U.S. patent application number 16/696817 was filed with the patent office on 2020-04-09 for substituted pyrazole compounds as serine protease inhibitors.
The applicant listed for this patent is VERSEON CORPORATION. Invention is credited to Maria de los Angeles ESTIARTE-MARTINEZ, David Ben KITA, Timothy Philip SHIAU, Kevin Michael SHORT.
Application Number | 20200109132 16/696817 |
Document ID | / |
Family ID | 56789853 |
Filed Date | 2020-04-09 |
View All Diagrams
United States Patent
Application |
20200109132 |
Kind Code |
A1 |
SHORT; Kevin Michael ; et
al. |
April 9, 2020 |
SUBSTITUTED PYRAZOLE COMPOUNDS AS SERINE PROTEASE INHIBITORS
Abstract
There are provided inter alia multisubstituted aromatic
compounds useful for the inhibition of thrombin and/or kallikrein,
which compounds include substituted pyrazolyl. There are
additionally provided pharmaceutical compositions. There are
additionally provided methods of treating and preventing certain
diseases or disorders, which diseases or disorders are amenable to
treatment or prevention by the inhibition of thrombin and/or
kallikrein.
Inventors: |
SHORT; Kevin Michael;
(Fremont, CA) ; ESTIARTE-MARTINEZ; Maria de los
Angeles; (Fremont, CA) ; KITA; David Ben;
(Fremont, CA) ; SHIAU; Timothy Philip; (Fremont,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VERSEON CORPORATION |
Fremont |
CA |
US |
|
|
Family ID: |
56789853 |
Appl. No.: |
16/696817 |
Filed: |
November 26, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15553540 |
Aug 24, 2017 |
10532995 |
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PCT/US16/20116 |
Feb 29, 2016 |
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16696817 |
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62126424 |
Feb 27, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/04 20130101;
A61K 31/454 20130101; A61K 45/06 20130101; A61K 31/5377 20130101;
A61P 35/00 20180101; A61K 9/0019 20130101; A61K 9/0048 20130101;
C07D 417/14 20130101; A61P 29/00 20180101; C07D 403/04 20130101;
A61K 31/4155 20130101; C07D 409/12 20130101; A61P 7/02 20180101;
A61K 31/55 20130101; A61P 3/10 20180101; C07D 405/04 20130101; A61P
9/00 20180101; C07D 405/14 20130101; C07D 409/14 20130101; A61K
31/4545 20130101; A61P 25/28 20180101 |
International
Class: |
C07D 403/04 20060101
C07D403/04; C07D 409/14 20060101 C07D409/14; C07D 417/14 20060101
C07D417/14; A61K 9/00 20060101 A61K009/00; A61K 31/4155 20060101
A61K031/4155; A61K 31/454 20060101 A61K031/454; A61K 31/4545
20060101 A61K031/4545; A61K 31/5377 20060101 A61K031/5377; A61K
31/55 20060101 A61K031/55; A61K 45/06 20060101 A61K045/06; C07D
401/04 20060101 C07D401/04; C07D 405/04 20060101 C07D405/04; C07D
405/14 20060101 C07D405/14; A61P 35/00 20060101 A61P035/00; A61P
9/00 20060101 A61P009/00; A61P 25/28 20060101 A61P025/28; A61P 7/02
20060101 A61P007/02; A61P 29/00 20060101 A61P029/00; A61P 3/10
20060101 A61P003/10; C07D 409/12 20060101 C07D409/12 |
Claims
1. A compound with the following structure: ##STR00296## or
pharmaceutically acceptable salt, ester, solvate, or prodrug
thereof, wherein: L.sup.1, L.sup.2, and L.sup.4 are independently a
bond, substituted or unsubstituted alkylene, substituted or
unsubstituted heteroalkylene, --C(O)--, --S--, --SO--,
--SO.sub.2--, --O--, --NHSO.sub.2--, --NHC(O)--, or --NR.sup.5--;
R.sup.1, R.sup.2, and R.sup.4 are independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted heteroalkenyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocycloalkenyl, substituted or unsubstituted aryl, substituted
or unsubstituted fused ring aryl, or substituted or unsubstituted
heteroaryl; R.sup.5 is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
fused ring aryl, or substituted or unsubstituted heteroaryl; V is
hydrogen or substituted or unsubstituted alkyl; W is absent,
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
heteroalkenyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted heterocycloalkenyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(O)R.sup.6, --C(O)OR.sup.6, C(O)NR.sup.6R.sup.7, --SR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, --SO.sub.2NR.sup.6R.sup.7,
--OR.sup.6, --NHSO.sub.2R.sup.6, or --NR.sup.6R.sup.7, where
R.sup.6 and R.sup.7 are independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted heteroalkenyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocycloalkenyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, wherein R.sup.6 and
R.sup.7 can be combined if both are present to form a substituted
or unsubstituted alkylene, or substituted or unsubstituted
heteroalkylene; X is a bond, substituted or unsubstituted alkylene,
--O--, or --NR.sup.5--; Y is a bond, substituted or unsubstituted
alkylene, --O--, or --N--, provided that when Y is --O--, W is
absent; and Z is a bond, --C(O)--, substituted or unsubstituted
alkylene, --O--, or --NR.sup.9--; wherein R.sup.8 and R.sup.9 are
independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7,
--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2NR.sup.6R.sup.7, --OR.sup.6, --NHSO.sub.2R.sup.6, or
--NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 are as defined
above; and provided that either at least one of X is --O-- or
--NR.sup.8--, Y is --O-- or --N--, or Z is --O-- or
--NR.sup.9--.
2. The compound of claim 1, wherein X is a bond or substituted or
unsubstituted alkylene.
3. The compound of claim 2, wherein Z is a bond or substituted or
unsubstituted alkylene.
4. The compound of claim 3, wherein Y is --N--, and W is hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, --C(O)R.sup.6,
--C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7, --SO.sub.2R.sup.6, or
SO.sub.2NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 are
independently substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, or substituted or unsubstituted
heterocycloalkyl, or R.sup.6 and R.sup.7 can be combined if both
are present to form a substituted or unsubstituted alkylene, or
substituted or unsubstituted heteroalkylene.
5. The compound of claim 4, wherein X is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and Z is a bond.
6. The compound of claim 4, wherein X is a bond, and Z is selected
from the group consisting of substituted or unsubstituted
methylene, substituted or unsubstituted ethylene, substituted or
unsubstituted propylene, substituted or unsubstituted butylene, and
substituted or unsubstituted pentylene.
7. The compound of claim 4, wherein X is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and wherein Z is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene.
8. The compound of claim 7, wherein X and Z are both branched
alkylene and X and Z are covalently attached.
9. The compound of any of claims 6-8, wherein Z is selected from
the group consisting of substituted methylene, substituted
ethylene, substituted propylene, substituted butylene, and
substituted pentylene, having one or more substituent groups
selected from the group consisting of --OH, --NH.sub.2, --SH, --CN,
--CF.sub.3, --NO.sub.2, oxo, halogen, --COOH, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
or substituted or unsubstituted heteroaryl.
10. The compound of claim 4, wherein X is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and wherein Z is --C(O)--.
11. The compound of any of claims 4-10, wherein W is hydrogen.
12. The compound of any of claims 4-10, wherein W is selected from
the group consisting of substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.6R.sup.7'--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
and --SO.sub.2NR.sup.6.
13. The compound of claim 12, wherein W is substituted alkyl,
substituted heteroalkyl, substituted alkenyl, substituted
heteroalkenyl, substituted cycloalkyl, or substituted
heterocycloalkyl, having one or more substituent groups selected
from the group consisting of --OH, --NH.sub.2, --SH, --CN,
--CF.sub.3, --NO.sub.2, Oxo, halogen, --COOH, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
or substituted or unsubstituted heteroaryl.
14. The compound of claim 12, wherein W is --COR.sup.6,
--C(O)OR.sup.6, C(O)NR.sup.6R.sup.7, --SO.sub.2R.sup.6 or
--SO.sub.2NR.sup.6R.sup.7, and wherein R.sup.6 and R.sup.7 are
selected from the group consisting of substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl, or
R.sup.6 and R.sup.7 combine to form a substituted or unsubstituted
alkylene.
15. The compound of claim 1, wherein W is absent, X is
--NR.sup.8--, Y is a bond or substituted or unsubstituted alkylene,
and Z is --NR.sup.9--.
16. The compound of claim 15, wherein Y is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene.
17. The compound of claim 16, wherein R.sup.8 is selected from the
group consisting of substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted heteroalkenyl, --COR.sup.6,
--C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7, --SR.sup.6, --SOR.sup.6,
--SO.sub.2R.sup.6, and --SO.sub.2NR.sup.6R.sup.7, and wherein
R.sup.9 is selected from the group consisting of substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
heteroalkenyl, --COR.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7,
--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, and
--SO.sub.2NR.sup.6R.sup.7.
18. The compound of claim 3, wherein Y is --O--, and W is
absent.
19. The compound of claim 18, wherein X is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and Z is a bond.
20. The compound of claim 18, wherein X is a bond, and Z is
selected from the group consisting of substituted or unsubstituted
methylene, substituted or unsubstituted ethylene, substituted or
unsubstituted propylene, substituted or unsubstituted butylene, and
substituted or unsubstituted pentylene.
21. The compound of claim 18, wherein X is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and wherein Z is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene.
22. The compound of any of claims 1-21, wherein V is hydrogen or
substituted or unsubstituted methyl.
23. The compound according to any of claims 1-22, wherein L.sup.1
is --S--, --O--, --NR.sup.5--, substituted or unsubstituted
alkylene, or substituted or unsubstituted heteroalkylene; R.sup.1
is substituted or unsubstituted alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted fused ring aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heterocycloalkyl; and R.sup.5 is hydrogen, substituted or
unsubstituted alkyl, or substituted or unsubstituted
heterocycloalkyl.
24. The compound according to claim 23, wherein L.sup.1 is
--NR.sup.5-- or substituted or unsubstituted heteroalkyl, and
R.sup.1 is substituted or unsubstituted alkyl or substituted or
unsubstituted heteroaryl.
25. The compound according to claim 24, wherein L.sup.1 is
--NR.sup.5--, and R.sup.1 is substituted alkyl having one or more
substituent groups selected from the group consisting of
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl.
26. The compound according to claim 25, wherein R.sup.1 is
substituted alkyl substituted by chloro-substituted thiophenyl.
27. The compound according to claim 24, wherein L.sup.1 is
substituted or unsubstituted heteroalkyl, and R.sup.1 is
substituted or unsubstituted heteroaryl.
28. The compound according to any of claims 1-27, wherein L.sup.2
is bond, substituted or unsubstituted alkylene, --C(O)--, or
--SO.sub.2--, and R.sup.2 is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted fused ring aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heterocycloalkyl.
29. The compound according to claim 28, wherein L.sup.2 is bond,
and R.sup.2 is hydrogen.
30. The compound according to claim 28, wherein L.sup.2 is-C(O)--,
and R.sup.2 is substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
fused ring aryl, substituted or unsubstituted heteroaryl, or
substituted or unsubstituted heterocycloalkyl.
31. The compound according to any of claims 1-30, wherein L.sup.4
is a bond, and R.sup.4 is hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl.
32. The compound according to any of claims 1 to 31 as set forth in
Table A, Table B, Table C, or Table D.
33. A pharmaceutical composition comprising a compound according to
any of claims 1 to 31, or a compound as set forth in Table A, Table
B, Table C, or Table D and a pharmaceutically acceptable
excipient.
34. A method for treating and/or preventing a disease or disorder
in a subject, comprising administering a compound according to any
of claims 1 to 32 or a pharmaceutical composition according to
claim 33, to a subject in need thereof in an amount effective to
treat or prevent said disease or disorder.
35. The method according to claim 34, wherein said disease or
disorder is a thrombotic disease or disorder and/or involves a
blood clot thrombus or the potential formation of a blood clot
thrombus.
36. The method according to claim 35, wherein said thrombotic
disease or disorder comprises acute coronary syndrome,
thromboembolism, and/or thrombosis.
37. The method according to claim 36, wherein the thromboembolism
comprises venous thromboembolism, arterial thromboembolism, and/or
cardiogenic thromboembolism.
38. The method according to claim 37, wherein the venous
thromboembolism comprises deep vein thrombosis and/or pulmonary
embolism.
39. The method according to claim 38, wherein the deep vein
thrombosis and/or pulmonary embolism occurs following a medical
procedure.
40. The method according to claim 35, wherein said thrombotic
disease or disorder involves dysfunctional coagulation or
disseminated intravascular coagulation.
41. The method according to claim 40, wherein the subject is
undergoing percutaneous coronary intervention (PCI).
42. The method according to claim 35, wherein said thrombotic
disease or disorder involves a blood clot thrombus or the potential
formation of a blood clot thrombus and further involves stroke
and/or one or more transient ischemic attacks (TIA).
43. The method according to claim 42, wherein said thrombotic
disease or disorder involving a blood clot thrombus or the
potential formation of a blood clot thrombus further involves
stroke and wherein the subject has non-valvular atrial
fibrillation.
44. The method according to claim 35, wherein said thrombotic
disease or disorder involves a blood clot thrombus or the potential
formation of a blood clot thrombus and further involves pulmonary
hypertension.
45. The method according to claim 44, wherein the pulmonary
hypertension is caused by one or more left heart disorder and/or
chronic thromboembolic disease.
46. The method according to claim 44, wherein the pulmonary
hypertension is associated with one or more lung disease, including
pulmonary fibrosis (idiopathic or otherwise), and/or hypoxia.
47. The method according to claim 34, wherein said disease or
disorder comprises fibrosis, Alzheimer's Disease, multiple
sclerosis, pain, cancer, inflammation, and/or Type I diabetes
mellitus.
48. The method according to claim 34, wherein the disease or
disorder involves recurrent cardiac events after myocardial
infarction.
49. The method according to claim 37, wherein the venous
thromboembolism is associated with formation of a thrombus within a
vein associated with one or more acquired or inherited risk factors
and/or embolism of peripheral veins caused by a detached
thrombus.
50. The method according to claim 49, wherein the one or more risk
factors comprise a previous venous thromboembolism.
51. The method according to claim 37, wherein the cardiogenic
thromboembolism is due to formation of a thrombus in the heart
associated with cardiac arrhythmia, heart valve defect, prosthetic
heart valves or heart disease, and/or embolism of peripheral
arteries caused by a detached thrombus.
52. The method according to claim 51, wherein the detached thrombus
is in the brain (ischemic stroke).
53. The method according to claim 52, wherein the detached thrombus
causes a transient ischemic attack (TIA).
54. The method according to claim 51, wherein the cardiogenic
thromboembolism is due to non-valvular atrial fibrillation.
55. The method according to claim 36, wherein the thrombosis is
arterial thrombosis.
56. The method according to claim 55, wherein the arterial
thrombosis is due to one or more underlying atherosclerotic
processes in the arteries.
57. The method according to claim 56, wherein the one or more
underlying atherosclerotic processes in the arteries obstruct or
occlude an artery, cause myocardial ischemia (angina pectoris,
acute coronary syndrome), cause myocardial infarction, obstruct or
occlude a peripheral artery (ischemic peripheral artery disease),
and/or obstruct or occlude the artery after a procedure on a blood
vessel (reocclusion or restenosis after transluminal coronary
angioplasty, reocclusion or restenosis after percutaneous
transluminal angioplasty of peripheral arteries).
58. The method according to claim 34, wherein the treatment or
prevention comprises an adjunct therapy.
59. The method according to claim 58, wherein the subject has
myocardial infarction, and the adjunct therapy is in conjunction
with thrombolytic therapy.
60. The method according to claim 58, wherein the subject has
unstable angina pectoris, thrombosis, and/or heparin-induced
thrombocytopenia, and the adjunct therapy is in combination with
antiplatelet therapy.
61. The method according to claim 58, wherein the subject has
non-valvular atrial fibrillation, and the adjunct therapy is in
conjunction with one or more other therapies.
62. The method according to claim 34, wherein said disease or
disorder is a kallikrein-related disorder.
63. The method according to claim 62, wherein said
kallikrein-related disorder is a thrombotic disease, a fibrinolytic
disease, a fibrotic disorder, a type of cancer, an inflammatory
condition, or a dermatological condition.
64. The method according to claim 62, wherein said
kallikrein-related disorder is an ophthalmic disease.
65. The method according to claim 64, wherein said compound or
pharmaceutical composition is administered in the form of an
ophthalmic composition applied topically to the eye.
66. The method according to claim 65, wherein the ophthalmic
composition is in the form of eye drops.
67. The method according to claim 64, wherein said compound or
pharmaceutical composition is administered in the form of an
ophthalmic composition via intravitreal injection.
68. The method according to claim 64, wherein said ophthalmic
disease is diabetic macular edema, hereditary angioedema,
age-related macular degeneration, or diabetic retinopathy.
69. The method according to claim 63, wherein said type of cancer
is selected from the group consisting of cervical-, testicular-, or
non-small-cell lung adenocarcinoma, limited small cell lung cancer,
glioma, malignant breast cancer, micrometastasis (e.g.
micrometastasis of blood or liver), lung metastasis, and prostatic
cancer.
70. The method according to claim 63, wherein said inflammatory
condition is sepsis, inflammatory bowel disease, inflammatory
arthritis, systemic inflammatory response syndrome, or rheumatoid
arthritis.
71. The method according to claim 63, wherein said dermatological
condition is atopic dermatitis, psoriasis, or Netherton
Syndrome.
72. The method according to any of claims 34-71, wherein said
compound acts by inhibiting thrombin and/or kallikrein.
73. The method according to claim 72, wherein said compound acts by
inhibiting tissue kallikrein and/or plasma kallikrein.
74. The method according to claim 34, wherein the amount of
compound administered is a therapeutically effective dose
sufficient to achieve an initial concentration of the compound or
its active metabolite(s) in plasma within a range of 1-10 nM,
10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200 .mu.M,
200-500 .mu.M, or 500-1000 .mu.M, or greater.
75. The method according to claim 74, wherein greater than 50% of
the initial compound concentration persists in the plasma for 1
hour, 3 hours, or longer, after intravenous injection.
76. A compound according to any of claims 1 to 32 or a
pharmaceutical composition according to claim 33 for use in a
method according to any of claims 34-75.
77. The compound according to any of claims 1-32, wherein the
compound has inhibitory activity against thrombin and/or plasma
kallikrein within a range of 1-10 nM, 10-100 nM, 0.1-1 .mu.M, 1-10
.mu.M, 10-100 .mu.M, 100-200 .mu.M, 200-500 .mu.M, or 500-1000
.mu.M, or greater.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a division of U.S. application
Ser. No. 15/553,540, filed on Aug. 24, 2017, which is a U.S.
National Stage entry under 35 U.S.C. .sctn. 371 of International
Application No. PCT/US2016/020116, filed on Feb. 29, 2016,
designating the United States of America and published in English
on Sep. 1, 2016, which in turn claims priority to U.S. Provisional
Application No. 62/126,424, filed on Feb. 27, 2015, each of which
is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The present disclosure relates to compounds, e.g., certain
substituted pyrazole compounds, which exhibit biological activity,
e.g., inhibitory action, against serine proteases, including
thrombin and plasma kallikrein.
[0003] Serine proteases are a large family of enzymes with diverse
biological functions, their commonality being the presence and
critical function of the active-site serine residue. Their central
function is the catalytic scission of peptide bond substrates via a
Ser, His, Asp triad within the active site (Kraut, J. Annual Review
of Biochemistry 1977, 46, 331-358). The present disclosure relates
to compounds, e.g., heterocycloalkyl-substituted pyrazolyl
compounds, which exhibit biological activity, e.g., inhibitory
action, against serine proteases, including thrombin and various
kallikreins.
[0004] In mammalian systems, blood vessel injuries result in
bleeding events, which are dealt with by the blood coagulation
cascade. The cascade includes the Extrinsic and Intrinsic pathways,
involving the activation of at least 13 interconnected factors and
a variety of co-factors and other regulatory proteins. Upon
vascular injury, plasma factor VII interacts with exposed Tissue
Factor (TF), and the resultant TF-fVIIa complex initiates a complex
series of events. Factor fXa is produced directly `downstream` from
the TF-fVIIa complex, and amplified manifold via the Intrinsic
Pathway. FXa then serves as the catalyst for formation of thrombin
(fIIa), which in turn is the direct precursor to fibrinolysis. The
outcome is a fibrinolytic clot, which stops the bleeding.
Fibrinolysis of the polymeric clot into fibrin monomers leads to
dissolution and a return of the system to the pre-clot state. The
cascade is a complex balance of factors and co-factors and is
tightly regulated.
[0005] In disease states, undesired up- or down-regulation of any
factor leads to conditions such as bleeding or thrombosis.
Historically, anticoagulants have been used in patients at risk of
suffering from thrombotic complications, such as angina, stroke and
heart attack. Warfarin has enjoyed dominance as a first-in-line
anticoagulant therapeutic. Developed in the 1940s, it is a Vitamin
K antagonist and inhibits factors II, VII, IX and X, amongst
others. It is administered orally, but its ease of use is tempered
by other effects: it has a very long half life (>2 days) and has
serious drug-drug interactions. Importantly, since Vitamin K is a
ubiquitous cofactor within the coagulation cascade, antagonism
results in the simultaneous inhibition of many clotting factors and
thus can lead to significant bleeding complications.
[0006] Much attention has been focused on heparin, the
naturally-occurring polysaccharide that activates AT III, the
endogenous inhibitor of many of the factors in the coagulation
cascade. The need for parenteral administration for the
heparin-derived therapeutics, and the inconvenient requirements for
close supervision for the orally available warfarin, has resulted
in a drive to discover and develop orally available drugs with wide
therapeutic windows for safety and efficacy.
[0007] Indeed, the position of thrombin in the coagulation cascade
has made it a popular target for drug discovery. Thrombin is a
central protein in the coagulation process, which is activated and
amplified upon vascular injury. Thrombin generation prompts a
cascade in various factors in the coagulation cascade, ultimately
depositing fibrin, the framework for a clot. The clot causes
cessation of the bleeding event accompanying the vascular injury.
Thrombin and associated protein ultimately cause dissolution of the
clot through `fibrinolysis`, returning the system back to the
pre-injury state. In a `normal` state of injury, this thrombin
generation and clot deposition is desired. In a disease state, clot
deposition is undesired. General thrombotic events are the clinical
result of clot deposition and accumulation in the arteries, veins
or within the heart. Eventual break-off of the accumulated clot
structure into the vascular system causes the clot to travel to the
brain and/or lungs, resulting in a stroke, myocardial infarction
(heart attack), pulmonary embolism, paralysis and consequent
death.
[0008] Compounds that inhibit thrombin have been shown in the
literature to be useful as anticoagulants in vitro and in vivo, and
in the clinic in patients have been shown to fulfil a critically
unmet medical need. A thorough discussion of thrombin and its roles
in the coagulation process can be found in a variety of references,
including the following which are incorporated herein by reference
in their entireties and for all purposes: Wieland, H. A., et al.,
2003, Curr Opin Investig Drugs, 4:264-71; Gross, P. L. & Weitz,
J. I., 2008, Arterioscler Thromb Vasc Biol, 28:380-6; Hirsh, J., et
al., 2005, Blood, 105:453-63; Prezelj, A., et al., 2007, Curr Pharm
Des, 13:287-312. Without further wishing to be bound by any theory,
it is believed that the use of direct thrombin inhibitors (DTIs) is
very well precedented, such as with the hirudin-based
anticoagulants, and thus there is strong interest in the discovery
and development of novel DTIs, particularly those with selectivity
for inhibiting thrombin over other related serine proteases.
Kallikreins are a subgroup of serine proteases, divided into plasma
kallikrein and tissue kallikreins. Plasma kallikrein (KLKB1)
liberates kinins (bradykinin and kallidin) from the kininogens,
peptides responsible for the regulation of blood pressure and
activation of inflammation. In the contact activation pathway of
the coagulation cascade, plasma kallikrein assists in the
conversion of factor XII to factor XIIa (Keel, M.; Trentz, O.
Injury 2005, 36, 691-709). Factor XIIa converts factor XI into
factor XIa, which in turn activates factor IX, which with its
co-factor factor VIIIa forms the tenase complex, which finally
activates factor X to factor Xa. In the fibrinolysis part of the
coagulation cascade, plasma kallikrein serves to convert
plasminogen to plasmin. Thus, it has been proposed that plasma
kallikrein inhibitors can be useful in the treatment of thrombotic
and fibrinolytic diseases and disease conditions (U.S. Pat. No.
7,625,944; Bird et al. Thrombosis and Hemostasis 2012, 107, Dhaval
Kolte, M D. et al., Cardiology in Review, 2015).
[0009] Tissue kallikreins (KLKs, for example, KLK1) are subdivided
into various types, and have been extensively investigated in
cancer and inflammation biology. Various kallikrein KLKs have been
found to be up- or down-regulated in various cancer types, such as
cervical-, testicular-, and non-small-cell lung adenocarcinoma
(Caliendo et al. J. Med. Chem., 2012, 55, 6669). Furthermore,
overexpression of various KLKs in the skin has led to the
recognition that certain kallikrein inhibitors can be useful for
certain dermatological conditions, including atopic dermatitis,
psoriasis and rare skin diseases such as Netherton Syndrome
(Freitas et al. Bioorganic & Medicinal Chemistry Letters 2012,
22, 6072-6075). A thorough discussion of tissue kallikreins, plasma
kallikrein, their functions and potential roles in various diseases
can be found in a variety of references, including the following
which are incorporated herein by reference in their entireties and
for all purposes: Renn6, T.; Gruber, A. Thromb Haemost 2012, 107,
1012-3; Sotiropoulou, G.; Pampalakis, G. Trends in Pharmacological
Sciences 2012, 33, 623-634; Pampalakis, G.; Sotiropoulou, G.
Chapter 9 Pharmacological Targeting of Human Tissue
Kallikrein-Related Peptidases. In Proteinases as Drug Targets,
Dunn, B., Ed. The Royal Society of Chemistry: 2012; pp 199-228;
Caliendo, G.; Santagada, V.; Perissutti, E.; Severino, B.; Fiorino,
F.; Frecentese, F.; Juliano, L. J Med Chem 2012, 55, 6669-86.
BRIEF SUMMARY OF THE INVENTION
[0010] Embodiments of the invention encompass compounds with the
following structure:
##STR00001##
or pharmaceutically acceptable salt, ester, solvate, or prodrug
thereof, wherein: [0011] L.sup.1, L.sup.2, and L.sup.4 are
independently a bond, substituted or unsubstituted alkylene,
substituted or unsubstituted heteroalkylene, --C(O)--, --S--,
--SO--, --SO.sub.2--, --O--, --NHSO.sub.2--, --NHC(O)--, or
--NR.sup.5--; [0012] R.sup.1, R.sup.2, and R.sup.4 are
independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
fused ring aryl, or substituted or unsubstituted heteroaryl; [0013]
R.sup.5 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
fused ring aryl, or substituted or unsubstituted heteroaryl; [0014]
V is hydrogen or substituted or unsubstituted alkyl; [0015] W is
absent, hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7,
--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2NR.sup.6R.sup.7, --OR.sup.6, --NHSO.sub.2R.sup.6, or
--NR.sup.6R.sup.7, where R.sup.6 and R.sup.7 are independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted heterocycloalkenyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl, wherein R.sup.6
and R.sup.7 can be combined if both are present to form a
substituted or unsubstituted alkylene, or substituted or
unsubstituted heteroalkylene; [0016] X is a bond, substituted or
unsubstituted alkylene, --O--, or --NR.sup.8--; [0017] Y is a bond,
substituted or unsubstituted alkylene, --O--, or --N--, provided
that when Y is --O--, W is absent; and [0018] Z is a bond,
--C(O)--, substituted or unsubstituted alkylene, --O--, or
--NR.sup.9--; [0019] wherein R.sup.8 and R.sup.9 are independently
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
heteroalkenyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted heterocycloalkenyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7, --SR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, --SO.sub.2NR.sup.6R.sup.7,
--OR.sup.6, --NHSO.sub.2R.sup.6, or --NR.sup.6R.sup.7, wherein
R.sup.6 and R.sup.7 are as defined above; and [0020] provided that
either at least one of X is --O-- or --NR.sup.8--, Y is --O-- or
--N--, or Z is --O-- or --NR.sup.9--.
[0021] In some embodiments, the compound can be a pharmaceutically
acceptable salt, ester, solvate, or prodrug of a compound of
Formula (IV). In some embodiments, the compound is not an ester,
not a solvate, and not a prodrug.
[0022] In some embodiments, X can be a bond or substituted or
unsubstituted alkylene. In some embodiments, Z can be a bond or
substituted or unsubstituted alkylene. In some embodiments, X can
be a bond or substituted or unsubstituted alkylene, and Z can be a
bond or substituted or unsubstituted alkylene.
[0023] Some embodiments include compounds where X is a bond or
substituted or unsubstituted alkylene and Z is a bond or
substituted or unsubstituted alkylene, Y can be --N--, and W can be
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
--C(O)R.sup.6, --C(O)OR.sup.6,
C(O)NR.sup.6R.sup.7'--SO.sub.2R.sup.6, or SO.sub.2NR.sup.6R.sup.7,
wherein R.sup.6 and R.sup.7 can be independently substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or
substituted or unsubstituted heterocycloalkyl, or R.sup.6 and
R.sup.7 can be combined if both are present to form a substituted
or unsubstituted alkylene, or substituted or unsubstituted
heteroalkylene.
[0024] Some embodiments include compounds where X can be
substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, or substituted or
unsubstituted pentylene, and Z can be a bond. In some embodiments,
X can be a bond, and Z can be substituted or unsubstituted
methylene, substituted or unsubstituted ethylene, substituted or
unsubstituted propylene, substituted or unsubstituted butylene, or
substituted or unsubstituted pentylene. In some embodiments, X can
be substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, or substituted or
unsubstituted pentylene, and Z can be substituted or unsubstituted
methylene, substituted or unsubstituted ethylene, substituted or
unsubstituted propylene, substituted or unsubstituted butylene, or
substituted or unsubstituted pentylene. In some embodiments, X and
Z can both be branched alkylene, and X and Z can be covalently
attached. In some embodiments, Z can be substituted methylene,
substituted ethylene, substituted propylene, substituted butylene,
or substituted pentylene, having one or more substituent groups
which can be --OH, --NH.sub.2, --SH, --CN, --CF.sub.3, --NO.sub.2,
oxo, halogen, --COOH, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted
or unsubstituted heteroaryl.
[0025] Some embodiments include compounds where X can be
substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, or substituted or
unsubstituted pentylene, and Z can be --C(O)--. In some
embodiments, W can be hydrogen. In some embodiments, W can be
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
--C(O)R.sup.6, --C(O)OR.sup.6, C(O)NR.sup.6R.sup.7--SR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, or --SO.sub.2NR.sup.6. In some
embodiments, W can be substituted alkyl, substituted heteroalkyl,
substituted alkenyl, substituted heteroalkenyl, substituted
cycloalkyl, or substituted heterocycloalkyl, having one or more
substituent which can be --OH, --NH.sub.2, --SH, --CN, --CF.sub.3,
--NO.sub.2, oxo, halogen, --COOH, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted
or unsubstituted heteroaryl. In some embodiments, W can be
--COR.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7,
--SO.sub.2R.sup.6 or --SO.sub.2NR.sup.6R.sup.7, where R.sup.6 and
R.sup.7 can be selected from the group consisting of substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl, or R.sup.6 and R.sup.7 can be combined to form a
substituted or unsubstituted alkylene.
[0026] Some embodiments include compounds where W can be absent, X
can be --NR.sup.8--, Y can be a bond or substituted or
unsubstituted alkylene, and Z can be --NR.sup.9--. In some
embodiments wherein W can be absent, X can be --NR.sup.8--, Y can
be a bond or substituted or unsubstituted alkylene, and Z can be
--NR.sup.9--, Y can be substituted or unsubstituted methylene,
substituted or unsubstituted ethylene, substituted or unsubstituted
propylene, substituted or unsubstituted butylene, or substituted or
unsubstituted pentylene. In some embodiments, R.sup.8 can be
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted heteroalkenyl, --COR.sup.6, --C(O)OR.sup.6,
C(O)NR.sup.6R.sup.7, --SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, or
--SO.sub.2NR.sup.6R.sup.7, and wherein R.sup.9 can be substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
heteroalkenyl, --COR.sup.6, --C(O)OR.sup.6, C(O)NR.sup.6R.sup.7,
--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, or
--SO.sub.2NR.sup.6R.sup.7.
[0027] Some embodiments include compounds where Y can be --O--, and
W can be absent. In some embodiments wherein Y can be --O--, and W
can be absent, X can be substituted or unsubstituted methylene,
substituted or unsubstituted ethylene, substituted or unsubstituted
propylene, substituted or unsubstituted butylene, or substituted or
unsubstituted pentylene, and Z can be a bond. In some embodiments,
X can be a bond, and Z can be substituted or unsubstituted
methylene, substituted or unsubstituted ethylene, substituted or
unsubstituted propylene, substituted or unsubstituted butylene, or
substituted or unsubstituted pentylene. In some embodiments, X can
be substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, or substituted or
unsubstituted pentylene, and wherein Z can be substituted or
unsubstituted methylene, substituted or unsubstituted ethylene,
substituted or unsubstituted propylene, substituted or
unsubstituted butylene, or substituted or unsubstituted
pentylene.
[0028] In some embodiments, V can be hydrogen or substituted or
unsubstituted methyl.
[0029] In some embodiments, L.sup.1 can be --S--, --O--,
--NR.sup.5--, substituted or unsubstituted alkylene, or substituted
or unsubstituted heteroalkylene; R.sup.1 can be substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted
or unsubstituted fused ring aryl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted heterocycloalkyl; and
R.sup.5 can be hydrogen, substituted or unsubstituted alkyl, or
substituted or unsubstituted heterocycloalkyl. In some embodiments,
L.sup.1 can be --NR.sup.5-- or substituted or unsubstituted
heteroalkyl, and R.sup.1 can be substituted or unsubstituted alkyl
or substituted or unsubstituted heteroaryl. In some embodiments,
L.sup.1 can be --NR.sup.5--, and R.sup.1 can be substituted alkyl
having one or more substituent groups which can be substituted or
unsubstituted heteroaryl or substituted or unsubstituted
heterocycloalkyl. In some embodiments, R.sup.1 can be substituted
alkyl substituted by chloro-substituted thiophenyl. In some
embodiments, L.sup.1 can be substituted or unsubstituted
heteroalkyl, and R.sup.1 can be substituted or unsubstituted
heteroaryl.
[0030] In some embodiments, L.sup.2 can be bond, substituted or
unsubstituted alkylene, --C(O)--, or --SO.sub.2--, and R.sup.2 can
be hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
fused ring aryl, substituted or unsubstituted heteroaryl, or
substituted or unsubstituted heterocycloalkyl. In some embodiments,
L.sup.2 can be bond, and R.sup.2 is hydrogen. In some embodiments,
L.sup.2 can be --C(O)--, and R.sup.2 can be substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted fused ring aryl,
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted heterocycloalkyl.
[0031] In some embodiments, L.sup.4 can be a bond, and R.sup.4 can
be hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0032] In some embodiments, the compound(s) can be included among
those set forth in Table A, Table B, Table C, or Table D.
[0033] Embodiments of the invention also relate to pharmaceutical
compositions comprising one or more compounds as set forth above,
or one or more compound(s) included among those set forth in Table
A, Table B, Table C, or Table D, and a pharmaceutically acceptable
excipient.
[0034] Embodiments of the invention also include methods for
treating and/or preventing one or more diseases or disorders in a
subject, comprising administering a compound as set forth above, or
a pharmaceutical composition including such a compound, to a
subject in need thereof in an amount effective to treat or prevent
said disease(s) or disorder(s).
[0035] In some embodiments of the methods described herein, the
disease or disorder to be treated can include one or more
thrombotic diseases or disorders and/or can involve a blood clot
thrombus or the potential formation of a blood clot thrombus. In
some embodiments, the thrombotic disease or disorder can be acute
coronary syndrome, thromboembolism, and/or thrombosis. In some
embodiments, the thromboembolism can be venous thromboembolism,
arterial thromboembolism, and/or cardiogenic thromboembolism. In
some embodiments, the venous thromboembolism can include deep vein
thrombosis and/or pulmonary embolism. In some embodiments, the deep
vein thrombosis and/or pulmonary embolism can occur following a
medical procedure. In some embodiments, the thrombotic disease or
disorder can involve dysfunctional coagulation or disseminated
intravascular coagulation. In some embodiments, the subject with
dysfunctional coagulation can be undergoing percutaneous coronary
intervention (PCI). In some embodiments, the thrombotic disease or
disorder can involve a blood clot thrombus or the potential
formation of a blood clot thrombus and further can involve stroke
and/or one or more transient ischemic attacks (TIA). In some
embodiments, the thrombotic disease or disorder involving a blood
clot thrombus or the potential formation of a blood clot thrombus
can further involve stroke, wherein the subject can have
non-valvular atrial fibrillation. In some embodiments, the
thrombotic disease or disorder can involve a blood clot thrombus or
the potential formation of a blood clot thrombus and further can
involve pulmonary hypertension. In some embodiments, the pulmonary
hypertension can be caused by one or more left heart disorder
and/or chronic thromboembolic disease. In some embodiments, the
pulmonary hypertension can be associated with one or more lung
disease, including pulmonary fibrosis (idiopathic or otherwise),
and/or hypoxia.
[0036] In some embodiments, the venous thromboembolism can be
associated with formation of a thrombus within a vein associated
with one or more acquired or inherited risk factors and/or embolism
of peripheral veins caused by a detached thrombus. In some
embodiments, the one or more risk factors can include a previous
venous thromboembolism. In some embodiments, the cardiogenic
thromboembolism can be due to formation of a thrombus in the heart
associated with cardiac arrhythmia, heart valve defect, prosthetic
heart valves or heart disease, and/or embolism of peripheral
arteries caused by a detached thrombus. In some embodiments, the
detached thrombus can be in the brain (ischemic stroke). In some
embodiments, the detached thrombus can cause a transient ischemic
attack (TIA). In some embodiments, the cardiogenic thromboembolism
can be due to non-valvular atrial fibrillation. In some
embodiments, the thrombosis can be arterial thrombosis. In some
embodiments, the arterial thrombosis can be due to one or more
underlying atherosclerotic processes in the arteries. In some
embodiments, the one or more underlying atherosclerotic processes
in the arteries can obstruct or occlude an artery, cause myocardial
ischemia (angina pectoris, acute coronary syndrome), cause
myocardial infarction, obstruct or occlude a peripheral artery
(ischemic peripheral artery disease), and/or obstruct or occlude
the artery after a procedure on a blood vessel (reocclusion or
restenosis after transluminal coronary angioplasty, reocclusion or
restenosis after percutaneous transluminal angioplasty of
peripheral arteries).
[0037] In some embodiments, the disease or disorder can include
fibrosis, Alzheimer's Disease, multiple sclerosis, pain, cancer,
inflammation, and/or Type I diabetes mellitus. In some embodiments,
the disease or disorder can involve recurrent cardiac events after
myocardial infarction.
[0038] In some embodiments, the treatment or prevention can include
an adjunct therapy. In some embodiments, the subject can have
myocardial infarction, and the adjunct therapy can be in
conjunction with thrombolytic therapy. In some embodiments, the
subject can have unstable angina pectoris, thrombosis, and/or
heparin-induced thrombocytopenia, and the adjunct therapy can be in
combination with antiplatelet therapy. In some embodiments, the
subject can have non-valvular atrial fibrillation, and the adjunct
therapy can be in conjunction with one or more other therapies.
[0039] In some embodiments of the methods described herein, the
disease or disorder can be a kallikrein-related disorder. In some
embodiments, the kallikrein-related disorder can be a thrombotic
disease, a fibrinolytic disease, a fibrotic disorder, a type of
cancer, an inflammatory condition, or a dermatological
condition.
[0040] In some embodiments, the kallikrein-related disorder can be
an ophthalmic disease. In some embodiments, the compound or
pharmaceutical composition can be administered in the form of an
ophthalmic composition applied topically to the eye. In some
embodiments, the ophthalmic composition can be in the form of eye
drops. In some embodiments, the compound or pharmaceutical
composition can be administered in the form of an ophthalmic
composition via intravitreal injection. In some embodiments, the
ophthalmic disease can be diabetic macular edema, hereditary
angioedema, age-related macular degeneration, or diabetic
retinopathy.
[0041] In some embodiments wherein the disease or disorder can be a
type of cancer, said type of cancer can be cervical-, testicular-,
or non-small-cell lung adenocarcinoma. In some embodiments, the
cancer can be limited small cell lung cancer. In some embodiments,
the cancer can be a glioma. In some embodiments, the cancer can be
malignant breast cancer. In some embodiments, the cancer can be a
micrometastasis. In some embodiments, the micrometastasis can be of
the blood or liver. In some embodiments, the cancer can be a lung
metastasis. In some embodiments, the cancer can be prostatic
cancer.
[0042] In some embodiments wherein the disease or disorder can be
an inflammatory condition, said inflammatory condition can be
sepsis, inflammatory bowel disease, systemic inflammatory response
syndrome, inflammatory arthritis, or rheumatoid arthritis.
[0043] In some embodiments wherein the disease or disorder can be a
dermatological condition, said dermatological condition can be
atopic dermatitis, psoriasis, or Netherton Syndrome.
[0044] In some embodiments, the compound can act by inhibiting
thrombin and/or kallikrein. In some embodiments, the compound can
act by inhibiting tissue kallikrein and/or plasma kallikrein. In
some embodiments, the compound can have inhibitory activity against
thrombin and/or plasma kallikrein within a range of 1-10 nM, 10-100
nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200 .mu.M, 200-500
.mu.M, or 500-1000 .mu.M, or greater.
[0045] In some embodiments, the amount of compound administered can
be a therapeutically effective dose sufficient to achieve a plasma
concentration of the compound or its active metabolite(s) within a
range of 1-10 nM, 10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M,
100-200 .mu.M, 200-500 .mu.M, or 500-1000 .mu.M, or greater.
[0046] Embodiments of the invention also relate to compounds or
pharmaceutical compositions as described herein, for use in methods
for treating and/or preventing one or more diseases or disorders in
a subject, as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0048] The abbreviations used herein have their conventional
meaning within the chemical and biological arts. The chemical
structures and formulae set forth herein are constructed according
to the standard rules of chemical valency known in the chemical
arts.
[0049] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents that would result
from writing the structure from right to left, e.g., --CH.sub.2O--
is equivalent to --OCH.sub.2--.
[0050] As used herein, the term "attached" signifies a stable
covalent bond, certain preferred points of attachment being
apparent to those of ordinary skill in the art.
[0051] The terms "halogen" or "halo" include fluorine, chlorine,
bromine, and iodine. Additionally, terms such as "haloalkyl" are
meant to include monohaloalkyl and polyhaloalkyl. For example, the
term "halo(C.sub.1-C.sub.4)alkyl" includes, but is not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0052] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight (i.e.,
unbranched) or branched chain, or combination thereof, which can be
fully saturated, mono- or polyunsaturated and can include di- and
multivalent radicals, having the number of carbon atoms designated
(i.e., C.sub.1-C.sub.10 means one to ten carbons). Examples of
saturated hydrocarbon radicals include, but are not limited to,
groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and
isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and
the like. An unsaturated alkyl group is one having one or more
double bonds or triple bonds. Examples of unsaturated alkyl groups
include, but are not limited to, vinyl, 2-propenyl, crotyl,
2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the
higher homologs and isomers. Accordingly, the term "alkyl" can
refer to C.sub.1-C.sub.16 straight chain saturated,
C.sub.1-C.sub.16 branched saturated, C.sub.3-C.sub.8 cyclic
saturated, C.sub.3-C.sub.8 cyclic unsaturated, and C.sub.1-C.sub.16
straight chain or branched saturated or unsaturated aliphatic
hydrocarbon groups substituted with C.sub.3-C.sub.8 cyclic
saturated or unsaturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, and the like. Examples of cyclic
alkyl groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclopropylmethyl, and the like.
[0053] The term "alkylene," by itself or as part of another
substituent, means, unless otherwise stated, a divalent radical
derived from a saturated or unsaturated alkyl, as defined above and
as exemplified, but not limited by,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like. Typically, an
alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with
those groups having 10 or fewer carbon atoms being preferred in the
compounds disclosed herein. A "lower alkyl" or "lower alkylene" is
a shorter chain alkyl or alkylene group, generally having eight or
fewer carbon atoms.
[0054] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or combinations thereof, consisting of at least one
carbon atom and at least one heteroatom selected from the group
consisting of O, N, P, Si, and S, and wherein the nitrogen and
sulfur atoms can optionally be oxidized, and the nitrogen
heteroatom can optionally be quaternized. The heteroatom(s) 0, N,
P, S, and Si can be placed at any interior position of the
heteroalkyl group or at the position at which the alkyl group is
attached to the remainder of the molecule. The heteroalkyl group
can be fully saturated, mono- or polyunsaturated and can include
di- and multivalent radicals, having the number of atoms
designated. Accordingly, the term "heteroalkyl" can refer to
saturated or unsaturated straight or branched chains containing two
through 16 atoms along the chain, cyclic saturated or unsaturated
groups containing 3-8 atoms in the cycle, and the like. Examples
include, but are not limited to: --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--C--H.dbd.N--OCH.sub.3,
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3, --O--CH.sub.3,
--O--CH.sub.2--CH.sub.3, --CN, and the like. Up to two heteroatoms
can be consecutive, such as, for example,
--CH.sub.2--NH--OCH.sub.3.
[0055] Similarly, the term "heteroalkylene," by itself or as part
of another substituent, means, unless otherwise stated, a divalent
radical derived from heteroalkyl, as defined above and as
exemplified, but not limited by,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--, and the like.
For heteroalkylene groups, heteroatoms can also occupy either or
both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents both --C(O).sub.2R'-- and
--R'C(O).sub.2--. As described above, heteroalkyl groups, as used
herein, include those groups that are attached to the remainder of
the molecule through a heteroatom, such as --C(O)R', --C(O)NR',
--NR'R'', --OR', --SR', and/or --SO.sub.2R'. Where "heteroalkyl" is
recited, followed by recitations of specific heteroalkyl groups,
such as --NR'R'' or the like, it will be understood that the terms
heteroalkyl and --NR'R'' are not redundant or mutually exclusive.
Rather, the specific heteroalkyl groups are recited to add clarity.
Thus, the term "heteroalkyl" should not be interpreted herein as
excluding specific heteroalkyl groups, such as --NR'R'' or the
like.
[0056] The terms "cycloalkyl" and "heterocycloalkyl," by themselves
or in combination with other terms, mean, unless otherwise stated,
cyclic versions of "alkyl" and "heteroalkyl," respectively. The
"cycloalkyl" and "heterocycloalkyl" groups include, for example,
monocyclic rings having 3-8 ring members, as well as bicyclic rings
having 4-16 ring members, tricyclic rings having 5-24 ring members,
and so on. Additionally, for heterocycloalkyl, a heteroatom can
occupy the position at which the heterocycle is attached to the
remainder of the molecule. Examples of cycloalkyl include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples
of heterocycloalkyl include, but are not limited to,
1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,
1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a
"heterocycloalkylene," alone or as part of another substituent,
means a divalent radical derived from a cycloalkyl and
heterocycloalkyl, respectively.
[0057] The term "alkenyl" includes C.sub.2-C.sub.16 straight chain
unsaturated, C.sub.2-C.sub.11 branched unsaturated, C.sub.5-C.sub.8
unsaturated cyclic, and C.sub.2-C.sub.16 straight chain or branched
unsaturated aliphatic hydrocarbon groups substituted with
C.sub.3-C.sub.8 cyclic saturated and unsaturated aliphatic
hydrocarbon groups having the specified number of carbon atoms.
Double bonds can occur in any stable point along the chain and the
carbon-carbon double bonds can have either the cis or trans
configuration. For example, this definition shall include but is
not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl,
heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl,
1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl,
1-pentenyl-3-cyclohexenyl, and the like. Similarly, "heteroalkenyl"
refers to heteroalkyl having one or more double bonds, wherein
heteroalkyl is as defined above.
[0058] The term "alkynyl" refers in the customary sense to alkyl,
as defined above, additionally having one or more triple bonds. The
term "cycloalkenyl" refers to cycloalkyl, as defined above,
additionally having one or more double bonds. The term
"heterocycloalkenyl" refers to heterocycloalkyl, as defined above,
additionally having one or more double bonds.
[0059] The term "acyl" means, unless otherwise stated, --C(O)R
where R is a substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0060] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, hydrocarbon substituent, which can be a
single ring or multiple rings (preferably from 1 to 3 rings) that
are fused together (i.e., a fused ring aryl) or linked covalently,
wherein each ring contains between 4-20 atoms, and preferably
between 5-10 atoms. A fused ring aryl refers to multiple rings
fused together wherein at least one of the fused rings is an aryl
ring. The term "heteroaryl" refers to aryl groups (or rings), as
defined above, that contain from one to four heteroatoms selected
from N, O, and S, wherein the nitrogen and sulfur atoms are
optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. Thus, the term "heteroaryl" includes fused ring
heteroaryl groups (i.e., multiple rings fused together wherein at
least one of the fused rings is a heteroaromatic ring). A 5,6-fused
ring heteroarylene refers to two rings fused together, wherein one
ring has 5 members and the other ring has 6 members, and wherein at
least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring
heteroarylene refers to two rings fused together, wherein one ring
has 6 members and the other ring has 6 members, and wherein at
least one ring is a heteroaryl ring. And a 6,5-fused ring
heteroarylene refers to two rings fused together, wherein one ring
has 6 members and the other ring has 5 members, and wherein at
least one ring is a heteroaryl ring. A heteroaryl group can be
attached to the remainder of the molecule through a carbon or
heteroatom. Non-limiting examples of aryl and heteroaryl groups
include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,
pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,
purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl, and the
like. Substituents for each of the above noted aryl and heteroaryl
ring systems are selected from the group of acceptable substituents
described below. An "arylene" and a "heteroarylene," alone or as
part of another substituent, mean a divalent radical derived from
an aryl and heteroaryl, respectively. Accordingly, the term "aryl"
can represent an unsubstituted, mono-, di- or trisubstituted
monocyclic, polycyclic, biaryl and heterocyclic aromatic groups
covalently attached at any ring position capable of forming a
stable covalent bond, certain preferred points of attachment being
apparent to those skilled in the art (e. g. 3-indolyl,
4-imidazolyl). The aryl substituents are independently selected
from the group consisting of halo, nitro, cyano, trihalomethyl,
C.sub.1-16alkyl, arylC.sub.1-16alkyl,
C.sub.0-16alkyloxyC.sub.0-16alkyl,
arylC.sub.0-16alkyloxyC.sub.0-16alkyl,
C.sub.0-16alkylthioC.sub.0-16alkyl,
arylC.sub.0-16alkylthioC.sub.0-16alkyl,
C.sub.0-16alkylaminoC.sub.0-16alkyl,
arylC.sub.0-16alkylaminoC.sub.0-16alkyl,
di(arylC.sub.1-16alkyl)aminoC.sub.0-16alkyl,
C.sub.1-16alkylcarbonylC.sub.0-16alkyl,
arylC.sub.1-16alkylcarbonylC.sub.0-16alkyl,
C.sub.1-16alkylcarboxyC.sub.0-16alkyl,
arylC.sub.1-16alkylcarboxyC.sub.0-16alkyl,
C.sub.1-16alkylcarbonylaminoC.sub.0-16alkyl,
arylC.sub.1-16alkylcarbonylaminoC.sub.0-16alkyl,
--C.sub.0-16alkylCOOR.sub.4, --C.sub.0-16alkylCONR.sub.5R.sub.6
wherein R.sup.4, R.sup.5 and R.sup.6 are independently selected
from hydrogen, C.sub.1-C.sub.11alkyl, arylC.sub.0-C.sub.11alkyl, or
R.sup.5 and R.sup.6 are taken together with the nitrogen to which
they are attached forming a cyclic system containing 3 to 8 carbon
atoms with or without one C.sub.1-16alkyl,
arylC.sub.0-C.sub.16alkyl, or C.sub.0--Cl.sub.16alkylaryl
substituent. Aryl includes but is not limited to pyrazolyl and
triazolyl.
[0061] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the terms
"arylalkyl," "aralkyl" and the like are meant to include those
radicals in which an aryl group is attached to an alkyl group
(e.g., benzyl, phenethyl, pyridylmethyl, and the like) including
those alkyl groups in which a carbon atom (e.g., a methylene group)
has been replaced by, for example, an oxygen atom (e.g.,
phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the
like), or a sulfur atom. Accordingly, the terms "arylalkyl" and the
like (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl,
pyridylcyclopentyl) represents an aryl group as defined above
attached through an alkyl group as defined above having the
indicated number of carbon atoms.
[0062] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl," and "heteroaryl") includes both substituted and
unsubstituted forms of the indicated radical. Preferred
substituents for each type of radical are provided herein.
[0063] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one
or more of a variety of groups selected from, but not limited to,
--OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R'').dbd.NR''', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN, and
--NO.sub.2 in a number ranging from zero to (2m'+1), where m' is
the total number of carbon atoms in such radical. R', R'', and R'''
each preferably independently refer to hydrogen, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl (e.g., aryl substituted with 1-3 halogens),
substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups,
or arylalkyl groups. When a compound disclosed herein includes more
than one R group, for example, each of the R groups is
independently selected as are each R', R'', and R''' group when
more than one of these groups is present. When R' and R'' are
attached to the same nitrogen atom, they can be combined with the
nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For
example, --NR'R'' includes, but is not limited to, 1-pyrrolidinyl
and 4-morpholinyl. From the above discussion of substituents, one
of skill in the art will understand that the term "alkyl" is meant
to include groups including carbon atoms bound to groups other than
hydrogen groups, such as haloalkyl (e.g., --CF.sub.3 and
--CH.sub.2CF.sub.3) and acyl (e.g., --C(O)CH.sub.3, --C(O)CF.sub.3,
--C(O)CH.sub.2OCH.sub.3, and the like).
[0064] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are varied and are
selected from, for example: --OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R'') .dbd.NR''', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN,
--NO.sub.2, --R', --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'', and R''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. When a compound
disclosed herein includes more than one R group, for example, each
of the R groups is independently selected as are each R', R'', and
R''' groups when more than one of these groups is present.
[0065] Two or more substituents can optionally be joined to form
aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such
so-called ring-forming substituents are typically, though not
necessarily, found attached to a cyclic base structure. In one
embodiment, the ring-forming substituents are attached to adjacent
members of the base structure. For example, two ring-forming
substituents attached to adjacent members of a cyclic base
structure create a fused ring structure. In another embodiment, the
ring-forming substituents are attached to a single member of the
base structure. For example, two ring-forming substituents attached
to a single member of a cyclic base structure create a spirocyclic
structure. In yet another embodiment, the ring-forming substituents
are attached to non-adjacent members of the base structure.
[0066] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring can optionally form a ring of the formula
-T-C(O)--(CRR').sub.q--U--, wherein T and U are independently
--NR--, --O--, --CRR'--, or a single bond, and q is an integer of
from 0 to 3. Alternatively, two of the substituents on adjacent
atoms of the aryl or heteroaryl ring can optionally be replaced
with a substituent of the formula -A-(CH.sub.2).sub.r--B--, wherein
A and B are independently --CRR'--, --O--, --NR--, --S--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2NR'--, or a single bond, and r is an
integer of from 1 to 4. One of the single bonds of the new ring so
formed can optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring can optionally be replaced with a
substituent of the formula --(CRR').sub.s--X'-- (C''R''').sub.d--,
where s and d are independently integers of from 0 to 3, and X' is
--O--, --NR'--, --S--, --S(O)--, --S(O).sub.2--, or
--S(O).sub.2NR'--. The substituents R, R', R'', and R''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0067] As used herein, the terms "heteroatom" or "ring heteroatom"
are meant to include oxygen (O), nitrogen (N), sulfur (S),
phosphorus (P), and silicon (Si).
[0068] The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy,
allyloxy, cyclohexyloxy) represents an alkyl group as defined above
having the indicated number of carbon atoms attached through an
oxygen bridge (--O--).
[0069] The term "alkylthio" (e.g. methylthio, ethylthio,
propylthio, cyclohexylthio and the like) represents an alkyl group
as defined above having the indicated number of carbon atoms
attached through a sulfur bridge (--S--).
[0070] The term "alkylamino" represents one or two alkyl groups as
defined above having the indicated number of carbon atoms attached
through an amine bridge. The two alkyl groups can be taken together
with the nitrogen to which they are attached forming a cyclic
system containing 3 to 8 carbon atoms with or without one
C.sub.1-C.sub.16alkyl, arylC.sub.0-C.sub.16alkyl, or
C.sub.0-C.sub.16alkylaryl substituent.
[0071] The term "alkylaminoalkyl" represents an alkylamino group
attached through an alkyl group as defined above having the
indicated number of carbon atoms.
[0072] The term "alkyloxy(alkyl)amino" (e.g. methoxy(methyl)amine,
ethoxy(propyl)amine) represents an alkyloxy group as defined above
attached through an amino group, the amino group itself having an
alkyl substituent.
[0073] The term "alkylcarbonyl" (e.g. cyclooctylcarbonyl,
pentylcarbonyl, 3-hexylcarbonyl) represents an alkyl group as
defined above having the indicated number of carbon atoms attached
through a carbonyl group.
[0074] The term "alkylcarboxy" (e.g. heptylcarboxy,
cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl
group as defined above wherein the carbonyl is in turn attached
through an oxygen.
[0075] The term "alkylcarboxyalkyl" represents an alkylcarboxy
group attached through an alkyl group as defined above having the
indicated number of carbon atoms.
[0076] The term "alkylcarbonylamino" (e.g. hexylcarbonylamino,
cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl)
represents an alkylcarbonyl group as defined above wherein the
carbonyl is in turn attached through the nitrogen atom of an amino
group.
[0077] The nitrogen group can itself be substituted with an alkyl
or aryl group.
[0078] The term "oxo," as used herein, means an oxygen that is
double bonded to a carbon atom.
[0079] The term "alkylsulfonyl," as used herein, means a moiety
having the formula --S(O.sub.2)--R', where R' is an alkyl group as
defined above. R' can have a specified number of carbons (e.g.,
"C.sub.1-C.sub.4 alkylsulfonyl").
[0080] The term "carbonyloxy" represents a carbonyl group attached
through an oxygen bridge.
[0081] In the above definitions, the terms "alkyl" and "alkenyl"
can be used interchangeably in so far as a stable chemical entity
is formed, as would be apparent to those skilled in the art.
[0082] The term "linker" refers to attachment groups interposed
between substituents, e.g., R.sup.1, R.sup.2, R.sup.3 or R.sup.4
described herein, e.g., Formula (Ia) and generically referred to as
R.sup.n, and the group which is substituted, e.g., "ring A" group
of e.g., Formula (Ia). In some embodiments, the linker includes
amido (--CONH--R.sup.n or --NHCO--R.sup.n), thioamido
(--CSNH--R.sup.n or --NHCS--R.sup.n), carboxyl (--CO.sub.2--R.sup.n
or --OCOR.sup.n), carbonyl (--CO--R.sup.n), urea
(--NHCONH--R.sup.n), thiourea (--NHCSNH--R.sup.n), sulfonamido
(--NHSO.sub.2--R.sup.n or --SO.sub.2NH--R.sup.n), ether
(--O--R.sup.n), sulfonyl (--SO.sub.2--R.sup.n), sulfoxyl
(--SO--R.sup.n), carbamoyl (--NHCO.sub.2--R.sup.n or
--OCONH--R.sup.n), or amino (--NHR.sup.n) linking moieties.
[0083] A "substituent group," as used herein, means a group
selected from the following moieties: [0084] (A) --OH, --NH.sub.2,
--SH, --CN, --CF.sub.3, --NO.sub.2, oxo, halogen, --COOH,
unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,
unsubstituted heteroaryl, and [0085] (B) alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted
with at least one substituent selected from: [0086] (i) oxo, --OH,
--NH.sub.2, --SH, --CN, --CF.sub.3, --NO.sub.2, halogen, --COOH,
unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,
unsubstituted heteroaryl, and [0087] (ii) alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted
with at least one substituent selected from: [0088] (a) oxo, --OH,
--NH.sub.2, --SH, --CN, --CF.sub.3, --NO.sub.2, halogen, --COOH,
unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,
unsubstituted heteroaryl, and [0089] (b) alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with
at least one substituent selected from: oxo, --OH, --NH.sub.2,
--SH, --CN, --CF.sub.3, --NO.sub.2, halogen, --COOH, unsubstituted
alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,
unsubstituted heterocycloalkyl, unsubstituted aryl, and
unsubstituted heteroaryl.
[0090] A "size-limited substituent" or "size-limited substituent
group," as used herein, means a group selected from all of the
substituents described above for a "substituent group," wherein
each substituted or unsubstituted alkyl is a substituted or
unsubstituted C.sub.1-C.sub.20 alkyl, each substituted or
unsubstituted heteroalkyl is a substituted or unsubstituted
2-20-membered heteroalkyl, each substituted or unsubstituted
cycloalkyl is a substituted or unsubstituted C.sub.4-C.sub.8
cycloalkyl, and each substituted or unsubstituted heterocycloalkyl
is a substituted or unsubstituted 4-8-membered
heterocycloalkyl.
[0091] A "lower substituent" or "lower substituent group," as used
herein, means a group selected from all of the substituents
described above for a "substituent group," wherein each substituted
or unsubstituted alkyl is a substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, each substituted or unsubstituted
heteroalkyl is a substituted or unsubstituted 2-8-membered
heteroalkyl, each substituted or unsubstituted cycloalkyl is a
substituted or unsubstituted C.sub.5-C.sub.7 cycloalkyl, and each
substituted or unsubstituted heterocycloalkyl is a substituted or
unsubstituted 5-7-membered heterocycloalkyl.
[0092] The term "about" used in the context of a numeric value
indicates a range of +/-10% of the numeric value, unless expressly
indicated otherwise.
II. Compounds
[0093] In one aspect, there is provided a compound with structure
of Formula (Ia):
##STR00002##
or pharmaceutically acceptable salt, ester, solvate, or prodrug
thereof. Ring A is substituted or unsubstituted pyrazolyl. L.sup.1,
L.sup.2 and L.sup.4 are independently a bond, substituted or
unsubstituted alkylene, substituted or unsubstituted
heteroalkylene, --S--, --SO--, --SO.sub.2--, --O--, --NHSO.sub.2--,
or --NR.sup.5--. L.sup.3 is a bond, substituted or unsubstituted
alkylene, or substituted or unsubstituted heteroalkylene. R.sup.1,
R.sup.2, and R.sup.4 are independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted fused ring aryl.
R.sup.3 is substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkyl, or
substituted or unsubstituted heterocycloalkenyl. R.sup.5 is
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted alkylene,
substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted fused ring aryl,
or substituted or unsubstituted heteroaryl.
[0094] In some embodiments, the compound is a pharmaceutically
acceptable salt, ester, solvate, or prodrug of a compound of
Formula (Ia). In some embodiments, the compound is not an ester,
not a solvate, and not a prodrug.
[0095] In some embodiments, L.sup.4 and R.sup.4 are absent,
providing a compound with structure of Formula (Ib) following.
##STR00003##
[0096] In some embodiments, there is provided a compound according
to Formula (Ib) with structure of Formula (II) following.
##STR00004##
[0097] In some embodiments, the compound has the structure of
Formula (II), wherein L.sup.3 is a bond or substituted or
unsubstituted alkylene, and R.sup.3 is substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, or substituted or unsubstituted
heterocycloalkyl. In some embodiments, R.sup.3 is substituted or
unsubstituted heteroalkyl. In some embodiments, R.sup.3 is
substituted or unsubstituted cycloalkyl. In some embodiments,
R.sup.3 is substituted or unsubstituted cyclohexyl, substituted or
unsubstituted cyclopentyl, substituted or unsubstituted
cycloheptyl. In some embodiments, R.sup.3 is substituted or
unsubstituted cycloalkenyl. In some embodiments, R.sup.3 is
substituted or unsubstituted cyclohexenyl. In some embodiments,
R.sup.3 is substituted or unsubstituted heterocycloalkyl. In some
embodiments, R.sup.3 is substituted or unsubstituted piperidinyl.
In some embodiments, R.sup.3 is substituted or unsubstituted
pyrrolidinyl. In some embodiments, R.sup.3 is substituted or
unsubstituted pyrrolidinyl. In some embodiments, R.sup.3 is
substituted or unsubstituted azetidinyl. In some embodiments,
R.sup.3 is substituted or unsubstituted oxetanyl. In some
embodiments, R.sup.3 is substituted or unsubstituted oxolanyl. In
some embodiments, R.sup.3 is substituted or unsubstituted
oxanyl.
[0098] Further to any embodiment above wherein the compound has the
structure of Formula (II), in some embodiments L.sup.1 is --S--,
--O--, --NR.sup.5--, substituted or unsubstituted alkylene, or
substituted or unsubstituted heteroalkylene, where R.sup.5 is as
described in formula Ia, and R.sup.1 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted
or unsubstituted fused ring aryl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted heterocycloalkyl. In
some embodiments, R.sup.1 is substituted or unsubstituted phenyl.
In some embodiments is an R.sup.1 is unsubstituted phenyl. In some
embodiments, R.sup.1 is a substituted or unsubstituted pyridyl. In
some embodiments, R.sup.1 is a substituted or unsubstituted
pyridazinyl. In some embodiments, R.sup.1 is a substituted or
unsubstituted pyrimidinyl. In some embodiments, R.sup.1 is a
substituted or unsubstituted thienyl. In some embodiments, R.sup.1
is a substituted or unsubstituted furyl. In some embodiments,
R.sup.1 is an unsubstituted pyridyl. In some embodiments, R.sup.1
is an unsubstituted pyridazinyl. In some embodiments, R.sup.1 is an
unsubstituted pyrimidinyl. In some embodiments, R.sup.1 is an
unsubstituted thienyl. In some embodiments, R.sup.1 is a
chloro-substituted thienyl. In some embodiments, R.sup.1 is an
unsubstituted furyl. In some embodiments, R.sup.1 is a substituted
or unsubstituted morpholinyl. In some embodiments, R.sup.1 is a
substituted or unsubstituted oxanyl. In some embodiments, R.sup.1
is a substituted or unsubstituted oxetanyl. In some embodiments,
R.sup.1 is an unsubstituted morpholinyl. In some embodiments,
R.sup.1 is an unsubstituted oxanyl. In some embodiments, R.sup.1 is
an unsubstituted oxetanyl. In some embodiments, R.sup.1 is
substituted or unsubstituted benzodioxinyl. In some embodiments,
R.sup.1 is substituted or unsubstituted naphthyl. In some
embodiments, R.sup.1 is unsubstituted benzodioxinyl. In some
embodiments, R.sup.1 is unsubstituted naphthyl. In some
embodiments, L.sup.2 and R.sup.2 are absent. In some embodiments,
L.sup.2 is a bond. In some embodiments, L.sup.2 is a bond and
R.sup.2 is hydrogen.
[0099] Further to any embodiment above wherein the compound has the
structure of Formula (II), R.sup.2 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, or substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted fused ring aryl, or substituted or unsubstituted
heteroaryl. In some embodiments, R.sup.2 is substituted or
unsubstituted phenyl. In some embodiments is an R.sup.2 is
unsubstituted phenyl. In some embodiments, R.sup.2 is a substituted
or unsubstituted pyridyl. In some embodiments, R.sup.2 is a
substituted or unsubstituted pyridazinyl. In some embodiments,
R.sup.2 is a substituted or unsubstituted pyrimidinyl. In some
embodiments, R.sup.2 is a substituted or unsubstituted thienyl. In
some embodiments, R.sup.2 is a substituted or unsubstituted furyl.
In some embodiments, R.sup.2 is an unsubstituted pyridyl. In some
embodiments, R.sup.2 is an unsubstituted pyridazinyl. In some
embodiments, R.sup.2 is an unsubstituted pyrimidinyl. In some
embodiments, R.sup.2 is an unsubstituted thienyl. In some
embodiments, R.sup.2 is a chloro-substituted thienyl. In some
embodiments, R.sup.2 is an unsubstituted furyl. In some
embodiments, R.sup.2 is a substituted or unsubstituted morpholinyl.
In some embodiments, R.sup.2 is a substituted or unsubstituted
oxanyl. In some embodiments, R.sup.2 is a substituted or
unsubstituted oxetanyl. In some embodiments, R.sup.2 is an
unsubstituted morpholinyl. In some embodiments, R.sup.2 is an
unsubstituted oxanyl. In some embodiments, R.sup.2 is an
unsubstituted oxetanyl. In some embodiments, R.sup.2 is substituted
or unsubstituted benzodioxinyl. In some embodiments, R.sup.2 is
substituted or unsubstituted naphthyl. In some embodiments, R.sup.2
is unsubstituted benzodioxinyl. In some embodiments, R.sup.2 is
unsubstituted naphthyl.
[0100] In some embodiments, there is provided a compound according
to Formula (Ia) with structure of Formula (III) following.
##STR00005##
[0101] In some embodiments, there is provided a compound according
to Formula (III) wherein L.sup.4 is a bond; and R.sup.4 is
hydrogen, halogen, substituted or unsubstituted alkyl, or
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl. In
some embodiments, R.sup.4 is halogen. In some embodiments, R.sup.4
is unsubstituted alkyl. Further to any embodiment wherein the
compound has the structure of Formula (III), in some embodiments
L.sup.3 is a bond or substituted or unsubstituted alkylene, and
R.sup.3 is substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, or substituted or unsubstituted heterocycloalkyl. In
some embodiments, R.sup.3 is substituted or unsubstituted
heteroalkyl. In some embodiments, R.sup.3 is substituted or
unsubstituted cycloalkyl. In some embodiments, R.sup.3 is
substituted or unsubstituted cyclohexyl, substituted or
unsubstituted cyclopentyl, substituted or unsubstituted
cycloheptyl. In some embodiments, R.sup.3 is substituted or
unsubstituted cycloalkenyl. In some embodiments, R.sup.3 is
substituted or unsubstituted cyclohexenyl. In some embodiments,
R.sup.3 is substituted or unsubstituted heterocycloalkyl. In some
embodiments, R.sup.3 is substituted or unsubstituted piperidinyl.
In some embodiments, R.sup.3 is substituted or unsubstituted
pyrrolidinyl. In some embodiments, R.sup.3 is substituted or
unsubstituted pyrrolidinyl. In some embodiments, R.sup.3 is
substituted or unsubstituted azetidinyl. In some embodiments,
R.sup.3 is substituted or unsubstituted oxetanyl. In some
embodiments, R.sup.3 is substituted or unsubstituted oxolanyl. In
some embodiments, R.sup.3 is substituted or unsubstituted
oxanyl.
[0102] Further to any embodiment above wherein the compound has the
structure of Formula (III), in some embodiments L.sup.1 is --S--,
--O--, --NR.sup.5--, substituted or unsubstituted alkylene, or
substituted or unsubstituted heteroalkylene, where R.sup.5 is as
described in formula Ia, and R.sup.1 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted
or unsubstituted fused ring aryl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted heterocycloalkyl. In
some embodiments, R.sup.1 is substituted or unsubstituted phenyl.
In some embodiments is an R.sup.1 is unsubstituted phenyl. In some
embodiments, R.sup.1 is a substituted or unsubstituted pyridyl. In
some embodiments, R.sup.1 is a substituted or unsubstituted
pyridazinyl. In some embodiments, R.sup.1 is a substituted or
unsubstituted pyrimidinyl. In some embodiments, R.sup.1 is a
substituted or unsubstituted thienyl. In some embodiments, R.sup.1
is a substituted or unsubstituted furyl. In some embodiments,
R.sup.1 is an unsubstituted pyridyl. In some embodiments, R.sup.1
is an unsubstituted pyridazinyl. In some embodiments, R.sup.1 is an
unsubstituted pyrimidinyl. In some embodiments, R.sup.1 is an
unsubstituted thienyl. In some embodiments, R.sup.1 is a
chloro-substituted thienyl. In some embodiments, R.sup.1 is an
unsubstituted furyl. In some embodiments, R.sup.1 is a substituted
or unsubstituted morpholinyl. In some embodiments, R.sup.1 is a
substituted or unsubstituted oxanyl. In some embodiments, R.sup.1
is a substituted or unsubstituted oxetanyl. In some embodiments,
R.sup.1 is an unsubstituted morpholinyl. In some embodiments,
R.sup.1 is an unsubstituted oxanyl. In some embodiments, R.sup.1 is
an unsubstituted oxetanyl. In some embodiments, R.sup.1 is
substituted or unsubstituted benzodioxinyl. In some embodiments,
R.sup.1 is substituted or unsubstituted naphthyl. In some
embodiments, R.sup.1 is unsubstituted benzodioxinyl. In some
embodiments, R.sup.1 is unsubstituted naphthyl. In some
embodiments, L.sup.2 and R.sup.2 are absent. In some embodiments,
L.sup.2 is a bond. In some embodiments, L.sup.2 is a bond and
R.sup.2 is hydrogen.
[0103] Further to any embodiment above wherein the compound has the
structure of Formula (III), R.sup.2 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted fused ring aryl, or substituted or unsubstituted
heteroaryl. In some embodiments, R.sup.2 is substituted or
unsubstituted phenyl. In some embodiments is an R.sup.2 is
unsubstituted phenyl. In some embodiments, R.sup.2 is a substituted
or unsubstituted pyridyl. In some embodiments, R.sup.2 is a
substituted or unsubstituted pyridazinyl. In some embodiments,
R.sup.2 is a substituted or unsubstituted pyrimidinyl. In some
embodiments, R.sup.2 is a substituted or unsubstituted thienyl. In
some embodiments, R.sup.2 is a substituted or unsubstituted furyl.
In some embodiments, R.sup.2 is an unsubstituted pyridyl. In some
embodiments, R.sup.2 is an unsubstituted pyridazinyl. In some
embodiments, R.sup.2 is an unsubstituted pyrimidinyl. In some
embodiments, R.sup.2 is an unsubstituted thienyl. In some
embodiments, R.sup.2 is a chloro-substituted thienyl. In some
embodiments, R.sup.2 is an unsubstituted furyl. In some
embodiments, R.sup.2 is a substituted or unsubstituted morpholinyl.
