6 alkyl)phenyl, --(C.sub.0-C.sub.6
alkyl)5-6 membered heteroaryl or --(C.sub.0-C.sub.6
alkyl)(3-6-membered heterocyclyl), wherein R.sup.4 is independently
optionally substituted by R.sup.15.
[0109] In certain embodiments, R.sup.3 is phenyl, pyridinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,
triazolyl, thiadiazolyl or furazanyl, and wherein R.sup.3 is
optionally substituted by 1-5 R.sup.5. In one embodiment, R.sup.3
is phenyl, optionally substituted by 1-3 R.sup.5.
[0110] In certain embodiments, R.sup.3 is phenyl, pyridinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,
triazolyl, thiadiazolyl, cyclohexenyl, dihydrobenzofuranyl,
piperidinyl, pyridinonyl, pyrrolidinyl or furazanyl, and wherein
R.sup.3 is optionally substituted by 1-5 R.sup.5.
[0111] In certain embodiments, R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --(C.sub.0-C.sub.3
alkyl)OR.sup.11, --(C.sub.0-C.sub.3 alkyl)SR.sup.11,
--(C.sub.0-C.sub.3 alkyl)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)OCF.sub.3 or --CF.sub.3, wherein said alkyl is independently
optionally substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo,
--CF.sub.3, --(C.sub.0-C.sub.3 alkyl)OR.sup.13 or
--(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14.
[0112] In certain embodiments, R.sup.3 is phenyl, optionally
substituted by 1-3 R.sup.5; and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --(C.sub.0-C.sub.3
alkyl)OR.sup.11, --(C.sub.0-C.sub.3 alkyl)SR.sup.11,
--(C.sub.0-C.sub.3 alkyl)NR.sup.11R.sup.12, --(C.sub.0-C.sub.3
alkyl)OCF.sub.3 or --CF.sub.3, wherein said alkyl is independently
optionally substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo,
--CF.sub.3, --(C.sub.0-C.sub.3 alkyl)OR.sup.13 or
--(C.sub.0-C.sub.3 alkyl)NR.sup.13R.sup.14.
[0113] In certain embodiments, R.sup.3 is phenyl, pyridinyl,
dihydrobenzofuranyl, piperidinyl, pyrrolidinyl, pyridinonyl,
imidazolyl or isoxazolyl, wherein R.sup.3 is optionally substituted
by 1-3 R.sup.5; and R.sup.5 is independently oxo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, halogen, --CN, --O(C.sub.1-C.sub.6
alkyl), --S(C.sub.1-C.sub.6 alkyl), --O(C.sub.3-C.sub.6
cycloalkyl), --S(C.sub.3-C.sub.6 cycloalkyl), --(C.sub.0-C.sub.3
alkyl)NR.sup.11R.sup.12, --OCF.sub.3, --OCHF.sub.2, or --CF.sub.3,
wherein said alkyl, alkenyl, alkynyl and cycloalkyl are
independently optionally substituted by halogen, C.sub.1-C.sub.3
alkyl, OH, OCH.sub.3, NH.sub.2, NMe.sub.2, oxo or --CF.sub.3.
[0114] In certain embodiments, R.sup.1 is hydrogen, OR.sup.8 or
--NR.sup.6R.sup.7. In one embodiment, R.sup.1 is hydrogen. In one
embodiment, R.sup.1 is --NH.sub.2.
[0115] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6
alkyl)OR.sup.6 or --(C.sub.0-C.sub.6 alkyl)SR.sup.6, and wherein
R.sup.4 is independently optionally substituted by C.sub.1-C.sub.3
alkyl, --OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment, R.sup.2
is pyrazolyl, optionally substituted by R.sup.4, wherein R.sup.4 is
--(C.sub.0-C.sub.6 alkyl)OR.sup.6 or --(C.sub.0-C.sub.3
alkyl)SR.sup.6, and wherein R.sup.4 is independently optionally
substituted by C.sub.1-C.sub.3 alkyl, --OR.sup.8 or
--NR.sup.8R.sup.9, R.sup.3 is phenyl, optionally substituted by 1-3
R.sup.5, and R.sup.5 is independently C.sub.1-C.sub.6 alkyl,
halogen, --CN, --OR.sup.11, --SR.sup.11 or --CF.sub.3, wherein said
alkyl is independently optionally substituted by halogen,
--CF.sub.3, --OR.sup.13 or --NR.sup.13R.sup.14.
[0116] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6
alkyl)CF.sub.3, and wherein R.sup.4 is independently optionally
substituted by C.sub.1-C.sub.3 alkyl, --OR.sup.8 or
--NR.sup.8R.sup.9. In one embodiment, R.sup.2 is pyrazolyl,
optionally substituted by R.sup.4, wherein R.sup.4 is
--(C.sub.0-C.sub.6 alkyl)CF.sub.3, and wherein R.sup.4 is
independently optionally substituted by C.sub.1-C.sub.3 alkyl,
--OR.sup.8 or --NR.sup.8R.sup.9, R.sup.3 is phenyl, optionally
substituted by 1-3 R.sup.5, and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --OR.sup.11, --SR.sup.11 or
--CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, --CF.sub.3, --OR.sup.13 or
--NR.sup.13R.sup.14.
[0117] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6
alkyl)NR.sup.6R.sup.7 or --(C.sub.0-C.sub.6 alkyl)(3-6-membered
heterocyclyl), and wherein R.sup.4 is independently optionally
substituted by C.sub.1-C.sub.3 alkyl, --OR.sup.8 or
--NR.sup.8R.sup.9. In one embodiment, R.sup.2 is pyrazolyl,
optionally substituted by R.sup.4, wherein R.sup.4 is
--(C.sub.0-C.sub.6 alkyl)NR.sup.6R.sup.7 or --(C.sub.0-C.sub.6
alkyl)(3-6-membered heterocyclyl), and wherein R.sup.4 is
independently optionally substituted by C.sub.1-C.sub.3 alkyl,
--OR.sup.8 or --NR.sup.8R.sup.9, R.sup.3 is phenyl, optionally
substituted by 1-3 R.sup.5, and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --OR.sup.11, --SR.sup.11 or
--CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, --CF.sub.3, --OR.sup.13 or
--NR.sup.13R.sup.14.
[0118] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl), and wherein R.sup.4 is
independently optionally substituted by C.sub.1-C.sub.3 alkyl,
--OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment, R.sup.2 is
pyrazolyl, optionally substituted by R.sup.4, wherein R.sup.4 is
--(C.sub.0-C.sub.6 alkyl)(C.sub.3-C.sub.6 cycloalkyl), and wherein
R.sup.4 is independently optionally substituted by C.sub.1-C.sub.3
alkyl, --OR.sup.8 or --NR.sup.8R.sup.9, R.sup.3 is phenyl,
optionally substituted by 1-3 R.sup.5, and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --OR.sup.11, --SR.sup.11 or
--CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, --CF.sub.3, --OR.sup.13 or
--NR.sup.13R.sup.14.
[0119] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.6 or --(C.sub.0-C.sub.6
alkyl)C(O)NR.sup.6NR.sup.7, and wherein R.sup.4 is independently
optionally substituted by C.sub.1-C.sub.3 alkyl, --OR.sup.8 or
--NR.sup.8R.sup.9. In one embodiment, R.sup.2 is pyrazolyl,
optionally substituted by R.sup.4, wherein R.sup.4 is
--(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.6, and wherein R.sup.4 is
independently optionally substituted by C.sub.1-C.sub.3 alkyl,
--OR.sup.8 or --NR.sup.8R.sup.9, R.sup.3 is phenyl, optionally
substituted by 1-3 R.sup.5, and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --OR.sup.11, --SR.sup.11 or
--CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, --CF.sub.3, --OR.sup.13 or
--NR.sup.13R.sup.14.
[0120] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is C.sub.0-C.sub.6 alkyl,
and wherein R.sup.4 is independently optionally substituted by
halogen, --OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment,
R.sup.2 is pyrazolyl, optionally substituted by R.sup.4, wherein
R.sup.4 is C.sub.0-C.sub.6 alkyl, and wherein R.sup.4 is
independently optionally substituted by halogen, --OR.sup.8 or
--NR.sup.8R.sup.9, R.sup.3 is phenyl, optionally substituted by 1-3
R.sup.5, and R.sup.5 is independently C.sub.1-C.sub.6 alkyl,
halogen, --CN, --OR.sup.11, --SR.sup.11 or --CF.sub.3, wherein said
alkyl is independently optionally substituted by halogen,
--CF.sub.3, --OR.sup.13 or --NR.sup.13R.sup.14.
[0121] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6
alkyl)CN, and wherein R.sup.4 is independently optionally
substituted by halogen, --OR.sup.8 or --NR.sup.8R.sup.9. In one
embodiment, R.sup.2 is pyrazolyl, optionally substituted by
R.sup.4, wherein R.sup.4 is --(C.sub.0-C.sub.6 alkyl)CN, and
wherein R.sup.4 is independently optionally substituted by halogen,
--OR.sup.8 or --NR.sup.8R.sup.9, R.sup.3 is phenyl, optionally
substituted by 1-3 R.sup.5, and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --OR.sup.11, --SR.sup.11 or
--CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, --CF.sub.3, --OR.sup.13 or
--NR.sup.13R.sup.14.
[0122] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is C.sub.1-C.sub.6 alkyl
optionally substituted by oxo, --OR.sup.8, --NR.sup.8R.sup.9, --CN,
halogen, C.sub.3-C.sub.6 cycloalkyl, or 5-6 membered heterocyclyl,
5-6 membered heterocyclyl optionally substituted by --OR.sup.8,
--NR.sup.8R.sup.9, --CN, halogen or oxo,
--CH.sub.2C(O)NR.sup.6NR.sup.7 optionally substituted by
--OR.sup.8, --NR.sup.8R.sup.9, --CN, halogen or C.sub.3-C.sub.6
cycloalkyl, or --CH.sub.2(5-6 membered heterocyclyl optionally
substituted by oxo, --OR.sup.8, --NR.sup.8R.sup.9, --CN, halogen or
C.sub.1-C.sub.3 alkyl, and R.sup.3 is phenyl optionally substituted
by 1-3 R.sup.5.
[0123] In certain embodiments, R.sup.2 is pyrazolyl, optionally
substituted by R.sup.4, wherein R.sup.4 is
--CH.sub.2C(OH)(C.sub.1-C.sub.3 alkyl optionally substituted by
halogen), --CH.sub.2C(O)NR.sup.6NR.sup.7 or --CH.sub.2C(O)(4-6
membered heterocyclyl), wherein R.sup.4 is optionally substituted
by oxo, --OR.sup.8, --NR.sup.8R.sup.9, --CN, halogen,
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl, and R.sup.3 is
phenyl optionally substituted by 1-3 R.sup.5.
[0124] In certain embodiments, R.sup.2 is pyridinyl, optionally
substituted by C.sub.1-C.sub.6 alkyl and said alkyl is optionally
substituted by halogen. In one embodiment, R.sup.2 is pyridinyl,
optionally substituted by C.sub.1-C.sub.6 alkyl and said alkyl is
optionally substituted by halogen, R.sup.3 is phenyl, optionally
substituted by 1-3 R.sup.5, and R.sup.5 is independently
C.sub.1-C.sub.6 alkyl, halogen, --CN, --OR.sup.11, --SR.sup.11 or
--CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, --CF.sub.3, --OR.sup.13 or --NR.sup.13 or
--NR.sup.13R.sup.14.
[0125] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)OR.sup.6 or --(C.sub.0-C.sub.6 alkyl)SR.sup.6, wherein said
alkyl is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In one
embodiment, R.sup.4 is selected from:
##STR00006## ##STR00007##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0126] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)CF.sub.3, wherein said alkyl is independently optionally
substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or
--NR.sup.8R.sup.9. In one embodiment, R.sup.4 is selected from:
##STR00008##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0127] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)NR.sup.6R.sup.7, wherein said alkyl is independently
optionally substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo,
--OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment, R.sup.4 is
selected from:
##STR00009##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0128] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)(3-6-membered heterocyclyl), wherein said alkyl and
heterocyclyl are independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In one
embodiment, said 3-6-membered heterocyclyl is oxetanyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl,
pyrrolidinonyl, tetrahydrofuranyl, oxazolyl, isoxazolyl and
tetrahydropyranyl, optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In one
embodiment, R.sup.4 is selected from:
##STR00010## ##STR00011##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0129] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)C(O)(3-6-membered heterocyclyl), wherein said alkyl and
heterocyclyl are independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In one
embodiment, said 3-6-membered heterocyclyl is oxetanyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl,
tetrahydrofuranyl, oxazolyl, isoxazolyl, dihydropyrrolyl and
tetrahydropyranyl, optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In one
embodiment, R.sup.4 is selected from:
##STR00012## ##STR00013## ##STR00014## ##STR00015##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0130] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl), wherein said alkyl and
cycloalkyl are independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In
certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)(C.sub.3-C.sub.6 cycloalkyl), wherein said cycloalkyl is
cyclopentyl or cyclohexyl optionally substituted by C.sub.1-C.sub.3
alkyl, --OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment, R.sup.4
is selected from:
##STR00016##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0131] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.6, --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.6NR.sup.7,
--(C.sub.0-C.sub.6 alkyl)OC(O)NR.sup.6, --(C.sub.0-C.sub.6
alkyl)NR.sup.6C(O)OR.sup.7, --(C.sub.0-C.sub.6
alkyl)NR.sup.6C(O)NR.sup.7 or --(C.sub.0-C.sub.6
alkyl)NR.sup.6C(O)R.sup.7, wherein said alkyl is independently
optionally substituted by halogen, C.sub.1-C.sub.3 alkyl, oxo,
--OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment, R.sup.4 is
selected from:
##STR00017## ##STR00018## ##STR00019## ##STR00020##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0132] In certain embodiments, R.sup.4 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl optionally
substituted by halogen, oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In
one embodiment, R.sup.4 is selected from:
##STR00021##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0133] In certain embodiments, R.sup.4 is --(C.sub.0-C.sub.6
alkyl)CN, wherein said alkyl is optionally substituted by halogen,
oxo, --OR.sup.8 or --NR.sup.8R.sup.9. In one embodiment, R.sup.4 is
--CH.sub.2CN, --CH.sub.2CH.sub.2CN or --CH(CH.sub.3)CN.
[0134] In certain embodiments, R.sup.4 is halogen. In one
embodiment, R.sup.4 is F, Cl, Br or I. In one embodiment, R.sup.4
is F or Cl.
[0135] In certain embodiments, R.sup.3 is:
##STR00022##
wherein n is 0, 1, 2 or 3 and the wavy line represents the point of
attachment to R.sup.2.
[0136] In one embodiment, n is 2. In one embodiment, R.sup.3 is
selected from:
##STR00023##
[0137] wherein the wavy line represents the point of attachment to
R.sup.2.
[0138] In certain embodiments, R.sup.3 is phenyl or pyridinyl,
optionally substituted by C.sub.1-C.sub.6 alkyl, halogen, --CN,
--(C.sub.0-C.sub.3 alkyl)OR.sup.6, --(C.sub.0-C.sub.3
alkyl)SR.sup.6, --(C.sub.0-C.sub.3 alkyl)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.3 alkyl)OCF.sub.3 or --CF.sub.3, wherein said
alkyl is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --CF.sub.3, --(C.sub.0-C.sub.3
alkyl)OR.sup.8 or --(C.sub.0-C.sub.3 alkyl)NR.sup.8R.sup.9. In one
embodiment, R.sup.3 is selected from:
##STR00024## ##STR00025## ##STR00026##
wherein the wavy line represents the point of attachment to
R.sup.2. In one embodiment, R.sup.3 is selected from:
##STR00027##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0139] In certain embodiments, R.sup.3 is 4-6 membered hererocyclyl
optionally substituted by C.sub.1-C.sub.6 alkyl, halogen, --CN,
--(C.sub.0-C.sub.3 alkyl)OR.sup.6, --(C.sub.0-C.sub.3
alkyl)SR.sup.6, --(C.sub.0-C.sub.3 alkyl)NR.sup.6R.sup.7,
--(C.sub.0-C.sub.3 alkyl)OCF.sub.3 or --CF.sub.3, wherein said
alkyl is independently optionally substituted by halogen,
C.sub.1-C.sub.3 alkyl, oxo, --CF.sub.3, --(C.sub.0-C.sub.3
alkyl)OR.sup.8 or --(C.sub.0-C.sub.3 alkyl)NR.sup.8R.sup.9. In
certain embodiments, said heterocyclyl is selected from azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
tetrahydropyridinyl, and pyridinonyl. In certain embodiments,
R.sup.3 is selected from:
##STR00028##
wherein the wavy line represents the point of attachment to
R.sup.2.
[0140] In certain embodiments, R.sup.2 is selected from:
##STR00029##
wherein R.sup.10 is independently selected from hydrogen or
R.sup.4, and the wavy line represents the point of attachment to
Formula I.
[0141] In certain embodiments, R.sup.2 is selected from:
##STR00030##
wherein R.sup.10 is independently selected from hydrogen or
R.sup.4, and the wavy line represents the point of attachment to
Formula I.
[0142] In certain embodiments, R.sup.2 is selected from:
##STR00031##
wherein R.sup.10 is independently selected from hydrogen or
R.sup.4, and the wavy line represents the point of attachment to
Formula I.
[0143] In certain embodiments, R.sup.2 is selected from:
##STR00032##
R.sup.3 is
##STR00033##
[0144] or pyridinyl, R.sup.10 is hydrogen or R.sup.4, and the wavy
line represents the point of attachment to Formula I and R.sup.2,
respectively.
[0145] In certain embodiments, --R.sup.2-R.sup.3 in Formula I
is
##STR00034##
wherein, R.sup.10 is hydrogen or R.sup.4, and the wavy line
represents the point of attachment to Formula I.
[0146] In certain embodiments, --R.sup.2-R.sup.3 in Formula I
is
##STR00035##
wherein n is 0, 1, 2 or 3, R.sup.10 is hydrogen or R.sup.4, and the
wavy line represents the point of attachment of R.sup.2 to Formula
I.
[0147] 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 one or more of the other Janus kinase
activities.
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] Synthesis of Pyrazolopyrimidine JAK Inhibitor Compounds
[0154] 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.
[0155] 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
[0156] For illustrative purposes, reaction Schemes 1-13 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.
[0157] 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.
[0158] Compounds of the invention may be prepared from readily
available starting materials using the general methods illustrated
in Reaction Schemes 1-21 below.
##STR00036##
[0159] Compounds of Formula I can be synthesized as shown in
Reaction Scheme 1. For example, commercially available benzoic
acids can be reacted with potassium 3-ethoxy-3-oxopropanoate in the
presence of carbonyldiimidazole (CDI) and magnesium chloride to
give .beta.-keto-ester 2. Compound 2 can be heated with
1,1-dimethoxy-N,N-dimethylmethanamine (DMFDMA) to give compound 3.
Cyclization of compound 3 with hydrazine in ethanol provides
pyrazole compound 4. Methylation of compound 4 with iodomethane in
the presence of a base such as cesium carbonate affords a mixture
of the regioisomers 5a and 5b. Hydrolysis of the ethyl ester,
followed by curtius rearrangement utilizing diphenylphosphonic
azide (dppa) and t-butanol provides the t-butylcarbamate protected
amino-pyrazole, which is unmasked with HCl to give amino-pyrazole
compounds 6a and 6b. The regioisomers 6a and 6b can be separated at
this stage using silica chromatography. Coupling of each
regioisomer separately with commercially available
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (PyAOP), diisopropylethylamine (DIEA), and
4-dimethylaminopyridine (DMAP) provides compounds of Formula 1a and
1b.
##STR00037##
[0160] An alternative method for the synthesis of compounds of
Formula I is illustrated in Reaction Scheme 2. Alkylation of
di-tert-butyl iminodicarbonate with sodium hydride and various
.alpha.-bromoketones 7 generates compound 8. Compound 8 can be
heated with DMFDMA to give compound 9. Cyclization of compound 9
with hydrazine in ethanol provides pyrazole compound 10. Coupling
of compound 10 with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in
the presence of PyAOP, DIEA, and DMAP provides compounds of Formula
1c. Compounds of Formula 1c can be subjected to alkylation with
iodomethane in the presence of cesium carbonate to yield compounds
of Formula 1a and 1b.
##STR00038##
[0161] Reaction Scheme 3 illustrates the synthesis of compounds of
Formula 1d. Subjection of commercially available anilines to
diazotization and tin chloride mediated reduction provides compound
11. Condensation of compound 11 with 3-aminocrotonitrile in
ethanolic hydrochloric acid generates amino-pyrazole compound 12.
Coupling of compound 12 with pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid in the presence of PyAOP, DIEA, and DMAP provides compounds of
Formula 1d.
##STR00039##
[0162] Reaction Scheme 4 illustrates the synthesis of compounds of
Formula 1e. 5-Bromo-2-methylpyridine can be oxidized with
m-chloroperoxybenzoic acid to give compound 13. Nitration of
compound 13 to give compound 14, followed by tin chloride reduction
yields amino-pyridine 15. Pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid can be converted to the corresponding acid chloride with
oxalyl chloride, and then reacted with compound 15 or other
commercially available amino pyridines to form compound 16. These
compounds may be subjected to Suzuki cross-coupling conditions with
aryl boronic acids to provide compounds of Formula 1e.
##STR00040##
[0163] An alternative method for the synthesis of compounds of
Formula 1 is described in Reaction Scheme 5. Alkylation of
potassium phthalimide with .alpha.-bromoketones 7 generates
compound 17. Condensation with DMFDMA yields compounds 18.
Compounds of Formula 18 may be cyclized with N-methylhydrazine to
provide a separable mixture of the regioisomers 6a and 6b. Coupling
of each regioisomer separately under amide formation methods using
hexafluorophosphate
o-(7-azabenzo-triazol-1-yl)-1,1,3,3-tetramethyluronium (HATU) with
commercially available pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
provides compounds of Formula 1a and 1b.
##STR00041##
[0164] Reaction Scheme 6 illustrates a method for the synthesis of
compounds of Formula 1 g and 1f. Compound 18 may be cyclized with
hydrazine to yield compound 10, which may then be coupled with
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid under amide formation
conditions using HATU to provide compounds of Formula 1c.
Alkylation of compound 1c with alkyl halides in the presence of
cesium carbonate gives compounds of Formula 1f. Reaction of
compound 1c with 2,2-dimethyloxirane in the presence of cesium
carbonate provides compounds of Formula 1 g.
##STR00042##
[0165] Reaction Scheme 7 illustrates the synthesis of compounds of
Formula 1 h. Amide formation using HATU with
4-bromo-1-methyl-1H-pyrazol-3-amine and
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid provides compound 19.
Palladium catalyzed Suzuki coupling of compound 19 with various
boronic acids provides compounds of Formula 1 h.
##STR00043##
[0166] Reaction Scheme 8 illustrates the synthesis of compounds of
Formula 1i. A solution of the appropriately substituted
phenylhydrazine can be heated under reflux with excess
acrylonitrile in a solvent such as ethanol to give compounds of
formula 21. Hydrazines 21 can be oxidized using iron(III) sulfate
in dilute sulfuric acid to give compounds of formula 22. Compounds
22 can be cyclized in dilute sodium hydroxide solution to give
compounds of formula 23. Reaction of 22 with previously prepared
pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride gives the final
compounds of formula 1i.
##STR00044##
[0167] An alternate method for the synthesis of compounds of
Formula 1a and 1b is shown in Reaction Scheme 9. Commercially
available 4-nitro-1H-pyrazole may be protected with a
[.beta.-(trimethylsilyl)ethoxy]methyl (SEM) group by treatment with
sodium hydride and (2-(chloromethoxy)ethyl)trimethylsilane. The
resulting compound 24 can be arylated with aryl bromides or iodides
under palladium catalyzed conditions to generated
4-nitro-5-aryl-pyrazoles of formula 25. The nitro group of
compounds 25 can be reduced in the presence of iron and ammonium
chloride to generate amino pyrazoles 26. Amide bond coupling with
commercially available pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
in the presence of PyAOP, DIEA, and DMAP provides compounds 27.
Removal of the SEM protecting group by aqueous HCl in ethanol
generates compounds 1c, which may be alkylated with alkyl halides
in the presence of a suitable base such as cesium carbonate or with
Michael acceptors to provide compounds of Formula 1a and 1b.
##STR00045##
[0168] Reaction Scheme 10 illustrates the synthesis of compounds of
Formula 1j and 1k. Pyrazole compounds 1c (prepared as described in
either Reaction Scheme 2 or Reaction Scheme 9) may be alkylated
with substituted epoxides in the presence of cesium carbonate to
give the regioisomeric compounds of Formula 1j and 1k.
##STR00046##
[0169] Compounds of Formula 1m can be synthesized as shown in
Reaction Scheme 11. Commercially available acetophenones can be
acylated with potassium tert-butoxide and ethyl acetate to generate
di-ketone compounds of formula 28. Compounds 28 can be treated with
sodium nitrite in the presence of acetic acid and water to provide
hydroxyimino compounds 29, which may be subsequently cyclized with
hydrazine to yield amino-pyrazole compounds 30. Amide bond coupling
with commercially available pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid in the presence of PyAOP, DIEA, and DMAP provides compounds of
Formula 1m.
##STR00047##
[0170] An alternate method for the synthesis of compounds of
Formula 1a and 1b is shown in Reaction Scheme 12. Commercially
available 4-Nitro-1H-pyrazole can be reacted with alkyl bromides in
the presence of cesium carbonate at 55.degree. C. for 12 hours to
give compound 31. Compound 31 can be reacted with aryl bromides in
N,N-Dimethylacetamide in the presence of Palladium (II) acetate,
Di(1-adamntyl)-n-butylphosphine, potassium carbonate and
trimethylacetic acid to give compounds 32a and 32b. The ratio of
products 32a:32b varies depending on the substituent R1, but the
reaction generally favors formation of product 32b. Compounds 32a
and 32b can be reduced to compounds 33a and 33b in the presence of
iron and ammonium chloride in ethanol and water. Coupling of
compounds 33a and 33b with pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid in the presence of PyAOP, DIEA, and DMAP can provide compounds
of Formula 1a and 1b.
##STR00048##
[0171] Compounds of formula 1n can be synthesized as shown in
reaction scheme 13. Trichloroacetonitrile can be reacted with
cyanoacetic acid ethyl ester to give compound 34. Compound 34 can
be condensed with hydrazine to give compound 35, which can then be
condensed with 1,1,3,3-tetramethoxypropane to give compound 36.
Amine 36 can be doubly Boc-protected to give compound 37, which can
then be hydrolyzed with lithium hydroxide to give carboxylic acid
38. Carboxylic acid 38 can then be coupled to various amines in the
presence of PyAOP, DIEA, and DMAP to give compounds of formula
1n.
##STR00049##
[0172] Compounds of formula to can be synthesized as shown in
reaction scheme 14. Pyrazole compounds 1c (prepared as described in
either Reaction Scheme 2 or Reaction Scheme 9) may be alkylated
with allyl halides in the presence of cesium carbonate to give the
regioisomeric compounds of Formula 39a and 39b. The regioisomeric
compounds may be separated by silica gel chromatography and the
appropriate isomer reacted with osmium tetroxide in the presence of
N-methylmorpholine-N-oxide to give compounds of Formula 10.
##STR00050##
[0173] Compounds of formula 1p and 1q can be synthesized as shown
in reaction scheme 15. Pyrazole compounds 1c (prepared as described
in either Reaction Scheme 2 or Reaction Scheme 9) may be alkylated
with 2-(chloromethyl)oxirane in the presence of cesium carbonate
and then treated with amines to give regioisomeric compounds of
Formula 1p and 1q.
##STR00051##
[0174] Reaction Scheme 16 illustrates the synthesis of compounds of
formula 1R. Nitro-SEM pyrazole compound 24, prepared as in Reaction
Scheme 9, may be regioselectively deprotonated with lithium
hexamethyldisilazide at low temperature and quenched with
hexachloroethane to yield 40. Upon heating in the microwave with an
amine HNRR', wherein RR' are taken together with the nitrogen to
which they are attached to form R.sup.3 (for example, a 3-10
membered heterocyclyl group), this compound may be converted to 41.
The nitro group of intermediate 41 can be reduced in the presence
of iron and ammonium chloride to generate amino pyrazoles 42. Amide
bond coupling with commercially available
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of
PyAOP, DIEA, and DMAP provides 1R. 1R may be further elaborated by
removal of the SEM group and functionalizing as in Reaction Schemes
9, 10 14, 15, 18, or 19.
##STR00052##
[0175] Reaction Scheme 17 illustrates an alternate synthesis for
compounds of formula 10. Nitro-SEM pyrazole compound 24, prepared
as in Reaction Scheme 9, may be regioselectively deprotonated with
lithium hexamethyldisilazide at low temperature and quenched with
iodine to yield 43. The nitro group of compound 43 can be reduced
in the presence of iron and ammonium chloride, followed by Boc
protection to generate compound 44. Compound 44 may be coupled
under Suzuki conditions with aryl boronic acids or aryl boronates
to yield compounds 45. After cleavage of the Boc group with tin
tetrachloride, compounds of formula 10 are obtained.
##STR00053##
[0176] Compounds of formula 1s can be synthesized as shown in
reaction scheme 18. Pyrazole compounds 1c (prepared as described in
either Reaction Scheme 2 or Reaction Scheme 9) may be alkylated
with t-butyl-bromoacetate in the presence of cesium carbonate to
give intermediate 46. 46 may be treated with trifluoroacetic acid
to give acids 47, which may then be reacted with primary or
secondary amines in the presence of a coupling reagent such as
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (HATU) to give compounds of formula 1s.
##STR00054##
[0177] Compounds of formula 1t can be synthesized as shown in
reaction scheme 19. Pyrazole compounds 1c (prepared as described in
either Reaction Scheme 2 or Reaction Scheme 9) may be alkylated
with 2-chloroethyl para-toluenesulfonate in the presence of cesium
carbonate to give alkyl chlorides 48. 48 may then be reacted with
primary or secondary amines in the presence of an appropriate base
such as N,N-diisopropylethylamine to give compounds of formula
1t.
##STR00055##
[0178] Compounds of Formula 1u can be synthesized as shown in
Reaction Scheme 20. For example, commercially available substituted
benzaldehydes can be converted to compounds 49 by treatment with a
cyanide source such as sodium cyanide in the presence of ammonium
chloride and ammonium hydroxide. Compounds 49 can be coupled to
carboxylic acids to provide compounds 50 using an amide coupling
reagent such as HATU and base such as diisopropylethylamine
Compounds 50 can be treated with hydrogen peroxide and potassium
carbonate to provide compounds 51. Cyclization of diamido compounds
51 using Lawesson's reagent and pyridine provides amino thiazolo
compounds 52. Compounds of formula 1u can prepared by treatment of
compounds 52 with previously prepared
pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride in pyridine.
##STR00056##
[0179] Alternatively compounds of Formula 1u can be synthesized as
shown in Reaction Scheme 21. For example, compounds 53 can be
prepared by treatment of commercially available substituted
acetophenones with diethyl carbonate and subsequent bromination
using for example bromine in dioxane. Treatment of compounds 53
with a suitably substituted thioamide or thiourea provides thiazole
compounds 54. Compounds 54 can be hydrolysed using an aqueous base
such as potassium hydroxide in a compatible solvent such as THF to
afford acid compounds 55. Compounds 56 can be prepared by treatment
of compounds 55 with diphenylphosphoryl azide (DPPA) in
tert-butanol. Deprotection of compounds 56 under acidic conditions
provides amino compounds 52. Compounds of formula 1u can prepared
by treatment of compounds 52 with previously prepared
pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride in pyridine.
[0180] 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.
[0181] 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.
[0182] 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.
[0183] 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.
[0184] 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).
[0185] 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.
[0186] 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.
[0187] 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.
[0188] Ester groups (--CO.sub.2R') may be converted into the
corresponding acid group (--CO.sub.2H) by acid- or base-catalused
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.
[0189] 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.
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] Methods of Separation
[0197] 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.
[0198] 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.
[0199] 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.
[0200] 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.
[0201] 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).
[0202] 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.
[0203] 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.
[0204] 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.
[0205] Biological Evaluation
[0206] 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).
[0207] 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 Ki 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 EC50 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.
[0208] Administration of Janus Kinase Inhibitor Compounds
[0209] Another embodiment includes a method of treating or
lessening the severity of a disease or condition responsive to the
inhibition of a Janus 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. In one embodiment, the
disease is an autoimmune disease.
[0210] Another embodiment includes the use of a compound of Formula
I for therapy.
[0211] Another embodiment includes the use of a compound of Formula
I for preventing, treating or lessening the severity of a disease.
In one embodiment, the disease is an autoimmune disease.
[0212] Another embodiment includes the use of a compound of Formula
I in the manufacture of a medicament for preventing, treating or
lessening the severity of a disease. In one embodiment, the disease
is an autoimmune disease.
[0213] In one embodiment, a compound of Formula I is administered
to a patient in a therapeutically effective amount to treat or
lessen the severity of a disease or condition responsive to the
inhibition of a Janus kinase activity, and said compound is at
least 15 fold, alternatively 10 fold, alternatively 5 fold or more
selective in inhibiting one Janus kinase activity over inhibiting
one or more of the other Janus kinase activities.
[0214] 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.
[0215] In one embodiment, the disease or condition is cancer.
[0216] In one embodiment, the disease is a myeloproliferative
disorder.
[0217] In one embodiment, the myeloproliferative disorder is
polycythemia vera, essential thrombocytosis, myelofibrosis or
chronic myelogenous leukemia (CML).
[0218] 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.
[0219] In one embodiment, the cardiovascular disease is restenosis,
cardiomegaly, atherosclerosis, myocardial infarction or congestive
heart failure.
[0220] 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.
[0221] In one embodiment, the inflammatory disease is inflammatory
bowel disease, rheumatoid arthritis, psoriasis, contact dermatitis
or delayed hypersensitivity reactions.
[0222] In one embodiment, the autoimmune disease is lupus or
multiple sclerosis.
[0223] In one embodiment, the autoimmune disease is Crohn's
disease, ulcerative colitis, Collagenous colitis, Lymphocytic
colitis, Ischaemic colitis, Diversion colitis, Behcet's syndrome,
Infective colitis and Indeterminate colitis.
[0224] 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).
[0225] 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.
[0226] 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.
[0227] 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).
[0228] 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.
[0229] 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.
[0230] Pharmaceutical Formulations of Janus Kinase Inhibitor
Compounds
[0231] Another embodiment includes a pharmaceutical composition
that includes a compound of Formula I and a pharmaceutically
acceptable carrier, adjuvant or vehicle.
[0232] 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.
[0233] In one embodiment, a compound of Formula I is present in a
pharmaceutical formulation in an amount to detectably inhibit Janus
kinase activity and a pharmaceutically acceptable carrier, adjuvant
or vehicle.
[0234] 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 one or more of the other JAK1, JAK2, JAK3
and/or Tyk-2 activity.
[0235] 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).
[0236] 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.
[0237] 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.
[0238] 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.
[0239] In an embodiment, the compound of Formula I for use in a
pharmaceutical composition is substantially sterile. The compound
ordinarily will be stored as a solid composition, although
lyophilized formulations or aqueous solutions are acceptable.
[0240] 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.
[0241] 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.
[0242] 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, trehalogense 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).
[0243] 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, 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.
[0244] The formulations to be used for in vivo administration must
be sterile, which is readily accomplished by filtration through
sterile filtration membranes.
[0245] 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 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.
[0246] 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.
[0247] 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.
[0248] 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.
[0249] 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.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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.
[0256] 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.
[0257] 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.
[0258] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] Combination Therapy
[0264] The compounds of Formula 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) or a hyperproliferative
disorder (e.g., cancer). 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 anti-hyperproliferative
properties or that is useful for treating an inflammation,
immune-response disorder, or hyperproliferative disorder (e.g.,
cancer). The second therapeutic agent may be a NSAID or other
anti-inflammatory agent. The second therapeutic agent may be a
chemotherapeutic agent. The second therapeutic agent of the
pharmaceutical combination formulation or dosing regimen preferably
has complementary activities to the compound of Formula I such that
they do not adversely affect each other. Such compounds are
suitably present in combination in amounts that are effective for
the purpose intended. 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.
[0265] Another embodiment, therefore, includes a method of treating
or lessening the severity of a disease or condition responsive to
the inhibition of a Janus kinase in a patient, comprising
administering to said patient a therapeutically effective amount of
a compound of Formula I, and further comprising, administering a
second therapeutic agent.
[0266] 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.
[0267] 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.
[0268] 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.
[0269] In a particular embodiment of therapy, a compound of Formula
I, or a stereoisomer, geometric isomer, tautomer, solvate,
metabolite, or pharmaceutically acceptable salt or prodrug thereof,
may be combined with other therapeutic, hormonal or antibody agents
such as those described herein, as well as combined with surgical
therapy and radiotherapy. Combination therapies according to the
present invention thus comprise the administration of at least one
compound of Formula I, or a stereoisomer, geometric isomer,
tautomer, solvate, metabolite, or pharmaceutically acceptable salt
or prodrug thereof, and the use of at least one other cancer
treatment method, or immunological disorder method. The amounts of
the compound(s) of Formula I and the other pharmaceutically active
immunologic or chemotherapeutic agent(s) and the relative timings
of administration will be selected in order to achieve the desired
combined therapeutic effect.
[0270] Metabolites of the Janus Kinase Inhibitor Compounds
[0271] 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.
[0272] 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.
[0273] Articles of Manufacture
[0274] Another embodiment includes a method of manufacturing a
compound of Formula I. The method includes reacting a compound of
formula (i):
##STR00057##
[0275] wherein R.sup.1 is defined in Formula I, and X is a leaving
group, for example, halogen, --OH, --O(C.sub.1-C.sub.12 alkyl);
with a compound of formulae (iia-c):
##STR00058##
[0276] wherein R.sup.5 is defined in Formula I, and R.sup.10 is
hydrogen or R.sup.4, and R.sup.4 is defined in Formula I; under
conditions sufficient to form a compound of Formula I.
[0277] In an embodiment, said conditions include basic conditions,
for example, carrying out the reaction in the presence of a base,
such as an amine base, for example pyridine or an alikylated amine,
such as dialkyl or trialkyl amine (e.g. trimethylamine,
triethylamine, diisoproplyamine or diethylamine).
[0278] In an embodiment, said conditions include coupling
conditions, for example, carrying out the reaction in the presence
of PyAOP, DMAP and an alkylated amine, for example,
diisopropylamine
[0279] Another embodiment includes a kit for treating a disease or
disorder responsive to the inhibition of a Janus kinase. The kit
includes: [0280] a first pharmaceutical composition comprising a
compound of Formula I; and [0281] instructions for use.
[0282] In another embodiment, the kit further includes: [0283] a
second pharmaceutical composition, which includes a
chemotherapeutic agent.
[0284] 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
therof.
[0285] In one embodiment, the first and second compositions are
contained in separate containers.
[0286] In one embodiment, the first and second compositions are
contained in the same container.
[0287] 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 acitivity.
The label or package insert may also indicate that the composition
can be used to treat other disorders.
[0288] 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.
[0289] 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
[0290] 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.
[0291] In an embodiment, the compounds of Formula I can be used to
control, modulate or inhibit tyrosine kinase activity, for example
Janus protein kinase activity, 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.
Example A
JAK1, JAK2 and TYK2 Inhibition Assay Protocol
[0292] The activity of the isolated JAK1, JAK2 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 1-508, 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 MgCl2, 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 B
JAK3 Inhibition Assay Protocol
[0293] 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 1-508,
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 C
Cell-Based Pharmacology Assays
[0294] The activities of Examples 1-508 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-2 or IL-12 (R&D systems; Minneapolis,
Minn.) was then added at a final concentration of 10 ng/mL or 30
ng/mL, respectively, 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 STAT5 (IL-2-mediated) or
STAT4 (IL-12-mediated) 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
[0295] CD.sub.3OD Deuterated Methanol [0296] CDCl.sub.3 Deuterated
Chloroform [0297] DAST Diethylaminosulfur trifluoride [0298] DCM
Dichloromethane [0299] DIPEA Diisopropylethylamine [0300] DMAP
4-Dimethylaminopyridine [0301] DMF Dimethylformamide [0302] DMF-DMA
N,N-Dimethylformamide Dimethylacetal [0303] DMSO Dimethylsulfoxide
[0304] DMSO-d6 Deuterated DMSO [0305] DME 1,2-Dimethoxyethane
[0306] DMF Dimethylformamide [0307] DPPA Diphenylphosphoryl azide
[0308] EtOAc Ethyl Acetate [0309] EtOH Ethanol [0310] HOAc Acetic
acid [0311] g gram [0312] HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) [0313] HCl Hydrochloric acid [0314] Hex Hexane
[0315] HM-N Isolute.RTM. HM-N is a modified form of diatomaceous
earth [0316] IMS industrial methylated spirits [0317] L liter
[0318] MeOH Methanol [0319] mg milligram [0320] mL milliliter
[0321] POCl.sub.3 Phosphorus oxychloride [0322] NaH Sodium Hydride
[0323] Na.sub.2SO.sub.4 Sodium Sulfate [0324] NaHCO.sub.3 Sodium
bicarbonate [0325] NaOH Sodium hydroxide [0326] Pd(PPh.sub.3).sub.4
Tetrakis(triphenylphosphine)palladium(0) [0327] PyAOP
(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate [0328] Lawesson's Reagent
2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane
2,4-disulphide [0329] NEt.sub.3 Triethylamine [0330]
Pd.sub.2dba.sub.3 Tris-(dibenzylideneacetone)dipalladium(0) [0331]
Si-SPE Pre-packed Isolute.RTM. silica flash chromatography
cartridge [0332] Si-ISCO Pre-packed ISCO.RTM. silica flash
chromatography cartridge [0333] THF Tetrahydrofuran [0334] SEM
2-(trimethylsilyl)ethoxymethyl [0335] SEMCl
2-(trimethylsilyl)ethoxymethyl chloride [0336] TEA Triethylamine
[0337] TFA Trifluoroacetic acid
[0338] General Experimental Conditions
[0339] .sup.1H NMR spectra were recorded at ambient temperature
using a Varian Unity Inova (400 MHz) spectrometer with a triple
resonance 5 mm probe, a Bruker AVIII spectrometer (400 MHz) using a
BBI Broad Band Inverse 5 mm probe, a Bruker Avance DRX400 (400 MHz)
spectrometer with a triple resonance 5 mm probe, or a Bruker AVIII
spectrometer (500 MHz) using a QNP (Quad Nucleus detect) 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.
[0340] High Pressure Liquid Chromatography-Mass Spectrometry (LCMS)
experiments to determine retention times (RT) and associated mass
ions were performed using one of the following methods.
[0341] 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.
[0342] 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.
[0343] Preparative High Pressure Liquid Chromatography (HPLC) was
used to purify certain compounds. The system used was a Varian LC
equipped with an automated UV-triggered fraction collector and a
Gemini NX column (3.times.10 cm). The mobile phase was a gradient
of 5-85% acetonitrile in water, containing 0.1% formic acid or
ammonium hydroxide, over 10 minutes.
[0344] Chiral Supercritical Fluid Chromatography (SFC) was used to
separate some racemic compounds into their component enantiomers.
The system used was a Berger Pronto SFC equipped with an automated
UV-triggered fraction collector. Chiral Technologies AD, OD, OJ, or
AS (21.2.times.250 mm) are examples of the columns used. Run
lengths varied from 5-10 minutes, and an isocratic mobile phase
consisting of 5-50% MeOH:carbon dioxide was used.
[0345] Microwave experiments were carried out using a Biotage
Initiator 60.TM. which uses a single-mode resonator and dynamic
field tuning Temperature from 40-250.degree. C. can be achieved,
and pressures of up to 30 bar can be reached.
Example 1
##STR00059##
[0346]
N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1-
,5-a]pyrimidine-3-carboxamide
##STR00060##
[0347] ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate
[0348] To a stirring solution of 5-chloro-2-methoxybenzoic acid
(1.87 g, 10.0 mmol, 1 eq) in 20 mL tetrahydrofuran was added
N,N-carbonyldiimidazole (1.64 g, 10.1 mmol, 1.01 eq), and stirring
was continued for twenty minutes to generate the acyl-imidazole.
Separately, potassium ethyl malonate (4.08 g, 24.0 mmol, 2.39 eq)
and magnesium chloride (1.15 g, 12.1 mmol, 1.20 eq) were suspended
in 20 mL tetrahydrofuran. To the magnesium chloride mixture was
added the acyl-imidazole solution. Stirring was continued at
50.degree. C. for 1.5 hours. The reaction mixture was partitioned
between ethyl acetate and water, and the organic portion dried over
magnesium sulfate, filtered through a pad of celite, and
concentrated to provide ethyl
3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate, which was used
without further purification. LCMS (ESI) m+H=257.2
##STR00061##
ethyl 2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate
[0349] A stirred mixture of ethyl
3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (10.02 mmol, 1 eq) and
1,1-dimethoxy-N,N-dimethylmethanamine (3.0 mL, 22 mmol, 2.2 eq) was
heated at 90.degree. C. for 2 hours. After evaporation of excess
1,1-dimethoxy-N,N-dimethylmethanamine, the crude product was
purified by flash chromatography on silica gel (0 to 80% ethyl
acetate in dichloromethane) to yield 2.493 g (80%) of ethyl
2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate. LCMS (ESI)
m+H=312.2.
##STR00062##
ethyl 5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate
[0350] A solution of ethyl
2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate (2.49 g,
8.00 mmol, 1 eq) and hydrazine (0.40 mL, 13 mmol, 1.6 eq) in 20 mL
ethanol was heated at 70.degree. C. for 2 hours. Solvent and excess
hydrazine were then evaporated to provide ethyl
5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate, which was
used without further purification. LCMS (ESI) m+H=281.3.
##STR00063##
ethyl
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate
[0351] To a solution of ethyl
5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate (2.24 g,
8.00 mmol, 1 eq) in 20 mL N,N-dimethylformamide was added cesium
carbonate (3.417 g, 10.49 mmol, 1.3 eq) and iodomethane (0.60 mL,
9.6 mmol, 1.2 eq). The reaction mixture was stirred at 40.degree.
C. for 4 hours, then additional iodomethane was added (0.20 mL, 3.2
mmol, 0.4 eq). After a further 2.5 hours, the reaction mixture was
partitioned between ethyl acetate and water. The organic portion
was dried over magnesium sulfate and concentrated. The crude
product was purified by flash chromatography on silica gel (0 to
35% ethyl acetate in dichloromethane) to yield 2.18 g (92%) of a
1:1 mixture of regioisomeric products, ethyl
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate and
ethyl
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate.
LCMS (ESI) m+H=295.1.
##STR00064##
tert-butyl
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate
[0352] A solution of ethyl
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate and
ethyl
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate
(1:1 mixture of regioisomers, 2.18 g, 7.40 mmol, 1 eq) in 15 mL
ethanol was treated with 1.0 M aqueous sodium hydroxide (12 mL,
0.020 mmol, 4.0 eq). The reaction mixture was heated at 50.degree.
C. for 14 hours. After evaporation of the ethanol, the residue was
diluted into water and adjusted to pH 2 with 1.0 M aqueous
phosphoric acid. This solution was extracted twice with
dichloromethane. The combined extracts were dried over MgSO.sub.4
and concentrated to yield 1.79 g (91%) of the corresponding
carboxylic acids which were carried forward immediately. LCMS (ESI)
m+H=267.2. To a solution of this material in 15 mL dioxane was
added triethylamine (2.0 mL, 14 mmol, 4.3 eq) and
diphenylphosphonic azide (1.6 mL, 7.4 mmol, 2.2 eq). The reaction
mixture was stirred at room temperature for 1 hour, at which time
the reaction was heated to 90.degree. C. and 15 mL t-butyl alcohol
was added. After stirring at 90.degree. C. for 2.5 hours, the
solvent was evaporated and the residue partitioned between ethyl
acetate and water. The organic portion was washed with brine, dried
over magnesium sulfate, and concentrated. The crude product was
purified by flash chromatography on silica gel (0 to 50% ethyl
acetate in dichloromethane), separating the two regioisomers to
obtain: 543.2 mg (48%) of tert-butyl
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate.
LCMS (ESI) m+H=338.3; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.84 (s, 1H), 7.39 (d, 1H), 7.23 (s, 1H), 6.96 (d, 1H), 5.92 (s,
1H), 3.89 (overlapping s and s, 6H), 1.48 (s, 9H), and 773.7 mg
(68%) of tert-butyl
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate.
LCMS (ESI) m+H=338.3; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.84 (s, 1H), 7.59 (s, 1H), 7.29 (d, 1H), 6.93 (d, 1H), 3.89
(overlapping s and s, 6H), 1.48 (s, 9H).
##STR00065##
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine
[0353] To a stirring solution of tert-butyl
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate
(543.2 mg, 1.608 mmol, 1 eq) was added hydrogen chloride (5.0 mL of
a 4.0 M solution in 1,4-dioxane, 0.020 mol, 12 eq). The reaction
mixture was stirred at room temperature for 9 hours and then
evaporated to dryness. The solid residue was partitioned between
dichloromethane and a saturated aqueous solution of sodium
bicarbonate. The aqueous portion was extracted once more with
dichloromethane, and the combined organic extracts dried over
magnesium sulfate and concentrated to give
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine, which was
carried forward without purification. LCMS (ESI) m+H=238.2; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.:7.53 (s, 1H), 7.28 (d, 1H), 7.02
(s, 1H), 6.91 (d, 1H), 3.91 (d, 2H), 3.87 (s, 3H), 3.84 (s,
3H).
##STR00066##
N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide
[0354] A mixture of
3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (258 mg,
0.869 mmol, 1.00 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(157 mg, 0.961 mmol, 1.11 eq),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (541 mg, 1.04 mmol, 1.20 eq),
N,N-diisopropylethylamine (0.40 mL, 2.3 mmol, 2.6 eq), and
4-dimethylaminopyridine (30.7 mg, 0.251 mmol, 0.29 eq) in 8.0 mL
N,N-dimethylformamide was stirred at 50.degree. C. for 3 hours. The
reaction mixture was partitioned between ethyl acetate and water,
and the organic portion washed with brine, dried over magnesium
sulfate, and concentrated to yield 232.3 mg (70%) of the crude
product. The crude product was purified by reverse phase HPLC and
lyophilized to give
N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 9.66 (s, 1H), 9.32 (d, 1H), 8.76 (d,
1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.48 (d, 1H), 7.40 (s, 1H), 7.28
(m, 2H), 3.91 (s, 3H), 3.84 (s, 3H).
Example 2
##STR00067##
[0355]
N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1-
,5-a]pyrimidine-3-carboxamide
[0356] To a solution of
N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide (145 mg, 0.379 mmol, 1 eq) in 3.0 mL
dichloromethane was added boron tribromide (1.1 mL of a 1.0 M
solution in dichloromethane, 1.1 mmol, 2.9 eq). The reaction was
stirred at room temperature for 16 hours. The reaction mixture was
then quenched with methanol, diluted into ethyl acetate, and washed
with saturated aqueous sodium bicarbonate and brine, dried over
magnesium sulfate and concentrated. The resulting solid material
was triturated with 2 mL DMSO, and the solids collected and dried
under vacuum to yield 47.8 mg (34%) of
N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide. LCMS (ESI) m+H=369.0; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.:10.45 (s, 1H), 9.99 (s, 1H), 9.33 (d,
1H), 8.76 (d, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 7.45 (s, 1H), 7.30
(m, 2H), 7.08 (d, 1H), 3.92 (s, 3H).
Example 3
##STR00068##
[0357]
N-(5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1-
,5-a]pyrimidine-3-carboxamide
##STR00069##
[0358] 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine
[0359] To a solution of tert-butyl
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate (774
mg, 2.29 mmol, 1 eq) was added hydrogen chloride (6.0 mL of a 4.0M
solution in 1,4-dioxane, 24 mmol, 10 eq). The reaction mixture was
stirred at room temperature for 4 hours and then evaporated to
dryness. The solid residue was partitioned between dichloromethane
and a saturated aqueous solution of sodium bicarbonate. The aqueous
portion was extracted once more with dichloromethane, and the
combined organic extracts dried over magnesium sulfate and
concentrated to give
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine, which was
carried forward without purification. LCMS (ESI) m+H=238.3; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.35 (d, 1H), 7.22 (overlapping
s and s, 2H), 6.94 (d, 1H), 3.83 (s, 3H), 3.70 (d, 2H), 3.66 (s,
3H).
##STR00070##
N-(5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide
[0360] A mixture of
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (0.100 g,
0.421 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(77.2 mg, 0.473 mmol, 1.12 eq),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (269 mg, 0.519 mmol, 1.23 eq),
N,N-diisopropylethylamine (0.15 mL, 0.86 mmol, 2.0 eq), and
4-dimethylaminopyridine (20.1 mg, 0.164 mmol, 0.39 eq) in 5.0 mL
N,N-dimethylformamide was stirred at 50.degree. C. for 2 hours. The
reaction mixture was partitioned between ethyl acetate and water,
and the organic portion washed with brine, dried over magnesium
sulfate, and concentrated. The crude product was purified by
reverse phase HPLC and lyophilized to give 82.2 mg (51%) of
N-(5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 9.51 (s, 1H), 9.31 (d, 1H), 8.67 (d,
1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.58 (d, 1H), 7.54 (s, 1H), 7.31
(d, 1H), 7.28 (d of d, 1H), 3.85 (s, 3H), 3.70 (s, 3H).
Example 4
##STR00071##
[0361]
N-(3-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide
and
Example 5
##STR00072##
[0362]
N-(5-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide
##STR00073##
[0363] di-tert-butyl
2-(2,5-dimethylphenyl)-2-oxoethyliminodicarbonate
[0364] In an oven-dried flask, di-tert-butyl iminodicarboxylate
(2.566 g, 11.81 mmol, 1.10 eq) was combined with sodium hydride
(60% on mineral oil, 0.586 g, 14.6 mmol, 1.37 eq) and 30 mL
N,N-dimethylformamide. The reaction mixture was stirred at room
temperature for 1.5 hours, and then
2-bromo-1-(2,5-dimethylphenyl)ethanone (2.432 g, 10.71 mmol, 1 eq)
was added. The reaction was stirred at room temperature for an
additional 1.5 hours, and then partitioned between ethyl acetate
and water. The organic portion was washed with water and brine,
dried over magnesium sulfate, and concentrated. The crude product
was purified by flash chromatography on silica gel (0 to 40% ethyl
acetate in heptanes) to obtain 3.008 g (77%) of di-tert-butyl
2-(2,5-dimethylphenyl)-2-oxoethyl-iminodicarbonate. LCMS (ESI)
m+Na=386.2.
##STR00074##
di-tert-butyl
1-(dimethylamino)-3-(2,5-dimethylphenyl)-3-oxoprop-1-en-2-yliminodicarbon-
ate
[0365] A stirred mixture of di-tert-butyl
2-(2,5-dimethylphenyl)-2-oxoethyliminodicarbonate (3.008 g, 8.275
mmol, 1 eq) and 1,1-dimethoxy-N,N-dimethylmethanamine (6.0 mL, 45
mmol, 5.4 eq) was heated at 70.degree. C. for 17 hours and then
100.degree. C. for 24 hours. After evaporation of excess
1,1-dimethoxy-N,N-dimethylmethanamine, the crude product was
purified by flash chromatography on silica gel (0 to 50% ethyl
acetate in heptanes) to yield 1.305 g (38%) of di-tert-butyl
1-(dimethylamino)-3-(2,5-dimethylphenyl)-3-oxoprop-1-en-2-yliminodicarbon-
ate. LCMS (ESI) m+H=419.3.
##STR00075##
3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine
[0366] Di-tert-butyl
1-(dimethylamino)-3-(2,5-dimethylphenyl)-3-oxoprop-1-en-2-yliminodicarbon-
ate (1.305 g, 3.118 mmol, 1 eq) and hydrazine (0.20 mL, 6.4 mmol,
2.0 eq) were dissolved together in 15 mL ethanol. The reaction
mixture was stirred at 70.degree. C. for 1 hour and then evaporated
to dryness under vacuum. The solid residue was dissolved in 8 mL
dichloromethane and hydrogen chloride (8.0 mL of a 4.0 M solution
in 1,4-dioxane, 0.10 mol, 40 eq) and stirred at room temperature
for 3.5 hours. The solvent and excess hydrogen chloride were
evaporated and the crude product partitioned between saturated
aqueous sodium bicarbonate and dichloromethane. The aqueous layer
was extracted once more with dichloromethane, and the combined
organic extracts dried over magnesium sulfate and concentrated to
give 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine, which was carried
forward without purification. LCMS (ESI) m+H=188.3.
##STR00076##
N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxamide
[0367] A mixture of 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine
(0.300 g, 1.60 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (289.2 mg, 1.773 mmol, 1.11 eq),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (1.087 g, 2.096 mmol, 1.31 eq),
N,N-diisopropylethylamine (1.0 mL, 5.7 mmol, 3.6 eq), and
4-dimethylaminopyridine (42.3 mg, 0.346 mmol, 0.22 eq) in 8.0 mL
N,N-dimethylformamide was stirred at 50.degree. C. for 3 hours. The
reaction mixture was partitioned between ethyl acetate and water,
and the organic portion washed with brine, dried over magnesium
sulfate, and concentrated. The crude product was purified by flash
chromatography on silica gel (40 to 100% ethyl acetate in
dichloromethane) to yield 299.8 mg (56%) of
N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxamide. LCMS (ESI) m+H=333.3; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 9.67 (s, 0.7H), 9.55 (s, 0.3H), 9.32 (d, 1H), 8.64 (s,
1H), 8.49 (d, 1H), 8.27 (s, 1H), 7.29 (d, 1H), 7.22 (m, 3H), 2.34
(s, 3H), 2.24 (s, 3H).
##STR00077##
N-(3-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide
##STR00078##
[0368]
N-(5-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide
[0369] To a solution of
N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxamide (0.255 g, 0.767 mmol, 1 eq) in 10 mL N,N-dimethylformamide
is added iodomethane (60.0 .mu.L, 0.964 mmol, 1.26 eq) and cesium
carbonate (0.562 g, 1.72 mmol, 2.25 eq).
[0370] The reaction mixture is stirred at 40.degree. C. for 2.5
hours. The reaction mixture was partitioned between ethyl acetate
and water, and the organic portion washed with brine, dried over
magnesium sulfate, and concentrated. The mixture of regioisomeric
products was separated and purified by flash chromatography on
silica gel (20 to 90% ethyl acetate in dichloromethane) to yield:
84.3 mg (32%) of
N-(3-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide. LCMS (ESI) m+H=347.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.65 (s, 1H), 9.30 (d, 1H), 8.65 (s, 1H),
8.47 (d, 1H), 8.27 (s, 1H), 7.27 (d, 1H), 7.23-7.19 (m, 3H), 3.91
(s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), and 81.8 mg (31%) of
N-(5-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide. LCMS (ESI) m+H=347.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.42 (s, 1H), 9.30 (d, 1H), 8.61 (s, 1H),
8.43 (d, 1H), 8.01 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H) 7.20 (m,
2H), 3.62 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H).
Example 6
##STR00079##
[0371]
N-(1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,-
5-a]pyrimidine-3-carboxamide
##STR00080##
[0372] (5-chloro-2-methylphenyl)hydrazine hydrochloride
[0373] To a stirred suspension of 5-chloro-2-methylaniline (1.436
g, 10.14 mmol, 1. eq) in 10 mL water at 0.degree. C. was added 10
mL concentrated hydrochloric acid. To this reaction mixture was
added dropwise a solution of sodium nitrite (0.791 g, 11.5 mmol,
1.13 eq) in 5 mL water. The reaction mixture was stirred at
0.degree. C. for 2 hours while tin chloride dihydrate (5.8826 g,
25.839 mmol, 2.55 eq), dissolved in 8 mL concentrated hydrochloric
acid, was slowly added. Water was added as needed to maintain the
stirring while solids formed. The reaction was kept at 0.degree. C.
for 45 minutes. The white solids were filtered and rinsed with two
50 mL portions of diethyl ether, then dried under vacuum to provide
1.49 g (76%) of (5-chloro-2-methylphenyl)hydrazine hydrochloride.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.08 (s, 3H), 7.98
(s, 1H), 7.13 (d, 1H), 6.97 (s, 1H), 6.91 (d, 1H), 2.14 (s,
3H).
##STR00081##
1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine
[0374] To a solution of (5-chloro-2-methylphenyl)hydrazine
hydrochloride (1.49 g, 7.72 mmol, 1 eq) in 8 mL ethanol was added
hydrogen chloride (4.0 mL of a 5 M aqueous solution, 20 mmol, 2 eq)
and 3-aminocrotonitrile (0.664 g, 8.09 mmol, 1.05 eq). The reaction
mixture was stirred at 80.degree. C. for 16 hours and then brought
to neutral pH with saturated aqueous sodium bicarbonate. The
resulting solution was extracted twice with dichloromethane, and
the combined extracts were dried over magnesium sulfate and
concentrated to give
1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine, which was
carried forward without further purification. LCMS (ESI) m+H=222.2;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.39 (d, 1H), 7.37 (d,
1H), 7.25 (s, 1H), 5.22 (s, 1H), 5.00 (s, 2H), 2.04 (overlapping s
and s, 6H).
##STR00082##
N-(1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]py-
rimidine-3-carboxamide
[0375] A mixture of
1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine (95.3 mg,
0.430 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(79.5 mg, 0.487 mmol, 1.13 eq),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (0.290 g, 0.558 mmol, 1.30 eq),
N,N-diisopropylethylamine (0.2 mL, 1.1 mmol, 2.7 eq), and
4-dimethylaminopyridine (11.0 mg, 0.09 mmol, 0.21 eq) in 4.0 mL
N,N-dimethylformamide was stirred at 75.degree. C. for 3 days. The
reaction mixture was partitioned between ethyl acetate and water,
and the organic portion washed with brine, dried over magnesium
sulfate, filtered through a silica gel plug, and concentrated. The
crude product was purified by reverse phase HPLC and lyophilized to
give 50.0 mg (30%) of
N-(1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]py-
rimidine-3-carboxamide. LCMS (ESI) m+H=367.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.03 (s, 1H), 9.32 (d, 1H), 8.68 (s, 1H),
8.36 (d, 1H), 7.60 (d, 1H), 7.58 (s, 1H), 7.55 (d, 1H), 7.27 (d of
d, 1H), 6.53 (s, 1H), 2.24 (s, 3H), 2.05 (s, 3H).
Example 7
##STR00083##
[0376]
N-(5-(2,5-dichlorophenyl)-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
##STR00084##
[0377] 5-bromo-2-methylpyridine 1-oxide
[0378] A solution of 5-bromo-2-methylpyridine (2.0 g, 12 mmol, 1.0
eq) and m-chloroperoxybenzoic acid (70%, 2.89 g, 12.9 mmol, 1.1 eq)
in 30 mL chloroform was stirred at room temperature for 4 hours.
The reaction mixture was then partitioned between dichloromethane
and 2 M aqueous sodium carbonate. The aqueous layer was extracted
once more with dichloromethane, and the combined organic portions
dried over magnesium sulfate and concentrated to give
5-bromo-2-methylpyridine 1-oxide. LCMS (ESI) m+H=189.0; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 8.57 (s, 1H), 7.50 (d, 1H), 7.45
(d, 1H), 2.30 (s, 3H).
##STR00085##
5-bromo-2-methyl-4-nitropyridine 1-oxide
[0379] 5-bromo-2-methylpyridine 1-oxide (2.269 g, 12.07 mmol, 1 eq)
was dissolved in sulfuric acid (4 mL, 80 mmol, 6 eq) and cooled at
0.degree. C. Fuming nitric acid (3 mL, 60 mmol, 5 eq) was added
dropwise. After addition of the nitric acid was complete, the
reaction mixture was first warmed to room temperature and then
heated to 90.degree. C. After 2 hours the reaction was cooled in an
ice bath and slowly adjusted to pH 10 with 2 M aqueous sodium
carbonate. This solution was extracted twice with dichloromethane.
The combined organic extracts were dried over magnesium sulfate and
concentrated to yield 2.54 g (90%) of
5-bromo-2-methyl-4-nitropyridine 1-oxide. LMCS (ESI) m+H=233.0.
##STR00086##
5-bromo-2-methylpyridin-4-amine
[0380] To a solution of 5-bromo-2-methyl-4-nitropyridine 1-oxide
(2.54 g, 10.9 mmol, 1 eq) in 10 mL concentrated hydrochloric acid
was added tin chloride dihydrate (9.96 g, 43.8 mmol, 4.01 eq). The
reaction mixture was stirred at 90.degree. C. for 24 hours, and
then additional tin chloride dihydrate (3.15 g, 13.8 mmol, 1.27 eq)
and 5 mL concentrated hydrochloric acid was added. The reaction
mixture was kept at 90.degree. C. for an additional 24 hours, and
then cooled to room temperature and adjusted to neutral pH with 2 M
aqueous sodium carbonate. The solution was extract three times with
dichloromethane, and the combined organic extracts dried over
magnesium sulfate and concentrated to give
5-bromo-2-methylpyridin-4-amine LCMS (ESI) m+H=187.2; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 8.07 (s, 1H), 6.51 (s, 1H), 6.13
(s, 2H), 2.22 (s, 3H).
##STR00087##
N-(5-bromo-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0381] To a suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (165.0 mg, 1.011 mmol, 1.2 eq) in 6 mL dichloromethane was
added oxalyl chloride (0.90 mL of a 2.0 M solution in
dichloromethane, 1.8 mmol, 2.1 eq) and three drops of
N,N-dimethylformamide. After stirring at room temperature for 1
hour, the reaction mixture was concentrated and dried under vacuum
to yield the acyl chloride. The solid residue was re-dissolved in 6
mL dichloromethane, and to this solution was added
5-bromo-2-methylpyridin-4-amine (157.6 mg, 0.8426 mmol, 1.0 eq) and
triethylamine (0.50 mL, 3.6 mmol, 4.2 eq). The reaction was stirred
at room temperature for one hour and then concentrated onto silica.
The crude product was purified by flash chromatography on silica
gel (0 to 100% ethyl acetate in dichloromethane) to yield 197.5 mg
(71%) of
N-(5-bromo-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
LCMS (ESI) m+H=332.2.
##STR00088##
N-(5-(2,5-dichlorophenyl)-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide
[0382]
N-(5-bromo-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide (82.2 mg, 0.247 mmol, 1 eq), 2,5-dichlorophenylboronic acid
(122.1 mg, 0.6399 mmol, 2.59 eq), and
bis(triphenylphosphine)palladium(II) chloride (15.4 mg, 0.0219
mmol, 0.09 eq) were combined in a microwave vial. To these solids
were added sodium carbonate (1.0 mL of a 1.0 M aqueous solution,
1.0 mmol, 4.0 eq) and 3.0 mL acetonitrile. The vial was sealed and
subjected to microwave irradiation (120.degree. C., 30 W) for 30
minutes. The reaction was partitioned between ethyl acetate and
water, and the organic layer dried over magnesium sulfate and
concentrated. The crude product was purified by reverse phase HPLC
and lyophilized to give 45.3 mg (46%) of
N-(5-(2,5-dichlorophenyl)-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide. LCMS (ESI) m+H=398.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.75 (s, 1H), 9.32 (d, 1H), 8.71 (s, 1H),
8.48 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1H), 7.78 (d, 1H), 7.75 (d,
1H), 7.69 (s, 1H), 7.26 (d of d, 1H), 2.55 (s, 3H).
Example 8
##STR00089##
[0383]
N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
##STR00090##
[0384] 2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione
[0385] A mixture of 2-bromo-3'-chloroacetophenone (0.927 g, 3.97
mmol, 1 eq) and potassium phthalimide (0.813 g, 4.39 mmol, 1.1 eq)
in 15 mL N,N-dimethylformamide was stirred at 50.degree. C. for one
hour. The solvent was removed under vacuum. The resulting solids
were triturated with ethyl acetate and filtered. The collected
solids were dried under vacuum to give
2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione, which was
carried forward without purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 8.13 (s, 1H), 8.05 (d, 1H), 7.96 (m, 2H),
7.93 (m, 2H), 7.83 (d, 1H), 7.65 (t, 1H), 5.29 (s, 2H).
##STR00091##
2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1-
,3-dione
[0386] A stirred mixture of
2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione (782.2 mg,
2.610 mmol, 1 eq) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.5
mL, 11 mmol, 4.3 eq) was heated at 100.degree. C. for 18 hours.
Excess 1,1-dimethoxy-N,N-dimethylmethanamine was removed under
vacuum. The crude product was purified by flash chromatography on
silica gel (50 to 100% ethyl acetate in heptanes) to yield 740 mg
(80%) of
2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1-
,3-dione. LCMS (ESI) m+H=355.2; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.90 (d of d, 2H), 7.77 (d of d, 2H), 7.57 (s, 1H), 7.44
(d, 1H), 7.37 (overlapping d and s, 2H), 7.31 (t, 1H), 3.00 (s,
6H).
##STR00092##
3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine
[0387] To a solution of
2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1-
,3-dione (2.30 g, 6.48 mmol, 1 eq) in 50 mL ethanol was added
N-methylhydrazine (1.4 mL, 26 mmol, 4.0 eq). The reaction mixture
was stirred at 80.degree. C. for 2 hours and then concentrated onto
silica gel. The crude mixture of regioisomers was separated and
purified by flash chromatography on silica gel (0 to 80% ethyl
acetate in dichloromethane) to yield: 715 mg (53%) of
3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine LCMS (ESI)
m+H=208.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.78 (s, 1H),
7.63 (d, 1H), 7.33 (t, 1H), 7.25 (overlapping with CDCl.sub.3, 1H),
7.04 (s, 1H), 3.84 (s, 3H), and 274.6 mg (20%) of
5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine LCMS (ESI)
m+H=208.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.43 (t, 1H),
7.38 (overlapping d and s, 2H), 7.27 (d, 1H), 7.23 (s, 1H), 3.76
(s, 3H).
##STR00093##
N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide
[0388] A mixture of 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine
(400.0 mg, 1.926 mmol, 1 eq),
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (342.9 mg, 2.102 mmol,
1.09 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (1.205 g, 2.324 mmol, 1.21 eq),
N,N-diisopropylethylamine (0.80 mL, 4.6 mmol, 2.4 eq), and
4-dimethylaminopyridine (43.4 mg, 0.355 mmol, 0.18 eq) in 15.0 mL
N,N-dimethylformamide was stirred at 50.degree. C. for 15 hours.
The reaction mixture was partitioned between dichloromethane and
water, and the aqueous layer extracted once more with
dichloromethane. The combined organic portions were dried over
magnesium sulfate and concentrated onto silica gel. The crude
product was separated by flash chromatography on silica gel (0 to
70% ethyl acetate (containing 2% methanol) in dichloromethane). The
resulting solid material was triturated with ethyl acetate. After
sonication the solids were collected by filtration and dried under
vacuum to yield 0.502 g (74%) of
N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide. LCMS (ESI) m+H=353.0; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 10.00 (s, 1H), 9.38 (d, 1H), 8.85 (d, 1H),
8.70 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H), 7.76 (d, 1H), 7.57 (t,
1H), 7.49 (d, 1H), 7.34 (d of d, 1H), 3.93 (s, 3H).