In some embodiments, R.sup.2 is a substituted or unsubstituted
oxanyl. In some embodiments, R.sup.2 is a substituted or
unsubstituted oxetanyl. In some embodiments, R.sup.2 is an
unsubstituted morpholinyl. In some embodiments, R.sup.2 is an
unsubstituted oxanyl. In some embodiments, R.sup.2 is an
unsubstituted oxetanyl. In some embodiments, R.sup.2 is substituted
or unsubstituted benzodioxinyl. In some embodiments, R.sup.2 is
substituted or unsubstituted naphthyl. In some embodiments, R.sup.2
is unsubstituted benzodioxinyl. In some embodiments, R.sup.2 is
unsubstituted naphthyl.
[0104] In some embodiments, there is provided a compound according
to Formula (III) wherein L.sup.3 is a bond, R.sup.3 is substituted
or unsubstituted heterocycloalkyl, or substituted or unsubstituted
heterocycloalkenyl, with structure of Formula (IV) following.
##STR00006##
wherein: L.sup.1, L.sup.2, and L.sup.4 are independently a bond,
substituted or unsubstituted alkylene, substituted or unsubstituted
heteroalkylene, --C(O)--, --S--, --SO--, --SO.sub.2--, --O--,
--NHSO.sub.2--, --NHC(O)--, or --NR.sup.5--; R.sup.1, R.sup.2, and
R.sup.4 are independently hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted heteroalkenyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocycloalkenyl, substituted or unsubstituted aryl, substituted
or unsubstituted fused ring aryl, or substituted or unsubstituted
heteroaryl; R.sup.5 is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
fused ring aryl, or substituted or unsubstituted heteroaryl; V is
hydrogen or substituted or unsubstituted alkyl; W is absent,
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
heteroalkenyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted heterocycloalkenyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7, --SR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, --SO.sub.2NR.sup.6R.sup.7,
--OR.sup.6, --NHSO.sub.2R.sup.6, or --NR.sup.6R.sup.7, where
R.sup.6 and R.sup.7 are independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted heteroalkenyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocycloalkenyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, wherein R.sup.6 and
R.sup.7 can be combined if both are present to form a substituted
or unsubstituted alkylene, or substituted or unsubstituted
heteroalkylene; X is a bond, substituted or unsubstituted alkylene,
--O--, or --NR.sup.5--; Y is a bond, substituted or unsubstituted
alkylene, --O--, or --N--, provided that when Y is --O--, W is
absent; and Z is a bond, --C(O)--, substituted or unsubstituted
alkylene, --O--, or --NR.sup.9--; wherein R.sup.8 and R.sup.9 are
independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted heteroalkenyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --C(O)R.sup.6, --C(O)OR.sup.6, C(O)NR.sup.6R.sup.7,
--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2NR.sup.6R.sup.7, --OR.sup.6, --NHSO.sub.2R.sup.6, or
--NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 are as defined
above; and provided that either at least one of X is --O-- or
--NR.sup.8-, Y is --O-- or --N--, or Z is --O-- or --NR.sup.9--. In
some embodiments, the compound is a pharmaceutically acceptable
salt, ester, solvate, or prodrug of a compound of Formula (IV). In
some embodiments, the compound is not an ester, not a solvate, and
not a prodrug.
[0105] In some embodiments, X is a bond or substituted or
unsubstituted alkylene. In some embodiments, Z is a bond or
substituted or unsubstituted alkylene. In some embodiments, X is a
bond or substituted or unsubstituted alkylene, and Z is a bond or
substituted or unsubstituted alkylene.
[0106] In some embodiments, wherein X is a bond or substituted or
unsubstituted alkylene and Z is a bond or substituted or
unsubstituted alkylene, Y is --N--, and W is hydrogen, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.6R.sup.7'--SO.sub.2R.sup.6, or
SO.sub.2NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 are
independently substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, or substituted or unsubstituted
heterocycloalkyl, or R.sup.6 and R.sup.7 can be combined if both
are present to form a substituted or unsubstituted alkylene, or
substituted or unsubstituted heteroalkylene.
[0107] In some embodiments, X is selected from the group consisting
of substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and Z is a bond. In some embodiments, X is
a bond, and Z is selected from the group consisting of substituted
or unsubstituted methylene, substituted or unsubstituted ethylene,
substituted or unsubstituted propylene, substituted or
unsubstituted butylene, and substituted or unsubstituted pentylene.
In some embodiments, X is selected from the group consisting of
substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and wherein Z is selected from the group
consisting of substituted or unsubstituted methylene, substituted
or unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene. In some embodiments, X and Z are both
branched alkylene and X and Z are covalently attached. In some
embodiments, Z is can be substituted methylene, substituted
ethylene, substituted propylene, substituted butylene, or
substituted pentylene, having one or more substituent groups
selected from the group consisting of --OH, --NH.sub.2, --SH, --CN,
--CF.sub.3, --NO.sub.2, oxo, halogen, --COOH, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
or substituted or unsubstituted heteroaryl.
[0108] In some embodiments, X is selected from the group consisting
of substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene, and wherein Z is --C(O)--. In some
embodiments, W is hydrogen. In some embodiments, W is selected from
the group consisting of substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.6R.sup.7--SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
and --SO.sub.2NR.sup.6. In some embodiments, W is substituted
alkyl, substituted heteroalkyl, substituted alkenyl, substituted
heteroalkenyl, substituted cycloalkyl, or substituted
heterocycloalkyl, having one or more substituent groups selected
from the group consisting of --OH, --NH.sub.2, --SH, --CN,
--CF.sub.3, --NO.sub.2, oxo, halogen, --COOH, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
or substituted or unsubstituted heteroaryl. In some embodiments, W
is --COR.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.6R.sup.7,
--SO.sub.2R.sup.6 or --SO.sub.2NR.sup.6R.sup.7, and wherein R.sup.6
and R.sup.7 are selected from the group consisting of substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl, or R.sup.6 and R.sup.7 combine to form a substituted or
unsubstituted alkylene.
[0109] In some embodiments, W is absent, X is --NR.sup.8--, Y is a
bond or substituted or unsubstituted alkylene, and Z is
--NR.sup.9--. In some embodiments wherein W is absent, X is
--NR.sup.8--, Y is a bond or substituted or unsubstituted alkylene,
and Z is --NR.sup.9--, Y is selected from the group consisting of
substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene. In some embodiments, R.sup.8 is selected
from the group consisting of substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl,
--COR.sup.6, --C(O)OR.sup.6, C(O)NR.sup.6R.sup.7, --SR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, and --SO.sub.2NR.sup.6R.sup.7, and
wherein R.sup.9 is selected from the group consisting of
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted heteroalkenyl, --COR.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.6R.sup.7, --SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
and --SO.sub.2NR.sup.6R.sup.7.
[0110] In some embodiments, Y is --O--, and W is absent. In some
embodiments wherein Y is --O--, and W is absent, X is selected from
the group consisting of substituted or unsubstituted methylene,
substituted or unsubstituted ethylene, substituted or unsubstituted
propylene, substituted or unsubstituted butylene, and substituted
or unsubstituted pentylene, and Z is a bond. In some embodiments, X
is a bond, and Z is selected from the group consisting of
substituted or unsubstituted methylene, substituted or
unsubstituted ethylene, substituted or unsubstituted propylene,
substituted or unsubstituted butylene, and substituted or
unsubstituted pentylene. In some embodiments, X is selected from
the group consisting of substituted or unsubstituted methylene,
substituted or unsubstituted ethylene, substituted or unsubstituted
propylene, substituted or unsubstituted butylene, and substituted
or unsubstituted pentylene, and wherein Z is selected from the
group consisting of substituted or unsubstituted methylene,
substituted or unsubstituted ethylene, substituted or unsubstituted
propylene, substituted or unsubstituted butylene, and substituted
or unsubstituted pentylene.
[0111] In some embodiments, V is hydrogen or substituted or
unsubstituted methyl.
[0112] Further to any embodiment above wherein the compound has the
structure of Formula (IV), in some embodiments, L.sup.1 is --S--,
--O--, --NR.sup.5--, substituted or unsubstituted alkylene, or
substituted or unsubstituted heteroalkylene; R.sup.1 is substituted
or unsubstituted alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted fused ring aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heterocycloalkyl; and R.sup.5 is hydrogen, substituted or
unsubstituted alkyl, or substituted or unsubstituted
heterocycloalkyl. In some embodiments, L.sup.1 is --NR.sup.5-- or
substituted or unsubstituted heteroalkyl, and R.sup.1 is
substituted or unsubstituted alkyl or substituted or unsubstituted
heteroaryl. In some embodiments, L.sup.1 is --NR.sup.5--, and
R.sup.1 is substituted alkyl having one or more substituent groups
selected from the group consisting of substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl. In
some embodiments, R.sup.1 is substituted alkyl substituted by
chloro-substituted thiophenyl. In some embodiments, L.sup.1 is
substituted or unsubstituted heteroalkyl, and R.sup.1 is
substituted or unsubstituted heteroaryl. In some embodiments,
L.sup.1 and R.sup.1 can be any specific group as set forth above
for any of Formulae (Ia), (Ib), (II), or (III).
[0113] Further to any embodiment above wherein the compound has the
structure of Formula (IV), in some embodiments, L.sup.2 is bond,
substituted or unsubstituted alkylene, --C(O)--, or --SO.sub.2--,
and R.sup.2 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted fused ring aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heterocycloalkyl. In some embodiments, L.sup.2 is bond, and R.sup.2
is hydrogen. In some embodiments, L.sup.2 is-C(O)--, and R.sup.2 is
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, substituted or unsubstituted fused ring
aryl, substituted or unsubstituted heteroaryl, or substituted or
unsubstituted heterocycloalkyl. In some embodiments, L.sup.2 and
R.sup.2 can be any specific group as set forth above for any of
Formulae (Ia), (Ib), (II), or (III).
[0114] Further to any embodiment above wherein the compound has the
structure of Formula (IV), in some embodiments, L.sup.4 is a bond,
and R.sup.4 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl. In
some embodiments, L.sup.4 and R.sup.4 can be any specific group as
set forth above for any of Formulae (Ia), (Ib), (II), or (III).
[0115] In some embodiments, there is provided a compound according
to Formula (IV) and its listed embodiments, wherein L.sup.2 is a
bond, and R.sup.2 is hydrogen, providing a compound with structure
of Formula (V) following.
##STR00007##
In some embodiments, the compound is a pharmaceutically acceptable
salt, ester, solvate, or prodrug of a compound of Formula (V). In
some embodiments, the compound is not an ester, not a solvate, and
not a prodrug.
[0116] Exemplary compounds, e.g., multisubstituted aromatic
compounds, in accordance with the present disclosure are provided
herein. In Table A and B following, entry number, chemical name
(i.e., International Union of Pure and Applied Chemistry [IUPAC]
name), calculated molecular weight (MW) and biological activity
(i.e., inhibition activity in thrombin and KLKB1 assays) are
disclosed. In Table C following, chemical names are disclosed.
[0117] For Table A following, the disclosed compounds were assayed
for inhibition of the protease activity of thrombin as described
herein. In Table A, the level of inhibition in the thrombin assay
is indicated as follows: a IC.sub.50.ltoreq.0.1 .mu.M; b: 0.1
.mu.M<IC.sub.50<1 .mu.M; c: 1 .mu.M<IC.sub.50<10 .mu.M;
d: 10 .mu.M<IC.sub.50<100 .mu.M; e: IC.sub.50.gtoreq.100
.mu.M. Accordingly, in some embodiments, there is provided a
compound as expressly set forth in Table A following.
TABLE-US-00001 TABLE A Throm- bin En- Activ- try IUPAC name MW ity
1 1,4-bis(prop-2-en-1-yl) 2-(5-[(5-chlorothiophen-2- 550 e
yl)methyl]amino-1-(2,2- dimethylpropanoyl)-1H-pyrazol-
3-yl)piperazine-1,4-dicarboxylate 2 1,4-bis(prop-2-en-1-yl)
2-(5-[(5-chlorothiophen-2- 466 e
yl)methyl]amino-1H-pyrazol-3-yl)piperazine-1,4- dicarboxylate 3
1-(3-8-azabicyclo[3.2.1]octan-3- 407 a yl-5-[(5-chlorothiophen-
2-yl)methyl]amino-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one 4
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1- 473 b
methanesulfonylazepan-4-yl)-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 5
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1- 431 b
methanesulfonylazetidin-3-yl)-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one 6
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1- 459 b
methanesulfonylpiperidin-4-yl)-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one 7
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1- 475 b
methanesulfonylpiperidin-4-yl)-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one 8
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1- 445 a
methanesulfonylpyrrolidin-2-yl)-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one 9
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1- 445 a
methanesulfonylpyrrolidin-3-yl)-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one 10
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1-[6- 540 b
(trifluoromethyl)pyridin-2-yl]methylpiperidin-4-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 11
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(2- 397 b
methylpyrrolidin-2-yl)-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one; formic acid 12
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(3- 411 c
methylpiperidin-3-yl)-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one; formic acid 13
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(3- 425 c
methylpiperidin-3-yl)-1H-pyrazol-1-yl)-3-
methoxy-2,2-dimethylpropan-1-one 14
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(4- 460 a
methanesulfonylpiperazin-2-yl)-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 15
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(4- 395 b
methylpiperidin-4-yl)-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one;
formic acid 16 1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(4- 411
c methylpiperidin-4-yl)-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one 17
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(4- 425 e
methylpiperidin-4-yl)-1H-pyrazol-1-yl)-3-
methoxy-2,2-dimethylpropan-1-one 18 1-(5-[(5-chlorothiophen-2- 382
b yl)methyl]amino-3-(oxan-4-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 19
1-(5-[(5-chlorothiophen-2- 368 a yl)methyl]amino-3-(oxolan-2-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 20
1-(5-[(5-chlorothiophen-2- 382 b yl)methyl]amino-3-(piperazin-
2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 21
1-(5-[(5-chlorothiophen-2- 381 a yl)methyl]amino-3-(piperidin-
3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one; formic acid 22
1-(5-[(5-chlorothiophen-2- 397 b yl)methyl]amino-3-(piperidin-
3-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2- dimethylpropan-1-one; formic
acid 23 1-(5-[(5-chlorothiophen-2- 411 b
yl)methyl]amino-3-(piperidin- 3-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2-
dimethylpropan-1-one 24 1-(5-[(5-chlorothiophen-2- 381 b
yl)methyl]amino-3-(piperidin-
4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 25
1-(5-[(5-chlorothiophen-2- 397 b yl)methyl]amino-3-(piperidin-
4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2- dimethylpropan-1-one 26
1-(5-[(5-chlorothiophen-2- 411 c yl)methyl]amino-3-(piperidin-
4-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2- dimethylpropan-1-one 27
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 367 a
(pyrrolidin-2-yl)-1H-pyrazol-1-yl)- 2,2-dimethylpropan-1-one 28
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 383 a
(pyrrolidin-2-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-
dimethylpropan-1-one 29
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 397 a
(pyrrolidin-2-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2-
dimethylpropan-1-one 30
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 367 a
(pyrrolidin-3-yl)-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one 31
1-(5-[(5-chlorothiophen-2- 463 a yl)methyl]amino-3-[1-(1,2,4-
oxadiazol-3-ylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 32
1-(5-[(5-chlorothiophen-2- 462 a yl)methyl]amino-3-[1-(1,3-
oxazol-4-ylmethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 33 1-(5-[(5-chlorothiophen-2- 462 b
yl)methyl]amino-3-[1-(1,3- oxazol-5-ylmethyl)piperidin-4-
yl]-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one 34
1-(5-[(5-chlorothiophen-2- 463 c yl)methyl]amino-3-[1-(1H-
1,2,3,4-tetrazol-5-ylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 35
1-(5-[(5-chlorothiophen-2- 462 b
yl)methyl]amino-3-[1-(1H-1,2,3-triazol-
5-ylmethyl)piperidin-4-yl]-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one 36 1-(5-[(5-chlorothiophen-2- 461 b
yl)methyl]amino-3-[1-(1H-imidazol-4-
ylmethyl)piperidin-4-yl]-1H-pyrazol-1-yl)- 2,2-dimethylpropan-1-one
37 1-(5-[(5-chlorothiophen-2- 463 c yl)methyl]amino-3-[1-(2,2,2-
trifluoroethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 38 1-(5-[(5-chlorothiophen-2- 479 a
yl)methyl]amino-3-[1-(2,2,2-
trifluoroethyl)piperidin-4-yl]-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one 39
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 465 a
[1-(2,2-dimethylpropanoyl)piperidin- 4-yl]-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one 40 1-(5-[(5-chlorothiophen-2- 465 a
yl)methyl]amino-3-[1-(2-
cyclopropoxyethyl)piperidin-4-yl]-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one 41 1-(5-[(5-chlorothiophen-2- 481 a
yl)methyl]amino-3-[1-(2-
cyclopropoxyethyl)piperidin-4-yl]-1H-pyrazol-1-
yl)-3-hydroxy-2,2-dimethylpropan-1-one 42
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1-(2- 439 b
methoxyethyl)piperidin-4-yl]-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one 43
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1-(2- 455 b
methoxyethyl)piperidin-4-yl]-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one 44
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 435 b
(cyclopropylmethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 45
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 451 c
(cyclopropylmethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 46
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 508 a
(morpholine-4-carbonyl)azepan-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 47
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 466 b
(morpholine-4-carbonyl)azetidin-3-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 48
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 494 a
(morpholine-4-carbonyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 49
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 510 a
(morpholine-4-carbonyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 50
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 480 b
(morpholine-4-carbonyl)pyrrolidin-2-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 51
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 480 a
(morpholine-4-carbonyl)pyrrolidin-3-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 52
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 530 a
(morpholine-4-sulfonyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 53
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 546 a
(morpholine-4-sulfonyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 54
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 451 b
(oxetan-3-ylmethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 55
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 467 b
(oxetan-3-ylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 56
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 472 a
(pyridin-2-ylmethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 57
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 488 a
(pyridin-2-ylmethyl)piperidin-4-yl]-1H-pyrazol-1-
yl)-3-hydroxy-2,2-dimethylpropan-1-one 58
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 472 a
(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 59
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[4- 495 a
(morpholine-4-carbonyl)piperazin-2-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 60
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[8- 520 a
(morpholine-4-carbonyl)- 8-azabicyclo[3.2.1]octan-3-yl]-
1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 61
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 464 b
1-[(1-methylazetidin-3-yl)methyl]piperidin-4-yl-
1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 62
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-1-[(2- 501 a
methoxyphenyl)methyl]piperidin-4-yl-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 63
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-1-[(3- 501 a
methoxyphenyl)methyl]piperidin-4-yl-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 64
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-1-[(4- 501 c
methoxyphenyl)methyl]piperidin-4-yl-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 65
1-(5-[(5-chlorothiophen-2-yl)methyl]amino- 486 a
3-1-[(6-methylpyridin-2- yl)methyl]piperidin-4-yl-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one; formic acid 66
1-(5-[(5-chlorothiophen-2- 540 a yl)methyl]amino-3-1-[2,2,2-
trifluoro-1-(pyridin-2-yl)ethyl]piperidin-4-yl-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 67
1-(5-[(5-chlorothiophen-2- 556 a yl)methyl]amino-3-1-[2,2,2-
trifluoro-1-(pyridin-2-yl)ethyl]piperidin-4-yl-1H-
pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 68
1-(5-[(5-chlorothiophen-2- 522 a
yl)methyl]amino-3-1-[2,2-difluoro-2-
(pyridin-2-yl)ethyl]piperidin-4-yl-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 69 1-(5-[(5-chlorothiophen-2- 538 a
yl)methyl]amino-3-1-[2,2-difluoro-2-
(pyridin-2-yl)ethyl]piperidin-4-yl-1H-pyrazol-
1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 70
1-(5-[(5-chlorothiophen-2- 508 a
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)-2-oxoethyl]piperidin-4-yl-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 71 1-(5-[(5-chlorothiophen-2- 524 b
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)-2-oxoethyl]piperidin-4-yl-1H-pyrazol-
1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 72
1-(5-[(5-chlorothiophen-2- 508 a
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)acetyl]piperidin-4-yl-1H-pyrazol-1-yl)- 2,2-dimethylpropan-1-one
73 1-(5-[(5-chlorothiophen-2- 551 e
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)acetyl]piperidin-4-yl-1H-pyrazol-1-yl)-
2-(morpholin-4-yl)ethan-1-one 74 1-(5-[(5-chlorothiophen-2- 524 a
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)acetyl]piperidin-4-yl-1H-pyrazol-1-yl)-
3-hydroxy-2,2-dimethylpropan-1-one 75 1-(5-[(5-chlorothiophen-2-
494 a yl)methyl]amino-3-1-[2-(morpholin-4-
yl)acetyl]pyrrolidin-2-yl-1H-pyrazol-1-yl)-
2,2-dimethylpropan-1-one 76 1-(5-[(5-chlorothiophen-2- 494 a
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)acetyl]pyrrolidin-3-yl-1H-pyrazol-1-yl)-
2,2-dimethylpropan-1-one 77 1-(5-[(5-chlorothiophen-2- 494 b
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)ethyl]piperidin-4-yl-1H-pyrazol-1-yl)- 2,2-dimethylpropan-1-one;
formic acid 78 1-(5-[(5-chlorothiophen-2- 510 b
yl)methyl]amino-3-1-[2-(morpholin-4-
yl)ethyl]piperidin-4-yl-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one; formic acid 79
1-(5-[(5-chlorothiophen-2- 486 a yl)methyl]amino-3-1-[2-(pyridin-2-
yl)ethyl]piperidin-4-yl-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one
80 1-(5-[(5-chlorothiophen-2- 502 a
yl)methyl]amino-3-1-[2-(pyridin-2-
yl)ethyl]piperidin-4-yl-1H-pyrazol-1-yl)-3-
hydroxy-2,2-dimethylpropan-1-one 81 1-(5-[(5-chlorothiophen-2- 485
a yl)methyl]amino-3-8-methanesulfonyl-
8-azabicyclo[3.2.1]octan-3-yl-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 82
1-(5-[(5-chlorothiophen-2- 400 a
yl)methyl]amino-4-fluoro-3-(oxan-4-yl)-
1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 83
1-(5-[(5-chlorothiophen-2- 416 a yl)methyl]amino-4-fluoro-3-
(oxan-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2- dimethylpropan-1-one 84
1-(5-[(5-chlorothiophen-2- 430 a yl)methyl]amino-4-fluoro-3-
(oxan-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2- dimethylpropan-1-one 85
1-(5-[(5-chlorothiophen-2- 399 a yl)methyl]amino-4-fluoro-3-
(piperidin-4-yl)-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one 86
1-(5-[(5-chlorothiophen-2- 415 b yl)methyl]amino-4-fluoro-3-
(piperidin-4-yl)-1H-pyrazol-1-yl)-2-methoxy-2- methylpropan-1-one
87 1-(5-[(5-chlorothiophen-2- 415 a yl)methyl]amino-4-fluoro-3-
(piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-
dimethylpropan-1-one 88 1-(5-[(5-chlorothiophen-2- 429 a
yl)methyl]amino-4-fluoro-3-
(piperidin-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2-
dimethylpropan-1-one 89 1-(5-[(5-chlorothiophen-2- 395 c
yl)methyl]amino-4-methyl-3- (piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one; formic acid 90 1-[2-(5-[(5-chlorothiophen-2-
501 b yl)methyl]amino-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl)pyrrolidin-
1-yl]-2,2-dimethylpropan-1-one 91
1-[2-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 487 b
methoxybenzoyl)-1H-pyrazol-3-yl)pyrrolidin-
1-yl]-2-methylpropan-1-one 92
1-[2-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 459 c
methoxybenzoyl)-1H-pyrazol-3-yl)pyrrolidin- 1-yl]ethan-1-one 93
1-[2-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 410 e
pyrazol-3-yl)pyrrolidin-1-yl]-2-(morpholin-4- yl)ethan-1-one 94
1-[3-(1-acetylpiperidin-4-yl)-5- 423 a [(5-chlorothiophen-2-
yl)methyl]amino-1H-pyrazol-1-yl]-2,2- dimethylpropan-1-one 95
1-[3-(1-benzylpiperidin-4-yl)-5- 471 a
[(5-chlorothiophen-2-yl)methyl]amino-
1H-pyrazol-1-yl]-2,2-dimethylpropan- 1-one 96
1-[3-(5-[(5-chlorothiophen-2- 437 b yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)azetidin-
1-yl]-2,2-dimethylpropan-1-one 97 1-[3-(5-[(5-chlorothiophen- 353 e
2-yl)methyl]amino-1H-pyrazol-3-
yl)azetidin-1-yl]-2,2-dimethylpropan-1-one 98
1-[3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 410 e
pyrazol-3-yl)pyrrolidin-1-yl]-2-(morpholin- 4-yl)ethan-1-one 99
1-[4-(5-[(5-chlorothiophen-2- 515 a
yl)methyl]amino-1-(2-methoxybenzoyl)-
1H-pyrazol-3-yl)piperidin-1-yl]-2,2- dimethylpropan-1-one 100
1-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 473 b
methoxybenzoyl)-1H-pyrazol-3-yl)piperidin- 1-yl]ethan-1-one 101
1-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 491 a
(thiophene-3-carbonyl)-1H-pyrazol-3-
yl)piperidin-1-yl]-2,2-dimethylpropan-1-one 102
1-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 449 b
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)piperidin-1- yl]ethan-1-one
103 1-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 424 e
pyrazol-3-yl)piperidin-1-yl]-2-(morpholin- 4-yl)ethan-1-one 104
1-[4-(5-[(5-chlorothiophen-2- 399 d
yl)methyl]amino-4-fluoro-1H-pyrazol-3-
yl)piperidine-1-carbonyl]cyclopropan-1-ol 105
1-benzoyl-N-[(5-chlorothiophen-2-yl)methyl]-3- 401 b
(piperidin-4-yl)-1H-pyrazol-5-amine hydrochloride 106
1-benzoyl-N-[(5-chlorothiophen- 420 a 2-yl)methyl]-4-fluoro-
3-(oxan-4-yl)-1H-pyrazol-5-amine 107
1-3-[1-(benzenesulfonyl)piperidin-4-yl]-5-[(5- 521 b
chlorothiophen-2-yl)methyl]amino- 1H-pyrazol-1-yl-2,2-
dimethylpropan-1-one 108
1-3-[1-(benzenesulfonyl)piperidin-4-yl]-5-[(5- 537 a
chlorothiophen-2-yl)methyl]amino- 1H-pyrazol-1-yl-3-
hydroxy-2,2-dimethylpropan-1-one 109 2-[4-(5-[(5-chlorothiophen-2-
439 b yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)piperidin-1- yl]acetic acid 110
2-[4-(5-[(5-chlorothiophen-2- 455 b yl)methyl]amino-1-(3-
hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-
yl)piperidin-1-yl]acetic acid 111
2-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 424 e
pyrazol-3-yl)piperidin-1-yl]-1-(morpholin- 4-yl)ethan-1-one 112
2-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 355 e
pyrazol-3-yl)piperidin-1-yl]acetic acid 113
3-(1-benzylpiperidin-4-yl)-N-[(5-chlorothiophen-2- 387 e
yl)methyl]-1H-pyrazol-5-amine 114
3-(1-benzylpyrrolidin-3-yl)-N-[(5-chlorothiophen-2- 467 c
yl)methyl]-1-(furan-3-carbonyl)-1H-pyrazol- 5-amine 115
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 409 b
dimethylpropanoyl)-1H-pyrazol-3-yl)-3- methylpiperidin-2-one 116
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 395 a
dimethylpropanoyl)-1H-pyrazol-3-yl)-3- methylpyrrolidin-2-one 117
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 459 b
methoxybenzoyl)-1H-pyrazol-3-yl)-3- methylpiperidin-2-one 118
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 445 b
methoxybenzoyl)-1H-pyrazol-3-yl)-3- methylpyrrolidin-2-one 119
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(3- 425 b
hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-
3-yl)-3-methylpiperidin-2-one 120
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(3- 439 c
methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-
3-yl)-3-methylpiperidin-2-one 121
3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(4- 451 c
methyloxane-4-carbonyl)-1H-pyrazol-3-yl)-3- methylpiperidin-2-one
122 3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(4- 437 b
methyloxane-4-carbonyl)-1H-pyrazol-3-yl)-3- methylpyrrolidin-2-one
123 3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 435 b
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3- methylpiperidin-2-one
124 3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 421 b
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3- methylpyrrolidin-2-one
125 3-(azepan-4-yl)-N-[(5-chlorothiophen-2- 311 e
yl)methyl]-1H-pyrazol-5-amine 126
3-(azetidin-3-yl)-N-[(5-chlorothiophen- 431 c
2-yl)methyl]-1-(2,3-dihydro-1,4-
benzodioxine-5-carbonyl)-1H-pyrazol- 5-amine; trifluoroacetic acid
127 3-(azetidin-3-yl)-N-[(5-chlorothiophen- 403 d 2-yl)methyl]-1-
(2-methoxybenzoyl)-1H-pyrazol- 5-amine hydrochloride 128
3-(azetidin-3-yl)-N-[(5-chlorothiophen- 363 c
2-yl)methyl]-1-(furan-3-carbonyl)- 1H-pyrazol-5-amine;
trifluoroacetic acid 129 3-(azetidin-3-yl)-N-[(5- 379 c
chlorothiophen-2-yl)methyl]-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine; trifluoroacetic acid 130
3-[1-(benzenesulfonyl)piperidin-4-yl]-N-[(5- 437 c
chlorothiophen-2-yl)methyl]-1H-pyrazol-5-amine 131
3-8-azabicyclo[3.2.1]octan- 323 e 3-yl-N-[(5-chlorothiophen-2-
yl)methyl]-1H-pyrazol-5-amine 132
4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 452 a
dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-
dimethylpiperidine-1-carboxamide 133
4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 488 b
dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-
dimethylpiperidine-1-sulfonamide 134
4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(3- 468 a
hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-
yl)-N,N-dimethylpiperidine-1-carboxamide 135
4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(3- 504 a
hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-
yl)-N,N-dimethylpiperidine-1-sulfonamide 136
4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 439 e
(dimethylcarbamoyl)-1H-pyrazol-3-yl)-N,N-
dimethylpiperidine-1-carboxamide 137 4-(5-[(5-chlorothiophen-2- 368
e yl)methyl]amino-1H-pyrazol-
3-yl)-N,N-dimethylpiperidine-1-carboxamide 138
4-(5-[(5-chlorothiophen-2- 404 e yl)methyl]amino-1H-pyrazol-
3-yl)-N,N-dimethylpiperidine-1-sulfonamide 139
4-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 550 a
(morpholine-4-carbonyl)piperidin- 4-yl]-1H-pyrazole-1-
carbonyl)-4-methylcyclohexan-1-ol 140
5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 519 a
dimethylpropanoyl)-3-[1-(morpholine-4-
carbonyl)piperidin-4-yl]-1H-pyrazole-4-carbonitrile 141
5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 435 e
(morpholine-4-carbonyl)piperidin-4-yl]- 1H-pyrazole-4-carbonitrile
142 N-[(5-chlorothiophen-2-yl)methyl]-1-(1,4- 549 b
dimethylpiperidine-4-carbonyl)-3-[1-
(morpholine-4-carbonyl)piperidin-4-yl]-1H- pyrazol-5-amine; formic
acid 143 N-[(5-chlorothiophen-2-yl)methyl]- 459 c
1-(2,3-dihydro-1,4-benzodioxine-5-
carbonyl)-3-(piperidin-4-yl)-1H-pyrazol- 5-amine hydrochloride 144
N-[(5-chlorothiophen-2-yl)methyl]- 445 a
1-(2,3-dihydro-1,4-benzodioxine-5-
carbonyl)-3-(pyrrolidin-2-yl)-1H- pyrazol-5-amine hydrochloride 145
N-[(5-chlorothiophen-2-yl)methyl]- 478 a
1-(2,3-dihydro-1,4-benzodioxine-5-
carbonyl)-4-fluoro-3-(oxan-4-yl)-1H- pyrazol-5-amine 146
N-[(5-chlorothiophen-2-yl)methyl]- 477 a
1-(2,3-dihydro-1,4-benzodioxine-5-
carbonyl)-4-fluoro-3-(piperidin-4-yl)- 1H-pyrazol-5-amine 147
N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4- 461 c
dimethoxybenzoyl)-3-(piperidin-4-yl)- 1H-pyrazol-5-amine 148
N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4- 447 a
dimethoxybenzoyl)-3-(pyrrolidin-2-yl)-1H- pyrazol-5-amine 149
N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4- 480 a
dimethoxybenzoyl)-4-fluoro-3-(oxan-4-yl)- 1H-pyrazol-5-amine 150
N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4- 479 a
dimethoxybenzoyl)-4-fluoro-3-(piperidin-4- yl)-1H-pyrazol-5-amine
151 N-[(5-chlorothiophen-2-yl)methyl]-1-(2,6- 435 c
dimethylcyclohexanecarbonyl)-3-(piperidin- 4-yl)-1H-pyrazol-5-amine
hydrochloride 152 N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 431 b
methoxybenzoyl)-3-(2-methylpyrrolidin-2-yl)-1H- pyrazol-5-amine;
formic acid 153 N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 445 c
methoxybenzoyl)-3-(3-methylpiperidin-3-yl)-1H- pyrazol-5-amine 154
N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 445 c
methoxybenzoyl)-3-(4-methylpiperidin-4-yl)-1H- pyrazol-5-amine 155
N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 432 c
methoxybenzoyl)-3-(oxan-4-yl)-1H- pyrazol-5-amine 156
N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 418 a
methoxybenzoyl)-3-(oxolan-2-yl)-1H- pyrazol-5-amine 157
N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 431 b
methoxybenzoyl)-3-(piperidin-3-yl)-1H- pyrazol-5-amine 158
N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 431 c
methoxybenzoyl)-3-(piperidin-4-yl)-1H- pyrazol-5-aminehydrochloride
159 N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 417 b
methoxybenzoyl)-3-(pyrrolidin-2-yl)-1H- pyrazol-5-amine 160
N-[(5-chlorothiophen-2-yl)methyl]-1-(2- 513 c
methoxybenzoyl)-3-[1-(2,2,2- trifluoroethyl)piperidin-4-
yl]-1H-pyrazol-5-amine 161 N-[(5-chlorothiophen-2-yl)methyl]-1- 423
b (4-methyloxane-4- carbonyl)-3-(2-methylpyrrolidin-2-yl)-
1H-pyrazol-5-amine 162 N-[(5-chlorothiophen-2-yl)methyl]-1-(4- 437
c methyloxane-4-carbonyl)-3-(3-methylpiperidin-
3-yl)-1H-pyrazol-5-amine 163
N-[(5-chlorothiophen-2-yl)methyl]-1-(4- 437 c
methyloxane-4-carbonyl)-3-(4-methylpiperidin-
4-yl)-1H-pyrazol-5-amine 164 N-[(5-chlorothiophen-2-yl)methyl]- 423
b 1-(4-methyloxane-4-
carbonyl)-3-(piperidin-3-yl)-1H-pyrazol-5-amine 165
N-[(5-chlorothiophen-2-yl)methyl]- 409 a 1-(4-methyloxane-4-
carbonyl)-3-(pyrrolidin-2-yl)-1H-pyrazol-5-amine 166
N-[(5-chlorothiophen-2-yl)methyl]- 391 b 1-(furan-3-carbonyl)-
3-(piperidin-4-yl)-1H-pyrazol-5- amine hydrochloride 167
N-[(5-chlorothiophen-2-yl)methyl]- 377 a 1-(furan-3-carbonyl)-
3-(pyrrolidin-2-yl)-1H-pyrazol-5-amine 168
N-[(5-chlorothiophen-2-yl)methyl]-1- 523 c
(morpholine-4-carbonyl)-3-[1-(morpholine-
4-carbonyl)piperidin-4-yl]- 1H-pyrazol-5-amine 169
N-[(5-chlorothiophen-2-yl)methyl]-1- 407 e
cyclohexanecarbonyl-3-(piperidin-4-yl)-1H- pyrazol-5-amine
hydrochloride 170 N-[(5-chlorothiophen-2-yl)methyl]-1- 393 e
cyclopentanecarbonyl-3-(piperidin-4-yl)-1H- pyrazol-5-amine
hydrochloride 171 N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 389 e
methanesulfonylazepan-4-yl)-1H-pyrazol-5-amine 172
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 347 e
methanesulfonylazetidin-3-yl)-1H-pyrazol-5-amine 173
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 375 e
methanesulfonylpiperidin-4-yl)-1H-pyrazol-5-amine 174
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 361 e
methanesulfonylpyrrolidin-2-yl)-1H-pyrazol- 5-amine 175
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 361 e
methanesulfonylpyrrolidin-3-yl)-1H- pyrazol-5-amine 176
N-[(5-chlorothiophen-2-yl)methyl]-3-(1-[6- 456 e
(trifluoromethyppyridin-2-yl]methylpiperidin-
4-yl)-1H-pyrazol-5-amine 177
N-[(5-chlorothiophen-2-yl)methyl]-3-(2- 407 a
methylpyrrolidin-2-yl)-1-(thiophene-3-carbonyl)-
1H-pyrazol-5-amine; formic acid 178
N-[(5-chlorothiophen-2-yl)methyl]- 421 b
3-(3-methylpiperidin-3-yl)-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine 179
N-[(5-chlorothiophen-2-yl)methyl]-3-(4- 376 e
methanesulfonylpiperazin-2-yl)-1H-pyrazol- 5-amine 180
N-[(5-chlorothiophen-2-yl)methyl]- 421 c 3-(4-methylpiperidin-
4-yl)-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 181
N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-1- 408 b
(thiophene-3-carbonyl)-1H-pyrazol-5-amine 182
N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan- 298 e
4-yl)-1H-pyrazol-5-amine 183
N-[(5-chlorothiophen-2-yl)methyl]-3-(oxolan-2- 394 a
yl)-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 184
N-[(5-chlorothiophen-2-yl)methyl]-3-(oxolan-2- 284 e
yl)-1H-pyrazol-5-amine 185 N-[(5-chlorothiophen-2- 407 b
yl)methyl]-3-(piperidin-3-yl)-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine 186
N-[(5-chlorothiophen-2-yl)methyl]-3- 297 c
(piperidin-3-yl)-1H-pyrazol-5-amine 187 N-[(5-chlorothiophen-2- 407
b yl)methyl]-3-(piperidin-4-yl)-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine hydrochloride 188
N-[(5-chlorothiophen-2-yl)methyl]-3- 297 e
(piperidin-4-yl)-1H-pyrazol-5-amine 189
N-[(5-chlorothiophen-2-yl)methyl]-3- 283 e
(pyrrolidin-2-yl)-1H-pyrazol-5-amine 190
N-[(5-chlorothiophen-2-yl)methyl]-3- 283 c
(pyrrolidin-3-yl)-1H-pyrazol-5-amine 191
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(1,2,4- 379 e
oxadiazol-3-ylmethyl)piperidin-4-yl]-1H-pyrazol-5- amine 192
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(1,2,4- 379 e
oxadiazol-5-ylmethyl)piperidin-4-yl]-1H-pyrazol-5- amine 193
N-[(5-chlorothiophen-2- 378 e yl)methyl]-3-[1-(1,3-oxazol-2-
ylmethyl)piperidin-4-yl]-1H-pyrazol-5-amine 194
N-[(5-chlorothiophen-2- 378 e yl)methyl]-3-[1-(1,3-oxazol-5-
ylmethyl)piperidin-4-yl]-1H-pyrazol-5-amine 195
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(1H- 379 c
1,2,3,4-tetrazol-5-ylmethyl)piperidin-4-yl]- 1H-pyrazol-5-amine 196
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(1H-1,2,3- 378 e
triazol-5-ylmethyl)piperidin-4-yl]- 1H-pyrazol-5-amine 197
N-[(5-chlorothiophen-2- 377 c yl)methyl]-3-[1-(1H-imidazol-4-
ylmethyl)piperidin-4-yl]-1H-pyrazol-5-amine 198
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(2,2,2- 379 e
trifluoroethyl)piperidin-4-yl]-1H-pyrazol-5-amine 199
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(2- 381 e
cyclopropoxyethyl)piperidin- 4-yl]-1H-pyrazol-5-amine; formic acid
200 N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(2- 355 e
methoxyethyl)piperidin-4-yl]-1H-pyrazol-5-amine 201
N-[(5-chlorothiophen-2-yl)methyl]-3-[1- 351 e
(cyclopropylmethyl)piperidin- 4-yl]-1H-pyrazol-5-amine 202
N-[(5-chlorothiophen-2- 424 e yl)methyl]-3-[1-(morpholine-4-
carbonyl)azepan-4-yl]-1H-pyrazol-5-amine 203
N-[(5-chlorothiophen-2- 410 e yl)methyl]-3-[1-(morpholine-4-
carbonyl)piperidin-4-yl]-1H-pyrazol-5-amine 204
N-[(5-chlorothiophen-2- 396 e yl)methyl]-3-[1-(morpholine-4-
carbonyl)pyrrolidin-2-yl]-1H-pyrazol-5-amine 205
N-[(5-chlorothiophen-2- 507 a yl)methyl]-3-[1-(morpholine-4-
carbonyl)pyrrolidin-3-yl]-1-(1,3-thiazole-
4-carbonyl)-1H-pyrazol-5-amine 206 N-[(5-chlorothiophen-2- 396 e
yl)methyl]-3-[1-(morpholine-4-
carbonyl)pyrrolidin-3-yl]-1H-pyrazol-5-amine 207
N-[(5-chlorothiophen-2- 446 e yl)methyl]-3-[1-(morpholine-4-
sulfonyl)piperidin-4-yl]-1H-pyrazol-5-amine 208
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(oxan-4- 381 e
yl)piperidin-4-yl]-1H-pyrazol-5-amine 209
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(oxetan-3- 367 e
ylmethyl)piperidin-4-yl]-1H-pyrazol- 5-amine; formic acid 210
N-[(5-chlorothiophen-2- 388 c yl)methyl]-3-[1-(pyridin-2-
ylmethyl)piperidin-4-yl]-1H-pyrazol-5-amine 211
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(pyridin-3- 388 e
ylmethyl)piperidin-4-yl]-1H-pyrazol-5-amine 212
N-[(5-chlorothiophen-2- 411 e yl)methyl]-3-[4-(morpholine-4-
carbonyl)piperazin-2-yl]-1H-pyrazol-5-amine hydrochloride 213
N-[(5-chlorothiophen-2- 547 a
yl)methyl]-3-[8-(morpholine-4-carbonyl)-8-
azabicyclo[3.2.1]octan-3-yl]-1-(1,3-thiazole-
4-carbonyl)-1H-pyrazol-5-amine 214 N-[(5-chlorothiophen-2- 436 e
yl)methyl]-3-[8-(morpholine-4-carbonyl)-8-
azabicyclo[3.2.1]octan-3-yl]-1H-pyrazol-5- amine 215
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(1- 380 e
methylazetidin-3-yl)methyl]piperidin-4-yl- 1H-pyrazol-5-amine 216
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(2- 417 e
methoxyphenyl)methyl]piperidin-4-yl-1H- pyrazol-5-amine 217
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(3- 417 c
methoxyphenyl)methyl]piperidin-4-yl-1H- pyrazol-5-amine 218
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(4- 527 c
methoxyphenyl)methyl]piperidin-4-yl-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine 219
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(4- 417 e
methoxyphenyl)methyl]piperidin-4-yl-1H-pyrazol-5- amine 220
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(6- 402 e
methylpyridin-2-yl)methyl]piperidin-4-yl- 1H-pyrazol-5-amine 221
N-[(5-chlorothiophen-2- 456 e
yl)methyl]-3-1-[2,2,2-trifluoro-1-(pyridin-2-
yl)ethyl]piperidin-4-yl-1H-pyrazol-5-amine 222
N-[(5-chlorothiophen-2- 438 e yl)methyl]-3-1-[2,2-difluoro-2-
(pyridin-2-yl)ethyl]piperidin-4-yl-1H- pyrazol-5-amine 223
N-[(5-chlorothiophen-2- 410 c yl)methyl]-3-1-[2-(morpholin-4-
yl)ethyl]piperidin-4-yl-1H-pyrazol-5-amine 224
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[2-(pyridin- 402 e
2-yl)ethyl]piperidin-4-yl-1H-pyrazol-5-amine 225
N-[(5-chlorothiophen-2- 512 a yl)methyl]-3-8-methanesulfonyl-
8-azabicyclo[3.2.1]octan-3-yl-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine 226 N-[(5-chlorothiophen-2- 401 e
yl)methyl]-3-8-methanesulfonyl-
8-azabicyclo[3.2.1]octan-3-yl-1H-pyrazol-5-amine 227
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 450 a
methoxybenzoyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine 228
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 449 a
methoxybenzoyl)-3-(piperidin- 4-yl)-1H-pyrazol-5-amine 229
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(4- 442 a
methyloxane-4-carbonyl)-3-(oxan-4-yl)-1H- pyrazol-5-amine 230
N-[(5-chlorothiophen-2- 410 a yl)methyl]-4-fluoro-1-(furan-3-
carbonyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine 231
N-[(5-chlorothiophen-2- 409 a
yl)methyl]-4-fluoro-1-(furan-3-
carbonyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine 232
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-[4-(2- 494 a
methoxyethoxy)benzoyl]-3-(oxan-4-yl)- 1H-pyrazol-5-amine 233
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-[4- 505 a
(morpholin-4-yl)benzoyl]-3-(oxan-4-yl)- 1H-pyrazol-5-amine 234
N-[(5-chlorothiophen-2- 426 a yl)methyl]-4-fluoro-3-(oxan-4-
yl)-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 236
N-[(5-chlorothiophen-2- 422 e yl)methyl]-4-methyl-3-[1-(1,3-
thiazole-4-carbonyl)piperidin- 4-yl]-1H-pyrazol-5-amine 237
N-[(5-chlorothiophen-2-yl)methyl]-4-methyl-3-[1- 424 d
(morpholine-4-carbonyl)piperidin-4- yl]-1H-pyrazol-5-amine 238
N-[(5-chlorothiophen-2- 595 c yl)methyl]-N-3-[1-(morpholine-
4-sulfonyl)piperidin-4-yl]-1H- pyrazol-5-ylmorpholine-4-
sulfonamide 239 [1-(5-[(5-chlorothiophen-2- 414 a
yl)methyl]amino-4-fluoro-3- (oxan-4-yl)-1H-pyrazole-1-
carbonyl)cyclopropyl]methanol 240 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 606 b
yl)methyl]amino-1-(1,3-thiazole-4-carbonyl)-1H-
pyrazol-3-yl)-4-(morpholine-4- carbonyl)piperazine-1-carboxylate
241 prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 620 b
yl)methyl]amino-1-(1,3-thiazole-4-carbonyl)-1H-
pyrazol-3-yl)-4-[2-(morpholin-4- yl)acetyl]piperazine-1-carboxylate
242 prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 571 b
yl)methyl]amino-1-(1,3-thiazole-4-carbonyl)-1H-
pyrazol-3-yl)-4-methanesulfonylpiperazine-1- carboxylate 243
prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 478 a
yl)methyl]amino-1-(1,3-thiazole-4-carbonyl)-1H-
pyrazol-3-yl)pyrrolidine-1-carboxylate 244 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 579 c
yl)methyl]amino-1-(2,2-dimethylpropanoyl)-
1H-pyrazol-3-yl)-4-(morpholine -4-carbonyl)piperazine-1-carboxylate
245 prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 593 c
yl)methyl]amino-1-(2,2- dimethylpropanoyl)-1H-pyrazol-
3-yl)-4-[2-(morpholin-4-yl)acetyl]piperazine-1- carboxylate 246
prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 544 e
yl)methyl]amino-1-(2,2- dimethylpropanoyl)-1H-pyrazol-
3-yl)-4-methanesulfonylpiperazine-1-carboxylate 247 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 451 a yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-1H-pyrazol- 3-yl)pyrrolidine-1-carboxylate 248
prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 464 e
yl)methyl]amino-1H-pyrazol-3-yl)-4-(2,2,2-
trifluoroethyl)piperazine-1-carboxylate 249 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 495 e
yl)methyl]amino-1H-pyrazol-3-yl)-4-(morpholine-4-
carbonyl)piperazine-1-carboxylate 250 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 531 e
yl)methyl]amino-1H-pyrazol-3-yl)-4-(morpholine-4-
sulfonyl)piperazine-1-carboxylate 251 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 509 e yl)methyl]amino-1H-pyrazol-3-
yl)-4-[2-(morpholin-4- yl)acetyl]piperazine-1-carboxylate 252
prop-2-en-1-yl 2-(5-[(5-chlorothiophen-2- 460 e
yl)methyl]amino-1H-pyrazol-3-yl)-4-
methanesulfonylpiperazine-1-carboxylate 253 prop-2-en-1-yl
2-(5-[(5-chlorothiophen-2- 367 e
yl)methyl]amino-1H-pyrazol-3-yl)pyrrolidine-1- carboxylate 254
prop-2-en-1-yl 3-(5-[(5-chlorothiophen-2- 491 a
yl)methyl]amino-1-(2,2- dimethylpropanoyl)-1H-pyrazol-
3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 255 prop-2-en-1-yl
3-(5-[(5-chlorothiophen-2- 437 a yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-1H-pyrazol- 3-yl)azetidine-1-carboxylate 256
prop-2-en-1-yl 3-(5-[(5-chlorothiophen-2- 451 a
yl)methyl]amino-1-(2,2- dimethylpropanoyl)-1H-pyrazol-
3-yl)pyrrolidine-1-carboxylate 257 prop-2-en-1-yl
3-(5-[(5-chlorothiophen-2- 407 d
yl)methyl]amino-1H-pyrazol-3-yl)-8-
azabicyclo[3.2.1]octane-8-carboxylate 258 prop-2-en-1-yl
3-(5-[(5-chlorothiophen-2- 353 d
yl)methyl]amino-1H-pyrazol-3-yl)azetidine-1- carboxylate 259
prop-2-en-1-yl 3-(5-[(5-chlorothiophen-2- 367 e
yl)methyl]amino-1H-pyrazol-3-yl)pyrrolidine-1- carboxylate 260
prop-2-en-1-yl 4-(5-[(5-chlorothiophen-2- 506 a
yl)methyl]amino-1-(1,3-thiazole-4-carbonyl)-1H-
pyrazol-3-yl)azepane-1-carboxylate 261 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 479 a yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-1H-pyrazol- 3-yl)azepane-1-carboxylate 262
prop-2-en-1-yl 4-(5-[(5-chlorothiophen-2- 465 a
yl)methyl]amino-1-(2,2- dimethylpropanoyl)-1H-pyrazol-
3-yl)piperidine-1-carboxylate 263 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 483 a yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-4-fluoro-
1H-pyrazol-3-yl)piperidine-1-carboxylate 264 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 479 a yl)methyl]amino-1-(2,2-
dimethylpropanoyl)-4-methyl-
1H-pyrazol-3-yl)piperidine-1-carboxylate 265 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 395 e yl)methyl]amino-1H-pyrazol-3-
yl)azepane-1-carboxylate 266 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 381 e
yl)methyl]amino-1H-pyrazol-3-yl)piperidine-1- carboxylate 267
prop-2-en-1-yl 4-(5-[(5-chlorothiophen-2- 490 a
yl)methyl]amino-4-cyano-1- (2,2-dimethylpropanoyl)-
1H-pyrazol-3-yl)piperidine-1-carboxylate 268 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 406 c
yl)methyl]amino-4-cyano-1H-pyrazol-3- yl)piperidine-1-carboxylate
269 prop-2-en-1-yl 4-(5-[(5-chlorothiophen-2- 399 e
yl)methyl]amino-4-fluoro-1H-pyrazol-3- yl)piperidine-1-carboxylate
270 prop-2-en-1-yl 4-(5-[(5-chlorothiophen-2- 506 a
yl)methyl]amino-4-methyl-1- (1,3-thiazole-4-carbonyl)-
1H-pyrazol-3-yl)piperidine-1-carboxylate 271 prop-2-en-1-yl
4-(5-[(5-chlorothiophen-2- 395 e
yl)methyl]amino-4-methyl-1H-pyrazol-3- yl)piperidine-1-carboxylate
272 tert-butyl 2-(5-[(5-chlorothiophen- 531 c 2-yl)methyl]amino-1-
(2-methoxybenzoyl)-1H-pyrazol-3-yl)-2-
methylpyrrolidine-1-carboxylate 273 tert-butyl
2-(5-[(5-chlorothiophen- 517 c 2-yl)methyl]amino-1-
(2-methoxybenzoyl)-1H-pyrazol-3-yl)pyrrolidine-1- carboxylate 274
tert-butyl 2-(5-[(5-chlorothiophen- 497 b
2-yl)methyl]amino-1-(3-hydroxy-
2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-
methylpyrrolidine-1-carboxylate 275 tert-butyl
2-(5-[(5-chlorothiophen- 523 c 2-yl)methyl]amino-1-
(4-methyloxane-4-carbonyl)-1H-pyrazol-3-yl)-2-
methylpyrrolidine-1-carboxylate 276 tert-butyl
2-(5-[(5-chlorothiophen- 507 e 2-yl)methyl]amino-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-2-
methylpyrrolidine-1-carboxylate 277 tert-butyl 2-(5-[(5- 383 e
chlorothiophen-2-yl)methyl]amino-
1H-pyrazol-3-yl)pyrrolidine-1-carboxylate 278 tert-butyl
3-(5-[(5-chlorothiophen- 495 a 2-yl)methyl]amino-1-
(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-
methylpiperidine-1-carboxylate 279 tert-butyl
3-(5-[(5-chlorothiophen- 481 a 2-yl)methyl]amino-1-
(2,2-dimethylpropanoyl)-1H-pyrazol-3- yl)piperidine-1-carboxylate
280 tert-butyl 3-(5-[(5-chlorothiophen- 545 a 2-yl)methyl]amino-1-
(2-methoxybenzoyl)-1H-pyrazol-3-yl)-3-
methylpiperidine-1-carboxylate 281 tert-butyl
3-(5-[(5-chlorothiophen- 531 a 2-yl)methyl]amino-1-
(2-methoxybenzoyl)-1H-pyrazol-3- yl)piperidine-1-carboxylate 282
tert-butyl 3-(5-[(5-chlorothiophen-2- 511 a
yl)methyl]amino-1-(3-hydroxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-3-
methylpiperidine-1-carboxylate 283 tert-butyl
3-(5-[(5-chlorothiophen- 497 a 2-yl)methyl]amino-1-
(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-
yl)piperidine-1-carboxylate 284 tert-butyl 3-(5-[(5-chlorothiophen-
525 b 2-yl)methyl]amino-1- (3-methoxy-2,2-dimethylpropanoyl)-
1H-pyrazol-3-yl)-3- methylpiperidine-1-carboxylate 285 tert-butyl
3-(5-[(5-chlorothiophen- 511 a 2-yl)methyl]amino-1-
(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-
yl)piperidine-1-carboxylate 286 tert-butyl 3-(5-[(5-chlorothiophen-
537 b 2-yl)methyl]amino-1-
(4-methyloxane-4-carbonyl)-1H-pyrazol-3-yl)-3-
methylpiperidine-1-carboxylate 287 tert-butyl
3-(5-[(5-chlorothiophen- 523 a 2-yl)methyl]amino-1-
(4-methyloxane-4-carbonyl)-1H-pyrazol-3-
yl)piperidine-1-carboxylate 288 tert-butyl 3-(5-[(5-chlorothiophen-
521 a 2-yl)methyl]amino-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-
methylpiperidine-1-carboxylate 289 tert-butyl
3-(5-[(5-chlorothiophen- 507 a 2-yl)methyl]amino-1-
(thiophene-3-carbonyl)-1H-pyrazol-3- yl)piperidine-1-carboxylate
290 tert-butyl 3-(5-[(5-chlorothiophen- 397 e 2-yl)methyl]amino-
1H-pyrazol-3-yl)piperidine-1-carboxylate 291 tert-butyl
4-(5-[(5-chlorothiophen- 495 a 2-yl)methyl]amino-1-
(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-
methylpiperidine-1-carboxylate 292 tert-butyl
4-(5-[(5-chlorothiophen- 481 a 2-yl)methyl]amino-1-
(2,2-dimethylpropanoyl)-1H-pyrazol-3- yl)piperidine-1-carboxylate
293 tert-butyl 4-(5-[(5-chlorothiophen- 495 b 2-yl)methyl]amino-1-
(2,2-dimethylpropanoyl)-4-methyl-1H-pyrazol-3-
yl)piperidine-1-carboxylate 294 tert-butyl 4-(5-[(5-chlorothiophen-
545 a 2-yl)methyl]amino-1- (2-methoxybenzoyl)-1H-pyrazol-3-yl)-4-
methylpiperidine-1-carboxylate 295 tert-butyl
4-(5-[(5-chlorothiophen- 531 a 2-yl)methyl]amino-1-
(2-methoxybenzoyl)-1H-pyrazol-3-yl)piperidine-1- carboxylate 296
tert-butyl 4-(5-[(5-chlorothiophen- 511 a 2-yl)methyl]amino-1-
(3-hydroxy-2,2-dimethylpropanoyl)- 1H-pyrazol-3-yl)-4-
methylpiperidine-1-carboxylate 297 tert-butyl
4-(5-[(5-chlorothiophen- 497 a 2-yl)methyl]amino-1-
(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-
yl)piperidine-1-carboxylate 298 tert-butyl 4-(5-[(5-chlorothiophen-
525 a 2-yl)methyl]amino-1- (3-methoxy-2,2-dimethylpropanoyl)-
1H-pyrazol-3-yl)-4- methylpiperidine-1-carboxylate 299 tert-butyl
4-(5-[(5-chlorothiophen- 537 a
2-yl)methyl]amino-1- (4-methyloxane-4-carbonyl)-1H-pyrazol-3-yl)-4-
methylpiperidine-1-carboxylate 300 tert-butyl
4-(5-[(5-chlorothiophen- 521 a 2-yl)methyl]amino-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-4-
methylpiperidine-1-carboxylate 301 tert-butyl
4-(5-[(5-chlorothiophen- 507 a 2-yl)methyl]amino-1-
(thiophene-3-carbonyl)-1H-pyrazol-3- yl)piperidine-1-carboxylate
302 tert-butyl 4-(5-[(5-chlorothiophen- 397 e 2-yl)methyl]amino-
1H-pyrazol-3-yl)piperidine-1-carboxylate 303 tert-butyl
4-(5-[(5-chlorothiophen- 411 e 2-yl)methyl]amino-4-
methyl-1H-pyrazol-3-yl)piperidine-1-carboxylate
[0118] For Table B following, the disclosed compounds were assayed
for inhibition of the protease activity of KLKB1 as described
herein. In Table B following, the level of inhibition in the KLKB1
assay is indicated as follows: a: IC.sub.50.ltoreq.1 .mu.M; b: 1
.mu.M<IC.sub.50<10 .mu.M; c: IC.sub.50.gtoreq.10 .mu.M.
Accordingly, in some embodiments, there is provided a compound as
expressly set forth in Table B following.
TABLE-US-00002 TABLE B En- KLKB1 try IUPAC name MW Activity 1
1,4-bis(prop-2-en-1-yl) 2-(5-[(5-chlorothiophen-2- 577 c
yl)methyl]amino-1-(1,3-thiazole-4-carbonyl)-
1H-pyrazol-3-yl)piperazine-1,4-dicarboxylate 2
1-(5-[(5-chlorothiophen-2- 382 c yl)methyl]amino-3-(piperazin-2-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 3
1-(5-[(5-chlorothiophen-2- 381 c yl)methyl]amino-3-(piperidin-3-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one; formic acid 4
1-(5-[(5-chlorothiophen-2- 381 c yl)methyl]amino-3-(piperidin-4-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 5
1-(5-[(5-chlorothiophen-2- 367 c yl)methyl]amino-3-(pyrrolidin-3-
yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 6
1-(5-[(5-chlorothiophen-2- 462 c yl)methyl]amino-3-[1-(1,3-
oxazol-4-ylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 7
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3- 463 c
[1-(1H-1,2,3,4-tetrazol-5-ylmethyl)piperidin-4-
yl]-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 8
1-(5-[(5-chlorothiophen-2- 462 c yl)methyl]amino-3-[1-(1H-1,2,3-
triazol-5-ylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 9 1-(5-[(5-chlorothiophen-2-
461 c yl)methyl]amino-3-[1-(1H-
imidazol-4-ylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 10
1-(5-[(5-chlorothiophen-2- 465 c yl)methyl]amino-3-[1-(2-
cyclopropoxyethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 11
1-(5-[(5-chlorothiophen-2- 481 c yl)methyl]amino-3-[1-(2-
cyclopropoxyethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 12
1-(5-[(5-chlorothiophen-2- 439 c yl)methyl]amino-3-[1-(2-
methoxyethyl)piperidin-4-yl]-1H-pyrazol-
1-yl)-2,2-dimethylpropan-1-one 13
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 435 c
(cyclopropylmethyl)piperidin-4-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 14
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-[1- 466 c
(morpholine-4-carbonyl)azetidin-3-yl]-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 15
1-(5-[(5-chlorothiophen-2- 451 c yl)methyl]amino-3-[1-(oxetan-3-
ylmethyl)piperidin-4-yl]-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one
16 1-(5-[(5-chlorothiophen-2- 472 c
yl)methyl]amino-3-[1-(pyridin-2-
ylmethyl)piperidin-4-yl]-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one
17 1-(5-[(5-chlorothiophen-2- 472 c
yl)methyl]amino-3-[1-(pyridin-3-
ylmethyl)piperidin-4-yl]-1H-pyrazol-1-yl)-2,2- dimethylpropan-1-one
18 1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-1- 501 c
[(4-methoxyphenyl)methyl]piperidin-4-yl-1H-
pyrazol-1-yl)-2,2-dimethylpropan-1-one 19
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-1-[2- 494 c
(morpholin-4-yl)ethyl]piperidin- 4-yl-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one; formic acid 20 1-(5-[(5-chlorothiophen-2- 486
c yl)methyl]amino-3-1-[2-(pyridin-
2-yl)ethyl]piperidin-4-yl-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one 21
1-(5-[(5-chlorothiophen-2-yl)methyl]amino-4- 399 b
fluoro-3-(piperidin-4-yl)-1H-pyrazol-1-yl)-
2,2-dimethylpropan-1-one 22 1-(5-[(5-chlorothiophen-2- 415 c
yl)methyl]amino-4-fluoro-3-
(piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-
dimethylpropan-1-one 23 1-[3-(1-benzylpiperidin-4-yl)-5-[(5- 471 c
chlorothiophen-2-yl)methyl]amino-1H-pyrazol-
1-yl]-2,2-dimethylpropan-1-one 24
1-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 449 c
(thiophene-3-carbonyl)-1H-pyrazol-3- yl)piperidin-1-yl]ethan-1-one
25 1-benzoyl-N-[(5-chlorothiophen-2- 401 b yl)methyl]-3-(piperidin-
4-yl)-1H-pyrazol-5-amine hydrochloride 26
3-(5-[(5-chlorothiophen-2- 435 c
yl)methyl]amino-1-(thiophene-3-carbonyl)-
1H-pyrazol-3-yl)-3-methylpiperidin-2-one 27
3-(5-[(5-chlorothiophen-2- 421 c
yl)methyl]amino-1-(thiophene-3-carbonyl)-
1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one 28
5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 519 b
dimethylpropanoyl)-3-[1- (morpholine-4-carbonyl)piperidin-
4-yl]-1H-pyrazole-4-carbonitrile 29
N-[(5-chlorothiophen-2-yl)methyl]-1-(2,3- 459 c
dihydro-1,4-benzodioxine-5-carbonyl)-
3-(piperidin-4-yl)-1H-pyrazol-5- amine hydrochloride 30
N-[(5-chlorothiophen-2- 431 c yl)methyl]-1-(2-methoxybenzoyl)-
3-(piperidin-3-yl)-1H-pyrazol-5-amine 31
N-[(5-chlorothiophen-2-yl)methyl]- 431 c
1-(2-methoxybenzoyl)-3-(piperidin- 4-yl)-1H-pyrazol-5-amine
hydrochloride 32 N-[(5-chlorothiophen-2- 423 c
yl)methyl]-1-(4-methyloxane-4- carbonyl)-3-(piperidin-3-yl)-1H-
pyrazol-5-amine 33 N-[(5-chlorothiophen-2-yl)methyl]- 391 c
1-(furan-3-carbonyl)-3-(piperidin-4- yl)-1H-pyrazol-5-amine
hydrochloride 34 N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 500 b
methanesulfonylazepan-4-yl)-1-(1,3-thiazole-
4-carbonyl)-1H-pyrazol-5-amine 35
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 458 b
methanesulfonylazetidin-3-yl)-1-(1,3-thiazole-
4-carbonyl)-1H-pyrazol-5-amine 36
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 472 b
methanesulfonylpyrrolidin-2-yl)-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine 37
N-[(5-chlorothiophen-2-yl)methyl]-3-(1- 472 b
methanesulfonylpyrrolidin-3-yl)-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine 38
N-[(5-chlorothiophen-2-yl)methyl]-3-(2- 407 c
methylpyrrolidin-2-yl)-1-(thiophene-3-carbonyl)-
1H-pyrazol-5-amine; formic acid 39 N-[(5-chlorothiophen-2- 421 c
yl)methyl]-3-(3-methylpiperidin-3-
yl)-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 40
N-[(5-chlorothiophen-2-yl)methyl]- 421 c 3-(4-methylpiperidin-4-
yl)-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 41
N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)- 408 c
1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 42
N-[(5-chlorothiophen-2-yl)methyl]-3-(oxolan-2- 394 c
yl)-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine 43
N-[(5-chlorothiophen-2- 407 b yl)methyl]-3-(piperidin-3-yl)-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine 44
N-[(5-chlorothiophen-2-yl)methyl]-3-(piperidin- 407 b
4-yl)-1-(thiophene-3-carbonyl)-1H-pyrazol- 5-amine hydrochloride 45
N-[(5-chlorothiophen-2-yl)methyl]-3-[1- 535 b
(morpholine-4-carbonyl)azepan-4-yl]-1-(1,3-
thiazole-4-carbonyl)-1H-pyrazol-5-amine 46
N-[(5-chlorothiophen-2-yl)methyl]- 493 b
3-[1-(morpholine-4-carbonyl)azetidin-
3-yl]-1-(1,3-thiazole-4-carbonyl)-1H- pyrazol-5-amine 47
N-[(5-chlorothiophen-2-yl)methyl]- 507 b
3-[1-(morpholine-4-carbonyl)pyrrolidin-
2-yl]-1-(1,3-thiazole-4-carbonyl)-1H- pyrazol-5-amine 48
N-[(5-chlorothiophen-2-yl)methyl]- 507 b
3-[1-(morpholine-4-carbonyl)pyrrolidin-3-
yl]-1-(1,3-thiazole-4-carbonyl)-1H- pyrazol-5-amine 49
N-[(5-chlorothiophen-2-yl)methyl]-3- 547 b
[8-(morpholine-4-carbonyl)-8-
azabicyclo[3.2.1]octan-3-yl]-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine 50
N-[(5-chlorothiophen-2-yl)methyl]-3-1-[(4- 527 b
methoxyphenyl)methyl]piperidin-4-yl-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-amine 51
N-[(5-chlorothiophen-2-yl)methyl]-3- 512 c
8-methanesulfonyl-8-azabicyclo[3.2.1]octan-
3-yl-1-(1,3-thiazole-4-carbonyl)-1H- pyrazol-5-amine 52
N-[(5-chlorothiophen-2- 410 c yl)methyl]-4-fluoro-1-(furan-3-
carbonyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine 53
[1-(5-[(5-chlorothiophen-2- 414 c
yl)methyl]amino-4-fluoro-3-(oxan-4-yl)-
1H-pyrazole-1-carbonyl)cyclopropyl]methanol 54 prop-2-en-1-yl
2-(5-[(5- 606 d chlorothiophen-2-yl)methyl]amino-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-4-
(morpholine-4-carbonyl)piperazine-1-carboxylate 55 prop-2-en-1-yl
2-(5-[(5- 620 c chlorothiophen-2-yl)methyl]amino-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-4-[2-
(morpholin-4-yl)acetyl]piperazine-1-carboxylate 56 prop-2-en-1-yl
2-(5-[(5- 571 b chlorothiophen-2-yl)methyl]amino-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-4-
methanesulfonylpiperazine-1-carboxylate 57 prop-2-en-1-yl 2-(5-[(5-
478 c chlorothiophen-2-yl)methyl]amino-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-
yl)pyrrolidine-1-carboxylate 58 prop-2-en-1-yl 3-(5-[(5- 518 c
chlorothiophen-2-yl)methyl]amino-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-8-
azabicyclo[3.2.1]octane-8-carboxylate 59 prop-2-en-1-yl 3-(5-[(5-
464 b chlorothiophen-2-yl)methyl]amino-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-
yl)azetidine-1-carboxylate 60 prop-2-en-1-yl
3-(5-[(5-chlorothiophen- 478 b 2-yl)methyl]amino-1-(1,3-thiazole-
4-carbonyl)-1H-pyrazol-3-yl)pyrrolidine-1- carboxylate 61
prop-2-en-1-yl 4-(5-[(5-chlorothiophen- 506 b
2-yl)methyl]amino-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)azepane-1- carboxylate 62 prop-2-en-1-yl
4-(5-[(5-chlorothiophen- 506 c 2-yl)methyl]amino-4-methyl-1-(1,3-
thiazole-4-carbonyl)-1H-pyrazol-3- yl)piperidine-1-carboxylate
[0119] In some embodiments, there is provided a compound as
expressly set forth in Table C following.