Example 9
##STR00094##
[0389]
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide
##STR00095##
[0390] 3-(3-chlorophenyl)-1H-pyrazol-4-amine
[0391] A mixture of
2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1-
,3-dione (255 mg, 0.719 mmol, 1 eq) and hydrazine (0.15 mL, 4.8
mmol, 6.6 eq) in 10 mL ethanol was stirred under reflux for 2
hours. The ethanol and excess hydrazine were removed under vacuum.
The crude product was purified by flash chromatography on silica
gel (50 to 100% ethyl acetate in heptanes) to yield 111.4 mg (80%)
of 3-(3-chlorophenyl)-1H-pyrazol-4-amine LCMS (ESI) m+H=194.0;
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.75 (broad, 1H), 7.65
(broad, 1H), 7.41 (t, 1H), 7.32 and 7.30 (overlapping s and s,
2H).
##STR00096##
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide
[0392] A mixture of 3-(3-chlorophenyl)-1H-pyrazol-4-amine (95.3 mg,
0.492 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(90.6 mg, 0.555 mmol, 1.13 eq),
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium
hexafluorophosphate (247.3 mg, 0.6504 mmol, 1.32 eq),
N,N-diisopropylethylamine (0.20 mL, 1.1 mmol, 2.3 eq), and
4-dimethylaminopyridine (24.1 mg, 0.197 mmol, 0.40 eq) in 5.0 mL
N,N-dimethylformamide was stirred at 50.degree. C. for 3 hours. The
reaction mixture was partitioned between ethyl acetate and water,
and the organic portion washed with brine, dried over magnesium
sulfate and concentrated. The crude product was purified by reverse
phase HPLC and lyophilized to give 33.8 mg (20%) of
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide. LCMS (ESI) m+H=339.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.05 (s, 1H), 9.99 (s, 1H), 9.38 (d, 1H), 8.84 (d, 1H),
8.70 (s, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.78 (d, 1H), 7.58 (t,
1H), 7.50 (d, 1H), 7.34 (d of d, 1H).
Example 10
##STR00097##
[0393]
N-(3-(3-chlorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]py-
rimidine-3-carboxamide
[0394]
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide (68.9 mg, 0.203 mmol, 1 eq) was dissolved in 4 mL
N,N-dimethylformamide. To this solution was added cesium carbonate
(148 mg, 0.454 mmol, 2.23 eq) and isopropyl iodide (23.0 .mu.L,
0.230 mmol, 1.13 eq). The reaction mixture was stirred at
50.degree. C. for 2 hours. The reaction mixture was partitioned
between ethyl acetate and water, and the organic portion washed
with brine, dried over magnesium sulfate and concentrated. The
crude product was purified by reverse phase HPLC and lyophilized to
give 47.2 mg (61%) of
N-(3-(3-chlorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide. LCMS (ESI) m+H=381.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.99 (s, 1H), 9.37 (d, 1H), 8.85 (d, 1H),
8.70 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.77 (d, 1H), 7.57 (t,
1H), 7.48 (d, 1H), 7.34 (d of d, 1H), 4.59 (d of q, 1H), 1.48 (d,
6H).
Example 11
##STR00098##
[0395]
N-(3-(3-chlorophenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0396]
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide (58.9 mg, 0.174 mmol, 1 eq) was dissolved in 5 mL
N,N-dimethylformamide. To this solution was added isobutylene oxide
(0.5 mL, 6 mmol, 30 eq) and cesium carbonate (56.4 mg, 0.173 mmol,
1.0 eq). The reaction mixture was stirred at 50.degree. C. for 7.5
hours. The reaction mixture was partitioned between ethyl acetate
and water, and the organic portion washed with brine, dried over
magnesium sulfate and concentrated. The crude product was purified
by reverse phase HPLC and lyophilized to give 33.1 mg (46%) of
N-(3-(3-chlorophenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazo-
lo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=411.1; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.02 (s, 1H), 9.36 (d, 1H),
8.83 (d, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.76 (d,
1H), 7.58 (t, 1H), 7.49 (d, 1H), 7.33 (d of d, 1H), 4.73 (s, 1H),
4.09 (s, 2H), 1.13 (s, 6H).
Example 12
##STR00099##
[0397]
N-(1-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pyrazolo[-
1,5-a]pyrimidine-3-carboxamide
##STR00100##
[0398]
N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxamide
[0399] A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(165.5 mg, 1.014 mmol, 1.01 eq),
4-bromo-1-methyl-1H-pyrazol-3-amine (177.4 mg, 1.008 mmol, 1.0 eq),
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium
hexafluorophosphate (497 mg, 1.31 mmol, 1.30 eq),
N,N-diisopropylethylamine (0.25 mL, 1.4 mmol, 1.4 eq), and
4-dimethylaminopyridine (33.8 mg, 0.277 mmol, 0.27 eq) in 5 mL
N,N-dimethylformamide was heated at 50.degree. C. for 4 days. The
reaction mixture was partitioned between ethyl acetate and water,
and the organic portion washed with brine, dried over magnesium
sulfate and concentrated. The crude product was purified by flash
chromatography on silica gel (20 to 80% ethyl acetate in
dichloromethane (containing 5% methanol)) to yield 203.6 mg (63%)
of
N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxami-
de. LCMS (ESI) m+H=321.1; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 9.16 (d, 1H), 8.84 (d, 1H), 8.68 (s, 1H), 7.76 (s, 1H),
7.28 (d of d, 1H), 3.88 (s, 3H).
##STR00101##
N-(1-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]-
pyrimidine-3-carboxamide
[0400] To a stir-bar equipped microwave vial was added:
N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxami-
de (101 mg, 0.313 mmol, 1 eq), 2-trifluoromethylphenyl boronic acid
(126.6 mg, 0.6666 mmol, 2.13 eq),
bis(triphenylphosphine)palladium(II) chloride (26.8 mg, 0.0382
mmol, 0.12 eq), sodium carbonate (1.0 mL of a 2.0 M aqueous
solution, 2 mmol, 6 eq), and 3 mL acetonitrile. The reaction
mixture was subjected to microwave irradiation at 130.degree. C.
for 30 minutes. The reaction mixture was partitioned between ethyl
acetate and water, and the organic portion washed with brine, dried
over magnesium sulfate and concentrated. The crude product was
purified by reverse phase HPLC and lyophilized to give 4.7 mg (4%)
of
N-(1-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]-
pyrimidine-3-carboxamide. LCMS (ESI) m+H=387.1; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 9.58 (s, 1H), 9.32 (d, 1H), 8.74 (d,
1H), 8.57 (s, 1H), 7.78 (s, 1H), 7.74 (d, 1H), 7.60 (t, 1H), 7.49
(m, 2H), 7.28 (d of d, 1H), 3.87 (s, 3H).
Example 13
##STR00102##
[0401]
N-(1-(2,5-difluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide
##STR00103##
[0402] 3-(2-(2,5-difluorophenyl)hydrazinyl)propanenitrile
[0403] A solution of acrylonitrile (10 mL), ethanol (20 mL) and
2,5-difluorophenylhydrazine (790 mg) was heated to reflux for 2
days. The reaction was concentrated under vacuum and the product
purified by flash chromatography on silica gel with methylene
chloride to give 790 mg (73%)
3-(2-(2,5-difluorophenyl)hydrazinyl)propanenitrile. LCMS (ESI)
m+H=198.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.99 (ddd,
1H), 6.89 (ddd, 1H), 6.38 (tt, 1H), 5.45 (s, 1H), 3.91 (s, 1H),
3.19 (td, 2H), 2.61 (t, 2H).
##STR00104##
(E)-3-((2,5-difluorophenyl)diazenyl)propanenitrile
[0404] To a solution of
3-(2-(2,5-difluorophenyl)hydrazinyl)propanenitrile (790 mg) in 15
mL of 2N sulfuric acid was added 2.0 g of iron(III) sulfate
hydrate. The reaction mixture was stirred at ambient temperature
for 30 min as the iron sulfate slowly dissolved and a yellow oil
precipitated. The reaction mixture was extracted with ether, and
the extracts were washed with water, brine, dried over sodium
sulfate, filtered through a plug of silica gel and concentrated to
give 710 mg (91%) of
(E)-3-((2,5-difluorophenyl)diazenyl)propanenitrile. LCMS (ESI)
m+H=196.2. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34-7.08 (m,
3H), 4.54-4.31 (m, 2H), 2.99 (t, 2H).
##STR00105##
1-(2,5-difluorophenyl)-1H-pyrazol-5-amine
[0405] A mixture of
(E)-3-((2,5-difluorophenyl)diazenyl)propanenitrile (710 mg) and 20
mL of 1N NaOH was heated to reflux with stirring for 30 min. The
reaction mixture was cooled to ambient temperature and extracted
with ether. The ether phase was washed with water, brine, dried
over sodium sulfate and filtered through a plug of silica gel.
Concentration under vacuum gave 630 mg (88%) of
1-(2,5-difluorophenyl)-1H-pyrazol-5-amine. LCMS (ESI) m+H=196.0;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.54-7.43 (m, 1H),
7.35-7.00 (m, 3H), 5.63 (d, 1H), 3.96-3.71 (m, 2H).
##STR00106##
N-(1-(2,5-difluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxamide
[0406] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.020 g, 0.12
mmol), 3 mL of phosphoryl chloride and 32 .mu.L of
N,N-diisopropylethylamine were heated to 120.degree. C. for 2 hr
and evaporated to dryness. The residue was taken up in
dichloromethane and added to a mixture of
1-(2,5-difluorophenyl)-1H-pyrazol-5-amine (18 mg),
N,N-diisoproplyethylamine (32 .mu.L) and dichloromethane (1 mL) and
stirred overnight. The reaction mixture was concentrated and the
product purified by flash chromatography on silica gel (95/5
dichloromethane/7M NH3 in MeOH) to give 8.0 mg (20%) of
N-(1-(2,5-difluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxamide. LCMS (ESI) m+H=341.2; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 10.14 (s, 1H), 8.80 (dd, 1H), 8.72 (d, 1H), 8.38 (dd, 1H),
7.72 (t, 1H), 7.38 (ddd, 1H), 7.33-7.27 (m, 1H), 7.22 (ddd, 1H),
7.03-6.99 (m, 1H), 6.88 (d, 1H).
Example 14
##STR00107##
[0407]
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4--
yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
and
Example 15
##STR00108##
[0408]
N-(5-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4--
yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00109##
[0409] 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
[0410] In an oven-dried flask equipped with stir bar,
4-nitro-1H-pyrazole (6.598 g, 58.35 mmol) was dissolved in 50 mL
THF. Sodium hydride (4.83 g of a 60% dispersion with mineral oil,
121 mmol) was added while cooling in an ice bath, and the reaction
then stirred at room temperature for 10 minutes.
[.beta.-(trimethylsilyl)ethoxy]methyl chloride (12.0 mL, 67.8 mmol)
was then added, and the reaction stirred at room temperature for
1.5 hours. The reaction was quenched with 50 mL water, and
extracted with ethyl acetate. The organic extract was dried over
magnesium sulfate and concentrated. The resulting crude material
was purified by flash chromatography on silica gel (0 to 30% ethyl
acetate in heptanes) to obtain 14.1 g (99%) of
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. LCMS
(ESI) m+H=244.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.28
(s, 1H), 8.08 (s, 1H), 5.43 (s, 2H), 3.61 (t, 2H), 0.92 (t,
2H).
##STR00110##
3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-pyrazole
[0411] To a solution of
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4.26 g,
17.5 mmol) in 40 mL N,N-dimethylacetamide was added
2-bromo-4-chloroanisole (3.35 mL, 24.6 mmol), palladium (II)
acetate (197.2 mg, 0.878 mmol), di(1-adamantyl)-n-butylphosphine
(469.5 mg, 1.309 mmol), potassium carbonate (7.27 g, 52.6 mmol),
and trimethylacetic acid (0.452 g, 4.43 mmol). While stirring at
room temperature, nitrogen gas was bubbled through the reaction
mixture for 10 minutes, and the reaction then heated at 120.degree.
C. for 6 hours. The reaction was then cooled to room temperature,
diluted into ethyl acetate, and washed with water and brine, dried
over magnesium sulfate and concentrated. The crude material was
purified by flash chromatography on silica gel (0 to 25% ethyl
acetate in heptanes) to obtain 6.719 g (89%) of
3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-pyrazole. LCMS (ESI) m+H=384.2; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 8.22 (s, 1H), 7.46 (d of d, 1H), 7.36 (d, 1H),
6.95 (d, 1H), 5.23 (m, 2H), 3.56 (m, 2H), 0.87 (m, 2H).
##STR00111##
3-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra-
zol-4-amine
[0412] To a solution of
3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-pyrazole (5.97 g, 15.6 mmol) in 25 mL ethanol was added 50 mL
water, ammonium chloride (3.37 g, 62.9 mmol), and iron powder
(4.367 g, 78.2 mmol). The reaction mixture was stirred at
75.degree. C. for 1.5 hours. After cooling to room temperature, the
reaction was diluted with dichloromethane and filtered through a
celite pad, rinsing with more dichloromethane. The filtrate was
added to 150 mL saturated aqueous sodium bicarbonate and extracted
twice with dichloromethane. The combined organic extracts were
dried over magnesium sulfate and concentrated to yield 5.50 g
(100%) of
3-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra-
zol-4-amine, which was carried forward without purification. LCMS
(ESI) m+H=354.3; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.44
(d, 1H), 7.34 (d of d, 1H), 7.28 (s, 1H), 6.92 (d, 1H), 5.24 (s,
2H), 3.52 (t, 2H), 0.85 (t, 2H), -0.04 (s, 9H).
##STR00112##
N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0413] A mixture of
3-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra-
zol-4-amine (179.6 mg, 0.5075 mmol),
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (91 mg, 0.560 mmol),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (326 mg, 0.630 mmol), N,N-diisopropylethylamine
(0.25 mL, 1.4 mmol), and 4-dimethylaminopyridine (11.5 mg, 0.094
mmol) in 5.0 mL N,N-dimethylformamide was stirred at 40.degree. C.
for 1.5 hours. The reaction mixture was partitioned between ethyl
acetate and water, and the organic portion washed with brine, dried
over magnesium sulfate, filtered through a pad of silica gel, and
concentrated to give 0.212 g (84%) of
N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was
carried forward without purification. LCMS (ESI) m+H=499.2; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 9.56 (s, 1H), 8.76 (d, J=7.0,
1H), 8.72 (s, 1H), 8.50 (d, J=4.1, 1H), 8.39 (s, 1H), 7.54 (d,
J=2.6, 1H), 7.44 (dd, J=8.8, 2.6, 1H), 7.04-6.92 (m, 2H), 5.35 (d,
2H), 3.82 (s, 3H), 3.57 (m, 2H), 0.86 (m, 2H), -0.04 (s, 9H).
##STR00113##
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide
[0414] To a solution of
N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (2.75 g, 5.51
mmol) in 105 mL ethanol was added HCl (8.0 mL of a 5 M solution in
water, 40 mmol). The reaction mixture was then stirred at
70.degree. C. for 2 hours. After cooling to room temperature, the
product was filtered as a light yellow solid, rinsing with methanol
and diethyl ether. The filtrate was reduced in volume, and more
solid product filtered. The combined collected solids were dried
under vacuum to yield 1.81 g (89%) of
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide. LCMS (ESI) m+H=369.2; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.66 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H),
8.78 (dd, J=4.2, 1.6, 1H), 8.65 (s, 1H), 8.20 (s, 1H), 7.50 (dd,
J=8.8, 2.7, 1H), 7.44 (d, J=2.7, 1H), 7.29 (dd, J=7.8, 4.8, 2H),
3.86 (s, 3H).
##STR00114##
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyr-
azolo[1,5-a]pyrimidine-3-carboxamide
##STR00115##
[0415]
N-(5-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4--
yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0416] To a solution of
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (39.1 mg, 0.106 mmol) in 3 mL DMF was added cesium
carbonate (109.7 mg, 0.3367 mmol) and 4-(2-chloroethyl)morpholine
HCl. The reaction mixture was stirred at 50.degree. C. for 5 hours.
The reaction mixture was partitioned between ethyl acetate and
water, and the organic portion washed with brine, dried over
magnesium sulfate, and concentrated. The mixture of regioisomer
products was separated and purified by reverse phase HPLC and
lyophilized to give 19.4 mg (38%)
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyr-
azolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI) m+H=482.1; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.50 (s, 1H), 9.31 (dd, 1H),
8.66 (d, 1H), 8.63 (s, 1H), 8.03 (s, 1H), 7.58 (dd, 1H), 7.54 (d,
1H), 7.32 (d, 1H), 7.27 (dd, 1H), 4.05 (m, 2H), 3.85 (s, 3H), 3.44
(m, 2H), 2.71 (m, 2H), 2.60 (m, 2H), 2.23 (m, 4H); and 9.3 mg (18%)
of
N-(5-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyr-
azolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI) m+H=482.1; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.67 (s, 1H), 9.31 (dd, 1H),
8.76 (d, 1H), 8.65 (s, 1H), 8.34 (s, 1H), 7.48 (dd, 1H), 7.39 (d,
1H), 7.30 (d, 1H), 7.38 (t, 1H), 4.29 (t, 2H), 3.84 (s, 3H), 3.58
(t, 2H), 2.77 (t, 2H), 2.46 (m, 4H).
Example 16
##STR00116##
[0417]
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyr-
azol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0418] To a solution of
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (102.7 mg, 0.279 mmol) in 3 mL DMF was added
isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (180.0
mg, 0.5524 mmol). The reaction was stirred at 40.degree. C. for 15
hours. The reaction mixture was partitioned between ethyl acetate
and water, and the organic portion washed with brine, dried over
magnesium sulfate, and concentrated. The crude product was purified
by reverse phase HPLC and lyophilized to give 49.3 mg (40%) of
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-
-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=441.1;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.68 (s, 1H), 9.32
(dd, 1H), 8.76 (d, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 7.48 (dd, 1H),
7.39 (d, 1H), 7.31 (s, 1H), 7.28 (t, 1H), 4.72 (s, 1H), 4.07 (s,
2H), 3.84 (s, 3H), 1.12 (s, 6H).
Example 17
##STR00117##
[0419]
N-(3-(5-chloro-2-ethoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,-
5-a]pyrimidine-3-carboxamide
##STR00118##
[0420]
N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1-
,5-a]pyrimidine-3-carboxamide
[0421] To a solution of
N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide (synthesized following the procedures
described for Example 14) (193.9 mg, 0.5065 mmol) in 8.0 mL
dichloromethane was added boron tribromide (1.50 mL of a 1.0M
solution in dichloromethane, 1.5 mmol). The reaction was stirred at
room temperature for 1 hour. The reaction was then quenched with 1
mL methanol, diluted with ethyl acetate, and washed with saturated
aqueous sodium bicarbonate and brine, dried over magnesium sulfate,
and concentrated to give 191.5 mg (100%) of
N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide, which was carried forward without
purification. LCMS (ESI) m+H=369.1.
##STR00119##
N-(3-(5-chloro-2-ethoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]py-
rimidine-3-carboxamide
[0422] To a solution of
N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide (61.1 mg, 0.166 mmol) in 3.0 mL acetone was
added iodoethane (26.0 .mu.L, 0.325 mmol) and potassium carbonate
(70.6 mg, 0.511 mmol). The reaction was stirred at 45.degree. C.
for 3 hours. The reaction mixture was partitioned between ethyl
acetate and water, and the organic portion washed with brine, dried
over magnesium sulfate, and concentrated. The crude product was
purified by reverse phase HPLC and lyophilized to give 34.8 mg
(54%)
N-(3-(5-chloro-2-ethoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]py-
rimidine-3-carboxamide. LCMS (ESI) m+H=397.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.68 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H),
8.73 (dd, J=4.2, 1.6, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 7.46 (dd,
J=8.8, 2.7, 1H), 7.38 (d, J=2.7, 1H), 7.32-7.23 (m, 2H), 4.12 (q,
J=6.9, 2H), 3.91 (s, 3H), 1.04 (t, J=6.9, 3H).
Example 18
##STR00120##
[0423]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-methyl-1H-pyrazol-4-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00121##
[0424] 2-bromo-4-chloro-1-(difluoromethoxy)benzene
[0425] To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol)
in 25 mL DMF was added sodium chlorodifluoroacetate (8.42 g, 55.2
mmol), cesium carbonate (10.97 g, 33.67 mmol) and 2.5 mL water. The
reaction was stirred at 100.degree. C. for 16 hours. The reaction
mixture was partitioned between ethyl acetate and water, and the
organic portion washed with brine, dried over magnesium sulfate,
and concentrated. The crude product was purified by flash
chromatography on silica gel (0 to 20% ethyl acetate in heptanes)
to yield 2.98 g (48%) of
2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless
oil. LCMS (ESI) no m/z signal; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t,
1H).
##STR00122##
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-methyl-1H-pyrazol-4-yl)pyrazo-
lo[1,5-a]pyrimidine-3-carboxamide
[0426] Using 2-bromo-4-chloro-1-(difluoromethoxy)benzene, the title
compound was synthesized following the synthetic procedures
described for Example 14. LCMS (ESI) m+H=419.0; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 9.71 (s, 1H), 9.34 (dd, J=7.0, 1.6,
1H), 8.67 (dd, J=4.7, 2.0, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 7.62
(dd, J=8.8, 2.7, 1H), 7.59 (d, J=2.6, 1H), 7.45 (d, J=8.7, 1H),
7.29 (dd, J=7.0, 4.2, 1H), 7.23 (t, 1H), 3.93 (s, 3H).
Example 19
##STR00123##
[0427]
N-(3-(5-chloro-2-(methylthio)phenyl)-1-methyl-1H-pyrazol-4-yl)pyraz-
olo[1,5-a]pyrimidine-3-carboxamide
##STR00124##
[0428] (4-chloro-2-iodophenyl)(methyl)sulfane
[0429] To a 0.degree. C. solution of concentrated sulfuric acid
(0.3 mL, 5.0 mmol) in 5.0 mL water and 5.0 mL acetonitrile was
added 5-chloro-2-(methylthio)aniline (472 mg, 2.72 mmol), followed
by slow addition of sodium nitrite (210 mg, 3.0 mmol) as a solution
in 1 mL water. The reaction mixture was stirred at 0.degree. C. for
30 minutes. This mixture was then slowly added to a 0.degree. C.
solution of potassium iodide (691.7 mg, 4.167 mmol) in 5 mL water.
The reaction was stirred for 1 hour, allowing the ice bath to warm
to room temperature. The reaction mixture was then partitioned
between water and ethyl acetate. The organic layer was dried with
brine and magnesium sulfate and concentrated. The crude product was
purified by flash chromatography on silica gel (0 to 30% ethyl
acetate in dichloromethane) to yield 598.4 mg (77%) of
(4-chloro-2-iodophenyl)(methyl)sulfane. LCMS (ESI) no m/z signal;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.87 (d, 1H), 7.47
(dd, 1H), 7.20 (d, 1H), 2.47 (s, 3H).
##STR00125##
N-(3-(5-chloro-2-(methylthio)phenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,-
5-a]pyrimidine-3-carboxamide
[0430] Using (4-chloro-2-iodophenyl)(methyl)sulfane, the title
compound was prepared following the synthetic procedures described
for Example 14. LCMS (ESI) m+H=399.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.69 (s, 1H), 9.32 (dd, J=7.0, 1.6, 1H),
8.65 (s, 1H), 8.57 (dd, J=4.2, 1.6, 1H), 8.27 (s, 1H), 7.55 (dd,
J=8.6, 2.4, 1H), 7.45 (d, J=8.6, 1H), 7.40 (d, J=2.4, 1H), 7.25
(dd, J=7.0, 4.2, 1H), 3.91 (s, 3H), 2.38 (s, 3H).
Example 20
##STR00126##
[0431]
N-(3-(5-chloro-2-ethoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyra-
zol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00127##
[0432] 2-bromo-4-chloro-1-ethoxybenzene
[0433] To a solution of 2-Bromo-4-chlorophenol (2.12 g, 10.2 mmol)
in 25 mL acetone was added iodoethane (0.850 mL, 10.6 mmol) and
cesium carbonate (4.08 g, 12.5 mmol). The reaction mixture was
stirred at 50.degree. C. for 2 hours. The reaction mixture was
partitioned between ethyl acetate and water, and the organic
portion washed with brine, dried over magnesium sulfate, and
concentrated to yield 2.37 g (98%) of
2-bromo-4-chloro-1-ethoxybenzene as a yellow oil, which was carried
forward without further purficiation. LCMS (ESI) no m/z signal;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.67 (d, J=2.6, 1H),
7.39 (dd, J=8.8, 2.6, 1H), 7.12 (d, J=8.9, 1H), 4.11 (q, J=7.0,
2H), 1.35 (t, J=7.0, 3H).
##STR00128##
N-(3-(5-chloro-2-ethoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4--
yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0434] Using 2-bromo-4-chloro-1-ethoxybenzene, the title compound
was prepared using the synthetic procedures described for Examples
14 and 16. LCMS (ESI) m+H=455.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.71 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H),
8.73 (dd, J=4.2, 1.6, 1H), 8.66 (s, 1H), 8.33 (s, 1H), 7.47 (dd,
J=8.8, 2.7, 1H), 7.38 (d, J=2.7, 1H), 7.28 (m, 2H), 4.73 (s, 1H),
4.12 (q, J=6.9, 2H), 4.07 (s, 2H), 1.13 (s, 6H), 1.03 (t, J=6.9,
3H).
Example 21
##STR00129##
[0435]
N-(1-(2-aminoethyl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)py-
razolo[1,5-a]pyrimidine-3-carboxamide
[0436] To a solution of
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H--
pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared
following the synthetic procedures described for Example 14) (104.1
mg, 0.192 mmol) in 8 mL ethanol was added hydrazine (78 .mu.L, 2.5
mmol). The reaction mixture was stirred at room temperature for 18
hours, and then concentrated. The crude product was purified by
reverse phase HPLC and lyophilized to give 17.7 mg (15.4%) of
N-(1-(2-aminoethyl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo-
[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=412.1; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 9.68 (s, 1H), 9.33 (dd, J=7.0,
1.6, 1H), 8.77 (dd, J=4.2, 1.6, 1H), 8.65 (s, 1H), 8.30 (s, 1H),
7.49 (dd, J=8.8, 2.7, 1H), 7.42 (d, J=2.7, 1H), 7.29 (m, 2H), 4.14
(t, J=6.2, 2H), 3.85 (s, 3H), 2.99 (t, J=6.2, 2H).
Example 22
##STR00130##
[0437]
(S)--N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-3-methylbutyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
and
Example 23
##STR00131##
[0438]
(R)--N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-3-methylbutyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0439] Racemic
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-3-methylbutyl)-1H-pyrazol-4--
yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described
for example 16) was subjected to chiral SFC chromatography to yield
the title compounds. LCMS (ESI) m+H=455.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.67 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H),
8.77 (dd, J=4.2, 1.6, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 7.49 (dd,
J=8.8, 2.8, 1H), 7.40 (d, J=2.7, 1H), 7.34-7.24 (m, 2H), 4.86 (d,
J=5.8, 1H), 4.19 (dd, J=13.8, 3.7, 1H), 4.04 (dd, J=13.8, 8.1, 1H),
3.84 (s, 3H), 3.64 (m, 1H), 1.63 (m, 1H), 0.93 (t, J=7.2, 6H).
Example 24
##STR00132##
[0440]
N-(3-(5-chloro-2-methoxyphenyl)-1-((1-hydroxycyclopentyl)methyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00133##
[0441] 1-(iodomethyl)cyclopentanol
[0442] In a 100 mL flask was placed samarium powder (40 mesh, 3.07
g, 2.02 mmol), and this flask was cooled under nitrogen in an ice
bath. An addition funnel was charged with a solution of
cyclopentanone (0.90 mL, 10.1 mmol) and diiodomethane (2.40 mL,
29.8 mmol) in 50 mL tetrahydrofuran, and this solution was dropwise
added to the stirring samarium powder over 1 hour. After addition
was complete, the reaction was stirred for one additional hour at
0.degree. C. The reaction was treated with 40 mL of 1N aqueous HCl
and extracted with 100 mL diethyl ether. The ether layer was washed
with 4% aqueous Na.sub.2S.sub.2O.sub.3 and brine, dried over
magnesium sulfate, and concentrated. The crude product was purified
by flash chromatography on silica gel (0 to 30% ethyl acetate in
heptane) to yield 1.17 g (51%) of 1-(iodomethyl)cyclopentanol as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 3.47 (s,
2H), 1.70-1.92 (m, 8H).
##STR00134##
N-(3-(5-chloro-2-methoxyphenyl)-1-((1-hydroxycyclopentyl)methyl)-1H-pyraz-
ol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0443] To a solution of
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (prepared as described for Example 14, 115.4 mg,
0.313 mmol) in 3 mL DMF is added 1-(iodomethyl)cyclopentanol (195.4
mg, 2.762 mmol) and cesium carbonate (339.2 mg, 3.327 mmol). The
reaction was stirred in a sealed vessel at 140.degree. C. for 18
hours. The reaction mixture was partitioned between ethyl acetate
and water, and the organic portion washed with brine, dried over
magnesium sulfate, and concentrated. The crude product was
separated from the other regioisomeric product and purified by
reverse phase HPLC and lyophilized to give 32.1 mg (22%) of
N-(3-(5-chloro-2-methoxyphenyl)-1-((1-hydroxycyclopentyl)methyl)-1H-pyraz-
ol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI)
m+H=467.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.68 (s,
1H), 9.33 (dd, J=7.0, 1.6, 1H), 8.77 (dd, J=4.2, 1.6, 1H), 8.64 (s,
1H), 8.33 (s, 1H), 7.49 (dd, J=8.9, 2.7, 1H), 7.39 (d, J=2.7, 1H),
7.32-7.25 (m, 2H), 4.67 (s, 1H), 4.19 (s, 2H), 3.84 (s, 3H), 1.61
(m, 8H).
Example 25
##STR00135##
[0444]
N-(3-(3-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
##STR00136##
[0445] 1-(3-chlorophenyl)butane-1,3-dione
[0446] To a solution of 3-chloroacetophenone (1.30 mL, 10.0 mmol)
in 20 mL THF was added Potassium tert-butoxide (11.0 mL of a 1.0 M
solution in THF, 11.0 mmol) and then anhydrous ethyl acetate (1.05
mL, 10.7 mmol). The reaction was stirred at room temperature for 2
hours and then at 50.degree. C. for 15 hours. The reaction mixture
was partitioned between ethyl acetate and water, and the organic
portion washed with brine, dried over magnesium sulfate, and
concentrated. The crude product was purified by flash
chromatography on silica gel (0 to 50% ethyl acetate in heptanes)
to yield 0.75 g (38%) of 1-(3-chlorophenyl)butane-1,3-dione. LCMS
(ESI) m+H=197.2.
##STR00137##
1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione
[0447] To a 0.degree. C. solution of
1-(3-chlorophenyl)butane-1,3-dione (0.75 g, 3.8 mmol) in 15 mL
acetic acid was slowly added sodium nitrite (0.560 g, 8.11 mmol) as
a solution in 1.5 mL water. The reaction was stirred at 0.degree.
C. for 30 minutes and then warmed to room temperature. After an
additional 4 hours, the reaction was poured into aqueous saturated
sodium bicarbonate and extracted three times with dichloromethane.
The combined extracts were dried over magnesium sulfate and
concentrated to yield 765.7 mg (89%) of
1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione, which was
carried forward without further purification. LCMS (ESI) m+H=226;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.81 (d, 1H), 7.80 (s,
1H), 7.75 (d, 1H), 7.62 (t, 1H), 2.60 (s, 1H), 2.48 (s, 3H).
##STR00138##
5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine
[0448] To a 0.degree. C. solution of
1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione (224.8 mg,
0.996 mmol) in 5 mL ethanol was dropwise added hydrazine (0.30 mL,
9.6 mmol). The reaction was warmed to room temperature and stirred
for 15 hours. The crude reaction mixture was concentrated and
purified by flash chromatography on silica gel (20 to 100% ethyl
acetate in dichloromethane) to yield 113.3 mg (55%) of
5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine LCMS (ESI)
m+H=208.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.20 (s,
1H), 7.94-7.57 (m, 2H), 7.40 (s, 1H), 7.27 (d, J=9.1, 1H), 2.12 (s,
3H).
##STR00139##
N-(3-(3-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide
[0449] A mixture of 5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine
(113.3 mg, 0.546 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(109.5 mg, 0.6712 mmol),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (338.2 mg, 0.652 mmol),
N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and
4-dimethylaminopyridine (19.1 mg, 0.156 mmol) in 8.0 mL
N,N-dimethylformamide was stirred at 50.degree. C. for 15 hours.
The reaction mixture was partitioned between ethyl acetate and
water, and the organic portion washed with brine, dried over
magnesium sulfate, and concentrated. The crude product was purified
by reverse phase HPLC and lyophilized to give 86.9 mg (45%) of
N-(3-(3-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide. LCMS (ESI) m+H=353.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.90 (s, 1H), 9.37 (d, J=7.0, 1H), 9.30 (s,
1H), 8.86 (dd, J=4.1, 1.3, 1H), 8.69 (s, 1H), 7.80 (d, J=12.1, 1H),
7.72 (d, J=7.6, 1H), 7.37 (t, J=7.8, 1H), 7.32 (dd, J=6.9, 4.4,
2H), 2.18 (s, 3H).
Example 26
##STR00140##
[0450]
N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazol-4-yl)pyrazol-
o[1,5-a]pyrimidine-3-carboxamide
##STR00141##
[0451] 1-isopentyl-4-nitro-1H-pyrazole
[0452] A mixture of 4-Nitro-1H-pyrazole (234 mg, 2.06 mmol, 1.0
eq), 1-Bromo-3-methylbutane (0.30 ml, 2.48 mmol, 1.2 eq), and
Cesium carbonate (1.01 g, 3.10 mmol, 1.5 eq) in 5.0 mL
1,2-Dimethoxyethane was stirred at 55.degree. C. for 12 hours. The
reaction mixture was cooled to room temperature and diluted with 25
mL ethyl acetate and filtered. The filtrate was then concentrated
and the residue was dissolved in 5 mL dichloromethane and purified
by flash column chromatography (silica, 0-80% ethyl acetate in
heptane in 30 minutes) to yield 357.6 mg (94.32%) of
Isopentyl-4-nitro-1H-pyrazole as a white solid. LCMS (ESI)
m+H=184.1 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11 (s, 1H),
8.06 (s, 1H), 4.20-4.14 (m, 2H), 1.80 (dd, J=14.8, 7.1, 2H), 1.60
(dp, J=13.4, 6.7, 1H), 0.97 (d, J=6.6, 6H).
##STR00142##
N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-4-nitro-1H-pyrazole
[0453] A mixture of 1-Isopentyl-4-nitro-1H-pyrazole (356.9 mg, 1.95
mmol, 1.00 eq), 2-Bromo-4-chloroanisole (0.37 ml, 2.72 mmol, 1.40
eq), Palladium (II) acetate (88 mg, 0.39 mmol, 0.20 eq),
Di(1-adamntyl)-n-butylphosphine (209 mg, 0.58 mmol, 0.30 eq),
potassium carbonate (807 mg, 5.84 mmol, 3.00 eq) and
trimethylacetic acid (52 mg, 0.50 mmol, 0.26 eq) in 5.0 mL
N,N-Dimethylacetamide was stirred at 120.degree. C. for 12 hours.