TABLE-US-00003 TABLE C
1-(2,2-dimethylpropanoyl)-3-[1-(2,2-dimethylpropanoyl)-4-fluoro-5-
{[(4-fluorophenyl)methyl]amino}-1H-pyrazol-3-yl]piperidine-2-
carboxylic acid 1-(2,2-dimethylpropanoyl)-4-(5-{[(4-
fluorophenyl)methyl](methyl)amino}-4-methoxy-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)piperidin-2-one
1-(2-chlorobenzoyl)-5-[(5-chlorothiophen-2-yl)methoxy]-3-[1-
methanesulfonyl-4-(trifluoromethyl)pyrrolidin-3-yl]-1H-pyrazole
1-(2-chlorobenzoyl)-5-{[(4-fluorophenyl)methyl](methyl)amino}-3-{1-
[(3-hydroxypyrrolidin-1-yl)sulfonyl]-6-oxo-4-(trifluoromethyl)piperidin-
3-yl}-1H-pyrazole-4-carbonitrile
1-(2-chlorobenzoyl)-5-{[(4-fluorophenyl)methyl]sulfanyl}-3-{4-[2-
(morpholin-4-yl)-2-oxoethyl]-3-(trifluoromethyl)piperazin-2-yl}-1H-
pyrazole-4-carbonitrile
1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-
fluoro-3-[3-(trifluoromethyl)azetidin-2-yl]-1H-pyrazole
1-(2-chlorobenzoyl)-N-[(4-fluorophenyl)methyl]-N-methyl-3-[1-
(morpholine-4-carbonyl)-3-(trifluoromethyl)piperazin-2-yl]-1H-pyrazol-
5-amine 1-(2-fluorobenzoyl)-N-[(4-fluorophenyl)methyl]-3-[3-
(trifluoromethyl)azetidin-2-yl]-1H-pyrazol-5-amine
1-(2-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(furan-2-carbonyl)-4-
methoxy-1H-pyrazol-3-yl}-3-methylpiperazin-1-yl)-2,2-dimethylpropan-
1-one
1-(3-{5-[(4-fluorophenyl)methoxy]-4-methyl-1-(4-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl}-2-(trifluoromethyl)azetidin-1-yl)-2-
(morpholin-4-yl)ethan-1-one
1-(3-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(2-methoxybenzoyl)-4-
methyl-1H-pyrazol-3-yl}-2-(trifluoromethyl)piperazin-1-yl)-2-
(morpholin-4-yl)ethan-1-one
1-(3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-fluoro-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl}-2-(trifluoromethyl)piperidin-1-yl)-2,2-
dimethylpropan-1-one
1-(3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-methoxy-1H-pyrazol-3-
yl}piperazin-1-yl)-2,2-dimethylpropan-1-one
1-(5-{[(4-fluorophenyl)methyl]amino}-3-[4-(morpholine-4-
carbonyl)piperazin-2-yl]-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
1-(5-{[(4-fluorophenyl)methyl]sulfanyl}-3-(1-methanesulfonyl-4-
methylpiperidin-3-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2-dimethylpropan-
1-one
1-(5-{[(4-fluorophenyl)methyl]sulfanyl}-3-[5-hydroxy-2-methyl-1-
(pyrrolidine-1-sulfonyl)pyrrolidin-3-yl]-4-methyl-1H-pyrazol-1-yl)-3-
methoxy-2,2-dimethylpropan-1-one
1-(5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methoxy-3-{4-methyl-1-[2-
(morpholin-4-yl)-2-oxoethyl]piperidin-3-yl}-1H-pyrazol-1-yl)-3-
methoxy-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-3-[5-hydroxy-1-
(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-3-{5-hydroxy-2-
methyl-1-[2-(morpholin-4-yl)-2-oxoethyl]pyrrolidin-3-yl}-4-methoxy-
1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-methoxy-3-
(morpholin-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-(morpholine-4-
carbonyl)pyrrolidin-3-yl]-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]-4-methylpyrrolidin-3-yl]-4-methyl-1H-
pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-2-methylpiperidin-3-yl]-1H-pyrazol-1-
yl)-3-methoxy-2,2-dimethylpropan-1-one
1-(5-{[4-(aminomethyl)phenyl]methoxy}-3-{3-methyl-1-[2-(morpholin-
4-yl)-2-oxoethyl]piperidin-4-yl}-1H-pyrazol-1-yl)-3-methoxy-2,2-
dimethylpropan-1-one
1-(5-{[4-(aminomethyl)phenyl]methoxy}-4-fluoro-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-3-methylpiperidin-4-yl]-1H-pyrazol-1-
yl)-3-methoxy-2,2-dimethylpropan-1-one
1-(dimethylcarbamoyl)-3-(5-{[(4-fluorophenyl)methyl]amino}-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-4-methylpiperidine-2-
carboxylic acid
1-(dimethylsulfamoyl)-3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-
1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-4-methylpyrrolidine-2-carboxylic
acid
1-(dimethylsulfamoyl)-3-{4-fluoro-5-[(4-fluorophenyl)methoxy]-1-(3-
hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl}-4-methylpyrrolidine-
2-carboxylic acid
1-({3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-benzoyl-
4-fluoro-1H-pyrazol-3-yl]-2-methylpiperidin-1-yl}sulfonyl)pyrrolidin-
3-ol
1-({3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(2-fluorobenzoyl)-
4-methoxy-1H-pyrazol-3-yl]-2-(trifluoromethyl)piperazin-1-
yl}sulfonyl)pyrrolidin-3-ol
1-[(2-{4-fluoro-5-[(4-fluorophenyl)methoxy]-1-(2-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl}-3-(trifluoromethyl)piperazin-1-
yl)sulfonyl]pyrrolidin-3-ol
1-[(3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-fluoro-1-(furan-3-
carbonyl)-1H-pyrazol-3-yl}-4-methylpyrrolidin-1-yl)sulfonyl]pyrrolidin-
3-ol
1-[2-(5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)piperazin-1-yl]-2-
(morpholin-4-yl)ethan-1-one
1-[2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(4-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)azetidin-1-yl]-2,2-
dimethylpropan-1-one
1-[2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-
carbonyl)-1H-pyrazol-3-yl)-3-methylpiperazin-1-yl]-2,2-
dimethylpropan-1-one
1-[3-(1-benzoyl-5-{[(4-fluorophenyl)methyl]amino}-4-methoxy-1H-
pyrazol-3-yl)-2-methylpiperidine-1-carbonyl]pyrrolidin-3-ol
1-[3-(4-fluoro-5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(1,3-
thiazole-4-carbonyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)azetidin-1-yl]-
2-(morpholin-4-yl)ethan-1-one
1-[3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(furan-2-carbonyl)-
1H-pyrazol-3-yl)-4-methylpyrrolidine-1-carbonyl]pyrrolidin-3-ol
1-[3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(furan-2-carbonyl)-
4-methyl-1H-pyrazol-3-yl)-4-methylpiperidin-1-yl]-2-(morpholin-4-
yl)ethan-1-one
1-[3-(5-{[(4-fluorophenyl)methyl]amino}-1-(4-methylfuran-3-carbonyl)-
1H-pyrazol-3-yl)-4-(trifluoromethyl)piperidine-1-carbonyl]pyrrolidin-
3-ol
1-[3-(5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(furan-3-carbonyl)-4-
methoxy-1H-pyrazol-3-yl)-2-methylpiperazine-1-carbonyl]pyrrolidin-
3-ol 1-[3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)piperidin-
1-yl]-2,2-dimethylpropan-1-one
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-fluoro-1-(2-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)piperazin-
1-yl]-2-(morpholin-4-yl)ethan-1-one
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(5-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)piperazin-1-yl]-2,2-dimethylpropan-1-one
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(thiophene-
3-carbonyl)-1H-pyrazol-3-yl)-2-methylazetidine-1-carbonyl]pyrrolidin-
3-ol 1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methyl-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)pyrrolidin-1-yl]-2,2-
dimethylpropan-1-one
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl]-4-methoxy-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)pyrrolidin-1-yl}-
2-(morpholin-4-yl)ethan-1-one
1-[3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methoxy-1-(1,3-thiazole-
4-carbonyl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)piperidine-1-
carbonyl]pyrrolidin-3-ol
1-[4-(1-benzoyl-5-{[(4-fluorophenyl)methyl]amino}-4-methyl-1H-
pyrazol-3-yl)-3-methylpiperidine-1-carbonyl]pyrrolidin-3-ol
1-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-3-(1-
methanesulfonylazetidin-2-yl)-1H-pyrazol-1-yl]-2,2-dimethylpropan-
1-one
1-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-fluoro-3-{1-
[2-(morpholin-4-yl)-2-oxoethyl]piperazin-2-yl}-1H-pyrazol-1-yl]-2,2-
dimethylpropan-1-one
1-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-methoxy-3-
{4-methyl-1-[2-(morpholin-4-yl)acetyl]pyrrolidin-3-yl}-1H-pyrazol-1-
yl]-3-hydroxy-2,2-dimethylpropan-1-one
1-[5-({[4-(aminomethyl)phenyl]methyl}amino)-3-[1-(pyrrolidine-1-
sulfonyl)piperidin-4-yl]-1H-pyrazol-1-yl]-2,2-dimethylpropan-1-one
1-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-fluoro-3-[5-hydroxy-
1-(3-hydroxypyrrolidine-1-carbonyl)-2-methylpyrrolidin-3-yl]-1H-
pyrazol-1-yl]-3-hydroxy-2,2-dimethylpropan-1-one
1-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-3-(5-hydroxy-1-
methanesulfonyl-2-methylpyrrolidin-3-yl)-4-methyl-1H-pyrazol-1-yl]-3-
methoxy-2,2-dimethylpropan-1-one
1-benzoyl-5-{[(4-fluorophenyl)methyl]amino}-3-(4-methyl-2-
oxopyrrolidin-3-yl)-1H-pyrazole-4-carbonitrile
1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-3-[1-(2,2-
dimethylpropanoyl)-2-methylpyrrolidin-3-yl]-1H-pyrazole-4-carbonitrile
1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-(4-
methyloxolan-3-yl)-1H-pyrazole-4-carbonitrile
1-benzoyl-N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-3-(1-
methanesulfonyl-4-methylpiperidin-3-yl)-N-methyl-1H-pyrazol-5-amine
1-{2-[1-(2-fluorobenzoyl)-5-{[(4-fluorophenyl)methyl]amino}-4-
methoxy-1H-pyrazol-3-yl]-3-(trifluoromethyl)piperazine-1-
carbonyl}pyrrolidin-3-ol
1-{2-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-methyl-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]azetidin-1-yl}-2-(morpholin-
4-yl)ethan-1-one
1-{2-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(furan-3-
carbonyl)-4-methoxy-1H-pyrazol-3-yl]-3-methylazetidine-1-
carbonyl}pyrrolidin-3-ol
1-{3-[1-(2,2-dimethylpropanoyl)-5-[(4-fluorophenyl)methoxy]-4-
methyl-1H-pyrazol-3-yl]azetidin-1-yl}-2,2-dimethylpropan-1-one
1-{3-[1-(2-chlorobenzoyl)-5-[(5-chlorothiophen-2-yl)methoxy]-4-
methoxy-1H-pyrazol-3-yl]-5-hydroxy-2-(trifluoromethyl)pyrrolidin-1-
yl}-2-(morpholin-4-yl)ethan-1-one
1-{3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(2-
methoxybenzoyl)-4-methyl-1H-pyrazol-3-yl]-4-
(trifluoromethyl)piperidin-1-yl}-2,2-dimethylpropan-1-one
1-{4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-methyl-1-
(2-methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-3-
(trifluoromethyl)piperidin-1-yl}-2,2-dimethylpropan-1-one
1-{4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-fluoro-1-(1,3-
thiazole-4-carbonyl)-1H-pyrazol-3-yl]-3-(trifluoromethyl)piperidin-1-
yl}-2-(morpholin-4-yl)ethan-1-one
1-{5-[(4-fluorophenyl)methoxy]-3-(1-methanesulfonyl-2-
methylazetidin-3-yl)-4-methoxy-1H-pyrazol-1-yl}-3-hydroxy-2,2-
dimethylpropan-1-one
1-{5-[(5-chlorothiophen-2-yl)methoxy]-3-[1-(2,2-dimethylpropanoyl)-2-
methylpyrrolidin-3-yl]-4-methoxy-1H-pyrazol-1-yl}-3-methoxy-2,2-
dimethylpropan-1-one
1-{[2-(5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(2-methoxybenzoyl)-4-
methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)piperazin-1-
yl]sulfonyl}pyrrolidin-3-ol
1-{[3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(thiophene-2-carbonyl)-
1H-pyrazol-3-yl)pyrrolidin-1-yl]sulfonyl}pyrrolidin-3-ol
1-{[4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-methoxy-1-(1,3-
thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)piperidin-1-
yl]sulfonyl}pyrrolidin-3-ol
2-(3-{5-[(4-fluorophenyl)methoxy]-1-(thiophene-3-carbonyl)-1H-
pyrazol-3-yl}-2-methylazetidin-1-yl)-1-(morpholin-4-yl)ethan-1-one
2-(3-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(furan-3-carbonyl)-1H-
pyrazol-3-yl}-5-hydroxy-2-methylpyrrolidin-1-yl)-1-(morpholin-4-
yl)ethan-1-one
2-(4-fluoro-5-{[(4-fluorophenyl)methyl]amino}-1-(3-hydroxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N,3-trimethylazetidine-1-
sulfonamide
2-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-methoxy-1-
(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-4-oxoazetidine-
1-carboxamide
2-(5-{[(4-fluorophenyl)methyl](methyl)amino}-4-methyl-1-(thiophene-
2-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperazine-1-carboxamide
2-(5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(furan-2-carbonyl)-4-methyl-
1H-pyrazol-3-yl)-N,N,3-trimethylazetidine-1-carboxamide
2-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-cyano-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-N,N,3-trimethylazetidine-1-
carboxamide
2-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(furan-3-carbonyl)-4-
methyl-1H-pyrazol-3-yl)-N,N,3-trimethylazetidine-1-sulfonamide
2-[2-(4-fluoro-5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(furan-2-
carbonyl)-1H-pyrazol-3-yl)-3-methylazetidin-1-yl]-1-(morpholin-4-
yl)ethan-1-one
2-[3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1H-
pyrazol-3-yl)-4-methylpiperidin-1-yl]-1-(morpholin-4-yl)ethan-1-one
2-[3-(4-fluoro-5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(furan-2-
carbonyl)-1H-pyrazol-3-yl)-2-methylazetidin-1-yl]-1-(morpholin-4-
yl)ethan-1-one
2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl)pyrrolidin-1-yl]-1-(morpholin-4-yl)ethan-
1-one
2-[4-cyano-1-(2,2-dimethylpropanoyl)-5-[(4-fluorophenyl)methoxy]-1H-
pyrazol-3-yl]-N,N-dimethylpiperazine-1-sulfonamide
2-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(2-fluorobenzoyl)-1H-
pyrazol-3-yl]-N,N-dimethyl-4-oxo-3-(trifluoromethyl)azetidine-1-
sulfonamide
2-chloro-3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-3-{1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]-5-oxopyrrolidin-3-yl}-4-methoxy-1H-
pyrazole-1-carbonyl)benzoic acid
2-chloro-3-(5-{[(4-fluorophenyl)methyl]sulfanyl}-3-(2-oxoazetidin-3-
yl)-1H-pyrazole-l-carbonyl)benzoic acid
2-chloro-3-(5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methyl-3-[1-
(morpholine-4-carbonyl)-6-oxopiperidin-3-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
2-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-cyano-3-[1-
(morpholine-4-carbonyl)-2-oxopyrrolidin-3-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
2-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-methoxy-3-
[4-(pyrrolidine-1-carbonyl)piperazin-2-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
2-chloro-3-{3-[1-(2,2-dimethylpropanoyl)-2-oxoazetidin-3-yl]-5-{[(4-
fluorophenyl)methyl](methyl)amino}-1H-pyrazole-1-carbonyl}benzoic
acid
2-chloro-3-{3-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]-4-fluoro-5-{[(4-
fluorophenyl)methyl](methyl)amino}-1H-pyrazole-1-carbonyl}benzoic
acid
2-chloro-3-{5-[(5-chlorothiophen-2-yl)methoxy]-3-(morpholin-3-yl)-
1H-pyrazole-1-carbonyl}benzoic acid
2-chloro-3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-fluoro-3-[5-hydroxy-
1-(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1H-pyrazole-1-
carbonyl}benzoic acid
2-{3-[1-(2-fluorobenzoyl)-5-[(4-fluorophenyl)methoxy]-4-methyl-1H-
pyrazol-3-yl]-2-(trifluoromethyl)piperazin-1-yl}-1-(morpholin-4-
yl)ethan-1-one
2-{4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-benzoyl-4-
methoxy-1H-pyrazol-3-yl]-3-methylpiperidin-1-yl}-1-(morpholin-4-
yl)ethan-1-one
3-(1-benzoyl-5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-4-
methoxy-1H-pyrazol-3-yl)-4-methyl-1-(morpholine-4-
carbonyl)piperidine-2-carboxylic acid
3-(1-benzoyl-5-{[(4-carbamimidoylphenyl)methyl]amino}-4-fluoro-1H-
pyrazol-3-yl)-N,N,2-trimethyl-4-oxopyrrolidine-1-carboxamide
3-(1-benzoyl-5-{[(4-carbamimidoylphenyl)methyl]amino}-4-methoxy-
1H-pyrazol-3-yl)-N,N,4-trimethylpiperidine-1-carboxamide
3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methyl-1H-
pyrazol-3-yl)-1-(dimethylcarbamoyl)-4-methylpyrrolidine-2-carboxylic
acid
3-(4-cyano-5-{[(4-fluorophenyl)methyl]amino}-3-{1-[2-(morpholin-4-
yl)acetyl]-5-oxopyrrolidin-3-yl}-1H-pyrazole-1-carbonyl)benzoic
acid
3-(4-cyano-5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(3-methoxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N,2-trimethylpyrrolidine-1-
carboxamide
3-(4-cyano-5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(furan-2-carbonyl)-
1H-pyrazol-3-yl)-N,N,2-trimethylpiperidine-1-sulfonamide
3-(4-fluoro-5-{[(4-fluorophenyl)methyl]amino}-1-(2-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-carbonyl)-4-
(trifluoromethyl)pyrrolidin-2-one
3-(4-fluoro-5-{[(4-fluorophenyl)methyl]amino}-1-(4-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-4-
(trifluoromethyl)pyrrolidine-1-sulfonamide
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-1-(2-
fluorobenzoyl)-4-methoxy-1H-pyrazol-3-yl)-N,N-dimethyl-2-
(trifluoromethyl)piperidine-1-carboxamide
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-1-(3-hydroxy-
2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-N,N,2-
trimethylpyrrolidine-1-carboxamide
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-4-oxopyrrolidin-3-yl]-4-methoxy-1H-
pyrazole-1-carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-3-[1-
(dimethylsulfamoyl)piperidin-4-yl]-4-fluoro-1H-pyrazole-1-
carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-3-[1-
(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-4-cyano-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyrrolidine-1-
carbonyl)piperidine-2-carboxylic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-4-cyano-3-[1-
(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-4-methoxy-1-
(2-methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-
yl)acetyl]-4-(trifluoromethyl)piperidine-2-carboxylic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-4-methyl-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyrrolidine-1-
sulfonyl)piperidine-2-carboxylic acid
3-(5-{[(4-carbamimidoylphenyl)methyl](methyl)amino}-4-methyl-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-N,N,4-trimethyl-2-
oxopyrrolidine-1-carboxamide
3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-1-(2,2-
dimethylpropanoyl)-4-fluoro-1H-pyrazol-3-yl)-1-
methanesulfonylpyrrolidine-2-carboxylic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-1-(3-carboxybenzoyl)-
1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]pyrrolidine-2-
carboxylic acid 3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-3-[1-
(dimethylcarbamoyl)piperazin-2-yl]-4-fluoro-1H-pyrazole-1-
carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-3-[1-
(dimethylsulfamoyl)-5-hydroxypyrrolidin-3-yl]-4-methyl-1H-pyrazole-
1-carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-3-{1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]-4-oxopyrrolidin-3-yl}-4-methoxy-1H-
pyrazole-1-carbonyl)benzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-4-fluoro-1-(3-hydroxy-
2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N,2-trimethylpiperazine-1-
carboxamide
3-(5-{[(4-carbamimidoylphenyl)methyl]amino}-4-methyl-1-(thiophene-
3-carbonyl)-1H-pyrazol-3-yl)-N,N,2-trimethyl-4-oxoazetidine-1-
carboxamide
3-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-cyano-3-(1-
methanesulfonyl-4-oxoazetidin-2-yl)-1H-pyrazole-1-carbonyl)-2-
chlorobenzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-fluoro-3-[1-
(morpholine-4-carbonyl)pyrrolidin-3-yl]-1H-pyrazole-1-carbonyl)-2-
chlorobenzoic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-methoxy-1-(1,3-
thiazole-4-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-
(trifluoromethyl)azetidine-1-carboxamide
3-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-methoxy-1H-
pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]piperidine-2-
carboxylic acid
3-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-methyl-3-{1-[2-
(morpholin-4-yl)acetyl]-2-oxoazetidin-3-yl}-1H-pyrazole-1-carbonyl)-2-
chlorobenzoic acid
3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(2-methoxybenzoyl)-
4-methyl-1H-pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-4-
(trifluoromethyl)piperidin-2-one
3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(3-methoxy-2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl)-N,N,2-trimethyl-4-
oxopyrrolidine-1-carboxamide
3-(5-{[(4-fluorophenyl)methyl](methyl)amino}-4-methoxy-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-
4-(trifluoromethyl)azetidin-2-one
3-(5-{[(4-fluorophenyl)methyl]amino}-1-(3-hydroxy-2,2-
dimethylpropanoyl)-4-methoxy-1H-pyrazol-3-yl)-1-methanesulfonyl-4-
methylpyrrolidin-2-one
3-(5-{[(4-fluorophenyl)methyl]amino}-4-methoxy-1-(2-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-1-(pyrrolidine-1-sulfonyl)-4-
(trifluoromethyl)pyrrolidin-2-one
3-(5-{[(4-fluorophenyl)methyl]amino}-4-methoxy-3-{1-[2-(morpholin-
4-yl)-2-oxoethyl]pyrrolidin-3-yl}-1H-pyrazole-1-carbonyl)benzoic
acid
3-(5-{[(4-fluorophenyl)methyl]amino}-4-methyl-1-(4-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-carbonyl)-4-
(trifluoromethyl)azetidin-2-one
3-(5-{[(4-fluorophenyl)methyl]amino}-4-methyl-1-(thiophene-3-
carbonyl)-1H-pyrazol-3-yl)-4-methyl-1-(morpholine-4-
carbonyl)pyrrolidine-2-carboxylic acid
3-(5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(thiophene-2-carbonyl)-1H-
pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-carbonyl)piperidin-2-one
3-(5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methyl-1H-pyrazol-3-yl)-1-
[2-(morpholin-4-yl)-2-oxoethyl]pyrrolidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl)pyrrolidine-2-carboxylic
acid
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(thiophene-3-
carbonyl)-1H-pyrazol-3-yl)-4-methyl-1-(pyrrolidine-1-sulfonyl)azetidin-
2-one 3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-5-oxopyrrolidin-3-yl]-4-methyl-1H-
pyrazole-1-carbonyl)benzoic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-cyano-3-(3-
oxopiperidin-4-yl)-1H-pyrazole-1-carbonyl)benzoic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-fluoro-1-(2-
fluorobenzoyl)-1H-pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-
4-(trifluoromethyl)pyrrolidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-fluoro-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-2-oxopiperidin-3-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-methoxy-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-N,N,2-trimethylpiperidine-1-
sulfonamide
3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-methyl-1-(2-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-
dimethylpropanoyl)-4-methoxy-1H-pyrazol-3-yl)-1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]pyrrolidine-2-carboxylic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-1-methanesulfonyl-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]azetidin-3-yl}-4-methoxy-1H-pyrazole-
1-carbonyl)benzoic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2,2-
dimethylpropanoyl)pyrrolidine-2-carboxylic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-4-
(trifluoromethyl)piperidine-1-sulfonamide
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[1-
(dimethylcarbamoyl)-4-oxoazetidin-2-yl]-1H-pyrazole-1-
carbonyl)benzoic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(2-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-(morpholine-4-carbonyl)-
4-(trifluoromethyl)piperidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-(2,2-dimethylpropanoyl)-
4-(trifluoromethyl)piperidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyrrolidine-1-carbonyl)-
4-(trifluoromethyl)azetidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methyl-3-[1-
(pyrrolidine-1-sulfonyl)pyrrolidin-3-yl]-1H-pyrazole-1-carbonyl)benzoic
acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2-methoxybenzoyl)-
1H-pyrazol-3-yl)-1-(pyrrolidine-1-sulfonyl)-4-
(trifluoromethyl)pyrrolidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(3-methoxy-2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl)-1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]-4-methylazetidin-2-one
3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(furan-3-carbonyl)-
4-methoxy-1H-pyrazol-3-yl)-5-hydroxy-N,N,2-trimethylpyrrolidine-1-
carboxamide
3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-cyano-1-(furan-2-
carbonyl)-1H-pyrazol-3-yl)-4-methyl-1-(morpholine-4-
carbonyl)pyrrolidine-2-carboxylic acid
3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-fluoro-1-(furan-2-
carbonyl)-1H-pyrazol-3-yl)-N,N,4-trimethyl-2-oxopyrrolidine-1-
carboxamide
3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-fluoro-1H-pyrazol-3-
yl)-1-(pyrrolidine-1-sulfonyl)piperidine-2-carboxylic acid
3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(2-chlorobenzoyl)-1H-
pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-carbonyl)-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(2-chlorobenzoyl)-4-methyl-
1H-pyrazol-3-yl)-N,N-dimethyl-2-(trifluoromethyl)piperazine-1-
sulfonamide
3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(2-methoxybenzoyl)-1H-
pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-carbonyl)-4-
(trifluoromethyl)pyrrolidin-2-one
3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(3-carboxy-2-
chlorobenzoyl)-4-cyano-1H-pyrazol-3-yl)-1-[2-(morpholin-4-
yl)acetyl]pyrrolidine-2-carboxylic acid
3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(3-methoxy-2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl)-4-methylpyrrolidin-
2-one 3-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(furan-2-carbonyl)-4-
methoxy-1H-pyrazol-3-yl)-1-(dimethylcarbamoyl)-4-methylpiperidine-
2-carboxylic acid
3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-fluoro-3-(1-
methanesulfonylazetidin-2-yl)-1H-pyrazole-1-carbonyl)-2-chlorobenzoic
acid 3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methoxy-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-4-
(trifluoromethyl)pyrrolidine-1-carboxamide
3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methoxy-1-(3-methoxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methyl-1-[2-(morpholin-4-
yl)acetyl]pyrrolidin-2-one
3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methoxy-1H-pyrazol-3-yl)-
1-(pyrrolidine-1-sulfonyl)piperidin-2-one
3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methoxy-3-[4-(morpholine-
4-carbonyl)piperazin-2-yl]-1H-pyrazole-1-carbonyl)-2-chlorobenzoic
acid
3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methyl-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)-1-methanesulfonyl-4-
(trifluoromethyl)azetidin-2-one
3-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methyl-3-{1-[2-(morpholin-
4-yl)-2-oxoethyl]piperazin-2-yl}-1H-pyrazole-1-carbonyl)-2-
chlorobenzoic acid
3-[1-(2,2-dimethylpropanoyl)-5-[(4-fluorophenyl)methoxy]-4-methoxy-
1H-pyrazol-3-yl]azetidin-2-one
3-[1-(2,2-dimethylpropanoyl)-5-{[(4-fluorophenyl)methyl]amino}-4-
methoxy-1H-pyrazol-3-yl]-1-[2-(morpholin-4-yl)acetyl]pyrrolidine-2-
carboxylic acid
3-[1-(2,2-dimethylpropanoyl)-5-{[(4-fluorophenyl)methyl]amino}-4-
methyl-1H-pyrazol-3-yl]-1-(morpholine-4-carbonyl)pyrrolidin-2-one
3-[1-(2-chlorobenzoyl)-4-fluoro-5-{[(4-fluorophenyl)methyl]sulfanyl}-
1H-pyrazol-3-yl]-1-(pyrrolidine-1-sulfonyl)-2-
(trifluoromethyl)piperidine
3-[1-(2-chlorobenzoyl)-5-{[(4-fluorophenyl)methyl](methyl)amino}-4-
methoxy-1H-pyrazol-3-yl]-N,N-dimethyl-2-(trifluoromethyl)azetidine-
1-sulfonamide
3-[1-(2-chlorobenzoyl)-5-{[(4-fluorophenyl)methyl]sulfanyl}-1H-
pyrazol-3-yl]-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-4-
(trifluoromethyl)pyrrolidin-2-one
3-[1-(2-chlorobenzoyl)-5-{[(4-fluorophenyl)methyl]sulfanyl}-4-
methoxy-1H-pyrazol-3-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrrolidine-
1-sulfonamide
3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-
cyano-1H-pyrazol-3-yl]-N,N-dimethyl-2-(trifluoromethyl)piperidine-1-
carboxamide
3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-
methyl-1H-pyrazol-3-yl]-1-(pyrrolidine-1-carbonyl)-4-
(trifluoromethyl)pyrrolidin-2-one
3-[1-(3-carboxy-2-chlorobenzoyl)-4-fluoro-5-{[(4-
fluorophenyl)methyl]sulfanyl}-1H-pyrazol-3-yl]pyrrolidine-2-carboxylic
acid
3-[1-(3-carboxy-2-chlorobenzoyl)-5-[(5-chlorothiophen-2-yl)methoxy]-
4-cyano-1H-pyrazol-3-yl]-1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]pyrrolidine-2-carboxylic acid
3-[1-(3-carboxy-2-chlorobenzoyl)-5-[(5-chlorothiophen-2-yl)methoxy]-
4-methyl-1H-pyrazol-3-yl]-1-(2,2-dimethylpropanoyl)pyrrolidine-2-
carboxylic acid
3-[1-(3-carboxy-2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-
yl)methyl]sulfanyl}-4-methyl-1H-pyrazol-3-yl]-1-(2,2-
dimethylpropanoyl)piperidine-2-carboxylic acid
3-[1-(3-carboxybenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-
fluoro-1H-pyrazol-3-yl]-1-(pyrrolidine-1-sulfonyl)pyrrolidine-2-
carboxylic acid
3-[4-cyano-1-(2-fluorobenzoyl)-5-[(4-fluorophenyl)methoxy]-1H-
pyrazol-3-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrrolidine-1-
sulfonamide
3-[4-cyano-1-(2-fluorobenzoyl)-5-{[(4-fluorophenyl)methyl]amino}-1H-
pyrazol-3-yl]-N,N-dimethyl-2-(trifluoromethyl)piperazine-1-
sulfonamide
3-[4-fluoro-1-(2-fluorobenzoyl)-5-{[(4-fluorophenyl)methyl]amino}-
1H-pyrazol-3-yl]-1-(pyrrolidine-1-carbonyl)-4-
(trifluoromethyl)pyrrolidin-2-one
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(2-
fluorobenzoyl)-4-methoxy-1H-pyrazol-3-yl]-1-(3-hydroxypyrrolidine-1-
carbonyl)-4-(trifluoromethyl)piperidine-2-carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-N,N-dimethyl-2-
(trifluoromethyl)azetidine-1-carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]piperidine-2-carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-3-[1-(2,2-
dimethylpropanoyl)-5-hydroxypyrrolidin-3-yl]-4-methyl-1H-pyrazole-1-
carbonyl]benzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-3-{1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]pyrrolidin-3-yl}-4-methoxy-1H-
pyrazole-1-carbonyl]benzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-cyano-1-(2-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-N,N-dimethyl-4-
(trifluoromethyl)pyrrolidine-1-carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-cyano-3-[1-
(dimethylsulfamoyl)-4-oxopyrrolidin-3-yl]-1H-pyrazole-1-
carbonyl]benzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-fluoro-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-1-methanesulfonyl-4-
(trifluoromethyl)azetidin-2-one
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-methoxy-1-
(4-methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-1-methanesulfonyl-4-
(trifluoromethyl)piperidin-2-one
3-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-methyl-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl]-4-methyl-1-(morpholine-4-
carbonyl)azetidin-2-one
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(2,2-
dimethylpropanoyl)-4-fluoro-1H-pyrazol-3-yl]-N,N-
dimethylpyrrolidine-1-sulfonamide
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(2-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl]-1-(dimethylsulfamoyl)-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(3-carboxybenzoyl)-4-
methoxy-1H-pyrazol-3-yl]-1-[2-(morpholin-4-yl)-2-oxoethyl]piperidine-
2-carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(3-hydroxy-2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl]-N,N,4-trimethyl-2-
oxopiperidine-1-sulfonamide
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(5-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl]-N,N-dimethyl-2-oxopiperidine-1-
carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-benzoyl-1H-pyrazol-
3-yl]-1-(3-hydroxypyrrolidine-1-carbonyl)-4-methylpyrrolidine-2-
carboxylic acid 3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-3-[1-
(dimethylsulfamoyl)-3-oxopiperidin-4-yl]-1H-pyrazole-1-
carbonyl]benzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-fluoro-3-[1-
(morpholine-4-carbonyl)-3-oxopiperidin-4-yl]-1H-pyrazole-1-
carbonyl]benzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-methyl-1-(thiophene-
3-carbonyl)-1H-pyrazol-3-yl]-4-methylpiperidin-2-one
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl]-N,N-dimethyl-2-oxo-4-
(trifluoromethyl)azetidine-1-sulfonamide
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(3-carboxy-2-
chlorobenzoyl)-1H-pyrazol-3-yl]-1-methanesulfonylpyrrolidine-2-
carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(furan-2-carbonyl)-
4-methoxy-1H-pyrazol-3-yl]-4-methyl-1-[2-(morpholin-4-yl)-2-
oxoethyl]piperidin-2-one
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(furan-3-carbonyl)-
1H-pyrazol-3-yl]-N,N,2-trimethylpiperazine-1-carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-cyano-1-(3-
methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl]-N,N,4-
trimethylpiperidine-1-carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-cyano-1-(furan-3-
carbonyl)-1H-pyrazol-3-yl]-N,N,4-trimethyl-2-oxopiperidine-1-
sulfonamide
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-cyano-3-[5-oxo-1-
(pyrrolidine-1-sulfonyl)pyrrolidin-3-yl]-1H-pyrazole-1-carbonyl]-2-
chlorobenzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-fluoro-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl]-1-(dimethylsulfamoyl)-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-fluoro-1-(3-
methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl]-1-(3-
hydroxypyrrolidine-1-carbonyl)-4-methylpyrrolidine-2-carboxylic
acid
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-fluoro-1-(furan-2-
carbonyl)-1H-pyrazol-3-yl]-N,N,2-trimethyl-4-oxoazetidine-1-
carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-fluoro-1H-pyrazol-
3-yl]-N,N-dimethyl-2-oxopiperidine-1-carboxamide
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-fluoro-3-{1-[2-
(morpholin-4-yl)acetyl]-3-oxopiperidin-4-yl}-1H-pyrazole-1-carbonyl]-
2-chlorobenzoic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-methoxy-1-
(thiophene-2-carbonyl)-1H-pyrazol-3-yl]-1-[2-(morpholin-4-yl)-2-
oxoethyl]pyrrolidine-2-carboxylic acid
3-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-methoxy-3-{1-[2-
(morpholin-4-yl)acetyl]piperidin-3-yl}-1H-pyrazole-1-carbonyl]-2-
chlorobenzoic acid
3-{1-benzoyl-5-[(4-fluorophenyl)methoxy]-4-methyl-1H-pyrazol-3-yl}-
N,N,2-trimethylpyrrolidine-1-carboxamide
3-{3-[1-(dimethylcarbamoyl)piperidin-4-yl]-5-{[(4-
fluorophenyl)methyl]amino}-1H-pyrazole-1-carbonyl}benzoic acid
3-{3-[1-(dimethylsulfamoyl)-5-oxopyrrolidin-3-yl]-5-[(4-
fluorophenyl)methoxy]-1H-pyrazole-1-carbonyl}benzoic acid
3-{3-[1-(dimethylsulfamoyl)-6-oxopiperidin-3-yl]-5-[(4-
fluorophenyl)methoxy]-4-methyl-1H-pyrazole-1-carbonyl}benzoic acid
3-{4-fluoro-5-[(4-fluorophenyl)methoxy]-1-(5-methylfuran-3-carbonyl)-
1H-pyrazol-3-yl}-1-[2-(morpholin-4-yl)-2-oxoethyl]pyrrolidin-2-one
3-{4-fluoro-5-[(4-fluorophenyl)methoxy]-3-(pyrrolidin-3-yl)-1H-
pyrazole-1-carbonyl}benzoic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-1-(2-methoxybenzoyl)-1H-
pyrazol-3-yl}-1-[2-(morpholin-4-yl)acetyl]-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-1-(3-methoxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl}-4-methyl-1-(morpholine-4-
carbonyl)piperidine-2-carboxylic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-3-[1-
(dimethylsulfamoyl)pyrrolidin-3-yl]-1H-pyrazole-1-carbonyl}-2-
chlorobenzoic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-4-cyano-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl}-1-[2-(morpholin-4-yl)-2-
oxoethyl]piperidine-2-carboxylic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-4-cyano-3-[2-oxo-1-
(pyrrolidine-1-carbonyl)piperidin-3-yl]-1H-pyrazole-1-carbonyl}-2-
chlorobenzoic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-4-methoxy-1H-pyrazol-3-yl}-
1-(pyrrolidine-1-carbonyl)piperidine-2-carboxylic acid
3-{5-[(4-carbamimidoylphenyl)methoxy]-4-methoxy-3-[1-(pyrrolidine-
1-sulfonyl)piperidin-4-yl]-1H-pyrazole-1-carbonyl}-2-chlorobenzoic
acid
3-{5-[(4-fluorophenyl)methoxy]-1-(2-methylfuran-3-carbonyl)-1H-
pyrazol-3-yl}-1-[2-(morpholin-4-yl)-2-oxoethyl]-4-
(trifluoromethyl)azetidin-2-one
3-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(2-methoxybenzoyl)-1H-
pyrazol-3-yl}-1-(morpholine-4-carbonyl)-4-(trifluoromethyl)piperidin-
2-one
3-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(furan-2-carbonyl)-4-methyl-
1H-pyrazol-3-yl}-1-methanesulfonyl-2-methylpiperazine
3-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(furan-3-carbonyl)-4-methyl-
1H-pyrazol-3-yl}-2-methyl-1-(pyrrolidine-1-carbonyl)piperidine
3-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(thiophene-2-carbonyl)-1H-
pyrazol-3-yl}-1-(pyrrolidine-1-sulfonyl)pyrrolidine-2-carboxylic
acid
3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-cyano-1-(2-methoxybenzoyl)-
1H-pyrazol-3-yl}-4-(trifluoromethyl)piperidine-2-carboxylic acid
3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-cyano-1H-pyrazol-3-yl}-1-
(pyrrolidine-1-carbonyl)pyrrolidine-2-carboxylic acid
3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-fluoro-1-(furan-2-carbonyl)-
1H-pyrazol-3-yl}-4-methyl-1-(pyrrolidine-1-sulfonyl)azetidin-2-one
3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-methoxy-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl}-1-methanesulfonyl-4-
(trifluoromethyl)piperidine-2-carboxylic acid
3-{5-[(5-chlorothiophen-2-yl)methoxy]-4-methyl-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl}-N,N-dimethyl-4-
(trifluoromethyl)piperidine-1-sulfonamide
4-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-
pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-3-methylpiperidin-
2-one
4-(4-cyano-5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl)-2-hydroxy-N,N-dimethylpyrrolidine-1-
sulfonamide
4-(4-fluoro-5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(furan-3-
carbonyl)-1H-pyrazol-3-yl)-1-methanesulfonyl-5-methylpiperidin-3-one
4-(4-fluoro-5-{[(4-fluorophenyl)methyl](methyl)amino}-1H-pyrazol-3-
yl)-1-(pyrrolidine-1-sulfonyl)piperidin-2-one
4-(4-fluoro-5-{[(4-fluorophenyl)methyl]amino}-1-(5-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl)-1-(pyrrolidine-1-carbonyl)piperidin-3-one
4-(4-fluoro-5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-carbonyl)-3-
(trifluoromethyl)azetidin-2-one
4-(4-fluoro-5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(furan-3-carbonyl)-
1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one
4-(4-fluoro-5-{[(4-fluorophenyl)methyl]sulfanyl}-1H-pyrazol-3-yl)-1-
methanesulfonylpyrrolidin-3-one
4-(5-{[(4-carbamimidoylphenyl)methyl]sulfanyl}-4-cyano-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-3-
(trifluoromethyl)pyrrolidine-1-carboxamide
4-(5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(furan-3-carbonyl)-4-
methoxy-1H-pyrazol-3-yl)-3-methyl-1-[2-(morpholin-4-yl)-2-
oxoethyl]azetidin-2-one
4-(5-{[(4-fluorophenyl)methyl](methyl)amino}-4-methoxy-1-(3-
methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methylpiperidin-
2-one 4-(5-{[(4-fluorophenyl)methyl](methyl)amino}-4-methoxy-1-
(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-
oxopyrrolidine-1-sulfonamide
4-(5-{[(4-fluorophenyl)methyl](methyl)amino}-4-methyl-1H-pyrazol-3-
yl)-1-[2-(morpholin-4-yl)acetyl]azetidin-2-one
4-(5-{[(4-fluorophenyl)methyl]amino}-1-(3-hydroxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]-5-methylpiperidin-3-one
4-(5-{[(4-fluorophenyl)methyl]sulfany}-1-(1,3-thiazole-4-carbonyl)-1H-
pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-3-
(trifluoromethyl)pyrrolidin-2-one
4-(5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methoxy-1H-pyrazol-3-yl)-
1-(3-hydroxypyrrolidine-1-carbonyl)piperidin-2-one
4-(5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methyl-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)azetidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(3-hydroxy-
2,2-dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl)-3-methylpyrrolidin-
2-one 4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-(3-hydroxypyrrolidine-1-
carbonyl)piperidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-methoxy-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)acetyl]-
5-(trifluoromethyl)pyrrolidin-3-one
4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-methoxy-1-
(5-methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-
oxoethyl]pyrrolidin-3-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methyl-1-(pyrrolidine-1-
sulfonyl)azetidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-
dimethylpropanoyl)-4-methoxy-1H-pyrazol-3-yl)-3-methyl-1-
(morpholine-4-carbonyl)pyrrolidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]azetidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methyl-1-(2-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-3-
(trifluoromethyl)pyrrolidine-1-carboxamide
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2-methoxybenzoyl)-
4-methyl-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)acetyl]-3-
(trifluoromethyl)piperidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(furan-2-carbonyl)-
1H-pyrazol-3-yl)-5-methyl-1-(pyrrolidine-1-carbonyl)pyrrolidin-3-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(furan-2-carbonyl)-4-
methoxy-1H-pyrazol-3-yl)-5-methylpyrrolidin-3-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1H-pyrazol-3-yl)-1-
(pyrrolidine-1-sulfonyl)piperidin-3-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-3-[1-(pyrrolidine-1-
carbonyl)-3-(trifluoromethyl)azetidin-2-yl]-1H-pyrazole-1-carbonyl)-
1,3-thiazole
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-fluoro-1-(3-methoxy-
2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-methanesulfonyl-3-
methylpiperidin-2-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-fluoro-1-(furan-3-
carbonyl)-1H-pyrazol-3-yl)-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-5-
methylpiperidin-3-one
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-fluoro-1-(thiophene-
2-carbonyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-carboxamide
4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-methoxy-1H-pyrazol-
3-yl)-1-(pyrrolidine-1-carbonyl)pyrrolidin-2-one
4-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(furan-2-carbonyl)-4-
methyl-1H-pyrazol-3-yl)-N,N,3-trimethyl-5-oxopiperidine-1-
carboxamide
4-(5-{[4-(aminomethyl)phenyl]methoxy}-1H-pyrazol-3-yl)-1-
(pyrrolidine-1-carbonyl)piperidin-3-one
4-(5-{[4-(aminomethyl)phenyl]methoxy}-4-cyano-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-3-
(trifluoromethyl)piperidine-1-carboxamide
4-(5-{[4-(aminomethyl)phenyl]methoxy}-4-fluoro-1-(furan-3-carbonyl)-
1H-pyrazol-3-yl)-3-methyl-1-[2-(morpholin-4-yl)-2-oxoethyl]piperidin-
2-one
4-(5-{[4-(aminomethyl)phenyl]methoxy}-4-methyl-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)acetyl]pyrrolidin-
2-one
4-({[1-(2,2-dimethylpropanoyl)-3-[1-(2,2-dimethylpropanoyl)-2-
oxoazetidin-3-yl]-4-methoxy-1H-pyrazol-5-yl]amino}methyl)benzene-1-
carboximidamide
4-({[1-(2,2-dimethylpropanoyl)-3-[4-(pyrrolidine-1-carbonyl)piperazin-
2-yl]-1H-pyrazol-5-yl](methyl)amino}methyl)benzene-1-
carboximidamide
4-({[1-(2,2-dimethylpropanoyl)-4-fluoro-3-[1-(morpholine-4-carbonyl)-
4-oxopyrrolidin-3-yl]-1H-pyrazol-5-yl](methyl)amino}methyl)benzene-
1-carboximidamide
4-({[1-(2,2-dimethylpropanoyl)-4-methyl-3-[2-oxo-1-(pyrrolidine-1-
carbonyl)piperidin-3-yl]-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[1-(2,2-dimethylpropanoyl)-4-methyl-3-{1-[2-(morpholin-4-
yl)acetyl]-3-oxopiperidin-4-yl}-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[1-(2-chlorobenzoyl)-3-[1-(dimethylsulfamoyl)-4-oxo-3-
(trifluoromethyl)azetidin-2-yl]-4-methoxy-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[1-(2-chlorobenzoyl)-3-[1-(pyrrolidine-1-sulfonyl)-4-
(trifluoromethyl)piperidin-3-yl]-1H-pyrazol-5-
yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[1-(2-chlorobenzoyl)-3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-3-
(trifluoromethyl)azetidin-2-yl}-4-methyl-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[1-(2-chlorobenzoyl)-4-cyano-3-{4-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]-3-(trifluoromethyl)piperazin-2-yl}-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[1-(2-chlorobenzoyl)-4-fluoro-3-[3-(trifluoromethyl)piperazin-2-yl]-
1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[1-(2-chlorobenzoyl)-4-methyl-3-[1-(pyrrolidine-1-sulfonyl)-3-
(trifluoromethyl)piperazin-2-yl]-1H-pyrazol-5-
yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[1-(2-fluorobenzoyl)-3-[4-(trifluoromethypoxan-3-yl]-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[1-(2-fluorobenzoyl)-3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-6-
oxo-4-(trifluoromethyl)piperidin-3-yl}-4-methyl-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[1-(2-fluorobenzoyl)-3-{1-[2-(morpholin-4-yl)-2-oxoethyl]-2-
(trifluoromethyl)piperidin-3-yl}-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[1-(2-methoxybenzoyl)-3-[6-oxo-4-(trifluoromethyl)piperidin-3-yl]-
1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[1-(2-methylfuran-3-carbonyl)-3-[1-(pyrrolidine-1-sulfonyl)-2-
(trifluoromethyl)pyrrolidin-3-yl]-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[1-(3-hydroxy-2,2-dimethylpropanoyl)-3-(1-methanesulfonyl-4-
methyl-5-oxopyrrolidin-3-yl)-4-methyl-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[1-(3-hydroxy-2,2-dimethylpropanoyl)-3-[1-(3-hydroxypyrrolidine-
1-carbonyl)-2-methylpyrrolidin-3-yl]-4-methyl-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[1-(3-hydroxy-2,2-dimethylpropanoyl)-4-methoxy-3-[3-methyl-4-
oxo-1-(pyrrolidine-1-carbonyl)azetidin-2-yl]-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[1-(5-methylfuran-3-carbonyl)-3-[2-oxo-1-(pyrrolidine-1-
sulfonyl)piperidin-4-yl]-1H-pyrazol-5-yl]amino}methyl)benzene-1-
carboximidamide
4-({[1-(furan-2-carbonyl)-3-[1-(3-hydroxypyrrolidine-1-carbonyl)-2-
methylazetidin-3-yl]-4-methyl-1H-pyrazol-5-
yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[1-(furan-2-carbonyl)-3-[3-methyl-1-(pyrrolidine-1-
carbonyl)piperazin-2-yl]-1H-pyrazol-5-yl]oxy}methyl)benzene-1-
carboximidamide
4-({[1-(furan-2-carbonyl)-4-methoxy-3-[2-methyl-1-(morpholine-4-
carbonyl)pyrrolidin-3-yl]-1H-pyrazol-5-yl]oxy}methyl)benzene-1-
carboximidamide
4-({[1-(furan-3-carbonyl)-3-[1-(3-hydroxypyrrolidine-1-carbonyl)-3-
methyl-5-oxopiperidin-4-yl]-4-methyl-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[1-(furan-3-carbonyl)-3-[4-methyl-1-(morpholine-4-carbonyl)-5-
oxopyrrolidin-3-yl]-1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-
carboximidamide
4-({[1-(furan-3-carbonyl)-3-[5-hydroxy-1-(3-hydroxypyrrolidine-1-
carbonyl)-2-methylpyrrolidin-3-yl]-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[3-(1-methanesulfonyl-3-methylpiperidin-4-yl)-1-(3-methoxy-2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-5-yl]oxy}methyl)benzene-1-
carboximidamide
4-({[3-(oxan-4-yl)-1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-
carboximidamide
4-({[4-cyano-1-(2,2-dimethylpropanoyl)-3-{1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]-5-oxopyrrolidin-3-yl}-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[4-cyano-1-(2-methylfuran-3-carbonyl)-3-{1-[2-(morpholin-4-
yl)acetyl]-2-oxo-3-(trifluoromethyl)piperidin-4-yl}-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-cyano-1-(3-hydroxy-2,2-dimethylpropanoyl)-3-{3-methyl-1-[2-
(morpholin-4-yl)-2-oxoethyl]-4-oxoazetidin-2-yl}-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[4-cyano-1-(3-methoxy-2,2-dimethylpropanoyl)-3-(2-
methylazetidin-3-yl)-1H-pyrazol-5-yl]oxy}methyl)benzene-1-
carboximidamide 4-({[4-cyano-1-(4-methylfuran-3-carbonyl)-3-[2-
(trifluoromethypoxolan-3-yl]-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-cyano-1-(furan-2-carbonyl)-3-[2-methyl-1-(pyrrolidine-1-
sulfonyl)azetidin-3-yl]-1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-
carboximidamide
4-({[4-cyano-1-(furan-3-carbonyl)-3-[1-(3-hydroxypyrrolidine-1-
carbonyl)-2-methylpyrrolidin-3-yl]-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[4-cyano-1-(furan-3-carbonyl)-3-{4-methyl-1-[2-(morpholin-4-
yl)acetyl]pyrrolidin-3-yl}-1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-
carboximidamide
4-({[4-cyano-3-(3-methylpiperazin-2-yl)-1-(thiophene-3-carbonyl)-1H-
pyrazol-5-yl]amino}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(2-fluorobenzoyl)-3-[4-(trifluoromethyl)piperidin-3-yl]-
1H-pyrazol-5-yl]amino}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(2-fluorobenzoyl)-3-{1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]-3-(trifluoromethyl)azetidin-2-yl}-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(2-methoxybenzoyl)-3-{1-[2-(morpholin-4-yl)-2-
oxoethyl]-3-oxo-5-(trifluoromethyl)piperidin-4-yl}-1H-pyrazol-5-
yl]oxy}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(3-hydroxy-2,2-dimethylpropanoyl)-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-3-methyl-5-oxopiperidin-4-yl]-1H-
pyrazol-5-yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(3-methoxy-2,2-dimethylpropanoyl)-3-[3-methyl-1-
(morpholine-4-carbonyl)-2-oxopiperidin-4-yl]-1H-pyrazol-5-
yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(4-methylfuran-3-carbonyl)-3-[1-(pyrrolidine-1-
carbonyl)-3-(trifluoromethyl)azetidin-2-yl]-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(5-methylfuran-3-carbonyl)-3-[3-oxo-1-(pyrrolidine-1-
sulfonyl)piperidin-4-yl]-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(furan-2-carbonyl)-3-(4-methyl-2-oxopiperidin-3-yl)-
1H-pyrazol-5-yl]oxy}methyl)benzene-1-carboximidamide
4-({[4-fluoro-1-(furan-3-carbonyl)-3-[3-methyl-4-oxo-1-(pyrrolidine-1-
sulfonyl)azetidin-2-yl]-1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-
carboximidamide 4-({[4-methoxy-1-(1,3-thiazole-4-carbonyl)-3-[2-
(trifluoromethyl)oxolan-3-yl]-1H-pyrazol-5-yl]oxy}methyl)benzene-1-
carboximidamide
4-({[4-methoxy-1-(2-methoxybenzoyl)-3-{1-[2-(morpholin-4-yl)-2-
oxoethyl]-4-(trifluoromethyl)pyrrolidin-3-yl}-1H-pyrazol-5-
yl]sulfanyl}methyl)benzene-1-carboximidamide
4-({[4-methoxy-1-(2-methylfuran-3-carbonyl)-3-[2-
(trifluoromethyl)oxetan-3-yl]-1H-pyrazol-5-yl]amino}methyl)benzene-
1-carboximidamide
4-({[4-methoxy-1-(3-methoxy-2,2-dimethylpropanoyl)-3-(4-
methyloxolan-3-yl)-1H-pyrazol-5-yl]sulfanyl}methyl)benzene-1-
carboximidamide
4-({[4-methoxy-1-(4-methylfuran-3-carbonyl)-3-{1-[2-(morpholin-4-
yl)acetyl]-3-(trifluoromethyl)piperazin-2-yl}-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({[4-methoxy-1-(5-methylfuran-3-carbonyl)-3-(piperidin-3-yl)-1H-
pyrazol-5-yl]amino}methyl)benzene-1-carboximidamide
4-({[4-methoxy-1-(5-methylfuran-3-carbonyl)-3-{1-[2-(morpholin-4-yl)-
2-oxoethyl]-6-oxopiperidin-3-yl}-1H-pyrazol-5-
yl](methyl)amino}methyl)benzene-1-carboximidamide
4-({[4-methyl-1-(4-methylfuran-3-carbonyl)-3-{1-[2-(morpholin-4-
yl)acetyl]-3-(trifluoromethyl)piperidin-4-yl}-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({methyl[1-(2-methylfuran-3-carbonyl)-3-{1-[2-(morpholin-4-yl)-2-
oxoethyl]-3-oxo-5-(trifluoromethyl)piperidin-4-yl}-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({methyl[4-methyl-1-(2-methylfuran-3-carbonyl)-3-[1-(morpholine-4-
carbonyl)-2-(trifluoromethyl)piperidin-3-yl]-1H-pyrazol-5-
yl]amino}methyl)benzene-1-carboximidamide
4-({methyl[4-methyl-1-(4-methylfuran-3-carbonyl)-3-[2-oxo-1-
(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)piperidin-4-yl]-1H-pyrazol-
5-yl]amino}methyl)benzene-1-carboximidamide
4-[({1-benzoyl-3-[2-methyl-4-oxo-1-(pyrrolidine-1-sulfonyl)pyrrolidin-
3-yl]-1H-pyrazol-5-yl}amino)methyl]benzene-1-carboximidamide
4-[({3-[1-(2,2-dimethylpropanoyl)-2-oxo-4-(trifluoromethyl)pipendin-3-
yl]-4-methyl-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-
yl}sulfanyl)methyl]benzene-1-carboximidamide
4-[({3-[1-(2,2-dimethylpropanoyl)-3-(trifluoromethyl)azetidin-2-yl]-4-
fluoro-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-
yl}sulfanyl)methyl]benzene-1-carboximidamide
4-[({3-[1-(2,2-dimethylpropanoyl)-3-oxo-5-(trifluoromethyl)pipendin-4-
yl]-1-(2-methoxybenzoyl)-4-methyl-1H-pyrazol-5-
yl}oxy)methyl]benzene-1-carboximidamide
4-[({3-[1-(2,2-dimethylpropanoyl)-4-methyl-2-oxopyrrolidin-3-yl]-1-
(furan-3-carbonyl)-4-methyl-1H-pyrazol-5-yl}sulfanyl)methyl]benzene-
1-carboximidamide
4-[({3-[1-(2,2-dimethylpropanoyl)-4-methyl-6-oxopiperidin-3-yl]-1-
(furan-3-carbonyl)-4-methoxy-1H-pyrazol-5-yl}oxy)methyl]benzene-1-
carboximidamide
4-[({3-[1-(2,2-dimethylpropanoyl)-5-hydroxypyrrolidin-3-yl]-4-fluoro-
1-(thiophene-2-carbonyl)-1H-pyrazol-5-yl}sulfanyl)methyl]benzene-1-
carboximidamide
4-[({3-[1-(3-hydroxypyrrolidine-1-carbonyl)-4-methylpyrrolidin-3-yl]-4-
methoxy-1-(thiophene-3-carbonyl)-1H-pyrazol-5-
yl}amino)methyl]benzene-1-carboximidamide
4-[({3-[1-(dimethylsulfamoyl)-3-methyl-2-oxopiperidin-4-yl]-1-(furan-
2-carbonyl)-4-methoxy-1H-pyrazol-5-yl}sulfanyl)methyl]benzene-1-
carboximidamide
4-[({3-[1-(dimethylsulfamoyl)-4-oxopyrrolidin-3-yl]-4-methyl-1-
(thiophene-2-carbonyl)-1H-pyrazol-5-yl}sulfanyl)methyl]benzene-1-
carboximidamide
4-[({3-[1-(dimethylsulfamoyl)piperidin-4-yl]-4-methyl-1-(thiophene-2-
carbonyl)-1H-pyrazol-5-yl}oxy)methyl]benzene-1-carboximidamide
4-[({3-[1-(morpholine-4-carbonyl)-4-oxo-3-(trifluoromethyl)azetidin-2-
yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-yl}oxy)methyl]benzene-1-
carboximidamide 4-[({4-cyano-3-[1-(2,2-dimethylpropanoyl)-2-oxo-3-
(trifluoromethyl)piperidin-4-yl]-1-(4-methylfuran-3-carbonyl)-1H-
pyrazol-5-yl}amino)methyl]benzene-1-carboximidamide
4-[({4-cyano-3-[1-(2,2-dimethylpropanoyl)-4-(trifluoromethyl)piperidin-
3-yl]-1-(2-methylfuran-3-carbonyl)-1H-pyrazol-5-
yl}amino)methyl]benzene-1-carboximidamide
4-[({4-cyano-3-[1-(2,2-dimethylpropanoyl)-4-oxoazetidin-2-yl]-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-5-yl}amino)methyl]benzene-1-
carboximidamide
4-[({4-cyano-3-[1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]-1H-pyrazol-
5-yl}sulfanyl)methyl]benzene-1-carboximidamide
4-[({4-cyano-3-[1-methanesulfonyl-2-oxo-4-(trifluoromethyl)piperidin-
3-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-
yl}sulfanyl)methyl]benzene-1-carboximidamide
4-[({4-cyano-3-[2-methyl-1-(morpholine-4-carbonyl)pyrrolidin-3-yl]-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-
yl}(methyl)amino)methyl]benzene-1-carboximidamide
4-[({4-cyano-3-[2-oxo-1-(pyrrolidine-1-carbonyl)-3-
(trifluoromethyl)piperidin-4-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-
5-yl}oxy)methyl]benzene-1-carboximidamide
4-[({4-fluoro-3-[1-(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1-
(thiophene-2-carbonyl)-1H-pyrazol-5-yl}oxy)methyl]benzene-1-
carboximidamide
4-[({4-fluoro-3-[2-methyl-4-oxo-1-(pyrrolidine-1-carbonyl)pyrrolidin-3-
yl]-1-(thiophene-3-carbonyl)-1H-pyrazol-5-
yl}(methyl)amino)methyl]benzene-1-carboximidamide
4-[({4-fluoro-3-[4-(pyrrolidine-1-sulfonyl)-3-(trifluoromethyl)piperazin-
2-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-yl}oxy)methyl]benzene-
1-carboximidamide
4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-fluoro-1-(2-
methoxybenzoyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)piperidine-1-
carbonyl]morpholine
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(2,2-
dimethylpropanoyl)-4-methoxy-1H-pyrazol-3-yl]-1-
methanesulfonylazetidin-2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(3-hydroxy-
2,2-dimethylpropanoyl)-1H-pyrazol-3-yl]-3-methyl-1-[2-(morpholin-4-
yl)-2-oxoethyl]piperidin-2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(thiophene-3-
carbonyl)-1H-pyrazol-3-yl]-N,N,3-trimethyl-2-oxopiperidine-1-
sulfonamide
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-benzoyl-4-
methyl-1H-pyrazol-3-yl]-3-methyl-1-(morpholine-4-carbonyl)piperidin-
2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-fluoro-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl]-N,N,3-trimethyl-5-
oxopiperidine-1-carboxamide
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-methyl-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-N,N-dimethyl-2-oxo-3-
(trifluoromethyl)piperidine-1-carboxamide
4-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-methyl-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]pyrrolidin-2-ol
4-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(2,2-
dimethylpropanoyl)-4-methyl-1H-pyrazol-3-yl]-1-(pyrrolidine-1-
sulfonyl)pyrrolidin-2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-benzoyl-4-fluoro-1H-
pyrazol-3-yl]-1-methanesulfonyl-5-methylpyrrolidin-2-ol
4-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-fluoro-1-(2-
fluorobenzoyl)-1H-pyrazol-3-yl]-1-(2,2-dimethylpropanoyl)-3-
(trifluoromethyl)pyrrolidin-2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-fluoro-1-(4-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-1-(morpholine-4-carbonyl)-3-
(trifluoromethyl)azetidin-2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-methoxy-1-(5-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-1-(2,2-
dimethylpropanoyl)pyrrolidin-3-one
4-[5-({[4-(aminomethyl)phenyl]methyl}amino)-4-methoxy-1-
(thiophene-3-carbonyl)-1H-pyrazol-3-yl]-1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]-5-methylpyrrolidin-2-ol
4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(2-chlorobenzoyl)-
4-methyl-1H-pyrazol-3-yl]-1-(2,2-dimethylpropanoyl)-3-
(trifluoromethyl)pyrrolidin-2-one
4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(furan-2-carbonyl)-
1H-pyrazol-3-yl]-1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-5-
methylpyrrolidin-2-ol
4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1H-pyrazol-3-yl]-1-
(2,2-dimethylpropanoyl)pyrrolidin-3-one
4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-methoxy-1-(3-
methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl]-5-methyl-1-
(pyrrolidine-1-sulfonyl)pyrrolidin-3-one
4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-methyl-1-
(thiophene-2-carbonyl)-1H-pyrazol-3-yl]-1-(morpholine-4-
carbonyl)piperidin-3-one
4-[5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-4-methyl-1H-pyrazol-
3-yl]-1-(2,2-dimethylpropanoyl)azetidin-2-one
4-fluoro-N-[(4-fluorophenyl)methyl]-1-(2-methoxybenzoyl)-N-methyl-
3-[1-(pyrrolidine-1-sulfonyl)-2-(trifluoromethyl)pyrrolidin-3-yl]-1H-
pyrazol-5-amine
4-{1-benzoyl-4-fluoro-5-[(4-fluorophenyl)methoxy]-1H-pyrazol-3-yl}-
5-methyl-1-(pyrrolidine-1-sulfonyl)pyrrolidin-2-ol
4-{1-benzoyl-5-[(4-fluorophenyl)methoxy]-1H-pyrazol-3-yl}-3-
methylpiperidin-2-one
4-{2-[4-fluoro-1-(2-fluorobenzoyl)-5-[(4-fluorophenyl)methoxy]-1H-
pyrazol-3-yl]-3-(trifluoromethyl)piperazine-1-carbonyl}morpholine
4-{3-[1-(2-chlorobenzoyl)-5-[(5-chlorothiophen-2-yl)methoxy]-4-fluoro-
1H-pyrazol-3-yl]-4-(trifluoromethyl)piperidine-1-carbonyl}morpholine
4-{5-[(4-fluorophenyl)methoxy]-1-(3-hydroxy-2,2-dimethylpropanoyl)-
4-methyl-1H-pyrazol-3-yl}-1-methanesulfonyl-5-methylpiperidin-3-one
4-{5-[(4-fluorophenyl)methoxy]-1-(4-methylfuran-3-carbonyl)-1H-
pyrazol-3-yl}-1-(3-hydroxypyrrolidine-1-carbonyl)-3-
(trifluoromethyl)azetidin-2-one
4-{5-[(4-fluorophenyl)methoxy]-1-(5-methylfuran-3-carbonyl)-1H-
pyrazol-3-yl}-1-methanesulfonylpyrrolidin-3-one
4-{5-[(4-fluorophenyl)methoxy]-4-methoxy-1-(4-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl}-1-[2-(morpholin-4-yl)-2-oxoethyl]-3-
(trifluoromethyl)pyrrolidin-2-one
4-{5-[(4-fluorophenyl)methoxy]-4-methoxy-1-(5-methylfuran-3-
carbonyl)-1H-pyrazol-3-yl}piperidine
4-{5-[(5-chlorothiophen-2-yl)methoxy]-1-(3-methoxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl}-1-[(3-hydroxypyrrolidin-1-
yl)sulfonyl]-3-methylpiperidin-2-one
4-{5-[(5-chlorothiophen-2-yl)methoxy]-4-methoxy-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl}piperidin-3-one
4-{[(1-benzoyl-3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-4-
methylpiperidin-3-yl}-1H-pyrazol-5-yl)(methyl)amino]methyl}benzene-
1-carboximidamide
4-{[(1-benzoyl-4-cyano-3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-2-
methyl-4-oxoazetidin-3-yl}-1H-pyrazol-5-
yl)(methyl)amino]methyl}benzene-1-carboximidamide
4-{[(3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-2-methylpiperidin-3-yl}-
1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-5-
yl)sulfanyl]methyl}benzene-1-carboximidamide
4-{[(3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-3-
(trifluoromethyl)piperidin-4-yl}-1-(4-methylfuran-3-carbonyl)-1H-
pyrazol-5-yl)(methyl)amino]methyl}benzene-1-carboximidamide
4-{[(3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-4-oxoazetidin-2-yl}-4-
methyl-1H-pyrazol-5-yl)sulfanyl]methyl}benzene-1-carboximidamide
4-{[(3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]azetidin-3-yl}-1-
(thiophene-2-carbonyl)-1H-pyrazol-5-yl)sulfanyl]methyl}benzene-1-
carboximidamide
4-{[(3-{1-[2-(morpholin-4-yl)-2-oxoethyl]-6-oxopiperidin-3-yl}-1H-
pyrazol-5-yl)oxy]methyl}benzene-1-carboximidamide
4-{[(3-{3-methyl-1-[2-(morpholin-4-yl)-2-oxoethyl]azetidin-2-yl}-1-
(thiophene-3-carbonyl)-1H-pyrazol-5-yl)amino]methyl}benzene-1-
carboximidamide
4-{[(4-fluoro-3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-2-oxo-4-
(trifluoromethyl)piperidin-3-yl}-1-(2-methylfuran-3-carbonyl)-1H-
pyrazol-5-yl)amino]methyl}benzene-1-carboximidamide
4-{[(4-fluoro-3-{1-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-4-
methylpiperidin-3-yl}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-
pyrazol-5-yl)oxy]methyl}benzene-1-carboximidamide
4-{[(4-fluoro-3-{1[2-(morpholin-4-yl)acetyl]azetidin-2-yl}-1H-pyrazol-
5-yl)oxy]methyl}benzene-1-carboximidamide
4-{[(4-methyl-3-{1-[2-(morpholin-4-yl)acetyl]-2-oxopiperidin-3-yl}-1H-
pyrazol-5-yl)oxy]methyl}benzene-1-carboximidamide
5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-
methyl-1H-pyrazol-3-yl)-4-methyl-1-(pyrrolidine-1-carbonyl)piperidin-
2-one
5-(4-cyano-5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxopiperidine-1-
sulfonamide
5-(4-fluoro-5-{[(4-fluorophenyl)methyl]amino}-1-(thiophene-3-
carbonyl)-1H-pyrazol-3-yl)-1-methanesulfonyl-4-methylpiperidin-2-one
5-(5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methoxy-1-(thiophene-2-
carbonyl)-1H-pyrazol-3-yl)-1-(pyrrolidine-1-sulfonyl)piperidin-2-one
5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-4-cyano-1-(3-
hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N,4-trimethyl-2-
oxopiperidine-1-carboxamide
5-(5-{[4-(aminomethyl)phenyl]methoxy}-1-(furan-2-carbonyl)-1H-
pyrazol-3-yl)-1-methanesulfonyl-4-methylpiperidin-2-one
5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(2-
fluorobenzoyl)-3-[1-(pyrrolidine-1-sulfonyl)-3-
(trifluoromethyl)piperazin-2-yl]-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-(5-methylfuran-
3-carbonyl)-3-[2-oxo-1-(pyrrolidine-1-sulfonyl)piperidin-3-yl]-1H-
pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-1-benzoyl-3-{4-
methyl-1-[2-(morpholin-4-yl)acetyl]-2-oxopyrrolidin-3-yl}-1H-
pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-3-[1-(2,2-
dimethylpropanoyl)-4-methyl-2-oxopyrrolidin-3-yl]-1-(3-hydroxy-2,2-
dimethylpropanoyl)-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(2,2-dimethylpropanoyl)-
3-{1-[2-(morpholin-4-yl)acetyl]piperidin-3-yl}-1H-pyrazole-4-
carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(4-methylfuran-3-
carbonyl)-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)piperidin-4-
yl]-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(5-methylfuran-3-
carbonyl)-3-{1-[2-(morpholin-4-yl)acetyl]-2-oxopiperidin-3-yl}-1H-
pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}amino)-1-benzoyl-3-(1-
methanesulfonyl-3-methylpiperidin-4-yl)-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}amino)-3-[1-(2,2-
dimethylpropanoyl)-3-oxo-5-(trifluoromethyl)piperidin-4-yl]-1-(2-
methylfuran-3-carbonyl)-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}amino)-3-{4-methyl-2-[2-
(morpholin-4-yl)-2-oxoethyl]-2-oxopiperidin-3-yl}-1-(thiophene-3-
carbonyl)-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(2-chlorobenzoyl)-3-
[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)piperidin-4-yl]-1H-
pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-1-(2-methoxybenzoyl)-3-
[2-(trifluoromethyl)oxetan-3-yl]-1H-pyrazole-4-carbonitrile
5-({[4-(aminomethyl)phenyl]methyl}sulfanyl)-3-{1-[(3-
hydroxypyrrolidin-1-yl)sulfonyl]-4-oxopyrrolidin-3-yl}-1-(thiophene-2-
carbonyl)-1H-pyrazole-4-carbonitrile
5-[(4-fluorophenyl)methoxy]-1-(3-hydroxy-2,2-dimethylpropanoyl)-3-
[4-(3-hydroxypyrrolidine-1-carbonyl)-3-methylpiperazin-2-yl]-1H-
pyrazole-4-carbonitrile
5-[(4-fluorophenyl)methoxy]-1-(4-methylfuran-3-carbonyl)-3-[1-
(morpholine-4-carbonyl)-3-(trifluoromethyl)azetidin-2-yl]-1H-pyrazole-
4-carbonitrile
5-[(4-fluorophenyl)methoxy]-1-(5-methylfuran-3-carbonyl)-3-{1-[2-
(morpholin-4-yl)acetyl]-4-oxoazetidin-2-yl}-1H-pyrazole-4-carbonitrile
5-[(4-fluorophenyl)methoxy]-3-{4-methyl-1-[2-(morpholin-4-
yl)acetyl]piperidin-3-yl}-1-(thiophene-3-carbonyl)-1H-pyrazole-4-
carbonitrile
5-[(4-fluorophenyl)methoxy]-4-methoxy-1-(2-methylfuran-3-carbonyl)-
3-[2-(trifluoromethypoxan-3-yl]-1H-pyrazole
5-[(4-fluorophenyl)methoxy]-4-methoxy-3-[3-methyl-1-(pyrrolidine-1-
sulfonyl)azetidin-2-yl]-1-(thiophene-3-carbonyl)-1H-pyrazole
5-[(5-chlorothiophen-2-yl)methoxy]-1-(3-methoxy-2,2-
dimethylpropanoyl)-3-[4-methyl-6-oxo-1-(pyrrolidine-1-
carbonyl)piperidin-3-yl]-1H-pyrazole-4-carbonitrile
5-[(5-chlorothiophen-2-yl)methoxy]-1-(furan-2-carbonyl)-3-[4-methyl-
1-(pyrrolidine-1-carbonyl)piperidin-3-yl]-1H-pyrazole-4-carbonitrile
5-[(5-chlorothiophen-2-yl)methoxy]-3-[1-(3-hydroxypyrrolidine-1-
carbonyl)-5-oxopyrrolidin-3-yl]-1-(thiophene-2-carbonyl)-1H-pyrazole-
4-carbonitrile
5-[(5-chlorothiophen-2-yl)methoxy]-3-[2-oxo-1-(pyrrolidine-1-
carbonyl)-4-(trifluoromethyl)azetidin-3-yl]-1-(1,3-thiazole-4-carbonyl)-
1H-pyrazole-4-carbonitrile
5-[(5-chlorothiophen-2-yl)methoxy]-4-fluoro-3-[1-(pyrrolidine-1-
sulfonyl)pyrrolidin-3-yl]-1-(thiophene-2-carbonyl)-1H-pyrazole
5-[(5-chlorothiophen-2-yl)methoxy]-4-methyl-3-(pyrrolidin-3-yl)-1H-
pyrazole
5-[5-({[4-(aminomethyl)phenyl]methyl}(methyl)amino)-4-fluoro-1-(2-
methylfuran-3-carbonyl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)piperidin-
2-one 5-[5-({[4-(aminomethyl)phenyl]methyl}amino)-1-(3-hydroxy-2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl]-1-(2,2-dimethylpropanoyl)-4-
methylpiperidin-2-one
5-{1-benzoyl-5-[(4-fluorophenyl)methoxy]-4-methoxy-1H-pyrazol-3-
yl}-1-(3-hydroxypyrrolidine-1-carbonyl)-4-methylpiperidin-2-one
5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(2-methoxybenzoyl)-3-
[2-(trifluoromethypoxan-3-yl]-1H-pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl](methyl)amino}-1-(furan-3-carbonyl)-3-(1-
methanesulfonyl-4-methyl-5-oxopyrrolidin-3-yl)-1H-pyrazole-4-
carbonitrile
5-{[(4-fluorophenyl)methyl](methyl)amino}-3-(piperidin-4-yl)-1H-
pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl](methyl)amino}-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-4-methyl-6-oxopiperidin-3-yl]-1-(3-
methoxy-2,2-dimethylpropanoyl)-1H-pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl]amino}-1-(2-methylfuran-3-carbonyl)-3-{1-
[2-(morpholin-4-yl)acetyl]-2-(trifluoromethyl)pyrrolidin-3-yl}-1H-
pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl]amino}-1-(5-methylfuran-3-carbonyl)-3-[5-
oxo-1-(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1H-pyrazole-4-
carbonitrile
5-{[(4-fluorophenyl)methyl]amino}-3-(2-methyl-4-oxopyrrolidin-3-yl)-
1-(thiophene-3-carbonyl)-1H-pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(2-methoxybenzoyl)-3-{1-[2-
(morpholin-4-yl)acetyl]-6-oxo-4-(trifluoromethyl)piperidin-3-yl}-1H-
pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl]sulfanyl}-1-(furan-3-carbonyl)-3-(1-
methanesulfonyl-2-methylazetidin-3-yl)-1H-pyrazole
5-{[(4-fluorophenyl)methyl]sulfanyl}-3-{1-[2-(morpholin-4-yl)-2-
oxoethyl]-4-oxopyrrolidin-3-yl}-1H-pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl]sulfanyl}-3-{1-[2-(morpholin-4-yl)acetyl]-
4-oxo-2-(trifluoromethyl)pyrrolidin-3-yl}-1-(1,3-thiazole-4-carbonyl)-
1H-pyrazole-4-carbonitrile
5-{[(4-fluorophenyl)methyl]sulfanyl}-4-methoxy-1-(2-
methoxybenzoyl)-3-[3-(trifluoromethyl)oxetan-2-yl]-1H-pyrazole
5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-
dimethylpropanoyl)-3-[1-(morpholine-4-carbonyl)-6-oxopiperidin-3-yl]-
1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2-fluorobenzoyl)-
3-{5-hydroxy-l-[2-(morpholin-4-yl)acetyl]-2-
(trifluoromethyl)pyrrolidin-3-yl}-1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(4-methylfuran-3-
carbonyl)-3-[4-oxo-3-(trifluoromethyl)azetidin-2-yl]-1H-pyrazole-4-
carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-3-[5-
hydroxy-1-(morpholine-4-carbonyl)-2-(trifluoromethyl)pyrrolidin-3-yl]-
1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methylfuran-3-
carbonyl)-3-{1-[2-(morpholin-4-yl)-2-oxoethyl]-4-
(trifluoromethyl)pyrrolidin-3-yl}-1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-
dimethylpropanoyl)-3-[2-methyl-1-(pyrrolidine-1-carbonyl)piperidin-3-
yl]-1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(furan-3-carbonyl)-3-[3-
methyl-4-oxo-1-(pyrrolidine-1-carbonyl)azetidin-2-yl]-1H-pyrazole-4-
carbonitrile 5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-2-oxo-4-(trifluoromethyl)azetidin-3-yl]-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-3-[1-(3-
hydroxypyrrolidine-1-carbonyl)-4-oxopyrrolidin-3-yl]-1-(thiophene-2-
carbonyl)-1H-pyrazole-4-carbonitrile
5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-4-methyl-3-[1-
(pyrrolidine-1-carbonyl)pyrrolidin-3-yl]-1-(thiophene-2-carbonyl)-1H-
pyrazole
5-{[4-(aminomethyl)phenyl]methoxy}-1-(2-chlorobenzoyl)-3-[1-(3-
hydroxypyrrolidine-l-carbonyl)-3-(trifluoromethyl)piperazin-2-yl]-1H-
pyrazole-4-carbonitrile
5-{[4-(aminomethyl)phenyl]methoxy}-1-(furan-2-carbonyl)-3-[2-
methyl-1-(morpholine-4-carbonyl)-4-oxoazetidin-3-yl]-1H-pyrazole-4-
carbonitrile
5-{[4-(aminomethyl)phenyl]methoxy}-1-(furan-3-carbonyl)-3-(1-
methanesulfonyl-4-methyl-2-oxopyrrolidin-3-yl)-1H-pyrazole-4-
carbonitrile
5-{[4-(aminomethyl)phenyl]methoxy}-3-(5-hydroxypyrrolidin-3-yl)-1H-
pyrazole-4-carbonitrile
N-[(4-fluorophenyl)methyl]-3-[1-methanesulfonyl-2-
(trifluoromethyl)piperidin-3-yl]-4-methyl-1-(2-methylfuran-3-carbonyl)-
1H-pyrazol-5-amine
N-[(4-fluorophenyl)methyl]-4-methyl-1-(5-methylfuran-3-carbonyl)-3-
(morpholin-2-yl)-1H-pyrazol-5-amine
N-[(4-fluorophenyl)methyl]-N,4-dimethyl-3-[1-(morpholine-4-
carbonyl)-3-(trifluoromethyl)azetidin-2-yl]-1-(1,3-thiazole-4-carbonyl)-
1H-pyrazol-5-amine
N-[(4-fluorophenyl)methyl]-N-methyl-3-(pyrrolidin-3-yl)-1-(thiophene-
2-carbonyl)-1H-pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-1-(2-fluorobenzoyl)-3-[1-
methanesulfonyl-4-(trifluoromethyl)pyrrolidin-3-yl]-4-methoxy-N-
methyl-1H-pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-1-(2-fluorobenzoyl)-4-methoxy-3-[1-
(pyrrolidine-1-sulfonyl)-4-(trifluoromethyl)piperidin-3-yl]-1H-pyrazol-
5-amine
N-[(5-chlorothiophen-2-yl)methyl]-1-(2-fluorobenzoyl)-4-methyl-3-[1-
(morpholine-4-carbonyl)-4-(trifluoromethyl)piperidin-3-yl]-1H-pyrazol-
5-amine
N-[(5-chlorothiophen-2-yl)methyl]-1-(2-fluorobenzoyl)-N,4-dimethyl-3-
[1-(pyrrolidine-1-sulfonyl)-2-(trifluoromethyl)piperidin-3-yl]-1H-
pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-3-(4-methanesulfonyl-3-
methylpiperazin-2-yl)-N-methyl-1-(thiophene-3-carbonyl)-1H-pyrazol-
5-amine
N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-N-methyl-1-(5-methylfuran-
3-carbonyl)-3-(pyrrolidin-3-yl)-1H-pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-4-methoxy-3-[4-methyl-1-
(pyrrolidine-1-carbonyl)piperidin-3-yl]-1-(thiophene-3-carbonyl)-1H-
pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-4-methyl-3-[2-methyl-1-(pyrrolidine-
1-sulfonyl)azetidin-3-yl]-1-(thiophene-3-carbonyl)-1H-pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-N-methyl-1-(2-methylfuran-3-
carbonyl)-3-[3-(trifluoromethypoxetan-2-yl]-1H-pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-1-(2-fluorobenzoyl)-3-[1-
methanesulfonyl-2-(trifluoromethyl)pyrrolidin-3-yl]-N-methyl-1H-
pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-1-(2-fluorobenzoyl)-4-methyl-3-
[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)piperidin-4-yl]-1H-
pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-1-(2-fluorobenzoyl)-N,4-dimethyl-
3-[3-(trifluoromethyl)piperazin-2-yl]-1H-pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-1-benzoyl-4-methoxy-3-(2-
methylazetidin-3-yl)-1H-pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-4-fluoro-N-methyl-1-(5-
methylfuran-3-carbonyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-4-methoxy-1-(2-methylfuran-3-
carbonyl)-3-[1-(morpholine-4-carbonyl)-2-(trifluoromethyl)azetidin-3-
yl]-1H-pyrazol-5-amine
N-{[4-(aminomethyl)phenyl]methyl}-4-methyl-1-(4-methylfuran-3-
carbonyl)-3-[4-(pyrrolidine-1-sulfonyl)-3-(trifluoromethyl)piperazin-2-
yl]-1H-pyrazol-5-amine
[4-({[1-(2-chlorobenzoyl)-3-[4-(trifluoromethyl)pipendin-3-yl]-1H-
pyrazol-5-yl]sulfanyl}methyl)phenyl]methanamine
[4-({[1-(2-chlorobenzoyl)-4-fluoro-3-[1-methanesulfonyl-2-
(trifluoromethyl)pyrrolidin-3-yl]-1H-pyrazol-5-
yl]oxy}methyl)phenyl]methanamine
[4-({[1-(2-chlorobenzoyl)-4-methoxy-3-[4-(trifluoromethypoxan-3-yl]-
1H-pyrazol-5-yl]sulfanyl}methyl)phenyl]methanamine
[4-({[1-(2-methoxybenzoyl)-3-[1-(morpholine-4-carbonyl)-2-
(trifluoromethyl)azetidin-3-yl]-1H-pyrazol-5-
yl]sulfanyl}methyl)phenyl]methanamine
[4-({[1-(furan-2-carbonyl)-4-methyl-3-(3-methylpiperazin-2-yl)-1H-
pyrazol-5-yl]sulfanyl}methyl)phenyl]methanamine
[4-({[1-(furan-3-carbonyl)-4-methyl-3-[2-methyl-1-(pyrrolidine-1-
carbonyl)azetidin-3-yl]-1H-pyrazol-5-
yl]oxy}methyl)phenyl]methanamine
[4-({[4-fluoro-3-(1-methanesulfonylpiperazin-2-yl)-1-(thiophene-2-
carbonyl)-1H-pyrazol-5-yl]oxy}methyl)phenyl]methanamine
[4-({[4-fluoro-3-(morpholin-2-yl)-1H-pyrazol-5-
yl]oxy}methyl)phenyl]methanamine
{4-[({4-fluoro-3-[1-methanesulfonyl-2-(trifluoromethyl)piperidin-3-yl]-
1-(2-methoxybenzoyl)-1H-pyrazol-5- yl}oxy)methyl]phenyl}methanamine
{4-[({4-methoxy-3-[1-(morpholine-4-carbonyl)-3-
(trifluoromethyl)piperidin-4-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-
5-yl}sulfanyl)methyl]phenyl}methanamine
N-[(5-chlorothiophen-2-yl)methyl]-3-(piperazin-2-yl)-1H-pyrazol-5-
amine
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-[2-(morpholin-4-
yl)acetyl]piperazin-2-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-
yl)piperazin-1-yl]-2-(morpholin-4-yl)ethan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(morpholine-4-
sulfonyl)piperazin-2-yl]-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(2,2,2-
trifluoroethyl)piperazin-2-yl]-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-
one
N-[(5-chlorothiophen-2-yl)methyl]-3-(pyrrolidin-2-yl)-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine
1-[2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)pyrrolidin-1-yl]-2-(morpholin-4-yl)ethan-1-
one
N-[(5-chlorothiophen-2-yl)methyl]-3-(pyrrolidin-3-yl)-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)pyrrolidin-1-yl]-2-(morpholin-4-yl)ethan-1-
one
N-[(5-chlorothiophen-2-yl)methyl]-3-(piperazin-2-yl)-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine
1-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-3-yl)piperazin-1-yl]-2-(morpholin-4-yl)ethan-1-
one
N-[(5-chlorothiophen-2-yl)methyl]-3-(4-methanesulfonylpiperazin-2-yl)-
1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]-3-[4-(morpholine-4-
carbonyl)piperazin-2-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-5-
amine
1-[3-(azepan-4-yl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-
pyrazol-1-yl]-2,2-dimethylpropan-1-one
3-(azepan-4-yl)-N-[(5-chlorothiophen-2-yl)methyl]-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine
1-[3-(azetidin-3-yl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-
pyrazol-1-yl]-2,2-dimethylpropan-1-one
N-[(5-chlorothiophen-2-yl)methyl]-3-[1-(morpholine-4-
carbonyl)azetidin-3-yl]-1H-pyrazol-5-amine
3-(azetidin-3-yl)-N-[(5-chlorothiophen-2-yl)methyl]-1-(1,3-thiazole-4-
carbonyl)-1H-pyrazol-5-amine
3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-
pyrazol-3-yl]-N,N-dimethylpyrrolidine-1-sulfonamide
1-(2-chlorobenzoyl)-N-[(5-chlorothiophen-2-yl)methyl]-3-[1-
(pyrrolidine-1-sulfonyl)pyrrolidin-3-yl]-1H-pyrazol-5-amine
1-(2-chlorobenzoyl)-N-[(5-chlorothiophen-2-yl)methyl]-3-[1-
(piperazine-1-sulfonyl)pyrrolidin-3-yl]-1H-pyrazol-5-amine
1-(2-chlorobenzoyl)-N-[(5-chlorothiophen-2-yl)methyl]-3-[1-
(piperazine-1-carbonyl)pyrrolidin-3-yl]-1H-pyrazol-5-amine
3-[1-(2-chlorobenzoyl)-5-{5[(5-chlorothiophen-2-yl)methyl]amino}-1H-
pyrazol-3-yl]-N,N-dimethylazetidine-1-sulfonamide
1-(2-chlorobenzoyl)-N-[(5-chlorothiophen-2-yl)methyl]-3-[1-
(pyrrolidine-1-sulfonyl)azetidin-3-yl]-1H-pyrazol-5-amine
1-(2-chlorobenzoyl)-N-[(5-chlorothiophen-2-yl)methyl]-3-[1-
(piperazine-1-sulfonyl)azetidin-3-yl]-1H-pyrazol-5-amine
1-(2-chlorobenzoyl)-N-[(5-chlorothiophen-2-yl)methyl]-3-[1-
(piperazine-1-carbonyl)azetidin-3-yl]-1H-pyrazol-5-amine
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(2-
cyclopropoxyethyl)piperazin-2-yl]-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one
4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)piperazine-1-carbonyl]morpholine-
3-carboxylic acid
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(3-
methylmorpholine-4-carbonyl)piperazin-2-yl]-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(3,5-
dimethylmorpholine-4-carbonyl)piperazin-2-yl]-1H-pyrazol-1-yl)-2,2-
dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-[2-(morpholin-4-yl)-
2-oxoethyl]piperazin-2-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-[2-(morpholin-4-
yl)ethyl]piperazin-2-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
4-{2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)piperazin-1-yl]ethyl}morpholine-
3-carboxylic acid
1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-[4-(hydroxymethyl)-
1,3-oxazol-2-yl]piperazin-2-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-
one 1-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-(4-{[4-
(hydroxymethyl)-1,3-oxazol-2-yl]methyl}piperazin-2-yl)-1H-pyrazol-1-
yl)-2,2-dimethylpropan-1-one
2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-
dimethylpropanoyl)-1H-pyrazol-3-yl)piperazin-1-yl]acetic acid
[0120] For Table D following, the disclosed compounds were assayed
for inhibition of the protease activity of chymotrypsin and Factor
XIa as described herein. In Table D, the level of inhibition in the
assay is indicated as follows: a IC.sub.50.ltoreq.0.1 .mu.M; b: 0.1
.mu.M<IC.sub.50<1 .mu.M; c: 1 .mu.M<IC.sub.50<10 .mu.M;
d: 10 .mu.M<IC.sub.50<100 .mu.M; e: IC.sub.50.gtoreq.100
.mu.M. Accordingly, in some embodiments, there is provided a
compound as expressly set forth in Table D following.
TABLE-US-00004 TABLE D Chymotrypsin Factor XIa Table, Entry or
IUPAC name Inhibition Inhibition A, 24 d d A, 25 c d A, 26 e d A,
37 e e A, 56 e (no data) A, 57 d (no data) A, 291 d e A, 292 e e
N-[(5-chlorothiophen-2-yl)methyl]- a c
1-(2-methoxybenzoyl)-3-phenyl- 1H-1,2,4-triazol-5-amine
N-[(5-chlorothiophen-2-yl)methyl]- b c
1-(2-methoxybenzoyl)-3-(pyridin- 2-yl)-1H-pyrazol-5-amine
[0121] Compounds disclosed herein also include racemic mixtures,
stereoisomers and mixtures of the compounds, including
isotopically-labeled and radio-labeled compounds. See e.g., Goding,
1986, MONOCLONAL ANTIBODIES PRINCIPLES AND PRACTICE; Academic
Press, p. 104. Such isomers can be isolated by standard resolution
techniques, including e.g., fractional crystallization, chiral
chromatography, and the like. See e.g., Eliel, E. L. & Wilen S.
H., 1993, STEREOCHEMISTRY IN ORGANIC COMPOUNDS; John Wiley &
Sons, New York.
[0122] In some embodiments, compounds disclosed herein have
asymmetric centers and can occur as racemates, racemic mixtures,
and as individual enantiomers or diastereoisomers, with all
isomeric forms as well as mixtures thereof being contemplated for
use in the compounds and methods described herein. The compounds
contemplated for use in the compounds and methods described herein
do not include those that are known in the art to be too unstable
to synthesize and/or isolate.
[0123] The compounds disclosed herein can also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds can be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I), or carbon-14 (.sup.14C). All
isotopic variations of the compounds disclosed herein, whether
radioactive or not, are encompassed within the contemplated
scope.
[0124] In some embodiments, metabolites of the compounds disclosed
herein are useful for the methods disclosed herein.
[0125] In some embodiments, compounds contemplated herein are
provided in the form of a prodrug. The term "prodrug" refers to a
compound that can be converted into a compound (e.g., a
biologically active compound) described herein in vivo. Prodrugs
can be useful for a variety of reason known in the art, including
e.g., ease of administration due e.g., to enhanced bioavailability
in oral administration, and the like. The prodrug can also have
improved solubility in pharmaceutical compositions over the
biologically active compounds. An example, without limitation, of a
prodrug is a compound which is administered as an ester (i.e., the
"prodrug") to facilitate transmittal across a cell membrane where
water solubility is detrimental to mobility but which then is
metabolically hydrolyzed to the carboxylic acid, the active entity,
once inside the cell where water solubility is beneficial.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in DESIGN
OF PRODRUGS, (ed. H. Bundgaard, Elsevier, 1985), which is hereby
incorporated herein by reference for the limited purpose describing
procedures and preparation of suitable prodrug derivatives.
[0126] Accordingly, in some embodiments, compounds contemplated
herein are provided in the form of a prodrug ester. The term
"prodrug ester" refers to derivatives of the compounds disclosed
herein formed by the addition of any of a variety of ester-forming
groups, e.g., groups known in the art, that are hydrolyzed under
physiological conditions. Examples of prodrug ester groups include
pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
methoxymethyl, as well as other such groups known in the art,
including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other
examples of prodrug ester groups can be found in, for example, T.
Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems",
Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975);
and BIOREVERSIBLE CARRIERS IN DRUG DESIGN: THEORY AND APPLICATION,
edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987)
(providing examples of esters useful as prodrugs for compounds
containing carboxyl groups). Each of the above-mentioned references
is herein incorporated by reference for the limited purpose of
disclosing ester-forming groups that can form prodrug esters.
[0127] In some embodiments, prodrugs can be slowly converted to the
compounds described herein useful for the methods described herein
when placed in a transdermal patch reservoir with a suitable enzyme
or chemical reagent.
[0128] Certain compounds disclosed herein can exist in unsolvated
forms as well as solvated forms, including hydrated forms. In
general, the solvated forms are equivalent to unsolvated forms and
are encompassed within the scope of contemplated compounds. Certain
compounds of the present invention can exist in multiple
crystalline or amorphous forms. In general, all physical forms are
equivalent for the compounds and methods contemplated herein and
are intended to be within the scope disclosed herein.
III. Biological Activities
[0129] In some embodiments, compounds described herein exhibit
inhibitory activity against thrombin with activities .gtoreq.1
.mu.M, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 100 .mu.M, or even greater. In some
embodiments, the compounds exhibit inhibitory activity against
thrombin with activities between 0.1 .mu.M and 1 .mu.M, e.g., about
0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 .mu.M. In some
embodiments, compounds described herein exhibit inhibitory activity
against thrombin with activities .ltoreq.0.1 .mu.M, e.g., about 1,
2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of
values using a combination of any of the values recited herein as
upper and/or lower limits are also contemplated, for example, but
not limited to, 1-10 nM, 10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100
.mu.M, 100-200 .mu.M, 200-500 .mu.M, or even 500-1000 .mu.M. In
some embodiments, the inhibitory activity is in the range of about
1-10 nM, 10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200
.mu.M, 200-500 .mu.M, or even 500-1000 .mu.M. It is understood that
for purposes of quantification, the terms "activity," "inhibitory
activity," "biological activity," "thrombin activity and the like
in the context of an inhibitory compound disclosed herein can be
quantified in a variety of ways known in the art. Unless indicated
otherwise, as used herein such terms refer to IC.sub.50 in the
customary sense (i.e., concentration to achieve half-maximal
inhibition).
[0130] Inhibitory activity against thrombin in turn inhibits the
blood coagulation process. Accordingly, compounds disclosed herein
are indicated in the treatment or management of thrombotic
disorders. In some embodiments, a dose or a therapeutically
effective dose of a compound disclosed herein will be that which is
sufficient to achieve a plasma concentration of the compound or its
active metabolite(s) within a range set forth herein, e.g., about
1-10 nM, 10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200
.mu.M, 200-500 .mu.M, or even 500-1000 .mu.M, preferably about 1-10
nM, 10-100 nM, or 0.1-1 .mu.M. Without wishing to be bound by any
theory, it is believe that such compounds are indicated in the
treatment or management of thrombotic disorders.
[0131] In some embodiments, compounds described herein exhibit
inhibitory activity against KLKB1 with activities between 1 .mu.M
and 10 .mu.M, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 .mu.M. In
some embodiments, compounds described herein exhibit inhibitory
activity against KLKB1 with activities >10 .mu.M, e.g., about
10, 20, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000
.mu.M or even greater. In some embodiments, compounds described
herein exhibit inhibitory activity against KLKB1 with activities
.ltoreq.1 .mu.M, e.g., about 900, 800, 700, 600, 500, 400, 300,
200, 100, 50 nM or even lower. Ranges of values using a combination
of any of the values recited herein as upper and/or lower limits
are also contemplated, for example, but not limited to, 1-10 nM,
10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200 .mu.M,
200-500 .mu.M, or even 500-100 .mu.M. In some embodiments, the
inhibitory activity is in the range of about 1-10 nM, 10-100 nM,
0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200 .mu.M, 200-500
.mu.M, or even 500-1000 .mu.M. It is understood that for purposes
of quantification, the terms "activity," "inhibitory activity,"
"biological activity," "KLKB1 activity" and the like in the context
of an inhibitory compound disclosed herein can be quantified in a
variety of ways known in the art. Unless indicated otherwise, as
used herein such terms refer to IC.sub.50 in the customary sense
(i.e., concentration to achieve half-maximal inhibition).
[0132] Inhibitory activity against KLKB1 has an effect on the
coagulation cascade and the inflammatory response. Thus, it has
been proposed that KLKB1 inhibitors can be useful in the treatment
of thrombotic and fibrinolytic diseases and disease conditions.
[0133] Accordingly, compounds disclosed herein are indicated in the
treatment or management of a variety of diseases or disorders. In
some embodiments, a dose or a therapeutically effective dose of a
compound disclosed herein will be that which is sufficient to
achieve a plasma concentration of the compound or its active
metabolite(s) within a range set forth herein, e.g., about 1-10 nM,
10-100 nM, 0.1-1 .mu.M, 1-10 .mu.M, 10-100 .mu.M, 100-200 .mu.M,
200-500 .mu.M, or even 500-1000 .mu.M, preferably about 1-10 nM,
10-100 nM, or 0.1-1 .mu.M. Without wishing to be bound by any
theory, it is believe that such compounds are indicated in the
treatment or management of diseases associated with thrombin or
kallikrein.
[0134] In some embodiments, the compounds selectively inhibit
thrombin and/or plasma kallikrein over related serine proteases
such as trypsin, chymotrypsin, factor XIIa, factor XIa, factor Xa,
and factor VIIa. In some embodiments, the compounds inhibit
chymotrypsin with an IC.sub.50 greater than 1 uM. In some
embodiments, the compounds inhibit chymotrypsin with an IC.sub.50
greater than 10 uM. In some embodiments, the compounds inhibit
chymotrypsin with an IC.sub.50 greater than 100 uM. In some
embodiments, the compounds inhibit Factor XIa with an IC.sub.50
greater than 1 uM. In some embodiments, the compounds inhibit
Factor XIa with an IC.sub.50 greater than 10 uM. In some
embodiments, the compounds inhibit Factor XIa with an IC.sub.50
greater than 100 uM.
[0135] In some embodiments, the compounds persist in the blood
plasma after intravenous infusion. In some embodiments, greater
than 50% of the initial compound concentration persists in the
blood plasma of mice 1 hour after intravenous injection. In some
embodiments, greater than 50% of the initial compound concentration
persists in the blood plasma of mice 3 hours or longer after
intravenous injection.
IV. Methods of Treating and Preventing Disease
[0136] Thrombin-Related Diseases and Conditions (e.g.
Thrombosis).
[0137] Thrombotic diseases are the primary indications for thrombin
inhibition, because of thrombin's location in the coagulation
cascade and, in turn, the importance of the coagulation cascade in
the progression of blood clotting processes. However, without
wishing to be bound by any theory, it is believed the coagulation
cascade in general, and thrombin in particular, is important in a
variety other disease states.
[0138] It has been discovered that compounds described herein,
e.g., multisubstituted aromatic compounds, exhibit inhibitory
action against thrombin (activated blood-coagulation factor II; EC
3.4.21.5). This, in turn inhibits the blood coagulation
process.
[0139] This inhibitory action is useful in the treatment of a
variety of thrombotic disorders, such as, but not limited to, acute
vascular diseases such as acute coronary syndromes; venous-,
arterial- and cardiogenic thromboembolisms; the prevention of other
states such as disseminated intravascular coagulation, or other
conditions that involve the presence or the potential formation of
a blood clot thrombus. Other indications for methods described
herein include the following.
[0140] It has long been recognized that cancer progression is
accompanied by venous thrombosis, but it has not been understood
how each disease is related. From several clinical trials studying
the treatment of VTE, meta-analyses have shown that low molecular
weight heparins (LMWHs) improve overall survival in subgroups of
cancer patients. See e.g., Zacharski, L. R. & Lee, A. Y., 2008,
Expert Opin Investig Drugs, 17:1029-1037; Falanga, A. &
Piccioli, A., 2005, Current Opinion in Pulmonary Medicine,
11:403-407; Smorenburg, S. M., et al., 1999, Thromb Haemost,
82:1600-1604; Hettiarachchi, R. J., et al., 1999, Thromb Haemost,
82:947-952. This finding was substantiated in later clinical trials
that measured specifically the survival of cancer patients. See
e.g., Lee, A. Y. et al., 2005, J Clin Oncol, 23:2123-2129; Klerk,
C. P. et al., J Clin Oncol 2005, 23:2130-2135; Kakkar, A. K., et
al., 2004, J Clin Oncol, 22:1944-1948; Altinbas, M., et al., 2004,
J Thromb Haemost, 2:1266-1271.
[0141] More recently, researchers have focused on the specific
anticancer effect of DTIs. For example, it was shown that heparin
significantly prolonged the survival of patients with limited small
cell lung cancer. See e.g., Akl, E. A., et al., 2008, J Exp Clin
Cancer Res, 27:4. Other investigators found that systemic use of
argatroban reduced tumor mass and prolonged survival time in rat
glioma models leading to the conclusion that argatroban should be
considered as a novel therapeutic for glioma, a notoriously
difficult to treat cancer type. See e.g., Hua, Y., et al., 2005,
Acta Neurochir, Suppl 2005, 95:403-406; Hua, Y., et al., 2005, J
Thromb Haemost, 3:1917-1923. Very recently, it was demonstrated
that dabigatran etexilate, a DTI recently FDA-approved (see e.g.,
Hughes, B., 2010, Nat Rev Drug Discov, 9:903-906) for DVT
indications, inhibited both the invasion and metastasis of
malignant breast tumors. See e.g., DeFeo, K. et al., 2010,
Thrombosis Research, 125 (Supplement 2): S188-S188; Defeo, K., et
al., 2010, Cancer Biol Ther, 10:1001-1008. Thus, dabigatran
etexilate treatment led to a 50% reduction in tumor volume at 4
weeks with no weight loss in treated mice. Dabigatran etexilate
also reduced tumor cells in the blood and liver micrometastases by
50-60%. These investigators concluded that dabigatran etexilate can
be beneficial in not only preventing thrombotic events in cancer
patients, but also as adjunct therapy to treat malignant
tumors.
[0142] Further, hirudin and the LMWH nadroparin dramatically
reduced the number of lung metastases when administered prior to
cancer cell inoculation. See e.g., Hu, L., et al., 2004, Blood,
104:2746-51.
[0143] The de novo thrombin inhibitor d-Arg-Oic-Pro-d-Ala-Phe(p-Me)
has been found to block thrombin-stimulated invasion of prostate
cancer cell line PC-3 in a concentration dependent manner. See
e.g., Nieman, M. T., et al., 2008, J Thromb Haemost, 6:837-845. A
reduced rate of tumor growth was observed in mice dosed with the
pentapeptide through their drinking water. The mice also showed
reduced fold rate in tumor size and reduced overall tumor weight
compared to untreated mice. Microscopic examination of treated
tumors showed reduced number of large blood vessels thus concluding
that the pentapeptide interfered with tumor angiogenesis. Nieman,
M. T., et al., Thromb Haemost, 104:1044-8.
[0144] In view of these and related studies, it is suggested that
anticoagulants affect tumor metastasis; that is, angiogenesis,
cancer cell adhesion, migration and invasion processes. See e.g.,
Van Noorden, C. J., et al., 2010, Thromb Res, 125 Suppl
2:S77-79.
[0145] Alzheimer's Disease.
[0146] Very recent experiments confirm higher thrombin levels in
brain endothelial cells of patients with Alzheimer's disease. While
`normal` thrombin levels are connected to regulatory CNS functions,
thrombin accumulation in the brain is toxic. It has also been found
that the neural thrombin inhibitor Protease Nexin 1 (PN-1) is
significantly reduced in the Alzheimer's disease brain, despite the
fact that PN-1 mRNA levels are unchanged. These observations have
led some investigators to suggest that reduction of CNS-resident
thrombin will prove useful in Alzheimer's Disease (AD) treatment.
See e.g., Vaughan, P. J., et al., 1994, Brain Res, 668:160-170;
Yin, X., et al., 2010, Am J Pathol, 176:1600-1606; Akiyama, H., et
al., 1992, Neurosci Lett, 146:152-154.
[0147] Multiple Sclerosis.
[0148] Investigators found that hirudin treatment in an animal
model of Multiple Sclerosis (MS) showed a dramatic improvement in
disease severity. See e.g., Han, M. H., et al., 2008, Nature,
451:1076-1081. Similar results were obtained following treatment
with heparin (a DTI) and dermatan sulfate, another coagulation
inhibitor. See e.g., Chelmicka-Szorc, E. & Amason, B. G., 1972,
Arch Neurol, 27:153-158; Inaba, Y., et al., 1999, Cell Immunol,
198:96-102. Other evidence shows that naturally occurring
antithrombin III has anti-inflammatory effects in diseases such as
endotoxemia and other sepsis-related conditions. See e.g.,
Wiedermann, C. J. & Romisch, J., 2002, Acta Med Austriaca,
29:89-92. Naturally occurring thrombin inhibitors are presumably
synthesized in situ and have protective roles in CNS inflammation.
Therefore, therapeutic thrombin inhibition has been proposed as a
potential MS treatment. See e.g., Luo, W., et al., 2009, In:
THROMBIN, Maragoudakis, M. E.; Tsopanoglou, N. E., Eds. Springer
New York: 2009; pp 133-159.
[0149] Pain. In a rat pain model with partial lesion of the sciatic
nerve, intrathecal hirudin prevented the development of neuropathic
pain and curbed pain responses for 7 days. The investigators found
that following injury, neuropathic pain was mediated by thrombin
generation, which in turn activated PAR-1 receptor in the spinal
cord. Hirudin inhibited thrombin generation and ultimately led to
pain relief. See e.g., Garcia, P. S., et al., 2010, Thromb Haemost,
103:1145-1151; Narita, M., et al., 2005, J Neurosci,
25:10000-10009. Researchers hypothesize that thrombin and the PARs
are involved not just as part of the coagulation cascade, but in
inflammation, nociception and neurodevelopment. Development of a
DTI to intersect an unexploited pharmacology will lead to pain
therapeutics distinct from opioids and NSAIDs, whose shortcomings
are well documented. See e.g., Garcia 2010, Id. Known thrombin
inhibitors have been reported to be useful in preventing stroke in
individuals with atrial fibrillation. The selective thrombin
inhibitor ximelagatran was studied in two phase III clinical trials
((SPORTIF III and SPORTIF V), which compared ximelagatran to
warfarin for the prevention of cardioembolic events in patients
with non-valvular atrial fibrillation. The investigators for the
SPORTIF III clinical trial that ximelagatran, administered in a
fixed dose without coagulation monitoring, protects high-risk
patients with atrial fibrillation against thromboembolism at least
as effectively as well-controlled warfarin, and is associated with
less bleeding. When the results of SPORTIF III and V were combined,
ximelagatran was associated with a 16% relative risk reduction in
the composite outcome measure of all strokes (ischemic or
hemorrhagic), systemic embolic events, major bleeding, and death.
(Olsson, S. B. Lancet 2003, 362 (9397), 1691-1698; Hirsh, J. et al.
Blood 2005, 105 (2), 453-463; Clemens, A. et al. WIPO Patent
Application WO/2008/009638). Without further wishing to be bound by
any theory, it is reasonable to believe that thrombin inhibition in
general can be useful in preventing stroke in individuals with
atrial fibrillation.
[0150] Known thrombin inhibitors have been reported to be useful in
the treatment and prevention of acute coronary syndrome (Clemens,
A. et al. WIPO Patent Application WO/2008/009638). ACS is a group
of symptoms that are caused by myocardial ischemia. The drug could
be used as a prophylaxis for myocardial infarction, or a certain
time after the event (e.g. after myocardial infarction, post-MI;
i.e. chronic therapy, secondary prevention). Without further
wishing to be bound by any theory, it is reasonable to believe that
thrombin inhibition in general can be useful in treating and
preventing acute coronary syndrome.
[0151] Known thrombin inhibitors have been reported to be useful in
the prevention of recurrent cardiac events after myocardial
infarction. The selective thrombin inhibitor ximelagatran was
studied in a phase II clinical trial entitled ESTEEM, measuring the
efficacy and safety of the oral direct thrombin inhibitor
ximelagatran in patients with recent myocardial damage. The result
of the ESTEEM trial supports the notion that long-term treatment
with an oral direct thrombin inhibitor reduces arterial thrombotic
events. Oral ximelagatran in combination with acetylsalicylic acid
was more effective than acetylsalicylic acid alone in reducing the
frequency of major cardiovascular events during 6 months of
treatment in patients with a recent myocardial infarction. (Hirsh,
J. et al. Blood 2005, 105 (2), 453-463.). Without further wishing
to be bound by any theory, it is reasonable to believe that
thrombin inhibition in general can be useful in preventing
recurrent cardiac events after myocardial infarction.
[0152] Known thrombin inhibitors have been reported to be useful in
post-operative prophylaxis of deep vein thrombosis. The selective
thrombin inhibitor ximelagatran was found to be efficacious for the
prevention of venous thromboembolism following a medical procedure
like total hip or knee replacement (Francis, C. W. et al. Ann
Intern Med 2002; 137:648-55; Heit, J. A. et al. Arch Intern Med
2001; 161: 2215-21; Eriksson B I et al. Thromb Haemost 2003; 89:
288-96). Without further wishing to be bound by any theory, it is
reasonable to believe that thrombin inhibition in general can be
useful in post-operative prophylaxis of deep vein thrombosis.
[0153] Known thrombin inhibitors like dabigatran have been reported
to be useful in long-term treatment of pulmonary embolism.
(Robertson L, Kesteven P, McCaslin J E. Cochrane Database Syst Rev.
2015 Dec. 4; 12). Without further wishing to be bound by any
theory, it is reasonable to believe that thrombin inhibition in
general can be useful in treating pulmonary embolism.
[0154] Known thrombin inhibitors have been reported to be useful
for the prevention of coagulation in patients undergoing
percutaneous coronary intervention. Percutaneous coronary
intervention (PCI) requires aggressive anticoagulation therapy, and
was historically achieved with unfractionated heparin. However, in
many patients heparin is contraindicated, especially in patients
with heparin-induced thrombocytopenia (HIT). In such instances, the
endovascular disruption and the hypercoagulable state that
characterized HIT means patients are put at risk of thrombosis
during PCI. (Lewis, B. E. et al. Catheterization and cardiovascular
interventions 2002, 57 (2), 177-184; Kokolis, S et al. Progress in
cardiovascular diseases 2004, 46 (6), 506-523.) Dabigatran, which
had already been claimed as a thrombin inhibitor and a useful
anticoagulant in the clinical setting, was also published as a
secondary medication in percutaneous interventional cardiac
catherization. (Reilly et al. WIPO Patent Application
WO/2010/020602). Without further wishing to be bound by any theory,
it is reasonable to believe that thrombin inhibition in general can
be useful in preventing coagulation in patients undergoing
percutaneous coronary intervention.
[0155] Known thrombin inhibitors have been reported to be useful
for the treatment of pulmonary-arterial hypertension. Dabigatran, a
selective thrombin inhibitor, has been published as a useful drug
for the treatment of pulmonary-arterial hypertension (PAH).
Furthermore, dabigatran had found use as a treatment of: (i);
pulmonary hypertension caused by left heart disorders, (ii);
pulmonary hypertension associated with lung diseases such as
pulmonary fibroses, particularly idiopathic pulmonary fibrosis,
and/or hypoxia, (iii); pulmonary hypertension caused by chronic
thromboembolic diseases. (Feuring, M. WIPO Patent Application
WO/2010/020600). Without further wishing to be bound by any theory,
it is reasonable to believe that thrombin inhibition in general can
be useful for the treatment of pulmonary-arterial hypertension.
[0156] Known thrombin inhibitors have been reported to be useful
for the treatment of pulmonary-arterial hypertension caused by left
heart disorders (Feuring, M. WIPO Patent Application
WO/2010/020600). Without further wishing to be bound by any theory,
it is reasonable to believe that thrombin inhibition in general can
be useful for the treatment of pulmonary-arterial hypertension
caused by left heart disorders.
[0157] Known thrombin inhibitors have been reported to be useful
for the treatment of pulmonary-arterial hypertension associated
with lung diseases such as pulmonary fibroses, particularly
idiopathic pulmonary fibrosis, and/or hypoxia (Feuring, M. WIPO
Patent Application WO/2010/020600). Without further wishing to be
bound by any theory, it is reasonable to believe that thrombin
inhibition in general can be useful for the treatment of
pulmonary-arterial hypertension associated with lung diseases.
[0158] Known thrombin inhibitors have been reported to be useful
for the treatment of pulmonary hypertension caused by chronic
thromboembolic diseases (Feuring, M. WIPO Patent Application
WO/2010/020600). Without further wishing to be bound by any theory,
it is reasonable to believe that thrombin inhibition in general can
be useful for the treatment of pulmonary hypertension caused by
chronic thromboembolic diseases.
[0159] Non-valvular atrial fibrillation is a sustained cardiac
disturbance often associated with heart disease. Known thrombin
inhbitors like ximelagatran have been reported to be useful for
stroke prevention in patients with non-valvular atrial fibrillation
(Diener H.-C. Cerebrovasc Dis 2006; 21:279-293). Without further
wishing to be bound by any theory, it is reasonable to believe that
thrombin inhibition in general can be useful for stroke prevention
in patients with non-valvular atrial fibrillation.
[0160] A Transient Ischemic Attack (TIA) is an acute episode of
temporary neurologic dysfunction that typically lasts less than an
hour; results from focal cerebral, spinal cord, or retinal
ischemia; and is not associated with acute tissue infarction. In
people who have a TIA, the incidence of subsequent stroke is as
high as 11% over the next 7 days and 24-29% over the following 5
years. In view of the high short-term risk of stroke after TIA,
many physicians believe antithrombotic therapy should be initiated
as soon as intracranial hemorrhage has been ruled out. Stroke
prevention medication typically recommended for cardioembolic TIA
is as follows: For patients with atrial fibrillation after TIA,
long-term anticoagulation with warfarin (aspirin 325 mg/day for
those unable to take oral anticoagulants); In acute myocardial
infarction (MI) with left ventricular thrombus, oral
anticoagulation with warfarin; concurrent aspirin up to 162 mg/day
for ischemic coronary artery disease [CAD]); In dilated
cardiomyopathy, oral anticoagulation with warfarin or antiplatelet
therapy; In rheumatic mitral valve disease, oral anticoagulation
with warfarin. For patients with TIA and ischaemic stroke of
cardiac origin due to atrial fibrillation, vitamin K antagonists
(VKAs) are highly effective in preventing recurrent ischaemic
stroke but have important limitations and are thus underused.
Antiplatelet therapy is much less effective than VKAs. The direct
thrombin inhibitor, dabigatran etexilate, has shown efficacy over
warfarin in a recent trial. Other new anticoagulants, including the
oral factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, the
parenteral factor Xa inhibitor, idrabiotaparinux, and the novel
VKA, tecarfarin, were being assessed in 2010. (Hankey, G. J.;
Eikelboom, J. W. `Antithrombotic Drugs for Patients with Ischaemic
Stroke and Transient Ischaemic Attack to Prevent Recurrent Major
Vascular Events.` The Lancet Neurology 2010, 9 (3), 273-284.)
[0161] Known thrombin inhibitors have been reported to be useful
for the treatment of venous thromboembolism due to formation of a
thrombus within a vein (venous thrombosis) associated with acquired
(prolonged bedrest, surgery, injury, malignancy, pregnancy and
postpartum states) or inherited (deficiency of natural coagulation
inhibitors) risk factors (Marsic, L. P. et al. WIPO Patent
Application WO/2003/048155). Without further wishing to be bound by
any theory, it is reasonable to believe that thrombin inhibition in
general can be useful for the treatment of venous thromboembolism
due to formation of a thrombus within a vein associated with
acquired or inherited risk factors and/or embolism of peripheral
veins caused by a detached thrombus. An example of an acquired risk
factor would be a previous venous thromboembolism and/or embolism
of peripheral veins caused by a detached thrombus. An example of an
acquired risk factor would be a previous venous
thromboembolism.
[0162] Known thrombin inhibitors have been reported to be useful
for the treatment of cardiogenic thromboembolism due to formation
of a thrombus in the heart associated with cardiac arrhythmia,
heart valve defect, prosthetic heart valves or heart disease,
embolism of peripheral arteries caused by a detached thrombus, most
commonly in the brain (ischemic stroke). See Marsic, L. P. et al.
WIPO Patent Application WO/2003/048155. Without further wishing to
be bound by any theory, it is reasonable to believe that thrombin
inhibition in general can be useful for the treatment of
cardiogenic thromboembolism.
[0163] Known thrombin inhibitors have been reported to be useful
for the treatment of arterial thrombosis due to underlying
atherosclerotic processes in the arteries which obstructs or
occludes an artery and causes myocardial ischemia (angina pectoris,
acute coronary syndrome) or myocardial infarction, obstructs or
occludes a peripheral artery (ischemic peripheral artery disease)
and obstructs or occludes the artery after the procedure on the
blood vessel (reocclusion or restenosis after transluminal coronary
angioplasty, reocclusion or restenosis after percutaneous
transluminal angioplasty of peripheral arteries). See Marsic, L. P.
et al. WIPO Patent Application WO/2003/048155. Without further
wishing to be bound by any theory, it is reasonable to believe that
thrombin inhibition in general can be useful for the treatment of
arterial thrombosis.
[0164] Known thrombin inhibitors have been reported to be useful
for the treatment of disseminated intravascular coagulation in a
number of states (e.g., in complications in pregnancy, in
metastasing malignant diseases, after extensive injuries, in
bacterial sepsis) when thrombogenic activation causes dysfunctional
coagulation with widespread formation of thrombi within the
vascular system. See Marsic, L. P. et al. WIPO Patent Application
WO/2003/048155. Without further wishing to be bound by any theory,
it is reasonable to believe that thrombin inhibition in general can
be useful for the treatment of disseminated intravascular
coagulation.
[0165] Known thrombin inhibitors have been reported to be useful as
an adjunct therapy in conjunction with thrombolytic therapy in
recent myocardial infarction, in combination with aspirin in
patients with unstable angina pectoris designed to undergo
percutaneous transluminal angioplasty and in the treatment of
patients with thrombosis and with heparin-induced thrombocytopenia
(Marsic, L. P. et al. WIPO Patent Application WO/2003/048155).
Without further wishing to be bound by any theory, it is reasonable
to believe that thrombin inhibition in general can be useful as an
adjunct therapy with other antithrombotic therapies.
[0166] Known thrombin inhibitors have been reported to be useful
for the treatment of inflammation (Kirk, I. WIPO Patent Application
WO/2000/041716), type I diabetes mellitus (Korsgren, O.; Nillson,
B. WIPO Patent Application WO/2003/061682), cancer (Kakkar, A. K.
et al. J Clin Oncol 2004, 22, (10), 1944-8; Hua, Y. et al. Acta
Neurochir Suppl 2005, 95, 403-6; Nieman, M. T. et al. J Thromb
Haemost, 6 (2008), 837-845; Van Ryn, J.; Clemens, A. WIPO Patent
Application WO/2010/020601), fibrosis (Duplantier, J. G. et al.
Gut, 2004, 53:1682-1687; Seijo, S. et al. J Hepatol, 2007,
46:286-294; Assy, N. et al. Dig Dis Sci, 2007, 52:1187-1193;
Bogatkevich, G. S. et al. Arthritis Rheum, 2009, 60:3455-3464), and
pain (Garcia, P. S. et al. Thromb Haemost, 103:1145-1151; Narita,
M. et al. J Neurosci, 2005, 25:10000-10009). Metaanalyses of
clinical trials that studied the use of anticoagulants in oncology
patients showed that low molecular weight heparins (LMWHs),
selective thrombin inhibitors, improve overall survival in
subgroups of cancer patients. This finding was substantiated in
later clinical trials, in particular the FAMOUS clinical trials,
that measured specifically the survival of cancer patients.
[0167] Without further wishing to be bound by any theory, it is
reasonable to believe that thrombin inhibition in general can be
useful for the treatment of thrombotic diseases or disorders and/or
diseases or disorders which involve a blood clot thrombus or the
potential formation of a blood clot thrombus and/or further
involves stroke and/or one or more transient ischemic attacks (TIA)
and/or pulmonary hypertension. Such conditions include, for
example, acute coronary syndrome, thromboembolism, thrombosis,
inflammation, diabetes mellitus, cancer, fibrosis, Alzheimer's
Disease, multiple sclerosis, pain, recurrent cardiac events after
myocardial infarction, or the like.
[0168] Kallikrein-Related Diseases and Conditions.
[0169] Kallikrein-related diseases or disorders are biological
conditions associated with or moderated by kallikrein. They
include, but are not limited by, those conditions associated with
biological pathways that are moderated by plasma kallikrein. An
example of such a pathway is the kallikrein-kinin system (Moreau,
M. E. 2005, Journal of Pharmacological Sciences, 99, 6).
Kallikrein-related diseases or disorders include, but are not
limited to, fibrosis, inflammation, thrombosis, hereditary
angioedema, skin disorders, cancer, and ophthalmic diseases.
Ophthalmic diseases include, but are not limited to, diabetic
macular edema, diabetic retinopathy, and age-related macular
degeneration.
[0170] Diabetic Macular Edema.
[0171] In rodent models, it has been shown that activation of KLKB1
in the eye increases retinal vascular permeability; whereas
inhibition of the kallikrein-kinin system reduces retinal leakage
induced by diabetes and hypertension. These findings suggest that
intraocular activation of the KLKB1 pathway can contribute to
excessive retinal vascular permeability that can lead to diabetic
macular edema. Thus, evidence suggests that KLKB1 inhibitors can
provide a new therapeutic opportunity to reduce retinal vascular
permeability (Feener, E. P. 2010, Curr Diab Rep 10, 270).
[0172] Hereditary Angioedema.
[0173] Ecallantide (Kalbitor) is a 60-amino acid recombinant
protein that acts as a potent reversible inhibitor of KLKB1
(Schneider L, et al. 2007, J Allergy Clin Immunol, 120, 416) and
has been approved by the FDA for the treatment of acute attacks of
hereditary angioedema (HAE). Thus plasma kallikrein inhibition can
be a useful treatment for HAE, and there is strong interest in the
development of plasma kallikrein inhibitors as a therapy for
HAE.
[0174] Hyperglycemic and diabetic individuals have an elevated risk
of hemorrhage during thrombolytic therapy. In rodent models of
intracerebral hemorrhage (ICH), it has been shown that KLKB1
inhibition or knockout reduces this effect. While the mechanism is
not fully understood, this evidence suggests that plasma kallikrein
inhibitors can be useful in the treatment of cerebral hemorrhage
(Feener, E. P. Curr Diab Rep 2010, 10, 270).
[0175] Plasma kallikrein and Factor XIIa inhibitors have been shown
to be neuroprotective in animal models of acute ischemic stroke and
traumatic brain injury, reducing edema formation, inflammation, and
thrombosis (Albert-Wei enberger C, Siren A L, Kleinschnitz C. Prog
Neurobiol. 2013, 101-102, 65-82.). Thus, evidence suggests that
plasma kallikrein inhibitors can be useful in the treatment of
acute ischemic stroke and traumatic brain injury.
[0176] Plasma kallikrein can also cleave glucagon-like peptide 1
(GLP-1) and neuropeptide Y (NPY), both substrates for dipeptidyl
peptidase-4 (DPP-4), a validated diabetes drug target. In the case
of GLP-1, cleavage by KLKB1 reduces both its potency as well as
plasma stability. In the case of NPY, cleavage by KLKB1 reduces its
affinity to the Y2 and Y5 receptors. Thus, evidence suggests that
plasma kallikrein inhibitors can be useful in the modulation of
energy homeostasis and in the treatment of diabetes. (Feener, E. P.
Curr Diab Rep 2010, 10, Feener, E. P. et al., Biol. Chem. 2013,
394, 319).
[0177] The Kallikrein-kinin system is involved in the regulation of
vascular endothelial growth factor (VEGF), endothelial NO synthase,
and fibroblast growth factor 2, all of which are involved in
angiogenesis (Bader M. 2009, Arteriosclerosis, Thrombosis, and
Vascular Biology, 29: 617). Tissue kallikrein (KLK1) has been
linked to blood vessel growth (Miura S., 2003, Hypertension, 41,
1118). Therapies that moderate angiogenesis have been proposed for
the treatment of both diabetic macular edema (DME) and age-related
macular degeneration (AMD) (Syed, B. A.; Evans, J. B.; Bielory, L.,
2012, Nature Reviews Drug Discovery, 11, 827). Without further
wishing to be bound by any theory, it is therefore reasonable to
conclude that KLK1 inhibitors can be useful in the treatment of
diabetic retinopathy, DME, and AMD.
[0178] Studies have shown that inflammation plays an important role
in the origin and development of AMD, and treatment often includes
anti-inflammatories such as corticosteroid (Telander, D., 2011,
Seminars in Ophthalmology, 26(3), 192). The connection between the
kallikrein-kinin system and inflammation is also well established
(Duchene, 2011, "Kallikrein-kinin kystem in inflammatory diseases".
Kinins. De Gruyter. 261). Without further wishing to be bound by
any theory, it is reasonable to conclude that the anti-inflammatory
nature of kallikrein (e.g. KLK1 and KLKB1) inhibitors can be useful
in the treatment of AMD.
[0179] PF-04886847 is an inhibitor of plasma kallikrein and has
shown to be effective at reducing 6-keto-PGF.sub.1.alpha. plasma
levels in lipopolysaccharide (LPS) treated rats (Kolte, D et al.
Cardiovascular & Hematological Agents in Medicinal Chemistry,
2012, 10, 154-166). Without further wishing to be bound by any
theory, it is reasonable to believe that plasma kallikrein
inhibitors can be useful in the treatment of hypotensive shock
during sepsis.
[0180] Daiichi Seiyaku Co Ltd received approval in Japan to market
cetraxate for gastritis and peptic ulcers. Cetraxate is reported as
a plasma kallikrein inhibitor (WIPO Patent Application
WO/2006/108643). Without further wishing to be bound by any theory,
it is reasonable to believe that plasma kallikrein inhibition in
general can be useful in the treatment of gastritis and peptic
ulcers.
[0181] Fibrosis.
[0182] Kallikreins are a subgroup of serine proteases, divided into
plasma kallikrein (KLKB1) and tissue kallikreins. KLKB1 liberates
kinins (bradykinin and kallidin) from the kininogens, peptides
responsible for the regulation of blood pressure and activation of
inflammation. In the Contact Activation Pathway of the coagulation
cascade, KLKB1 assists in the conversion of factor XII to factor
XIIa (Keel, M.; Trentz, O. Injury 2005, 36, 691-709). Factor XIIa
converts FXI into FXIa, which in turn activates FIX, which with its
co-factor FVIIIa forms the tenase complex, which finally activates
FX to FXa. In the fibrinolysis part of the coagulation cascade,
KLKB1 serves to convert plasminogen to plasmin. Thus, it has been
proposed that KLKB1 inhibitors can be useful in the treatment of
thrombotic and fibrinolytic diseases and disease conditions (U.S.
Pat. No. 7,625,944; Bird et al. Thrombosis and Hemostasis 2012,
107, 1141).
[0183] Several studies have shown the utility of anticoagulant
therapy in fibrotic disorders. For example, in a rat model of
CCl.sub.4-induced chronic liver injury, the DTI SSR182289 decreased
liver fibrogenesis significantly after 7 weeks of administration.
Similar observations were made in other studies using the LMWHs
nadroparin, tinzaparin, enoxaparin, and dalteparin sodium. See
e.g., Duplantier, J. G., et al., 2004, Gut, 53:1682-1687;
Abdel-Salam, O. M., et al., 2005, Pharmacol Res, 51:59-67; Assy,
N., et al., 2007, Dig Dis Sci, 52:1187-1193; Abe, W., et al., 2007,
J Hepatol, 46:286-294. Thus a thrombin inhibitor as an
anticoagulant can be useful in the treatment of fibrinolytic
diseases.
[0184] In another example, the DTI melagatran greatly reduced
ischemia reperfusion injury in a kidney transplant model in the
large white pig. This led to a drastically improved kidney graft
survival at 3 months. See e.g., Favreau, F., et al., 2010, Am J
Transplant, 10:30-39.
[0185] Recent studies have shown that in a bleomycin-induced mouse
model of pulmonary fibrosis, dabigatran etexilate treatment reduced
important profibrotic events in lung fibroblasts, including the
production of collagen and connective tissue growth factor. See
e.g., Silver, R. M., et al., 2010, Am. J. Respir. Crit. Care Med.,
181:A6780; Bogatkevich, G. S., et al., 2009, Arthritis Rheum,
60:3455-3464.
[0186] The above experimental evidence points to a close
relationship between thrombin and fibrosis and suggests novel
therapeutic opportunities for fibrosis using thrombin inhibitors.
See e.g., Calvaruso, V., et al., 2008, Gut, 57:1722-1727; Chambers,
R. C., 2008, Br J Pharmacol, 153 Suppl 1:S367-378; Chambers, R. C.
& Laurent, G. J., 2002, Biochem Soc Trans, 30:194-200; Howell,
D. C., et al., 2001, Am J Pathol, 159:1383-1395.
[0187] Inflammation.
[0188] Kallikrein has long been implicated in inflammation
(Clements, J. A. The Molecular Biology of the Kallikreins and Their
Roles in Inflammation, Academic Press: San Diego, Calif., 1997;
Vol. 5). There is experimental evidence that KLKB1 is associated
with sepsis and inflammatory arthritis (Colman, R. W., 1998,
Clinical Reviews in Allergy and Immunology, 16: 365). Thus a KLKB1
inhibitor can be useful in the treatment of inflammatory conditions
associated with the kallikrein-kinin system, such as systemic
inflammatory response syndrome, sepsis, rheumatoid arthritis, and
inflammatory bowel disease.
[0189] Without further wishing to be bound by any theory, it is
reasonable to believe that kallikrein inhibition in general can be
useful for the treatment of kallikrein-related diseases or
disorders and/or diseases or disorders. Such conditions include,
for example, thrombotic diseases, fibrinolytic diseases, fibrotic
disorders, cancer, inflammatory conditions, dermatological
conditions, or the like.
[0190] Accordingly, in a further aspect, there is provided a method
for treating a disease or disorder in a subject in need thereof.
The method includes administering a compound of any of Formulae
(Ia), (Ib), (II), (III), (IV), or (V) as disclosed herein, a
compound as set forth in Table A, Table B, Table C, or Table D,
pharmaceutically acceptable salt, ester, solvate, or prodrug
thereof, or pharmaceutical composition thereof, to a subject in
need thereof in an amount effective to treat the disease or
disorder. The terms "therapeutically effective amount," "amount
effective to treat," "amount effective to prevent" and the like
refer to that amount of drug or pharmaceutical agent (e.g.,
compound or pharmaceutical composition disclosed herein) that will
elicit the biological or medical response of a tissue, system,
animal, or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician.
[0191] Compounds useful for methods disclosed herein include the
compounds set forth for Formulae (Ia), (Ib), (II), (III), (IV), or
(V) and for the compounds set forth in Table A, Table B, Table C,
or Table D above.
[0192] In some embodiments of the methods described herein, the
disease or disorder to be treated can include one or more
thrombotic diseases or disorders and/or can involve a blood clot
thrombus or the potential formation of a blood clot thrombus. In
some embodiments, the thrombotic disease or disorder can be acute
coronary syndrome, thromboembolism, and/or thrombosis. In some
embodiments, the thromboembolism can be venous thromboembolism,
arterial thromboembolism, and/or cardiogenic thromboembolism. In
some embodiments, the venous thromboembolism can include deep vein
thrombosis and/or pulmonary embolism. In some embodiments, the deep
vein thrombosis and/or pulmonary embolism can occur following a
medical procedure. In some embodiments, the thrombotic disease or
disorder can involve dysfunctional coagulation or disseminated
intravascular coagulation. In some embodiments, the subject with
dysfunctional coagulation can be undergoing percutaneous coronary
intervention (PCI). In some embodiments, the thrombotic disease or
disorder can involve a blood clot thrombus or the potential
formation of a blood clot thrombus and further can involve stroke
and/or one or more transient ischemic attacks (TIA). In some
embodiments, the thrombotic disease or disorder involving a blood
clot thrombus or the potential formation of a blood clot thrombus
can further involve stroke, wherein the subject can have
non-valvular atrial fibrillation. In some embodiments, the
thrombotic disease or disorder can involve a blood clot thrombus or
the potential formation of a blood clot thrombus and further can
involve pulmonary hypertension. In some embodiments, the pulmonary
hypertension can be caused by one or more left heart disorder
and/or chronic thromboembolic disease. In some embodiments, the
pulmonary hypertension can be associated with one or more lung
disease, including pulmonary fibrosis (idiopathic or otherwise),
and/or hypoxia.
[0193] In some embodiments, the venous thromboembolism can be
associated with formation of a thrombus within a vein associated
with one or more acquired or inherited risk factors and/or embolism
of peripheral veins caused by a detached thrombus. In some
embodiments, the one or more risk factors can include a previous
venous thromboembolism. In some embodiments, the cardiogenic
thromboembolism can be due to formation of a thrombus in the heart
associated with cardiac arrhythmia, heart valve defect, prosthetic
heart valves or heart disease, and/or embolism of peripheral
arteries caused by a detached thrombus. In some embodiments, the
detached thrombus can be in the brain (ischemic stroke). In some
embodiments, the detached thrombus can cause a transient ischemic
attack (TIA). In some embodiments, the cardiogenic thromboembolism
can be due to non-valvular atrial fibrillation. In some
embodiments, the thrombosis can be arterial thrombosis. In some
embodiments, the arterial thrombosis can be due to one or more
underlying atherosclerotic processes in the arteries. In some
embodiments, the one or more underlying atherosclerotic processes
in the arteries can obstruct or occlude an artery, cause myocardial
ischemia (angina pectoris, acute coronary syndrome), cause
myocardial infarction, obstruct or occlude a peripheral artery
(ischemic peripheral artery disease), and/or obstruct or occlude
the artery after a procedure on a blood vessel (reocclusion or
restenosis after transluminal coronary angioplasty, reocclusion or
restenosis after percutaneous transluminal angioplasty of
peripheral arteries).
[0194] In some embodiments, the disease or disorder can include
fibrosis, Alzheimer's Disease, multiple sclerosis, pain, cancer,
inflammation, and/or Type I diabetes mellitus. In some embodiments,
the disease or disorder can involve recurrent cardiac events after
myocardial infarction.
[0195] In some embodiments, the treatment or prevention can include
an adjunct therapy. In some embodiments, the subject can have
myocardial infarction, and the adjunct therapy can be in
conjunction with thrombolytic therapy. In some embodiments, the
subject can have unstable angina pectoris, thrombosis, and/or
heparin-induced thrombocytopenia, and the adjunct therapy can be in
combination with antiplatelet therapy. In some embodiments, the
subject can have non-valvular atrial fibrillation, and the adjunct
therapy can be in conjunction with one or more other therapies.
[0196] In some embodiments of the methods described herein, the
disease or disorder can be a kallikrein-related disorder. In some
embodiments, the kallikrein-related disorder can be a thrombotic
disease, a fibrinolytic disease, a fibrotic disorder, a type of
cancer, an inflammatory condition, or a dermatological
condition.
[0197] In some embodiments, the kallikrein-related disorder can be
an ophthalmic disease. In some embodiments, the compound or
pharmaceutical composition can be administered in the form of an
ophthalmic composition applied topically to the eye. In some
embodiments, the ophthalmic composition can be in the form of eye
drops. In some embodiments, the compound or pharmaceutical
composition can be administered in the form of an ophthalmic
composition via intravitreal injection. In some embodiments, the
ophthalmic disease can be diabetic macular edema, hereditary
angioedema, age-related macular degeneration, or diabetic
retinopathy.
[0198] In some embodiments wherein the disease or disorder can be a
type of cancer, said type of cancer can be cervical-, testicular-,
or non-small-cell lung adenocarcinoma. In some embodiments, the
cancer can be limited small cell lung cancer. In some embodiments,
the cancer can be a glioma. In some embodiments, the cancer can be
malignant breast cancer. In some embodiments, the cancer can be a
micrometastasis. In some embodiments, the micrometastasis can be of
the blood or liver. In some embodiments, the cancer can be a lung
metastasis. In some embodiments, the cancer can be prostatic
cancer.
[0199] In some embodiments wherein the disease or disorder can be
an inflammatory condition, said inflammatory condition can be
sepsis, inflammatory bowel disease, systemic inflammatory response
syndrome, inflammatory arthritis, or rheumatoid arthritis.
[0200] In some embodiments wherein the disease or disorder can be a
dermatological condition, said dermatological condition can be
atopic dermatitis, psoriasis, or Netherton Syndrome.
[0201] In another aspect, there is provided a method for preventing
a disease or disorder in a subject. The method includes
administering a compound of any of Formulae (Ia), (Ib), (II),
(III), (IV), or (V) as disclosed herein, compound as set forth in
any of Table A, Table B, Table C, or Table D herein,
pharmaceutically acceptable salt, ester, solvate, or prodrug
thereof, or pharmaceutical composition thereof, to a subject in
need thereof in an amount effective to prevent the disease or
disorder.
V. Assays
[0202] Compounds described herein can be assayed, by a variety of
methods known in the art and described herein, for inhibition of
biological activity, e.g., protease activity, of a variety of
proteins, e.g., thrombin and KLKB1.
[0203] The thrombin activity reported herein (e.g., Table A) was
obtained as follows. Human thrombin was obtained from Haematologic
Technologies Inc. The chromogenic substrate S-2238 was obtained
from DiaPharma. Thrombin was assayed in buffer containing 0.05 M
Tris (pH 7.4), 0.015 M NaCl and 0.01% PEG-8000. The final
concentration of enzyme used was 3 nM thrombin. The final
concentration of substrate used was 125 .mu.M S-2238 for thrombin.
All assays were performed in 96-well microtiter plates at room
temperature (RT). The enzyme and inhibitor were pre-incubated for
10 minutes then substrate was added and read at 405 nm in a
SpectraMax Plus Spectrophotometer (Molecular Devices). Inhibitor
IC.sub.50 values were determined by adding test compound as ten
point, three-fold serial dilutions in buffer solution, as known in
the art. The plate was read at 10 minutes after substrate addition.
The IC.sub.50 was calculated by plotting the percent (%) inhibition
against compound concentration and fitting the data to a
constrained four parameter sigmoidal curve, as known in the
art.
[0204] The KLKB1 kallikrein activity reported herein (e.g., Table
B) was obtained as follows. Human KLKB1 protein was obtained from
Enzyme Research Labs. The chromogenic substrate S-2302 was obtained
from DiaPharma. KLKB1 was assayed in buffer containing 0.05 M Tris
(pH 7.4), 0.01 M NaCl and 0.2% w/v PEG-8000. The final
concentration of enzyme used was 3 nM KLKB1. The final
concentration of substrate used was 250 .mu.M S-2302 for KLKB1. All
assays were performed in 96-well microtiter plates at room
temperature (RT). The enzyme and inhibitor were pre-incubated for
10 minutes then substrate was added and read at 405 nm in a
SpectraMax Plus Spectrophotometer (Molecular Devices). Inhibitor
IC.sub.50 values were determined by adding test compound as ten
point, three-fold serial dilutions in buffer solution, as known in
the art. The plate was read at 10 minutes after substrate addition.
The IC.sub.50 was calculated by plotting the percent (%) inhibition
against compound concentration and fitting the data to a
constrained four parameter sigmoidal curve, as known in the
art.
[0205] The chymotrypsin activity reported herein (e.g., Table D)
was obtained as follows. Human pancreas a-chymotrypsin was obtained
from Sigma. The chromogenic substrate S-7388 was obtained from
Sigma. The final concentration of substrate used was 250 uM for
chymotrypsin. All assays were performed in 96-well microtiter
plates at room temperature (RT). The enzyme and inhibitor were
pre-incubated for 10 minutes then substrate was added and read at
405 nm in a SpectraMax Plus Spectrophotometer (Molecular Devices).
Inhibitor IC.sub.50 values were determined by adding test compound
as ten point, three-fold serial dilutions in buffer solution, as
known in the art. The plate was read at 5 minutes after substrate
addition. The IC.sub.50 was calculated by plotting the percent (%)
inhibition against compound concentration and fitting the data to a
constrained four parameter sigmoidal curve, as known in the
art.
[0206] The Factor XIa activity reported herein (e.g., Table D) was
obtained as follows. Human Factor XIa was obtained from Enzyme
Research. The chromogenic substrate S-2366 was obtained from
DiaPharma. The final concentration of substrate used was 10 mM for
Factor XIa. All assays were performed in 96-well microtiter plates
at room temperature (RT). The enzyme and inhibitor were
pre-incubated for 10 minutes then substrate was added and read at
405 nm in a SpectraMax Plus Spectrophotometer (Molecular Devices).
Inhibitor IC.sub.50 values were determined by adding test compound
as ten point, three-fold serial dilutions in buffer solution, as
known in the art. The plate was read at 10 minutes after substrate
addition. The IC.sub.50 was calculated by plotting the percent (%)
inhibition against compound concentration and fitting the data to a
constrained four parameter sigmoidal curve, as known in the
art.
VI. Pharmaceutical Compositions
[0207] In another aspect, there is provided a pharmaceutical
composition comprising a compound disclosed herein and a
pharmaceutically acceptable excipient. The compound is a compound
of any of Formulae (Ia), (Ib), (II), (III), (IV), or (V) as
disclosed herein, a compound as set forth in Table A, Table B,
Table C, or Table D herein, or pharmaceutically acceptable salt,
ester, solvate, or prodrug thereof. In some embodiments, the
compound is set forth in Table A, Table B, Table C, or Table D
herein.
[0208] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds that are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds disclosed herein contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino, or magnesium salt, or
a similar salt. When compounds disclosed herein contain relatively
basic functionalities, acid addition salts can be obtained by
contacting the neutral form of such compounds with a sufficient
amount of the desired acid, either neat or in a suitable inert
solvent. Examples of pharmaceutically acceptable acid addition
salts include those derived from inorganic acids like hydrochloric,
hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galacturonic acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds
disclosed herein contain both basic and acidic functionalities that
allow the compounds to be converted into either base or acid
addition salts.
[0209] Compounds disclosed herein can exist as salts, such as with
pharmaceutically acceptable acids. Accordingly, the compounds
contemplated herein include such salts. Examples of such salts
include hydrochlorides, hydrobromides, sulfates, methanesulfonates,
nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g.,
(+)-tartrates, (-)-tartrates, or mixtures thereof including racemic
mixtures), succinates, benzoates, and salts with amino acids such
as glutamic acid. These salts can be prepared by methods known to
those skilled in the art.
[0210] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar
solvents.
[0211] Pharmaceutically acceptable salts of the compounds above,
where a basic or acidic group is present in the structure, are also
included within the scope of compounds contemplated herein. When an
acidic substituent is present, such as --NHSO.sub.3H, --COOH and
--P(O)(OH).sub.2, there can be formed the ammonium, sodium,
potassium, calcium salt, and the like, for use as the dosage form.
Basic groups, such as amino or basic heteroaryl radicals, or
pyridyl and acidic salts, such as hydrochloride, hydrobromide,
acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate,
and the like, can be used as the dosage form.
[0212] Also, in the embodiments in which R--COOH is present,
pharmaceutically acceptable esters can be employed, e. g., methyl,
ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those
esters known in the art for modifying solubility or hydrolysis
characteristics for use as sustained release or prodrug
formulations.
[0213] A. Formulations
[0214] The compounds disclosed herein can be prepared and
administered in a wide variety of ophthalmic, oral, parenteral, and
topical dosage forms. The compounds described herein can be
administered by eye drop. Also, compounds described herein can be
administered by injection (e.g. intravenously, intramuscularly,
intravitreally, intracutaneously, subcutaneously, intraduodenally,
or intraperitoneally). As such, compounds described herein can also
be administered by intravitreal injection. Also, the compounds
described herein can be administered by inhalation, for example,
intranasally. Additionally, the compounds disclosed herein can be
administered transdermally. It is also envisioned that multiple
routes of administration (e.g., intramuscular, oral, ocular) can be
used to administer the compounds disclosed herein.
[0215] In some embodiments, the compounds disclosed herein can be
prepared in liquid pharmaceutical compositions for ocular
administration. The composition for ocular use can contain one or
more agents selected from the group of buffering agents,
solubilizing agents, coloring agents, viscosity enhancing agents,
and preservation agents in order to produce pharmaceutically
elegant and convenient preparations.
[0216] In some embodiments, the composition for ocular use can
contain preservatives for protection against microbiological
contamination, including but not limited to benzalkonium chloride
and/or EDTA. Other possible preservatives include but are not
limited to benzyl alcohol, methyl parabens, propyl parabens, and
chlorobutanol. Preferably, a preservative, or combination of
preservatives, will be employed to impart microbiological
protection in addition to protection against oxidation of
components.
[0217] In some embodiments, the compounds disclosed herein can be
administered orally as tablets, aqueous or oily suspensions,
lozenges, troches, powders, granules, emulsions, capsules, syrups
or elixirs. The composition for oral use can contain one or more
agents selected from the group of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to produce
pharmaceutically elegant and palatable preparations. Accordingly,
there are also provided pharmaceutical compositions comprising a
pharmaceutically acceptable carrier or excipient and one or more
compounds disclosed herein.
[0218] In some embodiments, tablets contain the acting ingredient
in admixture with non-toxic pharmaceutically acceptable excipients
that are suitable for the manufacture of tablets. These excipients
can be, for example, (1) inert diluents, such as calcium carbonate,
lactose, calcium phosphate, carboxymethylcellulose, or sodium
phosphate; (2) granulating and disintegrating agents, such as corn
starch or alginic acid; (3) binding agents, such as starch, gelatin
or acacia; and (4) lubricating agents, such as magnesium stearate,
stearic acid or talc. These tablets can be uncoated or coated by
known techniques to delay disintegration and absorption 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 can be employed.
[0219] For preparing pharmaceutical compositions from the compounds
disclosed herein, pharmaceutically acceptable carriers can be
either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substance that can
also act as diluents, flavoring agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.
[0220] A compound disclosed herein, in the form of a free compound
or a pharmaceutically-acceptable pro-drug, metabolite, analogue,
derivative, solvate or salt, can be administered, for in vivo
application, parenterally by injection or by gradual perfusion over
time. Administration can be intravenously, intraperitoneally,
intramuscularly, subcutaneously, intracavity, or transdermally. For
in vitro studies the compounds can be added or dissolved in an
appropriate biologically acceptable buffer and added to a cell or
tissue.
[0221] In powders, the carrier is a finely divided solid in a
mixture with the finely divided active component. In tablets, the
active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0222] The powders and tablets preferably contain from 5% to 70% of
the active compound. Suitable carriers are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as a carrier
providing a capsule in which the active component with or without
other carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid dosage forms suitable for oral administration.
[0223] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0224] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water/propylene glycol solutions.
For parenteral injection, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
[0225] When parenteral application is needed or desired,
particularly suitable admixtures for the compounds disclosed herein
are injectable, sterile solutions, preferably oily or aqueous
solutions, as well as suspensions, emulsions, or implants,
including suppositories. In particular, carriers for parenteral
administration include aqueous solutions of dextrose, saline, pure
water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil,
polyoxyethylene-block polymers, and the like. Ampoules are
convenient unit dosages. The compounds disclosed herein can also be
incorporated into liposomes or administered via transdermal pumps
or patches. Pharmaceutical admixtures suitable for use in the
pharmaceuticals compositions and methods disclosed herein include
those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed.,
Mack Pub. Co., Easton, Pa.) and WO 96/05309, the teachings of both
of which are hereby incorporated by reference.
[0226] In some embodiments, preparations for parenteral
administration include sterile aqueous or non-aqueous solutions,
suspensions, and emulsions. Examples of non-aqueous solvents are
propylene glycol, polyethylene glycol, vegetable oils such as olive
oil, and injectable organic esters such as ethyl oleate. Aqueous
carriers include water, alcoholic/aqueous solutions, emulsions or
suspensions, including saline and buffered media. Parenteral
vehicles include sodium chloride solution, Ringer's dextrose,
dextrose and sodium chloride, lactated Ringer's intravenous
vehicles include fluid and nutrient replenishers, electrolyte
replenishers (such as those based on Ringer's dextrose), and the
like. Preservatives and other additives can also be present such
as, for example, antimicrobials, anti-oxidants, chelating agents,
growth factors and inert gases and the like.
[0227] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizers, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material,
such as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, and other well-known suspending agents.
[0228] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations can contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0229] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[0230] The quantity of active component in a unit dose preparation
can be varied or adjusted from 0.1 mg to 10000 mg, more typically
1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the
particular application and the potency of the active component. The
composition can, if desired, also contain other compatible
therapeutic agents.
[0231] Some compounds can have limited solubility in water and
therefore can require a surfactant or other appropriate co-solvent
in the composition. Such co-solvents include: Polysorbate 20, 60,
and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl
35 castor oil. Such co-solvents are typically employed at a level
between about 0.01% and about 2% by weight.
[0232] Viscosity greater than that of simple aqueous solutions can
be desirable to decrease variability in dispensing the
formulations, to decrease physical separation of components of a
suspension or emulsion of formulation, and/or otherwise to improve
the formulation. Such viscosity building agents include, for
example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl
cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,
carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin
sulfate and salts thereof, hyaluronic acid and salts thereof, and
combinations of the foregoing. Such agents are typically employed
at a level between about 0.01% and about 2% by weight.
[0233] The compositions disclosed herein can additionally include
components to provide sustained release and/or comfort. Such
components include high molecular weight, anionic mucomimetic
polymers, gelling polysaccharides, and finely-divided drug carrier
substrates. These components are discussed in greater detail in
U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The
entire contents of these patents are incorporated herein by
reference in their entirety for all purposes.
[0234] By the present, there are provided methods for ameliorating
wound healing and for mediating tissue repair (including but not
limited to treatment of peripheral and coronary vascular disease).
According to these methods, a subject having a wound or in need of
tissue repair, is treated at the site of the wound or damaged
tissue or treated systemically, with a compound disclosed herein in
the form of a free compound or a pharmaceutically-acceptable
prodrug, metabolite, analogue, derivative, solvate or salt.
[0235] Generally, the terms "treating", "treatment" and the like
are used herein to mean affecting a subject, tissue or cell to
obtain a desired pharmacologic and/or physiologic effect. The
effect can be prophylactic in terms of completely or partially
preventing a disease or disorder or sign or symptom thereof, and/or
can be therapeutic in terms of a partial or complete cure for a
disorder and/or adverse effect attributable to it, e.g. pulmonary
embolism following a medical procedure. "Treating" as used herein
covers any treatment of, or prevention of a disease or disorder in
a vertebrate, a mammal, particularly a human, and includes: (a)
preventing the disease or disorder from occurring in a subject that
can be predisposed to the disease or disorder, but has not yet been
diagnosed as having it; (b) inhibiting the disease or disorder,
i.e., arresting its development; or (c) relieving or ameliorating
the disease or disorder, i.e., cause regression of the disease or
disorder.
[0236] There are provided various pharmaceutical compositions
useful for ameliorating certain diseases and disorders. The
pharmaceutical compositions according to one embodiment are
prepared by formulating a compound disclosed herein in the form of
a free compound or a pharmaceutically-acceptable pro-drug,
metabolite, analogue, derivative, solvate or salt, either alone or
together with other pharmaceutical agents, suitable for
administration to a subject using carriers, excipients and
additives or auxiliaries. Frequently used carriers or auxiliaries
include magnesium carbonate, titanium dioxide, lactose, mannitol
and other sugars, talc, milk protein, gelatin, starch, vitamins,
cellulose and its derivatives, animal and vegetable oils,
polyethylene glycols and solvents, such as sterile water, alcohols,
glycerol and polyhydric alcohols. Intravenous vehicles include
fluid and nutrient replenishers.