The reaction mixture was cooled to room temperature and diluted
with 20 mL ethyl acetate and filtered. The filtrate was then
concentrated and used as is for the next step. LCMS (ESI)
m+H=324.3
##STR00143##
N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazole-4-amine
[0454] A mixture of
5-(5-Chloro-2-methoxyphenyl)-1-isopenyl-4-nitro-1H-pyrazole (632
mg, 1.95 mmol, 1.00 eq), iron (642.5 mg, 11.50 mmol, 5.90 eq), and
ammonium chloride (500.7 mg, 9.36 mmol, 4.80 eq) in 5.0 mL ethanol
and 10 mL water was stirred at 75.degree. C. for 2 hours. The
reaction mixture was concentrated, 10 mL of saturated bicarbonate
solution was added, and the aqueous layer was extracted with
dichloromethane (20 mL*3). The combined dichloromethane layers were
dried with magnesium sulfate, filtered and concentrated. The
reddish yellow oil was used as is for the next step LCMS (ESI)
m+H=293.8.
##STR00144##
N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazol-4-yl)pyrazolo[1,5--
a]pyrimidine-3-carboxamide
[0455] A mixture of
5-(5-Chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazole-4-amine (573.0
mg, 1.95 mmol, 1.00 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (349.9 mg, 2.145 mmol, 1.10 eq),
7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium
hexafluorophosphate (1.25 g, 2.42 mmol, 1.24 eq), and
N,N-diisopropylethylamine (0.95 mL, 5.5 mmol, 2.8 eq) in 5.0 mL
N,N-dimethylformamide was stirred at room temperature for 12 hours.
The reaction mixture was concentrated. The crude product was
purified by reverse phase HPLC and lyophilized to give 105.2 mg
(12.3%) of
N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazol-4-yl)pyrazolo[1,5--
a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=439.1; .sup.1H NMR (400
MHz, DMSO) .delta. 9.50 (s, 1H), 9.32 (dd, J=7.0, 1.6, 1H),
8.73-8.57 (m, 2H), 8.01 (s, 1H), 7.60 (dd, J=8.9, 2.7, 1H), 7.48
(d, J=2.7, 1H), 7.33 (d, J=9.0, 1H), 7.27 (dd, J=7.0, 4.2, 1H),
3.97 (dq, J=16.6, 6.8, 2H), 3.84 (s, 3H), 1.54 (q, J=7.1, 2H),
1.45-1.31 (m, 1H), 0.75 (dd, J=12.0, 6.6, 6H).
Example 27
##STR00145##
[0456]
2-amino-N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)py-
razolo[1,5-a]pyrimidine-3-carboxamide
##STR00146##
[0457] (Z)-ethyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate
[0458] To a mixture of trichloroacetonitrile (38 mL, 0.38 mol) and
cyanoacetic acid ethyl ester (20 mL, 0.2 mol) in ethanol (63 mL)
was added triethylamine (1 mL, 7 mmol). The reaction mixture began
to turn red and an exotherm occured after .about.1 minute. The
reaction mixture was cooled to 0.degree. C., then stirred for two
hours while slowly warming to room temperature. The reaction
mixture was concentrated in vacuo to a red oil, which was taken up
in DCM, filtered through a plug of silica gel, and concentrated in
vacuo to afford 44.95 g (90%) of (Z)-ethyl
3-amino-4,4,4-trichloro-2-cyanobut-2-enoate as a colorless oil that
slowly solidified to a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.19 (s, 1H), 6.85 (s, 1H), 4.31 (q, J=7.1,
1H), 1.37 (t, J=7.1, 3H).
##STR00147##
ethyl 3,5-diamino-1H-pyrazole-4-carboxylate
[0459] Hydrazine (2.19 mL, 70 mmol) was added to (Z)-ethyl
3-amino-4,4,4-trichloro-2-cyanobut-2-enoate (15.0 g, 58 mmol) in
DMF (50 mL). The reaction mixture was heated to 100.degree. C. for
1 hr, then cooled to room temperature. The DMF was removed in
vacuo, then the residue was slurried in a 95:5 mixture of DCM:2M
methanolic ammonia solution. The resulting precipitate was filtered
off, washed with a 95:5 mixture of DCM:MeOH, and dried under vacuum
to afford 5.72 g (58%) of ethyl
3,5-diamino-1H-pyrazole-4-carboxylate as a white solid. .sup.1H NMR
(400 MHz, DMSO) .delta. 10.53 (s, 1H), 5.28 (br, 4H), 4.14 (q,
J=7.1, 2H), 1.33-1.15 (t, J=7.1, 3H).
##STR00148##
ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate
[0460] A mixture of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate
(1.0 g, 5.9 mmol), 1,1,3,3-tetramethoxypropane (2.9 mL, 18 mmol),
triethylamine (2 mL, 10 mmol), and DMF (15 mL) was heated at
100.degree. C. for 14 hrs, then a further 2 mL of
1,1,3,3-tetramethoxypropane was added.
[0461] After adding the additional 1,1,3,3-tetramethoxypropane, a
significant by-product was noted and heating was stopped
immediately. The reaction was cooled to room temperature and the
DMF was removed in vacuo. The residue was partitioned between DCM
and water, then the organic layer was concentrated and the residue
purified by silica chromatography, eluting with 95:5 DCM: 2M
methanolic ammonia solution to afford 420 mg (35%) of ethyl
2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.57 (dd, J=4.3, 1.6, 1H), 8.43 (dd,
J=6.7, 1.6, 1H), 6.84 (dd, J=6.7, 4.4, 1H), 5.52 (s, 2H), 4.48 (q,
J=7.1, 2H), 1.45 (t, J=7.1, 3H).
##STR00149##
ethyl
2-(bis(tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbox-
ylate
[0462] Di-tert-butyldicarbonate (1.30 g, 5.9 mmol) was added to a
solution of ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate
(810 mg, 3.9 mmol), 4-dimethylaminopyridine (96 mg, 0.78 mmol), and
N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) in acetonitrile (100
mL). The reaction was stirred at room temperature for 3 hours, then
concentrated in vacuo. The residue was partitioned between EtOAc
and water, then the layers were separated and the organic layer was
washed with brine, then dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by silica chromatography,
eluting with a 97:3 mixture of DCM: 2M methanolic ammonia solution
to afford 370 mg (31%) of ethyl
2-(bis(tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbox-
ylate. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.79 (dd, J=4.2,
1.8, 1H), 8.69 (dd, J=7.0, 1.8, 1H), 7.05 (dd, J=7.0, 4.2, 1H),
4.40 (q, J=7.1, 2H), 1.43 (s, 18H), 1.38 (t, J=7.1, 3H).
##STR00150##
2-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[0463] To a solution of
2-(bis(tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
(220 mg, 0.54 mmol) in ethanol (15 mL) was added 4 mL of a 10%
aqueous lithium hydroxide solution. The reaction mixture was heated
to 70.degree. C. for 18 hrs, then cooled to room temperature. 15 mL
of a 10% aqueous solution of citric acid was added and the reaction
mixture concentrated in vacuo. The residue was partitioned between
EtOAc and a saturated aqueous solution of citric acid, then the
organic layer was washed with water and brine, then dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford 150
mg of
2-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid. .sup.1H NMR (400 MHz, DMSO) .delta. 9.34 (s, 1H), 9.12 (dd,
J=6.9, 1.7, 1H), 8.71 (dd, J=4.3, 1.7, 1H), 7.20 (dd, J=6.9, 4.3,
1H), 1.49 (s, 9H).
##STR00151##
tert-butyl
3-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)pyrazol-
o[1,5-a]pyrimidin-2-ylcarbamate
[0464] To a solution of
2-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (88 mg, 0.32 mmol),
5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (75 mg,
0.32 mmol), 4-dimethylaminopyridine (7.7 mg, 0.063 mmol), and
N,N-diisopropylethylamine (0.16 mL, 0.95 mmol) in DMF (3 mL) was
added PyAOP (200 mg, 0.38 mmol). The reaction mixture was stirred
for 14 hrs at 50.degree. C., then diluted with EtOAc. The organic
layer was washed twice with water, and once with brine, then dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel chromatography, eluting with EtOAc to afford
98 mg (62%) of tert-butyl
3-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)pyrazol-
o[1,5-a]pyrimidin-2-ylcarbamate. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.85 (s, 1H), 9.65 (s, 1H), 8.76 (dd, J=6.8, 1.7, 1H), 8.44
(dd, J=4.3, 1.7, 1H), 8.20 (s, 1H), 7.56 (d, J=2.7, 1H), 7.36 (dd,
J=8.8, 2.7, 1H), 6.97 (d, J=8.9, 1H), 6.90 (dd, J=6.9, 4.3, 1H),
3.97 (s, 3H), 3.87 (s, 3H), 1.56 (s, 9H).
##STR00152##
2-amino-N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo-
[1,5-a]pyrimidine-3-carboxamide
[0465] TFA (0.5 mL) was added to a solution of tert-butyl
3-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)pyrazol-
o[1,5-a]pyrimidin-2-ylcarbamate (80 mg, 0.2 mmol) in DCM (10 mL).
The reaction mixture was stirred for 3 hrs at room temperature,
then concentrated in vacuo. The residue was purified by silica gel
chromatography to afford 55 mg (90%) of
2-amino-N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo-
[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (ESI)
m+H=398.1; .sup.1H NMR (400 MHz, DMSO) .delta. 9.46 (s, 1H), 8.91
(dd, J=6.7, 1.6, 1H), 8.44 (dd, J=4.5, 1.6, 1H), 8.21 (s, 1H), 7.47
(dd, J=8.9, 2.7, 1H), 7.37 (d, J=2.7, 1H), 7.27 (d, J=8.9, 1H),
6.99 (dd, J=6.7, 4.5, 1H), 6.56 (s, 2H), 3.89 (s, 3H), 3.83 (s,
3H).
[0466] Examples 28-131 shown in Table 1 were prepared generally
following the above-described Examples. For each compound shown in
Table 1, the Example number followed is given in the Method
column.
TABLE-US-00001 TABLE 1 LCMS Ex Structure Name Mthd (ESI) m/z 28
##STR00153## N-(1-(2-chloro-5-methylphenyl)- 3-methyl-1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 367.0 29 ##STR00154##
N-(3-(2,5-dichlorophenyl)-1- methyl-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 4 387.0 30 ##STR00155##
N-(3-(2,5-dichlorophenyl)-1- methyl-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 373.2 31
##STR00156## N-(5-(2,5-dichlorophenyl)-1- methyl-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 5 387.0 32 ##STR00157##
N-(3-(2,5-dichlorophenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 4 373.2 33 ##STR00158##
N-(1-(2-ethynylphenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 342.9 34 ##STR00159##
N-(3-methyl-1-(2- (methylthio)phenyl)-1H-pyrazol-
5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 6 364.9 35
##STR00160## N-(1-(2,6-dimethylphenyl)-3- methyl-1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 346.9 36 ##STR00161##
N-(1-(2-iodophenyl)-1H-pyrazol- 5-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 13 430.8 37 ##STR00162## N-(1-(2,4-difluorophenyl)-1H-
pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 340.9 38
##STR00163## N-(1-(2-chloro-5-cyanophenyl)-3- methyl-1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 377.8 39 ##STR00164##
N-(1-o-tolyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 13 318.9 40 ##STR00165## N-(1-(2,4-difluorophenyl)-3-
methyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6
355.2 41 ##STR00166## N-(1-(2,5-dichlorophenyl)-3-
methyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6
387.1 42 ##STR00167## N-(1-(2-fluorophenyl)-1H-pyrazol-
5-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 323.2 43
##STR00168## N-(1-(2-ethylphenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 347.2 44 ##STR00169##
N-(1-(2-bromophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 397.2 45 ##STR00170##
N-(1-(3,5-dimethylphenyl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 333.2 46
##STR00171## N-(1-(2,5-dimethylphenyl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 333.2 47
##STR00172## N-(1-m-tolyl-1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 319.2 48
##STR00173## N-(1-(2,5-dichlorophenyl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 373.0 49
##STR00174## N-(1-(2-(trifluoromethyl)phenyl)- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 373.1 50
##STR00175## N-(1-(3,5-dichlorophenyl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 373.0 51
##STR00176## N-(1-(2-chlorophenyl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 338.9 52
##STR00177## N-(5-(3-chlorophenyl)-2- methylpyridin-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 364.0 53 ##STR00178##
N-(3-(2,5-dichlorophenyl)pyridin- 4-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 7 384.3 54 ##STR00179## N-(1-(4-chlorophenyl)-1H-
pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 338.9 55
##STR00180## N-(1-(3-chlorophenyl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13 338.9 56
##STR00181## N-(3-(2,3-dichlorophenyl)pyridin-
4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 384.0 57
##STR00182## N-(3-(2,3-dimethylphenyl)pyridin-
4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 344.1 58
##STR00183## N-(3-(2,3-difluorophenyl)pyridin-
4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 352.0 59
##STR00184## N-(3-(3-chlorophenyl)-1-(2-
hydroxyethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 10 383.1 60 ##STR00185## N-(3-(3-chlorophenyl)-1-(2-
hydroxy-3-methoxypropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 10 427.1 61
##STR00186## N-(3-o-tolylpyridin-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 7 330.0 62 ##STR00187## N-(3-(2-fluorophenyl)pyridin-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 334.1 63 ##STR00188##
N-(3-(3-fluorophenyl)pyridin-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 7 334.1 64 ##STR00189##
N-(3-methyl-1-(pyridin-3-yl)-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 319.8 65 ##STR00190##
N-(1-(2-cyanophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 344.1 66 ##STR00191##
N-(1-(3-fluorophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 336.9 67 ##STR00192##
N-(1-(3-cyanophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 344.0 68 ##STR00193##
N-(3-(3-chlorophenyl)-1-(2- morpholinoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 10 452.1 69
##STR00194## N-(3-(3-chlorophenyl)-1-(2-
(diethylamino)ethyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 10 438.1 70 ##STR00195##
(R)-N-(3-(3-chlorophenyl)-1-(2,3- dihydroxypropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 10 413.1 71
##STR00196## (S)-N-(3-(3-chlorophenyl)-1-(2,3-
dihydroxypropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 10 413.1 72 ##STR00197##
N-(5-(3-fluorophenyl)-1-methyl- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 8 337.3 73 ##STR00198##
N-(3-(3-fluorophenyl)-1-methyl- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 8 337.3 74 ##STR00199##
N-(3-(3-fluorophenyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 9 323.0 75 ##STR00200## N-(1-(4-fluorophenyl)-3-methyl-
1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 337.1
76 ##STR00201## N-(1-(2-fluorophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 337.0 77 ##STR00202##
N-(1-(2-chlorophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 353.1 78 ##STR00203##
N-(1-phenyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 13 305.0 79 ##STR00204## N-(2-(2-
(trifluoromethyl)phenyl)pyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 7 384.1 80 ##STR00205## N-(2-(3-chlorophenyl)pyridin-3-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 350.0 81 ##STR00206##
N-(3-(3-chlorophenyl)pyridin-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 7 350.0 82 ##STR00207## N-(4-(3-chlorophenyl)-1-methyl-
1H-pyrazol-3- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 12 353.0
83 ##STR00208## N-(3-methyl-1-(3- (trifluoromethyl)phenyl)-1H-
pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 386.8 84
##STR00209## N-(3-methyl-1-(2- (trifluoromethyl)phenyl)-1H-
pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 387.2 85
##STR00210## N-(3-methyl-1-m-tolyl-1H- pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 333.2 86 ##STR00211##
N-(3-methyl-1-o-tolyl-1H-pyrazol- 5-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 6 332.9 87 ##STR00212## N-(1-(4-chlorophenyl)-3-methyl-
1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 353.1
88 ##STR00213## N-(1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 353.1 89 ##STR00214##
N-(1-(4-methoxyphenyl)-3- methyl-1H-pyrazol-5-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 6 349.2 90 ##STR00215##
N-(5-(5-chloro-2-methoxyphenyl)- 1-((1-hydroxycyclopentyl)methyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 24 467.1
91 ##STR00216## (R)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-hydroxy-2- methylbutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 22 455.1 92
##STR00217## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
2-methylbutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 22 455.1 93 ##STR00218##
N-(1-(2-aminoethyl)-3-(5-chloro- 2-ethoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 20, 21 426.1 94
##STR00219## N-(3-(5-chloro-2-ethoxyphenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 20 383.0 95
##STR00220## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxypentyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 22 455.1 96 ##STR00221## (R)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- hydroxypentyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 22 455.1 97
##STR00222## N-(5-(5-chloro-2-methoxyphenyl)-
1-(2-hydroxypentyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 455.1 98 ##STR00223## (S)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- hydroxybutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 22 441.1 99
##STR00224## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxybutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 22 441.1 100 ##STR00225##
N-(5-(5-chloro-2-methoxyphenyl)- 1-(2-hydroxybutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 441.1 101
##STR00226## N-(3-(5-chloro-2-methoxyphenyl)-
1-((1S,2S)-2-hydroxycyclohexyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 467.1 And And
##STR00227## N-(3-(5-chloro-2-methoxyphenyl)-
1-((1R,2R)-2-hydroxycyclohexyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 102 ##STR00228##
(S)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(4,4,4-trifluoro- 2-hydroxybutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 22 495.1 103
##STR00229## (R)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(4,4,4-trifluoro- 2-hydroxybutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 22 495.1 104
##STR00230## N-(5-(5-chloro-2-methoxyphenyl)-
1-(4,4,4-trifluoro-2-hydroxybutyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 495.1 105
##STR00231## N-(5-(5-chloro-2-methoxyphenyl)-
1-(2-hydroxy-3-methylbutyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 455.1 106
##STR00232## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-hydroxyethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 14 413.1 107 ##STR00233##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(3-hydroxypropyl)-1H-pyrazol-
4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 427.1 108
##STR00234## N-(5-(5-chloro-2-methoxyphenyl)-
1-(3-hydroxypropyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 15 427.1 109 ##STR00235##
N-(5-(5-chloro-2-methoxyphenyl)- 1-(2-hydroxyethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 15 413.1 110
##STR00236## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-methoxyethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 14 427.0 111 ##STR00237##
N-(5-(5-chloro-2-methoxyphenyl)- 1-(2-methoxyethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 15 427.1 112
##STR00238## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2,3-dihydroxypropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 443.1 113
##STR00239## N-(5-(5-chloro-2-methoxyphenyl)-
1-(2,3-dihydroxypropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 443.1 114
##STR00240## N-(1-(2-amino-2-oxoethyl)-3-(5-
chloro-2-methoxyphenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 426.1 115
##STR00241## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxypropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 427.1 116 ##STR00242##
N-(5-(5-chloro-2-methoxyphenyl)- 1-((S)-2-hydroxypropyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 427.1 117
##STR00243## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxypropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 427.1 118 ##STR00244##
N-(5-(5-chloro-2-methoxyphenyl)- 1-((R)-2-hydroxypropyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 427.1 119
##STR00245## N-(3-(5-chloro-2- isopropoxyphenyl)-1-methyl-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 17 411.1 120
##STR00246## N-(3-(2,5-dimethylphenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 4 333.1 121
##STR00247## N-(1-(2-aminoethyl)-5-(5-chloro-
2-methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 21 412.1 122 ##STR00248##
N-(5-(5-chloro-2-methoxyphenyl)- 1-(2-(dimethylamino)ethyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 15 440.1 123
##STR00249## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(dimethylamino)ethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 440.1 124
##STR00250## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-1-(2-
hydroxy-2-methylpropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 and 18 477.1 125
##STR00251## N-(5-(5-chloro-2-methoxyphenyl)-
1-(piperidin-4-ylmethy;)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 466.1 126
##STR00252## N-(5-(5-chloro-2-methoxyphenyl)-
2-(2-methoxyethoxy)ethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 471.1 127
##STR00253## N-(5-(5-chloro-2-methoxyphenyl)-
1-((tetrahydro-2H-pyran-4- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 467.1 128
##STR00254## 4-(5-(5-chloro-2-methoxyphenyl)- 4-(pyrazolo-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamido)-1H-pyrazol-1-
yl)butanoic acid 26 455.1 129 ##STR00255## Ethyl-4-(5-(5-chloro-2-
methoxyphenyl)-4-(pyrazolo-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamido)-1H-pyrazol-1- yl)butanoate 26 483.1 130 ##STR00256##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(3-methyloxetan-3-yl)methyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 453.1
131 ##STR00257## N-(5-(5-chloro-2-methoxyphenyl)-
1-(cyclopropylmethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 423.1
Example 132
##STR00258##
[0468]
(S)--N-(3-(5-chloro-2-methoxyphenyl)-1-(2,3-dihydroxy-3-methylbutyl-
)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00259##
(R)--N-(3-(5-chloro-2-methoxyphenyl)-1-(2,3-dihydroxy-3-methylbutyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0469] To a suspension of
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (114.0 mg, 0.31 mmol) and cesium carbonate (201.4
mg, 0.62 mmol) in N,N-dimethylformamide (2 mL), was added
4-bromo-2-methyl-2-butene (53 .mu.L, 0.46 mmol). The reaction
mixture was stirred for 3 hours at room temperature, then EtOAc was
added. The organic layer was washed 1.times. each with water and
saturated brine solution. The organic layer was separated, then
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
was purified by silica gel chromatography (20-100% EtOAc:Hex) to
afford
N-(3-(5-chloro-2-methoxyphenyl)-1-(3-methylbut-2-enyl)-1H-pyrazol-4-yl)py-
razolo[1,5-a]pyrimidine-3-carboxamide as a light yellow foam (67
mg, 0.15 mmol). Acetone and water (1 mL each) were then added,
followed by osmium tetraoxide (1.89 mg, 0.0074 mmol), and
N-methylmorpholine-N-oxide in water (1:1,
N-methylmorpholine-N-oxide:Water, 37 mg). The reaction mixture was
stirred for 3 hours at room temperature. Celite was added and the
mixture was concentrated in vacuo. The residue was purified by
silica gel chromatography (50-100% EtOAc*:Hex, *EtOAc also
contained 10% MeOH), and then by chiral SFC to separate enantiomers
to give 11.2 mg and 15.8 mg of the title compounds as white solids.
LCMS (ESI) m+H=471.1; .sup.1H NMR (500 MHz, DMSO) .delta. 9.69 (s,
1H), 9.34 (d, J=6.9, 1H), 8.78 (d, J=4.0, 1H), 8.66 (s, 1H), 8.30
(s, 1H), 7.49 (dd, J=8.8, 2.6, 1H), 7.42 (d, J=2.6, 1H), 7.29 (dd,
J=10.0, 4.6, 2H), 5.05 (d, J=6.3, 1H), 4.53 (s, 1H), 4.43 (d,
J=13.5, 1H), 3.95 (dd, J=13.5, 10.1, 1H), 3.85 (s, 3H), 3.60 (s,
1H), 1.16 (s, 3H), 1.10 (s, 3H).
Example 133
##STR00260##
[0470]
(S)--N-(1-(3-(azetidin-1-yl)-2-hydroxypropyl)-3-(5-chloro-2-methoxy-
phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0471] To a suspension of
N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (60 mg, 0.16 mmol) and cesium carbonate (212 mg,
0.65 mmol) in N,N-Dimethylformamide (1 mL) was added
(S)-2-(chloromethyl)oxirane (26.3 mg, 0.28 mmol). The reaction
mixture was stirred for 8 hours at room temperature, at which time
LCMS analysis showed complete consumption of starting material.
Azetidine (44 uL, 0.65 mmol) was added and the reaction mixture was
stirred for an additional 16 hours at room temperature. The
reaction mixture was filtered and purified by reverse phase HPLC to
afford the title compound as a white solid (7.8 mg). LCMS (ESI)
m+H=482.2; .sup.1H NMR (400 MHz, DMSO) .delta. 9.69 (s, 1H), 9.34
(dd, J=7.0, 1.6, 1H), 8.78 (dd, J=4.2, 1.6, 1H), 8.66 (s, 1H), 8.27
(s, 1H), 7.50 (dd, J=8.9, 2.7, 1H), 7.40 (d, J=2.7, 1H), 7.33-7.26
(m, 2H), 4.94 (d, J=5.4, 1H), 4.21 (dd, J=13.7, 3.8, 1H), 3.99 (dd,
J=13.8, 7.8, 1H), 3.84 (s, 3H), 3.77 (s, 1H), 3.17 (t, J=6.9, 4H),
2.39 (qd, J=12.0, 5.9, 2H), 2.02-1.93 (m, 2H).
Example 134
##STR00261##
[0472]
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(3,3-dimethylpyrrolidin-1-yl)--
2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00262##
[0473] tert-butyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)acetate
[0474]
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyri-
midine-3-carboxamide (2.0 g, 5.4 mmol), t-butyl-bromoacetate (0.88
mL, 6.0 mmol), and cesium carbonate (2.1 g, 6.5 mmol) were combined
and stirred at 30.degree. C. overnight. The mixture was warmed to
65.degree. C. at which time additional carbonate and
t-butylbromoacetate was added and stirred 8 hrs. The mixture was
cooled to ambient temperature and stirred overnight, then
partitioned EtOAc/water. The organic phase was separated, washed
with brine, dried (Na.sub.2SO.sub.4), filtered through silica gel,
and concentrated to a solid. The solid was washed with 1:1
EtOAc/hexanes to yield 1.85 g (71%) of tert-butyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)acetate as yellow crystals. LCMS (ESI)
m+H=483.0. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.74 (s, 1H),
8.77 (m, 1H), 8.73 (s, 1H), 8.51 (m, 1H0, 8.38 (s, 1H), 8.02 (s,
1H), 7.58 (s, 1H), 7.31 (m, 1H), 6.97 (m, 2H), 4.85 (s, 2H), 3.83
(s, 3H), 1.49 (s, 9H).
##STR00263##
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)acetic acid
[0475] To tert-butyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)acetate (1.85 g, 3.83 mmol) in 50 mL
dichloromethane was added 30 ml of TFA. The mixture was stirred 2 h
at ambient temperature, then concentrated and recrystallized from
EtOAc to furnish 1.4 g (86%) of
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)acetic acid as a colorless solid. LCMS (ESI)
m+H=427.1. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.95 (s, 1H),
9.08 (m, 1H), 8.69 (m, 1H), 8.63 (s, 1H), 8.34 (s, 1H), 7.47 (m,
2H), 7.21 (m, 2H), 5.03 (s, 2H), 3.86 (s, 3H).
##STR00264##
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(3,3-dimethylpyrrolidin-1-yl)-2-oxoe-
thyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0476] To
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-c-
arboxamido)-1H-pyrazol-1-yl)acetic acid (31.9 mg, 0.075 mmol) in 1
mL DMF was added 3,3-dimethylpyrrolidine HCl (15 mg, 0.11 mmol)
followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (43 mg, 0.11 mmol), then triethylamine (42 uL,
0.30 mmol) and the whole stirred 30 min. The crude mixture was
purified by reverse phase HPLC and lyophilized to afford 28.9 mg
(76%) as a colorless solid. LCMS (ESI) m+H=508.1. .sup.1H NMR (400
MHz, DMSO) .delta. 9.72 (s, 1H), 9.34 (d, J=6.9 Hz, 1H), 8.77 (s,
1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.37 (s,
1H), 7.30 (t, J=9.3 Hz, 2H), 5.09 (d, J=17.8 Hz, 2H), 3.85 (s, 3H),
3.62 (t, J=6.7 Hz, 1H), 3.43 (t, J=7.1 Hz, 1H), 3.29 (s, 1H), 3.12
(s, 1H), 1.74 (t, J=7.0 Hz, 1H), 1.63 (t, J=6.9 Hz, 1H), 1.08 (d,
J=9.9 Hz, 6H).
Example 135
##STR00265##
[0477]
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(cyclopropylamino)-1-fluoro-2--
oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00266##
[0478]
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carb-
oxamido)-1H-pyrazol-1-yl)-2-fluoroacetic acid
[0479] To
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p-
yrimidine-3-carboxamide (37.1 mg, 0.10 mmol) in 1.5 DMF was added
sodium hydride (10 mg, 0.40 mmol) and the mixture stirred for 5 min
at which time ethyl bromofluoroacetate (37 mg, 0.20 mmol) was
added. The mixture was stirred overnight, then purified by reverse
phase HPLC and lyophilized to afford 13.3 mg (30%) of
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)-2-fluoroacetic acid as a colorless solid. LCMS
(ESI) m+H=445.1. .sup.1H NMR (400 MHz, DMSO) .delta. 9.71 (s, 1H),
9.33 (d, J=7.0 Hz, 1H), 8.76-8.71 (m, 1H), 8.66 (d, J=8.3 Hz, 1H),
8.38 (s, 1H), 7.58-7.20 (m, 5H), 5.98 (d, J=56.5 Hz, 1H), 3.84 (s,
3H).
##STR00267##
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(cyclopropylamino)-1-fluoro-2-oxoeth-
yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0480] To
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-c-
arboxamido)-1H-pyrazol-1-yl)-2-fluoroacetic acid (39.1 mg, 0.088
mmol) and cyclopropylamine (10 mg, 0.18 mmol) in 1.0 mL DMF was
added (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (91 mg, 0.18 mmol) and the mixture stirred for
1 h. The crude mixture was purified by reverse phase HPLC and
lyophilized to give 9.1 mg (21%) of
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(cyclopropylamino)-1-fluoro-2-oxoeth-
yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
colorless solid. LCMS (ESI) m+H=484.1. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.77 (s, 1H), 9.34 (dd, J=7.0, 1.4 Hz, 1H), 8.83 (d, J=4.4
Hz, 1H), 8.76 (dd, J=4.2, 1.5 Hz, 1H), 8.68 (s, 1H), 8.55 (s, 1H),
7.58 (dd, J=8.9, 2.7 Hz, 1H), 7.37 (t, J=5.7 Hz, 2H), 7.29 (dd,
J=7.0, 4.2 Hz, 1H), 6.80 (d, J=50.7 Hz, 1H), 3.85 (s, 3H), 2.82
(dd, J=7.3, 3.3 Hz, 1H), 0.70 (t, J=7.0 Hz, 2H), 0.64-0.57 (m,
2H).
Example 136
##STR00268##
[0481]
N-(3-(5-chloro-2-methoxyphenyl)-1-((1S,2R)-2-hydroxycyclohexyl)-1H--
pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
and
N-(3-(5-chloro-2-methoxyphenyl)-1-((1R,2S)-2-hydroxycyclohexyl)-1H-pyrazol-
-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0482] To a stirring solution of
N-(3-(5-chloro-2-methoxyphenyl)-1-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrazo-
l-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and
N-(3-(5-chloro-2-methoxyphenyl)-1-((1R,2R)-2-hydroxycyclohexyl)-1H-pyrazo-
l-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (mixture of trans
enantiomers; 107 mg, 0.229 mmol), 4-nitrobenzoic acid (50.6 mg,
0.303 mmol) and triphenylphosphine (81.8 mg, 0.312 mmol) in 3.0 mL
tetrahydrofuran was dropwise added diethylazodicarboxylate (47.0
.mu.L, 0.298 mmol). The reaction mixture was stirred at room
temperature for one hour and then heated at 50.degree. C. for 2.5
hours. 4-Nitrobenzoic acid (51 mg), triphenylphosphine (86 mg), and
diethylazodicarboxylate (53 .mu.L) were then added and the reaction
mixture heated 50.degree. C. overnight. The reaction mixture was
partitioned between ethyl acetate and water, and the organic
portion washed with brine, dried over magnesium sulfate, and
evaporated in vacuo. The crude product was subjected to flash
chromatography on silica gel (0 to 100% ethyl acetate in
dichloromethane) to yield the mixture of enantiomers (1R,2S)- and
(1S,2R)-2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamido)-1H-pyrazol-1-yl)cyclohexyl 4-nitrobenzoate as a mixture
with triphenyl phosphine oxide. This material was carried forward
without further purification.
[0483] The crude material from the previous step was dissolved in 3
mL tetrahydrofuran with 5.0 M sodium hydroxide in water (1.0 mL).
The reaction mixture was stirred at room temperature for 18 hours.
The reaction mixture was poured into ethyl acetate and washed twice
with 2M aqueous sodium hydroxide. The organic layer was dried over
magnesium sulfate and evaporated in vacuo. The crude product was
purified by reverse phase HPLC and lyophilized to give 8.5 mg of
the mixture of enantiomers
N-(3-(5-chloro-2-methoxyphenyl)-1-((1S,2R)-2-hydroxycyclohexyl)-1H-pyrazo-
l-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and
N-(3-(5-chloro-2-methoxyphenyl)-1-((1R,2S)-2-hydroxycyclohexyl)-1H-pyrazo-
l-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI)
m+H=467.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 9.68 (s, 1H), 9.33
(dd, J=7.0, 1.6 Hz, 1H), 8.78 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (s,
1H), 8.33 (s, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 7.42 (d, J=2.7 Hz,
1H), 7.33-7.25 (m, 2H), 4.84 (d, J=4.3 Hz, 1H), 4.24 (d, J=12.1 Hz,
1H), 4.11 (s, 1H), 3.84 (s, 3H), 2.16 (td, J=12.4, 8.6 Hz, 1H),
1.81 (m, 3H), 1.62 (dt, J=26.0, 13.0 Hz, 2H), 1.43 (d, J=6.1 Hz,
2H).
Example 137
##STR00269##
[0484]
N-(3-(5-chloro-2-methoxyphenyl)-1-(3-hydroxycyclopentyl)-1H-pyrazol-
-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0485] To a solution of
N-(3-(5-chloro-2-methoxyphenyl)-1-(3-hydroxycyclopentyl)-1H-pyrazol-4-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide (171.1 mg, 0.3795 mmol) in
5.0 mL tetrahydrofuran at -78.degree. C. was added 1.0 M lithium
tri-tert-butoxyaluminum hydride in tetrahydrofuran (0.6 mL, 0.6
mmol). The reaction mixture was kept at -60.degree. C. for 4 hours,
and then 1.0 M lithium tri-tert-butoxyaluminum hydride in
tetrahydrofuran (0.6 mL, 0.6 mmol) was added. The reaction mixture
was kept at -25.degree. C. for 8 hours. 1.0 M lithium
tri-tert-butoxyaluminum hydride in tetrahydrofuran (0.9 mL, 0.9
mmol) was added and the reaction mixture was kept at -25.degree. C.
for an additional 6 hours until reduction of the ketone is judged
complete by LCMS. The reaction mixture was then cooled at
-40.degree. C. and quenched with 3 mL saturated aqueous ammonium
chloride. After warming to room temperature, this mixture was
extracted with dichloromethane, and the organic extract was dried
over magnesium sulfate and evaporated in vacuo. The crude product
was purified by reverse phase HPLC and lyophilized to give 34 mg
(20%) of
N-(3-(5-chloro-2-methoxyphenyl)-1-(3-hydroxycyclopentyl)-1H-pyrazol-4-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=453.1; 1H
NMR (400 MHz, DMSO-d6) .delta.: 9.67 (s, 1H), 9.34 (dd, J=7.0, 1.6
Hz, 1H), 8.78 (dd, J=4.2, 1.6 Hz, 1H), 8.64 (s, 1H), 8.38 (s, 1H),
7.50 (dd, J=8.8, 2.7 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.34-7.25 (m,
2H), 4.90 (d, J=4.6 Hz, 1H), 4.83-4.69 (m, 1H), 4.21 (dd, J=10.2,
5.5 Hz, 1H), 3.85 (s, 3H), 2.42 (ddd, J=14.6, 8.7, 6.2 Hz, 1H),
2.21-2.04 (m, 2H), 2.00-1.87 (m, 1H), 1.86-1.70 (m, 2H).
Example 138
##STR00270##
[0486]
N-(3-(5-chloro-2-cyclopropylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazo-
lo[1,5-a]pyrimidine-3-carboxamide
##STR00271##
[0487]
4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-
-5-yl)phenol
[0488] To a solution of
5-(5-chloro-2-(4-methoxybenzyloxy)phenyl)-4-nitro-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazole (prepared according to the procedure
described for Example 14) (1.193 g, 2.434 mmol) in 17 mL
dichloromethane was added 3 mL water followed by
dichlorodicyanoquinone (1.2208 g). The reaction was stirred at room
temperature for 48 hours, and then additional
Dichlorodicyanoquinone (0.4946 g) was added. After an additional 24
hours, the reaction was poured into saturated aqueous sodium
bicarbonate and extracted with dichloromethane. The organic portion
was dried over magnesium sulfate and evaporated in vacuo. The crude
product was purified via flash chromatography on silica gel (0 to
35% ethyl acetate in heptanes) to yield 745.2 mg (83%) of
4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
phenol. LCMS (ESI) m+H=270.2; 1H NMR (400 MHz, DMSO-d6) .delta.:
10.47 (s, 1H), 8.44 (s, 1H), 7.47 (d, J=2.6, 1H), 7.43 (dd, J=8.8,
2.7, 1H), 7.00 (d, J=8.8, 1H), 5.30 (dd, J=65.1, 10.8, 2H), 3.42
(t, J=8.1, 2H), 0.74 (t, 2H), -0.08 (s, 9H).
##STR00272##
4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
phenyl trifluoromethanesulfonate
[0489] To a solution of
4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
phenol (190.4 mg, 0.5148 mmol) in 8 mL dichloromethane at
-40.degree. C. was added triethylamine (0.30 mL, 2.2 mmol) followed
by trifluoromethanesulfonic anhydride (0.15 mL, 0.89 mmol). After
30 minutes at this temperature the reaction mixture was warmed to
room temperature. After 3 hours, the reaction mixture was poured
into water and extracted twice with dichloromethane. The combined
organic portions were dried over magnesium sulfate and evaporated
in vacuo. The crude product was purified via flash chromatography
on silica gel (0 to 30% ethyl acetate in heptanes) to yield 239.8
mg (93%) of
4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
phenyl trifluoromethanesulfonate. LCMS (ESI) m+Na=524.0.
##STR00273##
5-(5-chloro-2-cyclopropylphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)met-
hyl)-1H-pyrazole
[0490] To a mixture of
4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
phenyl trifluoromethanesulfonate (72.4 mg, 0.144 mmol),
cyclopropylboronic acid (55.0 mg, 0.640 mmol),
tetrakis(triphenylphosphine)palladium(0) (79.2 mg, 0.685 mmol),
potassium phosphate (152.7 mg, 0.7194 mmol), and sodium bromide
(149.2 mg, 1.450 mmol) was added water (13.0 .mu.L, 0.722 mmol) and
toluene (3.0 mL). The reaction mixture was heated at 90.degree. C.
for 72 hours. The reaction mixture was partitioned between ethyl
acetate and water, and the organic layer washed with brine, dried
over magnesium sulfate, and evaporated in vacuo. The crude product
was purified via flash chromatography on silica gel (0 to 30% ethyl
acetate in heptanes) to yield 30.1 mg (53%) of
5-(5-chloro-2-cyclopropylphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)met-
hyl)-1H-pyrazole. LCMS (ESI) m+Na=416.2.
##STR00274##
N-(3-(5-chloro-2-cyclopropylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-
-a]pyrimidine-3-carboxamide
[0491] The title compound was synthesized from
5-(5-chloro-2-cyclopropylphenyl)-4-nitro-1((2-(trimethylsilyl)ethoxy)meth-
yl)-1H-pyrazole following the procedures described for Example 14.
LCMS (ESI) m+H=393.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 9.66 (s,
1H), 9.31 (dd, J=7.0, 1.5 Hz, 1H), 8.65 (s, 1H), 8.54-8.50 (m, 1H),
8.29 (s, 1H), 7.43 (dd, J=8.5, 2.3 Hz, 1H), 7.35 (d, J=2.3 Hz, 1H),
7.24 (dd, J=7.0, 4.2 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 3.92 (s, 3H),
1.98 (s, 1H), 0.79 (dt, J=6.2, 4.3 Hz, 2H), 0.66-0.59 (m, 2H).
Example 139
##STR00275##
[0492]
N-(3-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1-(2-hydroxy-2-methylpro-
pyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00276##
[0493] 1-(allyloxy)-2-bromo-4-chlorobenzene
[0494] To a solution of 2-Bromo-4-chlorophenol (7.7897 g, 37.549
mmol) in 20 mL DMF was added potassium carbonate (5.784 g, 41.85
mmol) and allyl bromide (3.30 mL, 38.1 mmol). The reaction mixture
was stirred at 50.degree. C. for 15 hours. The reaction mixture was
partitioned between ethyl acetate and water, and the organic layer
washed with brine, dried over magnesium sulfate, and evaporated in
vacuo to yield 9.4 g (100%) of
1-(allyloxy)-2-bromo-4-chlorobenzene, which was carried forward
without further purification. 1H NMR (400 MHz, CDCl3) .delta.: 7.54
(d, J=2.5, 1H), 7.21 (dd, J=8.8, 2.5, 1H), 6.81 (d, J=8.8, 1H),
6.10-5.98 (m, 1H), 5.46 (dd, J=17.3, 1.4, 1H), 5.31 (dd, J=10.6,
1.3, 1H), 4.59 (d, J=5.0, 2H).
##STR00277##
2-allyl-6-bromo-4-chlorophenol
[0495] A solution of 1-(allyloxy)-2-bromo-4-chlorobenzene (4.122 g,
16.65 mmol) in N,N-diethylaniline (20 mL, 100 mmol) was heated at
200.degree. C. for 15 hours. After cooling to room temperature, the
reaction mixture was partitioned between ethyl acetate and 1M
aqueous HCl, and the organic layer washed with an additional
portion of 1M aqueous HCl and then brine. The organic layer was
dried over magnesium sulfate and evaporated in vacuo. The crude
product was purified via flash chromatography on silica gel (0 to
20% ethyl acetate in heptanes) to yield 3.1761 g (77%) of
2-allyl-6-bromo-4-chlorophenol as a clear, colorless oil. 1H NMR
(400 MHz, CDCl3) .delta.: 7.33 (d, J=2.4, 1H), 7.07 (d, J=2.3, 1H),
5.94 (ddt, J=16.8, 10.3, 6.6, 1H), 5.53 (s, 1H), 5.18-5.06 (m, 2H),
3.40 (d, J=6.6, 2H).
##STR00278##
2-bromo-4-chloro-6-(2-hydroxyethyl)phenol
[0496] A solution of 2-allyl-6-bromo-4-chlorophenol (1.378 g, 5.567
mmol) in 20 mL dichloromethane was cooled at -78.degree. C. While
stirring at this temperature, ozone was bubbled through the
reaction solution for 6.5 hours. After flushing the reaction vessel
with oxygen, while still at -78.degree. C., the reaction was
quenched with sodium tetrahydroborate (1.064 g, 28.12 mmol). The
reaction was then warmed to room temperature and stirred overnight.
The reaction mixture was partitioned between ethyl acetate and
water, and the organic layer washed with brine, dried over
magnesium sulfate, and evaporated in vacuo. The crude product was
purified via flash chromatography on silica gel (10 to 60% ethyl
acetate in heptanes) to yield 0.5911 g (42%) of
2-bromo-4-chloro-6-(2-hydroxyethyl)phenol. 1H NMR (400 MHz, CDCl3)
.delta.: 7.38 (d, J=2.5, 1H), 7.27 (s, 1H), 7.06 (d, J=2.4, 1H),
3.96 (br s, 2H), 2.91 (t, J=5.7, 2H), 1.98 (s, 1H).
##STR00279##
7-bromo-5-chloro-2,3-dihydrobenzofuran
[0497] To a mixture of 2-bromo-4-chloro-6-(2-hydroxyethyl)phenol
(99.8 mg, 0.397 mmol), triethylamine (0.40 mL, 2.9 mmol), and
dichloromethane (4 mL) at 0.degree. C. was added methanesulfonyl
chloride (56.0 .mu.L, 0.724 mmol). The reaction was stirred at
0.degree. C. for 1.5 hours, at which point additional methane
sulfonyl chloride (10 .mu.L) was added and the reaction mixture
warmed to room temperature. After stirring overnight, the reaction
mixture was re-cooled to 0.degree. C. and triethylamine (0.2 mL)
and methanesulfonyl chloride (15 .mu.L) were added. After two hours
the reaction mixture was partitioned between ethyl acetate and
water, and the organic layer washed with brine, dried over
magnesium sulfate, and evaporated in vacuo. The crude product was
purified via flash chromatography on silica gel (0 to 30% ethyl
acetate in heptanes) to yield 40.0 mg (40%) of
7-bromo-5-chloro-2,3-dihydrobenzofuran. 1H NMR (400 MHz, CDCl3)
.delta.: 7.26 (d, 1H), 7.09 (d, 1H), 4.67 (t, J=8.8, 2H), 3.30 (t,
J=8.8, 2H).
##STR00280##
N-(3-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1-(2-hydroxy-2-methylpropyl)-1-
H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0498] The title compound was prepared using
7-bromo-5-chloro-2,3-dihydrobenzofuran and following the procedures
described for examples 14 and 16. LCMS (ESI) m+H=453.1; 1H NMR (400
MHz, DMSO-d6) .delta.: 9.72 (s, 1H), 9.33 (d, J=7.0, 1H), 8.82 (dd,
J=4.2, 1.5, 1H), 8.65 (s, 1H), 8.35 (s, 1H), 7.36 (s, 1H),
7.33-7.23 (m, 2H), 4.70 (s, 1H), 4.62 (t, J=8.8, 2H), 4.07 (s, 2H),
3.37 (t, J=8.8, 2H), 1.12 (s, 6H).
Example 140
##STR00281##
[0499]
N-(1-methyl-3-(3-methylpiperidin-1-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-
-a]pyrimidine-3-carboxamide
##STR00282##
[0500]
5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
[0501] In an oven-dried flask,
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (412.4 mg,
1.695 mmol) was dissolved in 5 mL THF and cooled at -78.degree. C.
To this solution was slowly added 1.0M Lithium hexamethyldisilazide
in tetrahydrofuran (2.0 mL, 2.0 mmol). After stirring for 30
minutes at -78.degree. C., a solution of hexachloroethane (455.2
mg, 1.923 mmol) in 3 mL THF was slowly added. The reaction mixture
was kept at -78.degree. C. for an additional hour, and then
quenched with saturated aqueous ammonium chloride and warmed to
room temperature. The reaction mixture was partitioned between
ethyl acetate and water, and the organic layer dried over magnesium
sulfate and evaporated in vacuo to yield 0.4592 g (98%) of
5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-
e, which was carried forward without further purification. LCMS
(ESI) m+H=220.2; 1H NMR (400 MHz, DMSO-d6) .delta.: 8.52 (s, 1H),
5.56 (s, 2H), 3.67-3.57 (m, 2H), 0.91-0.83 (m, 2H), -0.04 (s,
9H).
##STR00283##
3-methyl-1-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
piperidine
[0502] To a solution of
5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
(348.3 mg, 1.254 mmol) in 1 mL n-butanol was added
3-methyl-piperidine (0.20 mL, 1.7 mmol). The reaction mixture was
subjected to microwave irradiation at a temperature of 120.degree.
C. for 30 minutes. The solvent was evaporated in vacuo and the
crude product purified via flash chromatography on silica gel (0 to
40% ethyl acetate in heptanes) to yield 486.5 mg of
3-methyl-1-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
piperidine. LCMS (ESI) m+H=341.4; 1H NMR (400 MHz, DMSO-d6)
.delta.: 8.04 (s, 1H), 5.36 (s, 2H), 3.71-3.62 (m, 2H), 3.20 (m,
3H), 2.96-2.85 (m, 1H), 1.84-1.76 (m, 4H), 1.15 (m, 1H), 0.97-0.87
(m, 5H), 0.00 (s, 9H).
##STR00284##
N-(1-methyl-3-(3-methylpiperidin-1-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr-
imidine-3-carboxamide
[0503] The title compound was prepared using
3-methyl-1-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-
piperidine and following the procedures described for Example 14.
LCMS (ESI) m+H=340.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 9.59 (s,
1H), 9.36 (dd, J=7.0, 1.5, 1H), 8.83 (dd, J=4.2, 1.6, 1H), 8.66 (s,
1H), 7.98 (s, 1H), 7.32 (dd, J=7.0, 4.2, 1H), 3.71 (s, 3H), 3.25
(s, 1H), 2.64 (s, 1H), 2.41-2.29 (m, 1H), 1.96-1.70 (m, 4H), 1.04
(s, 1H), 0.91 (d, J=6.7, 3H).
Example 141
##STR00285##
[0504]
N-(3-(5-chloro-2-methoxypyridin-3-yl)-1-(2-hydroxy-2-methylpropyl)--
1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00286##
[0505]
5-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
[0506] In an oven-dried flask,
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5192 g,
6.2432 mmol) was dissolved in 20 mL THF and cooled at -78.degree.
C. To this solution was slowly added 1.0M lithium
hexamethyldisilazide in tetrahydrofuran (7.5 mL, 7.5 mmol). After
stirring for 40 minutes at -78.degree. C., a solution of iodine
(1.7602 g, 6.9351 mmol) in 8 mL THF was slowly added. The reaction
mixture was kept at -78.degree. C. for an additional 1.5 hours, and
then quenched with saturated aqueous ammonium chloride and warmed
to room temperature. The reaction mixture was partitioned between
ethyl acetate and half-saturated aqueous Na.sub.2S.sub.2O.sub.3.
The organic layer was dried with magnesium sulfate, filtered, and
evaporated in vacuo. The crude product was purified via flash
chromatography on silica gel (0 to 15% ethyl acetate in heptanes)
to yield 2.2349 g (97%) of
5-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. 1H
NMR (400 MHz, DMSO-d6) .delta.: 8.48 (s, 1H), 5.59 (s, 2H), 3.61
(t, J=8.0, 2H), 0.86 (t, J=8.0, 2H), -0.04 (s, 9H).
##STR00287##
tert-butyl
5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate
[0507] To a solution of
5-iodo-4-nitro-1((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
(2.234 g, 6.050 mmol) in ethanol (20 mL) was added ammonium
chloride (1.303 g, 24.36 mmol), iron powder (1.695 g, 30.35 mmol),
and water (30 mL). The reaction mixture was then stirred at
70.degree. C. for 45 minutes and then cooled to room temperature,
diluted with dichloromethane, and filtered through celite, rinsing
with additional dichloromethane. Saturated aqueous sodium
bicarbonate was added to the filtrate and the layers separated. The
aqueous layer was extracted once more with dichloromethane, and the
combined organic portions then dried over magnesium sulfate,
filtered, and evaporated in vacuo. To the resulting residue was
added dioxane (20 mL), triethylamine (2.0 mL, 14 mmol) and
di-tert-butyldicarbonate (1.513 g, 6.932 mmol). This mixture was
stirred at 60.degree. C. for 4 hours. After cooling to room
temperature, the reaction mixture was diluted in ethyl acetate,
washed with water and brine, dried over magnesium sulfate,
filtered, and evaporated in vacuo. The crude product was purified
via flash chromatography on silica gel (0 to 40% ethyl acetate in
heptanes) to yield 1.4353 g (54%) of tert-butyl
5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate.
1H NMR (400 MHz, DMSO-d6) .delta.: 8.44 (s, 1H), 7.56 (s, 1H), 5.39
(s, 2H), 3.53 (t, J=8.0, 2H), 1.43 (s, 9H), 0.83 (t, J=8.0, 2H),
-0.04 (s, 9H).
##STR00288##
tert-butyl
5-(5-chloro-2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1-
H-pyrazol-4-ylcarbamate
[0508] A mixture of tert-butyl
5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate
(390.7 mg, 0.8892 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid
pinacol ester (364.0 mg, 1.350 mmol),
tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (48.5
mg, 0.0468 mmol), S-Phos (74.2 mg, 0.181 mmol), potassium phosphate
(597.1 mg, 2.813 mmol), and 1-butanol (10 mL) was degassed with
nitrogen and then stirred at 80.degree. C. for 15 hours. The
reaction mixture was diluted in ethyl acetate, washed with water
and brine, dried over magnesium sulfate, filtered, and evaporated
in vacuo. The crude product was purified via flash chromatography
on silica gel (0 to 50% ethyl acetate in heptanes) to yield 212.3
mg (52%) of tert-butyl
5-(5-chloro-2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1-
H-pyrazol-4-ylcarbamate. LCMS (ESI) m+H=455.2; 1H NMR (400 MHz,
DMSO-d6) .delta.: 8.53 (s, 1H), 8.33 (s, 1H), 7.79 (d, J=2.6, 1H),
5.22 (s, 2H), 3.85 (s, 3H), 3.35 (t, 2H), 1.38 (s, 9H), 0.70 (t,
J=8.1, 2H), -0.10 (s, 9H).
##STR00289##
5-(5-chloro-2-methoxypyridin-3-yl)-1H-pyrazol-4-amine
[0509] To a solution of tert-butyl
5-(5-chloro-2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1-
H-pyrazol-4-ylcarbamate (211.7 mg, 0.4652 mmol) in 5 mL ethyl
acetate was added tin tetrachloride (0.52 mL, 4.4 mmol). The
reaction mixture was stirred at room temperature for 2 hours and
then evaporated in vacuo. The residual oil was partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate, and the
aqueous layer extracted twice more with ethyl acetate. The combined
organic layers were dried over magnesium sulfate, filtered, and
evaporated in vacuo. The crude product was purified via flash
chromatography on silica gel (0 to 20% methanol in dichloromethane)
to yield 32.4 mg (31%) of
5-(5-chloro-2-methoxypyridin-3-yl)-1H-pyrazol-4-amine LCMS (ESI)
m+H=225.1.
##STR00290##
N-(3-(5-chloro-2-methoxypyridin-3-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyr-
azol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0510] The title compound was prepared using
5-(5-chloro-2-methoxypyridin-3-yl)-1H-pyrazol-4-amine and following
the procedures described for Examples 4 and 16. LCMS (ESI)
m+H=442.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 9.72 (s, 1H), 9.34
(d, J=6.8 Hz, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 8.35 (s, 2H), 7.88
(s, 1H), 7.28 (s, 1H), 4.75 (s, 1H), 4.09 (s, 2H), 3.95 (s, 3H),
1.13 (s, 6H).
Example 142
##STR00291##
[0511]
N-(1-(2-hydroxy-2-methylpropyl)-3-(1-methyl-2-oxo-5-(trifluoromethy-
l)-1,2-dihydropyridin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide
##STR00292##
[0512] 3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one
[0513] To a solution of
3-bomo-2-hydroxy-5-(trifluoromethyl)pyridine (1.0097 g, 4.1724
mmol) in chloroform (20 mL) was added silver carbonate (1.1964 g,
4.3388 mmol) and methyl iodide (0.40 mL, 6.4 mmol). The reaction
mixture was stirred at room temperature for two hours and then at
40.degree. C. for 24 hours. Additional methyl iodide (0.40 mL, 6.4
mmol) was added and the reaction kept at 40.degree. C. for an
additional 15 hours. The reaction mixture was then diluted with
dichloromethane, filtered through celite, and evaporated in vacuo.
The crude product was purified via flash chromatography on silica
gel (0 to 80% ethyl acetate in heptanes) to yield 0.5297 g (50%) of
3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. 1H NMR (400
MHz, DMSO-d6) .delta.: 8.47 (d, J=0.9, 1H), 8.22 (d, J=2.5, 1H),
3.56 (s, 3H).
##STR00293##
N-(1-(2-hydroxy-2-methylpropyl)-3-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-
-dihydropyridin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide
[0514] The title compound was prepared using
3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one and following
the procedures as described for Examples 14 and 16. LCMS (ESI)
m+H=476.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 10.23 (s, 1H), 9.31
(dd, J=7.0, 1.5, 1H), 8.77 (dd, J=4.1, 1.6, 1H), 8.64 (s, 1H), 8.58
(s, 1H), 8.39 (s, 1H), 7.88 (d, J=2.7, 1H), 7.27 (dd, J=7.0, 4.2,
1H), 4.74 (s, 1H), 4.08 (s, 2H), 3.71 (s, 3H), 1.11 (s, 6H).
Example 143
##STR00294##
[0515]
N-(1-(2-hydroxy-2-methylpropyl)-3-(5-methoxy-2-(trifluoromethyl)pyr-
idin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00295##
[0516] 4-iodo-5-methoxy-2-(trifluoromethyl)pyridine
[0517] In an oven-dried flask,
5-methoxy-2-(trifluoromethyl)pyridine was dissolved in THF (20 mL).
This mixture was cooled at -78.degree. C., and then 2.5 M
n-butyllithium in hexane (2.60 mL, 6.5 mmol) was added. After
stirring at this same temperature for 40 minutes,
1-chloro-2-iodoethane (0.60 mL, 6.6 mmol) was added. The reaction
was kept at -78.degree. C. for an additional 30 minutes, and then
quenched with saturated aqueous ammonium chloride. The mixture was
warmed to room temperature, partitioned between ethyl acetate and
water, and the organic layer dried with magnesium sulfate and
evaporated in vacuo. The crude product was purified via flash
chromatography on silica gel (0 to 40% ethyl acetate in heptanes)
to yield 0.3128 g (16%) of
4-iodo-5-methoxy-2-(trifluoromethyl)pyridine. 1H NMR (400 MHz,
DMSO-d6) .delta.: 8.38 (s, 1H), 8.29 (s, 1H), 4.05 (s, 3H).
##STR00296##
N-(1-(2-hydroxy-2-methylpropyl)-3-(5-methoxy-2-(trifluoromethyl)pyridin-4-
-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0518] The title compound was prepared using
4-iodo-5-methoxy-2-(trifluoromethyl)pyridine and following the
procedures as described for Examples 14 and 16. LCMS (ESI)
m+H=476.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 9.71 (s, 1H), 9.36
(d, J=6.9, 1H), 8.88 (d, J=3.8, 1H), 8.82 (s, 1H), 8.67 (s, 1H),
8.41 (s, 1H), 7.85 (s, 1H), 7.36-7.27 (m, 1H), 4.77 (s, 1H), 4.12
(s, 2H), 4.09 (s, 3H), 1.13 (s, 6H).
Example 144
##STR00297##
[0519]
N-(3-(6-cyano-3-methoxypyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)-1-
H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00298##
[0520]
N-(3-(6-cyano-5-methoxypyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)-1-
H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00299##
[0521] 6-bromo-5-methoxypicolinonitrile
and
##STR00300##
[0522] 6-iodo-3-methoxypicolinonitrile
[0523] To a solution of 2-bromo-6-iodo-3-methoxypyridine (627.4 mg,
1.999 mmol) in N-methylpyrrolidinone (10 mL) was added copper
cyanide (202.6 mg, 2.262 mmol). The reaction mixture was stirred at
130.degree. C. for 3.5 hours and then cooled to room temperature.
The crude reaction was partitioned between ethyl acetate and water,
the organic layer washed with brine, dried with magnesium sulfate,
filtered, and evaporated in vacuo. The crude product was purified
via flash chromatography on silica gel (20 to 100% ethyl acetate in
heptanes) to yield 157.8 mg (37%) of a mixture of the two
regioisomeric products 6-bromo-5-methoxypicolinonitrile and
6-iodo-3-methoxypicolinonitrile. 1H NMR (400 MHz, DMSO) .delta.:
8.12 (d, J=8.3 Hz, 0.75H), 7.98 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.1
Hz, 1H), 7.69 (d, J=8.5 Hz, 0.75H), 3.98 (overlapping s and s,
6H).
##STR00301##
N-(3-(6-cyano-3-methoxypyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyra-
zol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00302##
[0524]
N-(3-(6-cyano-5-methoxypyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)-1-
H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0525] The title compounds were prepared using a mixture of
6-bromo-5-methoxypicolinonitrile and
6-iodo-3-methoxypicolinonitrile and following the procedures
described for Examples 14 and 16, separating the two regioisomeric
final products by reverse-phase HPLC to yield:
N-(3-(6-cyano-3-methoxypyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyra-
zol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI)
m+H=433.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 10.55 (s, 2H), 9.35
(d, J=6.9 Hz, 2H), 8.93 (s, 2H), 8.68 (s, 2H), 8.48 (s, 2H), 8.10
(d, J=8.6 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.42-7.26 (m, 2H), 6.54
(s, 1H), 4.80 (s, 2H), 4.12 (s, 4H), 3.94 (s, 6H), 1.12 (s,
12H).
[0526] And
N-(3-(6-cyano-5-methoxypyridin-2-yl)-1-(2-hydroxy-2-methylpropy-
l)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LCMS
(ESI) m+H=433.1; 1H NMR (400 MHz, DMSO-d6) .delta.: 10.97 (s, 1H),
9.36 (d, J=6.8 Hz, 1H), 9.09 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H),
8.26 (d, J=9.4 Hz, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.42-7.32 (m, 1H),
4.78 (s, 1H), 4.11 (s, 2H), 4.04 (s, 3H), 1.13 (s, 6H).
Example 145
##STR00303##
[0527]
N-(5-(3-bromophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide
##STR00304##
[0528]
5-(3-bromophenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-p-
yrazole
[0529] To a solution of
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4 g, 16.4
mmol) in 40 mL of N,N-dimethylacetamide was added
1,3-dibromo-Benzene (4.6 g, 19.7 mmol), palladium (II) acetate (242
mg, 1.08 mmol), di(1-adamantyl)-n-butyl phosphine (565 mg, 1.58
mmol), potassium carbonate (8.28 g, 60 mmol), and trimethylacetic
acid (552 mg, 5.2 mmol). While stirring at room temperature,
nitrogen gas was bubbled through the reaction mixture for 10
minutes, and the reaction was then heated at 120.degree. C. for 12
hours. The reaction was cooled to room temperature, diluted into
ethyl acetate, and washed with water and brine, dried over
magnesium sulfate and concentrated. The crude material was purified
by flash chromatography on silica gel (0 to 25% ethyl acetate in
hexanes) to obtain 800 mg (12%) of
5-(3-bromophenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-
e. LCMS (ESI) m+H=398.0; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
8.24 (d, 1H), 7.70 (m, 1H), 7.53 (s, 1H), 7.46 (d, 1H), 7.42 (d,
1H), 7.41 (d, 1H), 5.27 (s, 1H), 3.72 (m, 2H), 0.95 (m, 2H), 0.00
(s, 9H).
##STR00305##
5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine
[0530] To a solution of
5-(3-bromophenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-
e (800 mg, 2.4 mmol) in 25 mL ethanol was added 50 mL of water,
ammonium chloride (636 mg, 12 mmol), and iron powder (806 mg, 14
mmol). The reaction mixture was stirred at 75.degree. C. for 6
hours. After cooling to room temperature, the reaction was diluted
with dichloromethane and filtered through a celite pad, rinsing
with more dichloromethane. The filtrate was added to 150 mL of
saturated aqueous sodium bicarbonate and extracted twice with
dichloromethane. The combined organic extracts were dried over
magnesium sulfate and concentrated to yield 530 mg (71%) of
5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine-
, which was carried forward without purification. LCMS (ESI)
m+H=368.0.
##STR00306##
N-(5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl-
)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0531] A mixture of
5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine
(533 mg, 1.45 mmol), in tetrahydrofuran (5 mL) was added of
pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (262 mg, 1.45 mmol)
in tetrahydrofuran (5 mL) at 0.degree. C. After addition, the
mixture was warmed to room temperature, and then stirred overnight
at this temperature. The mixture was concentrated to give 742 mg
(99%) of
N-(5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl-
)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward
without purification. LCMS (ESI) m+H=513.1.
##STR00307##
N-(5-(3-bromophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide
[0532] To a solution of
N-(5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl-
)pyrazolo[1,5-a]pyrimidine-3-carboxamide (742 mg, 1.45 mmol) in 20
mL of ethanol was added HCl (1.0 mL of a 6 M solution in water, 6
mmol). The reaction mixture was then stirred at 70.degree. C. for 6
hours. After cooling to room temperature a light yellow precipitate
formed, which was isolated by filtration and washed with methanol
and diethyl ether. The filtrate was reduced in volume, and more
solid product filtered. The combined collected solids were dried
under vacuum to yield 320 mg (58%) of
N-(5-(3-bromophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbo-
xamide. LCMS (ESI) m+H=383.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.13.01 (s, 1H), 9.93 (s, 1H), 9.33 (dd, 1H), 8.83 (dd, 1H),
8.66 (d, 1H), 8.26 (s, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 7.28 (dd,
1H).
Example 146
##STR00308##
[0534] To a solution of
N-(5-(3-bromophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide (200 mg, 0.523 mmol) in 20 mL DMF was added isobutylene oxide
(0.20 mL, 2.2 mmol) and cesium carbonate (340 mg, 1.04 mmol). The
reaction mixture was stirred at 80.degree. C. for 6 hours, then
cooled to room temperature, diluted with ethyl acetate, and
filtered. The fitrrate was washed with brine, dried over magnesium
sulfate, and concentrated. The residue was purified by reverse
phase HPLC and lyophilized to give 14.2 mg (6%) of desired
compound. LCMS (ESI) m+H=456.8. .sup.1H NMR (CDCl.sub.3, 400 MHz):
.delta.10.16 (d, J=1.2 Hz, 1H), 8.83-8.77 (m, 2H), 8.76 (t, J=5.2
Hz, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.55
(d, J=8.4 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.06 (dd, J=3.6, 6.8 Hz,
1H), 4.12 (s, 2H), 1.30 (s, 6H).
Example 147
##STR00309##
[0535]
N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
##STR00310##
[0536]
4-methoxy-3-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazo-
l-5-yl)benzonitrile
[0537] To a solution of
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2 g, 8.2
mmol) in 50 mL of N,N-dimethylacetamide was added
3-bromo-4-methoxybenzonitrile (2.1 g, 9.8 mmol), palladium (II)
acetate (120 mg, 0.54 mmol), di(1-adamantyl)-n-butylphosphine (250
mg, 0.7 mmol), potassium carbonate (6.0 g, 43.3 mmol), and
trimethylacetic acid (200 mg, 1.95 mmol). While stirring at room
temperature, nitrogen gas was bubbled through the reaction mixture
for 10 minutes, and the reaction mixture was then heated at
120.degree. C. for 12 hours. The reaction was cooled to room
temperature, diluted into ethyl acetate, and washed with water and
brine, dried over magnesium sulfate and concentrated. The crude
material was purified by flash chromatography on silica gel (0 to
25% ethyl acetate in heptanes) to obtain 730 mg (12%) of
4-methoxy-3-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl-
)benzonitrile. LCMS (ESI) m+H=375.1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 8.24 (d, 1H), 7.86 (m, 1H), 7.72 (s, 1H), 7.12
(d, 1H), 5.27 (q, 2H), 3.86 (s, 3H), 3.68 (m, 2H), 0.89 (m, 2H),
0.00 (s, 9H).
##STR00311##
3-(4-amino-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)-4-methox-
ybenzonitrile
[0538] To a solution of
4-methoxy-3-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl-
)benzonitrile (900 mg, 2.4 mmol) in 25 mL ethanol was added 50 mL
water, ammonium chloride (636 mg, 12 mmol), and iron powder (806
mg, 14 mmol). The reaction mixture was stirred at 75.degree. C. for
6 hours. After cooling to room temperature, the reaction was
diluted with dichloromethane and filtered through a celite pad,
rinsing with more dichloromethane. The filtrate was added to 150 mL
saturated aqueous sodium bicarbonate and extracted twice with
dichloromethane. The combined organic extracts were dried over
magnesium sulfate and concentrated to yield 717 mg (84%) of
3-(4-amino-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)-4-methox-
ybenzonitrile, which was carried forward without purification. LCMS
(ESI) m+H=375.1.
##STR00312##
N-(5-(5-cyano-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-py-
razol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0539]
3-(4-amino-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)-4--
methoxybenzonitrile (717 mg, 2.08 mmol) in tetrahydrofuran (20 mL)
was added to pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (262 mg,
1.45 mmol) in tetrahydrofuran (5 mL) at 0.degree. C. After
addition, the mixture was warmed to room temperature, and then
stirred overnight at this temperature. The mixture was concentrated
to give 1.0 g (98%) of
N-(5-(5-cyano-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-py-
razol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was
carried forward without purification. LCMS (ESI) m+H=490.1.
##STR00313##
N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide
[0540] To a solution of
N-(5-(5-cyano-2-methoxyphenyl)-1-(2-((trimethylsilyl)
methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
(1.0 g, 2.04 mmol) in 20 mL ethanol was added HCl (2.0 mL of a 6 M
solution in water, 12 mmol). The reaction mixture was then stirred
at 70.degree. C. for 4 hours. After cooling to room temperature, a
light yellow precipitate formed, which was filtered off and rinsed
with methanol and diethyl ether. The filtrate was reduced in volume
to precipiate more solid product, which was filtered off. The
combined collected solids were dried under vacuum to yield 530 mg
(72%) of
N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide. LCMS (ESI) m+H=360.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.12.98 (s, 1H), 9.59 (s, 1H), 9.30 (dd, 1H),
8.73 (d, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 7.78 (s,
1H), 7.43 (d, 1H), 7.25 (s, 1H), 3.9 (s, 3H).
Example 148
##STR00314##
[0541]
N-(3-(5-cyano-2-methoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyra-
zol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0542] To a solution of
N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide (200 mg, 0.557 mmol) in 20 mL DMF was added
isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (363 mg,
1.11 mmol). The reaction mixture was stirred at 80.degree. C. for 6
hours, then diluted with ethyl acetate and filtered, and the
organic portion washed with brine, dried over magnesium sulfate,
and concentrated. The crude product was purified by reverse phase
HPLC and lyophilized to give 27.2 mg (11%) of desired product. LCMS
(ESI) m+H=431.9. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.9.68 (s,
1H), 8.78 (dd, J=2.0, 6.8 Hz, 1H), 8.71 (s, 1H), 8.56 (q, J=1.6 Hz,
1H), 8.37 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.0, 8.4 Hz,
1H), 7.1 (d, J=8.8 Hz, 1H), 7.01 (dd, J=4.4, 7.2 Hz, 1H), 4.11 (s,
2H), 3.91 (s, 3H), 1.23 (s, 6H).
Example 149
##STR00315##
[0543]
N-(5-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyri-
midine-3-carboxamide
##STR00316##
[0544]
5-(5-fluoro-2-methoxyphenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)-
ethyl)-1H-pyrazole
[0545] To a solution of
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.98 g,
12.28 mmol) in 25 mL N,N-dimethylacetamide was added
2-bromo-4-fluoro-1-methoxybenzene (3.54 g, 17.35 mmol), palladium
(II) acetate (144 mg, 0.62 mmol), di(1-adamantyl)-n-butylphosphine
(330 mg, 0.93 mmol), potassium carbonate (5.1 g, 37.1 mmol), and
trimethylacetic acid (330 mg, 2.68 mmol). While stirring at room
temperature, nitrogen gas was bubbled through the reaction mixture
for 10 minutes, and the reaction mixture was then heated at
120.degree. C. for 12 hours. The reaction was then cooled to room
temperature, diluted into ethyl acetate, and washed with water and
brine, dried over magnesium sulfate and concentrated. The crude
material was purified by flash chromatography on silica gel (0 to
25% ethyl acetate in heptanes) to obtain 1.0 g (22%) of
5-(5-fluoro-2-methoxyphenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-
-1H-pyrazole. LCMS (ESI) m+H=368.1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 8.25 (s, 1H), 7.29 (m, 1H), 7.18 (dd, 1H),
7.01 (dd, 1H), 5.31 (d, 2H), 3.77 (s, 3H), 3.65 (t, 2H), 2.03 (t,
2H), 0.92 (q, 2H), 0 (s, 9H).