[0237] Preservatives include antimicrobial, anti-oxidants,
chelating agents and inert gases. Other pharmaceutically acceptable
carriers include aqueous solutions, non-toxic excipients, including
salts, preservatives, buffers and the like, as described, for
instance, in Remington's Pharmaceutical Sciences, 15th ed. Easton:
Mack Publishing Co., 1405-1412, 1461-1487 (1975) and The National
Formulary XIV., 14th ed. Washington: American Pharmaceutical
Association (1975), the contents of which are hereby incorporated
by reference. The pH and exact concentration of the various
components of the pharmaceutical composition are adjusted according
to routine skills in the art. See e.g., Goodman and Gilman (eds.),
1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).
[0238] The pharmaceutical compositions are preferably prepared and
administered in dose units. Solid dose units are tablets, capsules
and suppositories. For treatment of a subject, depending on
activity of the compound, manner of administration, nature and
severity of the disease or disorder, age and body weight of the
subject, different daily doses can be used.
[0239] Under certain circumstances, however, higher or lower daily
doses can be appropriate. The administration of the daily dose can
be carried out both by single administration in the form of an
individual dose unit or else several smaller dose units and also by
multiple administrations of subdivided doses at specific
intervals.
[0240] The pharmaceutical compositions contemplated herein can be
administered locally or systemically in a therapeutically effective
dose. Amounts effective for this use will, of course, depend on the
severity of the disease or disorder and the weight and general
state of the subject. Typically, dosages used in vitro can provide
useful guidance in the amounts useful for in situ administration of
the pharmaceutical composition, and animal models can be used to
determine effective dosages for treatment of particular
disorders.
[0241] Various considerations are described, e. g., in Langer,
1990, Science, 249: 1527; Goodman and Gilman's (eds.), 1990, Id.,
each of which is herein incorporated by reference and for all
purposes. Dosages for parenteral administration of active
pharmaceutical agents can be converted into corresponding dosages
for oral administration by multiplying parenteral dosages by
appropriate conversion factors. As to general applications, the
parenteral dosage in mg/mL times 1.8=the corresponding oral dosage
in milligrams ("mg"). As to oncology applications, the parenteral
dosage in mg/mL times 1.6=the corresponding oral dosage in mg. An
average adult weighs about 70 kg. See e.g., Miller-Keane, 1992,
ENCYCLOPEDIA & DICTIONARY OF MEDICINE, NURSING & ALLIED
HEALTH, 5th Ed., (W. B. Saunders Co.), pp. 1708 and 1651.
[0242] The method by which the compound disclosed herein can be
administered for oral use would be, for example, in a hard gelatin
capsule wherein the active ingredient is mixed with an inert solid
diluent, or soft gelatin capsule, wherein the active ingredient is
mixed with a co-solvent mixture, such as PEG 400 containing
Tween-20. A compound disclosed herein can also be administered in
the form of a sterile injectable aqueous or oleaginous solution or
suspension. The compound can generally be administered
intravenously or as an oral dose of 0.1 .mu.g to 20 mg/kg given,
for example, every 3-24 hours.
[0243] Formulations for oral use can be in the form of hard gelatin
capsules wherein the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or
kaolin. They can also be in the form of soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium,
such as peanut oil, liquid paraffin or olive oil.
[0244] Aqueous suspensions normally contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspension. Such excipients can be (1) suspending agent such as
sodium carboxymethyl cellulose, methyl cellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing
or wetting agents which can be (a) naturally occurring phosphatide
such as lecithin; (b) a condensation product of an alkylene oxide
with a fatty acid, for example, polyoxyethylene stearate; (c) a
condensation product of ethylene oxide with a long chain aliphatic
alcohol, for example, heptadecaethylenoxycetanol; (d) a
condensation product of ethylene oxide with a partial ester derived
from a fatty acid and hexitol such as polyoxyethylene sorbitol
monooleate, or (e) a condensation product of ethylene oxide with a
partial ester derived from fatty acids and hexitol anhydrides, for
example polyoxyethylene sorbitan monooleate.
[0245] The pharmaceutical compositions can be in the form of a
sterile injectable aqueous or oleagenous suspension. This
suspension can be formulated according to known methods using those
suitable dispersing or wetting agents and suspending agents that
have been mentioned above. The sterile injectable preparation can
also a sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose, any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0246] A compound disclosed herein can also be administered in the
form of ophthalmic compositions applied topically to the eye,
preferably in the form of eye drops. A compound disclosed herein
can also be administered in the form of intravitreal injection.
[0247] A compound disclosed herein can also be administered in the
form of suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient that is solid at ordinary temperature but
liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene glycols.
[0248] The compounds disclosed herein as used in the methods
disclosed herein can also be administered in the form of liposome
delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles, and multilamellar vesicles. Liposomes can be
formed from a variety of phospholipids, such as cholesterol,
stearylamine, or phosphatidylcholines.
[0249] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the compounds disclosed herein, are
employed.
[0250] In addition, some of the compounds disclosed herein can form
solvates with water or common organic solvents. Such solvates are
encompassed within the scope of the methods contemplated
herein.
[0251] B. Effective Dosages
[0252] Pharmaceutical compositions provided herein include
compositions wherein the active ingredient is contained in a
therapeutically effective amount, i.e., in an amount effective to
achieve its intended purpose. The actual amount effective for a
particular application will depend, inter alia, on the condition
being treated.
[0253] The dosage and frequency (single or multiple doses) of
compound administered can vary depending upon a variety of factors,
including route of administration; size, age, sex, health, body
weight, body mass index, and diet of the recipient; nature and
extent of symptoms of the disease being treated (e.g., the disease
responsive to inhibition of thrombin, and/or KLKB1); presence of
other diseases or other health-related problems; kind of concurrent
treatment; and complications from any disease or treatment regimen.
Other therapeutic regimens or agents can be used in conjunction
with the methods and compounds disclosed herein.
[0254] For any compound described herein, the therapeutically
effective amount can be initially determined from a variety of
techniques known in the art, e.g., biochemical characterization of
inhibition of enzyme (thrombin or KLKB1), cell culture assays, and
the like. Target concentrations will be those concentrations of
active compound(s) that are capable of decreasing enzymatic
activity as measured, for example, using the methods described.
[0255] Therapeutically effective amounts for use in humans can be
determined from animal models. For example, a dose for humans can
be formulated to achieve a concentration that has been found to be
effective in animals. The dosage in humans can be adjusted by
monitoring enzymatic inhibition and adjusting the dosage upwards or
downwards, as described above.
[0256] Dosages can be varied depending upon the requirements of the
patient and the compound being employed. The dose administered to a
patient, in the context of the methods disclosed herein, should be
sufficient to affect a beneficial therapeutic response in the
patient over time. The size of the dose also will be determined by
the existence, nature, and extent of any adverse side effects.
Generally, treatment is initiated with smaller dosages, which are
less than the optimum dose of the compound. Thereafter, the dosage
is increased by small increments until the optimum effect under
circumstances is reached. In some embodiments of a method disclosed
herein, the dosage range is 0.001% to 10% w/v. In some embodiments,
the dosage range is 0.1% to 5% w/v.
[0257] Dosage amounts and intervals can be adjusted individually to
provide levels of the administered compound effective for the
particular clinical indication being treated. This will provide a
therapeutic regimen that is commensurate with the severity of the
individual's disease state.
[0258] Utilizing the teachings provided herein, an effective
prophylactic or therapeutic treatment regimen can be planned that
does not cause substantial toxicity and yet is entirely effective
to treat the clinical symptoms demonstrated by the particular
patient. This planning should involve the careful choice of active
compound by considering factors such as compound potency, relative
bioavailability, patient body weight, presence and severity of
adverse side effects, preferred mode of administration, and the
toxicity profile of the selected agent.
[0259] Accordingly, in some embodiments, dosage levels of the
compounds disclosed herein as used in the present methods are of
the order of e.g., about 0.1 mg to about 1 mg, about 1 mg to about
10 mg, about 0.5 mg to about 20 mg per kilogram body weight, an
average adult weighing 70 kilograms, with a preferred dosage range
between about 0.1 mg to about 20 mg per kilogram body weight per
day (from about 7.0 mg to about 1.4 gm per patient per day). The
amount of the compound disclosed herein that can be combined with
the carrier materials to produce a single dosage will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for oral
administration to humans can contain about 5 .mu.g to 1 g of a
compound disclosed herein with an appropriate and convenient amount
of carrier material that can vary from about 5 to 95 percent of the
total composition. Dosage unit forms will generally contain between
from about 0.1 mg to 500 mg of a compound disclosed herein.
[0260] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, rate of excretion, drug combination and
the severity of the particular disease undergoing therapy.
[0261] C. Toxicity
[0262] The ratio between toxicity and therapeutic effect for a
particular compound is its therapeutic index and can be expressed
as the ratio between LD.sub.50 (the amount of compound lethal in
50% of the population) and ED.sub.50 (the amount of compound
effective in 50% of the population). Compounds that exhibit high
therapeutic indices are preferred. Therapeutic index data obtained
from in vitro assays, cell culture assays and/or animal studies can
be used in formulating a range of dosages for use in humans. The
dosage of such compounds preferably lies within a range of plasma
concentrations that include the ED.sub.50 with little or no
toxicity. The dosage can vary within this range depending upon the
dosage form employed and the route of administration utilized. See,
e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,
Ch. 1, p. 1, 1975. The exact formulation, route of administration,
and dosage can be chosen by the individual practitioner in view of
the patient's condition and the particular method in which the
compound is used. For in vitro formulations, the exact formulation
and dosage can be chosen by the individual practitioner in view of
the patient's condition and the particular method in which the
compound is used.
VII. Examples
[0263] The examples below are meant to illustrate certain
embodiments of the invention and not to limit the scope of the
invention. Abbreviations used herein have their conventional
meaning in the art, unless indicated otherwise. Specific
abbreviations include the following: A=Angstrom; Ac.sub.2O=acetic
anhydride; AcOH=acetic acid; aq=aqueous; Bt=benzotriazole;
BOC=N-tert-butoxycarbonyl; br=broad; t-BuOH=tert-butanol; .degree.
C.=degree Celsius; d=doublet; DABCO=1,4-diazabicyclo[2.2.2]octane;
DCE=1,2-dichloroethane; DCM=dichloromethane; dd=doublet of
doublets; DIEA=diethylisopropylamine; DMAP=4-dimethylaminopyridine;
DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide; 8=chemical shift
(given in ppm, unless otherwise indicated);
EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; eq=equivalent;
Et.sub.2O=diethyl ether; Et.sub.3N=triethylamine; EtOAc=ethyl
acetate; EtOH=ethanol; g=gram; h (or hr)=hour;
HOBt=hydroxybenzotriazole; HPLC=high performance liquid
chromatography; Hz=Hertz; IC.sub.50=inhibitory concentration at 50%
inhibition; J=coupling constant (given in Hz, unless otherwise
indicated); LC=liquid chromatography; LHMDS=lithium
hexamethyldisilazide; m=multiplet; M=molar; [M+H].sup.+=parent mass
spectrum peak plus H+; MS=mass spectrum; ms=molecular sieves;
MP=melting point; Me.sub.2NH=dimethylamine; MeOH=methanol;
mg=milligram; mL=milliliter; mM=millimolar; mmol=millimole;
min=minute; .mu.L=microliter; .mu.M=micromolar; ng=nanogram;
nM=nanomolar; NMR=nuclear magnetic resonance; ppm=parts per
million; q=quartet; R.sub.f=retention factor; RT=room temperature;
s=singlet; t=triplet; TFA=trifluoroacetic acid;
THF=tetrahydrofuran; TLC=thin layer chromatography.
List of General Procedures
##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013##
[0264] Synthetic Examples
Example 1--Preparation of Intermediate 1
[0265] The synthesis of Intermediate 1 followed General Procedure 1
following.
##STR00014##
[0266] To a solution of diisopropylamine (6.55 g, 64.7 mmol, 2.1
eq) in cold THF (-78.degree. C., 80 mL) was added n-butyllithium
(4.04 g, 63.1 mmol, 2.05 eq), and then stirred for 1 hour at
0.degree. C. The reaction mixture was then cooled to -78.degree. C.
and to it was then added
1-(tert-butyl)-3-methylpiperidine-1,3-dicarboxylate (7.5 g, 30.8
mmol, 1 eq). The mixture was stirred for 1 hour, and to it was
added methyl iodide (13.12 g, 97.4 mmol, 3.0 eq). The reaction
mixture was warmed to room temperature overnight. It was monitored
by TLC and LC-MS. After completion, the reaction mixture was
quenched with ammonium chloride and extracted with ethyl acetate
(2.times.150 mL). The combined organic phases were washed with
water and brine, then dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash
chromatography using silica gel (60-120 mesh size), eluting with
5-10% ethyl acetate in n-hexane to give product (Intermediate 1,
4.8 g, yield: 60.5%) m/z 202 [M-56]+ .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.87 (d, J=13.3 Hz, 1H), 3.70 (s, 3H), 3.46 (s,
1H), 3.27 (d, J=5.9 Hz, 1H), 3.15 (d, J=13.3 Hz, 1H), 2.04 (dd,
J=12.7, 6.2 Hz, 1H), 1.58 (s, 1H), 1.49 (m, 11H), 1.18 (s, 3H)
ppm.
Example 2--Preparation of Intermediate 2
[0267] The synthesis of Intermediate 2 followed the procedure of
General Procedure 2 following.
##STR00015##
[0268] To a cold solution (-78.degree. C.) of acetonitrile (1.67 g,
40.8 mmol, 1.5 eq) in tetrahydrofuran (70 mL) was added n-BuLi (23%
in hexane, 2.61 g, 40.8 mmol, 1.5 eq) under inert N.sub.2
atmosphere over a period of 20 minutes. After completion of
addition, the reaction was stirred for another 60 minutes. To the
cold (-78.degree. C.) mixture was then added Intermediate 1 (7.0 g,
27.2 mmol, 1.0 eq) in portions, and the reaction mixture was
stirred for 3 hours. The reaction mixture was quenched with
saturated ammonium chloride solution and the product was extracted
with ethyl acetate. The organic phase was dried with sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography using silica gel (60-120 mesh size)
eluting with 10-40% ethyl acetate in n-hexane, yielding product
tert-butyl 3-(2-cyanoacetyl)-3-methylpiperidine-1-carboxylate
(Intermediate 2; 4.775 g, yield: 65.9%) m/z 211.0 [M-56]+ .sup.1H
NMR (400 MHz, DMSO) .delta. 4.26 (q, J=20.1 Hz, 2H), 3.74 (d,
J=12.6 Hz, 1H), 3.38-3.32 (m, 1H), 3.21-3.06 (m, 2H), 1.94-1.77 (m,
1H), 1.56-1.31 (m, 12H), 1.06 (s, 3H) ppm.
Example 3--Preparation of Compound 1
[0269] The synthesis of Compound 1 followed the procedure of
General Procedure 3 following.
##STR00016##
[0270] To a solution of tert-butyl
3-(2-cyanoacetyl)-3-methylpiperidine-1-carboxylate (Intermediate 2,
9.5 g, 35 mmol, 1.0 eq) in acetic acid (0.2 mL) and isopropanol (80
mL) was added hydrazine monohydrate (2.67 g, 53 mmol, 1.5 eq)
dropwise. The reaction mixture was stirred at 60.degree. C. for 3
hours. The reaction mixture was monitored by LC-MS, and on
completion was concentrated under reduced pressure. The residue was
purified by column chromatography using silica gel (60-120 mesh),
eluting with 5-10% methanol in dichloromethane to yield tert-butyl
3-(5-amino-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate
(Compound 1; 9.005 g, yield: 90.0%) m/z 225.05 [M-56]+ .sup.1H NMR
(400 MHz, DMSO) .delta. 11.26 (s, 1H), 4.62 (s, 2H), 3.38 (d,
J=22.7 Hz, 2H), 3.32 (d, J=12.2 Hz, 1H), 3.16 (d, J=12.5 Hz, 1H),
1.58-1.43 (m, 2H), 1.38 (d, J=9.7 Hz, 11H), 1.09 (d, J=8.6 Hz, 3H)
ppm.
Example 4--Preparation of Compound 2
[0271] The synthesis of Compound 2 followed the procedure of
General Procedure 4 following.
##STR00017##
[0272] To a cold solution (0.degree. C.) of tert-butyl
3-(5-amino-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate
(Compound 1, 9.0 g, 32.1 mmol, 1.0 eq) and
5-chlorothiophene-2-carbaldehyde (5.64 g, 38.5 mmol, 1.2 eq) in
methanol (100 mL) was added acetic acid (1.92 g, 32.1 mmol, 1.0
eq). After stirring for 3 hours, sodium cyanoborohydride (4.03 g,
64.2 mmol, 2.0 eq) was added. The reaction mixture was warmed to
room temperature overnight and monitored by TLC. The reaction
mixture was poured into water (200 mL) and extracted with ethyl
acetate (2.times.150 mL). The combined organic phases were washed
with water, brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography using silica gel (60-120 mesh size), eluting
with 10-40% ethyl acetate in n-hexane yielding tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (Compound 2, 7.0 g, yield: 53.0%) m/z 411.40
[M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 6.92 (d, J=3.7 Hz, 1H),
6.84 (s, 1H), 5.67 (s, 1H), 5.35 (s, 1H), 4.28 (d, J=5.5 Hz, 2H),
3.44-3.34 (m, 2H), 3.29-3.26 (m, 2H), 1.90 (s, 1H), 1.54-1.43 (m,
3H), 1.39 (s, 9H), 1.12 (s, 3H) ppm.
Example 5--Preparation of Compound 3
[0273] The synthesis of Compound 3 followed the procedure of
General Procedure 5a following.
##STR00018##
[0274] To a solution of pivalic acid (0.373 g, 3.65 mmol, 1.5 eq)
in cold (0.degree. C.) THF (15 mL) under a nitrogen atmosphere was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.701 g, 3.65 mmol, 1.5 eq) and triethylamine (0.74 g,
7.31 mmol, 3.0 eq). The reaction mixture was stirred for 30
minutes, and to it was added hydroxybenzotriazole (HOBt, 0.065 g,
0.48 mmol, 0.2 eq), followed by tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (Compound 2, 1.0 g, 3.43 mmol, 1.0 eq). The
mixture was stirred overnight at room temperature. The reaction was
monitored by LC-MS, and after completion was poured into water (20
mL), extracted with ethyl acetate (2.times.20 mL), washed with
water, brine, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by flash
chromatography using silica gel (60-120 mesh size), eluting with
0-20% ethyl acetate in n-hexane, yielding tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-3-
-methylpiperidine-1-carboxylate (Compound 3, 0.500 g, yield: 41.4%)
m/z 494.88 [M+1]+ 1H NMR (400 MHz, DMSO) .delta. 7.63 (d, J=5.6 Hz,
1H), 6.97 (s, 2H), 5.47 (s, 1H), 4.41 (s, 2H), 3.44 (d, J=45.8 Hz,
2H), 3.24 (s, 2H), 1.94 (s, 1H), 1.50 (d, J=47.4 Hz, 3H), 1.40 (s,
9H), 1.34 (s, 9H), 1.12 (s, 3H) ppm.
Example 6--Preparation of Compound 4
[0275] The synthesis of Compound 4 followed the procedure of
General Procedure 5b following.
##STR00019##
[0276] To a cold solution (0.degree. C.) of
3-hydroxy-2,2-dimethylpropanoic acid (0.576 g, 4.85 mmol, 2.0 eq)
in THF (25 mL) was added 1-propanephosphonic anhydride (T3P, 1.551
g, 4.85 mmol, 2.0 eq), followed by diisopropylethylamine (DIPEA,
0.986 g, 9.75 mmol, 4.0 eq) under nitrogen. The reaction mixture
was stirred for 1 hour, and to it was added tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (Compound 2, 1.0 g, 3.43 mmol, 1.0 eq). The
reaction was stirred for 48 hours and monitored by TLC. After
reaction completion, the mixture was poured into water (50 mL),
extracted with ethyl acetate (2.times.20 mL), washed with water and
then brine, then dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by flash
chromatography using silica gel (60-120 mesh size) eluting with
10-20% ethyl acetate in n-hexane, yielding tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound
4, 0.410 g, yield: 32.9%) m/z 511.8 [M+1]+ 1H NMR (400 MHz, DMSO)
.delta. 7.63 (s, 1H), 6.92 (d, J=37.7 Hz, 2H), 5.46 (s, 1H), 4.83
(t, J=5.3 Hz, 1H), 4.41 (s, 2H), 3.87 (s, 2H), 3.42 (s, 2H), 3.19
(d, J=5.2 Hz, 2H), 1.91 (s, 1H), 1.55 (s, 2H), 1.36 (s, 3H), 1.30
(s, 6H), 1.12 (s, 3H) ppm.
Example 7--Preparation of Compound 5
[0277] The synthesis of Compound 5 followed the procedure of
General Procedure 6a following.
##STR00020##
[0278] To a cold (0.degree. C.) solution of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound
4, 0.4 g, 0.78 mmol, 1.0 eq) in ethyl acetate (600 mL) was added
iodotrimethylsilane (0.5 mL) dropwise. The reaction mixture was
allowed to room temperature and stirred for 30 hours. The reaction
was monitored by LC-MS and TLC. After completion, the reaction
mixture was washed with sodium bicarbonate solution (20%, 150 mL),
water (150 mL), followed by brine (150 mL). The organic layer was
dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by preparative HPLC using ammonia-water as
mobile phase, yielding
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(3-methylpiperidin-3-yl)-1H-
-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 5,
0.030 g, yield: 9.3%) m/z 410.90 [M+1]+ 1H NMR (400 MHz, DMSO)
.delta. 7.71 (s, 1H), 7.00 (s, 2H), 5.57 (s, 1H), 4.89-4.75 (m,
1H), 4.44 (s, 2H), 3.85 (s, 2H), 2.89 (s, 4H), 2.02-1.99 (m, 1H),
1.62 (s, 3H), 1.32 (s, 6H), 1.19 (s, 3H) ppm.
Example 8--Preparation of Compound 6
[0279] The synthesis of Compound 6 followed the procedure of
General Procedure 5a following.
##STR00021##
[0280] To a cold solution (0.degree. C.) of
3-methoxy-2,2-dimethylpropanoic acid (0.483 g, 3.65 mmol, 1.5 eq)
in THF (15 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, (0.701 g, 3.65 mmol, 1.5 eq) and then triethylamine
(TEA, 0.74 g, 7.31 mmol, 3.0 eq) under nitrogen. After stirring for
30 minutes, to the mixture was then added hydroxybenzotriazole
(HOBt, 0.065 g, 0.48 mmol, 0.2 eq), followed by tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (Compound 2, 1.0 g, 3.43 mmol, 1.0 eq). The
reaction mixture was monitored by LC-MS, and stirred for 72 hours
at room temperature. After completion the reaction mixture was
poured into water (20 mL) and extracted with ethyl acetate
(2.times.20 mL). The combined organic phases were washed with
water, brine, then dried over sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
flash chromatography using silica gel (60-120 mesh size), eluting
with 0-20% ethyl acetate in n-hexane, to yield tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound
6, 0.625 g, yield: 48.9%) m/z 524.93 [M+1]+ 1H NMR (400 MHz, DMSO)
.delta. 7.60 (t, J=5.6 Hz, 1H), 6.97 (s, 2H), 5.47 (s, 1H), 4.41
(s, 2H), 3.84 (s, 2H), 3.52 (d, J=13.0 Hz, 1H), 3.24 (s, 3H), 3.13
(s, 3H), 1.95 (s, 1H), 1.57 (s, 3H), 1.35 (d, J=4.6 Hz, 6H), 1.33
(s, 9H), 1.13 (s, 3H) ppm.
Example 9--Preparation of Compound 7
[0281] The synthesis of Compound 7 followed the procedure of
General Procedure 6b following.
##STR00022##
[0282] To a cold solution (0.degree. C.) of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound
6, 0.4 g (0.76 mmol, 1.0 eq) in dichloromethane (300 mL) was added
a solution of trifluoroacetic acid (TFA, 2.5 mL) in dichloromethane
(6 mL). The reaction was monitored by LC-MS and TLC, and after
completion (12 hours) the reaction mixture was washed with 20%
sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The
organic layer was dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by preparative HPLC
using ammonia-water as mobile phase to yield
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(3-methylpiperidin-3-yl)-1H-
-pyrazol-1-yl)-3-methoxy-2,2-dimethylpropan-1-one (Compound 7, 0.22
g, yield: 83.4%) m/z 425.36 [M+1]+ 1H NMR (400 MHz, DMSO) .delta.
8.27 (s, 1H), 7.63 (d, J=6.2 Hz, 1H), 6.98 (q, J=3.8 Hz, 2H), 5.52
(s, 1H), 4.42 (d, J=6.3 Hz, 2H), 3.82 (dd, J=20.7, 8.4 Hz, 4H),
3.14 (s, 4H), 2.86-2.61 (m, 3H), 1.98 (s, 2H), 1.41 (t, J=44.2 Hz,
6H), 1.16 (s, 3H) ppm.
Example 10--Preparation of Compound 8
[0283] The synthesis of Compound 8 followed the procedure of
General Procedure 5a following.
##STR00023##
[0284] To a cooled solution (0.degree. C.) of 2-methoxybenzoic acid
(0.278 g, 1.82 mmol, 1.5 eq) in THF (12 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.351 g, 1.82 mmol, 1.5 eq) and then triethylamine (TEA,
0.369 g, 3.65 mmol, 3.0 eq) under nitrogen. After stirring for 30
minutes, hydroxybenzotriazole (HOBt, 0.032 g, 0.24 mmol, 0.2 eq)
and then tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (Compound 2, 0.5 g, 1.21 mmol, 1.0 eq) were
added. The reaction was monitored by LC-MS, and after stirring
overnight the reaction mixture was poured into water (20 mL) and
extracted with ethyl acetate (2.times.20 mL). The combined organic
phases were washed with water, brine, dried over sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by flash chromatography using silica gel (60-120 mesh
size), eluting with 0-20% ethyl acetate in n-hexane, to yield
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)-3-methylpiperidine-1-carboxylate (Compound 8, 0.25 g,
yield: 46%) m/z 545.49 [M+1] 1H NMR (400 MHz, DMSO) .delta. 7.60
(t, J=6.2 Hz, 1H), 7.47 (dt, J=35.7, 14.2 Hz, 1H), 7.38 (dd, J=7.5,
1.6 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.05-6.98 (m, 3H), 6.50-6.50
(m, 1H), 5.55 (s, 2H), 4.43 (d, J=38.0 Hz, 2H), 3.73 (s, 3H),
3.48-3.11 (m, 4H), 1.73 (s, 1H), 1.60-1.06 (m, 13H), 1.03 (s, 3H)
ppm.
Example 11--Preparation of Compound 9
[0285] The synthesis of Compound 9 followed the procedure of
General Procedure 6b following:
##STR00024##
[0286] To a cooled solution (0.degree. C.) of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)-3-methylpiperidine-1-carboxylate (Compound 8, 0.4 g, 0.73
mmol, 1.0 eq) in dichloromethane (250 mL) was added a solution of
TFA (2.5 mL) in DCM (10 mL) dropwise. The reaction was monitored by
LC-MS and TLC, and after stirring at 0.degree. C. for 12 hours, the
mixture was washed with 20% sodium bicarbonate (200 mL), water (200
mL) and then brine (200 mL). The organic layer was dried over
sodium sulfate, filtered and evaporated under reduced pressure. The
residue was purified by preparative HPLC eluting with ammonia-water
as mobile phase, yielding product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(3-methylpiperidin-3-yl)-1H-p-
yrazol-1-yl)(2-methoxyphenyl)methanone (Compound 9, 0.08 g, yield:
24%) m/z 444.81 [M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 7.71 (t,
J=6.4 Hz, 1H), 7.50 (dd, J=11.4, 4.4 Hz, 1H), 7.44 (dd, J=7.5, 1.6
Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.02 (dd, J=12.5, 4.5 Hz, 3H),
5.64 (s, 1H), 4.49 (d, J=6.3 Hz, 2H), 3.07 (d, J=13.1 Hz, 1H), 2.81
(s, 1H), 2.69 (d, J=12.1 Hz, 2H), 1.85 (s, 1H), 1.49 (d, J=11.6 Hz,
3H), 1.09 (s, 3H) ppm.
Example 12--Preparation of Compound 10
[0287] The synthesis of Compound 10 followed the procedure of
General Procedure 5a following.
##STR00025##
[0288] To a cooled solution (0.degree. C.) of
thiophene-3-carboxylic acid (0.374 g, 2.9 mmol, 1.5 eq) in THF (20
mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 0.561 g, 2.9 mmol, 1.5 eq) and
triethylamine (0.591 g, 5.8 mmol, 3.0 eq) under nitrogen. The
reaction mixture was stirred for 30 minutes, and to it was added
hydroxybenzotriazole (HOBt, 0.052 g, 0.39 mmol, 0.2 eq) followed by
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (compound 2, 0.8 g, 1.9 mmol, 1.0 eq). The
reaction was monitored by LC-MS, and after stirring overnight at
room temperature the reaction mixture was poured into water (20 mL)
and extracted with ethyl acetate (2.times.20 mL). The combined
organic phases were washed with water and then brine, dried over
sodium sulfate, filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography using silica gel
(60-120 mesh size) eluting with 0-20% ethyl acetate in n-hexane,
yielding product tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-p-
yrazol-3-yl)-3-meethylpiperidine-1-carboxylate (compound 10, 0.4 g,
yield: 49%) m/z 521.77 [M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta.
8.95 (d, J=58.3 Hz, 1H), 7.78 (dd, J=12.2, 5.9 Hz, 2H), 7.66 (d,
J=3.0 Hz, 1H), 6.99 (dd, J=11.6, 3.7 Hz, 2H), 5.61 (s, 1H), 4.49
(s, 2H), 3.70-3.53 (m, 1H), 3.29-3.15 (m, 3H), 1.98 (s, 1H), 1.59
(d, J=14.8 Hz, 3H), 1.33 (s, 9H), 1.16 (s, 3H) ppm.
Example 13--Preparation of Compound 11
[0289] The synthesis of Compound 11 followed the procedure of
General Procedure 6b following:
##STR00026##
[0290] To a cooled solution (0.degree. C.) of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-p-
yrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound 10, 0.4 g,
0.76 mmol, 1.0 eq) in dichloromethane (250 mL) was added a solution
of TFA (2.5 mL) in DCM (10 mL) dropwise. The reaction was monitored
by LC-MS and TLC, and after stirring at 12 hours at 0.degree. C.
the solution was washed with sodium bicarbonate (20%, 200 mL),
water (200 mL) and brine (200 mL). The organic layer was dried over
sodium sulfate, filtered and evaporated under reduced pressure. The
residue was concentrated and purified by preparative HPLC, eluting
with ammonia-water as the mobile phase, yielding desired product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(3-methylpiperidin-3-yl)-1H-p-
yrazol-1-yl)(thiophen-3-yl)methanone (Compound 11, 0.075 g, yield:
23%) m/z 420.80 [M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 8.90 (d,
J=1.8 Hz, 1H), 8.31 (s, 1H), 7.85-7.77 (m, 2H), 7.66 (dd, J=5.1,
3.0 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.98 (d, J=3.7 Hz, 1H), 5.68
(s, 1H), 4.50 (d, J=6.2 Hz, 2H), 3.34 (d, J=12.3 Hz, 1H), 2.81 (d,
J=12.0 Hz, 3H), 2.00 (s, 1H), 1.60 (d, J=8.9 Hz, 2H), 1.48 (s, 1H),
1.19 (d, J=12.7 Hz, 3H) ppm.
Example 14--Preparation of Compound 12
[0291] The synthesis of Compound 12 followed the procedure of
General Procedure 5a following.
##STR00027##
[0292] To a cooled solution (0.degree. C.) of
4-methyltetrahydro-2H-pyran-4-carboxylic acid (0.527 g, 3.6 mmol,
1.5 eq) in THF (20 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.701 g, 3.6 mmol, 1.5 eq) and triethylamine (0.74 g,
7.3 mmol, 3.0 eq) under nitrogen. After stirring for 30 minutes at
0.degree. C., to the reaction mixture was added
hydroxybenzotriazole (HOBt, 0.065 g, 4.8 mmol, 0.2 eq) followed by
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridine-1-carboxylate (Compound 2, 1.0 g, 2.4 mmol, 1.0 eq). The
reaction mixture was stirred for 48 hours at room temperature, and
monitored by LC-MS. The solution was poured into water (20 mL) and
extracted with ethyl acetate (2.times.20 mL). The combined organic
phases were washed with water, brine, and then dried over sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography using silica gel
(60-120 mesh size), eluting with 0-20% ethyl acetate in n-hexane,
yielding tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-methyltetrahydro-2H-pyra-
n-4-carbonyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate
(Compound 12, 0.610 g, yield: 47%) m/z 536.89 [M+1]+ .sup.1H NMR
(400 MHz, DMSO) .delta. 7.67 (s, 1H), 6.97 (s, 2H), 5.48 (s, 1H),
4.42 (s, 2H), 3.67 (s, 2H), 3.47 (s, 3H), 3.22 (s, 1H), 2.34 (s,
2H), 1.91 (s, 1H), 1.71 (s, 2H), 1.51 (s, 5H), 1.33 (s, 9H), 1.11
(s, 3H) ppm.
Example 15--Preparation of Compound 13
[0293] The synthesis of Compound 13 followed the procedure of
General Procedure 6b following.
##STR00028##
[0294] To a cooled solution (0.degree. C.) of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-methyltetrahydro-2H-pyra-
n-4-carbonyl)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate
(Compound 12, 0.4 g, 0.74 mmol, 1.0 eq) in dichloromethane (300 mL)
was added a solution of TFA (2.5 mL) in dichloromethane (6 mL)
dropwise. The reaction was monitored by LC-MS and TLC, and after
stirring at 0.degree. C. for 12 hours the reaction mixture was
washed with sodium bicarbonate (20%, 200 mL), water (200 mL) and
brine (200 mL). The organic layer was dried over sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by preparative HPLC using ammonia-water as mobile phase,
yielding
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(3-methylpiperidin-3-yl)-1H-p-
yrazol-1-yl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (Compound
13, 0.09 g, yield: 28%) m/z 436.81 [M+1]+ .sup.1H NMR (400 MHz,
DMSO) .delta. 8.29 (s, 1H), 7.67 (s, 1H), 6.99 (d, J=5.4 Hz, 2H),
5.53 (s, 1H), 4.44 (d, J=6.2 Hz, 2H), 3.69 (s, 2H), 3.48 (s, 2H),
3.10 (s, 1H), 2.72 (s, 2H), 2.34 (s, 2H), 1.94 (s, 1H), 1.70 (s,
2H), 1.52 (s, 5H), 1.14 (s, 3H) ppm.
Example 16--Preparation of Intermediate 3
[0295] The synthesis of Intermediate 3 followed the procedure of
General Procedure 2 following:
##STR00029##
[0296] To a cooled solution (-78.degree. C.) of acetonitrile (3.86
mL, 69.8 mmol, 1.7 eq) in tetrahydrofuran (150 mL) was added n-BuLi
(2.5M in hexane, 27.9 mL, 69.8 mmol, 1.7 eq) dropwise over a period
of 30 minutes, followed by stirring at -78.degree. C. for a further
30 minutes. To this was then added 1-(tert-butyl) 4-methyl
piperidine-1,4-dicarboxylate (10.0 g, 41.1 mmol, 1.0 eq)
portionwise, and the mixture stirred at -78.degree. C. for a
further 3 hours. The reaction mixture was quenched with saturated
aqueous ammonium chloride, then extracted with ethyl acetate. The
organic phase were dried (sodium sulfate), filtered and evaporated
to an oil, used without further purification (Intermediate 3, 9.28
g, yield: 89%) m/z 252.15.
Example 17--Preparation of Compound 14
[0297] The synthesis of Compound 14 followed the procedure of
General Procedure 3 following:
##STR00030##
[0298] To a solution of tert-butyl
4-(2-cyanoacetyl)piperidine-1-carboxylate) (Intermediate 3, 7.0 g,
27.6 mmol, 1.0 eq) in isopropanol (210 mL) was added hydrazine
monohydrate (1.65 mL, 33.2 mmol, 1.2 eq) dropwise, followed by the
addition of acetic acid (1.65 mL, 27.6 mmol, 1.0 eq). The reaction
mixture was stirred at 85.degree. C. for 4-5 hours. After
completion, the reaction mixture was evaporated under reduced
pressure. The residue was purified by column chromatography using
silica gel (60-120 mesh), eluting with 10-15% methanol in
dichloromethane to yield tert-butyl
4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 14,
6.2 g, yield: 84%) m/z 266.17. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 5.182 (1H, s), 3.935-3.965 (2H, d), 3.172 (2H, s), 2.791
(1H, m), 1.747-1.802 (2H, d), 1.424 (9H, s), 1.361-1.402 (2H, d),
1.341-1.351 (1H, d) ppm.
Example 18--Preparation of Compound 15
[0299] The synthesis of Compound 15 followed the procedure of
General Procedure 4 following:
##STR00031##
[0300] To a solution of tert-butyl
4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 14,
3.0 g, 11.3 mmol, 1.0 eq) in methanol (30 mL) was added acetic acid
(0.67 mL, 11.3 mmol, 1.0 eq), followed by
5-chlorothiophene-2-carbaldehyde (1.81 g, 12.4 mmol, 1.1 eq)
portionwise. The reaction was stirred for 2 hours at room
temperature. To the reaction mixture was then added sodium
cyanoborohydride (1.42 g, 22.6 mmol, 1.5 eq) portionwise over a
period of 45 minutes. The reaction mixture was stirred for a
further 3 hours. After reaction completion, the reaction mixture
was concentrated under reduced pressure, and the residue was poured
into stirred ice cold water and extracted with ethyl acetate. The
organic layer was dried over sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
column chromatography using neutral silica gel, eluting with 5-10%
methanol in dichloromethane, yielding tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 3.0 g, yield: 68%) m/z[M+H]+ 396.14
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 11.34 (1H, s),
6.87-6.94 (1H, q), 6.834-6.843 (1H, q), 5.68 (1H, s), 4.275-4.288
(1H, s), 3.945-3.975 (2H, d), 2.786-2.796 (2H, d), 2.623-2.681 (1H,
d), 1.725-1.995 (2H, d), 1.402-1.559 (12H, m) ppm.
Example 19--Preparation of Compound 16
[0301] The synthesis of Compound 16 followed the procedure of
General Procedure 5a following:
##STR00032##
[0302] To a cooled solution (0.degree. C.) of pivalic acid (0.19 g,
1.9 mmol, 1.5 eq) in THF (10 mL) was added diisopropylethylamine
(DIPEA, 0.24 mL, 1.4 mmol, 1.5 eq) and then
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.365 g, 1.9 mmol, 1.5 eq). After stirring for a further
20 minutes, to the reaction mixture was added tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 0.5 g, 1.3 mmol, 1.0 eq), followed by
hydroxybenzotriazole (HOBt, 0.035 g, 0.25 mmol, 0.2 eq). The
reaction was stirred for 16 hours at room temperature. After
completion, the reaction mixture was diluted with stirred ice cold
water, and the product was extracted with ethyl acetate. The
organic layer was dried over sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
column chromatography using silica gel (60-120 mesh, pre-rinsed
with triethylamine) eluting with 20-40% ethyl acetate in hexane to
yield tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pi-
peridine-1-carboxylate (Compound 16, 0.5 g, yield: 83%) m/z[M+H]+
480.20 1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.691-7.66 (1H, t),
6.957-6.984 (2H, t), 5.415 (1H, s), 4.4-4.416 (2H, d), 3.916-3.948
(2H, d), 2.867 (2H, s), 2.624-2.681 (2H, m), 1.818-1.852 (2H, d),
1.402-1.484 (16H, s) ppm.
Example 20--Preparation of Compound 17
[0303] The synthesis of Compound 17 followed the procedure of
General Procedure 6a following:
##STR00033##
[0304] To a cooled solution (0.degree. C.) of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pi-
peridine-1-carboxylate (Compound 16, 0.5 g, 1.0 mmol, 1.0 eq) in
ethyl acetate was added iodotrimethylsilane (0.148 g, 1.0 mmol, 1.0
eq) diluted in ethyl acetate dropwise. The reaction was stirred for
15 minutes with the temperature below 10.degree. C. After reaction
completion, the mixture was diluted with sodium bicarbonate
solution under stirring and extracted with ethyl acetate. The
organic layer was dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
preparative HPLC method to yield
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-
-1-yl)ethan-1-one (Compound 17, 0.042 g, yield: 10%) m/z[M+H]+
380.14 1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.473 (1H, s), 8.189
(1H, s), 7.733-7.764 (1H, t), 6.945-6.971 (2H, s), 5.39 (1H, d),
4.421-4.436 (2H, d), 3.289-3.344 (2H, d), 2.985-3.035 (2H, d),
2.896-2.736 (1H, m), 2.029-2.057 (2H, d), 1.715-1.782 (2H, d),
1.366-1.413 (9H, s) 1.247-1.127 (1H, m) ppm.
Example 21--Preparation of Intermediate 4
[0305] The synthesis of Intermediate 4 followed the procedure of
General Procedure 7 following:
##STR00034##
[0306] To a cooled solution (0.degree. C.) of ethyl
piperidine-4-carboxylate (10.0 g, 64.1 mmol, 1.0 eq) and
triethylamine (6.4 g, 64.1 mmol, 1.0 eq) in dichloromethane (300
mL) was added allyl chloroformate (7.7 g, 64.1 mmol, 1.0 eq)
dropwise. The reaction was stirred at room temperature for 16
hours. After completion, the mixture was diluted with ice cold
water under stirring and extracted with dichloromethane
(3.times.100 ml). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography using silica gel
(60-120 mesh) to furnish 1-allyl 4-ethyl
piperidine-1,4-dicarboxylate (10.0 g, yield: 89%) m/z 241.13 1H NMR
(400 MHz, CDCl.sub.3) .delta. 5.96-5.81 (m, 1H), 5.32-5.10 (m, 2H),
4.53 (dt, J=5.5, 1.4 Hz, 2H), 4.16-4.05 (m, 2H), 4.06-3.93 (m, 2H),
2.88 (s, 2H), 2.42 (tt, J=10.9, 3.9 Hz, 1H), 1.82 (dd, J=24.3, 8.9
Hz, 2H), 1.60 (dtd, J=13.6, 11.2, 4.3 Hz, 2H), 1.21 (t, J=7.1 Hz,
3H) ppm.
Example 22--Preparation of Intermediate 5
[0307] The synthesis of Intermediate 5 followed the procedure of
General Procedure 2 following:
##STR00035##
[0308] To a cooled solution (-78.degree. C.) of acetonitrile (3.9
mL, 70.5 mmol, 1.7 eq) in tetrahydrofuran (150 mL) was added n-BuLi
(2.5 M in hexane, 28.2 mL, 70.5 mmol, 1.7 eq) dropwise over a
period of 30 minutes, followed by another period of stirring for 30
minutes. To this mixture, 1-allyl 4-ethyl
piperidine-1,4-dicarboxylate (Intermediate 4, 10.0 g, 41.5 mmol,
1.0 eq) was added portionwise, and the reaction mixture maintained
at -78.degree. C. for 3 hours. The reaction was quenched with the
addition of saturated aqueous ammonium chloride, and the product
was extracted with ethyl acetate. After drying (sodium sulfate),
the product was stirred in ethyl acetate/hexane mixture and then
dried in vacuum to yield allyl
4-(2-cyanoacetyl)piperidine-1-carboxylate (Intermediate 5, 9.8 g,
yield: 99%) m/z 236.12 1H NMR (400 MHz, CDCl.sub.3) .delta. 5.95
(ddd, J=22.7, 10.8, 5.6 Hz, 1H), 5.27 (ddd, J=13.8, 11.7, 1.4 Hz,
2H), 4.60 (d, J=5.5 Hz, 2H), 4.22 (s, 2H), 3.56 (s, 2H), 2.92 (s,
2H), 2.77 (tt, J=11.3, 3.7 Hz, 1H), 1.92 (d, J=11.4 Hz, 2H),
1.68-1.54 (m, 2H) ppm.
Example 23--Preparation of Compound 18
[0309] The synthesis of Compound 18 followed the procedure of
General Procedure 3 following:
##STR00036##
[0310] To a solution of allyl 4-(2-cyanoacetyl)
piperidine-1-carboxylate (Intermediate 5, 9.5 g, 40.1 mmol, 1.0 eq)
in isopropanol (285 mL) was added hydrazine monohydrate (2.0 mL,
40.1 mmol, 1.0 eq) dropwise, followed by acetic acid (2.88 mL, 48.1
mmol, 1.2 eq). The reaction was stirred at room temperature for 3-4
hours. After completion, the reaction mixture was concentrated
under reduced pressure, and the residue was purified by column
chromatography using silica gel (60-120 mesh), eluting with 10-15%
methanol in dichloromethane to yield allyl
4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 18,
7.0 g, yield: 70%) m/z 250.14. 1H NMR (400 MHz, DMSO) .delta.
11.84-10.78 (m, 1H), 5.94 (ddd, J=22.4, 10.5, 5.2 Hz, 1H), 5.28 (d,
J=17.3 Hz, 1H), 5.19 (d, J=6.0 Hz, 2H), 4.53 (d, J=5.1 Hz, 2H),
4.01 (d, J=13.1 Hz, 2H), 3.17 (s, 2H), 2.89 (s, 2H), 2.62 (dd,
J=34.1, 22.6 Hz, 1H), 1.82 (d, J=12.7 Hz, 2H), 1.52-1.21 (m, 2H)
ppm.
Example 24--Preparation of Compound 19
[0311] The synthesis of Compound 19 followed the procedure of
General Procedure 4 following:
##STR00037##
[0312] To a cooled solution (0.degree. C.) of allyl
4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 18,
7.0 g, 28 mmol, 1.0 eq) in MeOH (140 mL) was added acetic acid
(2.52 mL, 42 mmol, 1.5 eq), followed by
5-chlorothiophene-2-carbaldehyde (4.9 g, 33.6 mmol, 1.2 eq)
portionwise. The reaction was stirred for 4-5 hours at room
temperature. To this was then added sodium cyanoborohydride (3.5 g,
56 mmol, 2.0 eq) portionwise over a period of 45 minutes, and the
reaction mixture was stirred for a further 4-5 hours. After
completion of reaction, the reaction mixture was concentrated under
reduced pressure, and the residual mass was poured into ice cold
water under stirring. The produce was then extracted with ethyl
acetate, and the organic layer was dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography using neutral silica gel, eluting
with 2-4% methanol in dichloromethane to give pure allyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperid-
ine-1-carboxylate (Compound 19, 4.5 g, yield: 45%) m/z[M+H]+ 380.11
1H NMR (400 MHz, DMSO) .delta. 11.41 (s, 1H), 6.88 (dd, J=30.0, 3.7
Hz, 2H), 5.94 (ddd, J=22.4, 10.5, 5.2 Hz, 1H), 5.68 (d, J=6.2 Hz,
1H), 5.28 (dd, J=16.4, 2.5 Hz, 2H), 5.19 (dd, J=10.5, 1.5 Hz, 1H),
4.60-4.46 (m, 2H), 4.28 (d, J=6.1 Hz, 2H), 4.12 (d, J=4.8 Hz, 1H),
4.02 (d, J=13.2 Hz, 2H), 3.17 (d, J=4.0 Hz, 2H), 2.90 (s, 2H), 2.69
(t, J=11.6 Hz, 1H) ppm.
Example 25--Preparation of Compound 20
[0313] The synthesis of Compound 20 followed the procedure of
General Procedure 5a following:
##STR00038##
[0314] To a cooled solution (0.degree. C.) of pivalic acid (0.644
g, 6.3 mmol, 1.2 eq) in THF (10 mL) was added diisopropylethylamine
(DIEA, 1.38 mL, 7.9 mmol, 1.5 eq) and then
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 1.52 g, 7.9 mmol, 1.5 eq). After stirring for 20
minutes, allyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 19, 2.0 g, 5.3 mmol, 1.0 eq) was added,
followed by hydroxybenzotriazole (HOBt, 0.142 g, 1.05 mmol, 0.2
eq). The reaction was stirred for 16 hours at room temperature.
After completion, the reaction mixture was diluted with stirred ice
cold water, and then extracted with ethyl acetate. The organic
layer was dried over sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by column chromatography
using silica gel (60-120 mesh) pre-washed with triethylamine, and
the product was eluted with 2-5% ethyl acetate in hexane to give
allyl 4-(5-(((5-chlorothiophen-2-yl)
methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)piperidine-1-carboxylate
(Compound 20, 1.5 g, yield: 61%) m/z[M+H]+ 464.16 1H NMR (400 MHz,
DMSO) .delta. 7.69 (t, J=6.2 Hz, 1H), 6.97 (dd, J=8.1, 3.7 Hz, 2H),
5.94 (ddd, J=22.4, 10.4, 5.2 Hz, 1H), 5.42 (s, 1H), 5.28 (dd,
J=17.2, 1.5 Hz, 1H), 5.19 (d, J=10.5 Hz, 1H), 4.53 (d, J=5.1 Hz,
2H), 4.41 (d, J=6.1 Hz, 2H), 3.99 (d, J=13.2 Hz, 2H), 2.96 (s, 2H),
2.69 (t, J=11.0 Hz, 1H), 1.86 (d, J=11.1 Hz, 2H), 1.56-1.44 (m,
2H), 1.40 (s, 9H) ppm.
Example 26--Preparation of Compound 21
[0315] The synthesis of Compound 21 followed the procedure of
General Procedure 8a following:
##STR00039##
[0316] A solution of allyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pi-
peridine-1-carboxylate (Compound 20, 0.1 g, 0.22 mmol, 1.0 eq) and
zinc chloride (0.003 g, 21.6 mmol, 0.1 eq) in dichloromethane (10
mL) was degassed with a nitrogen stream for 15 minutes. To the
mixture was then added tris(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3, 0.0098 g, 0.011 mmol, 0.05 eq), and then
solution again degassed with a nitrogen stream for 15 minutes.
Poly(methylhydrosiloxane) (PMHS, 0.818 g, 0.43 mmol, 2.0 eq) was
then added dropwise at room temperature, and the reaction mixture
was stirred for 3-4 hours at room temperature. After completion,
the reaction mixture was filtered through Celite.RTM., and the
solvent then evaporated solvent under reduced pressure. To the
residue was added hexane and then acetonitrile, and the mixture
then stirred for 10 minutes. The black particles were filtered, and
the acetonitrile and hexane layers were separated. The acetonitrile
layer was washed with hexane 3 times and the solvent evaporated.
The residue was purified by preparative HPLC to yield
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-
-1-yl)-2,2-dimethylpropan-1-one (Compound 21, 0.0375 g, yield: 32%)
m/z[M+H]+ 380.14 1H NMR (400 MHz, DMSO) .delta. 8.36 (s, 1H), 7.72
(t, J=6.2 Hz, 1H), 6.97 (s, 2H), 5.38 (s, 1H), 4.42 (d, J=6.1 Hz,
2H), 3.21 (d, J=12.6 Hz, 2H), 2.88 (dd, J=12.2, 9.6 Hz, 2H), 2.75
(dd, J=12.9, 9.4 Hz, 1H), 1.98 (d, J=11.2 Hz, 2H), 1.76-1.61 (m,
2H), 1.41 (s, 9H) ppm.
Example 27--Preparation of Intermediate 6
[0317] The synthesis of Intermediate 6 followed the procedure of
General Procedure 9 following:
##STR00040##
[0318] To a cooled solution (-78.degree. C.) of diisopropylamine
(8.74 g, 86.4 mmol, 1.6 eq) in THF (200 mL) was added n-BuLi (34.5
mL, 86.4 mmol, 1.6 eq), and the mixture stirred for 1 hour at
0.degree. C. The mixture was cooled to -78.degree. C. and to it was
added tert-butyl 2-oxopiperidine-1-carboxylate (10.0 g, 54.0 mmol,
1.0 eq). The mixture was stirred for 1 hour and methyl
chloroformate (6.12 g, 64.8 mmol, 1.2 eq) was added. The reaction
mixture was allowed to warm to room temperature overnight, and was
monitored by TLC and LC-MS. After completion, the reaction mixture
was quenched with ammonium chloride and evaporated under reduced
pressure. The residue was extracted with ethyl acetate (2.times.150
mL), and the combined organic phases were washed with water, brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by flash chromatography
using silica gel (60-120 mesh) eluting with 40% ethyl acetate in
n-hexane to yield
1-(tert-butyl)-3-methyl-2-oxopiperidine-1,3-dicarboxylate
(Intermediate 6, 9.2 g, yield: 70%) m/z 202.13 [M-56].sup.+;
.sup.1H NMR (400 MHz, DMSO) .delta. 3.70 (s, 1H), 3.62-3.50 (m,
3H), 2.10-1.89 (m, 2H), 1.88-1.72 (m, 2H), 1.42 (s, 9H) ppm.
Example 28--Preparation of Intermediate 7
[0319] The synthesis of Intermediate 7 followed the procedure of
General Procedure 1 following:
##STR00041##
[0320] To a cooled solution (0.degree. C.) of
1-(tert-butyl)-3-methyl-2-oxopiperidine-1,3-dicarboxylate
(Intermediate 6, 10.0 g, 38.9 mmol, 1.0 eq) in DMF (100 mL) was
added potassium carbonate (27.0 g. 194 mmol, 5.0 eq), and the
reaction mixture stirred for 1 hour. To the mixture was added
methyl iodide (6.62 g, 46.7 mmol, 1.2 eq). The reaction mixture was
allowed to come at room temperature and stirred overnight. After
completion, the reaction mixture was poured into ice-cold water and
filtered to yield product
1-(tert-butyl)-3-methyl-3-methyl-2-oxopiperidine-1,3-dicarboxylate
(Intermediate 7, 7.91 g, yield: 75%) m/z 272.2 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 3.72-3.61 (m, 4H), 3.56-3.45 (m, 1H),
2.17 (d, J=8.0 Hz, 1H), 1.78 (dd, J=17.4, 12.4 Hz, 3H), 1.45 (s,
9H), 1.36 (s, 3H) ppm.
Example 29--Preparation of Intermediate 8
[0321] The synthesis of Intermediate 8 followed the procedure of
General Procedure 6b following:
##STR00042##
[0322] To a cooled solution (0.degree. C.) of
1-(tert-butyl)-3-methyl-3-methyl-2-oxopiperidine-1,3-dicarboxylate
(Intermediate 7, 5.0 g, 18.4 mmol, 1.0 eq) in dichloromethane (50
mL) was added trifluoroacetic acid (2.5 mL), and the reaction
mixture stirred for 1 hour at 0.degree. C. The reaction mixture was
allowed to warm to room temperature overnight. After reaction
completion, the reaction mixture was treated with saturated
NaHCO.sub.3 and extracted with dichloromethane (2.times.50 mL). The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate and evaporated under reduced pressure to
yield methyl 3-methyl-2-oxopiperidine-3-carboxylate (Intermediate
8, 2.8 g yield: 89%); m/z 173.16 [M+2].sup.+; .sup.1H NMR (400 MHz,
DMSO) .delta. 7.94 (s, 1H), 3.63 (s, 3H), 3.32-3.14 (m, 2H),
2.58-2.37 (m, 2H), 2.04-1.99 (m, 2H), 1.26 (s, 3H) ppm.
Example 30--Preparation of Intermediate 9
[0323] The synthesis of Intermediate 9 followed the procedure of
General Procedure 2 following:
##STR00043##
[0324] To a cooled (-78.degree. C.) solution of acetonitrile (1.0
g, 24.3 mmol, 1.6 eq) in tetrahydrofuran (30 mL) was added n-BuLi
(2.5M in hexane, 9.73 mL, 24.3 mmol, 1.6 eq) dropwise over a period
of 20 minutes. The reaction was stirred for another 60 minutes at
-78.degree. C. To the mixture was added methyl
3-methyl-2-oxopiperidine-3-carboxylate (Intermediate 8, 2.6 g, 15.2
mmol, 1.0 eq) portionwise, and the solution stirred at -78.degree.
C. for 3 hours. The mixture was quenched with saturated ammonium
chloride solution and extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography using silica gel (60-120 mesh size), eluting
with 70% ethyl acetate in n-hexane, to give
3-(3-methyl-2-oxopiperidin-3-yl)-3-oxopropanenitrile (Intermediate
9, 2.41 g, yield: 88%) m/z 181.11 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO) .delta. 7.89 (s, 1H), 4.39-4.05 (m, 2H), 3.27-3.06 (m,
2H), 2.14 (ddd, J=19.7, 10.0, 5.2 Hz, 1H), 1.80-1.60 (m, 2H),
1.60-1.43 (m, 1H), 1.32 (s, 3H) ppm.
Example 31--Preparation of Compound 22
[0325] The synthesis of Compound 22 followed the procedure of
General Procedure 3 following:
##STR00044##
[0326] To a solution of
3-(3-methyl-2-oxopiperidin-3-yl)-3-oxopropanenitrile (Intermediate
9, 2.0 g, 11.0 mmol, 1.0 eq) in isopropanol (10 mL) and acetic acid
(2.0 mL) was added hydrazine monohydrate (0.825 g, 16.5 mmol, 1.5
eq) dropwise, and the reaction then stirred at 60.degree. C. for 3
hours. The reaction mixture was monitored by TLC and LC-MS, and
after completion concentrated under reduced pressure. The residue
was purified by column chromatography using silica gel (60-120
mesh), eluting with 0-5% methanol in dichloromethane to give
3-(5-amino-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 22,
1.16 g, yield: 54%); m/z 195.19 [M+1].sup.+.
Example 32--Preparation of Compound 23
[0327] The synthesis of Compound 23 followed the procedure of
General Procedure 4 following:
##STR00045##
[0328] To a cooled solution (0.degree. C.) of
3-(5-amino-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 22,
1.0 g, 5.15 mmol, 1.0 eq) in methanol (20 mL) was added acetic acid
(0.3 g, 5.15 mmol, 1.0 eq) dropwise. To the mixture was added
5-chlorothiophene-2-carbaldehyde (0.91 g, 6.18 mmol, 1.2 eq)
dropwise and the mixture was warmed to room temperature over 45
minutes. Sodium cyanoborohydride (0.644 g, 10.3 mmol, 2.0 eq) was
added portionwise over a period of 15 minutes, and the reaction
mixture was stirred at room temperature for 12 hours. After
completion of reaction, the mixture was concentrated under reduced
pressure. The residue was purified by column chromatography using
silica gel (60-100 mesh), eluting with 0-5% methanol in
dichloromethane to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridin-2-one (Compound 23, 0.686 g, yield: 41%); m/z 325.25; .sup.1H
NMR (400 MHz, DMSO) .delta. 11.26 (s, 1H), 7.50 (s, 1H), 6.88 (dd,
J=31.3, 3.6 Hz, 2H), 5.66 (s, 1H), 5.30 (s, 1H), 4.29 (d, J=6.2 Hz,
2H), 3.14 (s, 2H), 2.10 (s, 1H), 1.65 (s, 3H), 1.37 (s, 3H)
ppm.
Example 33--Preparation of Compound 24
[0329] The synthesis of Compound 24 followed the procedure of
General Procedure 5a following:
##STR00046##
[0330] To a cooled solution (0.degree. C.) of pivalic acid (0.188
g, 1.84 mmol, 1.5 eq) in THF (15 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.352 g, 1.84 mmol, 1.5 eq), followed by triethylamine
(TEA, 0.373 g, 3.69 mmol, 3.0 eq). The reaction mixture was stirred
for 30 minutes, then to the mixture was added hydroxybenzotriazole
(HOBt, 0.033 g, 0.24 mmol, 0.2 eq), followed by
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridin-2-one (Compound 23, 0.4 g, 1.23 mmol, 1.0 eq). The reaction
was monitored by LC-MS, and after completion the reaction mixture
was poured into water (50 mL) and extracted with ethyl acetate
(3.times.25 mL). The combined organic phases were washed with
water, brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
preparative HPLC using acetonitrile-water as mobile phase to give
product
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-3-
-methylpiperidin-2-one (Compound 24, 0.21 g, yield: 42%) m/z 408.95
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta. 7.62 (t, J=6.2 Hz,
1H), 7.53 (s, 1H), 6.96 (dd, J=12.1, 3.7 Hz, 2H), 5.42 (s, 1H),
4.41 (d, J=6.1 Hz, 2H), 3.25-3.06 (m, 2H), 2.29-2.17 (m, 1H), 1.73
(ddd, J=21.5, 11.1, 7.2 Hz, 3H), 1.41 (s, 9H), 1.37 (s, 3H)
ppm.
Example 34--Preparation of Compound 25
[0331] The synthesis of Compound 25 followed the procedure of
General Procedure 5c following:
##STR00047##
[0332] To a cooled solution (0.degree. C.) of
3-hydroxy-2,2-dimethylpropanoic acid (0.130 g, 1.1 mmol, 1.2 eq) in
THF (10 mL) under nitrogen was added
N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate (TBTU, 0.320 g, 1.0 mmol, 1.1 eq) and
diisopropylethylamine (DIEA, 0.280 g, 2.9 mmol, 3.0 eq). The
reaction mixture was stirred for 30 minutes, and to it was added
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridin-2-one (Compound 23, 0.3 g, 0.9 mmol, 1.0 eq). The reaction
was monitored by LC-MS, and after completion the mixture was poured
into water (40 mL) and extracted with ethyl acetate (3.times.25
mL). The combined organic phases were washed with water, brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by preparative HPLC
using acetonitrile-water as mobile phase to give desired product
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 25,
0.0129 g, yield: 3%) m/z 425.30 [M+1].sup.+; .sup.1H NMR (400 MHz,
CD.sub.3CN) .delta. 7.48 (s, 1H), 6.88 (q, J=3.8 Hz, 2H), 6.10 (s,
1H), 5.44 (s, 1H), 4.45 (d, J=6.2 Hz, 2H), 3.89 (d, J=6.2 Hz, 2H),
3.43 (t, J=6.2 Hz, 1H), 3.27 (d, J=6.6 Hz, 2H), 2.34-2.23 (m, 1H),
1.91-1.70 (m, 3H), 1.49-1.34 (m, 3H), 1.30 (s, 6H) ppm.
Example 35--Preparation of Compound 26
[0333] The synthesis of Compound 26 followed the procedure of
General Procedure 5c following:
##STR00048##
[0334] To a cooled solution (0.degree. C.) of
3-methoxy-2,2-dimethylpropanoic acid (0.134 g, 1.0 mmol, 1.1 eq) in
THF (12 mL) under nitrogen was added
N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate (TBTU, 0.326 g, 1.0 mmol, 1.1 eq) and
diisopropylethylamine (DIPEA, 0.280 g, 2.8 mmol, 3.0 eq). The
reaction mixture was stirred for 30 minutes, and to it was added
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridin-2-one (Compound 23, 0.3 g, 0.92 mmol, 1.0 eq). The reaction
was monitored by LC-MS, and after completion the mixture was poured
into water (30 mL) and extracted with ethyl acetate (3.times.25
mL). The combined organic phases were washed with water, brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by preparative HPLC
using acetonitrile-water as mobile phase to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 26, 0.061
g, yield: 15%); m/z 439.21 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO)
.delta. 7.59 (s, 1H), 7.54 (s, 1H), 6.96 (t, J=6.9 Hz, 2H), 5.42
(s, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.83 (d, J=5.1 Hz, 2H), 3.13 (s,
3H), 2.22 (s, 1H), 1.70 (s, 3H), 1.40-1.29 (m, 6H) ppm.
Example 36--Preparation of Compound 27
[0335] The synthesis of Compound 27 followed the procedure of
General Procedure 5a following:
##STR00049##
[0336] To a cooled solution (0.degree. C.) of 2-methoxybenzoic acid
(0.351 g, 2.3 mmol, 1.5 eq) in THF (15 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.441 g, 2.3 mmol, 1.5 eq) and then triethylamine (TEA,
0.467 g, 4.6 mmol, 3.0 eq). The reaction mixture was stirred for 30
minutes, and to it was added hydroxybenzotriazole (HOBt, 0.041 g,
0.3 mmol, 0.2 eq) followed by
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylp-
iperidin-2-one (Compound 23, 0.5 g, 1.53 mmol, 1.0 eq). The
reaction was monitored by LC-MS, and after completion the reaction
mixture was poured into water (5 mL) and extracted with ethyl
acetate (3.times.25 mL). The combined organic phases were washed
with water, brine, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was purified by
preparative HPLC using ammonia-water as mobile phase to give
desired product
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)-3-methylpiperidin-2-one (Compound 27, 0.23 g, yield:
-32%); m/z 458.91 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
7.59 (t, J=6.0 Hz, 1H), 7.55-7.34 (m, 3H), 7.12 (d, J=8.3 Hz, 1H),
7.01 (dd, J=13.4, 5.8 Hz, 2H), 5.48 (s, 1H), 4.48 (d, J=6.0 Hz,
2H), 3.73 (s, 3H), 3.07 (s, 2H), 2.15-1.94 (m, 2H), 1.73-1.45 (m,
3H), 1.25 (s, 3H) ppm.
Example 37--Preparation of Compound 28
[0337] The synthesis of Compound 28 followed the procedure of
General Procedure 5a following:
##STR00050##
[0338] To a cooled solution (0.degree. C.) of 3-thiophene
carboxylic acid (0.177 g, 1.38 mmol, 1.5 eq) in THF (15 mL) under
nitrogen was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 0.264 g, 1.38 mmol, 1.5 eq) and then
triethylamine (TEA, 0.28 g, 2.77 mmol, 3.0 eq). The reaction
mixture was stirred for 30 minutes, and to it was added
hydroxybenzotriazole (HOBt, 0.024 g, 0.18 mmol, 0.2 eq) followed by
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridin-2-one (Compound 23, 0.3 g, 0.92 mmol, 1.0 eq). The reaction
was monitored by LC-MS, and after completion the reaction mixture
was poured into water (30 mL) and extracted with ethyl acetate
(3.times.25 mL). The combined organic phases were washed with
water, brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
preparative HPLC using ammonia-water as mobile phase to yield
desired product
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-p-
yrazol-3-yl)-3-methylpiperidin-2-one (Compound 28, 0.12 g, yield:
30%) m/z 436.06 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
8.90 (d, J=2.4 Hz, 1H), 7.90-7.49 (m, 4H), 6.98 (s, 2H), 5.55 (s,
1H), 4.49 (d, J=6.2 Hz, 2H), 3.18 (s, 2H), 2.23 (d, J=10.4 Hz, 1H),
1.75 (d, J=10.8 Hz, 3H), 1.42 (s, 3H) ppm.
Example 38--Preparation of Compound 29
[0339] The synthesis of Compound 29 followed the procedure of
General Procedure 5a following:
##STR00051##
[0340] To a cooled solution (0.degree. C.) of
4-methyltetrahydro-2H-pyran-4-carboxylic acid (0.2 g, 1.4 mmol, 1.5
eq) in THF (15 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.265 g, 1.4 mmol, 1.5 eq) and then triethylamine (TEA,
0.283 g, 2.8 mmol, 3.0 eq). The reaction mixture was stirred for 30
minutes, and to it was added hydroxybenzotriazole (HOBt, 0.025 g,
0.19 mmol, 0.2 eq) and
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpipe-
ridin-2-one (Compound 23, 0.3 g, 0.92 mmol, 1.0 eq). The reaction
was stirred for 2 days and monitored by LC-MS. After completion
reaction the mixture was poured into water (40 mL) and extracted
with ethyl acetate (3.times.25 mL). The combined organic phases
were washed with water, brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by preparative HPLC using acetonitrile-water as mobile
phase to give desired product
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(1-methylcyclohexane-1-carb-
onyl)-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 29, 0.052
g, yield--13%) m/z 450.96 [M+2].sup.+; .sup.1H NMR (400 MHz, DMSO)
.delta. 7.65 (t, J=6.3 Hz, 1H), 7.53 (s, 1H), 6.96 (dd, J=11.0, 3.7
Hz, 2H), 5.43 (s, 1H), 4.42 (d, J=6.1 Hz, 2H), 3.81-3.60 (m, 2H),
3.45 (dd, J=11.8, 8.8 Hz, 2H), 3.14 (s, 2H), 2.34 (s, 2H), 2.18 (d,
J=9.3 Hz, 1H), 1.70 (d, J=8.5 Hz, 5H), 1.51 (s, 3H), 1.36 (s, 3H)
ppm.
Example 39--Preparation of Intermediate 10
[0341] The synthesis of Intermediate 10 followed the procedure of
General Procedure 9 following:
##STR00052##
[0342] To a cooled solution (-78.degree. C.) of diisopropylamine
(8.74 g, 86.4 mmol, 1.6 eq) in anhydrous THF (200 mL) was added
n-BuLi (34.5 mL, 86.4 mmol, 1.6 eq), followed by stirring at
0.degree. C. for 1 hour. The mixture was re-cooled to -78.degree.
C. and to it was added tert-butyl-2-oxopyrrolidine-1-carboxylate
(10.0 g, 54 mmol, 1.0 eq) portionwise, stirred for 1 hour and to it
added methyl chloroformate (6.12 g, 64.8 mmol, 1.2 eq). The
reaction mixture was allowed to come at room temperature and
stirred overnight. It was monitored by TLC and LC-MS. After
completion, the reaction mixture was quenched with ammonium
chloride and evaporated to a residue, which was extracted with
ethyl acetate (2.times.150 mL). The combined organic phases were
washed with water, brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by flash chromatography using silica gel (60-120 mesh)
eluting with 40% ethyl acetate in n-hexane to give 1-(tert-butyl)
3-methyl 2-oxopyrrolidine-1,3-dicarboxylate (Intermediate 10, 9.46
g, yield: 45%) m/z 188.17 [M-56].sup.+; 1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.90 (ddd, J=10.8, 8.5, 5.4 Hz, 1H), 3.81 (s,
3H), 3.73 (ddd, J=10.8, 8.1, 6.6 Hz, 1H), 3.62-3.52 (m, 1H),
2.50-2.34 (m, 1H), 2.25 (dddd, J=13.3, 9.1, 8.1, 5.4 Hz, 1H), 1.55
(s, 9H) ppm.
Example 40--Preparation of Intermediate 11
[0343] The synthesis of Intermediate 11 followed the procedure of
General Procedure 1 following:
##STR00053##
[0344] To a cooled solution (0.degree. C.) of
1-(tert-butyl)-3-methyl-2-oxopyrrolidine-1,3-dicarboxylate
(Intermediate 10, 10.0 g, 41.1 mmol, 1.0 eq) in DMF (100 mL) was
added potassium carbonate (28.4 g, 205.5 mmol, 5.0 eq). After
stirring for 1 hour at 0.degree. C., methyl iodide (7.02 g, 49.3
mmol, 1.2 eq) was added. The reaction mixture was allowed to come
at room temperature and stirred overnight. It was monitored by TLC
and LC-MS. After completion, the reaction mixture was poured into
ice-cooled water and filtered to yield 1-(tert-butyl)-3-methyl
3-methyl-2-oxopyrrolidine-1,3-dicarboxylate (Intermediate 11, 7.3
g, yield: 69%) m/z 202.13 [M-56].sup.+1H NMR (400 MHz, CDCl.sub.3)
.delta. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.78 (d, J=6.0
Hz, 5H), 2.54 (ddd, J=13.0, 7.4, 4.3 Hz, 1H), 1.91 (dt, J=13.1, 8.2
Hz, 1H), 1.54 (d, J=11.7 Hz, 9H), 1.49 (d, J=11.6 Hz, 3H) ppm.
Example 41--Preparation of Intermediate 12
[0345] The synthesis of Intermediate 12 followed the procedure of
General Procedure 6b following:
##STR00054##
[0346] To a cooled solution (0.degree. C.) of
1-(tert-butyl)-3-methyl-3-methyl-2-oxopiperidine-1,3-dicarboxylate
(Intermediate 11, 5.0 g, 19.4 mmol, 1.0 eq.) in dichloromethane (50
mL) was added trifluoroacetic acid (2.5 mL). After stirring for 1
hour, the mixture was allowed to come to room temperature
overnight. It was monitored by TLC and LC-MS. After completion, the
reaction mixture was treated with saturated solution of NaHCO.sub.3
and extracted with dichloromethane (2.times.50 mL). The combined
organic layers were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated to give methyl
3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12, 2.26 g,
yield: 74%) m/z 158.04 [M+1].sup.+1H NMR (400 MHz, DMSO) .delta.
.sup.1H NMR (400 MHz, DMSO) .delta. 7.94 (s, 1H), 3.63 (s, 3H),
3.32-3.14 (m, 2H), 2.58-2.37 (m, 1H), 2.04-1.86 (m, 1H), 1.26 (s,
3H) ppm.
Example 42--Preparation of Intermediate 13
[0347] The synthesis of Intermediate 13 followed the procedure of
General Procedure 2 following:
##STR00055##
[0348] To a cooled solution (-78.degree. C.) of acetonitrile (1.2
g, 26.5 mmol, 1.6 eq) in anhydrous tetrahydrofuran (30 mL) was
added n-BuLi (2.5M in hexane, 10.6 mL, 26.5 mmol, 1.6 eq) dropwise
over a period of 20 minutes. After stirring for 1 hour,
methyl-3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12,
2.6 g, 16.5 mmol, 1.0 eq) was added portionwise, and the reaction
mixture stirred at -78.degree. C. for 3 hours. The reaction was
quenched with saturated ammonium chloride solution and product was
extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography using
silica gel (60-120 mesh size), eluting with 70% ethyl acetate in
n-hexane to give desired product
3-(3-methyl-2-oxopyrrolidin-3-yl)-3-oxopropanenitrile (Intermediate
13, 2.17 g, yield: 79%) m/z 167.1 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO) .delta. 8.09 (s, 1H), 4.27 (q, J=20.3 Hz, 2H), 3.35 (s,
3H), 3.20 (dd, J=13.0, 5.6 Hz, 2H), 1.81 (ddd, J=13.1, 7.7, 5.6 Hz,
1H), 1.35-1.20 (m, 1H) ppm.
Example 43--Preparation of Compound 30
[0349] The synthesis of Compound 30 followed the procedure of
General Procedure 3 following:
##STR00056##
[0350] To a solution of
3-(3-methyl-2-oxopyrrolidin-3-yl)-3-oxopropanenitrile (Intermediate
13, 0.5 g, 3.0 mmol, 1.0 eq) in isopropanol (10 mL) and acetic acid
(2.0 mL) was added hydrazine monohydrate (0.25 g, 4.5 mmol, 1.5 eq)
dropwise. The reaction was stirred at 60.degree. C. for 3 hours and
monitored by TLC and LC-MS. After completion the reaction mixture
was concentrated under reduced pressure to obtain a residue, which
was purified by column chromatography using silica gel (60-120
mesh). Product was eluted with 0-5% methanol in dichloromethane to
give 3-(5-amino-1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one (Compound
30, 0.435 g, yield: 80%) m/z 181.19 [M+1].sup.+.
Example 44--Preparation of Compound 31
[0351] The synthesis of Compound 31 followed the procedure of
General Procedure 4 following:
##STR00057##
[0352] To a cooled solution (0.degree. C.) of
3-(5-amino-1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one (Compound 30,
1.0 g, 5.5 mmol, 1.0 eq) in methanol (20 mL) was added acetic acid
(0.3 g, 5.5 mmol, 1.0 eq) dropwise, followed by
5-chlorothiophene-2-carbaldehyde (0.92 g, 6.6 mmol, 1.2 eq). The
reaction was stirred for 30-45 minutes at room temperature. Sodium
cyanoborohydride (0.65 g, 11.0 mmol, 2.0 eq) was then added
portionwise over a period of 15 minutes. The reaction was stirred
at room temperature for 12 hours. After completion of reaction, the
reaction mixture was concentrated under reduced pressure. The
residue was purified by column chromatography using silica gel
(60-100 mesh, eluting with 0-5% methanol in dichloromethane to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpyrr-
olidin-2-one (Compound 31, 0.21 g, yield: 12%) m/z 311.3
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta. 11.43 (s, 1H),
7.70 (s, 1H), 6.89 (dd, J=29.1, 3.5 Hz, 2H), 5.77 (s, 1H), 5.35 (s,
1H), 4.29 (s, 2H), 3.20 (t, J=6.5 Hz, 2H), 2.33 (s, 1H), 2.01 (d,
J=11.9 Hz, 1H), 1.32 (s, 3H) ppm.
Example 45--Preparation of Compound 32
[0353] The synthesis of Compound 32 followed the procedure of
General Procedure 5a following:
##STR00058##
[0354] To a cooled solution (0.degree. C.) of pivalic acid (0.147
g, 1.45 mmol, 1.5 eq) in THF (15 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.276 g, 1.45 mmol, 1.5 eq) followed by triethylamine
(TEA, 0.4 mL, 2.89 mmol, 3.0 eq). After stirring for 30 minutes,
hydroxybenzotriazole (HOBt, 0.026 g, 0.2 mmol, 0.2 eq) and
3-(5-(((5-chlorothiophen-2-yl)
methyl)amino)-1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one (Compound
31, 0.3 g, 0.96 mmol, 1.0 eq) were then added. The reaction was
monitored by LC-MS, and after completion the reaction mixture was
poured into water (50 mL) and extracted with ethyl acetate
(3.times.25 mL). The combined organic phases were washed with
water, brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
preparative HPLC using acetonitrile-water as mobile phase to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3--
yl)-3-methylpyrrolidin-2-one (Compound 32, 0.05 g, yield: 13%) m/z
395.7 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta. 7.74 (s,
1H), 7.66 (t, J=6.2 Hz, 1H), 6.97 (s, 2H), 5.43 (s, 1H), 4.43 (d,
J=6.2 Hz, 2H), 3.30-3.18 (m, 2H), 2.54 (s, 1H), 2.00 (dt, J=12.6,
7.7 Hz, 1H), 1.41 (s, 9H), 1.34 (s, 3H) ppm.
Example 46--Preparation of Compound 33
[0355] The synthesis of Compound 33 followed the procedure of
General Procedure 5a following:
##STR00059##
[0356] To a cooled solution (0.degree. C.) of 2-methoxybenzoic acid
(0.219 g, 1.45 mmol, 1.5 eq) in THF (15 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.276 g, 1.45 mmol, 1.5 eq) followed by triethylamine
(TEA, 0.4 mL, 2.89 mmol, 3.0 eq). After stirring for 30 minutes,
hydroxybenzotriazole (HOBt, 0.026 g, 0.19 mmol, 0.2 eq) and
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpyrr-
olidin-2-one (Compound 31, 0.3 g, 0.96 mmol, 1.0 eq) were added.
The reaction was monitored by LC-MS, and after completion the
mixture was poured into water (40 mL) and extracted with ethyl
acetate (3.times.25 mL). The combined organic phases were washed
with water, brine, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was purified by
preparative HPLC using acetonitrile-water as mobile phase to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)-3-methylpyrrolidin-2-one (Compound 33, 0.05 g, yield: 12%)
m/z 447.18; .sup.1H NMR (400 MHz, DMSO) .delta. 7.70-7.58 (m, 2H),
7.55-7.44 (m, 1H), 7.38 (dd, J=7.5, 1.7 Hz, 1H), 7.13 (d, J=8.2 Hz,
1H), 7.09-6.95 (m, 3H), 5.51 (s, 1H), 4.49 (d, J=6.2 Hz, 2H), 3.74
(s, 3H), 3.18-3.00 (m, 2H), 2.35 (ddd, J=12.0, 7.1, 4.7 Hz, 1H),
1.84 (dt, J=12.5, 7.5 Hz, 1H), 1.27-1.18 (m, 3H) ppm.
Example 47--Preparation of Compound 34
[0357] The synthesis of Compound 34 followed the procedure of
General Procedure 5a following:
##STR00060##
[0358] To a cold solution (0.degree. C.) of thiophene-3-carboxylic
acid (0.123 g, 0.96 mmol, 1.5 eq) in THF (12 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.187 g, 0.96 mmol, 1.5 eq) and then triethylamine (TEA,
0.26 mL, 1.93 mmol, 3.0 eq) under nitrogen. After stirring for 30
minutes, hydroxybenzotriazole (HOBt, 0.0173 g, 0.138 mmol, 0.2 eq)
and then
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpyrr-
olidin-2-one (Compound 31, 0.2 g, 0.643 mmol, 1.0 eq) were added.
The reaction was stirred for 2 days and monitored by LC-MS. After
completion the reaction mixture was poured into water (40 mL) and
extracted with ethyl acetate (3.times.25 mL). The combined organic
phases were washed with water, brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by preparative HPLC using acetonitrile-water
as mobile phase to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-p-
yrazol-3-yl)-3-methylpyrrolidin-2-one (Compound 34, 0.05 g,
yield-19%) m/z 421.01 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO)
.delta. 8.90 (dd, J=3.0, 1.1 Hz, 1H), 7.86-7.73 (m, 3H), 7.66 (dd,
J=5.1, 3.0 Hz, 1H), 6.98 (q, J=3.8 Hz, 2H), 5.57 (s, 1H), 4.50 (d,
J=6.2 Hz, 2H), 3.32-3.17 (m, 2H), 2.54-2.60 (m, 1H), 2.12-1.96 (m,
2H), 1.38 (s, 3H) ppm.
Example 48--Preparation of Compound 35
[0359] The synthesis of Compound 35 followed the procedure of
General Procedure 5a following:
##STR00061##
[0360] To a cold solution (0.degree. C.) of
4-methyltetrahydro-2H-pyran-4-carboxylic acid (0.184 g, 1.45 mmol,
1.5 eq) in THF (15 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 0.276 g, 1.45 mmol, 1.5 eq), followed by triethylamine
(TEA, 0.3 g, 2.9 mmol, 3.0 eq) under nitrogen. After stirring for
30 minutes, hydroxybenzotriazole (HOBt, 0.026 g, 0.19 mmol, 0.2 eq)
was added, followed by 3-(5-(((5-chlorothiophen-2-yl) methyl)
amino)-1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one (Compound 31, 0.3
g, 0.96 mmol, 1.0 eq). The reaction was stirred for 2 days and
monitored by LC-MS, and after completion the reaction mixture was
poured into water (40 mL) and extracted with ethyl acetate
(3.times.25 mL). The combined organic phases were washed with
water, brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
preparative HPLC using acetonitrile-water as mobile phase to give
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-methyltetrahydro-2H-
-pyran-4-carbonyl)-1H-pyrazol-3-yl)-3-methylpyrrolidin-2-one
(Compound 35, 0.05 g, yield: 12%) m/z 437.39 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 7.71 (dd, J=15.0, 8.8 Hz, 2H), 6.96 (d,
J=4.3 Hz, 2H), 5.44 (s, 1H), 4.44 (d, J=6.2 Hz, 2H), 3.69 (d,
J=11.6 Hz, 2H), 3.48 (t, J=8.6 Hz, 2H), 3.24 (dd, J=9.2, 5.0 Hz,
2H), 2.35 (d, J=6.8 Hz, 3H), 1.99 (dt, J=12.5, 7.5 Hz, 1H), 1.69
(s, 2H), 1.52 (s, 3H), 1.33 (s, 3H) ppm.
Example 49--Preparation of Intermediate 14
[0361] The synthesis of Intermediate 14 followed the procedure of
General Procedure 10 following:
##STR00062##
[0362] To a stirred solution of (+/-)-piperazine-2-carboxylic acid
dihydrochloride (25 g, 123.2 mmol) in water (200 mL) at room
temperature was added aqueous sodium hydroxide (2.5M, 200 mL)
followed by copper sulfate pentahydrate (CuSO.sub.4.5H.sub.2O
solution, 15.88 g, 61.5 mmol in 100 mL H.sub.2O) dropwise. The
mixture was cooled to 0.degree. C., and to it was added solid
sodium bicarbonate (12.5 g, 148.8 mmol). After stirring at
0.degree. C. for 15 minutes, a solution of CBZ--Cl in 1,4-dioxane
was added. The reaction mixture was stirred at room temperature for
16 hours. (NOTE: The pH was maintained >7 throughout the
reaction). The volatiles were evaporated under reduced pressure to
afford 4-(benzyloxycarbonyl)piperazine-2-carboxylic acid
(Intermediate 14, 45 g, crude) as a blue color copper complex
solid. It was considered for the next step without any
purification; TLC: 5% MeOH in dichloromethane, R.sub.f: 0.4.
Example 50--Preparation of Intermediate 15
[0363] The synthesis of Intermediate 15 followed the procedure of
General Procedure 11 following:
##STR00063##
[0364] To a stirred solution of
4-(benzyloxycarbonyl)piperazine-2-carboxylic acid-copper complex
(Intermediate 15, 40 g, 122.6 mmol) in water (200 mL) was added
ethylenediamine tetraacetic acid (EDTA, 20 g, 61.4 mmol in 200 mL
water), and the mixture was heated to 100.degree. C. for 16 hours.
The reaction mixture was concentrated under reduced pressure to
afford the crude 4-(benzyloxycarbonyl)piperazine-2-carboxylic acid
(Intermediate 15, 30 g) as blue color solid which was taken forward
to the next step without further purification; TLC System: 5% MeOH
in dichloromethane R.sub.f: 0.2.
Example 51--Preparation of Intermediate 16
[0365] The synthesis of Intermediate 16 followed the procedure of
General Procedure 12 following:
##STR00064##
[0366] To a cooled solution (0.degree. C.) of
4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (Intermediate 15,
48 g, 181.8 mmol) in water (10 volumes, 480 mL) was added solid
NaHCO.sub.3(45.8 g, 545.4 mmol) followed by di-tert-butyl
dicarbonate ((Boc).sub.2O, 109 mL, 490.9 mmol). The reaction
mixture was stirred at room temperature for 17 hours. After cooling
to room temperature it was extracted into EtOAc (4.times.100 mL).
The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 50% EtOAc/n-hexane, to afford
4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic
acid (Intermediate 16, 25 g, yield: 55%) as an off-white solid;
TLC: 5% Methanol-dichloromethane, R.sub.f: 0.3.
Example 52--Preparation of Intermediate 17
[0367] The synthesis of Intermediate 17 followed the procedure of
General Procedure 13 following:
##STR00065##
[0368] To a cooled solution (0.degree. C.) of
4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic
acid (Intermediate 16, 20 g, 54.9 mmol) in dry DMF (200 mL) was
added cesium carbonate (Cs.sub.2CO.sub.3, 35.8 g, 109.9 mmol)
followed by methyl iodide (10.26 mL, 164.83 mmol). The reaction
mixture was stirred at room temperature for 4 hours. After cooling
to 0.degree. C. the mixture was quenched with ice-cold water (90
mL), and extracted with EtOAc (2.times.100 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 20%
EtOAc/n-hexane, to afford 4-benzyl 1-tert-butyl 2-methyl
piperazine-1,2,4-tricarboxylate (Intermediate 17, 25 g, yield-55%)
as an off-white solid. TLC: 30% ethyl acetate in hexane. R.sub.f:
0.5.
Example 53--Preparation of Intermediate 18
[0369] The synthesis of Intermediate 18 followed the procedure of
General Procedure 14 following:
##STR00066##
[0370] To a stirred solution of 4-benzyl 1-tert-butyl 2-methyl
piperazine-1,2,4-tricarboxylate (Intermediate 17, 10 g, 26.5 mmol)
in MeOH (100 mL) in a steel vessel was added 10% Pd/C (30% w/w, 3.0
g), and the mixture stirred under 50 psi hydrogen pressure at room
temperature for 5 hours. The reaction mixture was filtered through
a Celite pad and the volatiles were concentrated under reduced
pressure to afford 1-tert-butyl 2-methyl
piperazine-1,2-dicarboxylate (Intermediate 18, 5.6 g, yield: 88%)
as a light yellow liquid; TLC: 5% Methanol-dichloromethane.
R.sub.f-0.3.
Example 54--Preparation of Intermediate 19
[0371] The synthesis of Intermediate 19 followed the procedure of
General Procedure 15 following:
##STR00067##
[0372] To a cooled solution (0.degree. C.) of 1-tert-butyl 2-methyl
piperazine-1,2-dicarboxylate (Intermediate 18, 3.5 g, 14.3 mmol) in
dry dichloromethane (70 mL) was added triethylamine (TEA, 5 mL,
35.9 mmol) followed by morpholine-4-carbonyl chloride (3.35 mL,
28.7 mmol). The reaction mixture was stirred at room temperature
for 3 hours. To the mixture was added ice-cold water (20 mL), then
it was extracted into EtOAc (2.times.50 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography using 30% EtOAc/n-hexane to afford 1-tert-butyl
2-methyl 4-(morpholine-4-carbonyl)piperazine-1,2-dicarboxylate
(Intermediate 19, 3.6 g, yield: 72%) as an off white solid; TLC:
50% ethyl acetate in hexane. R.sub.f-0.5.
Example 55--Preparation of Intermediate 20
[0373] The synthesis of Intermediate 20 followed the procedure of
General Procedure 6c following:
##STR00068##
[0374] To a cooled solution (0.degree. C.) of
1-tert-butyl-2-methyl-4-(morpholine-4-carbonyl)piperazine-1,2-dicarboxyla-
te (Intermediate 19, 1.0 g, 2.8 mmol) in 1,4-dioxane (10 mL) was
added HCl (4M in dioxane, 10 mL), and the mixture was then stirred
at room temperature for 5 hours. The reaction mixture was
concentrated and triturated with diethyl ether to afford methyl
4-(morpholine-4-carbonyl)piperazine-2-carboxylate hydrochloride
salt (Intermediate 20, 800 mg, yield: 86%) as an off white solid;
TLC: 5% Methanol-dichloromethane. R.sub.f-0.3.
Example 56--Preparation of Intermediate 21
[0375] The synthesis of Intermediate 21 followed the procedure of
General Procedure 7 following:
##STR00069##
[0376] To a cooled (0.degree. C.) stirred solution of methyl
4-(morpholine-4-carbonyl)piperazine-2-carboxylate (Intermediate 20,
8.2 g, 28.0 mmol) in H.sub.2O (300 mL) at 0.degree. C. was added
solid NaHCO.sub.3(7.05 g, 83.2 mmol), followed by allyl
chloroformate (8 mL, 30.8 mmol) in THF (50 mL). After stirring at
room temperature for 16 hours, ice-cold water (100 mL) was added to
the reaction mixture and extracted into EtOAc (2.times.100 mL). The
combined organic layers were dried over sodium sulfate, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (100-200 mesh), eluting with
40-50% EtOAc/n-hexane to afford 1-allyl 2-methyl
4-(morpholine-4-carbonyl)piperazine-1,2-dicarboxylate (Intermediate
21, 7.2 g, yield: 84%) as a pale yellow color liquid; TLC System:
5% Methanol-dichloromethane R.sub.f-0.6.
Example 57--Preparation of Intermediate 22
[0377] The synthesis of Intermediate 22 followed the procedure of
General Procedure 2 following:
##STR00070##
[0378] To a cooled solution (-78.degree. C.) of acetonitrile (4.04
mL, 77 mmol) in dry THF (120 mL) was added n-BuLi (2.5M in hexane,
26 mL, 65 mmol). After stirring at -78.degree. C. for 30 minutes,
to the mixture was added a solution of
1-allyl-2-methyl-4-(morpholine-4-carbonyl)piperazine-1,2-dicarboxylate
(Intermediate 21, 7.5 g, 22 mmol) in dry THF (30 mL). The mixture
was stirred at -78.degree. C. for a further 30 minutes. The
reaction mixture was quenched with saturated NH.sub.4Cl solution
(80 mL) and extracted into EtOAc (2.times.120 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 50%
EtOAc/n-hexane, to afford
allyl-2-(2-cyanoacetyl)-4-(morpholine-4-carbonyl)piperazine-1-carboxylate
(Intermediate 22, 6.5 g, yield-85%) as a light yellow liquid; TLC
System: 5% Methanol-dichloromethane R.sub.f-0.5.
Example 58--Preparation of Compound 36
[0379] The synthesis of Compound 36 followed the procedure of
General Procedure 3 following:
##STR00071##
[0380] To a solution of allyl
2-(2-cyanoacetyl)-4-(morpholine-4-carbonyl)piperazine-1-carboxylate
(Intermediate 22, 6.5 g, 18.6 mmol) in ethanol (65 mL) was added
N.sub.2H.sub.4 (1.1 mL, 22.3 mmol) and the reaction mixture was
heated to 80.degree. C. for 5 hours. The reaction mixture was
cooled to room temperature, the volatiles were evaporated and the
resultant residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 3% methanol-dichloromethane, to afford
allyl-2-(5-amino-1H-pyrazol-3-yl)-4-(morpholine-4-carbonyl)piperazine-1-c-
arboxylate (Compound 36, 4.5 g, yield: 67%) as a pale yellow color
semi solid; TLC System: 5% Methanol-dichloromethane R.sub.f-0.3;
m/z 365.28 [M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 11.2 (s, 1H),
5.9 (m, 1H), 5.0-5.3 (m, 4H), 4.8 (br s, 2H), 4.6 (br s, 2H), 3.85
(m, 2H), 3.4-3.6 (m, 4H), 3.0-3.2 (m, 6H), 2.8 (m, 1H) ppm.
Example 59--Preparation of Compound 37
[0381] The synthesis of Compound 37 followed the procedure of
General Procedure 4 following:
##STR00072##
[0382] To a cooled solution (0.degree. C.) of allyl
2-(5-amino-1H-pyrazol-3-yl)-4-(morpholine-4-carbonyl)piperazine-1-carboxy-
late (Compound 36, 3.5 g, 9.6 mmol) in dry MeOH (70 mL) was added
5-chlorothiophene-2-carbaldehyde (2.1 mL, 19.2 mmol), AcOH (0.2 mL)
and 4 .ANG. powdered molecular sieves. The reaction mixture was
stirred at room temperature for 1 hour. (Formation of imine was
observed as a less polar spot by TLC). To the reaction mixture was
added sodium cyanoborohydride (NaCNBH.sub.3 0.73 g, 11.5 mmol)
portionwise, and the mixture stirred at room temperature for 1
hour. To the mixture was then added ice-cold water (50 mL), then
filtered through a Celite pad and the filtrate was extracted into
EtOAc (4.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 3% MeOH-DCM, to afford the desired
product (1.95 g, yield: 41%) as a light yellow liquid which was
used in the next step. A sample (120 mg) was further purified by
preparative HPLC to afford allyl
2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-4-(morpholine--
4-carbonyl)piperazine-1-carboxylate (Compound 37; 55 mg) as a gummy
liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=11.55-11.41 (br
s, 1H), 6.96-6.77 (m, 2H), 6.15-5.71 (m, 2H), 5.41-4.97 (m, 4H),
4.56 (br s, 2H), 4.27 (br s, 2H), 3.83 (br t, J=12.5 Hz, 2H),
3.67-3.32 (m, 5H), 3.25-2.85 (m, 6H), 2.81-2.64 (m, 1H); TLC
System: 5% Methanol-dichloromethane R.sub.f-0.5.
Example 60--Preparation of Compound 38
[0383] The synthesis of Compound 38 followed the procedure of
General Procedure 5d following:
##STR00073##
[0384] To a cooled solution (0.degree. C.) of allyl
2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-4-(morpholine--
4-carbonyl)piperazine-1-carboxylate (Compound 37, 1.0 g, 2.0 mmol)
in dry dichloromethane (20 mL) was added triethylamine (TEA, 0.4
mL, 3.0 mmol), followed by trimethylacetyl chloride (0.23 mL, 1.8
mmol). The mixture was stirred at room temperature for 4 hours, and
then quenched with water (25 mL). This was extracted into
dichloromethane (3.times.40 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 20% EtOAc/n-hexane, to
afford allyl
2-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)-4-(-
morpholine-4-carbonyl)piperazine-1-carboxylate (Compound 38, 600
mg, yield: 69%) as a pale yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=7.71 (t, J=6.1 Hz, 1H), 6.97-6.91 (m, 2H),
5.87 (br s, 1H), 5.37 (s, 1H), 5.14 (br s, 1H), 5.05 (br d, J=2.0
Hz, 1H), 4.53 (br s, 2H), 4.40 (d, J=6.4 Hz, 2H), 3.94-3.79 (m,
2H), 3.60-3.36 (m, 6H), 3.22-3.15 (m, 1H), 3.19 (br dd, J=4.4, 13.2
Hz, 2H), 2.93-2.78 (m, 3H), 1.35 (s, 9H) ppm; TLC System: 30% ethyl
acetate in hexane R.sub.f-0.5.
Example 61--Preparation of Compound 39
[0385] The synthesis of Compound 39 followed the procedure of
General Procedure 8b following:
##STR00074##
[0386] A stirred solution of allyl
2-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)-4-(-
morpholine-4-carbonyl)piperazine-1-carboxylate (Compound 38, 500
mg, 0.86 mmol) in dichloromethane (10 mL) was degassed with a
stream of argon for 15 minutes, then to the solution was added
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4, 100
mg, 0.087 mmol) followed by phenylsilane (PhSiH.sub.3, 0.64 mL, 5.2
mmol). The reaction mixture was stirred at room temperature for 45
minutes, then filtered through a pad of Celite pad and evaporated.
The crude residue was purified by CombiFlash.RTM. chromatography
eluting with 4% MeOH-dichloromethane to afford
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(4-(morpholine-4-carbonyl)pip-
erazin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound
39, 130 mg, yield: 31%) as an off-white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.=7.72 (t, J=6.4 Hz, 1H), 6.98-6.94 (m,
2H), 5.47 (s, 1H), 4.42 (d, J=6.4 Hz, 2H), 3.67 (br d, J=12.7 Hz,
1H), 3.61-3.53 (m, 5H), 3.43 (br d, J=11.7 Hz, 1H), 3.11 (dd,
J=3.7, 5.1 Hz, 4H), 2.92-2.63 (m, 5H), 1.41 (s, 9H) ppm; TLC
System: 5% Methanol-dichloromethane R.sub.f-0.5.
Example 62--Preparation of Compound 40
[0387] The synthesis of Compound 40 followed the procedure of
General Procedure 6c following:
##STR00075##
[0388] To a cooled (0.degree. C.) solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(4-(morpholine-4-carbonyl)pip-
erazin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound
39, 100 mg, 0.2 mmol) in 1,4-dioxane (10 mL) was added HCl (10 mL
in dioxane), and the reaction was then stirred at room temperature
for 5 hours. The reaction mixture was concentrated under reduced
pressure and triturated with diethyl ether to afford 100 mg of a
semi-pure sample. This was purified by preparative HPLC to afford
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)piperazin-1-yl-
)(morpholino)methanone hydrochloride (Compound 40, 28 mg, yield:
34%) as an off-white solid .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=12.02 (br s, 1H), 11.61 (br s, 1H), 9.06 (s, 2H), 6.92 (br
d, J=13.7 Hz, 2H), 6.39 (br s, 1H), 5.81 (br s, 1H), 5.53 (br s,
1H), 4.32 (br d, J=5.9 Hz, 2H), 4.17 (br s, 1H), 3.95-3.40 (m, 6H),
3.27-2.57 (m, 8H) ppm; TLC System: 10% Methanol-dichloromethane
R.sub.f-0.5.
Example 63--Preparation of Compound 41
[0389] The synthesis of Compound 41 followed the procedure of
General Procedure 5d following:
##STR00076##
[0390] To a cooled solution (0.degree. C.) of allyl
2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-4-(morpholine--
4-carbonyl)piperazine-1-carboxylate (Compound 40, 2.0 g, 4 mmol) in
dry dichloromethane (20 mL) was added triethylamine (TEA, 1.1 mL,
8.1 mmol) followed by 1,3-thiazole-4-carbonyl chloride (896 mg, 1.8
mmol). After stirring at room temperature for 4 hours, the reaction
mixture was combined with water (25 mL) and extracted into
dichloromethane (3.times.40 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 20% EtOAc/n-hexane, to
afford allyl
2-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyra-
zol-3-yl)-4-(morpholine-4-carbonyl)piperazine-1-carboxylate
(Compound 41, 600 mg, yield: 69%) as a light yellow liquid. 300 mg
of this sample was further purified by preparative HPLC to give
pure compound as a light yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.22 (d, J=2.0 Hz, 1H), 8.98 (d, J=2.0 Hz,
1H), 7.87 (br t, J=6.1 Hz, 1H), 6.96 (s, 2H), 5.88 (br s, 1H), 5.48
(s, 1H), 5.12 (br d, J=2.4 Hz, 3H), 4.59-4.48 (m, 4H), 4.02 (br d,
J=13.7 Hz, 1H), 3.84 (br d, J=12.7 Hz, 1H), 3.56 (br d, J=13.2 Hz,
1H), 3.39 (br d, J=2.9 Hz, 2H), 3.33 (br s, 2H), 3.23-3.18 (m, 2H),
3.06-2.99 (m, 2H), 2.90-2.81 (m, 3H) ppm; TLC System: 10%
Methanol-dichloromethane R.sub.f-0.5.
Example 64--Preparation of Intermediate 23
[0391] The synthesis of Intermediate 23 followed the procedure of
General Procedure 16 following:
##STR00077##
[0392] To a cold solution (-78.degree. C.) of benzyl
4-oxopiperidine-1-carboxylate (20 g, 8.6 mmol) in diethyl ether
(Et.sub.2O, 250 mL) was added ethyl diazoacetate (11.6 mL, 11.1
mmol), followed by boron trifluoride diethyl etherate
(BF.sub.3OEt.sub.2, 10.7 mL, 8.6 mmol). The reaction mixture was
allowed to stir at -78.degree. C. for 1 h, then stirred at room
temperature for 1 hour, then was quenched with saturated
K.sub.2CO.sub.3. The solution was stirred until nitrogen evolution
ceased, then extracted with EtOAc (300 mL). The combined organic
layer was dried over sodium sulfate, filtered and concentrated
under reduced pressure to obtain 1-benzyl 4-ethyl
5-oxoazepane-1,4-dicarboxylate (Intermediate 23, 26 g) as a yellow
liquid. The crude compound was taken forward to the next step
without further purification. MS (ESI): m/z 320.1 [M+H].sup.+; TLC
System: 20% ethyl acetate in hexane. R.sub.f-0.3.
Example 65--Preparation of Intermediate 24
[0393] The synthesis of Intermediate 24 followed the procedure of
General Procedure 17 following:
##STR00078##
[0394] To a cold solution (0.degree. C.) of 1-benzyl 4-ethyl
5-oxoazepane-1,4-dicarboxylate (Intermediate 23, 26 g, 81.5 mmol)
in EtOH (250 ml) was added sodium borohydride (NaBH.sub.4, 3 g,
81.5 mmol) portionwise. After 10 minutes the reaction was raised to
room temperature and stirred for a further 30 minutes. The reaction
was concentrated and was diluted with EtOAc (350 mL) and washed
with water (2.times.150 ml), dried over Na.sub.2SO.sub.4, filtered
and concentrated at reduced pressure. The residue was purified by
silica gel (100-200 mesh) eluting with 20% EtOAc in hexane to give
1-benzyl 4-ethyl 5-hydroxyazepane-1,4-dicarboxylate (Intermediate
24, 12 g, 46%) as a colorless oil MS (ESI): m/z 321.96
([M+H].sup.+); TLC System: 50% ethyl acetate in hexane.
R.sub.f-0.3.
Example 66--Preparation of Intermediate 25
[0395] The synthesis of Intermediate 25 followed the procedure of
General Procedure 18 following: General Procedure 18
##STR00079##
[0396] To a stirred solution of 1-benzyl
4-ethyl-5-hydroxyazepane-1,4-dicarboxylate (Intermediate 24, 12 g,
37.3 mmol) in THF (270 mL) was added methanesulfonyl chloride
(MsCl, 7.1 mL, 93.4 mmol) and triethylamine (TEA, 15.5 mL, 112.1
mmol) in two portions, and the mixture stirred for 12 hours. The
mixture was then concentrated under reduced pressure, diluted with
EtOAc (300 mL) washed with saturated aqueous
NaHCO.sub.3(2.times.100 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure. The residue was dissolved in
THF (270 mL), and to it was added 1,8-diazabicycloundec-7-ene (DBU,
8.4 mL, 56.3 mmol), and the resulting mixture was heated at
80.degree. C. for 1 hour. The reaction was then concentrated,
diluted with EtOAc (300 mL), washed with saturated aqueous
NaHCO.sub.3(3.times.80 mL) and water (200 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(100-200 mesh) eluting with 20% EtOAc in hexane to give 1-benzyl
4-ethyl 2,3-dihydro-1H-azepine-1,4(6H,7H)-dicarboxylate
(Intermediate 25, 10.5 g, 92%) as a colorless oil; MS (ESI): m/z
304 ([M+H].sup.+); TLC System: 20% ethyl acetate in hexane.
R.sub.f-0.9.
Example 67--Preparation of Intermediate 26
[0397] The synthesis of Intermediate 26 followed the procedure of
General Procedure 19 following:
##STR00080##
[0398] A suspension of 1-benzyl 4-ethyl
2,3-dihydro-1H-azepine-1,4(6H,7H)-dicarboxylate (Intermediate 25,
10.5 g, 34.6 mmol) and 20% Pd/C (2.1 g) in ethanol and ethyl
acetate (1:1, 200 mL) was stirred under 80 psi hydrogen atmosphere
for 12 hours. The mixture was then filtered on a pad of Celite and
the Celite bed was washed with methanol (2.times.50 mL). The
combined organic layers were concentrated to give crude ethyl
azepane-4-carboxylate (Intermediate 26, 5.6 g, 94%) as a yellow
oil; TLC System: 10% MeOH in dichloromethane. R.sub.f-0.1.
Example 68--Preparation of Intermediate 27
[0399] The synthesis of Intermediate 27 followed the procedure of
General Procedure 7 following:
##STR00081##
[0400] To a cooled solution (0.degree. C.) of ethyl
azepane-4-carboxylate (Intermediate 26, 5.6 g, 32.9 mmol) in
dichloromethane (100 mL) was added triethylamine (TEA, 13.7 mL,
98.8 mmol) followed by allyl chloroformate (7 mL, 65.8 mmol), and
the mixture was then stirred at room temperature for 12 hours. The
reaction mixture was quenched with water (100 mL) and extracted
into dichloromethane (2.times.200 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 20% EtOAc/n-hexane, to
afford 1-allyl 4-ethyl azepane-1,4-dicarboxylate (Intermediate 27,
6.5 g, 77%) as a colorless liquid; MS (ESI): m/z 256.59
[M+H].sup.+; TLC System: 20% ethyl acetate in hexane.
R.sub.f-0.7.
Example 69--Preparation of Intermediate 28
[0401] The synthesis of Intermediate 28 followed the procedure of
General Procedure 2 following:
##STR00082##
[0402] To a cooled solution (-78.degree. C.) of acetonitrile (1.2
mL, 23.5 mmol) in dry THF (30 mL) was added n-BuLi in THF (2.5M,
9.4 mL, 23.5 mmol). After stirring for 30 minutes, a solution of
1-allyl 4-ethyl azepane-1,4-dicarboxylate (Intermediate 27, 5 g,
19.6 mmol) in dry THF (10 mL) was added. The reaction mixture was
stirred at -78.degree. C. for 1 hour, then quenched with saturated
NH.sub.4Cl solution (10 mL) and extracted into EtOAc (2.times.120
mL). The combined organic layer was dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 50% EtOAc/n-hexane, to afford allyl
4-(2-cyanoacetyl)azepane-1-carboxylate (Intermediate 28, 3.1 g,
63%) as a light yellow liquid. MS (ESI): m/z 251.55 [M+H].sup.+;
TLC System: 50% ethyl acetate in hexane R.sub.f-0.5.
Example 70--Preparation of Compound 42
[0403] The synthesis of Compound 42 followed the procedure of
General Procedure 3 following:
##STR00083##
[0404] To a stirred solution of allyl
4-(2-cyanoacetyl)azepane-1-carboxylate (Intermediate 28, 3.1 g,
12.4 mmol) in ethanol (30 mL) was added hydrazine hydrate
(N.sub.2H.sub.4.H.sub.2O, 0.74 mL, 14.8 mmol), and the reaction
mixture was then heated to 80.degree. C. for 5 hours. The reaction
mixture was cooled to room temperature and the volatiles were
evaporated. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 5%
MeOH-dichloromethane, to afford allyl
4-(5-amino-1H-pyrazol-3-yl)azepane-1-carboxylate (Compound 42, 2.8
g, 87%) as an orange liquid. MS (ESI): m/z 265.13 [M+H].sup.+; TLC
System: 10% Methanol-dichloromethane. R.sub.f-0.3.
Example 71--Preparation of Compound 43
[0405] The synthesis of Compound 43 followed the procedure of
General Procedure 4 following:
##STR00084##
[0406] To a cold solution (0.degree. C.) of allyl
4-(5-amino-1H-pyrazol-3-yl)azepane-1-carboxylate (Compound 42, 2.8
g, 10.6 mmol) in dry MeOH (28 mL) was added
5-chlorothiophene-2-carbaldehyde (1.2 mL, 12.6 mmol), AcOH (0.6 mL)
and then 4 .ANG. powdered molecular sieves (1.6 g). The reaction
mixture was stirred at room temperature for 1 hour. (The formation
of imine was observed as a less polar spot on TLC). To this was
then added sodium cyanoborohydride (NaCNBH.sub.3, 0.8 g, 12.6 mmol)
portionwise at 0.degree. C., and stirring was continued at room
temperature for 2 hours. The reaction mixture was quenched with
ice-cold water (50 mL), filtered through a Celite pad and the
filtrate was extracted into EtOAc (4.times.100 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 60%
EtOAc/n-hexane, to afford desired product (2.5 g, 60%) as a light
yellow liquid. A portion (200 mg) of semi-pure sample was further
purified by preparative HPLC to afford allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azepane-1-carbo-
xylate (Compound 43, 110 mg) as a gum. MS (ESI): m/z 395.05
[M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.23 (s,
1H), 6.89-6.91 (d, J=6.0 Hz, 1H), 6.83 (d, J=3.0 Hz, 1H), 5.89-5.91
(m, 1H), 5.62 (brs, 1H), 5.16-5.29 (m, 3H), 4.54 (d, J=6.0 Hz, 2H),
4.27 (d, J=6.1 Hz, 2H), 3.23-3.61 (m, 4H), 2.63 (t, J=9.0 Hz, 1H),
1.83-1.97 (m, 4H), 1.70-1.97 (m, 2H) ppm; TLC System: Ethyl
acetate. R.sub.f-0.5.
Example 72--Preparation of Compound 44
[0407] The synthesis of Compound 44 followed the procedure of
General Procedure 5d following:
##STR00085##
[0408] To a cooled solution (0.degree. C.) of allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azepane-1-carbo-
xylate (Compound 43, 2.5 g, 6.3 mmol) in dry dichloromethane (100
mL) was added triethylamine (TEA, 1.3 mL, 9.5 mmol) followed by
trimethylacetyl chloride (0.7 mL, 5.7 mmol). After stirring at room
temperature for 4 hours, the reaction mixture was diluted with
water (25 mL) and extracted into dichloromethane (3.times.40 mL).
The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 10% EtOAc/n-hexane, to afford desired product allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)azep-
ane-1-carboxylate (Compound 44, 1.8 g, 60%) as a colorless liquid.
MS (ESI): m/z 479.26 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.63 (t, J=6.0 Hz, 1H), 6.95 (s, 2H),
5.88-5.96 (m, 1H), 5.37 (d, J=3.2 Hz, 1H), 5.14-5.28 (m, 2H), 4.53
(d, J=5.2 Hz, 2H), 4.40 (d, J=6.0 Hz, 2H), 3.28-3.61 (m, 4H),
2.64-2.61 (m, 1H), 1.84-1.88 (m, 4H), 1.54-1.72 (m, 2H), 1.39 (s,
9H).
[0409] TLC System: 20% ethyl acetate in hexane. R.sub.f-0.5.
Example 73--Preparation of Compound 45
[0410] The synthesis of Compound 45 followed the procedure of
General Procedure 8b following:
##STR00086##
[0411] A stirred solution of allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)azep-
ane-1-carboxylate (Compound 44, 400 mg, 0.8 mmol) in
dichloromethane (30 mL) was degassed with stream of argon for 15
minutes, then to it was added phenylsilane (PhSiH.sub.3, 0.6 mL,
4.8 mmol) followed by tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh.sub.3).sub.4, 93 mg, 0.08 mmol). The reaction mixture was
stirred at room temperature for 45 minutes, then the mixture was
filtered through a Celite pad and then evaporated. The crude
residue was purified by flash chromatography using 30% MeOH-DCM to
afford the semi-pure
1-(3-(azepan-4-yl)-5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-1-yl-
)-2,2-dimethylpropan-1-one (Compound 45, 200 mg; 94% by LCMS). MS
(ESI) m/z 395.19 [M+H].sup.+, .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 7.62 (t, J=6.0 Hz, 1H), 6.96 (s, 2H), 5.34 (s, 1H), 4.40
(d, J=5.7 Hz, 2H), 3.18-2.68 (m, 6H), 2.05-1.62 (m, 6H), 1.38 (s,
9H) ppm; TLC System: 20% MeOH-dichloromethane, R.sub.f-0.2.
Example 74--Preparation of Compound 46
[0412] The synthesis of Compound 46 followed the procedure of
General Procedure 15 following:
##STR00087##
[0413] To a cold solution (0.degree. C.) of
1-(3-(azepan-4-yl)-5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-1-yl-
)-2,2-dimethylpropan-1-one (Compound 45, 317 mg, 0.8 mmol) in dry
dichloromethane (50 mL) was added triethylamine (TEA, 0.28 mL, 2
mmol) followed by morpholine carbamyl chloride (0.14 mL, 1.2 mmol).
The mixture was stirred at room temperature for 3 hours. The
reaction mixture was diluted with water (20 mL) and extracted into
dichloromethane (2.times.20 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by CombiFlash, eluting with 30%
EtOAc/n-hexane, to afford
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)aze-
pan-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 46,
140 mg, 34%) as an off-white semi-solid; MS (ESI): m/z 508.28
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.63 (t,
J=6.4 Hz, 1H), 6.95 (s, 2H), 5.36 (s, 1H), 4.40 (d, J=6.0 Hz, 2H),
3.57-3.55 (m, 4H), 3.51-3.41 (m, 2H), 3.31-3.21 (m, 2H), 3.06-2.98
(m, 4H), 2.64-2.62 (m, 1H), 2.00-1.83 (m, 5H), 1.81-1.51 (m, 1H),
1.39 (s, 9H) ppm; TLC System: 50% ethyl acetate in hexane.
R.sub.f-0.5.
Example 75--Preparation of Compound 47
[0414] The synthesis of Compound 47 followed the procedure of
General Procedure 6d following:
##STR00088##
[0415] To a stirred solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)aze-
pan-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 46,
200 mg, 0.39 mmol) in methanol (5 mL) was added sodium bicarbonate
(NaHCO.sub.3, 100 mg, 1.1 mmol). The reaction mixture was stirred
at 50.degree. C. for 3 hours. The reaction mixture was cooled to
room temperature and the volatiles were evaporated and the
resultant residue was diluted with EtOAc (20 mL) and washed with
water (2.times.10 mL). The organic layer was dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
resulting solid was triturated with diethyl ether and pentane and
dried under high vacuum for 1 hour affording
(4-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azepan-1-yl)(m-
orpholino)methanone (Compound 47, 150 mg, 90%) as an off-white
solid. LCMS: m/z 424.24 [M+H].sup.+; .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.21 (s, 1H), 6.90-6.82 (dd, J=10.0, 3.2 Hz,
2H), 5.58 (brs, 1H), 5.25 (s, 1H), 4.27 (d, J=5.6 Hz, 2H),
3.57-3.53 (m, 4H), 3.50-3.42 (m, 2H), 3.27-3.17 (m, 2H), 3.08-2.98
(m, 4H), 2.66-2.62 (m, 1H), 1.69-1.92 (m, 5H), 1.46-1.49 (m, 1H)
ppm; TLC System: 50% ethyl acetate in hexane. R.sub.f-0.2.
Example 76--Preparation of Compound 48
[0416] The synthesis of Compound 48 followed the procedure of
General Procedure 5d following:
##STR00089##
[0417] To a cooled solution (0.degree. C.) of
(4-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azepan-1-yl)(m-
orpholino)methanone (Compound 47, 187 mg, 0.44 mmol) in dry
dichloromethane (10 mL) was added triethylamine (TEA, 1.84 mL, 1.32
mmol) followed by thiazole-4-carbonyl chloride (78 mg, 0.53 mmol).
The mixture was stirred at room temperature for 3 hours. The
reaction mixture was diluted with water (15 mL) and extracted into
dichloromethane (3.times.40 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by CombiFlash, eluting with 60%
EtOAc/n-hexane, to afford
(4-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyr-
azol-3-yl)azepan-1-yl)(morpholino)methanone (Compound 48, 60 mg,
25%) as a yellow solid. MS (ESI): m/z 535.21 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.19 (d, J=1.2 Hz, 1H), 9.03
(d, J=1.2 Hz, 1H), 7.77 (t, J=6.4 Hz, 1H), 6.98 (dd, J=9.2, 3.2 Hz,
2H), 5.52 (s, 1H), 4.50 (d, J=6.4 Hz, 2H), 3.56-3.42 (m, 6H),
3.31-3.21 (m, 2H), 3.06-2.96 (m, 4H), 2.68-2.64 (m, 1H), 2.04-1.85
(m, 4H), 1.72-1.67 (m, 1H), 1.60-1.59 (m, 1H) ppm; TLC System: 80%
ethyl acetate in hexane. R.sub.f-0.7.
Example 77--Preparation of Intermediate 29
[0418] The synthesis of Intermediate 29 followed the procedure of
General Procedure 20 following:
##STR00090##
[0419] To a stirred solution of allyl
4-(3-amino-cyanoacetyl)piperidine-1-carboxylate (Intermediate 5,
2.5 g, 10.6 mmol) in ethanol (30 mL) was added
trichloroacetonitrile (2.1 mL, 21.2 mmol) and triethylamine (TEA,
0.2 mL). The reaction mixture was stirred at room temperature for 2
hours. The volatiles were evaporated and the resultant residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 50% EtOAc/n-hexane, to afford the desired product
(Z)-allyl
4-(3-amino-4,4,4-trichloro-2-cyanobut-2-enoyl)piperidine-1-carboxylate
(Intermediate 29, 3.2 g, 80%) as a brown liquid. MS (ESI): m/z
380.13 [M+H].sup.+; TLC System: 30% Ethyl acetate in hexane
R.sub.f-0.5.
Example 78--Preparation of Compound 49
[0420] The synthesis of Compound 49 followed the procedure of
General Procedure 21 following:
##STR00091##
[0421] To a stirred solution of (Z)-allyl
4-(3-amino-4,4,4-trichloro-2-cyanobut-2-enoyl)piperidine-1-carboxylate
(Intermediate 29, 3.2 g, 8.4 mmol) in toluene (30 mL) was added
N.sub.2H.sub.4 (1M in THF) (16.8 mL, 16.8 mmol) and the reaction
mixture was heated to 100.degree. C. for 15 hours. The reaction
mixture was cooled to room temperature, the volatiles were
evaporated and the resultant residue was purified by silica gel
column chromatography (100-200 mesh), eluting with 5%
MeOH-dichloromethane, to afford the desired product allyl
4-(5-amino-4-cyano-1H-pyrazol-3-yl)piperidine-1-carboxylate
(Compound 49, 1.4 g, 61%) as an off-white solid. MS (ESI): m/z
275.13 [M+H].sup.+. TLC System: 10% Methanol-dichloromethane.
R.sub.f-0.3.
Example 79--Preparation of Compound 50
[0422] The synthesis of Compound 50 followed the procedure of
General Procedure 4 following:
##STR00092##
[0423] To a cold solution (0.degree. C.) of allyl
4-(5-amino-4-cyano-1H-pyrazol-3-yl)piperidine-1-carboxylate
(Compound 49, 3.2 g, 11.6 mmol) in dry MeOH (30 mL) was added
5-chlorothiophene-2-carbaldehyde (1.8 mL, 14 mmol), AcOH (2 mL) and
powdered 4 .ANG. molecular sieves (1.6 g). The reaction mixture was
stirred at room temperature for 1 hour. Formation of imine was
observed as a less polar spot on TLC. To the mixture was then added
sodium cyanoborohydride (NaCNBH.sub.3, 1.08 g, 17.5 mmol)
portionwise at 0.degree. C. and the reaction was stirred at room
temperature for 2 hours. The reaction mixture was quenched with
ice-cold water (50 mL), filtered through a Celite pad and the
Celite bed was rinsed several times with EtOAc. The two layers were
separated and the aqueous layer was extracted into EtOAc
(4.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 60% EtOAc/n-hexane, to afford desired
product (2.5 g, 60%) as a light yellow liquid. A portion of the
sample (200 mg) was further purified by preparative HPLC to afford
allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-4-cyano-1H-pyrazol-3-yl)piperid-
ine-1-carboxylate (Compound 50, 110 mg) as a gummy liquid. MS
(ESI): m/z 405.05 [M+H].sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 6.81-6.74 (m, 2H), 5.98-5.89 (m, 1H), 5.32-5.21 (m, 2H),
4.60 (d, J=8.0 Hz, 2H), 4.52 (s, 2H), 4.48-4.42 (br s, 1H),
4.40-4.24 (m, 2H), 3.00-2.84 (m, 3H), 2.04-1.96 (m, 2H), 1.76-1.67
(m, 2H) ppm; TLC System: 80% Ethyl acetate in hexane
R.sub.f-0.4.
Example 80--Preparation of Compound 51
[0424] The synthesis of Compound 51 followed the procedure of
General Procedure 5d following:
##STR00093##
[0425] To a cooled solution (0.degree. C.) of compound 50 (2.1 g,
5.2 mmol) in dry dichloromethane (100 mL) was added triethylamine
(2.2 mL, 15.5 mmol) followed by pivaloyl chloride (0.66 mL, 6.2
mmol), and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was diluted with water (25 mL) and extracted
into dichloromethane (3.times.40 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10% EtOAc/n-hexane, to
afford desired product (1.8 g, 72%) as a colorless liquid. A 200 mg
portion of sample was further purified by preparative HPLC to
afford allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-4-cyano-1-pivaloyl-1H-pyrazol-3-
-yl)piperidine-1-carboxylate (Compound 51, 104 mg/99%) as a gummy
liquid. MS (ESI): m/z 479.26 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.44 (t, J 5.6 Hz, 1H), 6.90 (d, J 4.0 Hz, 1H),
6.80 (d, J 4.0 Hz, 1H), 6.00-5.91 (m, 1H), 5.33-5.20 (m, 2H), 4.85
(d, J 4.0 Hz, 2H), 4.61 (d, J 4.0 Hz, 2H), 4.30-4.14 (m, 2H),
3.04-2.90 (m, 2H), 2.89-2.81 (m, 1H), 2.01 (d, J 10.8 Hz, 2H), 1.73
(d, J 10.8 Hz, 2H), 1.42 (s, 9H); TLC System: 20% ethyl acetate in
hexane. R.sub.f-0.5.
Example 81--Preparation of Compound 52
[0426] The synthesis of Compound 52 followed the procedure of
General Procedure 8b following:
##STR00094##
[0427] A stirred solution of Compound 51 (250 mg, 0.51 mmol) in
dichloromethane (10 mL) was degassed with a stream of argon for 15
minutes, then to it was added phenylsilane (PhSiH.sub.3, 0.19 mL,
1.53 mmol) followed by tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh.sub.3).sub.4, 58 mg, 0.05 mmol). The reaction mixture was
stirred at room temperature for 45 minutes, then filtered through a
Celite pad and the filtrate was evaporated. The residue was
purified by flash chromatography using 30% MeOH-dichloromethane to
afford the semi-pure desired product
1-(3-(piperdine-4-yl)-5-((5-chlorothiophen-2-yl)methylamino)-4-cyano-1H-p-
yrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 52, 280 mg/74% by
LCMS), used directly for the next reaction without further
purification; TLC System: 20% MeOH-dichloromethane,
R.sub.f-0.2.
Example 82--Preparation of Compound 53
[0428] The synthesis of Compound 53 followed the procedure of
General Procedure 15 following:
##STR00095##
[0429] To a cooled solution (0.degree. C.) of
1-(3-(piperdine-4-yl)-5-((5-chlorothiophen-2-yl)methylamino)-4-cyano-1H-p-
yrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 52, 280 mg, 0.69
mmol) in dry dichloromethane (50 mL) was added triethylamine (TEA,
0.28 mL, 2.1 mmol), followed by morpholine carbamyl chloride (0.12
mg, 0.83 mmol). The mixture was stirred at room temperature for 3
hours. The reaction mixture was diluted with water (20 mL) and
extracted into dichloromethane (2.times.20 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
CombiFlash, eluting with 30% EtOAc/n-hexane followed by preparative
HPLC to afford desired product
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)pip-
erdine-4-yl)-4-cyano-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 53, 140 mg, 34%) as an off-white semi-solid. MS (ESI):
m/z 508.28 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.45 (t, J=6.0 Hz, 1H), 6.90 (d, J=4.0 Hz, 1H), 6.80 (d, J=4.0 Hz,
1H), 4.85 (d, J 6.0 Hz, 2H), 3.80 (d, J=13.2 Hz, 2H), 3.71-3.68 (m,
4H), 3.28-3.25 (m, 4H), 2.97-2.90 (m, 2H), 2.87-2.81 (m, 1H),
2.04-2.00 (m, 2H), 1.80-1.71 (m, 2H), 1.42 (s, 9H) ppm; TLC System:
50% ethyl acetate in hexane. R.sub.f-0.5.
Example 83--Preparation of Intermediate 31
[0430] The synthesis of Intermediate 31 followed the procedure of
General Procedure 2 following:
##STR00096##
[0431] To a cooled solution (-40.degree. C.) of propionitrile (5.8
mL, 74.7 mmol) in dry THF (120 mL) was added lithium
hexamethylsilazide (LHMDS, 1M in THF, 99 mL, 99.6 mmol). After
stirring at -40.degree. C. for 15 minutes, a solution of
1-allyl-4-ethyl piperidine-1,4-dicarboxylate (Intermediate 5, 12 g,
49.8 mmol) in dry THF (30 mL) was added and the reaction mixture
was stirred at the same temperature for 30 minutes. The reaction
mixture was quenched with saturated NH.sub.4Cl solution (80 mL) and
extracted with EtOAc (2.times.120 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 50% EtOAc/n-hexane, to
afford allyl 4-(2-cyanopropanoyl)piperidine-1-carboxylate
(Intermediate 31, 9 g, yield: 72%) as alight yellow liquid. m/z
250.87 [M+H].sup.+; TLC System: 30% ethyl acetate in hexane
R.sub.f-0.5.
Example 84--Preparation of Compound 54
[0432] The synthesis of Compound 54 followed the procedure of
General Procedure 3 following:
##STR00097##
[0433] To a stirred solution of allyl
4-(2-cyanopropanoyl)piperidine-1-carboxylate (Intermediate 31, 9 g,
36 mmol) in ethanol (90 mL) was added N.sub.2H.sub.4 (1.6 mL, 32.4
mmol) and the reaction mixture was heated to 70.degree. C. for 5
hours. The reaction mixture was cooled to room temperature, the
volatiles were evaporated and the resultant residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 3%
MeOH-dichloromethane, to afford allyl
4-(5-amino-4-methyl-1H-pyrazol-3-yl)piperidine-1-carboxylate
(Compound 54, 8 g, yield: 84%) colorless liquid. m/z 265.13
[M+H].sup.+; TLC System: 5% Methanol-dichloromethane.
R.sub.f-0.5.
Example 85--Preparation of Compound 55
[0434] The synthesis of Compound 55 followed the procedure of
General Procedure 4 following:
##STR00098##
[0435] To a cooled solution (0.degree. C.) of allyl
4-(5-amino-4-methyl-1H-pyrazol-3-yl)piperidine-1-carboxylate
(Compound 54, 5 g, 18.9 mmol) in dry MeOH (50 mL) was added
5-chlorothiophene-2-carbaldehyde (4.2 mL, 37.8 mmol), AcOH (0.2
mL), and then powdered 4 .ANG. molecular sieves. The reaction
mixture was stirred at room temperature for 1 hour. The formation
of imine was observed as a less polar spot by TLC. To the reaction
mixture was then added sodium cyanoborohydride (NaCNBH.sub.3, 1.4
g, 22.7 mmol) portionwise, and the mixture stirred at room
temperature for 2 hours. To the mixture was added ice-cold water
(50 mL), then filtered through a Celite pad and the filtrate was
extracted with EtOAc (4.times.100 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 50% EtOAc/n-hexane, to
afford desired product (3.5 g, yield: 46%) as a light yellow
liquid. A portion (300 mg) of semi-pure sample was further purified
by preparative HPLC to afford allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-4-methyl-1H-pyrazol-3-yl)piperi-
dine-1-carboxylate (Compound 55, 110 mg) as a gummy liquid. m/z
395.16 [M+H]+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.08 (br
s, 1H), 6.89 (d, J=3.9 Hz, 1H), 6.82 (d, J=3.4 Hz, 1H), 5.94 (tdd,
J=5.2, 10.5, 17.2 Hz, 1H), 5.38-5.26 (m, 2H), 5.19 (dd, J=1.5, 10.3
Hz, 1H), 4.56-4.50 (m, 2H), 4.33 (d, J=6.4 Hz, 2H), 4.08 (br d,
J=13.2 Hz, 2H), 2.86 (br s, 2H), 2.73 (tt, J=3.5, 12.2 Hz, 1H),
1.79-1.71 (m, 3H), 1.70-1.63 (m, 2H), 1.59-1.48 (m, 2H) ppm; TLC
System: 50% ethyl acetate in hexane. R.sub.f-0.5.
Example 86--Preparation of Compound 56
[0436] The synthesis of Compound 56 followed the procedure of
General Procedure 5d following:
##STR00099##
[0437] To a cooled solution (0.degree. C.) of allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-4-methyl-1H-pyrazol-3-yl)piperi-
dine-1-carboxylate (Compound 55, 1.9 g, 4.8 mmol) in dry
dichloromethane (20 mL) was added trimethylacetyl chloride (0.57
mL, 4.3 mmol), followed by triethylamine (TEA, 1 mL, 7.2 mmol), and
the mixture was stirred at room temperature for 4 hours. The
reaction mixture was combined with water (25 mL) and extracted with
dichloromethane (3.times.40 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 20% EtOAc/n-hexane, to
afford desired product (1.3 g, yield-69%) as a light yellow liquid.
A portion (300 mg) of semi-pure sample was further purified by
preparative HPLC to afford allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-4-methyl-1-pivaloyl-1H-pyrazol--
3-yl)piperidine-1-carboxylate (Compound 56, 70 mg) as a light
yellow liquid. m/z 479.23 [M+H]+ 1H NMR (400 MHz, CDCl.sub.3)
.delta.=7.26 (s, 1H), 6.74 (d, J=3.9 Hz, 1H), 6.69 (d, J=3.4 Hz,
1H), 6.02-5.91 (m, 1H), 5.32 (dd, J=1.5, 17.1 Hz, 1H), 5.22 (dd,
J=1.2, 10.5 Hz, 1H), 4.61 (br d, J=5.4 Hz, 2H), 4.51 (br d, J=5.4
Hz, 2H), 4.20 (br d, J=10.8 Hz, 2H), 2.98 (br t, J=10.8 Hz, 2H),
2.68 (tt, J=3.7, 10.8 Hz, 1H), 2.01-1.97 (m, 3H), 1.86 (br d,
J=11.2 Hz, 2H), 1.78-1.69 (m, 2H), 1.43 (s, 9H) ppm; TLC System:
50% ethyl acetate in hexane. R.sub.f-0.5.
Example 87--Preparation of Compound 57
[0438] The synthesis of Compound 57 followed the procedure of
General Procedure 8b following:
##STR00100##
[0439] A stirred solution of allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-4-methyl-1-pivaloyl-1H-pyrazol--
3-yl)piperidine-1-carboxylate (Compound 56, 1 g, 2.1 mmol) in
dichloromethane (10 mL) was degassed with a stream of argon for 15
minutes, then to the solution was added
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4, 240
mg, 0.21 mmol), followed by phenylsilane (PhSiH.sub.3, 1.6 mL, 12.5
mmol). The reaction mixture was stirred at room temperature for 45
minutes, then filtered through a Celite pad and the filtrate was
evaporated. The crude residue was purified by flash chromatography
eluting with 4% MeOH-dichloromethane to afford the semi-pure
desired product (600 mg (91% by LCMS), yield: 72%). A portion (130
mg) of the semi-pure sample was purified by preparative HPLC to
afford
1-(5-((5-chlorothiophen-2-yl)methylamino)-4-methyl-3-(piperidin-4-yl)-1H--
pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 57, 40 mg) as an
off-white solid. m/z 395.19 [M+H].sup.+, .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=8.37 (br s, 1H), 7.26 (br t, J=7.1 Hz, 1H),
6.96 (d, J=3.9 Hz, 1H), 6.82 (d, J=3.9 Hz, 1H), 4.55 (d, J=6.8 Hz,
2H), 3.16 (br d, J=12.2 Hz, 2H), 2.86-2.72 (m, 3H), 1.92 (s, 3H),
1.83 (br d, J=12.7 Hz, 2H), 1.67 (q, J=10.9 Hz, 2H), 1.38 (s, 9H)
ppm; TLC System: 10% MeOH-dichloromethane, R.sub.f-0.5.
Example 88--Preparation of Compound 58
[0440] The synthesis of Compound 58 followed the procedure of
General Procedure 6d following:
##STR00101##
[0441] To a solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)pip-
erdine-4-yl)-4-cyano-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 53, 350 mg, 0.67 mmol) in methanol (15 mL) was added
sodium bicarbonate (NaHCO.sub.3, 113 mg, 1.3 mmol). The reaction
mixture was stirred at 50.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature, the volatiles were
evaporated and the resultant residue was diluted with EtOAc (20 mL)
and washed with water (2.times.10 mL). The organic layer was dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The solid obtained was triturated with diethyl ether and
pentane and dried under high vacuum for 1 h to afford
5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)piperi-
din-4-yl)-1H-pyrazole-4-carbonitrile (Compound 58, 250 mg, 90%) as
an off-white solid. m/z 424.24 [M+H].sup.+; 1H-NMR (400 MHz,
DMSO-d.sub.6, mixture of rotamers) .delta. 12.30 (s, 0.7H), 12.12
(s, 0.3H), 7.45 (br s, 0.3H), 7.00-6.80 (m, 2H), 6.60 (t, J=5.2 Hz,
0.7H), 4.48-4.32 (m, 2H), 3.74-3.62 (m, 2H), 3.56 (br s, 4H), 3.11
(br s, 4H), 2.93-2.66 (3H), 1.86-1.78 (m, 2H), 1.70-1.52 (m, 2H)
ppm; TLC System: 50% ethyl acetate in hexane. R.sub.f-0.2.
Example 89--Preparation of Intermediate 32
[0442] The synthesis of Intermediate 32 followed the procedure of
General Procedure 6c following:
##STR00102##
[0443] To a cooled solution (0.degree. C.) of
dl-1-tert-butyl-3-methylpyrrolidine-1,3-dicarboxylate (12 g, 52.4
mmol) in 1,4-dioxane (30 mL) was added 4M HCl in dioxane (24 mL).
The solution was allowed to warm to room temperature for 4 hours.
The reaction mixture was concentrated under reduced pressure to
obtain dl-methyl pyrrolidine-3-carboxylate hydrochloride (8.6 g,
yield: 100%). It was used `as is` for the next step without any
purification.
Example 90--Preparation of Intermediate 33
[0444] The synthesis of Intermediate 33 followed the procedure of
General Procedure 7 following:
##STR00103##
[0445] To a cooled solution (0.degree. C.) of
dl-methylpyrrolidine-3-carboxylate hydrochloride (Intermediate 32,
14.4 g, 87.3 mmol) in THF (150 mL) was added pyridine (28.1 mL,
349.3 mmol) and 4-(dimethylamino)pyridine (DMAP, 1.07 g, 8.7 mmol),
followed by allyl chloroformate (18.5 mL, 174.7 mmol). After
warming to room temperature for 16 hours, to the reaction mixture
was added water (100 mL) and then extracted into dichloromethane
(2.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluted with 20-25% EtOAc/n-hexanes, to obtain
dl-1-allyl-3-methylpyrrolidine-1,3-dicarboxylate (Intermediate 33,
15 g, yield: 80%) as a colorless liquid. m/z 214.07 [M+H].sup.+;
TLC System: 50% ethyl acetate in hexane R.sub.f-0.5.
Example 91--Preparation of Intermediate 34
[0446] The synthesis of Intermediate 34 followed the procedure of
General Procedure 2 following:
##STR00104##
[0447] To a cooled solution (-78.degree. C.) of acetonitrile (5.5
mL, 105.6 mmol) in dry THF (25 mL) was added n-butyllithium (2.5 M
in n-hexane, 42.2 mL, 105.6 mmol). After stirring for minutes, a
solution of dl-1-allyl-3-methylpyrrolidine-1,3-dicarboxylate
(Intermediate 33, 15 g, 70.4 mmol) in dry THF (30 mL) was added and
stirred at -78.degree. C. for 30 minutes. The reaction mixture was
quenched with saturated NH.sub.4Cl solution (50 mL) and extracted
into EtOAc (2.times.100 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30-35% EtOAc/n-hexane,
to afford dl-allyl-3-(2-cyanoacetyl)pyrrolidine-1-carboxylate
(Intermediate 34, 11 g, yield: 70%) as a light yellow liquid; TLC
System: 50% ethyl acetate in hexane R.sub.f-0.2.
Example 92--Preparation of Compound 59
[0448] The synthesis of Compound 59 followed the procedure of
General Procedure 3 following:
##STR00105##
[0449] To a stirred solution of
dl-allyl-3-(2-cyanoacetyl)pyrrolidine-1-carboxylate (Intermediate
34, 15 g, 67.6 mmol) in ethanol (150 mL) was added hydrazine
monohydrate (2.9 mL, 60.8 mmol), and then the reaction mixture was
heated to 70.degree. C. for 5 hours. The mixture was cooled to room
temperature, the volatiles were evaporated and the resultant
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 3% methanol-dichloromethane, to afford
dl-allyl-3-(5-amino-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate
(Compound 59, 12 g, yield: 75%) as a colorless liquid. m/z 237.54
[M+H].sup.+; TLC System: 5% methanol in dichloromethane
R.sub.f-0.3.
Example 93--Preparation of Compound 60
[0450] The synthesis of Compound 60 followed the procedure of
General Procedure 4 following:
##STR00106##
[0451] To a cooled solution (0.degree. C.) of
dl-allyl-3-(5-amino-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate
(Compound 59, 3 g, 12.7 mmol) in dry MeOH (30 mL) was added
5-chlorothiophene-2-carbaldehyde (2.7 mL, 25.4 mmol), AcOH (0.1 mL)
and powdered 4 .ANG. molecular sieves. The reaction mixture was
stirred at room temperature for 1 hour (formation of imine was
observed as a less polar spot on TLC). Sodium cyanoborohydride
(NaCNBH.sub.3, 1.18 g, 19.1 mmol) was added portionwise. After the
reaction mixture was stirred at room temperature for 2 hours,
ice-cold water (30 mL) was added, the mixture filtered through a
Celite pad and the filtrate was extracted into EtOAc (3.times.50
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by Reveleris C-18 reverse phase column using 35%-40%
acetonitrile in aqueous formic acid (0.1%) to obtain
dl-allyl-3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrol-
idine-1-carboxylate (Compound 60, 1.6 g, yield: 34%) as an
off-white solid. m/z 367.10 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.43 (br s, 1H), 6.91 (d, J=3.9 Hz, 1H),
6.84 (br s, 1H), 5.98-5.88 (m, 1H), 5.67 (br s, 1H, exchangeable),
5.37-5.24 (m, 2H), 5.18 (br d, J=10.3 Hz, 1H), 4.52 (td, J=1.5, 3.3
Hz, 2H), 4.28 (d, J=6.4 Hz, 2H), 3.67 (br s, 1H), 3.49-3.35 (m,
2H), 3.30-3.21 (m, 2H), 2.16 (br s, 1H), 1.99-1.85 (m, 1H) ppm; TLC
System: 10% methanol in dichloromethane R.sub.f-0.4.
Example 94--Preparation of Compound 61
[0452] The synthesis of Compound 61 followed the procedure of
General Procedure 5d following:
##STR00107##
[0453] To a cooled solution (0.degree. C.) of dl-allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidine-1-c-
arboxylate (Compound 60, 900 mg, 2.45 mmol) in dry dichloromethane
(10 mL) was added trimethylacetyl chloride (0.27 mL, 2.2 mmol)
followed by triethylamine (TEA, 0.51 mL, 3.7 mmol). After stirring
at room temperature for 3 hours, the reaction mixture was diluted
with water (25 mL) and extracted into dichloromethane (3.times.40
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 10% EtOAc/n-hexane, yielding dl-allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol--
3-yl)pyrrolidine-1-carboxylate (Compound 61, 450 mg, yield: 40%) as
a colorless gummy liquid. m/z 451.47 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.69 (t, J=6.4 Hz, 1H), 6.98-6.94 (m,
2H), 5.97-5.86 (m, 1H), 5.44 (s, 1H), 5.27 (dd, J=1.5, 17.1 Hz,
1H), 5.17 (dd, J=1.7, 10.5 Hz, 1H), 4.51 (br d, J=5.4 Hz, 2H), 4.41
(d, J=6.4 Hz, 2H), 3.65-3.55 (m, 1H), 3.53-3.37 (m, 3H), 3.36-3.33
(m, 1H), 2.24-2.12 (m, 1H), 2.03-1.94 (m, 1H), 1.39 (s, 9H) ppm;
TLC System: 50% ethyl acetate in hexane R.sub.f-0.7.
Example 95--Preparation of Compound 62
[0454] The synthesis of Compound 62 followed the procedure of
General Procedure 5d following:
##STR00108##
[0455] To an ice-cold solution of
dl-allyl-3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrol-
idine-1-carboxylate (Compound 60, 300 mg, 0.8 mmol) in dry
dichloromethane (10 mL) was added 1,3-thiazole-4-carbonyl chloride
(158 mg, 1.1 mmol) followed by triethylamine (TEA, 0.28 mL, 2.0
mmol). After stirring at 0.degree. C. for 2 hours, ice-cold water
(15 mL) was added and extracted into dichloromethane (3.times.20
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by flash silica gel column chromatography (100-200 mesh),
eluting using 2-4% MeOH-dichloromethane, to obtain semi-pure
product (270 mg, yield: 69%). It was further purified by
preparative HPLC to give dl-allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyra-
zol-3-yl)pyrrolidine-1-carboxylate (Compound 62, 62 mg) as a pale
yellow solid. m/z 478.17 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.12 (d, J=8.8 Hz, 1H), 8.88 (s, 1H), 7.70 (t,
J=5.6 Hz, 1H), 6.82-6.76 (m, 2H), 6.00-5.90 (m, 1H), 5.35-5.26 (m,
2H), 5.21 (dd, J=1.2, 10.5 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 4.47
(d, J=5.9 Hz, 2H), 3.86-3.76 (m, 1H), 3.68-3.50 (m, 3H), 3.36 (td,
J=7.0, 13.5 Hz, 1H), 2.28 (br s, 1H), 2.10 (dt, J=4.2, 8.2 Hz, 1H)
ppm; TLC System: 5% Methanol-dichloromethane. R.sub.f-0.6.
Example 96--Preparation of Compound 63
[0456] The synthesis of Compound 63 followed the procedure of
General Procedure 8b following:
##STR00109##
[0457] A stirred solution of
allyl-3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-y-
l)pyrrolidine-1-carboxylate (Compound 61, 1.5 g, 3.3 mmol) in dry
dichloromethane (30 mL) was degassed with a stream of argon for 15
minutes., then to it was added
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4, 385
mg, 0.33 mmol) followed by phenylsilane (PhSiH.sub.3, 1.2 mL, 10
mmol). The reaction mixture was stirred at room temperature for 45
minutes. The reaction mixture was filtered through a Celite pad and
the filtrate was evaporated. The crude residue was purified by
combi-flash silica chromatography using 4% MeOH-dichloromethane
afforded
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-3-yl)-1H-pyrazol--
1-yl)-2,2-dimethylpropan-1-one (Compound 63, 1.1 g, yield: 91%) as
an off-white solid. m/z 367.26 [M+H].sup.+, .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.11 (br s, 2H, exchangeable), 7.78 (br t,
J=6.1 Hz, 1H, exchangeable), 7.02-6.95 (m, 2H), 5.50 (s, 1H), 4.42
(br d, J=5.9 Hz, 2H), 3.57-3.34 (m, 2H), 3.32-3.16 (m, 3H),
2.34-2.20 (m, 1H), 2.05-1.90 (m, 1H), 1.41 (s, 9H) ppm; TLC System:
10% methanol in dichloromethane R.sub.f-0.1.
Example 97--Preparation of Compound 64
[0458] The synthesis of Compound 64 followed the procedure of
General Procedure 15 following:
##STR00110##
[0459] To a cooled solution (at 0.degree. C.) of
dl-1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-3-yl)-1H-pyraz-
ol-1-yl)-2,2-dimethylpropan-1-one (Compound 63, 450 mg, 1.2 mmol)
in dry dichloromethane (10 mL) was added morpholine-4-carbonyl
chloride (366 mg, 2.45 mmol) followed by triethylamine (0.31 mL,
3.0 mmol). After the mixture was stirred at room temperature for 2
hours, to the mixture was added ice-cold water (10 mL). The mixture
was extracted into dichloromethane (2.times.15 mL), and the
combined organic layers were dried over sodium sulfate, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (100-200 mesh), eluting with
50% EtOAc-hexanes, to afford the desired product (370 mg, yield:
62%) as a light yellow semi solid. A portion (160 mg) of semi-pure
material (85% by LCMS) was further purified by preparative HPLC to
obtain
dl-1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)-
pyrrolidin-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 64, 60 mg) as an off-white solid. m/z 480.16 [M+H]+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.70 (t, J=6.1 Hz, 1H,
exchangeable), 6.96 (s, 2H), 5.42 (s, 1H), 4.41 (d, J=6.4 Hz, 2H),
3.58-3.47 (m, 6H), 3.36 (d, J=3.9 Hz, 2H), 3.24-3.19 (m, 1H),
3.15-3.10 (m, 4H), 2.11 (dd, J=6.1, 12.5 Hz, 1H), 1.97-1.89 (m,
1H), 1.39 (s, 9H) ppm; TLC System: 70% ethyl acetate in
n-hexane--R.sub.f-0.6.
Example 98--Preparation of Compound 65
[0460] The synthesis of Compound 65 followed the procedure of
General Procedure 6d following:
##STR00111##
[0461] To a solution of
dl-1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)-
pyrrolidin-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 64, 500 mg, 1.0 mmol) in methanol (10 mL) was added
sodium bicarbonate (438 mg, 5.2 mmol) at room temperature. The
mixture was then stirred at 50.degree. C. for 4 hours. The reaction
mixture was cooled back to room temperature, water (20 mL) was
added and then extracted into dichloromethane (3.times.20 mL). The
combined organic layers were dried over sodium sulfate, filtered
and concentrated under reduced pressure. The residue was partially
purified by silica gel column chromatography (100-200 mesh),
eluting with 5-7% methanol in dichloromethane, to obtain desired
product (300 mg, yield: 72%) as a light yellow semi solid. A
portion (150 mg, 72% by LCMS) of semi-pure material was further
purified by preparative HPLC purification to yield
dl-(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidin--
1-yl)(morpholino)methanone (Compound 65, 62 mg) as an off-white
solid. m/z 396.21 [M+H]+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.42 (br s, 1H, exchangeable), 6.91 (d, J=3.4 Hz, 1H),
6.83 (br s, 1H), 5.67 (br s, 1H, exchangeable), 5.35 (br s, 1H),
4.28 (d, J=5.9 Hz, 2H), 3.56 (td, J=3.8, 5.6 Hz, 5H), 3.37 (td,
J=3.7, 7.7 Hz, 2H), 3.21-3.07 (m, 6H), 2.12 (br s, 1H), 1.84 (dd,
J=8.6, 12.0 Hz, 1H) ppm; TLC System: 10% methanol in
dichloromethane--R.sub.f-0.3.