##STR00317##
5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyra-
zol-4-amine
[0546] To a solution of
5-(5-fluoro-2-methoxyphenyl)-4-nitro-1-(2-((trimethylsilyl)
methoxy)ethyl)-1H-pyrazole (1.0 g, 2.7 mmol) in 8 mL ethanol was
added 16 mL water, ammonium chloride (570 mg, 10.8 mmol), and iron
powder (760 mg, 13.5 mmol). The reaction mixture was stirred at
75.degree. C. for 6 hours. After cooling to room temperature, the
reaction was diluted with dichloromethane and filtered through a
celite pad, rinsing with more dichloromethane. The filtrate was
added to 150 mL saturated aqueous sodium bicarbonate and extracted
twice with dichloromethane. The combined organic extracts were
dried over magnesium sulfate and concentrated to yield 640 mg (70%)
of
5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyra-
zol-4-amine, which was carried forward without purification. LCMS
(ESI) m+H=338.1. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.37
(m, 2H), 7.20 (t, 1H), 7.04 (dd, 1H), 5.42 (t, 2H), 3.90 (d, 3H),
3.65 (t, 2H), 0.96 (t, 2H), 0 (s, 9H).
##STR00318##
N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0547]
5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1-
H-pyrazol-4-amine (580 mg, 1.72 mmol) in tetrahydrofuran (40 mL)
was added of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (320 mg,
1.72 mmol) in THF (5 mL) at 0.degree. C. After the addition, the
mixture was warmed to room temperature, and then stirred overnight
at this temperature. The mixture was concentrated to give 330 mg
(40%) of
N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was
carried forward without purification. LCMS (ESI) m+H=483.1. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 9.63 (s, 1H), 8.82 (m, 1H), 8.76
(s, 1H), 8.52 (m, 1H), 8.42 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H),
7.22 (m, 1H), 7.06 (m, 2H), 5.42 (d, 2H), 3.86 (s, 3H), 3.72 (m,
2H), 0.92 (q, 2H), 0 (s, 9H)
##STR00319##
N-(5-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide
[0548] To a solution of
N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-p-
yrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (330 mg, 0.68
mmol) in 14 mL ethanol was added HCl (1.0 mL of a 6 M solution in
water, 6.0 mmol). The reaction mixture was then stirred at
70.degree. C. for 6 hours. After cooling to room temperature, a
light yellow precipitate formed, which was filtered off and rinsed
with methanol and diethyl ether. The filtrate was reduced in volume
to precipitate more product, which was filtered off. The combined
collected solids were dried under vacuum to yield 220 mg (92%) of
N-(5-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide. LCMS (ESI) m+H=353.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.68 (s, 1H), 9.32 (dd, 1H), 8.77 (dd, 1H),
8.63 (s, 1H), 8.19 (s, 1H), 7.30 (m, 4H), 3.82 (d, 3H).
Example 150
##STR00320##
[0549]
N-(3-(5-fluoro-2-methoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyr-
azol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0550] To a solution of compound 8 (200 mg, 0.57 mmol) in 10 mL DMF
is added isobutylene oxide (0.41 g, 5.7 mmol) and cesium carbonate
(560 mg, 1.71 mmol). The reaction was stirred at 80.degree. C. for
6 hours, then diluted with ethyl acetate and filtered, and the
organic portion washed with brine, dried over magnesium sulfate,
and concentrated. The crude product was purified by reverse phase
HPLC and lyophilized to give 69.5 mg (29%) of desired compound.
LCMS (ESI) m+Na=447.1. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.:
9.83 (s, 1H), 8.80-8.78 (dd, J=2.0, 6.8 Hz, 1H), 8.73 (s, 1H),
8.56-8.54 (dd, J=1.6, 4.0 Hz, 1H), 8.3.6 (s, 1H), 7.33 (dd, J=3.2,
8.8 Hz, 1H), 7.11-7.08 (m, 1H), 7.02-6.97 (m, 2H), 4.12 (s, 1H),
3.85 (s, 3H), 1.24 (s, 6H).
Example 151
##STR00321##
[0551]
N-(3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a-
]pyrimidine-3-carboxamide
##STR00322##
[0552] methyl 5-chloro-2-(2-chloroethoxyl)benzoate
[0553] To a solution of methyl 5-chloro-2-hydroxybenzoate (54.06 g,
0.29 mol) in 300 mL of anhydrous DMF was added 2-chloroethyl
4-methylbenzenesulfonate (81.6 g, 0.35 mol) and Cs2CO3 (142 g, 0.44
mol). The mixture was stirred at 60-70.degree. C. overnight, then
water was added. A white solid precipitated from the solution,
which was collected by filtration and coevaporated with toluene to
afford 76.1 g (88%) of methyl 5-chloro-2-(2-chloroethoxyl)benzoate.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.76 (d, 1H), 7.40 (dd,
1H), 6.91 (d, 1H), 4.27 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H).
##STR00323##
methyl 5-chloro-2-(vinyloxy)benzoate
[0554] Potassium tert-butoxide (40.4 g, 0.36 mol) was added
portionwise to a solution of 5-chloro-2-(2-chloroethoxyl)benzoate
(76 g, 0.3 mol) in 600 mL of THF at 0.degree. C. After stirring at
that temperature for 1 hour, TLC showed complete consumption of
starting material and the mixture was poured into ice water. The
aqueous layer was extracted twice with EtOAc (200 mL), and the
combined organics were evaporated to dryness. The residue was
purified by silica gel column chromatography
(Hexanes/EtOAc=50:1.about.30:1) to afford 22 g (34%) of methyl
5-chloro-2-(vinyloxy)benzoate. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.76 (d, 1H), 7.38 (dd, 1H), 7.00 (d, 1H), 6.52 (dd, 1H),
4.67 (dd, 1H), 4.44 (dd, 1H), 3.83 (s, 3H).
##STR00324##
methyl 5-chloro-2-cyclopropoxybenzoate
[0555] To a solution of methyl 5-chloro-2-(vinyloxy)benzoate in 100
mL dichloromethane was added diethylzinc (1 M hexanes solution)
(200 mL, 0.2 mol) under N2 atmosphere. The solution was cooled in
an ice bath and a solution of trifluoroacetic acid (16 mL) in
dichloromethane (100 mL) was dropped very slowly into the mixture.
After stirring for 20 minutes, a solution of CH2I2 (16.4 mL, 0.2
mol) in dichloromethane (100 mL) was added dropwise. After stirring
an additional 20 minutes, a solution of methyl
5-chloro-2-(vinyloxy)benzoate (21.3 g, 0.1 mol) in dichloromethane
(100 mL) was added and the ice bath was removed. 8 hours later, the
mixture was quenched with saturated NH4Cl solution and extracted
twice with dichloromethane. The combined organics were dried over
Na2SO4, filtered and evaporated to dryness to afford 21 g (92%) of
methyl 5-chloro-2-cyclopropoxybenzoate. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.75 (d, 1H), 7.43 (q, 1H), 3.86 (s, 3H), 3.80
(m, 1H), 0.85 (m, 4H).
##STR00325##
5-chloro-2-cyclopropoxybenzoic acid
[0556] Methyl 5-chloro-2-cyclopropoxybenzoate was dissolved in
THF/H2O (1:1, 400 mL), then sodium hydroxide (16 g, 0.4 mol) was
added. The mixture was heated to 60.degree. C. and stirred for 1
hour. The reaction mixture was cooled to room temperature, then the
pH was adjusted to 4 using 4N aqueous HCl, resulting in
precipitation of the product. The precipitate was collected by
filtration and azeotroped with toluene to afford 19 g (96%) of
5-chloro-2-cyclopropoxybenzoic acid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 12.96 (br, 1H), 7.58 (m, 2H), 7.43 (q, 1H),
3.91 (m, 1H), 0.81 (m, 4H).
##STR00326##
5-chloro-2-cyclopropoxybenzoyl chloride
[0557] 5-chloro-2-cyclopropoxybenzoic acid (18.5 g, 87 mmol) was
dissolved in SOCl.sub.2 and the solution was refluxed for 4 hours.
The reaction mixture was concentrated in vacuo, then coevaporated
with toluene to afford the desired acid chloride as a colorless oil
that was used directly in the next step.
##STR00327##
ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate
[0558] Acetonitrile (200 mL) was added to potassium
3-ethoxy-3-oxopropanoate (31.1 g, 182.7 mmol), in a 1000 mL
3-necked flask under N.sub.2 with stirring. The reaction mixture
was cooled to 0.degree. C., then triethylamine (38.8 mL, 278.4
mmol) was added, followed by MgCl.sub.2 (20.71 g, 217.5 mmol). The
reaction mixture was warmed to room temperature and stirred for an
additional 2.5 h. The resulting slurry was cooled to 0.degree. C.
and 5-chloro-2-cyclopropoxybenzoyl chloride (18.5 g, 87 mmol) was
added dropwise followed by the addition of more triethylamine (3.9
mL, 28 mmol). The mixture was stirred at room temperature
overnight, then concentrated in vacuo. 1 L of toluene was added,
the mixture was cooled to 0.degree. C., then 125 mL of HCl (13%
aqueous solution) was added. The ice bath was removed, the mixture
was stirred for 30 minutes, then the layers were separated and the
organics washed with water and evaporated to dryness. The residue
was purified by silica gel chromatography (Hexanes/EtOAc=3:1) to
afford 21.8 g of ethyl
3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate. LCMS (ESI)
m+H=283.0; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (t, 1H),
7.44 (dd, 1H), 7.29 (d, 1H), 4.24 (m, 2H), 3.87 (s, 2H), 3.78 (m,
1H), 1.23 (t, 2H), 0.85 (m, 4H).
##STR00328##
ethyl
2-(5-chloro-2-cyclopropoxybenzoyl)-3-(dimethylamino)acrylate
[0559] Ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate
(21.8 g, 77 mmol) was dissolved in 150 mL of DMF-DMA. The mixture
was heated to reflux for 2 hours. Evaporation gave a yellow solid
which was used in the next step without further purification.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 7.69 (s, 1H), 7.39 (s,
1H), 7.29 (dd, J=2.4, 8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 3.92 (q,
J=6.8 Hz, 2H), 3.69-3.65 (m, 1H), 3.10 (br, 6H), 0.88 (t, J=6.8 Hz,
3H), 0.77-0.71 (m, 4H).
##STR00329##
ethyl
3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazole-4-carboxylate
[0560] Ethyl
2-(5-chloro-2-cyclopropoxybenzoyl)-3-(dimethyl-amino)acrylate (24
g, 71 mmol) was dissolved in 150 mL of HOAc. The reaction mixture
was cooled to 0.degree. C. then 85% hydrazine in water (25 mL) was
added dropwise. The mixture was warmed to room temperature and
stirred for 6 hours, then concentrated in vacuo. The residue was
purified by EtOAc/Hexanes=1:2 to afford 24 g of the title compound
as a syrup. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 13.41 (s,
.sup.1H), 8.26 (s, 0.5H), 7.88 (s, 0.5H), 7.49-7.24 (m, 3H),
4.07-3.99 (m, 2H), 3.82-3.74 (m, 1H), 1.17-1.10 (m, 3H), 0.73-0.46
(m, 4H)
##STR00330##
ethyl
3-(5-chloro-2-cyclopropoxyphenyl)-1-((2-trimethylsilyl)ethoxy)methy-
l)-1H-pyrazole-4-carboxylate
and
##STR00331##
[0561] ethyl
5-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazole-4-carboxylate
[0562] To a solution of ethyl
3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazole-4-carboxylate (12 g,
39 mmol) in THF (200 mL) was added 60% sodium hydride in mineral
oil (1.72 g, 43 mmol) and the reaction mixture was stirred for 10
min. SEMCl (7.2 g, 43 mmol) was added and the reaction mixture was
stirred at room temperature overnight. The mixture was quenched
with ice-water and extracted with EtOAc (300 mL.times.2). The
combined organics were dried over sodium sulfate and concentrated
in vacuo afford 16 g of the title compounds.
##STR00332##
3-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazole-4-carboxylic acid
and
##STR00333##
[0563]
5-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)meth-
yl)-1H-pyrazole-4-carboxylic acid
[0564] The resulting crude ester from last step was dissolved in
200 mL of water. NaOH (7.32 g, 0.18 mmol) was added into the
solution and the mixture was refluxed for 6 hours, then cooled to
room temperature and neutralized with 4 N HCl to pH.about.7. The
resulting precipitate was collected by filtration, then dissolved
in MeOH. The remaining solids were filtered off and discarded and
the filtrate evaporated to dryness to afford the title compounds
(11.9 g) as a yellow solid.
##STR00334##
tert-butyl
3-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazol-4-ylcarbamate
and
##STR00335##
[0565] tert-butyl
5-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazol-4-ylcarbamate
[0566] The product from the previous step (8.5 g, 20.8 mmol) was
dissolved in toluene. DPPA (5.4 mL, 25 mmol) and TEA (3.5 mL, 25
mmol) were added and the mixture was stirred at room temperature
for 1 hour. Tert-Butyl alcohol (5.3 mL, 50 mmol) was added. The
mixture was heated to 90.degree. C. and stirred overnight. The
reaction mixture was concentrated in vacuo and the residue was
purified by silica gel column chromatography eluting with
Hexanes/EtOAc=10:1 to afford 2.5 g of the title compounds (not
separated), which were used directly in the next step.
##STR00336##
3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-amine
[0567] Tert-butyl
3-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazol-4-ylcarbamate and tert-butyl
5-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazol-4-ylcarbamate were dissolved in 50 mL of MeOH. 50 mL of 4
M HCl/MeOH was added dropwise. The mixture was stirred at room
temperature overnight. The mixture was evaporated to dryness and
purified by silica gel chromatography, eluting with EtOAc to afford
0.25 g of 3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-amine LCMS
(ESI) m+H=249.8. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.:
12.32-12.10 (br, 1H), 7.41-7.34 (m, 3H), 7.09 (s, 1H), 4.12 (q,
J=5.2 Hz, 2H), 2.94-3.88 (m, 3H), 0.79-0.74 (m, 4H)
##STR00337##
N-(3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
[0568] 3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-amine (0.2 g,
0.8 mmol) was dissolved in 15 mL of anhydrous THF.
Pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.17 g, 0.96 mmol)
was added followed by DIPEA (0.2 g, 1.6 mmol). The mixture was
stirred at room temperature for 2 h, then evaporated to dryness.
The residue was purified by silica gel chromatography (EtOAc as
eluant) to afford 0.3 g of the title compound. Yield: 95%. .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta.: 12.93 (d, 1H), 9.56 (d, J=5.2
Hz, 1H), 9.34 (d, J=7.2 Hz, 1H), 8.75-8.74 (m, 1H), 8.65 (s, 1H),
8.22 (s, 0.5H), 8.05 (s, 0.5H), 7.55-7.25 (m, 4H), 3.97-3.94 (m,
1H), 0.70-0.44 (m, 4H).
Example 152
##STR00338##
[0569]
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-pyrazol-5-yl)methyl)-
-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00339##
[0570] 5-(chloromethyl)-1-methyl-1H-pyrazole
[0571] To a stirred solution of (1-methyl-1H-pyrazol-5-yl)methanol
(200 mg, 1.8 mmol) in 20 mL of DCM was added SOCl.sub.2 (262 mg,
2.2 mmol). The reaction mixture was refluxed for 2 hours, then the
solvent was evaporated and the residue co-evaporated with DCM. The
residue was partitioned between DCM and water. The organic phase
was separated and washed with saturated aqueous NaHCO.sub.3, water,
and brine, then dried over magnesium sulfate, filtered, and
concentrated to give 93 mg of
5-(chloromethyl)-1-methyl-1H-pyrazole. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.40 (s, 1H), 6.27 (s, 1H), 4.60 (s, 2H), 3.92
(s, 3H).
##STR00340##
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-py-
razol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0572] To a solution of
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide (144 mg, 0.40 mmol) in 3 mL of DMF was added
5-(chloromethyl)-1-methyl-1H-pyrazole (78 mg, 0.6 mmol) and cesium
carbonate (391 mg, 1.20 mmol). The reaction mixture was stirred at
60.degree. C. for 6 hours, then cooled to room temperature, diluted
with ethyl acetate and filtered. The filtrate was washed with
brine, dried over magnesium sulfate, and concentrated. The crude
product was purified by reverse phase HPLC and lyophilized to give
58.3 mg (32%) of
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-py-
razol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI)
m+H=454.1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:9.58 (s, 1H),
8.74 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.21 (s, 1H), 7.81 (s,
1H), 7.69 (dd, 1H), 7.39 (s, 1H), 7.07 (d, 1H), 6.96 (dd, 1H), 6.31
(s, 2H), 5.33 (s, 2H), 3.86 (d, 6H).
Example 153
##STR00341##
[0573]
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-imidazol-2-yl)methyl-
)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0574] To a solution of
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine--
3-carboxamide (200 mg, 0.56 mmol) in 3 mL of DMF was added
2-(chloromethyl)-1-methyl-1H-imidazole (109 mg, 0.84 mmol) and
cesium carbonate (547 mg, 1.68 mmol). The reaction mixture was
stirred at room temperature for 3 hours, then diluted with ethyl
acetate and filtered. The filtrate was washed with brine, dried
over magnesium sulfate, and concentrated. The crude product was
purified by reverse phase HPLC and lyophilized to give 82.2 mg
(32%) of
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-p-
yrazol-4-yl) pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI)
m+H=454.1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.53 (s, 1H),
8.73 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.26 (s, 1H), 7.80 (d,
1H), 7.68 (dd, 1H), 7.06 (d, 1H), 6.97 (m, 2H), 6.83 (s, 1H), 5.42
(s, 2H), 3.85 (s, 3H), 3.63 (s, 3H).
Example 154
##STR00342##
[0575]
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-1,2,4-triazol-3-yl)m-
ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00343##
[0576] 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole
hydrochloride
[0577] (1-methyl-1H-1,2,4-triazol-3-yl)methanol (0.25 g, 2.2 mmol)
was dissolved in 10 mL of SOCl.sub.2 and refluxed for 2 hours. The
mixture was evaporated to dryness and coevaporated with toluene.
The resulting white solid (0.2 g) was used in the next step without
further purification.
##STR00344##
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-
-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0578]
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide (0.15 g, 0.42 mmol) was dissolved in 10 mL of
DMF, then 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride
(82 mg, 0.63 mmol) and Cs.sub.2CO.sub.3 (0.41 g, 1.26 mmol) were
added. The mixture was stirred at room temperature for 2 hours,
then filtered through celite and purified by reverse phase HPLC to
give 44.8 mg (23%) of
N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-1,2,4-triazol-3-yl)meth-
yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS
(ESI) m+H=455.1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.64
(s, 1H), 9.34 (d, 1H), 8.75 (d, 1H), 8.64 (s, 1H), 8.44 (s, 1H),
8.35 (s, 1H), 7.95 (d, 1H), 7.73 (d, 1H), 7.47 (d, 1H), 7.28 (dd,
1H), 5.39 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
Example 155
##STR00345##
[0579]
N-(3-(5-cyano-2-methoxyphenyl)-1-((2-methyl-2H-1,2,4-triazol-3-yl)m-
ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00346##
[0580] 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole
hydrochloride
[0581] (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.1 g, 0.88 mmol)
was dissolved in 10 mL of SOCl.sub.2 and refluxed for 2 hours. The
mixture was evaporated to dryness and coevaporated with toluene.
The resulting white solid (about 0.1 g) was used in the next step
without further purification
##STR00347##
N-(3-(5-cyano-2-methoxyphenyl)-1-((2-methyl-2H-1,2,4-triazol-3-yl)methyl)-
-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0582]
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide (0.21 g, 0.58 mmol) was dissolved in 10 mL of
DMF. 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride
(about 0.1 g, 0.88 mmol) and Cs.sub.2CO.sub.3 (0.57 g, 1.75 mmol)
were added and the mixture was stirred at room temperature
overnight. The reaction mixture was filtered through Celite and
purified by reverse phase HPLC to afford 60.8 mg (23%) of
N-(3-(5-cyano-2-methoxy
phenyl)-1-((2-methyl-2H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-4-yl)pyrazo-
lo[1,5-a]pyramidine-3-carboxamide. LCMS (ESI) m+H=455.1; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 9.64 (s, 1H), 9.64 (s, 1H), 9.33
(dd, 1H), 8.74 (dd, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 7.95 (dd, 1H),
7.89 (s, 1H), 7.74 (d, 1H), 7.46 (d, 1H), 7.28 (dd, 1H), 5.65 (s,
2H), 3.90 (s, 3H), 3.88 (s, 3H).
Example 156
##STR00348##
[0583]
N-(3-(5-cyano-2-methoxyphenyl)-1-((4-methyl-4H-1,2,4-triazol-3-yl)m-
ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00349##
[0584] 2-hydroxyacetohydrazide
[0585] Ethyl-2-hydroxyacetate (6 g, 0.12 mol) was added dropwise to
a solution of hydrazine monohydrate (10.4 g, 0.1 mol) in EtOH (50
ml) at 0.degree. C. The mixture was warmed to room temperature and
stirred overnight. The mixture was concentrated in vacuo to give
the desired product which was used in the next step without
purification. Yield: 97%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta.: 8.82 (s, 1H), 5.32-5.13 (m, 1H), 4.38-4.09 (m, 2H), 3.80
(s, 2H).
##STR00350##
2-(2-hydroxyacetyl)-N-methylhydrazinecarbimidothioic acid
[0586] To a solution of 2-hydroxyacetohydrazide (4.5 g, 50 mmol) in
EtOH was added dropwise methyl isothiocyanate (3.7 g, 50 mmol)
under ice cooling. After addition was complete the reaction mixture
was brought to room temperature and then stirred for 24 hr at
60.degree. C. Ice water was then added and stirring was continued
for 15 min. The reaction mixture was concentrated in vacuuo to give
the title compound. Yield: 100%. LCMS (ESI) m+H=164.0.
##STR00351##
(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methanol
[0587] 5N NaOH (50 mmol) was added to a solution of
2-(2-hydroxyacetyl)-N-methylhydrazinecarbimidothioic acid (8.15 g,
50 mmol) in EtOH, and then the mixture was stirred for 4 hr at
60.degree. C. The mixture was cooled in an ice bath and the pH was
adjusted to .about.5-6 with concentrated HCl. The precipitated
solid was filtered, washed with EtOH, and dried under vacuum to
give the title compound. Yield: 83%. .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta.: 5.64 (s, 1H), 4.46 (s, 2H), 3.44 (s, 3H).
##STR00352##
(4-methyl-4H-1,2,4-triazol-3-yl)methanol
[0588] NaNO.sub.2 (70 mg, 1 mmol) was added to 5N HNO.sub.3 (10 mL)
at room temperature. The reaction mixture was cooled in an ice
bath, then (5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methanol (360
mg, 2.5 mmol) was added. The reaction mixture was then warmed to
room temperature and stirred for one hour. Water (30 mL) was added,
then the resulting mixture was neutralized using solid
K.sub.2CO.sub.3 until the pH was .about.7-8. The reaction mixture
was concentrated in vacuo and the residue was dissolved in DCM/MeOH
(5:1), filtered, and concentrated in vacuo to afford the title
compound. Yield: 92%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.:
8.38 (s, 1H), 5.57 (s, 1H), 4.56 (d, J=10.8 Hz, 2H), 3.65 (s,
3H).
##STR00353##
3-(chloromethyl)-4-methyl-4H-1,2,4-triazole
[0589] A solution of (4-methyl-4H-1,2,4-triazol-3-yl)methanol (260
mg, 2.3 mmol) in SOCl.sub.2 (10 mL) was refluxed for 1 hour, and
then concentrated in vacuo to give the desired compound. Yield:
100%. LCMS (ESI) m+H=132.1.
##STR00354##
N-(3-(5-cyano-2-methoxyphenyl)-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-
-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0590]
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide (120 mg, 0.334 mmol),
3-(chloromethyl)-4-methyl-4H-1,2,4-triazole (65 mg, 0.5 mmol) and
Cs.sub.2CO.sub.3 (325 mg, 1 mmol) were suspended in DMF. The
mixture was stirred overnight at room temperature, then filtered
and concentrated in vacuo. The residue was purified by preparative
HPLC to afford
N-(3-(5-cyano-2-methoxyphenyl)-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-
-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (23.2 mg,
yield: 15%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 9.59 (s,
1H), 8.77 (dd, J=2.0, 7.2 Hz, 1H), 8.70 (s, 1H), 8.51 (dd, J=2.0,
4.4 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.82 (d, J=2.0 Hz, 1H),
7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.99 (q,
J=4.4, 6.8 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 3H).
Example 157
##STR00355##
[0591]
N-(3-(3,3-difluoropiperidin-1-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]py-
rimidine-3-carboxamide
##STR00356##
[0592]
1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)pip-
eridin-3-one
[0593] To a solution of oxalyl chloride (0.82 g, 6.44 mmol) and
DMSO (1.07 g, 13.75 mmol) was added dropwise
1-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-
-3-ol (2.0 g, 5.85 mmol) at -78.degree. C. the reaction mixture was
stirred at that temperature for 15 min, then Et.sub.3N (4.1 mL,
29.25 mmol) was added. The reaction mixture was warmed to room
temperature and stirred for an additional 90 minutes. The reaction
mixture was concentrated in vacuo and the residue was purified by
silica gel column chromatography (hexanes/EtOAc=50:1) to afford 1.9
g (95%) of 1-(4-nitro-1-(2-((trimethylsilyl)
methoxy)ethyl)-1H-pyrazol-5-yl)piperidin-3-one.
[0594] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.09 (s, 1H),
5.30 (s, 2H), 3.68 (m, 2H), 3.69 (m, 2H), 3.48 (m, 2H), 2.63 (m,
2H), 2.14 (m, 2H), 0.93 (m, 2H), 0 (s, 9H).
##STR00357##
3,3-difluoro-1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-
-yl)piperidine
[0595] To a solution of
1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)piperidin-
-3-one (1.8 g, 5.28 mmol) in 20 mL of ethanol was added DAST (1.3
g, 7.92 mmol). The reaction mixture was stirred at room temperature
for 3 hours, then 100 mL of water was added to the mixture. The
mixture was extracted twice with dichloromethane and the combined
organic extracts were dried over magnesium sulfate and concentrated
to afford 1.4 g (73%) of
3,3-difluoro-1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-
-yl)piperidine. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.08 (s,
1H), 5.41 (m, 2H), 3.70 (m, 6H), 2.11 (m, 2H), 1.92 (s, 2H), 0.94
(m, 2H), 0 (s, 9H).
##STR00358##
5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-py-
razol-4-amine
[0596] To a solution of
3,3-difluoro-1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-
-yl)piperidine (1.4 g, 3.86 mmol) in 20 mL of ethanol was added 40
mL of water, ammonium chloride (0.82 mg, 15.44 mmol), and iron
powder (1.08 g, 19.3 mmol). The reaction mixture was stirred at
70.degree. C. for 1 hour. After cooling to room temperature, the
reaction mixture was diluted with dichloromethane and filtered
through a celite pad, rinsing with more dichloromethane. The
filtrate was extracted twice with dichloromethane, then the
combined organic extracts were dried over magnesium sulfate and
concentrated to afford 1.2 g (93%) of
5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-py-
razol-4-amine LCMS (ESI) m+H=333.1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.09 (s, 1H), 5.38 (m, 2H), 3.74 (m, 6H), 2.01
(s, 1H), 1.96 (s, 2H), 1.52 (m, 2H), 0.92 (m, 2H), 0 (s, 9H).
##STR00359##
N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0597] To a solution of
5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)
methoxy)ethyl)-1H-pyrazol-4-amine (1.2 g, 3.61 mmol) in 30 mL THF
was added DIPEA (1.3 mL, 7.22 mmol) and
pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (720 mg, 3.97 mmol)
in THF (50 mL) at 0.degree. C. After addition was complete, the
mixture was warmed to room temperature, then stirred overnight. The
mixture was concentrated in vacuo and the residue was purified by
silica gel column chromatogaphy (hexanes:EtOAc=3:1 to 1:1) to
afford 1.0 g (60%) of
N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI)
m+H=478.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.49 (s, 1H),
8.87 (dd, 1H), 8.75 (s, 1H), 8.71 (dd, 1H), 7.94 (s, 1H), 7.10 (dd,
1H), 5.40 (s, 2H), 3.67 (m, 6H), 2.06 (s, 2H), 1.93 (m, 2H), 0.95
(m, 2H), 0 (s, 9H).
##STR00360##
N-(3-(3,3-difluoropiperidin-1-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide
[0598] To a solution of
N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.1
mmol) in 50 mL of ethanol was added HCl (1.75 mL of a 6 M solution
in water, 10.5 mmol). The reaction mixture was stirred at
70.degree. C. for 1 hour. After cooling to room temperature, a
light yellow precipitate formed, which was filtered off and rinsed
with methanol and diethyl ether. The filtrate was then reduced in
volume, and more solid product isolated by filteration. The
combined collected solids were dried under vacuum to afford 0.77 g
(94%) of
N-(3-(3,3-difluoropiperidin-1-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide. LCMS (ESI) m+H=348.1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 9.59 (s, 1H), 9.37 (dd, 1H), 8.84 (m, 2H),
8.01 (s, 1H), 7.32 (dd, 1H), 3.74 (s, 1H), 3.33 (m, 2H), 3.12 (m,
2H), 2.10 (m, 2H), 2.00 (m, 2H).
Example 158
##STR00361##
[0599]
N-(3-(5-Cyano-2-methoxypyridin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a-
]pyrimidine-3-carboxamide
##STR00362##
[0600]
6-Hydroxy-5-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo-
l-5-yl)nicotinonitrile
[0601] The title compound was prepared by following the procedures
described for
N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-4-nitro-1H-pyrazole.
##STR00363##
6-Methoxy-5-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl-
)nicotinonitrile
[0602] To an ice-cooled solution of
6-methoxy-5-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl-
)nicotinonitrile (57 mg, 0.16 mmol, 1 equiv) in a 1:1
methanol/toluene solution (3 mL) was added
trimethylsilyldiazomethane (0.8 mL, 1.6 mmol, 2.0 M solution in
diethyl ether). The reaction mixture was warmed to 24.degree. C.
after 50 min and concentration in vacuo. Purification by flash
column chromatography (1:1 heptane/ethyl acetate) provided product
(3.3 mg, 5.6%). .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.: 8.63
(d, J=2.2 Hz, 1H), 8.21 (s, 1H), 7.96 (d, J=2.2 Hz, 1H), 5.27 (m,
2H), 3.97 (s, 3H), 3.63 (m, 2H), 0.86 (m, 2H), -0.02 (s, 9H).
##STR00364##
5-(4-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-methox-
ynicotinonitrile
[0603] A solution of
6-methoxy-5-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl-
)nicotinonitrile (11 mg, 0.029 mmol, 1 equiv) in methanol (4 mL)
was 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 (7.1 mg, 70% crude yield). .sup.1H NMR
(400 MHz, CDCl.sub.3), .delta.: 8.52 (d, J=2.2 Hz, 1H), 8.09 (d,
J=2.2 Hz, 1H), 5.21 (s, 2H), 4.06 (s, 3H), 3.58 (m, 2H), 0.85 (m,
2H), -0.04 (s, 9H).
##STR00365##
N-(3-(5-Cyano-2-methoxypyridin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
[0604] To a suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (22.0 mg, 0.135 mmol, 6.56 equiv),
5-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-methox-
ynicotinonitrile (7.1 mg, 0.020 mmol, 1 equiv), and
2-chloro-2,4-dimethoxy-1,3,5-triazine (23.7 mg, 0.135 equiv, 6.56
equiv) in acetonitrile (2 mL) was added 4-methylmorpholine (23 uL,
0.21 mmol, 10 equiv) at 24.degree. C. After 2 days, the reaction
mixture was partitioned between saturated aqueous sodium
bicarbonate solution (2 mL), saturated aqueous sodium chloride
solution (2 mL), and ethyl acetate (5 mL). The organic was
separated, and the aqueous was extracted with ethyl acetate
(2.times.5 mL). The combined organic was dried over anhydrous
sodium sulfate, filtered, and concentrated. The crude material was
dissolved in ethanol (3 mL) and 6 N aqueous hydrochloric acid (1
mL) and heated to 50.degree. C. After 5 h, the reaction mixture was
concentrated in vacuo and purified by preparative HPLC to afford a
white solid (1.1 mg, 15% yield). .sup.1H NMR (400 MHz, CDCl.sub.3),
.delta.: 9.72 (s, 1H), 8.80 (dd, J=7.0, 1.6 Hz, 1H), 8.74 (s, 1H),
8.66 (m, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=1.9
Hz, 1H), 7.04 (dd, J=7.0, 4.2 Hz, 1H), 4.11 (s, 3H). LCMS (ESI):
M+H=361.1
Example 159
##STR00366##
[0605]
N-(1-(Azetidin-3-yl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)p-
yrazolo[1,5-a]pyrimidine-3-carboxamide
[0606] A suspension of
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (50.0 mg, 0.136 mmol, 1 equiv), tert-butyl
3-iodoazetidine-1-carboxylate (230.3 mg, 0.813 mmol, 6.00 equiv),
and cesium carbonate (177 mg, 0.542 mmol, 4.00 equiv) in
N,N-dimethylformamide (1 mL) was heated at 50.degree. C. After 5 h,
the reaction mixture was partitioned between saturated aqueous
sodium chloride solution (5 mL) and ethyl acetate (5 mL). The
aqueous layer was extracted with ethyl acetate (2.times.5 mL). The
combined organic was dried over anhydrous sodium sulfate, filtered,
and concentrated. The crude residue was dissolved in
dichloromethane (2 mL) and trifluoroacetic acid (2 mL) at
24.degree. C. After 5 h, the reaction mixture was concentrated in
vacuo and purified by preparative HPLC to afford product (12.7 mg,
22% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6), .delta.: 9.75 (s,
1H), 9.36 (m, 1H), 8.79 (m, 1H), 8.67 (s, 1H), 8.46 (s, 1H),
7.53-7.56 (m, 2H), 7.29-7.34 (m, 2H), 5.45 (m, 1H), 4.33 (m, 2H),
4.23 (m, 2H), 3.86 (s, 3H). LCMS (ESI): M+H=424.1.
Example 160
##STR00367##
[0607]
N-(3-(5-chloro-2-methoxyphenyl)-1-(1-(oxetan-3-ylamino)-1-oxopropan-
-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00368##
[0608] tert-Butyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)propanoate
[0609] A suspension of
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), tert-butyl
2-bromopropanoate (0.54 mL, 3.2 mmol, 1.2 equiv), and cesium
carbonate (1.1 g, 3.2 mmol, 1.2 equiv) in N,N-dimethylformamide (15
mL) was heated at 75.degree. C. for 3 h. The reaction mixture was
concentrated, and the resulting residue was partitioned between
half-saturated aqueous sodium chloride solution (50 mL) and ethyl
acetate (50 mL). The aqueous was extracted with ethyl acetate
(2.times.50 mL). The collected organic was dried over anhydrous
sodium sulfate, filtered, and concentrated. Purification by flash
column chromatography (90% ethyl acetate in heptane) provided
product (0.945 g, 70%). LCMS (ESI): M+H=497.2.
##STR00369##
2-(3-(5-Chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)propanoic acid
[0610] Trifluoroacetic acid (10 mL) was added dropwise to a
solution of tert-butyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)propanoate (0.945 g, 1.90 mmol, 1 equiv) in
dichloromethane (10 mL). After 2 h, the reaction mixture was
concentrated in vacuo to afford crude product (quantitative) which
was used without further purification. LCMS (ESI): M+H=441.1.