Example 99--Preparation of Compound 66
[0462] The synthesis of Compound 66 followed the procedure of
General Procedure 5d following:
##STR00112##
[0463] To a cooled solution (0.degree. C.) of
dl-(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidin--
1-yl)(morpholino)methanone (Compound 65, 150 mg, 0.37 mmol) in dry
dichloromethane (10 mL) was added 1,3-thiazole-4-carbonyl chloride
(73 mg, 0.5 mmol), followed by triethylamine (TEA, 0.13 mL, 0.9
mmol) and the mixture was stirred at 0.degree. C. for 2 hours.
Ice-cold water (10 mL) was added to the reaction mixture, and then
extracted into dichloromethane (2.times.15 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude residue was
initially purified by flash chromatography using 4-5%
MeOH-dichloromethane to give the desired product (146 mg, yield:
76%) as a light yellow semi solid. It was further purified by
preparative HPLC to afford
dl-(3-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H--
pyrazol-3-yl)pyrrolidin-1-yl)(morpholino)methanone (Compound 66, 55
mg) as a pale yellow solid. m/z: 507.22 [M+H].sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.13 (d, J=2.4 Hz, 1H), 8.88 (d,
J=2.0 Hz, 1H), 7.70 (t, J=5.9 Hz, 1H, exchangeable), 6.82-6.77 (m,
2H), 5.28 (s, 1H), 4.47 (d, J=5.4 Hz, 2H), 3.73-3.67 (m, 5H),
3.62-3.53 (m, 3H), 3.36-3.28 (m, 5H), 2.27-2.22 (m, 1H), 2.10-2.03
(m, 1H) ppm; TLC System: 10% Methanol-dichloromethane.
R.sub.f-0.6.
Example 100--Preparation of Compound 67
[0464] The synthesis of Compound 67 followed the procedure of
General Procedure 22 following:
##STR00113##
[0465] To a cold solution (0.degree. C.) of
dl-1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-3-yl)-1H-pyraz-
ol-1-yl)-2,2-dimethylpropan-1-one (Compound 63, 650 mg, 1.77 mmol)
in dry dichloromethane (20 mL) was added methanesulfonyl chloride
(304.4 mg, 2.65 mmol) followed by triethylamine (TEA, 0.62 mL, 4.42
mmol). The mixture was stirred at room temperature for 2 hours. The
reaction mixture was quenched with NaHCO.sub.3 solution (10 mL) and
extracted into dichloromethane (3.times.20 mL). The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 20-25% ethyl acetate in n-hexane, to obtain the
desired product (550 mg, yield: 69%). A portion of the sample (170
mg) was further purified by preparative HPLC to afford
dl-1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfon-
yl)pyrrolidin-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 67, 60 mg) as a pale yellow liquid. m/z 445.20
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (t,
J=5.4 Hz, 1H, exchangeable), 6.89-6.62 (m, 2H), 5.16 (s, 1H), 4.36
(d, J=5.9 Hz, 2H), 3.73 (dd, J=7.3, 9.8 Hz, 1H), 3.61-3.42 (m, 3H),
3.40-3.28 (m, 1H), 2.80 (s, 3H), 2.39-2.10 (m, 2H), 1.45 (s, 9H)
ppm; TLC System: 30% ethyl acetate in n-hexane--R.sub.f-0.6.
Example 101--Preparation of Compound 68
[0466] The synthesis of Compound 68 followed the procedure of
General Procedure 6d following:
##STR00114##
[0467] To a cooled solution (0.degree. C.) of
dl-1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)pyrroli-
din-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 67,
380 mg, 0.86 mmol) in dry methanol (10 mL) was added sodium
bicarbonate (431.2 mg, 5.13 mmol) and the mixture was stirred at
70.degree. C. for 4 hours. The reaction mixture was cooled to room
temperature, then added water (20 mL) and extracted into
dichloromethane (3.times.20 mL). The residue was purified by silica
gel column chromatography (100-200 mesh), eluting with 5-7%
methanol in dichloromethane, to obtain the desired compound (300
mg, yield: 72%) as a light yellow semi-solid. Preparative HPLC
purification of a portion of this material (130 mg; 89% of LCMS
purity) yielded
dl-N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)pyrrolidin-3-yl-
)-1H-pyrazol-5-amine (Compound 68, 30 mg) as a white solid. m/z
360.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.44 (br s, 1H, exchangeable), 6.94-6.82 (m, 2H), 5.69 (br s, 1H,
exchangeable), 5.41 (br s, 1H), 4.29 (d, J=6.4 Hz, 2H), 3.59 (br d,
J=4.4 Hz, 1H), 3.36 (br d, J=6.8 Hz, 2H), 3.28 (br s, 1H), 3.15 (br
s, 1H), 2.88 (br s, 3H), 2.20 (br s, 1H), 2.01-1.89 (m, 1H) ppm;
TLC System: 5% methanol in dichloromethane--R.sub.f-0.3.
Example 102--Preparation of Compound 69
[0468] The synthesis of Compound 69 followed the procedure of
General Procedure 5d following:
##STR00115##
[0469] To a cooled solution (0.degree. C.) of
dl-N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)pyrrolidin-3-yl-
)-1H-pyrazol-5-amine (Compound 68, 170 mg, 0.47 mmol) in dry
dichloromethane (10 mL) was added 1,3-thiazole-4-carbonyl chloride
(83.4 mg, 0.56 mmol) followed by triethylamine (TEA, 0.13 mL, 0.94
mmol). After stirring the mixture at room temperature for 2 hours,
the reaction mixture was quenched with NaHCO.sub.3 solution (10 mL)
and extracted into dichloromethane (3.times.20 mL). The combined
organic extracts were dried over sodium sulfate, filtered and
concentrated under reduced pressure to afford the crude product
(200 mg, yield-89%) as a light yellow semi-solid. Preparative HPLC
purification of a portion of the material (200 mg, 87% LCMS purity)
yielded
dl-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)pyrrolidi-
n-3-yl)-1H-pyrazol-1-yl)(thiazol-4-yl)methanone (Compound 69, 65
mg) as a pale yellow solid. m/z 472.10 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.20 (d, J=1.5 Hz, 1H), 9.04 (d,
J=1.5 Hz, 1H), 7.85 (t, J=6.4 Hz, 1H, exchangeable), 7.03-7.00 (d,
1H), 6.97 (d, J=3.9 Hz, 1H), 5.64 (s, 1H), 4.51 (d, J=5.9 Hz, 2H),
3.66-3.59 (m, 1H), 3.42-3.33 (m, 4H), 2.87 (s, 3H), 2.29-2.20 (m,
1H), 2.12-2.02 (m, 1H) ppm; TLC System: 5% methanol in
dichloromethane--R.sub.f-0.6.
Example 103--Preparation of Compound 70
[0470] The synthesis of Compound 70 followed the procedure of
General Procedure 6d following:
##STR00116##
[0471] To a solution of
1-(3-(azepan-4-yl)-5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-1-yl-
)-2,2-dimethylpropan-1-one (Compound 45, 100 mg, 0.25 mmol) in
methanol (5 mL) was added NaHCO.sub.3(63 mg, 0.76 mmol). The
reaction mixture was stirred at 50.degree. C. for 3 hours. The
reaction mixture was cooled to room temperature, the volatiles were
evaporated under reduced pressure and the resultant residue was
diluted with 30% .sup.iPrOH--CHCl.sub.3 (20 mL) and washed with
water (2.times.10 mL). The organic layer was dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
resulting residue (70 mg) was purified by preparative HPLC to
afford
3-(azepan-4-yl)-N-((5-chlorothiophen-2-yl)methyl)-1H-pyrazol-5-amine
(Compound 70, 15 mg, yield: 19%) as a brown solid. MS: m/z 311.15
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.24 (s,
1H), 6.90 (d, J=3.6 Hz, 1H), 6.83 (d, J=4.0 Hz, 1H), 5.60-5.57 (m,
1H), 5.24 (s, 1H), 4.27 (d, J=6.0 Hz, 2H), 3.97-3.18 (m, 2H),
2.86-2.64 (m, 4H), 1.90-1.80 (m, 2H), 1.71-1.47 (m, 4H) ppm; TLC
System: 10% ethyl acetate in hexane. R.sub.f-0.1.
Example 104--Preparation of Compound 71
[0472] The synthesis of Compound 71 followed the procedure of
General Procedure 22 following:
##STR00117##
[0473] To a cooled solution (0.degree. C.) of
1-(3-(azepan-4-yl)-5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-1-yl-
)-2,2-dimethylpropan-1-one (Compound 45, 280 mg, 0.71 mmol) in dry
dichloromethane (10 mL) was added triethylamine (TEA, 0.25 mL, 1.77
mmol), followed by methanesulfonyl chloride (MsCl, 0.082 mL, 1.06
mmol). After the reaction was stirred at room temperature for 2
hours, the mixture was diluted with water (10 mL) and extracted
into dichloromethane (2.times.20 mL). The combined organic layer
was dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by CombiFlash, eluting
with 10% EtOAc/n-hexane, to afford desired product
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)azepan-4-y-
l)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 71, 100 mg,
yield: 40%) as an off-white solid. MS (ESI): m/z 473.08
[M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) (7.65 (t, J=6.3
Hz, 1H), 6.96 (s, 2H), 5.39 (s, 1H), 4.41 (d, J=6.0 Hz, 2H),
3.49-3.34 (m, 2H), 3.32-3.17 (m, 2H), 2.97 (s, 3H), 2.72-2.50 (m,
1H), 2.07-1.60 (m, 6H), 1.40 (s, 9H) ppm; TLC System: 50% ethyl
acetate in hexane. R.sub.f-0.7.
Example 105--Preparation of Compound 72
[0474] The synthesis of Compound 72 followed the procedure of
General Procedure 6d following:
##STR00118##
[0475] To a stirred solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)azepan-4-y-
l)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 71, 80 mg,
0.17 mmol) in methanol (5 mL) was added NaHCO.sub.3(37 mg, 0.51
mmol). The reaction mixture was stirred at 50.degree. C. for 3
hours. The reaction mixture was cooled to room temperature, the
volatiles were evaporated and the resultant residue was diluted
with EtOAc (20 mL) and washed with water (2.times.10 mL). The
organic layer was dried over sodium sulfate, filtered and
concentrated under reduced pressure. The resulting solid was
triturated with diethyl ether and pentane and dried under reduced
pressure for 1 hour to afford
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)azepan-4-yl)-1H-py-
razol-5-amine (Compound 72, 55 mg, yield: 84%) as an off-white
solid. MS (ESI): m/z 389.15 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.24 (s, 1H), 6.90-6.83 (m, 2H), 5.60 (br s,
1H), 5.28 (s, 1H), 4.28 (s, 2H), 3.42-3.31 (m, 2H), 3.26-3.14 (m,
2H), 2.87 (s, 3H), 2.80-2.70 (m, 1H), 2.04-1.60 (m, 3H), 1.72-1.62
(m, 3H) ppm; TLC System: 70% ethyl acetate in hexane.
R.sub.f-0.2.
Example 106--Preparation of Compound 73
[0476] The synthesis of Compound 73 followed the procedure of
General Procedure 5d following:
##STR00119##
[0477] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)azepan-4-yl)-1H-py-
razol-5-amine (Compound 72, 110 mg, 0.28 mmol) in dry
dichloromethane (10 mL) was added triethylamine (TEA, 0.12 mL, 0.85
mmol) followed by thiazole-4-carbonyl chloride (54 mg, 0.36 mmol).
After the mixture was stirred at room temperature for 3 hours, the
reaction mixture was diluted with water (10 mL) and extracted into
dichloromethane (3.times.10 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by CombiFlash, eluting with 50%
EtOAc/n-hexane, to afford
(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)azepan-4-yl)-
-1H-pyrazol-1-yl)(thiazol-4-yl)methanone (Compound 73, 60 mg,
yield: 41%) as an off-white solid. MS (ESI): m/z 500.13
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.18 (s,
1H), 9.03 (s, 1H), 7.78 (br s, 1H), 6.98 (d, J=12.8 Hz, 2H), 5.55
(s, 1H), 4.50 (d, J=5.2 Hz, 2H), 3.47-3.39 (m, 2H), 3.24-3.22 (m,
2H), 2.88 (s, 3H), 2.75 (br s, 1H), 2.07-1.67 (m, 6H) ppm; TLC
System: 80% ethyl acetate in hexane. R.sub.f-0.7.
Example 107--Preparation of Compound 74
[0478] The synthesis of Compound 74 followed the procedure of
General Procedure 5d following:
##STR00120##
[0479] To a cooled solution (0.degree. C.) of allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azepane-1-carbo-
xylate (Compound 43, 250 mg, 0.634 mmol) in dry dichloromethane (10
mL) was added triethylamine (TEA, 0.26 mL, 1.9 mmol) followed by
thiazole-4-carbonyl chloride (112 mg, 0.76 mmol). After the mixture
was stirred at room temperature for 3 hours, the reaction mixture
was diluted with water (10 mL) and extracted into dichloromethane
(3.times.10 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by CombiFlash, eluting with 30%
EtOAc/n-hexane, then trituration with diethyl ether and pentane, to
afford allyl
4-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyra-
zol-3-yl)azepane-1-carboxylate (Compound 74, 180 mg, yield: 61%) as
a yellow solid. m/z 506.13 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.18 (d, J=1.6 Hz, 1H), 9.02-9.01 (m, 1H),
7.77 (t, J=6.0 Hz, 1H), 7.00 (d, J=4.0 Hz, 1H), 6.97 (d, J=3.6 Hz,
1H), 5.93-5.92 (m, 1H), 5.53 (d, J=2.8 Hz, 1H), 5.28-5.23 (m, 1H),
5.18-5.15 (m, 1H), 4.53-4.48 (m, 4H), 3.64-3.58 (m, 1H), 3.48-3.31
(m, 3H), 2.68-2.64 (m, 1H), 2.04-1.86 (m, 3H), 1.76-1.54 (m, 3H)
ppm; TLC System: 50% ethyl acetate in hexane. R.sub.f-0.8.
Example 108--Preparation of Intermediate 35
[0480] The synthesis of Intermediate 35 followed the procedure of
General Procedure 23 following:
##STR00121##
[0481] To a cooled solution (-78.degree. C.) of
tert-butyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (30 g,
133.3 mmol) in dry THF (300 mL) was added LiHMDS (lithium
hexamethyldisilazide, 1M in THF, 146 mL, 146.7 mmol). After
stirring for 30 minutes, a solution of
N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf.sub.2, 52 g, 146.7
mmol) in dry THF (30 mL) was added and the mixture stirred at room
temperature for 5 hours. The reaction mixture was quenched with
saturated ammonium chloride solution (80 mL), and extracted with
EtOAc (2.times.300 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 3-5% EtOAc/n-hexane, to afford
tert-butyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8--
carboxylate (Intermediate 35, 40 g, yield: 84%) as a pale yellow
liquid; TLC System: 20% ethyl acetate in hexane. R.sub.f-0.5.
Example 109--Preparation of Intermediate 36
[0482] The synthesis of Intermediate 36 followed the procedure of
General Procedure 24 following:
##STR00122##
[0483] To a stirred solution of
tert-butyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8--
carboxylate (Intermediate 35, 21 g, 58.8 mmol) in 1,4-dioxane:water
(5:1, 125 mL) in a sealed tube was added molybdenum hexacarbonyl
(Mo(CO).sub.6, 7.7 g, 29.4 mmol), 4-dimethylaminopyridine (DMAP,
14.3 g, 117.6 mmol), and N,N-diisopropylethylamine (DIEA, 25 mL,
141.2 mmol). After degassing with a stream of argon for 15 minutes,
palladium acetate (Pd(OAc).sub.2, 1.3 g, 5.9 mmol) was added,
followed by 1,1'-bis(diphenylphosphino)ferrocene (dppf, 3.3 g, 5.9
mmol). The reaction mixture was stirred at 120.degree. C. for 5
hours. The reaction mixture was filtered through a Celite pad and
poured into aqueous sodium bicarbonate (60 mL) and extracted with
EtOAc (200 mL). The aqueous layer was acidified with HCl (2N, to
pH=2) and extracted with EtOAc (2.times.200 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure to afford
8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-ene-3-carboxylic
acid (Intermediate 36, 14 g, yield: 94%) as a light brown liquid;
TLC System: 50% ethyl acetate in hexane. R.sub.f-0.2.
Example 110--Preparation of Intermediate 37
[0484] The synthesis of Intermediate 37 followed the procedure of
General Procedure 13 following:
##STR00123##
[0485] To a cooled solution (0.degree. C.) of
8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-ene-3-carboxylic
acid (Intermediate 36, 14 g, 55.3 mmol) in acetonitrile (105 mL)
was added cesium carbonate (36 g, 110.7 mmol). After stirring for
15 minutes, iodomethane (MeI, 14 mL, 221.3 mmol) was added and then
stirred at room temperature for 16 hours. After cooling to
0.degree. C. it was quenched with ice cold water (50 mL), and
extracted with EtOAc (2.times.150 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 5-10% EtOAc/n-hexane,
to afford 8-tert-butyl-3-methyl
8-azabicyclo[3.2.1]oct-3-ene-3,8-dicarboxylate (Intermediate 37,
11.8 g, yield: 80%) as an off-white solid; TLC System: 50% ethyl
acetate in hexane. R.sub.f-0.6.
Example 111--Preparation of Intermediate 38
[0486] The synthesis of Intermediate 38 followed the procedure of
General Procedure 19 following:
##STR00124##
[0487] To a solution of
8-tert-butyl-3-methyl-8-azabicyclo[3.2.1]oct-3-ene-3,8-dicarboxylate
(Intermediate 37, 11.8 g, 44.2 mmol) in MeOH (120 mL) in a steel
vessel was added 10% Pd/C (2.7 g), and stirred under 80 psi
hydrogen pressure at room temperature for 16 hours. The reaction
mixture was filtered through a Celite pad, and the volatiles were
concentrated under reduced pressure to give
8-tert-butyl-3-methyl-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate
(Intermediate 38, 11 g, yield: 92%) as a white solid; TLC System:
10% ethyl acetate in hexane. R.sub.f-0.5.
Example 112--Preparation of Intermediate 39
[0488] The synthesis of Intermediate 39 followed the procedure of
General Procedure 6c following:
##STR00125##
[0489] To a cooled solution (0.degree. C.) of
8-tert-butyl-3-methyl-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate
(Intermediate 38, 11 g, 40.9 mmol) in 1,4-dioxane (33 mL) was added
HCl (4M in 1,4-dioxane, 66 mL) at 0.degree. C. and then warmed to
room temperature for 3 hours. The reaction mixture was concentrated
and triturated with diethyl ether to afford methyl
8-azabicyclo[3.2.1]octane-3-carboxylate hydrochloride (Intermediate
39, 8 g, yield: 95%) as a white solid; TLC System: 50% ethyl
acetate in hexane. R.sub.f-0.1.
Example 113--Preparation of Intermediate 40
[0490] The synthesis of Intermediate 40 followed the procedure of
General Procedure 7 following:
##STR00126##
[0491] To a cooled (0.degree. C.) solution of
8-azabicyclo[3.2.1]octane-3-carboxylate hydrochloride (Intermediate
39, 10 g, 48.8 mmol) in water (130 mL) was added sodium bicarbonate
(12.3 g, 146.3 mmol), followed by a solution of allyl chloroformate
(5.7 mL, 53.7 mmol) in THF (60 mL). After stirring at room
temperature for 16 hours, ice-cold water (100 mL) was added and
then extracted into EtOAc (2.times.150 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (100-200 mesh), eluting with 15%
EtOAc/n-hexane, to give
8-allyl-3-methyl-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate
(Intermediate 40, 8 g, yield: 64%) as a colorless liquid; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.5.
Example 114--Preparation of Intermediate 41
[0492] The synthesis of Intermediate 41 followed the procedure of
General Procedure 2 following:
##STR00127##
[0493] To a cooled solution (-78.degree. C.) of acetonitrile (4.1
mL, 79.1 mmol) in dry THF (50 mL) was added n-BuLi (2.5M in hexane,
28 mL, 69.2 mmol). After stirring for 1 hour, a solution of
8-allyl-3-methyl-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate
(Intermediate 40, 5 g, 19.8 mmol) in dry THF (10 mL) was added and
then stirred at -78.degree. C. for 2 hours. The reaction mixture
was quenched with saturated NH.sub.4Cl solution (80 mL) and
extracted into EtOAc (2.times.100 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 25% EtOAc/n-hexane, to
give allyl
3-(2-cyanoacetyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Intermediate 41, 2.7 g, yield: 52%) as a light yellow liquid; TLC
System: 50% ethyl acetate in hexane. R.sub.f-0.3.
Example 115--Preparation of Compound 74
[0494] The synthesis of Compound 74 followed the procedure of
General Procedure 3 following:
##STR00128##
[0495] To a stirred solution of
allyl-3-(2-cyanoacetyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Intermediate 41, 6 g, 22.9 mmol) in ethanol (60 mL) was added
hydrazine (1 mL, 20.6 mmol), and the reaction mixture was heated to
75.degree. C. for 3 hours. The reaction mixture was cooled to room
temperature, the volatiles were evaporated and the resultant
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 2-3% MeOH-dichloromethane, to give
allyl-3-(5-amino-1H-pyrazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 74, 4 g, yield: 63%) as a pale yellow color semi-solid;
TLC System: 5% Methanol-dichloromethane R.sub.f-0.2.
Example 116--Preparation of Compound 75
[0496] The synthesis of Compound 75 followed the procedure of
General Procedure 4 following:
##STR00129##
[0497] To a cooled solution (0.degree. C.) of
allyl-3-(5-amino-1H-pyrazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 74, 3.2 g, 11.6 mmol) in dry MeOH (35 mL) was added
5-chlorothiophene-2-carbaldehyde (2.6 mL, 23.18 mmol), followed by
AcOH (0.2 mL), and then powdered 4 .ANG. molecular sieves. The
reaction mixture was stirred at room temperature for 1 hour
(formation of imine was observed as a less polar spot by TLC). To
this was added sodium cyanoborohydride (NaCNBH.sub.3, 575 mg, 9.3
mmol) portionwise, and the mixture was stirred at room temperature
for 2 hours. To the mixture was added ice-cold water (50 mL), then
filtered through a Celite pad, and the filtrate was extracted with
EtOAc (4.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 2-5% MeOH-dichloromethane, to afford
desired product (2.1 g, yield: 44%) as a light yellow solid. A
portion (170 mg of semi-pure sample) was further purified by
preparative HPLC to afford allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-8-azabicyclo[3-
.2.1]octane-8-carboxylate (Compound 75, 50 mg) as an off white
solid. m/z 407.27 [M+H]+. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.=11.28 (s, 1H, exchangeable), 6.90 (d, J=4.0 Hz, 1H), 6.82
(d, J=3.7 Hz, 1H), 5.93 (tdd, J=5.3, 10.4, 17.2 Hz, 1H), 5.61 (br
s, 1H, exchangeable), 5.33-5.14 (m, 3H), 4.54 (br d, J=4.4 Hz, 2H),
4.31-4.15 (m, 4H), 3.11 (br s, 1H), 1.92 (br s, 2H), 1.82-1.57 (m,
6H) ppm; TLC System: 5% Methanol-dichloromethane R.sub.f-0.4.
Example 117--Preparation of Compound 76
[0498] The synthesis of Compound 76 followed the procedure of
General Procedure 5d following:
##STR00130##
[0499] To a cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-8-azabicyclo[3-
.2.1]octane-8-carboxylate (Compound 75, 1 g, 2.5 mmol) in dry
dichloromethane (15 mL) was added triethylamine (TEA, 0.52 mL, 3.7
mmol) followed by trimethylacetyl chloride (0.27 mL, 2.2 mmol).
After stirring at room temperature for 2 hours, the reaction
mixture was added to water (25 mL) and extracted into
dichloromethane (2.times.40 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 1-2%
MeOH-dichloromethane, to give the desired product (900 mg, yield:
75%) as a light yellow liquid. A portion (250 mg) of semi-pure
material was further purified by preparative HPLC to give allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate (Compound 76, 60 mg) as a
white solid. m/z 491.21 [M+H]+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=7.65 (t, J=6.4 Hz, 1H, exchangeable), 6.97-6.93 (m, 2H),
5.97-5.86 (m, 1H), 5.33 (s, 1H), 5.26 (dd, J=1.5, 17.1 Hz, 1H),
5.16 (dd, J=1.5, 10.3 Hz, 1H), 4.61-4.47 (m, 2H), 4.40 (d, J=5.9
Hz, 2H), 4.21 (br s, 2H), 3.11-3.01 (m, 1H), 1.93 (br s, 2H),
1.83-1.65 (m, 6H), 1.39 (s, 9H) ppm; TLC System: 5%
Methanol-dichloromethane R.sub.f-0.7.
Example 118--Preparation of Compound 77
[0500] The synthesis of Compound 77 followed the procedure of
General Procedure 8b following:
##STR00131##
[0501] A stirred solution of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate (Compound 76, 500 mg, 1 mmol)
in dichloromethane (10 mL) was degassed with a stream of argon for
15 minutes, then to the solution was added
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4, 70
mg, 0.06 mmol) followed by phenylsilane (PhSiH.sub.3, 0.5 mL, 4.1
mmol). After stirring for 45 minutes, the reaction mixture was
filtered through a Celite pad and the filtrate evaporated. The
crude residue was purified by silica gel column chromatography
eluting with 5-10% MeOH-dichloromethane to give
1-(3-(8-azabicyclo[3.2.1]octan-3-yl)-5-((5-chlorothiophen-2-yl)methylamin-
o)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (60 mg) as an
off-white solid. m/z 407.24 [M+H]+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=8.89 (br s, 2H, exchangeable), 7.72 (t, J=6.1
Hz, 1H), 6.98-6.93 (m, 2H), 5.36 (s, 1H), 4.41 (d, J=6.4 Hz, 2H),
4.00 (br s, 2H), 3.00 (tt, J=5.9, 11.5 Hz, 1H), 2.03-1.86 (m, 8H),
1.41 (s, 9H) ppm; TLC System: 10% Methanol-dichloromethane
R.sub.f-0.2.
Example 119--Preparation of Compound 78
[0502] The synthesis of Compound 78 followed the procedure of
General Procedure 8b following:
##STR00132##
[0503] A solution of
allyl-3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-8-azabic-
yclo[3.2.1]octane-8-carboxylate (Compound 75, 250 mg, 0.6 mmol) in
dry dichloromethane (10 mL) was degassed with a stream of argon for
15 minutes, then to the solution was added
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4, 42
mg, 0.03 mmol) followed by phenylsilane (PhSiH.sub.3, 0.3 mL, 2.5
mmol). After stirring at room temperature for 45 minutes, the
reaction mixture was filtered through a Celite pad and the filtrate
was evaporated. The crude residue was purified by silica gel column
chromatography using 10% MeOH-dichloromethane to give the desired
product (150 mg, yield: 75%) as a light brown solid. It was further
purified by preparative HPLC to give
3-(8-azabicyclo[3.2.1]octan-3-yl)-N-((5-chlorothiophen-2-yl)methyl)-1H-py-
razol-5-amine (25 mg) as a light yellow solid as the formic acid
salt; m/z 323.23 [M+H]+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=12.89-8.82 (m, 3H, exchangeable), 8.40 (br s, 1H), 6.91 (d,
J=3.9 Hz, 1H), 6.83 (d, J=3.4 Hz, 1H), 5.71 (br s, 1H), 5.25 (s,
1H), 4.28 (br s, 2H), 3.79 (br s, 2H), 2.97 (ddd, J=5.9, 10.9, 17.0
Hz, 1H), 1.95-1.74 (m, 8H) ppm; TLC System: 10%
Methanol-dichloromethane R.sub.f-0.1.
Example 120--Preparation of Compound 79
[0504] The synthesis of Compound 79 followed the procedure of
General Procedure 5d following:
##STR00133##
[0505] To a cooled solution (0.degree. C.) of
allyl-3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-8-azabic-
yclo[3.2.1]octane-8-carboxylate (Compound 75, 300 mg, 0.73 mmol) in
dry dichloromethane (15 mL) was added triethylamine (TEA, 0.26 mL,
1.84 mmol), then 1,3-thiazole-4-carbonyl chloride (218 mg, 1.47
mmol). After stirring at room temperature for 2 hours, this was
added to ice-cold water (10 mL) and extracted into dichloromethane
(2.times.20 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography using 1-2%
MeOH-dichloromethane to give the desired product (300 mg, yield:
78%) as a light brown liquid. A portion was further purified by
preparative HPLC to give
allyl-3-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1-
H-pyrazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound
79, 75 mg) as pale yellow solid. m/z 518.18 [M+H]+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.=9.19 (d, J=2.0 Hz, 1H), 9.02 (d,
J=2.0 Hz, 1H), 7.79 (t, J=6.4 Hz, 1H), 7.00-6.95 (m, 2H), 5.93
(tdd, J=5.3, 10.4, 17.2 Hz, 1H), 5.50 (s, 1H), 5.27 (dd, J=1.5,
17.1 Hz, 1H), 5.16 (dd, J=1.5, 10.3 Hz, 1H), 4.57-4.47 (m, 4H),
4.23 (br s, 2H), 3.16-3.08 (m, 1H), 1.96-1.66 (m, 8H) ppm; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.7.
Example 121--Preparation of Compound 80
[0506] The synthesis of Compound 80 followed the procedure of
General Procedure 15 following:
##STR00134##
[0507] To a cooled solution (0.degree. C.) of
1-(3-(8-azabicyclo[3.2.1]octan-3-yl)-5-((5-chlorothiophen-2-yl)methylamin-
o)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 77, 350 mg,
0.86 mmol) in dry dichloromethane (10 mL) was added triethylamine
(TEA, 0.3 mL, 2.15 mmol) and then morpholine-4-carbonyl chloride
(0.2 mL, 1.72 mmol). After stirring at room temperature for 2
hours, ice-cold water (5 mL) was added, and washed with
dichloromethane (2.times.20 mL). The combined organic layers were
dried with sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography using
1-2% MeOH-dichloromethane, to give the desired semi-pure product
(320 mg, yield: 71%) as a light brown liquid. A portion (120 mg)
was further purified by preparative HPLC to afford
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(8-(morpholine-4-carbonyl)-8--
azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 80, 60 mg) as an off white solid. m/z 520.25 [M+H]+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=7.65 (t, J=6.1 Hz, 1H,
exchangeable), 6.97-6.93 (m, 2H), 5.35 (s, 1H), 4.40 (d, J=6.4 Hz,
2H), 4.03 (br s, 2H), 3.58-3.52 (m, 4H), 3.25-3.18 (m, 4H), 2.93
(tt, J=5.7, 11.7 Hz, 1H), 1.85-1.66 (m, 8H), 1.39 (s, 9H) ppm; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.6.
Example 122--Preparation of Compound 81
[0508] The synthesis of Compound 81 followed the procedure of
General Procedure 6d following:
##STR00135##
[0509] To a solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(8-(morpholine-4-carbonyl)-8--
azabicyclo[3.2.
1]octan-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound
80, 140 mg, 0.26 mmol) in methanol (5 mL) at room temperature was
added sodium bicarbonate (113 mg, 1.34 mmol). After stirring at
50.degree. C. for 4 hours, the reaction mixture was concentrated
and washed with dichloromethane (2.times.15 mL). The combined
organic layers were dried with sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-8-azabicyclo[-
3.2.1]octan-8-yl)(morpholino)methanone (Compound 81, 30 mg) as an
off-white solid. m/z 436.22 [M+H]+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=11.25 (s, 1H), 6.90 (d, J=3.4 Hz, 1H), 6.82
(br d, J=2.9 Hz, 1H), 5.59 (br s, 1H, exchangeable), 5.26 (br s,
1H), 4.27 (d, J=6.4 Hz, 2H), 4.01 (br s, 2H), 3.59-3.52 (m, 4H),
3.27-3.19 (m, 4H), 2.99 (br s, 1H), 1.84-1.64 (m, 8H) ppm; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.2.
Example 123--Preparation of Compound 82
[0510] The synthesis of Compound 82 followed the procedure of
General Procedure 5d following:
##STR00136##
[0511] To a cooled solution (0.degree. C.) of
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)-8-azabicyclo[-
3.2.1]octan-8-yl)(morpholino)methanone (Compound 81, 175 mg, 0.4
mmol) in dry dichloromethane (10 mL) was added triethylamine (TEA,
0.14 mL, 1 mmol), followed by 1,3-thiazole-4-carbonyl chloride (119
mg, 0.8 mmol). After stirring at room temperature for 2 hours,
ice-cold water (5 mL) was added, and then washed with
dichloromethane (2.times.15 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with 1-2% MeOH-dichloromethane, to give the desired product
(165 mg, yield: 75%) as a light brown liquid. It was further
purified by preparative HPLC to give
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyr-
azol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)(morpholino)methanone
(Compound 82, 55 mg) as an off-white solid. m/z 547.23 [M+H]+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.19 (d, J=2.0 Hz, 1H),
9.04 (d, J=2.0 Hz, 1H), 7.78 (br t, J=6.4 Hz, 1H, exchangeable),
6.98 (q, J=3.9 Hz, 2H), 5.52 (s, 1H), 4.50 (br d, J=5.9 Hz, 2H),
4.04 (br s, 2H), 3.58-3.53 (m, 4H), 3.25-3.21 (m, 4H), 2.98 (br dd,
J=5.9, 11.7 Hz, 1H), 1.86-1.69 (m, 8H) ppm; TLC System: 5%
Methanol-dichloromethane. R.sub.f-0.5.
Example 124--Preparation of Compound 83
[0512] The synthesis of Compound 83 followed the procedure of
General Procedure 22 following:
##STR00137##
[0513] To a cooled solution (0.degree. C.) of
1-(3-(8-azabicyclo[3.2.1]octan-3-yl)-5-((5-chlorothiophen-2-yl)methylamin-
o)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 77, 350 mg,
0.86 mmol) in dry dichloromethane (10 mL) was added triethylamine
(TEA, 0.3 mL, 2.15 mmol) followed by methanesulfonyl chloride (0.1
mL, 1.3 mmol). After stirring at room temperature for 2 hours,
ice-cold water (5 mL) was added, and washed with dichloromethane
(2.times.20 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography using 1%
MeOH-dichloromethane, to give
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(8-(methylsulfonyl)-8-azabicy-
clo[3.2.1]octan-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 83, 310 mg, yield: 74%) as an off white solid. m/z 485.15
[M+H]+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=7.67 (br t,
J=6.1 Hz, 1H, exchangeable), 6.96 (s, 2H), 5.36 (s, 1H), 4.41 (d,
J=5.9 Hz, 2H), 4.18 (br s, 2H), 3.00-2.90 (m, 4H), 2.05-1.96 (m,
2H), 1.89-1.69 (m, 6H), 1.40 (s, 9H) ppm; TLC System: 5%
Methanol-dichloromethane. R.sub.f-0.6.
Example 125--Preparation of Compound 84
[0514] The synthesis of Compound 84 followed the procedure of
General Procedure 6d following:
##STR00138##
[0515] To a stirred solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(8-(methylsulfonyl)-8-azabicy-
clo[3.2.1]octan-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 83, 145 mg, 0.3 mmol) in methanol (5 mL) at room
temperature was added sodium bicarbonate (126 mg, 1.5 mmol). After
stirring at 50.degree. C. for 4 hours, the reaction mixture was
concentrated and extracted into dichloromethane (2.times.15 mL).
The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by preparative HPLC to give
N-((5-chlorothiophen-2-yl)methyl)-3-(8-(methylsulfonyl)-8-azabicyclo[3.2.-
1]octan-3-yl)-1H-pyrazol-5-amine (Compound 84, 25 mg) as an
off-white solid. m/z 401.20 [M+H]+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=11.28 (s, 1H), 6.90 (d, J=3.9 Hz, 1H), 6.83
(br d, J=3.4 Hz, 1H), 5.62 (br s, 1H, exchangeable), 5.27 (br s,
1H), 4.27 (d, J=6.4 Hz, 2H), 4.16 (br s, 2H), 2.94 (s, 4H),
2.05-1.97 (m, 2H), 1.86-1.74 (m, 4H), 1.73-1.64 (m, 2H) ppm; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.2.
Example 126--Preparation of Compound 85
[0516] The synthesis of Compound 85 followed the procedure of
General Procedure 5d following:
##STR00139##
[0517] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(8-(methylsulfonyl)-8-azabicyclo[3.2.-
1]octan-3-yl)-1H-pyrazol-5-amine (Compound 84, 170 mg, 0.42 mmol)
in dry dichloromethane (10 mL) was added triethylamine (TEA, 0.15
mL, 1.06 mmol) and then 1,3-thiazole-4-carbonyl chloride (125 mg,
0.85 mmol). After stirring at room temperature for 2 hours,
ice-cold water (5 mL) was added and then washed with
dichloromethane (2.times.15 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with 1-2% MeOH-dichloromethane, to give the desired product
(170 mg, yield: 78%) as a light brown liquid. It was purified
further by preparative HPLC to give the 50 mg of pure
(5-((5-chlorothiophen-2-yl)methylamino)-3-(8-(methylsulfonyl)-8-azabicycl-
o[3.2.1]octan-3-yl)-1H-pyrazol-1-yl)(thiazol-4-yl)methanone
(Compound 85, 50 mg) as a pale yellow solid. m/z 512.14 [M+H]+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.19 (s, 1H), 9.04 (s,
1H), 7.80 (br s, 1H), 7.19 (br s, 1H), 7.05-6.93 (m, 2H), 5.54 (s,
1H), 4.50 (br d, J=5.4 Hz, 2H), 4.19 (br s, 2H), 3.07-2.90 (m, 4H),
2.01 (br s, 2H), 1.92-1.73 (m, 6H) ppm; TLC System: 5%
Methanol-dichloromethane. R.sub.f-0.5.
Example 127--Preparation of Intermediate 42
[0518] The synthesis of Intermediate 42 followed the procedure of
General Procedure 7 following:
##STR00140##
[0519] To a cooled solution (0.degree. C.) of methyl
azetidine-3-carboxylate hydrochloride (10 g, 66 mmol) in
THF/H.sub.2O (3:6, 100 mL) was added sodium bicarbonate (16.6 g,
198 mmol) portionwise, followed by allyl chloroformate (7.73 mL,
72.6 mmol). After stirring at room temperature for 5 hours, the
mixture was extracted into EtOAc (3.times.100 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 2%
MeOH/dichloromethane, to give 1-allyl 3-methyl
azetidine-1,3-dicarboxylate (Intermediate 42, 11 g, yield: 83%) as
a colorless syrup. m/z 200.03 [M+H].sup.+; TLC System: 5%
Methanol-dichloromethane; R.sub.f-0.7.
Example 128--Preparation of Intermediate 43
[0520] The synthesis of Intermediate 43 followed the procedure of
General Procedure 2 following:
##STR00141##
[0521] To a cooled solution (-78.degree. C.) of acetonitrile (3.1
mL, 60.3 mmol) in dry THF (60 mL) was added n-BuLi (2.5M in THF,
24.1 mL, 60.3 mmol) then stirred for 1 hour, and then to it added a
solution of 1-allyl-3-methyl azetidine-1,3-dicarboxylate
(Intermediate 42, 10 g, 50.3 mmol) in dry THF (20 mL). After
stirring at -78.degree. C. for 1 hour, the mixture was quenched
with saturated NH.sub.4Cl solution (20 mL) and extracted into EtOAc
(2.times.120 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 50% EtOAc/n-hexane, to afford desired
allyl 3-(2-cyanoacetyl)azetidine-1-carboxylate (Intermediate 43,
5.1 g, 49%) as a light yellow liquid; TLC System: 60% ethyl acetate
in hexane. R.sub.f-0.3.
Example 129--Preparation of Compound 86
[0522] The synthesis of Compound 86 followed the procedure of
General Procedure 3 following:
##STR00142##
[0523] To a solution of allyl
3-(2-cyanoacetyl)azetidine-1-carboxylate (Intermediate 43, 5 g, 24
mmol) in ethanol (30 mL) was added hydrazine hydrate
(N.sub.2H.sub.4.H.sub.2O, 1.2 mL, 24 mmol) and the reaction mixture
was then heated to 80.degree. C. for 5 hours. The reaction mixture
was cooled to room temperature and the volatiles were evaporated.
The residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 4% MeOH-dichloromethane, to afford
allyl 3-(5-amino-1H-pyrazol-3-yl)azetidine-1-carboxylate (Compound
86, 3.6 g, 68%) as an orange liquid; m/z 223.11 [M+H].sup.+; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.3.
Example 130--Preparation of Compound 87
[0524] The synthesis of Compound 87 followed the procedure of
General Procedure 4 following:
##STR00143##
[0525] To a cooled solution (0.degree. C.) of allyl
3-(5-amino-1H-pyrazol-3-yl)azetidine-1-carboxylate (Compound 86,
3.5 g, 15.8 mmol) in dry EtOH (40 mL) was added
5-chlorothiophene-2-carbaldehyde (1.9 mL, 18.9 mmol), acetic acid
(0.5 mL) and then powdered 4 .ANG. molecular sieves (1 g). The
reaction mixture was stirred at room temperature for 1 hour.
(Formation of imine was observed as a less polar spot on TLC). To
the mixture was then added sodium cyanoborohydride (1.19 g, 18.9
mmol) portionwise and stirring continued at room temperature for 2
hours. The reaction mixture was quenched with ice-cold water (50
mL), filtered through a Celite pad and the filtrate was extracted
into EtOAc (3.times.100 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 5%
MeOH/dichloromethane, to afford allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azetidine-1-car-
boxylate (Compound 87, 3.2 g, 58%) as a light yellow gummy liquid;
m/z 353.17 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.54 (br s, 1H), 6.97-6.79 (m, 2H), 5.98-5.84 (m, 1H), 5.73 (br s,
1H), 5.47 (br s, 1H), 5.28 (dd, J=1.5, 17.1 Hz, 1H), 5.19 (dd,
J=1.2, 10.5 Hz, 1H), 4.50 (d, J=5.4 Hz, 2H), 4.36-4.10 (m, 4H),
3.97-3.64 (m, 3H) ppm; TLC System: 5% Methanol in dichloromethane
R.sub.f-0.4.
Example 131--Preparation of Compound 88
[0526] The synthesis of Compound 88 followed the procedure of
General Procedure 5d following:
##STR00144##
[0527] To a cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azetidine-1-car-
boxylate (Compound 87, 3 g, 8.5 mmol) in dry dichloromethane (45
mL) was added triethylamine (TEA, 1.84 mL, 12.8 mmol), followed by
trimethylacetyl chloride (1.0 mL, 8.5 mmol). After stirring at room
temperature for 2 hours, the reaction mixture was diluted with
water (50 mL) and extracted into dichloromethane (3.times.50 mL).
The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 15% EtOAc/hexanes, to afford allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-y-
l)azetidine-1-carboxylate (Compound 88, 1.9 g, 51%) as a colorless
liquid. MS (ESI): m/z 437.44 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.75 (t, J=6.1 Hz, 1H), 6.96 (q, J=3.4 Hz,
2H), 5.90 (tdd, J=5.3, 10.4, 17.1 Hz, 1H), 5.52 (s, 1H), 5.31-5.23
(m, 1H), 5.18 (dd, J=1.5, 10.8 Hz, 1H), 4.53-4.47 (m, 2H), 4.43 (d,
J=5.9 Hz, 2H), 4.24 (br s, 2H), 3.96 (br s, 2H), 3.70 (tt, J=5.9,
8.8 Hz, 1H), 1.41 (s, 9H) ppm; TLC System: 30% Ethyl acetate in
hexane. R.sub.f-0.6.
Example 132--Preparation of Compound 89
[0528] The synthesis of Compound 89 followed the procedure of
General Procedures 8b and 15 following:
##STR00145##
[0529] A cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)azet-
idine-1-carboxylate (Compound 88, 600 mg, 1.4 mmol) in
dichloromethane (30 mL) was degassed with a stream of argon for 15
minutes, then to it was added phenylsilane (PhSiH.sub.3, 0.5 mL,
4.1 mmol), followed by tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh.sub.3).sub.4, 79.4 mg, 0.068 mmol). The reaction mixture
was stirred at room temperature for 3 hours. After complete
consumption of starting material (monitored by TLC), the mixture
was re-cooled to 0.degree. C., and to it added triethylamine (TEA,
0.39 mL, 2.75 mmol), followed by morpholine-4-carbamyl chloride
(0.16 mL, 1.4 mmol) and the mixture was stirred at room temperature
for 3 hours. The reaction mixture was diluted with water (20 mL)
and extracted into dichloromethane (2.times.20 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
Combi-Flash column chromatography, eluting with 2%
MeOH/dichloromethane, to give
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carb-
onyl)azetidin-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 89, 200 mg, 31% over two steps) as an off-white solid. MS
(ESI) m/z 466.49 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.75 (t, J=6.1 Hz, 1H), 6.96 (s, 2H), 5.47 (s, 1H), 4.43
(d, J=5.9 Hz, 2H), 4.20 (t, J=8.3 Hz, 2H), 3.94 (dd, J=6.1, 7.6 Hz,
2H), 3.64 (ddd, J=6.4, 8.7, 14.8 Hz, 1H), 3.57-3.45 (m, 4H),
3.25-3.14 (m, 4H), 1.40 (s, 9H) ppm; TLC System: 5% Methanol in
dichloromethane R.sub.f-0.6.
Example 133--Preparation of Compound 90
[0530] The synthesis of Compound 90 followed the procedure of
General Procedure 6d following:
##STR00146##
[0531] To a solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)aze-
tidin-3-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 89,
200 mg, 0.43 mmol) in methanol (5 mL) was added sodium bicarbonate
(NaHCO.sub.3, 108 mg, 1.3 mmol). After stirring the reaction
mixture at 50.degree. C. for 4 hours, the reaction mixture was
cooled to room temperature, the volatiles were evaporated and the
resultant residue was diluted with EtOAc (20 mL) and washed with
water (2.times.10 mL). The organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
resulting solid was triturated with diethyl ether and n-pentane and
dried under high vacuum for 1 hour to afford
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azetidin-1-yl)-
(morpholino)methanone (Compound 90, 150 mg, 92%) as a pale yellow
gummy solid; TLC System: 5% Methanol in dichloromethane
R.sub.f-0.3.
Example 134--Preparation of Compound 91
[0532] The synthesis of Compound 91 followed the procedure of
General Procedure 5d following:
##STR00147##
[0533] To a cooled solution (0.degree. C.) of
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azetidin-1-yl)-
(morpholino)methanone (Compound 90, 120 mg, 0.31 mmol) in dry
dichloromethane (5 mL) was added triethylamine (TEA, 0.09 mL, 0.63
mmol), followed by thiazole-4-carbonyl chloride (51 mg, 0.35 mmol).
After stirring at room temperature for 3 hours, the reaction
mixture was diluted with water (10 mL) and extracted into
dichloromethane (3.times.20 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by Combi Flash column
chromatography, eluting with 20% acetone/dichloromethane, to give
(3-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyr-
azol-3-yl)azetidin-1-yl)(morpholino)methanone (Compound 91, 50 mg,
32%) as a pale yellow solid. m/z 493.16 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.20 (d, J=1.5 Hz, 1H), 9.04 (s,
1H), 7.87 (t, J=6.1 Hz, 1H), 6.99 (dd, J=3.4, 13.2 Hz, 2H), 5.65
(s, 1H), 4.53 (d, J=6.4 Hz, 2H), 4.22 (t, J=8.6 Hz, 2H), 3.98 (t,
J=6.8 Hz, 2H), 3.75-3.64 (m, 1H), 3.59-3.49 (m, 4H), 3.26-3.17 (m,
4H) ppm; TLC System: 30% acetone in dichloromethane
R.sub.f-0.6.
Example 135--Preparation of Compound 92
[0534] The synthesis of Compound 92 followed the procedure of
General Procedure 8b following:
##STR00148##
[0535] A cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)azet-
idine-1-carboxylate (Compound 88, 100 mg, 0.23 mmol) in
dichloromethane (10 ml) was degassed with a stream of argon for 15
minutes, then to it was added phenylsilane (PhSiH.sub.3, 0.075 ml,
0.69 mmol) followed by tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh.sub.3).sub.4, 13 mg, 0.01 mmol). The reaction mixture was
stirred at room temperature for 3 hours, then filtered through a
Celite pad and the filtrate was evaporated. The residue was
purified by flash chromatography, eluting with 4%
MeOH-dichloromethane to give
1-(3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azetidin-1-y-
l)-2,2-dimethylpropan-1-one (Compound 92, 30 mg, 37%) as a pale
yellow gummy liquid. MS (ESI) m/z 353.27 [M+H].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.54 (s, 1H), 7.01-6.70 (m, 2H),
5.71 (br s, 1H), 5.48 (s, 1H), 4.65 (s, 1H), 4.40-3.97 (m, 4H),
3.71 (s, 2H), 1.30-0.83 (s, 9H) ppm; TLC System: 5% MeOH in
dichloromethane, R.sub.f-0.4.
Example 136--Preparation of Compound 93
[0536] The synthesis of Compound 93 followed the procedures of
General Procedures 8b and 5d following:
##STR00149##
[0537] A cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)azet-
idine-1-carboxylate (Compound 88, 200 mg, 0.46 mmol) in
dichloromethane (15 ml) was degassed with a stream of argon for 15
minutes, then to it was added phenylsilane (PhSiH.sub.3, 0.16 mL,
1.38 mmol) followed by tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh.sub.3).sub.4, 26 mg, 0.02 mmol). The reaction mixture was
stirred at room temperature for 3 hours. After complete consumption
of starting material (monitored by TLC), the mixture was cooled to
0.degree. C. and to it added triethylamine (TEA, 0.16 mL, 1.1 mmol)
followed by pivaloyl chloride (0.06 ml, 0.46 mmol). After stirring
at room temperature for 2 hours, the reaction mixture was diluted
with water (10 mL) and extracted into dichloromethane (3.times.15
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by Combi-Flash column chromatography, eluting with 20%
EtOAc/hexane, to afford
1-(3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)a-
zetidin-1-yl)-2,2-dimethylpropan-1-one (Compound 93, 40 mg, 20%;
over two steps) as a pale yellow gummy material. m/z: 437.21
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.72 (t,
J=6.4 Hz, 1H), 6.94-6.90 (m, 2H), 5.44 (s, 1H), 4.63 (s, 1H),
4.43-4.28 (m, 3H), 4.10 (s, 1H), 3.79 (s, 1H), 3.63-3.58 (m, 1H),
1.37 (s, 9H), 1.07 (s, 9H) ppm; TLC System: 30% Ethyl acetate in
Hexane, R.sub.f-0.4.
Example 137--Preparation of Compound 94
[0538] The synthesis of Compound 94 followed the procedures of
General Procedures 8b and 22 following:
##STR00150##
[0539] A cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-yl)azet-
idine-1-carboxylate (Compound 88, 550 mg, 1.3 mmol) in
dichloromethane (25 mL) was degassed with a stream of argon for 15
minutes, then to it was added phenylsilane (PhSiH.sub.3, 0.46 ml,
3.8 mmol) followed by tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh.sub.3).sub.4, 72 mg, 0.06 mmol). The reaction mixture was
stirred at room temperature for 3 hours. After complete consumption
of starting material (monitored by TLC), the mixture was cooled to
0.degree. C. and to it added triethylamine (TEA, 0.35 mL, 2.52
mmol), followed by methanesulfonyl chloride (MsCl, 0.1 mL, 1.3
mmol). The mixture was stirred at room temperature for 2 hours. The
reaction mixture was diluted with water (20 mL) and extracted into
dichloromethane (3.times.20 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by Combi-Flash column
chromatography, eluting with 70% dichloromethane/hexane, to afford
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)azetidin-3-
-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 94, 160
mg, 29% over two steps) as an off-white solid; m/z 431.17
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.78 (t,
J=6.1 Hz, 1H), 7.01-6.93 (m, 2H), 5.51 (s, 1H), 4.44 (d, J=6.4 Hz,
2H), 4.18-4.08 (m, 2H), 3.96 (t, J=7.6 Hz, 2H), 3.78-3.65 (m, 1H),
3.02 (s, 3H), 1.42 (s, 9H) ppm; TLC System: dichloromethane
R.sub.f-0.4.
Example 138--Preparation of Compound 95
[0540] The synthesis of Compound 95 followed the procedure of
General Procedure 6d following:
##STR00151##
[0541] To a solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)azetidin-3-
-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 94, 140
mg, 0.33 mmol) in methanol (5 mL) was added sodium bicarbonate
(NaHCO.sub.3, 82 mg, 0.98 mmol) and the reaction mixture was
stirred at room temperature for 4 hours. The volatiles were
evaporated and the resultant residue was diluted with EtOAc (20 mL)
and washed with water (2.times.10 mL). The organic layer was dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was triturated with diethyl ether and
n-pentane and dried under high vacuum to afford
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)azetidin-3-yl)-1H--
pyrazol-5-amine (Compound 95, 90 mg, 80%) as a pale yellow solid;
m/z 347.19 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.54 (br s, 1H), 6.96-6.78 (m, 2H), 5.85-5.44 (m, 2H), 4.30 (d,
J=6.4 Hz, 2H), 4.10 (t, J=7.8 Hz, 2H), 3.87 (t, J=7.3 Hz, 2H), 3.73
(br s, 1H), 3.03 (s, 3H) ppm; TLC System: 5% Methanol in
dichloromethane, R.sub.f-0.4.
Example 139--Preparation of Compound 96
[0542] The synthesis of Compound 96 followed the procedure of
General Procedure 5d following:
##STR00152##
[0543] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)azetidin-3-yl)-1H--
pyrazol-5-amine (Compound 95, 70 mg, 0.202 mmol) in dry
dichloromethane (4 mL) was added triethylamine (TEA, 0.07 mL, 0.51
mmol), followed by thiazole-4-carbonyl chloride (32.7 mg, 0.22
mmol). The mixture was then stirred at room temperature for 3
hours. The reaction mixture was diluted with water (10 mL) and
extracted into dichloromethane (3.times.15 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The resultant residue was
purified by Combi-Flash column chromatography, eluting with 5%
acetone/dichloromethane, to afford
(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)azetidin-3-y-
l)-1H-pyrazol-1-yl)(thiazol-4-yl)methanone (Compound 96, 50 mg,
54%) as a pale yellow solid; m/z 458.14 [M+H].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.20 (d, J=2.0 Hz, 1H), 9.08 (d,
J=2.0 Hz, 1H), 7.91 (t, J=6.1 Hz, 1H), 7.07-6.85 (m, 2H), 5.66 (s,
1H), 4.53 (d, J=5.9 Hz, 2H), 4.21-4.11 (m, 2H), 4.02 (t, J=7.3 Hz,
2H), 3.83-3.72 (m, 1H), 3.03 (s, 3H) ppm; TLC System: 10% Acetone
in dichloromethane, R.sub.f-0.5.
Example 140--Preparation of Compound 97
[0544] The synthesis of Compound 97 followed the procedure of
General Procedure 5d following:
##STR00153##
[0545] To a cooled solution (0.degree. C.) of allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)azetidine-1-car-
boxylate (Compound 87, 100 mg, 0.28 mmol) in dry dichloromethane (5
mL) was added triethylamine (TEA, 0.1 mL, 0.71 mmol), followed by
thiazole-4-carbonyl chloride (41.8 mg, 0.28 mmol). The mixture was
stirred at room temperature for 3 hours. The reaction mixture was
diluted with water (10 mL) and extracted into dichloromethane
(3.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by Combi-Flash column chromatography, eluting
with 2% MeOH/dichloromethane, to afford allyl
3-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-pyra-
zol-3-yl)azetidine-1-carboxylate (Compound 97, 60 mg, 45%) as a
pale yellow solid; m/z 464.15 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.20 (d, J=1.5 Hz, 1H), 9.03 (d, J=2.0 Hz,
1H), 7.88 (t, J=6.4 Hz, 1H), 7.02 (d, J=3.4 Hz, 1H), 6.97 (d, J=3.9
Hz, 1H), 5.98-5.84 (m, 1H), 5.70 (s, 1H), 5.27 (dd, J=1.7, 17.4 Hz,
1H), 5.18 (dd, J=1.5, 10.3 Hz, 1H), 4.51 (dd, J=5.9, 10.3 Hz, 4H),
4.25 (br s, 2H), 4.00 (br s, 2H), 3.76 (tt, J=6.2, 8.7 Hz, 1H) ppm;
TLC System: 5% MeOH in dichloromethane, R.sub.f-0.6.
Example 141--Preparation of Intermediate 44
[0546] The synthesis of Intermediate 44 followed the procedure of
General Procedure 13 following:
##STR00154##
[0547] To a cooled solution (0.degree. C.) of
1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (20 g, 92.9
mmol) in dry dimethylformamide (DMF, 100 mL) was added cesium
carbonate (Cs.sub.2CO.sub.3, 103 g, 316 mmol) followed by
iodomethane (MeI, 12 mL, 186 mmol). After stirring at room
temperature for 16 hours, water (100 mL) was added and extracted
into EtOAc (2.times.100 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10-15% EtOAc/n-hexanes,
to obtain 1-tert-butyl-2-methyl pyrrolidine-1,2-dicarboxylate
(Intermediate 44, 19 g, yield: 90%) as a pale yellow liquid; TLC
System: 20% ethyl acetate in hexane R.sub.f-0.5.
Example 142--Preparation of Intermediate 45
[0548] The synthesis of Intermediate 45 followed the procedure of
General Procedure 6c following:
##STR00155##
[0549] To a cooled solution (0.degree. C.) of 1-tert-butyl-2-methyl
pyrrolidine-1,2-dicarboxylate (Intermediate 44, 19 g, 83 mmol) in
1,4-dioxane (120 mL) was added HCl (4M in 1,4-dioxane, 95 mL) and
the reaction was then stirred at room temperature for 5 hours. The
reaction mixture was concentrated under reduced pressure and
triturated with diethyl ether to afford methyl
pyrrolidine-2-carboxylate hydrochloride (Intermediate 45, 12 g,
yield-88%) as a white solid.
Example 143--Preparation of Intermediate 46
[0550] The synthesis of Intermediate 46 followed the procedure of
General Procedure 7 following:
##STR00156##
[0551] To a cooled solution (0.degree. C.) of
methylpyrrolidine-2-carboxylate hydrochloride (Intermediate 45, 12
g, 72.7 mmol) in THF (150 mL) was added pyridine (23.5 mL, 290.9
mmol), then 4-(dimethylamino)pyridine (DMAP, 889 mg, 7.3 mmol),
followed by allyl chloroformate (15.5 mL, 145.4 mmol). The reaction
mixture was stirred at room temperature for 16 hours, then water
(100 mL) was added and extracted into dichloromethane (2.times.100
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 10-15% EtOAc/n-hexanes, to obtain 1-allyl-2-methyl
pyrrolidine-1,2-dicarboxylate (Intermediate 46, 13 g, yield: 80%)
as a colorless liquid. m/z 236.00 [M+Na].sup.+; TLC System: 20%
ethyl acetate in hexane R.sub.f-0.5.
Example 144--Preparation of Intermediate 47
[0552] The synthesis of Intermediate 47 followed the procedure of
General Procedure 2 following:
##STR00157##
[0553] To a cold solution (-78.degree. C.) of acetonitrile (1.8 mL,
35.2 mmol) in dry THF (50 mL) was added n-butyllithium (2.5M in
n-hexane, 14 mL, 35.2 mmol). After stirring at -78.degree. C. for
45 minutes, a solution of 1-allyl-2-methyl
pyrrolidine-1,2-dicarboxylate (Intermediate 46, 5 g, 23.5 mmol) in
dry THF (10 mL) was added and the reaction stirred at -78.degree.
C. for 1 hour. The reaction mixture was quenched with saturated
NH.sub.4Cl solution (20 mL) and extracted into EtOAc (2.times.50
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 20-25% EtOAc/n-hexane, to give
allyl-2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (Intermediate 47,
4.3 g, yield: 82%) as a brown color liquid; TLC System: 50% ethyl
acetate in hexane R.sub.f-0.2.
Example 145--Preparation of Compound 98
[0554] The synthesis of Compound 98 followed the procedure of
General Procedure 3 following:
##STR00158##
[0555] To a stirred solution of
allyl-2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (Intermediate 47,
4.3 g, 19.4 mmol) in ethanol (40 mL) was added hydrazine
monohydrate (0.85 mL, 17.4 mmol). The reaction mixture was then
heated to 70.degree. C. for 5 hours. The reaction mixture was then
cooled to room temperature and the volatiles were evaporated. The
resultant residue was purified by silica gel column chromatography
(100-200 mesh), eluting with 3% MeOH-dichloromethane, to give
allyl-2-(5-amino-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate
(Compound 98, 4 g, yield: 87%) as a colorless liquid. m/z 237.14
[M+H].sup.+; TLC System: 5% methanol in dichloromethane
R.sub.f-0.3.
Example 146--Preparation of Compound 99
[0556] The synthesis of Compound 99 followed the procedure of
General Procedure 4 following:
##STR00159##
[0557] To a cooled solution (0.degree. C.) of
allyl-2-(5-amino-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate
(Compound 98, 4 g, 16.9 mmol) in dry MeOH (70 mL) was added
5-chlorothiophene-2-carbaldehyde (3.9 mL, 33.9 mmol) and acetic
acid (0.1 mL), followed by powdered 4 .ANG. molecular sieves. The
reaction mixture was stirred at room temperature for 1 hour (the
formation of imine was observed as a less polar spot on TLC). After
cooling the reaction mixture back to 0.degree. C., sodium
cyanoborohydride (NaCNBH.sub.3, 1.52 g, 8.5 mmol) was added
portionwise. The mixture was then stirred at room temperature for 2
hours. The reaction mixture was quenched with ice-cold water (30
mL), filtered through a Celite pad and the filtrate was extracted
into EtOAc (3.times.50 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by preparative HPLC using a
Reveleris C-18 reverse phase column, eluting with 35-40%
acetonitrile in aqueous formic acid (0.1%), to obtain the required
compound (3 g, yield: 45%). A portion (100 mg) of this was further
purified by preparative HPLC purification to give
allyl-2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidi-
ne-1-carboxylate (Compound 99, 50 mg) as a pale yellow gummy
liquid. m/z 367.07 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.39 (br s, 1H, exchangeable), 7.02-6.92 (m, 1H), 6.83 (br
d, J=3.7 Hz, 1H, exchangeable), 6.09-5.47 (m, 2H), 5.38-4.97 (m,
3H), 4.81 (br s, 1H), 4.47 (br d, J=15.0 Hz, 2H), 4.28 (d, J=6.2
Hz, 2H), 3.48 (br s, 2H), 2.08 (br d, J=6.2 Hz, 1H), 1.95-1.58 (m,
3H) ppm; TLC System: 5% methanol in dichloromethane
R.sub.f-0.4.
Example 147--Preparation of Compound 100
[0558] The synthesis of Compound 100 followed the procedure of
General Procedure 5d following:
##STR00160##
[0559] To a cooled solution (0.degree. C.) of
allyl-2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidi-
ne-1-carboxylate (Compound 99, 3.5 g, 9.6 mmol) in dry
dichloromethane (50 mL) was added trimethylacetyl chloride (1.1 mL,
8.6 mmol) followed by triethylamine (TEA, 1.9 mL, 14.3 mmol). After
stirring at room temperature for 2 hours, water (25 mL) was added
and the mixture was extracted into dichloromethane (3.times.40 mL).
The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 10% EtOAc/n-hexane, to afford the desired compound (3
g, yield: 69%) as a pale yellow gummy liquid. A portion (120 mg)
was further purified by preparative HPLC purification to afford
allyl-2-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyra-
zol-3-yl)pyrrolidine-1-carboxylate (Compound 100, 50 mg) as a pale
yellow gummy liquid; m/z 451.17 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.49-7.31 (m, 1H), 6.83-6.66 (m, 2H), 6.07-5.74
(m, 1H), 5.38-5.26 (m, 1H), 5.24-5.06 (m, 2H), 4.98-4.77 (m, 1H),
4.64-4.46 (m, 2H), 4.34 (d, J=5.9 Hz, 2H), 3.67-3.41 (m, 2H),
2.27-1.80 (m, 4H), 1.44 (s, 9H) ppm; TLC System: 50% ethyl acetate
in hexane R.sub.f-0.7.
Example 148--Preparation of Compound 101
[0560] The synthesis of Compound 101 followed the procedure of
General Procedure 8b following:
##STR00161##
[0561] A stirred solution of
allyl-2-(5-((5-chlorothiophen-2-yl)methylamino)-1-pivaloyl-1H-pyrazol-3-y-
l)pyrrolidine-1-carboxylate (Compound 100, 1.5 g, 3.3 mmol) in
dichloromethane (30 mL) was degassed with a stream of argon for 15
minutes., then to the mixture was added
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4, 193
mg, 0.16 mmol) followed by phenylsilane (PhSiH.sub.3, 1.2 mL, 10
mmol). The reaction mixture was stirred at room temperature for 45
minutes, then was filtered through a Celite pad and the filtrate
was evaporated. The crude residue was purified by combi-flash
silica chromatography eluting with 4% MeOH-dichloromethane to
afford
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-3-yl)-1H-pyrazol--
1-yl)-2,2-dimethylpropan-1-one (Compound 101, 1 g, yield: 81%) as a
pale yellow gummy liquid. m/z 367.26 [M+H].sup.+, .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.72 (br t, J=6.1 Hz, 1H, exchangeable),
6.96 (s, 2H), 5.44 (s, 1H), 4.42 (br d, J=6.2 Hz, 2H), 4.05 (br t,
J=6.6 Hz, 1H), 3.11-2.82 (m, 2H), 2.13-1.95 (m, 1H), 1.87-1.65 (m,
3H), 1.41 (s, 9H) ppm; TLC System: 10% methanol in dichloromethane
R.sub.f-0.3
Example 149--Preparation of Compound 102
[0562] The synthesis of Compound 102 followed the procedure of
General Procedure 5d following:
##STR00162##
[0563] To a cooled solution (0.degree. C.) of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)-2,2-dimethylpropan-1-one (Compound 101, 200 mg, 1.2 mmol) in
dry dichloromethane (10 mL) was added 4-morpholineacetic acid
chloride (94 mg, 0.66 mmol) followed by triethylamine (TEA, 0.22
mL, 1.6 mmol). After stirring at room temperature for 2 hours,
ice-cold water (10 mL) was added, then washed with dichloromethane
(2.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 50% EtOAc-hexanes, to give the desired product
(120 mg, yield: 81%) as a light yellow semi-solid. A portion (160
mg) of this material (85% by LCMS) was purified by preparative HPLC
to give
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(2-morpholinoacetyl)pyrrol-
idin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 102,
60 mg) as an off-white gummy semi solid; m/z 494.22 [M+H]+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.49 (br s, 1H), 6.90 (s, 2H),
5.34 (br s, 1H), 5.10 (br s, 2H), 4.42 (br s, 2H), 3.49 (br s, 8H),
2.98 (s, 2H), 2.48 (br s, 3H), 1.94 (br s, 2H), 1.39 (s, 9H) ppm;
TLC System: 70% ethyl acetate in n-hexane--R.sub.f-0.6.
Example 150--Preparation of Compound 103
[0564] The synthesis of Compound 103 followed the procedure of
General Procedure 6d following:
##STR00163##
[0565] To a room temperature solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(2-morpholinoacetyl)pyrrol-
idin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 102,
230 mg, 0.54 mmol) in methanol (10 mL) was added sodium bicarbonate
(NaHCO.sub.3, 230 mg, 2.7 mmol). The mixture was stirred at
50.degree. C. for 4 hours, then cooled back to room temperature,
water (20 mL) was added and washed with dichloromethane (3.times.20
mL). The combined organic phases were dried with sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 5-7% methanol in dichloromethane to afford the desired
product (130 mg, yield: 67%). A portion (130 mg, 72% by LCMS) of
this material was further purified by preparative HPLC to afford
1-(2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidin-1-
-yl)-2-morpholinoethanone (Compound 103, 25 mg) as a pale yellow
solid; m/z 410.15 [M+H]+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.84-10.62 (m, 1H, exchangeable), 7.46-5.87 (m, 2H), 5.27
(br s, 2H), 5.04 (br s, 1H), 4.29 (br d, J=6.6 Hz, 2H), 3.53 (br s,
6H), 3.07 (br d, J=6.6 Hz, 1H), 2.97-2.71 (m, 1H), 2.48 (br d,
J=1.5 Hz, 4H), 2.07 (br s, 1H), 1.85 (br s, 3H) ppm; TLC System:
10% methanol in dichloromethane--R.sub.f-0.3.
Example 151--Preparation of Compound 104
[0566] The synthesis of Compound 104 followed the procedure of
General Procedure 22 following:
##STR00164##
[0567] To a cold solution (0.degree. C.) of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)-2,2-dimethylpropan-1-one (Compound 101, 700 mg, 1.9 mmol) in
dry dichloromethane (20 mL) was added methanesulfonyl chloride
(MsCl, 0.22 mL, 2.8 mmol) followed by triethylamine (TEA, 0.6 mL,
4.4 mmol). After the mixture was stirred at room temperature for 1
hour, ice-cold water (20 mL) was added and extracted into
dichloromethane (3.times.20 mL). The combined organic phases were
dried with sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 20-25% ethyl acetate in
n-hexane, to give the desired product (550 mg, yield: 64%). A
portion (170 mg) was further purified by preparative HPLC
chromatography to yield
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)pyrrolidin-
-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 104, 50
mg) as a pale yellow gummy liquid; m/z 445.17 [M+H].sup.+; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.52-7.35 (m, 1H, exchangeable),
6.91-6.61 (m, 2H), 5.37 (s, 1H), 4.83 (dd, J=2.7, 7.1 Hz, 1H), 4.37
(d, J=5.9 Hz, 2H), 3.63-3.36 (m, 2H), 2.75 (s, 3H), 2.33-1.89 (m,
4H), 1.45 (s, 9H) ppm; TLC System: 5% methanol in
dichloromethane--R.sub.f-0.6.
Example 152--Preparation of Compound 105
[0568] The synthesis of Compound 105 followed the procedure of
General Procedure 6d following:
##STR00165##
[0569] To a cooled solution (0.degree. C.) of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)pyrrolidin-
-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 104, 200
mg, 0.45 mmol) in dry methanol (10 mL) was added sodium bicarbonate
(189 mg, 2.25 mmol). After warming the mixture at 50.degree. C. for
4 hours, the reaction mixture was cooled to room temperature, water
(15 mL) was added and extracted into dichloromethane (3.times.20
mL). The combined organic phases were dried with sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200 mesh),
eluting with 5-7% methanol in dichloromethane, to give the required
semi-pure compound (145 mg, yield: 89%) as an off-white solid. A
portion (130 mg of 89% of LCMS purity) was further purified by
preparative HPLC to yield
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)pyrrolidin-2-yl)-1-
H-pyrazol-5-amine (Compound 105, 50 mg) as a white solid; m/z
361.16 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.52-11.30 (m, 1H, exchangeable), 6.99-6.80 (m, 2H), 5.68 (br s,
1H, exchangeable), 5.41 (br s, 1H), 4.74 (br s, 1H), 4.29 (d, J=6.4
Hz, 2H), 3.46-3.24 (m, 2H), 2.84 (br s, 3H), 2.21-2.06 (m, 1H),
1.89 (br d, J=5.4 Hz, 3H) ppm; TLC System: 5% methanol in
dichloromethane--R.sub.f-0.3.
Example 153--Preparation of Compound 106
[0570] The synthesis of Compound 106 followed the procedure of
General Procedure 5d following:
##STR00166##
[0571] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)pyrrolidin-2-yl)-1-
H-pyrazol-5-amine (Compound 105, 200 mg, 0.56 mmol) in dry
dichloromethane (10 mL) was added 1,3-thiazole-4-carbonyl chloride
(148 mg, 1.11 mmol) followed by triethylamine (TEA, 0.18 mL, 1.4
mmol). After stirring at room temperature for 2 hours, the reaction
mixture was quenched with NaHCO.sub.3 solution (10 mL) and
extracted into dichloromethane (3.times.20 mL). The combined
organic phases were dried over sodium sulfate and concentrated
under reduced pressure to afford the desired compound (150 mg,
yield: 57%) as a light yellow semi-solid. A portion (100 mg with
87% LCMS purity) was further purified by preparative HPLC
chromatography to yield
(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(methylsulfonyl)pyrrolidin-2-
-yl)-1H-pyrazol-1-yl)(thiazol-4-yl)methanone (Compound 106, 40 mg)
as an off-white solid. m/z 472.10 [M+H].sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.13 (d, J=2.0 Hz, 1H), 8.88 (d, J=2.0 Hz,
1H), 7.65 (br t, J=5.6 Hz, 1H, exchangeable), 6.89-6.69 (m, 2H),
5.44 (s, 1H), 4.88 (dd, J=3.2, 8.1 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H),
3.66-3.39 (m, 2H), 2.78 (s, 3H), 2.37-2.16 (m, 2H), 2.14-1.95 (m,
2H) ppm; TLC System: 5% methanol in
dichloromethane--R.sub.f-0.5.
Example 154--Preparation of Compound 107
[0572] The synthesis of Compound 107 followed the procedure of
General Procedure 15 following:
##STR00167##
[0573] To a cooled solution (0.degree. C.) of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)-2,2-dimethylpropan-1-one (Compound 101, 320 mg, 0.87 mmol) in
dry dichloromethane (10 mL) was added morpholine-4-carbonyl
chloride (0.2 mL, 1.7 mmol) followed by triethylamine (TEA, 0.29
mL, 2.1 mmol). After stirring at room temperature for 1 hour,
ice-cold water (10 mL) was added and then extracted into
dichloromethane (2.times.15 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 50% EtOAc-hexanes, to
give the desired product (170 mg, yield: 40%) as a light yellow
semi-solid. A portion (160 mg, 85% by LCMS) was purified by
preparative HPLC to obtain
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)pyr-
rolidin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound
107, 45 mg) as a pale yellow gummy liquid; m/z 480.25 [M+H]+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (br t, J=5.6 Hz, 1H,
exchangeable), 6.79-6.71 (m, 2H), 5.17 (s, 1H), 5.04 (t, J=6.8 Hz,
1H), 4.34 (d, J=5.4 Hz, 2H), 3.71-3.58 (m, 4H), 3.57-3.41 (m, 2H),
3.36 (ddd, J=3.4, 6.4, 13.2 Hz, 2H), 3.20 (ddd, J=2.9, 6.4, 13.2
Hz, 2H), 2.32-2.19 (m, 1H), 2.06-1.79 (m, 3H), 1.45 (s, 9H) ppm;
TLC System: 5% Methanol-dichloromethane. R.sub.f-0.5.