##STR00370##
N-(3-(5-chloro-2-methoxyphenyl)-1-(1-(oxetan-3-ylamino)-1-oxopropan-2-yl)-
-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0611] A solution of
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)propanoic acid (66.0 mg, 0.150 mmol, 1 equiv),
oxetan-3-amine hydrochloride (41.0 mg, 0.374 mmol, 2.50 equiv),
N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium
hexafluorophosphate (114 mg, 0.299 mmol, 2.00 equiv), and
N,N-diisopropylethylamine (522 .mu.L, 2.99 mmol, 20.0 equiv) in
N,N-dimethylformamide (1.0 mL) was heated at 50.degree. C. After 6
h, the reaction mixture was concentrated, and the resulting residue
was partitioned between saturated aqueous sodium bicarbonate (10
mL) and ethyl acetate (10 mL). The aqueous was extracted with ethyl
acetate (2.times.5 mL). The combined organic was dried over
anhydrous sodium sulfate, filtered, and concentrated. Purification
by preparative HPLC afforded product (39 mg, 51% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6), .delta.: 9.70 (s, 1H), 9.33 (m, 1H),
9.02 (d, J=6.5 Hz, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.65 (s, 1H),
8.36 (s, 1H), 7.50 (dd, J=8.9, 2.7 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H),
7.27-7.31 (m, 2H), 5.06 (q, J=7.1 Hz, 1H), 4.80 (m, 1H), 4.73 (m,
2H), 4.44 (m, 2H), 3.84 (s, 3H), 1.66 (d, J=7.1 Hz, 3H). LCMS
(ESI): M+H=496.1.
Example 161
##STR00371##
[0612]
N-(1-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)-3-(5-chloro-2-me-
thoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00372##
[0613] Ethyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)-2-methylpropanoate
[0614] A suspension of
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), ethyl 2-bromoisobutyrate
(0.597 mL, 4.07 mmol, 1.50 equiv), and cesium carbonate (1.77 g,
5.42 mmol, 2.00 equiv) in N,N-dimethylformamide (15 mL) was heated
at 50.degree. C. After 5 h, the reaction mixture was concentrated
in vacuo, and the resulting residue was partitioned between
saturate aqueous sodium chloride solution (30 mL) and ethyl acetate
(20 mL). The aqueous was extracted with ethyl acetate (2.times.20
mL). The combined organic was dried over anhydrous sodium sulfate,
filtered, and concentrated to provide crude product (1.13 g, 84%
yield). LCMS (ESI): M+H=483.2.
##STR00373##
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)-2-methylpropanoic acid
[0615] To a solution of ethyl
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)-2-methylpropanoate (0.918 g, 1.90 mmol, 1
equiv) was added 2 N aqueous sodium hydroxide solution (4 mL).
After 18 h, additional 2 N aqueous sodium hydroxide solution (4 mL)
was added. After 5 h, the reaction mixture was concentrated in
vacuo, and the resulting residue was dissolved in water (15 mL).
The aqueous solution was acidified with 6 N aqueous hydrochloric
acid until pH=2. The resulting aqueous solution was extracted with
ethyl acetate (3.times.30 mL). The combined organic was dried over
anhydrous sodium sulfate, filtered, and concentrated to provide
crude acid (quantitative). LCMS (ESI): M+H=455.1.
##STR00374##
N-(1-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)-3-(5-chloro-2-methoxyp-
henyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0616] A solution of
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)-2-methylpropanoic acid (0.050 g, 0.11 mmol, 1
equiv), azetidine (18.5 .mu.L, 0.275 mmol, 2.50 equiv),
N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium
hexafluorophosphate (84 mg, 0.20 mmol, 2.00 equiv), and
N,N-diisopropylethylamine (380 .mu.L, 2.2 mmol, 20 equiv) in
N,N-dimethylformamide (1 mL) was heated at 50.degree. C. After 6 h,
the reaction mixture was concentrated, and the resulting residue
was partitioned between saturated aqueous sodium bicarbonate (5 mL)
and ethyl acetate (5 mL). The aqueous was extracted with ethyl
acetate (2.times.5 mL). The combined organic was dried over
anhydrous sodium sulfate, filtered, and concentrated. Purification
by preparative HPLC afforded product (32 mg, 60% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6), .delta.: 9.70 (s, 1H), 9.34 (m, 1H),
8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 7.52 (dd,
J=8.9, 2.7 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.28-7.32 (m, 2H), 3.88
(s, 2H), 3.86 (s, 3H), 3.41 (m, 2H), 2.04 (m, 2H), 1.72 (s, 6H).
LCMS (ESI): M+H=494.1.
Example 162
##STR00375##
[0617]
N-(3-(5-Chloro-2-methoxyphenyl)-1-(2-(tetrahydrofuran-3-ylamino)eth-
yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00376##
[0618]
N-(3-(5-Chloro-2-methoxyphenyl)-1-(2-chloroethyl)-1H-pyrazol-4-yl)p-
yrazolo[1,5-a]pyrimidine-3-carboxamide
[0619] A suspension of
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-
-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), 2-chloroethyl
para-toluenesulfonate (745 .mu.L, 4.11 mmol, 1.5 equiv), and cesium
carbonate (2.16 g, 6.62 mmol, 2.4 equiv) in N,N-dimethylformamide
(10 mL) was heated at 50.degree. C. After 3 h, the reaction mixture
was concentrated in vacuo, and the resulting residue was
partitioned between ethyl acetate (30 mL) and half-saturated
aqueous sodium chloride solution (30 mL). The aqueous was extracted
with ethyl acetate (2.times.20 mL). The combined organic was dried
over anhydrous sodium sulfate, filtered, and concentrated.
Purification by flash column chromatography (ethyl acetate)
provided product (950 mg, 77% yield). LCMS (ESI): M+H=432.1.
##STR00377##
N-(3-(5-Chloro-2-methoxyphenyl)-1-(2-(tetrahydrofuran-3-ylamino)ethyl)-1H-
-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0620] A solution of
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-chloroethyl)-1H-pyrazol-4-yl)pyrazol-
o[1,5-a]pyrimidine-3-carboxamide (0.040 g, 0.090 mmol, 1 equiv),
3-aminotetrahydrofuran hydrochloride (29 mg, 0.23 mmol, 2.50
equiv), and N,N-diisopropylethylamine (73 .mu.L, 0.42 mmol, 4.5
equiv) in N-methylpyrrolidinone (1 mL) was heated at 100.degree. C.
After 18 h, the reaction mixture was partitioned between ethyl
acetate (10 mL) and half-saturated aqueous sodium chloride solution
(10 mL). The aqueous was extracted with ethyl acetate (2.times.10
mL). The combined organic was dried over anhydrous sodium sulfate,
filtered, and concentrated. Purification by preparative HPLC
provided product (13.3 mg, 30% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6), .delta.: 9.67 (s, 1H), 9.32 (dd, J=7.0, 1.5 Hz, 1H),
8.77 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 7.49 (dd,
J=8.9, 2.7 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.27-7.30 (m, 2H), 4.21
(t, J=6.4 Hz, 2H), 3.85 (s, 3H), 3.60-3.76 (m, 4H), 3.38 (m, 2H),
2.96 (m, 2H), 1.96 (m, 1H), 1.62 (m, 1H). LCMS (ESI):
M+H=482.2.
Example 163
##STR00378##
[0621]
N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(cyclopropanecarboxamido)ethyl-
)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0622] To a solution of
N-(1-(2-aminoethyl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo-
[1,5-a]pyrimidine-3-carboxamide (0.030 g, 0.073 mmol, 1 equiv) and
N,N-diisopropylethylamine (51 .mu.L, 0.29 mmol, 4.0 equiv) in
dichloromethane (1 mL) was added dropwise cyclopropanecarbonyl
chloride (0.020 mL, 0.22 mmol, 3.0 equiv) at 24.degree. C. After 1
h, the reaction mixture was concentrated in vacuo. Purification by
preparative HPLC provided product (16.5 mg, 47% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6), .delta.: 9.69 (s, 1H), 9.33 (dd, J=7.0,
1.6 Hz, 1H), 8.78 (dd, J=4.1, 1.5 Hz, 1H), 8.66 (s, 1H), 8.28 (s,
1H), 8.22 (t, J=5.5 Hz, 1H), 7.50 (dd, J=8.8, 2.8 Hz, 1H), 7.44 (d,
J=2.7 Hz, 1H), 7.27-7.31 (m, 2H), 4.22 (t, J=6.1 Hz, 2H), 3.85 (s,
3H), 3.52 (q, J=6.0 Hz, 2H), 1.55 (m, 1H), 0.62-0.71 (m, 4H). LCMS
(ESI): M+H=480.2.
Example 164
##STR00379##
[0623]
(S)--N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(2-hydroxypropylamino)-2--
oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0624] A solution of
2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamid-
o)-1H-pyrazol-1-yl)acetic acid (51 mg, 0.12 mmol, 1 equiv),
(25)-1-aminopropan-2-ol (24 .mu.L, 0.30 mmol, 2.5 equiv),
triethylamine (20 .mu.L), and
N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium
hexafluorophosphate (91 mg, 0.24 mmol, 2.0 equiv) in
N,N-dimethylformamide (1.2 mL) was heated at 80.degree. C. After 6
h, the reaction mixture was concentrated in vacuo, and the
resulting residue was partitioned between saturated aqueous sodium
bicarbonate (5 mL) and ethyl acetate (5 mL). The aqueous was
extracted with ethyl acetate (2.times.5 mL). The combined organic
was dried over anhydrous sodium sulfate, filtered, and
concentrated. Purification by preparative HPLC afforded product (17
mg, 29% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6), .delta.: 9.70
(s, 1H), 9.35 (dd, J=7.0, 1.5 Hz, 1H), 8.70 (dd, J=4.2, 1.5 Hz,
1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.50 (dd,
J=8.9, 2.7 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.27-7.32 (m, 2H), 4.88
(s, 2H), 4.74 (d, J=4.7 Hz, 1H), 3.85 (s, 3H), 3.68 (m, 1H), 3.06
(m, 2H), 1.04 (d, J=6.2 Hz, 3H). LCMS (ESI): M+H=484.2.
Example 165
##STR00380##
[0625]
(E)-N-(3-(5-chloro-2-methoxyphenyl)-1-(3,3,3-trifluoroprop-1-enyl)--
1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00381##
[0626]
(R)-3-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-c]pyrimidine-3--
carboxamido)-1H-pyrazol-1-yl)-1,1,1-trifluoropropan-2-yl
methanesulfonate
[0627] Under a nitrogen atmosphere, a solution of
(R)--N-(3-(5-chloro-2-methoxyphenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)--
1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (188.7 mg,
0.3724 mmol, a 88:12 mixture of pyrazole regioisomers as determined
by .sup.1H NMR) in anhydrous dichloromethane (3.5 mL, 0.1 M) was
charged with mesyl chloride (61 .mu.L, 0.78 mmol), followed by
degassed triethylamine (164 .mu.L, 1.18 mmol). After stirring for
16.5 h, the reaction mixture was diluted with dichloromethane and
washed with saturated aqueous ammonium chloride. The organic was
dried over magnesium sulfate. Concentration in vacuo afforded a
residue whose purification via flash column chromatography
(dichloromethane/methanol, 100:0-96:4) afforded the target compound
as a yellow solid (198.1 mg, 90%); R.sub.F=0.28
(CH.sub.2Cl.sub.2:MeOH, 95:5); Major regioisomer: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.75 (s, 1H), 8.79 (dd, J=7.1, 1.3 Hz,
1H), 8.72 (s, 1H), 8.54 (dd, J=4.0, 1.4 Hz, 1H), 8.41 (s, 1H), 7.55
(d, J=2.6 Hz, 1H), 7.41 (dd, J=8.7, 2.6 Hz, 1H), 7.03-6.98 (m, 2H),
5.56 (m, 1H), 4.67 (dd, J=14.7, 2.4 Hz, 1H), 4.43 (dd, J=14.6, 10.2
Hz, 1H), 3.84 (s, 3H), 2.76 (s, 3H).
##STR00382##
(E)-N-(3-(5-chloro-2-methoxyphenyl)-1-(3,3,3-trifluoroprop-1-enyl)-1H-pyr-
azol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0628] A mixture of
(R)-3-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carbox-
amido)-1H-pyrazol-1-yl)-1,1,1-trifluoropropan-2-yl methanesulfonate
(35.4 mg, 0.0633 mmol), cesium carbonate (310 mg, 0.950 mmol), and
dimethylamine hydrochloride (155 mg, 1.90 mmol) in
N,N-dimethylformamide (1 mL, 0.06 M) was submitted to microwave
irradiation (180.degree. C.) for 45 min. After dilution with
dichloromethane and filtration of solids, the organics were
concentrated to dryness. Purification by flash column
chromatography (dichloromethane:methanol, 100:0-95:5) afforded the
target compound as a yellow solid (18.8 mg, 58%). The undesired
regioisomer was removed by RP-HPLC, leaving 8.0 mg of product;
R.sub.F=0.36 (CH.sub.2Cl.sub.2:iPrOH, 90:10); LCMS (ESI) m+H=463.1;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.82 (s, 1H), 8.80 (dd,
J=7.0, 1.6 Hz, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.52 (dd, J=4.1,
1.6 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.52 (dd, J=14.0, 1.9 Hz, 1H),
7.45 (dd, J=8.8, 2.6 Hz, 1H), 7.07-6.95 (m, 2H), 6.24 (m, 1H), 3.85
(s, 3H).
Example 166
##STR00383##
[0629]
N-(4-(5-chloro-2-methoxyphenyl)-2-(2-hydroxy-2-methylpropyl)thiazol-
-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00384##
[0630] 2-amino-2-(5-chloro-2-methoxyphenyl)acetonitrile
[0631] A solution of 5-chloro-2-methoxy-benzaldehyde (prepared
according to U.S. Pat. No. 4,602,035) (2.04 g, 12.0 mmol) in
methanol (80 mL) was added to a stirred solution of sodium cyanide
(0.90 g) and ammonium chloride (1.50 g) in aqueous ammonium
hydroxide (33% solution, 30 mL) at 0.degree. C. then warmed to room
temperature for 18 hours. The mixture was evaporated to dryness,
the residues partitioned between DCM and water, the organics
separated, washed with brine and evaporated under vacuum to afford
2.21 g (94%) of 2-amino-2-(5-chloro-2-methoxyphenyl)acetonitrile as
an orange oil. LCMS (ESI) m+H=197.2.
##STR00385##
3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl-
)-3-methylbutanamide
[0632] 2-amino-2-(5-chloro-2-methoxyphenyl)acetonitrile (500 mg,
2.54 mmol) in DMF (2 mL) was added to a solution of
3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyric acid (prepared
according to patent EP2025667) (590 mg, 2.54 mmol),
diisopropylethylamine (0.87 mL, 5.08 mmol) and HATU (966 mg, 2.54
mmol) in DMF (5 mL) and stirred for 18 hours. Ethyl acetate was
added, the organics washed with sodium hydrogen carbonate (sat.aq.)
and brine, then evaporated to dryness. The residues were purified
by flash chromatography on silica gel (0 to 5% ethyl acetate in
dichloromethane) to yield 740 mg (73%) of
3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl-
)-3-methylbutanamide. LCMS (ESI) m+H=411.4.
##STR00386##
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethyl-
silyloxy)-3-methylbutanamide
[0633] Hydrogen peroxide (50% aq., 413 .mu.L) was added to a
solution of
3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl-
)-3-methylbutanamide (740 mg, 1.80 mmol) and potassium carbonate
(609 mg, 4.41 mmol) in DMSO (4 mL) and stirred for 18 hours. Ethyl
acetate was added, the organics washed with water and brine, then
evaporated to dryness to give 667 mg (86%) of
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethyl-
silyloxy)-3-methylbutanamide as a white solid. LCMS (ESI)
m+H=429.3.
##STR00387##
2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyph-
enyl)thiazol-5-amine
[0634] A mixture of
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethyl-
silyloxy)-3-methylbutanamide (327 mg, 0.76 mmol), Lawesson's
reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to
95.degree. C. for 18 hours. DCM was added, the organics washed with
sodium hydrogen carbonate (sat.aq.) and brine, then evaporated to
dryness. The residues were purified by flash chromatography on
silica gel (DCM) to afford 107 mg (33%) of
2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2--
methoxyphenyl)thiazol-5-amine LCMS (ESI) m+H=427.3.
##STR00388##
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0635] A solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride
(52.0 mg, 0.29 mmol),
2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyph-
enyl)thiazol-5-amine (103 mg, 0.24 mmol) and pyridine (2 mL) was
stirred at 60.degree. C. for 2 hours, then at room temperature for
an additional 72 hours. DCM was added, the organics washed with
water, sodium hydrogen carbonate (sat.aq.) and brine, then
evaporated to dryness. The residues were purified by flash
chromatography on silica gel (0 to 20% ethyl acetate in
dichloromethane) to yield 90.6 mg (66%) of
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
yellow solid. LCMS (ESI) m+H=572.1; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 10.45 (s, br, 1H); 9.38 (dd, 1H); 8.76 (s,
1H); 8.73-8.72 (m, 1H); 7.51 (dd, 1H); 7.45 (d, 1H); 7.35 (d, 1H);
7.31 (d, 1H); 3.79 (s, 3H); 3.06 (s, 2H); 1.32 (s, 6H); 0.90 (s,
9H); 0.11 (s, 6H).
##STR00389##
N-(4-(5-chloro-2-methoxyphenyl)-2-(2-hydroxy-2-methylpropyl)thiazol-5-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0636] A solution of
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20
mg, 35.0 .mu.mol) in trifluoroacetic acid (3 mL) was stirred for 7
days at room temperature. The reaction was evaporated under vacuum
and the crude product purified by reverse phase HPLC then
lyophilized to afford 11.3 mg (71%) of
N-(4-(5-chloro-2-methoxyphenyl)-2-(2-hydroxy-2-methylpropyl)thia-
zol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid.
LCMS (ESI) m+H=458.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
10.43 (s, br, 1H); 9.38 (dd, 1H); 8.74 (dd, 1H); 8.73 (s, 1H); 7.51
(dd, 1H); 7.46 (d, 1H); 7.35 (s, 1H); 7.32-7.31 (m, 1H); 4.76 (s,
1H); 3.79 (s, 3H); 3.01 (s, 2H); 1.19 (s, 6H).
Example 167
##STR00390##
[0637]
N-(4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-yl-
)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00391##
[0638]
N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-hydroxy-3-methylbutan-
amide
[0639] Using amino-(5-chloro-2-methoxy-phenyl)-acetonitrile and
3-hydroxy-3-methyl-butyric acid, the title compound was synthesized
following the synthetic procedures described for
3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl-
)-3-methylbutanamide to give
N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-hydroxy-3-methylbutanamide.
LCMS (ESI) m+H=297.1.
##STR00392##
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-hydroxy-3-methylbut-
anamide
[0640] Using
N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-hydroxy-3-methylbutanamide
the title compound was synthesized following the synthetic
procedures described for
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethyl-
silyloxy)-3-methylbutanamide to give
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-hydroxy-3-methylbut-
anamide as a yellow gum. LCMS (ESI) m+Na=337.4.
##STR00393##
4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-amine
[0641] A mixture of
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-hydroxy-3-methylbut-
anamide (240 mg, 0.762 mmol), Lawesson's reagent (308 mg, 0.76
mmol) and pyridine (2.5 mL) was heated to 100.degree. C. for 18
hours. After cooling, DCM was added and the mixture washed with
water, sodium hydrogen carbamate (sat.aq.) and brine, and
concentrated to dryness.
4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-amine
(51.0 mg) was isolated as a pale yellow solid. LCMS (ESI)
m+H=295.3; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.38 (d,
1H); 7.31 (dd, 1H); 7.09 (d, 1H); 6.24 (t, 1H); 5.50 (s, br, 2H);
3.83 (s, 3H); 2.02 (d, 3H); 1.89 (s, 3H).
##STR00394##
N-(4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-yl)pyraz-
olo[1,5-a]pyrimidine-3-carboxamide
[0642] Using
4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-amine
and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title
compound was synthesized following the synthetic procedures
described for
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with
further purification by reverse phase HPLC and lyophilized to give
N-(4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-yl)pyraz-
olo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=440.0; .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 10.50 (s, br, 1H); 9.39 (dd,
1H); 8.74 (d, 1H); 8.73 (s, 1H); 7.54 (dd, 1H); 7.49 (d, 1H); 7.37
(d, 1H); 7.34 (dd, 1H); 6.47 (t, 1H); 3.80 (s, 3H); 2.16 (s, 3H);
1.97 (s, 3H).
Example 168
##STR00395##
[0643]
N-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]-
pyrimidine-3-carboxamide
##STR00396##
[0644] ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate
[0645] Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.2
mmol) was added portionwise to a stirred solution of
1-(5-chloro-2-methoxy-phenyl)-ethanone (10.0 g, 54.2 mmol) in THF
(100 mL) at 0.degree. C. The mixture was then stirred for 10
minutes before addition of diethyl carbonate (7.68 g, 65.0 mmol)
and then for an additional 1 hour. The mixture was warmed to room
temperature for 2 hours and then heated to 65.degree. C. for 2
hours. Diethyl ether was added, the organics washed with water and
brine, then evaporated to dryness. The residues were purified by
flash chromatography on silica gel (50 to 100% dichloromethane in
cyclohexane) to yield 3.41 g of ethyl
3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=257.2;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.59 (d, 1H); 7.38 (dd,
1H); 6.89 (d, 1H); 4.18 (q, 2H); 3.95 (s, 2H); 3.88 (s, 3H); 1.24
(t, 3H).
##STR00397##
ethyl 2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate
[0646] Bromine (0.70 mL, 13.6 mmol) was added to a solution of
ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (3.39 g, 13.2
mmol) in dioxane (25 mL) and stirred for 1 hour. The reaction was
poured onto ice water, extracted with ethyl acetate, the organics
washed with water and brine and evaporated to dryness to give ethyl
2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (ESI)
m+H=337.2
##STR00398##
ethyl
2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate
[0647] A mixture of ethyl
2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (assumed to be
13.2 mmol) and thiourea (1.01 g, 13.3 mmol) in ethanol (25 mL) were
heated to reflux for 3 hours, then cooled to room temperature for
18 hours. The resultant solid was removed by filtration and the
filtrate evaporated under vacuum. DCM was added to the residue, the
organics washed with sodium hydrogen carbonate (sat.aq.), water and
brine, and evaporated to dryness. The residue was triturated (DCM)
to give 1.30 g (31%) of ethyl
2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate as a
yellow solid. LCMS (ESI) m+H=313.2. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.77 (s, br, 2H); 7.39 (dd, 1H); 7.22 (d,
1H); 7.05 (d, 1H); 4.00 (q, 2H); 3.70 (s, 3H); 1.04 (t, 3H).
##STR00399##
ethyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate
[0648] Copper bromide (1.07 g, 4.79 mmol) in acetonitrile (20 mL)
was degassed with nitrogen and cooled to 0.degree. C. before
addition of tert-butyl nitrite (0.80 mL, 6.00 mmol), then a
suspension of ethyl
2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.25 g,
3.99 mmol) in acetonitrile (20 mL) was added and stirred at room
temperature for 18 hours. The reaction was concentrated under
vacuum, ethyl acetate added, the organics washed with sodium
hydrogen carbonate (sat.aq.) and brine, then evaporated to dryness
to give 1.40 g (93%) of ethyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate. LCMS
(ESI) m+H=378.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.50
(dd, 1H); 7.42 (d, 1H); 7.14 (d, 1H) 4.16 (q, 2H); 3.73 (s, 3H);
1.12 (t, 3H).
##STR00400##
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid
[0649] A mixture of ethyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g,
3.72 mmol), potassium hydroxide (278 mg) in THF (40 mL) and water
(10 mL) was stirred for 20 hours at ambient temperature. The
mixture was treated with 1M HCl aq. (ca. 8 mL, 2 eq.), DCM was
added, and the organics separated and evaporated to dryness to give
1.23 g (95%) of
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid as a
yellow solid. LCMS (ESI) m+H=350.1. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.47 (dd, 1H); 7.39 (d, 1H); 7.13 (d, 1H);
3.73 (s, 3H).
##STR00401##
tert-butyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate
[0650] 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic
acid (1.22 g, 3.50 mmol), diphenylphosphoryl azide (963 mg, 3.50
mmol) and triethylamine (354 mg, 3.50 mmol) in tert-butanol (30 mL)
were stirred at 85.degree. C. for 4 hours. After cooling, the
reaction was partitioned between ethyl acetate and water, the
organics separated then washed with brine, and evaporated to
dryness. The resulting residues were purified by flash
chromatography on silica gel (50 to 100% dichloromethane in
cyclohexane) to yield 970 mg (66%) of tert-butyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate. LCMS
(ESI) m+H=421.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.43
(dd, 1H), 7.30 (d, 1H); 7.11 (d, 1H); 3.77 (s, 3H); 1.45 (s,
9H).
##STR00402##
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine
[0651] TFA (4.0 mL) was added to a solution of tert-butyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (360 mg,
0.86 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture
was stirred for 1.5 hours at room temperature and then evaporated
to dryness. The residue was taken up into DCM and washed with
sodium hydrogen carbonate (sat.aq.), water and brine, and
concentrated under vacuum to give
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine as an orange
residue. LCMS (ESI) m+H=321.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.36 (d, 1H); 7.34-7.32 (m, 1H); 7.10 (d, 1H); 3.83 (s,
3H).
##STR00403##
N-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimi-
dine-3-carboxamide
[0652] Using 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine
and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title
compound was prepared following the synthetic procedures described
for
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with
further purification by flash chromatography on silica gel (0 to
40% ethyl acetate in DCM) to give
N-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimi-
dine-3-carboxamide. LCMS (ESI) m+H=465.8. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 10.68 (s, br, 1H); 9.41 (dd, 1H); 8.78 (s,
1H); 8.76 (dd, 1H); 7.57 (dd, 1H); 7.50 (d, 1H); 7.37-7.34 (m, 2H);
3.81 (s, 3H).
Example 169
##STR00404##
[0653]
N-(4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide
[0654]
N-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (50.0 mg, 0.11 mmol), Pd(PPh.sub.3).sub.4
(6.20 mg, 5.35 .mu.mol), sodium formate (10.9 mg, 0.16 mmol) and
DMF (0.5 mL) were sealed, under nitrogen, in a microwave vial and
heated to 130.degree. C. for 10 minutes using microwave
irradiation. The reaction was cooled, DCM was then added and the
organics washed with sodium hydrogen carbonate (sat.aq.), water and
brine, dried and evaporated to dryness. The residues were purified
by flash chromatography on silica gel (0 to 40% ethyl acetate in
DCM) then further purified by reverse phase HPLC and lyophilized to
give 11.1 mg (27%) of
N-(4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide as a beige solid. LCMS (ESI) m+H=386.0. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 10.56 (s, 1H); 9.39 (dd, 1H); 8.74-8.73
(m, 3H); 7.55 (dd, 1H); 7.49 (d, 1H); 7.37 (d, 1H); 7.34 (dd, 1H);
3.80 (s, 3H).
Example 170
##STR00405##
[0655]
N-(4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-yl)pyrazolo[1,5-a-
]pyrimidine-3-carboxamide
##STR00406##
[0656] ethyl
4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate
[0657] Using 2-bromo-3-(5-chloro-2-methoxy-phenyl)-3-oxo-propionic
acid ethyl ester and thioacetamide, the title compound was prepared
following the synthetic procedures described for ethyl
2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate with
additional purification by flash chromatography on silica gel (50
to 100% DCM in cyclohexane) to give ethyl
4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate. LCMS
(ESI) m+H=321.4; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.38
(d, 1H); 7.33 (dd, 1H); 6.87 (d, 1H); 4.20 (q, 2H); 3.75 (s, 3H);
2.76 (s, 3H); 1.20 (t, 3H).
##STR00407##
4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid
[0658] A mixture of ethyl
4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate (520
mg, 1.67 mmol) and potassium hydroxide (125 mg) in THF (18 mL) and
water (4.5 mL) was stirred for 20 hours at room temperature and
then at 75.degree. C. for a further 8 hours. The solution was
treated with 1M HCl aq. (pH 2) and extracted with DCM. The organics
were evaporated to dryness to give 450 mg (95%) of
4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid as
a white solid. LCMS (ESI) m+H=284.3; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.43 (dd, 1H); 7.31 (d, .sup.1H); 7.10 (d,
1H); 3.71 (s, 3H); 2.69 (s, 3H).
##STR00408##
tert-butyl
4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate
[0659] Using
4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid,
the title compound was prepared following the synthetic procedures
described for tert-butyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate to give
tert-butyl
4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate. LCMS
(ESI) m+H=355.3; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.40
(dd, 1H); 7.32 (d, 1H); 7.11 (d, 1H); 3.77 (s, 3H); 2.55 (s, 3H);
1.42 (s, 9H).
##STR00409##
4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine
[0660] TFA (4.0 mL) was added to a solution of tert-butyl
4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate (315 mg,
0.89 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture
was stirred for 1.5 hours at room temperature, then evaporated to
dryness to give 215 mg (95%) of
4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine as a yellow
solid. LCMS (ESI) m+H=255.2.
##STR00410##
N-(4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
[0661] Using 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine
and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title
compound was synthesized following the synthetic procedures
described for
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with
further purification by flash chromatography on silica gel (0 to
100% ethyl aceate in DCM) to give
N-(4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxamide as an orange solid. LCMS (ESI) m+H=400.0;
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.43 (s, br, 1H);
9.38 (dd, 1H); 8.75-8.73 (m, 1H); 8.72 (s, 1H); 7.52 (dd, 1H); 7.47
(d, 1H); 7.34-7.32 (m, 2H); 3.79 (s, 3H); 2.62 (s, 3H).
Example 171
##STR00411##
[0662]
N-(4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-
-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
##STR00412##
[0663]
N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-ca-
rboxamide
[0664] Using amino-(5-chloro-2-methoxy-phenyl)-acetonitrile and
tetrahydro-2H-pyran-4-carboxylic acid, the title compound was
prepared following the synthetic procedures described for
3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl-
)-3-methylbutanamide to give
N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-carboxam-
ide as a white solid. LCMS (ESI) m+H=309.3.
##STR00413##
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4--
carboxamide
[0665] Using
N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-carboxam-
ide, the title compound was prepared following the synthetic
procedures described for
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethyl-
silyloxy)-3-methylbutanamide to give
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4--
carboxamide as a white solid. LCMS (ESI) m+H=327.3; .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.30 (d, br, 1H); 7.31-7.31 (m,
2H); 7.24 (s, br, 1H); 7.13 (s, br, 1H); 7.05-7.01 (d, 1H); 5.62
(d, 1H); 3.91-3.81 (m, 2H); 3.79 (s, 3H); 3.30-3.24 (m, 2H);
2.55-2.54 (m, 1H); 1.56-1.55 (m, 4H).
##STR00414##
4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-amine
[0666] Using
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4--
carboxamide, the title compound was prepared following the
synthetic procedures described for
2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyph-
enyl)thiazol-5-amine to give
4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-amine
as a white gum. LCMS (ESI) m+H=325.2; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.38 (d, 1H); 7.31 (dd, 1H); 7.09 (d, 1H);
5.31 (s, br, 2H); 3.90 (d, 2H); 3.84 (s, 3H); 3.43 (m, 2H);
3.04-2.99 (m, 1H); 1.90 (d, 2H); 1.66-1.66 (m, 2H).
##STR00415##
N-(4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0667] Using
N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4--
carboxamide, the title compound was prepared following the
synthetic procedures described for
N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methox-
yphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with
additional purification by trituration in diethyl ether to give
N-(4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=470.0;
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.44 (s, br, 1H);
9.38 (dd, 1H); 8.75 (dd, 1H); 8.73 (s, 1H); 7.52 (dd, 1H); 7.46 (d,
1H); 7.35 (d, 1H); 7.32-7.31 (m, 1H); 3.95-3.94 (m, 2H); 3.80 (s,
3H); 3.47 (m, 2H); 3.23 (m, 1H); 2.00 (dd, 2H); 1.77 (m, 2H).
[0668] Examples 172-508 shown in Table 2 were prepared generally
following the above-described Examples. For each compound shown in
Table 2, the Example number followed is given in the Method
column.
TABLE-US-00002 TABLE 2 LCMS (ESI) Ex Structure Name Mthd m/z 172
##STR00416## N-(3-(5-chloro-2- methoxyphenyl)-1-((2S,3R)-
2,3-dihydroxybutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 132 457.1 173 ##STR00417## N-(3-(5-chloro-2-
methoxyphenyl)-1-((2R,3R)- 2,3-dihydroxybutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 132 457.1 174
##STR00418## N-(3-(5-chloro-2- methoxyphenyl)-1-((2S,3S)-
2,3-dihydroxybutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 132 457.1 175 ##STR00419## N-(3-(5-chloro-2-
methoxyphenyl)-1-((2R,3S)- 2,3-dihydroxybutyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 132 457.1 176
##STR00420## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-3-
(pyrrolidin-1-yl)propyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 133 496.2 177
##STR00421## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxy-3-(pyrrolidin-1- yl)propyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 133 496.2 178
##STR00422## N-(1-(1-amino-2-methyl-1-
oxopropan-2-yl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 454.1 179
##STR00423## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
morpholino-2-oxoethyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 134 496.2 180 ##STR00424## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- (isopropylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 468.2 181
##STR00425## 2-(3-(5-chloro-2-methoxyphenyl)-
4-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-1H-pyrazol-1-
yl)acetic acid 134 427.1 182 ##STR00426##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(cyanomethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 408.0 183
##STR00427## N-(5-(5-chloro-2-methoxyphenyl)-
1-(cyanomethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 15 408.1 184 ##STR00428## N-(3-(5-chloro-2-
methoxyphenyl)-1-(pyridin-2- ylmethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 460.1 185
##STR00429## N-(1-(2-(1H-imidazol-1- yl)ethyl)-3-(5-chloro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 463.2 186 ##STR00430##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-(oxetan-3-ylamino)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 482.1 187 ##STR00431## N-(1-(1-amino-1-oxopropan-2-
yl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 440.1 188
##STR00432## N-(3-(5-chloro-2-methoxyphenyl)-
1-(1-cyanoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 422.1 189 ##STR00433## N-(3-(5-chloro-2-
methoxyphenyl)-1-((3- methylisoxazol-5-yl)methyl)-
1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 14 464.1
190 ##STR00434## N-(3-(5-chloro-2- methoxyphenyl)-1-(isoxazol-5-
ylmethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
14 450.1 191 ##STR00435## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
cyanoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 422.1 192 ##STR00436## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- cyanopropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 436.1 193
##STR00437## N-(3-(2-oxopyridin-1(2H)-yl)-
1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 140 322.0
194 ##STR00438## N-(3-(5-chloro-2-oxopyridin-
1(2H)-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
140 356.0 195 ##STR00439## N-(3-(5-chloro-2-methoxyphenyl)-
1-((2-hydroxy-4,4- dimethyloxazolidin-2- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 498.1 196
##STR00440## N-(3-(5-chloro-2-methoxypyridin-
3-yl)-1-(3,3,3-trifluoro-2-hydroxy- 2-(trifluoromethyl)propyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 141, 16
550.1 197 ##STR00441## N-(3-(5-chloro-2-methoxypyridin-
3-yl)-1-(2-(3-fluoroazetidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 141, 134 485.1 198
##STR00442## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
3-methylbutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 470.2 199 ##STR00443##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
3-methylbutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 470.2 200 ##STR00444##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-((4-
hydroxytetrahydro-2H-pyran- 4-yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 16 498.2 201
##STR00445## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-((4-
hydroxytetrahydro-2H-pyran- 4-yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 16 498.2 202
##STR00446## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-((1-
hydroxycyclohexyl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 27, 16 496.2 203
##STR00447## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
2-methylbutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 470.1 204 ##STR00448##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
2-methylbutyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 470.2 205 ##STR00449##
2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(pyrrolidin-
2-ylmethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 14 467.1 206 ##STR00450##
2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-neopentyl- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 14 454.2 207
##STR00451## 2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-neopentyl-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 15
454.2 208 ##STR00452## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-
((tetrahydro-2H-pyran-2- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 14 482.2 209
##STR00453## 2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-
((tetrahydro-2H-pyran-2- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 15 482.2 210
##STR00454## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-
(cyanomethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 14 423.0 211 ##STR00455##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxypentyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 470.1 212 ##STR00456##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-
(cyanomethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 15 423.1 213 ##STR00457##
2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
hydroxypentyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 470.1 214 ##STR00458##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-((R)-2-
hydroxy-3-methoxypropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 16 472.1 215
##STR00459## (S)-2-amino-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-hydroxy- 3-methoxypropyl)-1H-pyrazol-
4-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 16 472.2 216
##STR00460## 2-amino-N-(1-(2-amino-2- oxoethyl)-3-(5-chloro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 14 441.1 217 ##STR00461##
2-amino-N-(1-(2-amino-2- oxoethyl)-5-(5-chloro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 15 441.1 218 ##STR00462##
2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(4-
hydroxytetrahydrofuran-3-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 27, 16 470.1 219
##STR00463## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
morpholino-2-oxoethyl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 14 511.2 220 ##STR00464##
2-amino-N-(5-(5-chloro-2- methoxyphenyl)-1-(2-
morpholino-2-oxoethyl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 15 511.2 221 ##STR00465## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- (cyclobutylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 480.1 222
##STR00466## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-oxo-2-
((tetrahydrofuran-2- yl)methylamino)ethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.1 223
##STR00467## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2,2-
difluoroethylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 490.1 224
##STR00468## N-(1-(2-(azetidin-1-yl)-2- oxoethyl)-3-(5-chloro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 134 466.1 225 ##STR00469## (S)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3- hydroxypyrrolidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 496.1 226 ##STR00470## (R)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3- hydroxypyrrolidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 496.1 227 ##STR00471## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3- morpholinoazetidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 551.2 228 ##STR00472## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclopentylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 494.2 229
##STR00473## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(morpholinoamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 511.2 230
##STR00474## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
cyanamido-2-oxoethyl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 134 451.2 231 ##STR00475## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3- cyanoazetidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 491.2 232 ##STR00476## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3- fluoroazetidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 484.1 233 ##STR00477## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 482.2
234 ##STR00478## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
hydroxy-2- methylpropylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 498.2 235
##STR00479## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3,3-
difluoropyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 516.2 236
##STR00480## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(4,4-
difluorocyclohexylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 544.2 237
##STR00481## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(1-
methylazetidin-3-ylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 495.0 238
##STR00482## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(1-
(hydroxymethyl)cyclo- propylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 496.1 239
##STR00483## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(1-
hydroxypropan-2-ylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 484.1 240
##STR00484## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
cyanopropan-2-ylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 493.1 241
##STR00485## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3,3-
difluoroazetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 502.1 242
##STR00486## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
(hydroxymethyl)pyrrolidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.1 243
##STR00487## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclobutylamino)-1-fluoro-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 135 498.1 244
##STR00488## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclohexylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 508.2 245
##STR00489## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
(hydroxymethyl)pyrrolidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.1 246
##STR00490## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
(hydroxymethyl)pyrrolidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.2 247
##STR00491## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
methoxypyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.2 248
##STR00492## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
(hydroxymethyl)pyrrolidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.0 249
##STR00493## N-(1-(2-(tert-butylamino)-2- oxoethyl)-3-(5-chloro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 134 482.2 250 ##STR00494## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- (cyclopentylmethylamino)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 508.2 251 ##STR00495## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclopropylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 466.1 252
##STR00496## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2,5-
dihydro-1H-pyrrol-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 478.1 253
##STR00497## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclopentylamino)-1-fluoro- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 135 512.2 254
##STR00498## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3,3-
difluoropyrrolidin-1-yl)-1-fluoro- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 135 534.2 255
##STR00499## 2-(3-(5-chloro-2- methoxyphenyl)-4-
(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-1H-pyrazol-1-
yl)-2-fluoroacetic acid 135 445.1 256 ##STR00500##
N-(3-(5-chloro-2- methoxyphenyl)-1-(2-oxo-2-
(tetrahydro-2H-pyran-4- ylamino)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.2 257
##STR00501## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-oxo-2-
(tetrahydrofuran-3- ylamino)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 496.1 258
##STR00502## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(1-
methylcyclobutylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 494.1 259
##STR00503## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclopentyl(methyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 508.1 260
##STR00504## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3,3-
difluorocyclobutylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 516.1 261
##STR00505## N-(1-(2-(azetidin-3-ylamino)-
2-oxoethyl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 481.2 262
##STR00506## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-oxo-
2-(piperazin-1-yl)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 495.1 263
##STR00507## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-oxo-2-
(piperidin-4-ylamino)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 509.1 264
##STR00508## (S)-N-(1-(2-(3- aminopyrrolidin-1-yl)-2-
oxoethyl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 495.1 265
##STR00509## N-(3-(5-chloro-2- methoxyphenyl)-1-(1-fluoro-2-
(3-hydroxypyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 135 514.2 266
##STR00510## N-(3-(5-chloro-2- methoxyphenyl)-1-(1-fluoro-2-
(3-hydroxypyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 135 514.2 267
##STR00511## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclobutylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 495.1 268
##STR00512## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclopentylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 509.2 269
##STR00513## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
hydroxyethylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 470.1 270
##STR00514## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
methoxyethylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 484.1 271
##STR00515## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2,5-
dimethyl-2,5-dihydro-1H-pyrrol- 1-yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 134 506.1 272
##STR00516## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
hydroxycyclopentylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.1 273
##STR00517## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(ethylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 454.1 274
##STR00518## (R)-tert-butyl 1-(2-(3-(5- chloro-2-methoxyphenyl)-4-
(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-1H-pyrazol-1-
yl)acetyl)pyrrolidin-3- ylcarbamate 134 595.2 275 ##STR00519##
(S)-tert-butyl 1-(2-(3-(5- chloro-2-methoxyphenyl)-4-
(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-1H-pyrazol-1-
yl)acetyl)pyrrolidin-3- ylcarbamate 134 595.2 276 ##STR00520##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-(3,4-dihydroxy-2-
(hydroxymethyl)pyrrolidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 542.1 277
##STR00521## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(2,2-dimethylhydrazinyl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 469.1 278
##STR00522## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(1,3-dihydroxypropan-2- ylamino)-2-oxoethyl)-1H-pyrazol-
4-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 500.1 279
##STR00523## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(3-methoxyazetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 496.2 280
##STR00524## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
methyloxetan-3-ylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 496.2 281
##STR00525## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(methylamino)-2-oxoethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3-carboxamide 134 440.0 282 ##STR00526##
N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2- cyanopyrrolidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 505.1 283 ##STR00527## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(2-methylpyrrolidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 134 494.1 284
##STR00528## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-oxo-2-(piperidin-1- yl)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 134 494.1 285
##STR00529## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(4-methylpiperazin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 509.2 286
##STR00530## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(3-methylpiperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 508.1 287
##STR00531## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(isopropyl(methyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 482.1 288
##STR00532## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-((2-
hydroxyethyl)(methyl)amino)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 484.1 289
##STR00533## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-((2-
methoxyethyl)(methyl)amino)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 498.1 290
##STR00534## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclohexyl(methyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 522.2 291
##STR00535## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
cyanopyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 505.1 292
##STR00536## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2,2-
dimethylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 508.1 293
##STR00537## N-(1-(2-(tert- butyl(methyl)amino)-2-
oxoethyl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 496.1 294
##STR00538## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
methylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 494.1 295
##STR00539## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(3-methoxypiperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 524.1 296
##STR00540## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(ethyl(methyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 468.1 297
##STR00541## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
methylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 494.1 298
##STR00542## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
methylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 494.1 299
##STR00543## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(((1-
(hydroxymethyl)cyclopropyl) methyl)(methyl)amino)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 524.2 300 ##STR00544## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(5,6- dihydropyridin-1(2H)-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 492.1 301 ##STR00545## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(2- methylpiperidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 508.1 302 ##STR00546## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(3,3- dimethylpiperidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
134 522.2 303 ##STR00547## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-(((1- (hydroxymethyl)cyclo-
butyl)methyl)(methyl)amino)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 538.2 304
##STR00548## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-oxo-2-
(tetrahydro-2H-thiopyran-4- ylamino)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 526.1 305
##STR00549## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(cyclopentyl(propyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 536.2 306
##STR00550## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(diethylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 134 482.1 307
##STR00551## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(ethyl(isopropyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 496.2 308
##STR00552## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
(hydroxymethyl)piperidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 524.2 309
##STR00553## N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-(methyl(2,2,2-
trifluoroethyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 522.1 310
##STR00554## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
(hydroxymethyl)piperidin-1- yl)-2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 524.2 311
##STR00555## N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-((3R,4R)-3,4-
dihydroxypyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 512.2 312
##STR00556## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(cyclopentyl(ethyl)amino)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 522.2 313
##STR00557## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-((1-hydroxypropan-2- yl)(methyl)amino)-2-oxoethyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 498.2
314 ##STR00558## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
isopropylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 522.2 315
##STR00559## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
(methyl(pentan-3-yl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 510.2 316
##STR00560## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
ethylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 508.2 317
##STR00561## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-((2-
cyanopropan-2- yl)(methyl)amino)-2- oxoethyl)1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 134 508.3 318
##STR00562## 2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
2-methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27, 16 456.2 319 ##STR00563##
2-amino-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-
morpholinoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 27, 14 497.2 320 ##STR00564## 2-amino-N-(5-(5-chloro-2-
methoxyphenyl)-1-(2- morpholinoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 27, 15 497.2 321
##STR00565## tert-butyl 2-(3-(5-chloro-2- methoxyphenyl)-4-
(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-1H-pyrazol-1- yl)acetate
134 483.0 322 ##STR00566## 2-amino-N-(5-(5-chloro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 27 384.1 323 ##STR00567## N-(3-(3,5-dimethylphenyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 333.1
324 ##STR00568## N-(3-(3,5-dimethylphenyl)-1-
(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14, 16 405.1 325
##STR00569## N-(3-(3,5-dichlorophenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 373.1 326
##STR00570## N-(3-(3,5-dichlorophenyl)-1-
(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14, 16 445.1 327
##STR00571## N-(3-(3-chloro-5- methylphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 353.1 328
##STR00572## N-(3-(2-isopropoxyphenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 363.1 329
##STR00573## N-(1-(2-hydroxy-2- methylpropyl)-3-(2-
isopropoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 14, 16 435.1 330 ##STR00574## N-(3-(3-chloro-5-
cyanophenyl)-1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14, 16 436.1 331
##STR00575## N-(3-(3,4-dichlorophenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 373.1 332
##STR00576## N-(3-(3,4-dichlorophenyl)-1-
(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14, 16 445.1 333
##STR00577## N-(3-(2-ethoxyphenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 349.1 334
##STR00578## N-(3-(2-ethoxyphenyl)-1-(2-
hydroxy-2-methylpropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14, 16 421.1 335
##STR00579## N-(3-(2-ethoxy-5- fluorophenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 367.1 336
##STR00580## N-(3-(2-ethoxy-5- fluorophenyl)-1-(2-hydroxy-2-
methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14, 16 439.1 337 ##STR00581## N-(3-(3-chloro-4-
methylphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 353.1 338 ##STR00582## N-(3-(3-chloro-4-
methylphenyl)-1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14, 16 425.1 339
##STR00583## N-(3-(2-methoxy-5- (trifluoromethyl)phenyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 403.1 340
##STR00584## N-(1-(2-hydroxy-2- methylpropyl)-3-(2-methoxy-
5-(trifluoromethyl)phenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14, 16 475.1 341
##STR00585## N-(3-(5-fluoro-2- isopropoxyphenyl)-1H-pyrazol-
4-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 381.1 342
##STR00586## N-(3-(5-fluoro-2- isopropoxyphenyl)-1-(2-hydroxy-
2-methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 14, 16 453.1 343 ##STR00587##
N-(3-(2-methoxyphenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 335.1 344
##STR00588## N-(1-(2-hydroxy-2- methylpropyl)-3-(2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14, 16 407.1 345 ##STR00589## N-(3-(4-fluoro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 353.1 346 ##STR00590## N-(3-(4-fluoro-2-
methoxyphenyl)-1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14, 16 425.1 347
##STR00591## N-(3-(5-cyano-2-methoxyphenyl)-
1-(cyanomethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 147, 14 399.1 348 ##STR00592## N-(3-(2-
(difluoromethoxy)phenyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3-carboxamide 14 371.1 349 ##STR00593##
N-(3-(2-(difluoromethoxy)phenyl)- 1-(2-hydroxy-2-methylpropyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 18, 16
443.1 350 ##STR00594## N-(3-(2-(difluoromethoxy)-5-
fluorophenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 18 389.1 351 ##STR00595##
N-(3-(2-(difluoromethoxy)-5- fluorophenyl)-1-(2-hydroxy-2-
methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 18, 26 461.1 352 ##STR00596## N-(3-(5-cyano-2-
methylphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 147 344.1 353 ##STR00597## N-(3-(5-cyano-2-
methylphenyl)-1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 16 416.1 354
##STR00598## N-(3-(5-cyano-2- methoxyphenyl)-1-
((1-hydroxycyclohexyl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 16 472.1 355
##STR00599## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-
(isopropylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 134 459.1 356
##STR00600## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-
morpholino-2-oxoethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 134 487 357
##STR00601## N-(3-(5-cyano-2- methoxyphenyl)-1-(oxetan-3-
yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147,
14 416.1 358 ##STR00602## N-(3-(5-cyano-2-
(difluoromethoxy)phenyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 18 396.1 359
##STR00603## N-(3-(5-cyano-2- methoxyphenyl)-1-((1-
hydroxycyclopentyl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 24 458.1 360
##STR00604## (R)-3-(5-cyano-2- methoxyphenyl)-1-(2,3-
dihydroxy-2-methylpropyl)- 1H-pyrazol-4-yl
pyrazolo[1,5-a]pyrimidine-3- carboxylate 147, 16, 22 449.1 361
##STR00605## (S)-3-(5-cyano-2- methoxyphenyl)-1-(2,3-
dihydroxy-2-methylpropyl)- 1H-pyrazol-4-yl
pyrazolo[1,5-a]pyrimidine-3- carboxylate 147, 16, 22 449.1 362
##STR00606## N-(3-(5-cyano-2- methoxyphenyl)-1-((4-
hydroxytetrahydro-2H-pyran- 4-yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 16 474.1
363 ##STR00607## N-(3-(5-cyano-2-methoxyphenyl)-
1-(2-(cyclobutylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 471.1 364
##STR00608## N-(3-(5-fluoro-2- methoxyphenyl)-1-((4-
hydroxytetrahydro-2H-pyran- 4-yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 149, 16 467.1 365
##STR00609## N-(3-(5-fluoro-2- methoxyphenyl)-1-(2-(3-
fluoroazetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 149, 134 468.1 366
##STR00610## N-(1-(2-(cyclobutylamino)-2- oxoethyl)-3-(5-fluoro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 149, 134 464.1 367 ##STR00611## N-(3-(5-chloro-2-
methoxyphenyl)-1-(2- (dimethylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14, 134 454.1 368
##STR00612## N-(5-(5-chloro-2- cyclopropoxyphenyl)-1-(2-
hydroxy-2-methylpropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 151, 15 467.1 369
##STR00613## N-(3-(5-chloro-2- cyclopropoxyphenyl)-1-(2-
hydroxy-2-methylpropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 151, 16 467.1 370
##STR00614## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-(3-
fluoroazetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 475.1 371
##STR00615## (R)-N-(1-(2,3-dihydroxy-2-
methylpropyl)-3-(5-fluoro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 149, 16, 22 441.1 372
##STR00616## (S)-N-(1-(2,3-dihydroxy-2-
methylpropyl)-3-(5-fluoro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 149, 16, 22 441.1 373
##STR00617## N-(3-(5-cyano-2- methoxyphenyl)-1-(3,3,3-
trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 16 540.1 374
##STR00618## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-(3,3-
difluoroazetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 493.1 375
##STR00619## N-(1-(2-(3,3- difluoropyrrolidin-1-yl)-2-
oxoethyl)-3-(5-fluoro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14, 134 500.1 376
##STR00620## N-(3-(5-cyano-2-ethoxyphenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147 374.1 377
##STR00621## N-(3-(5-cyano-2- (ethylamino)phenyl)-1-(2-
hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 16 445.1 378
##STR00622## N-(3-(2-methylpiperidin-1-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140 326.1 379
##STR00623## N-(1-(2-hydroxy-2- methylpropyl)-3-(2-
methylpiperidin-1-yl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140, 16 398.1 380
##STR00624## N-(3-(5-cyano-2- methoxyphenyl)-1-(3-
(cyanomethyl)oxetan-3-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 14 455.1 381
##STR00625## N-(3-(2-methylmorpholino)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140 328.1 382
##STR00626## (R)-N-(3-(5-cyano-2- methoxyphenyl)-1-(2-
hydroxypropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 147, 16 418.1 383 ##STR00627## (S)-N-(3-(5-cyano-2-
methoxyphenyl)-1-(2- hydroxypropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 16 418.1 384
##STR00628## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-
(dimethylamino)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 134 445.1 385
##STR00629## N-(3-(5-fluoro-2- methylphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 337.1 386
##STR00630## N-(3-(5-fluoro-2- methylphenyl)-1-(2-hydroxy-
2-methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14, 16 409.1 387 ##STR00631## N-(3-(5-cyano-2-
methoxyphenyl)-1-(2-(3,3- difluoropyrrolidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
147, 134 507.1 388 ##STR00632## N-(3-(3-
(trifluoromethyl)piperidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 380.1 389
##STR00633## N-(1-(2-hydroxy-2- methylpropyl)-3-(3-
(trifluoromethyl)piperidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140, 16 452.1 390
##STR00634## (S)-N-(3-(5-cyano-2- methoxyphenyl)-1-(2-(2-
methylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 485.1 391
##STR00635## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-
(cyclopentyl(methyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 499.1 392
##STR00636## (S)-N-(3-(5-cyano-2- methoxyphenyl)-1-(2-(3-
methylmorpholino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 501.1 393
##STR00637## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-((2-
hydroxyethyl)(methyl)amino)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 475.1 394
##STR00638## N-(3-(5-cyano-2- methoxyphenyl)-1-(2-((2-
methoxyethyl)(methyl)amino)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 147, 134 489.1 395
##STR00639## N-(3-(4-cyanopiperidin-1-yl)-
1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 140 337.1
396 ##STR00640## N-(3-(3,3-dimethylpiperidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 340.1 397
##STR00641## N-(3-(3,3-dimethylpiperidin-1-
yl)-1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140, 16 412.1 398
##STR00642## (S)-N-(3-(5-cyano-2-
methoxyphenyl)-1-(3,3,3-trifluoro- 2-hydroxypropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 16 472.1 399
##STR00643## (R)-N-(3-(5-cyano-2-
methoxyphenyl)-1-(3,3,3-trifluoro- 2-hydroxypropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 147, 16 472.1 400
##STR00644## N-(3-(3-hydroxypiperidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 328.1 401
##STR00645## N-(3-(2-methylpyrrolidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 312.1 402
##STR00646## N-(1-(2-hydroxy-2-methylpropyl)-
3-(2-methylpyrrolidin-1-yl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140, 16 384.1 403
##STR00647## N-(1-(2-(dimethylamino)-2- oxoethyl)-3-(3-
(trifluoromethyl)piperidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140, 134 465.1 404
##STR00648## N-(3-(3-cyanopiperidin-1-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140 337.1 405
##STR00649## N-(3-(3-cyanopiperidin-1-yl)-
1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140, 16 409.1 406
##STR00650## N-(3-(3-methylpyrrolidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 312.1 407
##STR00651## N-(3-(3-fluoropiperidin-1-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140 330.1 408
##STR00652## N-(3-(3-fluoropiperidin-1-yl)-
1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140, 16 402.1 409
##STR00653## N-(3-(4-hydroxypiperidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 328.1 410
##STR00654## N-(3-(3,3-difluoropyrrolidin-1- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 140 334.1 411
##STR00655## N-(1-(2-(dimethylamino)-2- oxoethyl)-3-(5-fluoro-2-
methoxyphenyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 149, 134 438.1 412 ##STR00656##
N-(3-(3,3-difluoropiperidin-1- yl)-1-(2-hydroxy-2-
methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 157, 16 420.1 413 ##STR00657## N-(3-(5-cyano-2-
methoxyphenyl)-1-(2-(oxetan- 3-ylamino)-2-oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 147, 134
473.1 414 ##STR00658## N-(3-(5-chloro-2-ethoxyphenyl)-1-
((1S,2S)-2-hydroxycyclohexyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.1 And And
##STR00659## N-(3-(5-chloro-2-ethoxyphenyl)-1-
((1R,2R)-2-hydroxycyclohexyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 415 ##STR00660##
N-(3-(5-chloro-2-ethoxyphenyl)- 1-((1-hydroxycyclohexyl)methyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 20, 16
495.1 416 ##STR00661## N-(3-(5-chloro-2-ethoxyphenyl)-1-
((3R,4S)-4-hydroxytetrahydrofuran- 3-yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 20, 16 469.2 And And
##STR00662## N-(3-(5-chloro-2-ethoxyphenyl)-1-
((3S,4R)-4-hydroxytetrahydrofuran- 3-yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 417 ##STR00663##
N-(3-(5-chloro-2- ethoxyphenyl)-1-((1S,2R)-2-
hydroxycyclopentyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3-carboxamide 20, 16, 136 467.2 418 ##STR00664##
(R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-hydroxy-
3-methoxypropyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 457.2 419 ##STR00665## (S)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-hydroxy- 3-methoxypropyl)-1H-pyrazol-
4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 457.2 420
##STR00666## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2,3-
dihydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 457.2 421
##STR00667## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2,3-
dihydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 457.2 422
##STR00668## N-(3-(5-chloro-2-methoxyphenyl)-
1-(1-hydroxypropan-2-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 427.1 423
##STR00669## N-(3-(5-chloro-2- methoxyphenyl)-1-((1-
hydroxycyclohexyl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.2 424
##STR00670## N-(3-(5-chloro-2- (methylthio)phenyl)-1-(2-hydroxy-
2-methylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16, 19 457.1 425 ##STR00671## N-(3-(5-chloro-2-
methoxyphenyl)-1-((3R,4S)-4- hydroxytetrahydrofuran-3-yl)-
1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 16 455.1
And And
##STR00672## N-(3-(5-chloro-2- methoxyphenyl)-1-((3S,4R)-4-
hydroxytetrahydrofuran-3-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 426 ##STR00673##
N-(3-(5-chloro-2- methoxyphenyl)-1-(3- hydroxycyclohexyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 137 467.2 427
##STR00674## N-(3-(5-chloro-2-methoxyphenyl)-
1-((1S,2S)-2-hydroxycyclopentyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 453.1 And And
##STR00675## N-(3-(5-chloro-2-methoxyphenyl)-
1-((1R,2R)-2-hydroxycyclopentyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 428 ##STR00676##
N-(3-(5-chloro-2-methoxyphenyl)- 1-((4-hydroxytetrahydro-2H-pyran-
4-yl)methyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 483.2 429 ##STR00677##
N-(3-(5-chloro-2-methoxyphenyl)- 1-((1S,3R)-3-hydroxycyclohexyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 137 And
136 467.2 430 ##STR00678## N-(3-(5-chloro-2-
cyclopropylphenyl)-1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 138 And 16 451.1 431
##STR00679## N-(1-(2-hydroxy-2-methylpropyl)-
3-(3-methylpiperidin-1-yl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 140, 16 398.2 432
##STR00680## N-(3-(5-chloro-2-methoxyphenyl)-
1-(3,3,3-trifluoro-2-hydroxy-2- (trifluoromethyl)propyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 549.1 433
##STR00681## N-(5-(5-chloro-2-methoxyphenyl)-
1-(2-cyclohexylethyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 26 479.2 434 ##STR00682##
N-(5-(5-chloro-2-methoxyphenyl)- 1-(2-(tetrahydro-2H-pyran-4-
yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
26 481.1 435 ##STR00683## N-(5-(2-methoxyphenyl)-1-
methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 26
249.1 436 ##STR00684## N-(5-(5-chloro-2-methoxyphenyl)-
1-((3-(hydroxymethyl)oxetan-3- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 26 469.2 437
##STR00685## N-(5-(5-chloro-2-methoxyphenyl)-
1-(2-cyclopentyl-2-hydroxyethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 481.2 438
##STR00686## N-(3-(5-chloro-2-methoxyphenyl)-
1-((3-(hydroxymethyl)oxetan-3- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 469.2 439
##STR00687## N-(1-(2-hydroxy-2-methylpropyl)-
3-(2-methoxy-5-methylphenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 421.2 440
##STR00688## N-(3-(5-chloro-2-methoxyphenyl)-
1-((2R,3S)-3-hydroxybutan-2- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 16 441.2 441
##STR00689## N-(3-(5-chloro-2-methoxyphenyl)-
1-((2S,3R)-3-hydroxybutan-2- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 441.2 442
##STR00690## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-cyclopentyl-
2-hydroxyethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 481.2 443 ##STR00691## (R)-N-(3-(5-chloro-2-
methoxyphenyl)- 1-(2-cyclopentyl-2-hydroxyethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.2 444
##STR00692## N-(3-(5-chloro-2-methoxyphenyl)-
1-((2S,3S)-3-hydroxybutan-2-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 441.2 445
##STR00693## N-(3-(5-chloro-2-methoxyphenyl)-
1-((2R,3R)-3-hydroxybutan-2-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 441.2 446
##STR00694## N-(3-(5-chloro-2-methoxyphenyl)-
1-(4-hydroxypyrrolidin-3-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 454.1 447
##STR00695## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-cyclopropyl-2-oxoethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 451.1 448
##STR00696## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-cyclopropyl-
2-hydroxyethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 16 453.0 449 ##STR00697## (S)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(2-cyclopropyl- 2-hydroxyethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 453.0 450
##STR00698## (S)-N-(1-(3-amino-2-methyl-3-
oxopropyl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 454.1 451
##STR00699## (R)-N-(1-(3-amino-2-methyl-
3-oxopropyl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 454.1 452
##STR00700## N-(3-(5-chloro-2- methoxyphenyl)-1-(2,2,2-
trifluoroethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 451.1 453 ##STR00701## N-(5-(5-chloro-2-
methoxyphenyl)-1-(2,2,2- trifluoroethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 451.1 454
##STR00702## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(3,3,3-
trifluoro-2-hydroxypropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.0 455
##STR00703## N-(5-(5-chloro-2- methoxyphenyl)-1-((R)-3,3,3-
trifluoro-2-hydroxypropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.1 456
##STR00704## (S)-N-(3-(5-chloro-2-
methoxyphenyl)-1-(3,3,3-trifluoro- 2-hydroxypropyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.1 457
##STR00705## N-(5-(5-chloro-2- methoxyphenyl)-1-((S)-(3,3,3-
trifluoro-2-hydroxypropyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 481.1 458
##STR00706## N-(5-(5-chloro-2-methoxyphenyl)-
1-((tetrahydrofuran-2-yl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 26 453.1 459
##STR00707## N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
oxopyrrolidin-1-yl)ethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 480.1 460
##STR00708## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-1-
(tetrahydro-2H-pyran-4-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 18, 14 489.2 461
##STR00709## N-(3-(5-chloro-2-methoxyphenyl)-
1-(oxetan-3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 14 425.1 462 ##STR00710##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 453.1 463
##STR00711## N-(3-(5-chloro-2-methoxyphenyl)-
1-((tetrahydrofuran-2-yl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 453.2 464
##STR00712## N-(3-(5-chloro-2- methoxyphenyl)-1-(tetrahydro-
2H-pyran-3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 14 453.1 465 ##STR00713##
N-(5-(5-chloro-2-methoxyphenyl)- 1-(2-(pyrrolidin-1-yl)ethyl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 15 466.2 466
##STR00714## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(pyrrolidin-1-yl)ethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 466.2 467
##STR00715## N-(5-(5-chloro-2-methoxyphenyl)-
1-(2-ethoxyethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 15 441.2. 468 ##STR00716##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-ethoxyethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 441.2 469
##STR00717## N-(3-(5-chloro-2-methoxyphenyl)-
1-(piperidin-4-ylmethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 159 466.2 470
##STR00718## N-(1-(2-(1H-pyrazol-1-yl)ethyl)-
3-(5-chloro-2-methoxyphenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 463.2 471
##STR00719## N-(3-(5-chloro-2-methoxyphenyl)-
1-((5-oxo-1-((5-oxopyrrolidin-2- yl)methyl)pyrrolidin-2-yl)methyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 563.2
472 ##STR00720## N-(3-(5-chloro-2-methoxyphenyl)-
1-(piperidin-4-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide 159 452.2 473 ##STR00721##
N-(3-(5-chloro-2-methoxyphenyl)- 1-((5-oxopyrrolidin-2-yl)methyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 466.1
474 ##STR00722## N-(3-(5-chloro-2- methoxyphenyl)-1-(piperidin-
3-ylmethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 159 466.2 475 ##STR00723## N-(3-(5-chloro-2-
methoxyphenyl)-1-(pyrrolidin-2- ylmethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 159 452.2 476
##STR00724## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(diethylamino)ethyl)-1H- pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 468.2 477
##STR00725## N-(3-(5-chloro-2- methoxyphenyl)-1-(pyrrolidin-
3-ylmethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide 159 452.2 478 ##STR00726##
N-(3-(5-chloro-2-methoxyphenyl)- 1-(oxetan-2-ylmethyl)-1H-pyrazol-
4-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 439.1 479
##STR00727## N-(3-(5-chloro-2-methoxyphenyl)-
1-(tetrahydrofuran-3-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 439.1 480
##STR00728## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(2-
hydroxypropylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 164 484.1 481
##STR00729## N-(3-(5-chloro-2-methoxyphenyl)-
1-(1-(3-hydroxyazetidin-1-yl)-1- oxopropan-2-yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 160 496.1 482
##STR00730## N-(1-(1-(azetidin-1-yl)-1-
oxopropan-2-yl)-3-(5-chloro-2- methoxyphenyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 160 480.1 483
##STR00731## N-(3-(5-chloro-2-methoxyphenyl)-
1-(1-(ethylamino)-1-oxopropan-2- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 160 468.1 484
##STR00732## N-(3-(5-chloro-2-methoxyphenyl)-
1-(1-(3-hydroxyazetidin-1-yl)-2- methyl-1-oxopropan-2-yl)-1H-
pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 161 510.2
485 ##STR00733## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(3,3-difluoropyrrolidin-1- yl)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 502.2 486
##STR00734## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
fluoropyrrolidin-1-yl)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 484.2 487
##STR00735## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
hydroxypyrrolidin-1-yl)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 162 482.2 488
##STR00736## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
hydroxypyrrolidin-1-yl)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 482.2 489
##STR00737## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(cyclobutylamino)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 466.2 490
##STR00738## N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-(1-
methylcyclobutylamino)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 162 480.1 491
##STR00739## N-(1-(2-(azetidin-1-yl)ethyl)-
3-(5-chloro-2-methoxyphenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 452.2 492
##STR00740## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(3-fluoroazetidin-1- yl)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 470.1 493
##STR00741## N-(1-(2-acetamidoethyl)-3-(5- chloro-2-methoxyphenyl)-
1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 163 454.1
494 ##STR00742## N-(3-(5-chloro-2-methoxyphenyl)- 1-(2-
(cyclobutanecarboxamido)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 163 494.2 495
##STR00743## (R)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
(hydroxymethyl)pyrrolidin-1- yl)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 162 496.1 496
##STR00744## (S)-N-(3-(5-chloro-2- methoxyphenyl)-1-(2-(3-
(hydroxymethyl)pyrrolidin-1- yl)ethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 162 496.2 497
##STR00745## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(2-oxooxazolidin-3-yl)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 14 482.1 498
##STR00746## N-(3-(5-chloro-2-methoxypyridin- 3-yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 141 370.0 499
##STR00747## N-(3-(5-chloro-2-methoxypyridin-
3-yl)-1-(2-(dimethylamino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 141, 14 455.1 500
##STR00748## N-(3-(5-chloro-2- methoxypyridin-3-yl)-1-(2-
(cyclopentyl(methyl)amino)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 141, 164 509.2 501
##STR00749## N-(3-(5-chloro-2- methoxypyridin-3-yl)-1-(2-
(3,3-difluoropyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 141, 164 517.1 502
##STR00750## N-(3-(5-chloro-2- methoxypyridin-3-yl)-1-(2-(2-
methylpyrrolidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 141, 164 495.1 503
##STR00751## N-(3-(5-chloro-2-methoxyphenyl)-
1-((tetrahydro-2H-pyran-2- yl)methyl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 467.2 504
##STR00752## N-(3-(5-chloro-2-methoxyphenyl)-
1-(2-(oxetan-3-ylamino)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 162 468.2 505
##STR00753## N-(3-(1-methyl-1H-imidazol-5- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 309.1 506
##STR00754## N-(1-(2-hydroxy-2-methylpropyl)-
3-(1-methyl-1H-imidazol-5-yl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 16 381.1 507
##STR00755## N-(3-(3,5-dimethylisoxazol-4- yl)-1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 14 324.1 508
##STR00756## N-(3-(3,5-dimethylisoxazol-4-yl)-
1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide 16 396.1
[0669] The compounds of Examples 1-508 were tested in the above
assays (Examples A-C) and found to have K.sub.i values of less than
about 1 .mu.M for inhibiting one or both of JAK1 and JAK2 kinases.
The compounds of Examples 1-132 were tested in the above assays
(Examples A-C) and found to have K.sub.i values of less than about
1 .mu.M for inhibiting JAK2 kinase. The compounds of Examples
132-508 were tested in the above assays (Examples A-C) and found to
have K.sub.i values of less than about 1 .mu.M for inhibiting JAK1
kinase.
[0670] Table 3 below shows enzymatic activity data (K.sub.i, .mu.M)
for certain compounds of the present invention run in the above
assays (Examples A-C).
TABLE-US-00003 TABLE 3 Example JAK1 JAK2 JAK3 TYK2.sub.i 63 0.153
0.023 0.200 0.140 6 0.0462 0.0049 0.152 0.0996 194 0.775 0.110 4.10
0.980 44 0.131 0.018 0.140 0.480 217 0.0021 0.0005 0.0055 0.0023
379 0.0859 0.0263 0.2400 0.4100 158 0.0048 0.0015 0.0530 0.0066 155
0.0042 0.0026 0.2100 0.0650 364 0.0023 0.0062 0.7100 0.0470 283
0.0007 0.0031 0.2700 0.0091 359 0.0010 0.0042 0.6900 0.0460 432
0.0015 0.0057 0.5700 0.0310 300 0.0005 0.0025 0.1700 0.0100 170
0.0007 0.0004 0.0130 0.0021 499 0.0016 0.0058 0.7800 0.0140 414
0.0038 0.0125 0.2100 0.0760 143 0.0120 0.0385 1.500 0.3500 41
0.0351 0.0033 0.0739 0.1040 38 0.0403 0.0057 0.1020 0.1310 28
0.1100 0.0137 0.1350 0.4590 51 0.0837 0.0152 0.1500 0.0980 54 1.20
0.159 0.850 109 0.0044 0.0010 0.0180 0.0056 395 0.1760 0.0313
0.3900 0.2300 0.762 0.104 2.80 1.70
[0671] Reference is made to U.S. Provisional Application Ser. No.
61/222,918, filed Jul. 2, 2009, which is incorporated by reference
herein in its entirety for all purposes.
[0672] 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.
* * * * *