Example 155--Preparation of Compound 108
[0574] The synthesis of Compound 108 followed the procedure of
General Procedure 6d following:
##STR00168##
[0575] To a room temperature solution of
1-(5-((5-chlorothiophen-2-yl)methylamino)-3-(1-(morpholine-4-carbonyl)pyr-
rolidin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound
107, 200 mg, 0.42 mmol) in methanol (10 mL) was added sodium
bicarbonate (176 mg, 2.1 mmol), followed by heating of the mixture
to 50.degree. C. for 4 hours. The reaction mixture was cooled to
room temperature, water (20 mL) was added and extracted into
dichloromethane (3.times.20 mL). The residue was purified by silica
gel column chromatography (100-200 mesh), eluting with 5-7%
methanol in dichloromethane, to give the desired product (100 mg,
yield: 65%) as a light yellow semi-solid. A portion (150 mg, 70% by
LCMS) of material was further purified by preparative HPLC
chromatography to give
(2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrol-
idin-1-yl)(morpholino)methanone (Compound 108, 30 mg) as an off
white solid. m/z 396.21 [M+H]+. .sup.1H NMR (400 MHz, CDCl.sub.3)
10.04 (br s, 1H, exchangeable), 6.83-6.56 (m, 2H), 5.47 (s, 1H),
5.05 (dd, J=6.8, 9.3 Hz, 1H), 4.42 (br d, J=4.9 Hz, 2H), 3.95 (br
s, 1H, exchangeable), 3.76-3.51 (m, 4H), 3.50-3.31 (m, 4H), 3.20
(ddd, J=2.9, 6.4, 13.2 Hz, 2H), 2.51-2.15 (m, 1H), 2.10-1.95 (m,
2H), 1.93-1.73 (m, 1H) ppm; TLC System: 5% methanol in
dichloromethane--R.sub.f-0.3.
Example 156--Preparation of Compound 109
[0576] The synthesis of Compound 109 followed the procedure of
General Procedure 5d following:
##STR00169##
[0577] To a cooled (0.degree. C.) solution of
(2-(5-((5-chlorothiophen-2-yl)methylamino)-1H-pyrazol-3-yl)pyrrolidin-1-y-
l)(morpholino)methanone (Compound 108, 260 mg, 0.66 mmol) in dry
dichloromethane (15 mL) was added 1,3-thiazole-4-carbonyl chloride
(194 mg, 1.3 mmol) followed by triethylamine (TEA, 0.22 mL, 0.94
mmol) and the mixture was stirred at 0.degree. C. for a further 2
hours. To this was then added ice-cold water (15 mL) and the
mixture was washed with dichloromethane (2.times.15 mL). The
combined organic layers were dried over sodium sulfate, filtered
and concentrated under reduced pressure. The residue was purified
by flash chromatography, eluting with 5-10% THF-EtOAc, to yield
((2-(5-((5-chlorothiophen-2-yl)methylamino)-1-(thiazole-4-carbonyl)-1H-py-
razol-3-yl)pyrrolidin-1-yl)(morpholino)methanone (Compound 109, 75
mg) as a pale yellow solid. m/z: 507.22 [M+H].sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.=9.18 (d, J=2.0 Hz, 1H), 8.87 (d,
J=2.0 Hz, 1H), 7.64 (t, J=6 Hz, 1H, exchangeable), 6.95-6.65 (m,
2H), 5.27 (s, 1H), 5.07 (t, J=7.2 Hz, 1H), 4.46 (d, J=5.9 Hz, 2H),
3.73-3.46 (m, 6H), 3.38 (ddd, J=2.9, 6.4, 13.2 Hz, 2H), 3.20 (ddd,
J=2.9, 6.4, 13.2 Hz, 2H), 2.43-2.25 (m, 1H), 2.10-1.79 (m, 3H) ppm;
TLC System: 10% THF-EtOAc. R.sub.f-0.5.
Example 157--Preparation of Intermediate 48
[0578] The synthesis of Intermediate 48 followed the procedure of
General Procedure 25 following:
##STR00170##
[0579] Ethyl piperidine-4-carboxylate (1.0 g, 6.4 mmol, 1.0 eq) was
dissolved in anhydrous acetonitrile (25.0 mL), followed by the
addition of cesium carbonate (4.15 g, 12.7 mmol, 2.0 eq) and the
reaction mixture was stirred at room temperature for 30 minutes.
Then, the reaction was cooled to 0.degree. C. and
4-(2-chloroethyl)morpholine hydrochloride (1.42 g, 7.6 mmol, 1.2
eq) was added. The mixture was slowly brought to ambient
temperature and stirred at 80.degree. C. for 12 hours. After
completion of the reaction, as monitored by TLC and LC-MS, the
reaction mixture was diluted with cold water (10 mL) and extracted
with ethyl acetate (3.times.20 mL). The organic layer was washed
with water and concentrated under reduced pressure to obtain yellow
residue, which was purified by column chromatography (silica;
100-200 mesh) eluting with 45% ethyl acetate in hexane to obtain
ethyl 1-(2-morpholinoethyl)piperidine-4-carboxylate (Intermediate
48, 1.07 g, yield: 62%).
Example 158--Preparation of Intermediate 49
[0580] The synthesis of Intermediate 49 followed the procedure of
General Procedure 2 following:
##STR00171##
[0581] In an inert atmosphere with N.sub.2 gas flow, acetonitrile
(1.14 g, 27.8 mmol, 1.5 eq) was added in tetrahydrofuran (30.0 mL)
and cooled to -78.degree. C. To this was added n-BuLi (2.5M in
n-hexane, 1.77 mL, 27.8 mmol, 1.5 eq) dropwise over a period of 1
hour and the reaction was stirred for another 60 minutes.
Ethyl-1-(2-morpholinoethyl)piperidine-4-carboxylate (Intermediate
48, 5.0 g, 18.5 mmol, 1.0 eq) was added in portions to the reaction
mixture and stirred at -78.degree. C. for 3 hours. The reaction was
quenched with saturated ammonium chloride solution and product was
extracted with ethyl acetate (3.times.20 mL). The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to obtain a residue which was washed with ethyl acetate
and used `as is` for the next step
((3-(1-(2-morpholinoethyl)piperidin-4-yl)-3-oxopropanenitrile,
Intermediate 49, 4.5 g, yield: 92%) m/z 266.03;
Example 159--Preparation of Compound 110
[0582] The synthesis of Compound 110 followed the procedure of
General Procedure 3 following:
##STR00172##
[0583] To a solution of
3-(1-(2-morpholinoethyl)piperidin-4-yl)-3-oxopropanenitrile
(Intermediate 49, 4.5 g, 17.1 mmol, 1.0 eq) in isopropanol (50 mL)
and acetic acid (1.02 g) was added hydrazine monohydrate (0.9 g,
18.2 mmol, 1.1 eq) dropwise, and the reaction was stirred at
80.degree. C. for 5 hours. The reaction mixture was monitored by
TLC and LC-MS, and after completion the reaction mixture was
concentrated under reduced pressure to obtain a residue, which was
purified by column chromatography using silica gel (100-200 mesh).
The product was eluted with 10% methanol in dichloromethane to give
3-(1-(2-morpholinoethyl)piperidin-4-yl)-1H-pyrazol-5-amine
(Compound 110, 4.0 g. yield: 83%) m/z 280.13 [M+1].sup.+.
Example 160--Preparation of Compound 111
[0584] The synthesis of Compound 111 followed the procedure of
General Procedure 4 following:
##STR00173##
[0585] To a cooled solution (0.degree. C.) of
3-(1-(2-morpholinoethyl)piperidin-4-yl)-1H-pyrazol-5-amine
(Compound 110, 2.0 g, 7.2 mmol, 1.0 eq.) in MeOH (40.0 mL) and
glacial acetic acid (0.431 g) was added
5-chlorothiophene-2-carbaldehyde (1.265 g, 8.6 mmol, 1.2 eq)
dropwise. The reaction mixture was slowly brought to ambient
temperature and then stirred for one day. After completion, as
monitored by TLC and LC-MS, the mixture was cooled back to
0.degree. C. and sodium cyanoborohydride (0.68 g, 10.7 mmol, 1.5
eq.) was added. The mixture was stirred at room temperature for 4
hours. The reaction mixture was concentrated under reduced pressure
to obtain a yellow residue which was diluted with cold water (20
mL), extracted with ethyl acetate (3.times.20 mL) and purified by
column chromatography (60-120 mesh) eluting with 6% MeOH in
dichloromethane as mobile phase, to give
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-morpholinoethyl)piperidin-4-yl)-
-1H-pyrazol-5-amine (Compound 111, 0.60 g. yield: 20%); m/z 412.00
[M+2].sup.+1H NMR (400 MHz, DMSO) .delta. 11.33 (s, 1H), 6.91 (d,
J=2.9 Hz, 1H), 6.84 (s, 1H), 5.67 (s, 1H), 5.28 (s, 1H), 4.28 (d,
J=5.4 Hz, 2H), 3.56 (s, 5H), 2.98 (s, 2H), 2.42 (d, J=24.9 Hz, 7H),
2.10 (s, 2H), 1.81 (s, 2H), 1.58 (s, 2H) ppm.
Example 161--Preparation of Compound 112
[0586] The synthesis of Compound 112 followed the procedure of
General Procedure 5a following:
##STR00174##
[0587] To a solution of pivalic acid (49.0 mg, 0.49 mmol, 1.0 eq)
in THF (10.0 mL) was added DIEA (130 mg, 1.0 mmol, 2.0 eq), HOBt
(66.0 mg, 0.49 mmol, 1.0 eq.) and EDCI-HCl (143 mg, 0.75 mmol, 1.5
eq.), and the reaction mixture stirred at room temperature for
minutes. Then,
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-morpholinoethyl)piperidin-4-yl)-
-1H-pyrazol-5-amine (Compound 111, 200 mg, 0.49 mmol, 1.0 eq.) was
added to reaction mixture and allowed to stir room temperature for
another 12 hours. After completion, the reaction mixture was
concentrated, poured in ice-cold water and extracted with ethyl
acetate (3.times.50 mL). The combined organic layers were
concentrated under reduced pressure to give a residue which was
purified by preparative HPLC using 100% MeCN and 0.1% formic acid
in water to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholinoethyl)
piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound
112, 60.0 mg, yield: 25%) m/z 495.53 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO) .delta. 8.20 (s, 1H), 7.67 (t, J=6.2 Hz, 1H), 7.07-6.86
(m, 2H), 5.39 (s, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.62-3.51 (m, 4H),
2.93 (d, J=11.7 Hz, 2H), 2.50-2.31 (m, 9H), 2.10 (dd, J=13.3, 7.1
Hz, 2H), 1.83 (d, J=12.3 Hz, 2H), 1.66-1.53 (m, 2H), 1.40 (s, 9H),
1.35 (s, 1H) ppm.
Example 162--Preparation of Compound 113
[0588] The synthesis of Compound 113 followed the procedure of
General Procedure 5a following:
##STR00175##
[0589] To a solution of hydroxypivalic acid (60.0 mg, 0.49 mmol,
1.0 eq.) in THF (10 mL) was added DIPEA (130.0 mg, 0.98 mmol, 2.0
eq.), HOBt (66.0 mg, 0.49 mmol, 1.0 eq.) and then EDCI-HCl (143.0
mg, 0.75 mmol, 1.5 eq.). The mixture was stirred at room
temperature for 30 minutes. To it was added
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-morpholinoethyl)piperidin-
-4-yl)-1H-pyrazol-5-amine (Compound 111, 200.0 mg, 0.49 mmol, 1.0
eq.) and the mixture allowed to stir at room temperature for
another 12 hours. After completion, the reaction mixture was
concentrated and poured on to ice-cold water and extracted with
ethyl acetate (3.times.50 mL). The combined organic layers were
concentrated under reduced pressure to give a residue, which was
purified by preparative HPLC using 100% MeCN and 0.1% formic acid
in water to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholinoethyl)piper-
idin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
(Compound 113, 55.0 mg, yield: 22%) m/z 510.78 [M+1].sup.+; 1H NMR
(400 MHz, DMSO) .delta. 8.21 (s, 1H), 7.67 (t, J=6.2 Hz, 1H), 6.97
(q, J=3.8 Hz, 2H), 5.38 (s, 1H), 4.40 (d, J=6.2 Hz, 2H), 3.86 (s,
2H), 3.59-3.53 (m, 4H), 2.95 (d, J=11.2 Hz, 2H), 2.43 (d, J=6.7 Hz,
3H), 2.38 (s, 4H), 2.12 (t, J=11.1 Hz, 2H), 1.83 (d, J=11.8 Hz,
2H), 1.67-1.51 (m, 2H), 1.30 (s, 6H), 1.03 (s, 1H) ppm.
Example 163--Preparation of Intermediate 50
[0590] The synthesis of Intermediate 50 followed the procedure of
General Procedure 5d following:
##STR00176##
[0591] To a cooled solution (0.degree. C.) of ethyl
piperidine-4-carboxylate (0.2 g, 1.3 mmol, 1.0 eq) in
dichloromethane (2.0 mL) was added triethylamine (TEA, 0.34 mL, 2.6
mmol, 2.0 eq.), followed by chloroacetyl chloride (0.13 mL, 1.5
mmol, 1.2 eq.) dropwise. It was then stirred at room temperature
for 6 hours. The reaction was monitored by TLC and LCMS, and after
completion the reaction mixture was diluted with cold water (10
mL), and product was extracted using dichloromethane (2.times.10
mL). The organic layers were dried over sodium sulfate and
evaporated under vacuum to obtain a residue, was purified by column
chromatography, eluting with 3% methanol in dichloromethane, to
give ethyl 1-(2-chloroacetyl)piperidine-4-carboxylate (Intermediate
50, 210 mg, yield: 70%) m/z 234.21 [M+H]+ .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.39-4.32 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.09
(d, J=1.4 Hz, 2H), 3.85 (d, J=13.6 Hz, 1H), 3.22 (tt, J=16.0, 7.9
Hz, 1H), 2.99-2.86 (m, 1H), 2.58 (tt, J=10.5, 4.0 Hz, 1H),
2.05-1.94 (m, 1H), 1.87-1.76 (m, 1H), 1.69 (dt, J=11.0, 5.3 Hz,
2H), 1.28 (t, J=7.1 Hz, 3H) ppm.
Example 164--Preparation of Intermediate 51
[0592] The synthesis of Intermediate 51 followed the procedure of
General Procedure 25 following:
##STR00177##
[0593] To a solution of morpholine (0.08 mL, 1.0 mmol, 1.2 eq.) in
acetonitrile (2.0 mL) was added potassium carbonate (0.355 g, 2.4
mmol, 3.0 eq.) and stirred at room temperature for 10-15 minutes.
To the mixture was added a solution of
ethyl-1-(2-chloroacetyl)piperidine-4-carboxylate (Intermediate 50,
0.2 g, 0.8 mmol, 1.0 eq.) in acetonitrile (2.0 mL) and then stirred
at room temperature for 14 hours. After completion of reaction, as
monitored on TLC and LCMS, the reaction mixture was diluted with
ethyl acetate (20 mL) and washed with water (50 mL). The organic
layers were dried over sodium sulfate and evaporated under vacuum
to obtain a crude product.
[0594] This was purified by column chromatography through silica
(60-120 Mesh), eluting with 4% methanol in dichloromethane to give
ethyl-1-(2-morpholinoacetyl)piperidine-4-carboxylate (Intermediate
51, 0.141 g, yield: 69%) m/z 285.42 [M+H]+ .sup.1H NMR (400 MHz,
DMSO) .delta. 4.19 (d, J=13.1 Hz, 1H), 4.11-4.02 (m, 2H), 3.97 (d,
J=13.7 Hz, 1H), 3.60-3.50 (m, 4H), 3.21 (d, J=13.3 Hz, 1H), 3.07
(dd, J=21.2, 12.3 Hz, 2H), 2.76-2.65 (m, 1H), 2.59 (tt, J=11.0, 3.9
Hz, 1H), 2.41-2.33 (m, 4H), 1.83 (t, J=12.5 Hz, 2H), 1.54 (ddd,
J=24.5, 11.5, 4.0 Hz, 1H), 1.35 (dt, J=11.3, 7.5 Hz, 1H), 1.22-1.15
(m, 3H) ppm.
Example 165--Preparation of Intermediate 52
[0595] The synthesis of Intermediate 52 followed the procedure of
General Procedure 2 following:
##STR00178##
[0596] In an inert atmosphere with N.sub.2 gas flow, acetonitrile
(0.12 mL, 2.9 mmol, 1.7 eq) was added to THF (7.5 mL) and cooled to
-78.degree. C. n-BuLi (2.5M in n-hexane, 1.2 mL, 2.9 mmol, 1.7 eq)
was added dropwise over a period of 20 minutes, and the reaction
was stirred for another 60 minutes.
Ethyl-1-(2-morpholinoacetyl)piperidine-4-carboxylate (Intermediate
51, 0.5 g, 1.7 mmol, 1.0 eq) was added in one portion to the
reaction mixture and the temperature maintained at -78.degree. C.
for 1 hour, and then stirred at room temperature for 14 hours. The
reaction was quenched with saturated ammonium chloride solution,
and product was extracted with ethyl acetate (3.times.20 mL). The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain a crude product which
was washed with ethyl acetate and used for the next step.
3-(1-(2-morpholinoacetyl) piperidin-4-yl)-3-oxopropanenitrile
(Intermediate 52, 0.294 g, yield: 60%) m/z 280.44 [M+H].sup.+ 1H
NMR (400 MHz, DMSO) .delta. 4.39-4.25 (m, 1H), 4.07-3.97 (m, 2H),
3.60-3.52 (m, 4H), 3.20-3.12 (m, 1H), 3.02 (d, J=13.4 Hz, 2H),
2.91-2.83 (m, 1H), 2.37 (s, 4H), 1.99 (s, 2H), 1.51 (d, J=15.6 Hz,
1H), 1.45-1.36 (m, 1H), 1.17 (t, J=7.1 Hz, 2H) ppm.
Example 166--Preparation of Compound 114
[0597] The synthesis of Compound 114 followed the procedure of
General Procedure 3 following:
##STR00179##
[0598] To a solution of
3-(1-(2-morpholinoacetyl)piperidin-4-yl)-3-oxopropanenitrile
(Intermediate 52, 0.29 g, 1 mmol, 1.0 eq) in isopropanol (9.0 mL)
and acetic acid (0.6 mL) was added hydrazine monohydrate (0.5 mL,
1.0 mmol, 1.0 eq) dropwise, and the reaction was stirred at
80.degree. C. for 12 hours. The reaction mixture was monitored by
TLC and LC-MS, and after completion the mixture was concentrated
under reduced pressure to obtain a crude residue. This was purified
by column chromatography using silica gel (100-200 mesh), eluting
with 8% methanol in dichloromethane to give
1-(4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl)-2-morpholinoethan-1-one
(Compound 114, 0.164 g, yield: 54%) m/z 294.03 [M+1].sup.+1H NMR
(400 MHz, DMSO) .delta. 5.17 (s, 1H), 4.34 (d, J=13.1 Hz, 1H),
4.10-4.01 (m, 1H), 3.56 (s, 4H), 3.30-3.22 (m, 1H), 3.05 (t, J=14.3
Hz, 2H), 2.73-2.54 (m, 2H), 2.51 (s, 2H), 2.36 (d, J=19.7 Hz, 3H),
1.89 (d, J=15.2 Hz, 2H), 1.84 (t, J=13.0 Hz, 2H), 1.50 (dd, J=22.8,
10.4 Hz, 1H), 1.37-1.19 (m, 1H) ppm.
Example 167--Preparation of Compound 115
[0599] The synthesis of Compound 115 followed the procedure of
General Procedure 4 following:
##STR00180##
[0600] To a cooled solution (0.degree. C.) of
1-(4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl)-2-morpholinoethan-1-one
(Compound 114, 1.5 g, 5.0 mmol, 1.0 eq) in methanol (30 mL) was
added glacial acetic acid (0.33 mL) and then
5-chlorothiophene-2-carbaldehyde (0.75 g, 5.0 mmol, 1.0 eq)
dropwise. The reaction mixture was stirred at room temperature for
16 hours. After completion, as monitored by TLC and LC-MS, the
mixture was cooled back to 0.degree. C. and then sodium
cyanoborohydride (0.63 g, 10.0 mmol, 2.0 eq) was added and stirred
at room temperature for 14 hours. The reaction mixture was slowly
concentrated under reduced pressure to obtain a yellow residue, and
then diluted with ethyl acetate (100 mL) and then washed with water
(25 mL). After drying with sodium sulfate, and filtration, the
organic phase was concentrated under reduced pressure to give a
residue which was purified by column chromatography (60-120 mesh),
eluting with 5% methanol in dichloromethane to give
1-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin--
1-yl)-2-morpholinoethan-1-one (Compound 115, 0.75 g, yield: 60%);
m/z 424.67 [M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 11.41 (s,
1H), 6.88 (dd, J=29.5, 3.7 Hz, 2H), 5.69 (t, J=6.1 Hz, 1H), 5.28
(s, 1H), 4.32 (dd, J=27.0, 9.8 Hz, 2H), 4.09 (dd, J=21.6, 9.2 Hz,
1H), 3.65-3.52 (m, 4H), 3.28-3.10 (m, 1H), 3.04 (d, J=13.2 Hz, 2H),
2.76 (d, J=11.6 Hz, 1H), 2.62 (dd, J=25.3, 12.3 Hz, 2H), 2.36 (d,
J=22.6 Hz, 4H), 1.87 (dd, J=23.9, 12.8 Hz, 2H), 1.51 (dd, J=21.4,
12.1 Hz, 1H), 1.40-1.24 (m, 1H) ppm.
Example 168--Preparation of Compound 116
[0601] The synthesis of Compound 116 followed the procedure of
General Procedure 5a following:
##STR00181##
[0602] To a solution of pivalic acid (0.10 g, 1.0 mmol, 1.1 eq.) in
THF (2.5 mL) was added DIEA (0.21 mL, 1.2 mmol, 1.5 eq), HOBt
(0.021 g, 0.16 mmol, 0.2 eq) and then EDCI.HCl (0.23 g, 1.2 mmol,
1.5 eq), and the mixture stirred at room temperature for 30
minutes. Then,
1-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin--
1-yl)-2-morpholinoethan-1-one (Compound 115, 0.35 g, 0.8 mmol, 1.0
eq) was added to the mixture and allowed to stir at room
temperature for 14 hours. After completion, the reaction mixture
was concentrated and poured in to ice-cold water (5.0 mL) and
extracted with ethyl acetate (3.times.10 mL). The combined organic
layers were concentrated under reduced pressure to give a residue
which was purified by column chromatography (100-200 mesh), eluting
with 50% ethyl acetate in hexane, to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholinoace-
tyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 116, 46 mg, yield: 11%) m/z 509.03 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 7.69 (t, J=6.2 Hz, 1H), 6.96 (t, J=3.6
Hz, 2H), 5.39 (s, 1H), 4.41 (d, J=6.4 Hz, 2H), 4.29 (d, J=14.3 Hz,
1H), 4.03 (d, J=12.2 Hz, 1H), 3.56 (s, 4H), 3.25 (d, J=13.2 Hz,
1H), 3.10 (d, J=11.6 Hz, 1H), 3.04 (d, J=13.3 Hz, 1H), 2.70 (d,
J=22.7 Hz, 3H), 2.39 (s, 3H), 1.88 (s, 2H), 1.61 (s, 2H), 1.40 (s,
9H) ppm.
Example 169--Preparation of Compound 117
[0603] The synthesis of Compound 117 followed the procedure of
General Procedure 5a following:
##STR00182##
[0604] To a solution of hydroxypivalic acid (0.1 g, 0.9 mmol, 1.0
eq) in THF (6.0 mL) was added DIEA (0.18 mL, 1.0 mmol, 1.5 eq),
HOBt (0.018 g, 0.14 mmol, 0.2 eq) and then EDCI.HCl (0.13 g, 1.0
mmol, 1.5 eq), and the mixture stirred at room temperature for 30
minutes. To the mixture was then added
1-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin--
1-yl)-2-morpholinoethan-1-one (Compound 115, 0.30 g, 0.7 mmol, 1.0
eq) and the reaction mixture was stirred at room temperature for 16
hours. After completion, the reaction mixture was concentrated and
poured into ice-cold water (5.0 mL) and extracted with ethyl
acetate (3.times.10 mL). The combined organic layers were
concentrated under reduced pressure to give a residue, which was
purified by preparative HPLC using 100% MeCN and water as mobile
phase, to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholinoacetyl)pipe-
ridin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
(Compound 117, 38.0 mg, yield: 10%) m/z 524.83 [M+H].sup.+; 1HNMR
(400 MHz, DMSO) .delta. 7.69 (t, J=6.0 Hz, 1H), 6.96 (q, J=3.7 Hz,
2H), 5.39 (s, 1H), 4.83 (t, J=5.4 Hz, 1H), 4.41 (d, J=6.1 Hz, 2H),
4.28 (d, J=12.3 Hz, 1H), 4.03 (d, J=13.0 Hz, 1H), 3.86 (d, J=5.5
Hz, 2H), 3.56 (s, 4H), 3.24 (d, J=13.3 Hz, 1H), 3.18-3.01 (m, 2H),
2.73 (dd, J=23.5, 12.4 Hz, 2H), 2.36 (d, J=22.9 Hz, 4H), 1.87 (s,
2H), 1.60 (d, J=12.5 Hz, 1H), 1.37 (d, J=11.6 Hz, 1H), 1.31 (s, 6H)
ppm.
Example 169a--Preparation of Compound 118
[0605] The synthesis of Compound 118 followed the procedure of
General Procedure 15 following:
##STR00183##
[0606] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.5 g, 1.7 mmol, 1.0 eq) in dichloromethane (10 mL) was added
triethylamine (TEA, 0.26 g, 2.6 mmol, 1.5 eq) and stirred for 10-15
minutes. Then, morpholine-4-carbonyl chloride (0.25 g, 1.7 mmol,
1.0 eq) was added and stirred at room temperature for 2 hours. The
reaction was monitored by TLC and LC-MS. After completion, solvent
was evaporated to give a residue which was purified by column
chromatography using silica gel (60-120 mesh) eluting with 5%
methanol in dichloromethane to give
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1--
yl)(morpholino)methanone (Compound 118, 0.24 g, yield: 34%); m/z
410.37 [M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 11.34 (s, 1H),
6.91 (d, J=3.7 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 5.66 (s, 1H), 5.29
(s, 1H), 4.28 (d, J=6.1 Hz, 2H), 3.62 (d, J=13.1 Hz, 2H), 3.57 (dd,
J=13.4, 9.1 Hz, 4H), 3.18-3.01 (m, 4H), 2.80 (t, J=11.7 Hz, 2H),
2.66 (s, 1H), 1.81 (d, J=11.0 Hz, 2H), 1.53-1.32 (m, 2H) ppm.
Example 170--Preparation of Compound 119
[0607] The synthesis of Compound 119 followed the procedure of
General Procedure 5c following:
##STR00184##
[0608] To a cooled solution (0.degree. C.) of
4-hydroxy-1-methylcyclohexane-1-carboxylic acid (0.15 g, 0.95 mmol,
1.3 eq) in THF (5.0 mL) was added TBTU (0.35 g, 1.1 mmol, 1.5 eq)
and DIEA (0.38 mL, 2.2 mmol, 3.0 eq) under nitrogen. The reaction
mixture was stirred for 30 minutes, and to it was added
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-hydroxy-1-methylcyclohe-
xane-1-carbonyl)-1H-pyrazol-3-yl)piperidin-1-yl)(morpholino)methanone
(Compound 118, 0.298 g, 0.73 mmol, 1.0 eq) and then the mixture was
stirred at room temperature for 14 hours. The reaction was
monitored by LC-MS, and after completion the mixture was
concentrated to give a residue, which was purified by preparative
HPLC using 0.1% formic acid in water-acetonitrile as mobile phase
to give
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-hydroxy-1-methyl
cyclohexane-1-carbonyl)-1H-pyrazol-3-yl)piperidin-1-yl)(morpholino)methan-
one (Compound 119, 0.053 g, yield: 10%); m/z 550.68 [M+1]+.sup.1H
NMR (400 MHz, DMSO) .delta. 7.68 (s, 1H), 6.95 (s, 2H), 5.39 (s,
1H), 4.40 (t, 1H), 4.40 (d, 2H), 3.52 (d, J=29.7 Hz, 6H), 3.11 (m,
4H), 2.84 (m, 2H), 2.58 (m, 1H), 2.53 (m, 3H), 1.98 (d, J=36.1 Hz,
2H), 1.84 (m, 3H), 1.54 (d, J=30.8 Hz, 2H), 1.42 (m, 6H) ppm.
Example 171--Preparation of Compound 120
[0609] The synthesis of Compound 120 followed the procedure of
General Procedure 25 following:
##STR00185##
[0610] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.1 g, 2.4 mmol, 1 eq) in acetonitrile (10 mL) was added
2-chloro-1-morpholinoethan-1-one (1.23 mL, 2.4 mmol, 1.0 eq) and
then potassium carbonate (0.102 g, 7.2 mmol, 3.0 eq.). The reaction
mixture was stirred at room temperature for 12 hours. The progress
of reaction was monitored by TLC. The reaction mixture was diluted
with water (10 mL), extracted with dichloromethane (2.times.10 mL),
and the combined organic phases were dried over anhydrous sodium
sulfate and concentrated to give crude product. This residue was
purified by Combi-flash chromatography, eluting with 6% methanol in
dichloromethane, to give
2-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-
-1-yl)-1 1-morpholinoethan-1-one (Compound 120, 0.60 g, yield: 57%)
m/z 424.42[M+1].sup.+, .sup.1H NMR (400 MHz, DMSO) .delta. 11.29
(s, 1H), 6.91 (d, J=3.7 Hz, 1H), 6.84 (d, J=3.6 Hz, 1H), 5.62 (s,
1H), 5.28 (s, 1H), 4.29 (d, J=6.2 Hz, 2H), 3.50-3.56 (m, 4H),
3.40-3.43 (m, 4H), 3.14 (s, 2H), 2.84 (d, J=11.3 Hz, 2H), 2.44 (s,
1H), 2.07 (t, J=10.7 Hz, 2H), 1.81 (d, J=11.3 Hz, 2H), 1.53 (dd,
J=21.3, 11.9 Hz, 2H) ppm;
Example 172--Preparation of Compound 121
[0611] The synthesis of Compound 121 followed the procedure of
General Procedure 5d following:
##STR00186##
[0612] To a cooled solution (0.degree. C.) of
2-(4-(5-(((5-chlorothiophen-2-yl) methyl) amino)-1H-pyrazol-3-yl)
piperidin-1-yl)-1-morpholinoethan-1-one (Compound 120, 0.15 g, 3.5
mmol, 1.0 eq) in dichloromethane (10 mL) was added triethylamine
(TEA, 0.11 g, 11 mmol, 3 eq) followed by pivaloyl chloride (0.042
g, 3.5 mmol, 1 eq). The reaction mixture was stirred at room
temperature for 14 hours. After completion, the mixture was
concentrated under reduced pressure to give a crude residue. This
was purified by column chromatography, eluting with 60% ethyl
acetate in hexane, to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholino-2-oxoethyl-
) piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 121, 0.15 g, yield: 83%) m/z 508.48[M+1].sup.+, .sup.1H
NMR (400 MHz, DMSO) .delta. 7.68 (d, J=6.3 Hz, 1H), 6.96 (d, J=3.8
Hz, 2H), 5.39 (s, 1H), 4.41 (d, J=5.9 Hz, 2H), 3.50-3.55 (m, 5H),
3.41 (d, J=11.7 Hz, 2H), 3.13 (s, 2H), 2.83 (d, J=10.6 Hz, 2H),
2.38 (d, J=34.4 Hz, 1H), 2.09 (t, J=10.9 Hz, 2H), 1.84 (d, J=11.3
Hz, 2H), 1.56 (d, J=9.2 Hz, 2H), 1.40 (s, 9H), 1.11 (s, 1H)
ppm.
Example 173--Preparation of Compound 122
[0613] The synthesis of Compound 122 followed the procedure of
General Procedure 5c following:
##STR00187##
[0614] To a solution of hydroxypivalic acid (92 mg, 0.78 mmol, 1.0
eq) in acetonitrile (10 mL) was added DIEA (301 mg, 2.3 mmol, 3.0
eq) and then TBTU (375 mg, 0.78 mmol, 1.0 eq), and then the mixture
stirred at room temperature for 30 minutes. To this was added
2-(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin--
1-yl)-1-morpholinoethan-1-one (Compound 120, 0.33 g, 0.78 mmol, 1.0
eq) and the reaction was stirred at room temperature for 12 hours.
After completion, the mixture was concentrated under reduced
pressure to give a crude product, which was purified by preparative
HPLC using 100% MeCN and 0.1% formic acid in water, to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-morpholino-2-oxoethyl-
)
piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
(Compound 122, 50 mg, yield: 12%) m/z 524.63 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 7.74 (d, J=6.1 Hz, 1H), 6.97 (s, 2H),
5.39 (s, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.42 (d, J=6.2 Hz, 2H),
4.30-4.06 (m, 1H), 3.87 (d, J=5.4 Hz, 2H), 3.66-3.54 (m, 4H), 3.50
(s, 2H), 3.38 (d, J=17.7 Hz, 2H), 3.03 (s, 2H), 2.68 (s, 2H),
2.38-1.74 (m, 6H), 1.32 (s, 6H) ppm.
Example 174--Preparation of Compound 123
[0615] The synthesis of Compound 123 followed the procedure of
General Procedure 22 following:
##STR00188##
[0616] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.1 g, 0.24 mmol, 1.0 eq) in dichloromethane (4 mL) was added
triethylamine (TEA, 0.1 g, 0.98 mmol, 4.0 eq). After stirring for
15 minutes, methanesulfonyl chloride (MsCl, 0.025 g, 0.22 mmol, 0.9
eq) was added. The reaction mixture was stirred for 4 hours at room
temperature and monitored by TLC and LC-MS. After completion of
reaction, the reaction mixture was poured into water (10 mL) and
extracted with ethyl acetate (2.times.10 mL). The combined organic
phases were washed with water, brine, and dried over sodium sulfate
to give a residue, which was purified by preparative HPLC using
water-acetonitrile as mobile phase to give
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)piperidin-4-y-
l)-1H-pyrazol-5-amine (Compound 123, 0.05 g, yield: 40%) m/z 375.31
[M+1]+ 1347 .sup.1H NMR (400 MHz, DMSO) .delta. 11.39 (s, 1H),
6.97-6.81 (m, 2H), 5.73 (d, J=32.5 Hz, 1H), 5.32 (s, 1H), 4.29 (d,
J=6.0 Hz, 2H), 3.57 (d, J=12.6 Hz, 2H), 2.87 (s, 3H), 2.78 (t,
J=11.0 Hz, 2H), 2.61 (s, 1H), 1.93 (d, J=13.0 Hz, 2H), 1.66-1.52
(m, 2H) ppm.
Example 175--Preparation of Compound 124
[0617] The synthesis of Compound 124 followed the procedure of
General Procedure 5a following:
##STR00189##
[0618] To a cooled solution (0.degree. C.) of pivalic acid (0.098
g, 0.96 mmol, 1.5 eq) in THF (8 mL) was EDCI.HCl (0.18 g, 0.96
mmol, 1.5 eq) and then triethylamine (TEA, 0.194 g, 1.92 mmol, 3.0
eq.). The reaction mixture was stirred for 30 minutes, then to it
was added HOBt (0.017 g, 0.13 mmol, 0.2 eq) and
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-
-pyrazol-5-amine (Compound 123, 0.24 g, 0.64 mmol, 1 eq). The
reaction mixture was stirred at room temperature overnight. After
completion (as monitored by LC-MS), the reaction mixture was poured
into water (15 mL) and extracted with ethyl acetate (2.times.15
mL). The combined organic phases were washed with water, brine, and
dried over sodium sulfate to give a crude compound.
[0619] This was purified by preparative HPLC using
water-acetonitrile as the mobile phase to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(methylsulfonyl)piperidi-
n-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 124,
0.035 g, yield: 11%) m/z 459.43[M+]+ .sup.1H NMR (400 MHz, DMSO)
.delta. 7.70 (t, J=6.2 Hz, 1H), 7.04-6.92 (m, 2H), 5.46 (d, J=13.5
Hz, 1H), 4.42 (d, J=6.1 Hz, 2H), 3.57 (d, J=11.8 Hz, 2H), 2.99-2.73
(m, 5H), 2.60 (dd, J=24.9, 13.6 Hz, 1H), 1.98 (d, J=10.9 Hz, 2H),
1.62 (td, J=15.1, 3.7 Hz, 2H), 1.51-1.35 (m, 9H) ppm.
Example 176--Preparation of Compound 125
[0620] The synthesis of Compound 125 followed the procedure of
General Procedure 5b following:
##STR00190##
[0621] To a solution of hydroxypivalic acid (0.119 g, 1.1 mmol, 1.5
eq.) in THF (8 mL) was added propylphosphonic anhydride (T3P in 50%
solution in ethyl acetate, 0.318 g, 1.0 mmol, 1.5 eq), DIEA (0.20
g, 2 mmol, 3 eq) and then
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(methylsulfonyl)piperidin-
-4-yl)-1H-pyrazol-5-amine (Compound 123, 0.25 g, 0.66 mmol, 1 eq).
The reaction mixture was stirred at room temperature overnight.
After reaction completion (as monitored by LC-MS), the mixture was
poured into water (20 mL) and extracted with ethyl acetate
(2.times.30 mL). The combined organic phases were washed with
water, brine, and dried over sodium sulfate to give a residue,
which was purified by preparative HPLC using water-acetonitrile as
mobile phase, to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(methylsulfonyl)piperidi-
n-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
Compound 125, 0.051 g, yield: 16%) m/z 475.43 [M+]+ .sup.1H NMR
(400 MHz, DMSO) .delta. 7.70 (d, J=6.0 Hz, 1H), 6.97 (t, J=4.0 Hz,
2H), 5.43 (s, 1H), 4.83 (s, 1H), 4.41 (d, J=6.4 Hz, 2H), 3.87 (d,
J=5.1 Hz, 2H), 3.56 (d, J=11.2 Hz, 2H), 3.12-2.74 (m, 5H), 2.64 (d,
J=27.0 Hz, 2H), 1.97 (d, J=12.0 Hz, 2H), 1.62 (d, J=9.3 Hz, 2H),
1.27 (d, J=28.3 Hz, 6H) ppm.
Example 177--Preparation of Compound 126
[0622] The synthesis of Compound 126 followed the procedure of
General Procedure 22 following:
##STR00191##
[0623] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.1 g, 0.24 mmol, 1.0 eq) in dichloromethane (4 mL) was added
triethylamine (TEA, 0.1 g, 1.0 mmol, 4.0 eq). After stirring for 15
minutes, benzenesulphonyl chloride (0.039 g, 0.22 mmol, 0.9 eq) was
added. The reaction mixture was stirred at room temperature
overnight. The reaction was monitored by TLC and LC-MS. After
completion of reaction, the reaction mixture was poured into water
(10 mL) and extracted with ethyl acetate (2.times.10 mL). The
combined organic phases were washed with water, brine, and dried
over sodium sulfate to give a crude compound. This was purified by
preparative HPLC using water-acetonitrile as mobile phase to give
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(phenylsulfonyl)piperidin-4-yl)-1H-
-pyrazol-5-amine (Compound 126, 0.045 g, yield: 31%) m/z 437.2
[M+1]+ .sup.1H NMR (400 MHz, DMSO) .delta. 11.33 (s, 1H), 8.30-7.26
(m, 5H), 7.08-6.63 (m, 2H), 5.68 (s, 1H), 5.24 (s, 1H), 4.26 (d,
J=6.2 Hz, 2H), 3.65 (d, J=11.1 Hz, 2H), 2.32 (t, J=11.2 Hz, 2H),
1.89 (d, J=11.4 Hz, 2H), 1.72-1.38 (m, 2H) ppm.
Example 178--Preparation of Compound 127
[0624] The synthesis of Compound 127 followed the procedure of
General Procedure 5a following:
##STR00192##
[0625] To a cooled solution (0.degree. C.) of pivalic acid (0.080
g, 0.78 mmol, 1.5 eq) in THF (8 mL) was added EDCI.HCl (0.15 g,
0.78 mmol, 1.5 eq) and triethylamine (TEA, 0.16 g, 1.6 mmol, 3.0
eq). The reaction mixture was stirred for 30 minutes, then HOBt
(0.014 g, 0.1 mmol, 0.2 eq) and
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(phenylsulfonyl)piperidin-4-yl-
)-1H-pyrazol-5-amine (Compound 126, 0.23 g. 0.5 mmol, 1 eq) were
added. The reaction mixture was stirred at room temperature
overnight. After completion (as monitored by LC-MS), the reaction
mixture was poured into water (15 mL), extracted with ethyl acetate
(2.times.20 mL), and the combined organic phase then washed with
water, brine, dried over sodium sulfate, filtered and evaporated
under reduced pressure to give a residue. This was purified by
preparative HPLC using water-acetonitrile as mobile phase to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(phenylsulfonyl)piperidi-
n-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 127,
0.056 g, yield: 20%) m/z 521.48 [M+]+ .sup.1H NMR (400 MHz, DMSO)
.delta. 7.83-7.51 (m, 6H), 6.95 (s, 2H), 5.34 (s, 1H), 4.38 (d,
J=6.2 Hz, 2H), 3.55 (d, J=12.0 Hz, 2H), 1.91 (d, J=10.6 Hz, 2H),
1.58 (dt, J=34.4, 17.4 Hz, 2H), 1.34 (s, 9H) ppm.
Example 179--Preparation of Compound 128
[0626] The synthesis of Compound 128 followed the procedure of
General Procedure 5b following:
##STR00193##
[0627] To a solution of hydroxypivalic acid (0.102 g, 0.85 mmol,
1.5 eq) in THF (6 mL) was added propylphosphonic anhydride (T3P in
50% solution in ethyl acetate, 0.273 g, 0.85 mmol, 1.5 eq), DIEA
(0.173 g, 1.7 mmol, 3 eq) followed by
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(phenylsulfonyl)piperidin-4-yl)-1H-
-pyrazol-5-amine (Compound 126, 0.27 g, 0.57 mmol, 1 eq). The
reaction mixture was stirred at room temperature overnight. After
completion (as monitored by LC-MS), the mixture was poured into
water (20 mL) and extracted with ethyl acetate (2.times.25 mL). The
combined organic phases were washed with water, brine, and dried
over sodium sulfate, then filtered and evaporated under reduced
pressure to give a residue. This was purified by preparative HPLC
using water-acetonitrile as mobile phase to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(phenylsulfonyl)-
piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
(Compound 128, 0.054 g, yield: 16%) m/z 537.54 [M+]+.sup.1H NMR
(400 MHz, DMSO) .delta. 7.70 (ddd, J=29.6, 11.6, 7.1 Hz, 5H), 6.95
(s, 2H), 5.33 (s, 1H), 4.79 (t, J=5.3 Hz, 1H), 4.38 (d, J=6.2 Hz,
2H), 3.81 (d, J=5.2 Hz, 2H), 3.59 (d, J=11.7 Hz, 2H), 1.91 (d,
J=10.8 Hz, 2H), 1.59 (dd, J=21.2, 10.6 Hz, 2H), 1.25 (s, 6H)
ppm.
Example 179a--Preparation of Compound 129
[0628] The synthesis of Compound 129 followed the procedure of
General Procedure 15 following:
##STR00194##
[0629] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.8 g, 2.7 mmol, 1.0 eq) in dichloromethane (10 mL) was added
triethylamine (TEA, 1.36 g, 13.5 mmol, 5.0 eq). After stirring for
10-15 minutes, to the mixture was added N,N-dimethylcarbamoyl
chloride (0.22 g, 2.7 mmol, 1.0 eq) and the mixture stirred at room
temperature for 2 hours. The reaction was monitored by TLC and
LC-MS. After completion, solvent was evaporated to give a residue,
which was purified by column chromatography using silica gel
(100-200 mesh), eluting with 5% methanol in dichloromethane as
mobile phase, to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N-dimethyl-
piperidine-1-carboxamide, (Compound 129, 0.3 g, yield: 30%); m/z
368.31[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta. 11.37 (s,
1H), 6.92 (d, J=3.7 Hz, 1H), 6.84 (d, J=3.6 Hz, 1H), 5.70 (s, 1H),
5.29 (s, 1H), 4.28 (s, 2H), 3.56 (d, J=13.1 Hz, 2H), 3.35 (s, 2H),
3.15-3.02 (m, 1H), 2.80-2.67 (m, 8H), 2.62 (d, J=11.8 Hz, 1H), 1.81
(d, J=11.6 Hz, 2H), 1.48 (dt, J=12.1, 8.9 Hz, 2H), 1.18 (t, J=7.3
Hz, 1H) ppm.
Example 180--Preparation of Compound 130
[0630] The synthesis of Compound 130 followed the procedure of
General Procedure 5a following:
##STR00195##
[0631] To a solution of pivalic acid (50 mg, 0.49 mmol, 1.0 eq) in
THF (10 mL) were added DIEA (100 mg, 0.6 mmol, 1.5 eq), HOBt (11
mg, 0.08 mmol, 0.2 eq) and finally EDCI.HCl (118 mg, 0.6 mmol, 1.5
eq). The solution was stirred at room temperature for 30 minutes.
Then was added
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N-dimethyl-
piperidine-1-carboxamide (Compound 129, 150 mg, 0.41 mmol, 1.0 eq)
and the solution was stirred at room temperature for another 12
hours. After completion, reaction mixture was concentrated and
poured into ice-cold water and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were concentrated
under reduced pressure to give a residue. This was purified by
preparative HPLC using 100% acetonitrile and 0.1% formic acid in
water to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-N-
,N-dimethylpiperidine-1-carboxamide (Compound 130, 52 mg, yield:
28%) m/z 454.38 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
7.68 (t, J=6.3 Hz, 1H), 6.96 (t, J=3.0 Hz, 2H), 5.41 (s, 1H), 4.41
(d, J=6.1 Hz, 2H), 3.54 (d, J=13.2 Hz, 2H), 2.79 (t, J=11.4 Hz,
2H), 2.73 (s, 6H), 2.62 (d, J=11.3 Hz, 1H), 1.85 (d, J=11.0 Hz,
2H), 1.52 (dd, J=21.3, 11.6 Hz, 2H), 1.41 (s, 9H) ppm.
Example 181--Preparation of Compound 131
[0632] The synthesis of Compound 131 followed the procedure of
General Procedure 5a following:
##STR00196##
[0633] To a solution of hydroxypivalic acid (154 mg, 1.3 mmol, 1.0
eq) in THF (10 mL) was added DIEA (280 mg, 1.6 mmol, 1.5 eq), HOBt
(29 mg, 0.22 mmol, 0.2 eq) and finally EDCI.HCl (315 mg, 1.6 mmol,
1.5 eq). After stirring at room temperature for 30 minutes,
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N-dimethyl-
piperidine-1-carboxamide (Compound 129, 400 mg, 1.1 mmol, 1.0 eq)
was added and the reaction mixture was stirred at room temperature
for another 12 hours. After completion, the reaction mixture was
concentrated under reduced pressure, poured into ice-cold water and
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were concentrated under reduced pressure to give a residue,
which was purified by preparative HPLC using 100% acetonitrile and
0.1% formic acid in water to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dime-
thylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-carboxamide
(Compound 131, 56 mg, yield: 11%) m/z 468.63 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 7.68 (t, J=6.2 Hz, 1H), 6.97 (q, J=3.8
Hz, 2H), 5.40 (s, 1H), 4.83 (t, J=5.3 Hz, 1H), 4.41 (d, J=6.1 Hz,
2H), 3.87 (d, J=5.2 Hz, 2H), 3.55 (d, J=13.0 Hz, 2H), 2.80 (t,
J=11.4 Hz, 2H), 2.73 (s, 6H), 2.63 (t, J=11.3 Hz, 1H), 1.85 (d,
J=11.3 Hz, 2H), 1.51 (dt, J=15.0, 7.7 Hz, 2H), 1.31 (s, 6H)
ppm.
Example 182--Preparation of Compound 132
[0634] The synthesis of Compound 132 followed the procedure of
General Procedure 15 following:
##STR00197##
[0635] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(100 mg, 2.7 mmol, 1.0 eq) in dichloromethane (10 mL) was added
triethylamine (TEA, 200 mg, 1.6 mmol, 6.0 eq). After for 10-15
minutes, N,N-dimethylcarbamic chloride (87 mg, 0.82 mmol, 3.0 eq)
was added and the mixture stirred at room temperature for 16 hours.
The reaction was monitored by TLC and LC-MS. After completion,
solvent was evaporated to give a residue which was purified by
column chromatography using silica gel (60-120 mesh), eluting with
5% methanol in dichloromethane to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(dimethylcarbamoyl)-1H-pyra-
zol-3-yl)-N,N-dimethylpiperidine-1-carboxamide (Compound 132, 0.65
g, yield: 41%); m/z 439.57 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO)
.delta. 7.00-6.91 (m, 2H), 6.75 (t, J=6.0 Hz, 1H), 5.40 (s, 1H),
4.36 (d, J=6.0 Hz, 2H), 3.54 (d, J=13.2 Hz, 2H), 2.98 (d, J=66.8
Hz, 6H), 2.78 (d, J=12.1 Hz, 2H), 2.72 (s, 6H), 2.64-2.53 (m, 1H),
1.80 (d, J=10.9 Hz, 2H), 1.59-1.40 (m, 2H) ppm.
Example 182a--Preparation of Intermediate 53
[0636] The synthesis of Intermediate 53 followed the procedure of
General Procedure 26 following:
##STR00198##
[0637] To a cooled solution (0.degree. C.) of ethyl
piperidine-4-carboxylate (0.93 g, 5.9 mmol, 3.0 eq) in
1,2-dichloroethane (50 mL) was added acetic acid (0.12 g, 2 mmol,
1.0 eq) and tetrahydro-4H-pyran-4-one (0.2 g, 2 mmol, 1 eq). After
stirring for 1 hour at room temperature, sodium
triacetoxyborohydride (NaBH(OAc).sub.3, 0.63 g, 3 mmol, 1.5 eq.)
was added and the mixture stirred at room temperature for another
12 hours. The progress of reaction was monitored by TLC. The
reaction mixture was added to water (20 mL), extracted with
dichloromethane (3.times.30 mL), the combined organic layers were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude product was purified by column
chromatography (100-200 mesh) eluting with 3% methanol in
dichloromethane to give ethyl
1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate (Intermediate
53, 0.13 g, yield: 42%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
4.15 (q, J=7.1 Hz, 2H), 4.05 (dd, J=11.3, 4.3 Hz, 2H), 3.45-3.32
(m, 2H), 3.08-2.96 (m, 2H), 2.68 (s, 1H), 2.41 (dd, J=12.2, 7.1 Hz,
3H), 2.06 (d, J=11.2 Hz, 2H), 1.95-1.80 (m, 4H), 1.67 (ddd, J=24.4,
12.2, 4.4 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H) ppm.
Example 183--Preparation of Intermediate 54
[0638] The synthesis of Intermediate 54 followed the procedure of
General Procedure 2 following:
##STR00199##
[0639] To a cooled solution (-78.degree. C.) of acetonitrile (0.97
g, 24 mmol, 1.5 eq) in THF (50 mL) was added n-BuLi (2.5M in
n-hexane, 9.5 mL, 2.4 mmol, 1.5 eq) dropwise over a period of 20
minutes. After stirring for 60 minutes at -78.degree. C., ethyl
1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate (Intermediate
53, 3.8 g, 15.7 mmol, 1.0 eq) was added in one portion. The mixture
was then warmed to room temperature over 3 hours. The reaction was
quenched with saturated ammonium chloride solution and product was
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain a crude product. This
was washed with ethyl acetate to yield
3-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)propanenitrile
(Intermediate 54, 1.5 g, yield: 40%) and used `as is` for the next
step; m/z 237.04 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
4.16 (s, 2H), 3.88 (d, J=11.0 Hz, 2H), 3.25 (t, J=11.0 Hz, 2H),
2.91 (d, J=11.4 Hz, 2H), 2.45 (s, 1H), 2.14 (d, J=10.7 Hz, 2H),
1.81 (d, J=11.9 Hz, 3H), 1.65 (d, J=12.0 Hz, 2H), 1.49-1.33 (m, 4H)
ppm.
Example 184--Preparation of Compound 132
[0640] The synthesis of Compound 132 followed the procedure of
General Procedure 3 following:
##STR00200##
[0641] To a solution of
3-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)propanenitrile
(Intermediate 54, 1.3 g, 5.7 mmol, 1.0 eq) in isopropanol (15 mL)
and acetic acid (0.34 g, 5.7 mmol, 1.0 eq) was added hydrazine
monohydrate (0.31 g, 6.2 mmol, 1.1 eq) dropwise. The reaction
mixture was stirred at 80.degree. C. for 12 hours. The reaction
mixture was monitored by TLC and LC-MS, and after completion the
reaction mixture was concentrated to obtain a crude product. This
was purified by column chromatography using silica gel (60-120
mesh), eluting with 10% methanol in dichloromethane to give
3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-pyrazol-5-amine
(Compound 132, 1.3 g, yield: 95%) m/z 251.14 [M+1].sup.+1H NMR (400
MHz, DMSO) .delta. 8.95 (s, 1H), 5.18 (s, 1H), 3.88 (dd, J=10.8,
3.6 Hz, 2H), 3.26 (t, J=11.1 Hz, 2H), 3.17 (s, 2H), 2.90 (d, J=11.4
Hz, 2H), 2.40 (dd, J=21.3, 11.5 Hz, 2H), 2.15 (t, J=10.6 Hz, 2H),
1.80 (d, J=12.4 Hz, 2H), 1.71-1.60 (m, 2H), 1.57-1.33 (m, 4H)
ppm.
Example 185--Preparation of Compound 133
[0642] The synthesis of Compound 133 followed the procedure of
General Procedure 4 following:
##STR00201##
[0643] To a cooled solution (0.degree. C.) of
3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-pyrazol-5-amine
(Compound 132, 1.7 g, 6.8 mmol, 1.0 eq) in anhydrous methanol (30
mL) was added glacial acetic acid (0.41 g, 6.8 mmol, 1.0 eq) and
then 5-chlorothiophene-2-carbaldehyde (1.19 g, 8.2 mmol, 1.2 eq)
dropwise. The reaction mixture was slowly brought to room
temperature and then stirred for 1 hour. After completion, as
monitored by TLC and LC-MS, the mixture was cooled back to
0.degree. C. add to it was added sodium cyanoborohydride (2.16 g,
10 mmol, 1.5 eq). The mixture was stirred at room temperature for 4
hours. The reaction monitored by TLC. The reaction mixture was
slowly concentrated under reduced pressure to obtain a yellow
residue, which was diluted with ethyl acetate (100 mL) and washed
with water (3.times.25 mL). The organic layer was dried with sodium
sulfate, filtered and concentrated under reduced pressure to give a
residue, which was purified by column chromatography (silica gel,
60-120 mesh) eluting with 5% methanol in dichloromethane to give
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(tetrahydro-2H-pyran-4-yl)piperidi-
n-4-yl)-1H-pyrazol-5-amine (Compound 133, 0.5 g, yield: 19%); m/z
381.36[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta. 11.33 (s,
1H), 6.99-6.90 (m, 1H), 6.84 (d, J=3.5 Hz, 1H), 5.66 (s, 1H), 5.28
(s, 1H), 4.28 (d, J=6.2 Hz, 2H), 3.90 (d, J=7.4 Hz, 2H), 3.33-3.22
(m, 4H), 2.98 (s, 2H), 2.31-2.08 (m, 2H), 2.02-1.64 (m, 4H), 1.49
(s, 4H) ppm.
Example 186--Preparation of Compound 134
[0644] The synthesis of Compound 134 followed the procedure of
General Procedure 5a following:
##STR00202##
[0645] To a solution of pivalic acid (44.7 mg, 0.44 mmol, 1.2 eq)
in THF (3 mL) was added DIEA (0.09 mL, 0.55 mmol, 1.5 eq), HOBt
(9.8 mg, 0.07 mmol, 0.2 eq.) and then EDCI.HCl (106 mg, 0.55 mmol,
1.5 eq). After stirring for 30 minutes,
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1--
yl)(morpholino)methanone (Compound 118, 150 mg, 0.37 mmol, 1.0 eq)
was added and the reaction mixture was allowed to stir at room
temperature for another 16 hours. After completion, the mixture was
concentrated and poured into ice-cold water and extracted with
dichloromethane (3.times.50 mL). The combined organic layers were
dried with sodium sulfate, dried and evaporated under reduced
pressure. The residue was purified by preparative HPLC using 100%
acetonitrile and 0.1% formic acid in water to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(morpholine-4-carbo-
nyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 134, 53.3 mg, yield-29%) m/z 494.48 [M+1].sup.+; 1H NMR
(400 MHz, DMSO) .delta. 7.69 (d, J=6.1 Hz, 1H), 6.97 (s, 2H), 5.41
(s, 1H), 4.41 (d, J=6.1 Hz, 2H), 3.61 (d, J=13.2 Hz, 2H), 3.60-3.53
(m, 4H), 3.12 (d, J=4.6 Hz, 4H), 2.86 (t, J=11.7 Hz, 2H), 2.66 (d,
J=11.7 Hz, 1H), 1.85 (d, J=10.9 Hz, 2H), 1.57-1.44 (m, 2H), 1.40
(s, 9H) ppm.
Example 187--Preparation of Compound 135
[0646] The synthesis of Compound 135 followed the procedure of
General Procedure 5a following:
##STR00203##
[0647] To a solution of hydroxypivalic acid (138 mg, 1.2 mmol, 1.2
eq) in THF (8 mL) was added DIEA (0.25 mL, 1.46 mmol, 1.5 eq), HOBt
(26 mg. 0.2 mmol, 0.2 eq) and then EDCI.HCl (282 mg, 1.5 mmol, 1.5
eq). After stirring for another 30 minutes,
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidin-1--
yl)(morpholino)methanone (Compound 118, 400 mg, 0.98 mmol, 1.0 eq)
was added and the mixture allowed to stir at room temperature for
16 hours. After completion, the reaction mixture was concentrated,
poured into ice-cold water and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were concentrated
under reduced pressure to give a residue which was purified by
preparative HPLC using 100% acetonitrile and 100% water to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(morpholine-4-carbonyl)p-
iperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
(Compound 135, 58 mg, yield: 12%) m/z 510.53 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 7.68 (t, J=6.2 Hz, 1H), 6.96 (d, J=3.8
Hz, 2H), 5.40 (s, 1H), 4.83 (t, J=5.4 Hz, 1H), 4.41 (d, J=6.1 Hz,
2H), 3.87 (d, J=5.3 Hz, 2H), 3.61 (d, J=13.5 Hz, 2H), 3.59-3.53 (m,
4H), 3.15-3.08 (m, 4H), 2.86 (t, J=11.6 Hz, 2H), 2.66 (d, J=11.5
Hz, 1H), 1.85 (d, J=10.6 Hz, 2H), 1.50 (dd, J=21.0, 11.8 Hz, 2H),
1.31 (s, 6H) ppm.
Example 188--Preparation of Compound 136
[0648] The synthesis of Compound 136 followed the procedure of
General Procedure 15 following:
##STR00204##
[0649] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.1 g, 0.24 mmol, 1.0 eq) in dichloromethane (2 mL) was added
triethylamine (TEA, 0.2 mL, 1.46 mmol, 6.0 eq). After stirring for
15 minutes, morpholine-4-carbonyl chloride (0.1 g, 0.73 mmol, 3.0
eq) was added and the reaction stirred at room temperature for 16
hours. The reaction was monitored by TLC and LC-MS. After
completion, solvent was evaporated to give a residue which was
purified by preparative HPLC using 100% acetonitrile and 100% water
to give
(4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(morpholine-4-carbonyl)-1H-
-pyrazol-3-yl)piperidin-1-yl)(morpholino)methanone (Compound 136,
15 mg, yield: 2%) m/z 523.63 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO) .delta. 6.99-6.93 (m, 2H), 6.85 (t, J=6.2 Hz, 1H), 5.42 (s,
1H), 4.37 (d, J=6.1 Hz, 2H), 3.74-3.54 (m, 14H), 3.15-3.07 (m, 4H),
2.82 (t, J=11.5 Hz, 2H), 2.60 (t, J=11.5 Hz, 1H), 1.80 (d, J=10.9
Hz, 2H), 1.48 (dd, J=21.0, 11.9 Hz, 2H) ppm.
Example 189--Preparation of Compound 137
[0650] The synthesis of Compound 137 followed the procedure of
General Procedure 15 following:
##STR00205##
[0651] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(0.7 g, 2.4 mmol, 1.0 eq) in dichloromethane (10 mL) was added
triethylamine (TEA, 1.2 g. 12 mmol, 5 eq), followed by
dimethylsulfamoyl chloride (0.34 g, 2.3 mmol, 1.0 eq). The mixture
was stirred at room temperature for 3 hours. The progress of
reaction was monitored by TLC. The reaction mixture was added to
cold water (10 mL), extracted with dichloromethane (3.times.25 mL),
and the combined organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated to give a crude product. This
was purified by column chromatography on silica gel (60-120 mesh
size) with 45% ethyl acetate in n-hexane to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N-dimethyl-
piperidine-1-sulfonamide (Compound 137, 0.62 g, yield: 65%) m/z
404.30[M+H]+ 1H NMR (DMSO-d.sub.6, 400 MHz, 12092) .delta.: 11.36
(s, 1H), 7.03-6.76 (m, 2H), 5.65 (s, 1H), 5.31 (s, 1H), 4.29 (d,
J=6.3 Hz, 2H), 3.58 (d, J=12.5 Hz, 2H), 2.90 (td, J=12.3, 2.3 Hz,
2H), 2.76 (d, J=5.7 Hz, 6H), 2.64 (s, 1H), 1.89 (d, J=11.2 Hz, 2H),
1.54 (qd, J=12.6, 4.0 Hz, 2H) ppm.
Example 189--Preparation of Compound 138
[0652] The synthesis of Compound 138 followed the procedure of
General Procedure 5a following:
##STR00206##
[0653] To a cooled solution (0.degree. C.) of pivalic acid (0.085
g, 0.85 mmol, 1.5 eq) in acetonitrile (12 mL) was added EDCI.HCl
(0.16 g, 0.85 mmol, 1.5 eq.), HOBt (0.022 g, 0.17 mmol, 0.3 eq) and
DIEA (0.23 mL, 1.7 mmol, 3.0 eq). After stirring for 30 minutes,
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-N,N-dimethyl-
piperidine-1-sulfonamide (Compound 137, 0.27 g, 0.56 mmol, 1.0 eq),
was added and the mixture stirred at room temperature for 16 hours.
The reaction was monitored by LC-MS, and after completion of
reaction the reaction mixture was added to water (10 mL), extracted
with ethyl acetate (3.times.20 mL), dried with sodium sulfate,
filtered and concentrated to give crude product. The residue was
purified by Combi-flash chromatography, eluting with 30% ethyl
acetate in n-hexane to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-N-
,N-dimethylpiperidine-1-sulfonamide (Compound 138, 0.09 g, yield:
28%) m/z 488.53 [M+H]+ 1H NMR (DMSO-d.sub.6, 400 MHz, 12445)
.delta.: 7.69 (t, J=6.2 Hz, 1H), 6.97 (q, J=3.7 Hz, 2H), 5.42 (s,
1H), 4.42 (d, J=6.1 Hz, 2H), 3.57 (d, J=12.3 Hz, 2H), 2.95 (t,
J=10.9 Hz, 2H), 2.75 (s, 6H), 2.69-2.59 (m, 1H), 2.01-1.89 (m, 2H),
1.58 (td, J=15.2, 3.7 Hz, 2H), 1.41 (s, 9H) ppm.
Example 190--Preparation of Compound 139
[0654] The synthesis of Compound 139 followed the procedure of
General Procedure 5c following:
##STR00207##
[0655] To a cooled solution (0.degree. C.) of
3-hydroxy-2,2-dimethylpropanoic acid (Compound 137, 0.15 g, 1.3
mmol, 1.5 eq) in acetonitrile (12 mL) was added
N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate (TBTU, 0.42 g, 1.3 mmol, 1.5 eq) and then
(diisopropyl)ethylamine (DIEA, 0.24 mL, 2.6 mmol, 3.0 eq). After
stirring for 30 minutes, to the mixture was added
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-di-
methylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-sulfonamide
(Compound 137, 0.35 g, 0.9 mmol, 1.0 eq), and the mixture stirred
at room temperature for 12 hours. The reaction progress was
monitored by TLC. After completion, the mixture was poured into
water (10 mL) and extracted with ethyl acetate (3.times.20 mL). The
combined organic phases were dried over sodium sulfate, filtered
and evaporated to a residue. The crude compound was purified by
preparative HPLC eluting with water and acetonitrile as mobile
phase on a Sunfire C18, 5 micron column. The purified fractions
were lyophilized to give
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)-N,N-dimethylpiperidine-1-sulfonamide
(Compound 139, 0.05 g, yield: 11%) m/z 504.48 [M+H]+ 1H NMR
(DMSO-d.sub.6, 400 MHz, 13050) .delta.: 7.69 (t, J=6.1 Hz, 1H),
6.97 (d, J=2.3 Hz, 2H), 5.41 (s, 1H), 4.84 (t, J=5.3 Hz, 1H), 4.41
(d, J=6.0 Hz, 2H), 3.87 (d, J=5.3 Hz, 2H), 3.57 (d, J=12.1 Hz, 2H),
2.95 (t, J=10.9 Hz, 2H), 2.75 (s, 6H), 2.62 (dd, J=22.7, 11.4 Hz,
1H), 1.92 (d, J=11.5 Hz, 2H), 1.57 (dd, J=21.0, 11.1 Hz, 2H), 1.31
(s, 6H) ppm.
Example 191--Preparation of Compound 140
[0656] The synthesis of Compound 140 followed the procedure of
General Procedure 25 following:
##STR00208##
[0657] To a solution of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(1.0 g, 2.5 mmol, 1.0 eq) in acetonitrile (15 mL) was added
potassium carbonate (2.0 g, 14.7 mmol, 6.0 eq). After stirring the
reaction mixture at room temperature for 30 minutes,
2-cyclopropoxyethyl trifluoromethanesulfonate (0.576 g, 2.5 mmol, 1
eq) was added and the reaction mixture was allowed to stir at room
temperature for 16 hours. After completion (as monitored by LC-MS),
the reaction mixture was concentrated to give a crude product which
was purified by preparative HPLC using water-acetonitrile as mobile
phase to give
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-cyclopropoxyethyl)piperidin-4-y-
l)-1H-pyrazol-5-amine (Compound 140, 0.61 g, yield: 65%) m/z
381.56[M+1]+ .sup.1HNMR (400 MHz, DMSO) .delta. 11.65 (s, 1H),
6.97-6.81 (m, 2H), 5.80 (s, 1H), 5.35 (d, J=39.2 Hz, 1H), 4.29 (d,
J=6.0 Hz, 2H), 3.74 (s, 2H), 3.41-3.31 (m, 5H), 3.23 (s, 2H), 2.98
(s, 1H), 2.08-2.01 (m, 2H), 1.78 (s, 2H), 0.60-0.42 (m, 4H)
ppm.
Example 192--Preparation of Compound 141
[0658] The synthesis of Compound 141 followed the procedure of
General Procedure 5a following:
##STR00209##
[0659] To a cooled solution (0.degree. C.) of pivalic acid (0.2 g,
0.64 mmol, 1.2 eq) in THF (6 mL) was added EDCI.HCl (0.15 g, 0.78
mmol, 1.5 eq) and triethylamine (TEA, 0.16 g, 1.6 mmol, 3.0 eq).
After stirring for 30 minutes, HOBt (0.014 g, 0.1 mmol, 0.2 eq) and
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-cyclopropoxyethyl)
piperidin-4-yl)-1H-pyrazol-5-amine (Compound 140, 0.2 g, 0.52 mmol,
1 eq) were added. The reaction mixture was stirred at room
temperature for 16 hours. After completion (as monitored by LC-MS),
the reaction mixture was poured to water (15 mL) and extracted with
ethyl acetate (2.times.15 mL). The combined organic phases were
washed with water, brine, dried over sodium sulfate, filtered and
evaporated. The residue was purified by preparative HPLC using
water-acetonitrile as mobile phase to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-cyclopropoxyethyl)pip-
eridin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethyl propan-1-one (Compound
141, 0.06 g, yield: 25%) m/z 465.02 [M+H]+ .sup.1H NMR (400 MHz,
DMSO) .delta. 7.64 (t, J=6.1 Hz, 1H), 6.96 (q, J=3.8 Hz, 2H), 5.37
(s, 1H), 4.40 (d, J=6.2 Hz, 2H), 3.52 (t, J=6.0 Hz, 2H), 3.26 (ddd,
J=9.1, 5.9, 3.2 Hz, 1H), 2.85 (d, J=11.6 Hz, 2H), 2.45-2.31 (m,
3H), 2.13-1.95 (m, 3H), 1.79 (d, J=10.6 Hz, 2H), 1.56 (dd, J=21.1,
11.8 Hz, 2H), 1.39 (s, 9H), 0.46-0.33 (m, 4H) ppm.
Example 193--Preparation of Compound 142
[0660] The synthesis of Compound 142 followed the procedure of
General Procedure 5b following:
##STR00210##
[0661] To a solution of hydroxypivalic acid (0.093 g, 0.78 mmol,
1.5 eq) in THF (6 mL) were added propylphosphonic anhydride (T3P in
50% solution in ethyl acetate, 0.25 g, 0.8 mmol, 1.5 eq), DIEA (0.2
g, 1.6 mmol, 3 eq), followed by
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2-cyclopropoxyethyl)piperidin-4-y-
l)-1H-pyrazol-5-amine (Compound 140, 0.2 g, 0.5 mmol, 1.0 eq). The
reaction mixture was stirred at room temperature for 16 hours.
After completion (as monitored by LC-MS), the reaction mixture was
poured into water (10 mL) and extracted with ethyl acetate
(2.times.25 mL). The combined organic phases were washed with
water, brine, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by preparative
HPLC using water-acetonitrile as mobile phase to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2-cyclopropoxyethy-
l)
piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one
(Compound 142, 0.032 g, yield: 12%) m/z 481.1 [M+H]+ .sup.1H NMR
(400 MHz, DMSO) .delta. 7.65 (d, J=6.2 Hz, 1H), 6.96 (t, J=3.4 Hz,
2H), 5.38 (s, 1H), 4.82 (t, J=5.2 Hz, 1H), 4.40 (d, J=6.2 Hz, 2H),
3.86 (d, J=5.3 Hz, 2H), 3.52 (t, J=5.9 Hz, 2H), 3.26 (d, J=3.2 Hz,
1H), 2.87 (d, J=11.1 Hz, 2H), 2.40 (dd, J=28.5, 14.2 Hz, 3H), 2.04
(dd, J=22.2, 11.0 Hz, 3H), 1.78 (s, 2H), 1.56 (d, J=9.6 Hz, 2H),
1.30 (s, 6H), 0.51-0.28 (m, 4H) ppm.
Example 194--Preparation of Compound 143
[0662] The synthesis of Compound 143 followed the procedure of
General Procedure 25 following:
##STR00211##
[0663] To a solution of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
(1.0 g, 3.4 mmol, 1.0 eq) in acetonitrile (15 mL) was added
potassium carbonate (K.sub.2CO.sub.3, 3.26 g, 23.7 mmol, 7 eq),
followed by 2,2-difluoro-2-(pyridin-2-yl)ethyl
trifluoromethanesulfonate (1.1 g, 3.7 mmol, 1.1 eq). The mixture
was stirred at 80.degree. C. for 12 hours. The progress of reaction
was monitored by LC-MS. The reaction mixture was diluted with water
(50 mL), extracted with dichloromethane (3.times.80 mL), and the
combined organic phases were dried over anhydrous sodium sulfate,
filtered and concentrated to give crude product. This was purified
by column chromatography, eluting with 2% methanol in
dichloromethane to give
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2,2-difluoro-2-(pyridin-2-yl)ethy-
l)piperidin-4-yl)-1H-pyrazol-5-amine (Compound 143, 0.4 g,
27%).sup.1H NMR (400 MHz, DMSO) .delta. 11.26 (s, 1H), 8.68 (d,
J=3.9 Hz, 1H), 7.98 (t, J=7.7 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H),
7.59-7.49 (m, 1H), 6.90 (d, J=3.7 Hz, 1H), 6.82 (d, J=3.6 Hz, 1H),
5.62 (s, 1H), 5.23 (s, 1H), 4.26 (d, J=6.1 Hz, 2H), 3.21 (t, J=14.8
Hz, 2H), 2.81 (d, J=11.7 Hz, 2H), 2.32 (dd, J=29.7, 18.6 Hz, 3H),
1.78-1.62 (m, 2H), 1.39 (dd, J=21.2, 12.6 Hz, 2H) ppm.
Example 195--Preparation of Compound 144
[0664] The synthesis of Compound 144 followed the procedure of
General Procedure 5a following:
##STR00212##
[0665] To a cooled solution (0.degree. C.) of pivalic acid (77 mg,
0.76 mmol, 1.1 eq) in THF (10 mL) was added DIPEA (221 mg, 1.7
mmol, 2.5 eq), HOBt (46 mg, 0.34 mmol, 0.5 eq) and then EDCI.HCl
(197 mg, 1.0 mmol, 1.5 eq). After stirring at 0.degree. C. for 30
minutes, to the mixture was added
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2,2-difluoro-2-(pyridin-2-y-
l)ethyl)piperidin-4-yl)-1H-pyrazol-5-amine (Compound 143, 300 mg,
0.7 mmol, 1.0 eq), and the mixture allowed to stir at room
temperature for 12 hours. After completion, the reaction mixture
was concentrated and poured into ice-cold water and extracted with
ethyl acetate (3.times.50 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated on reduced
pressure. The residue was purified by preparative HPLC using
acetonitrile/water to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2,2-difluoro-2-(pyridin-
-2-yl)ethyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one
(Compound 144, 74.5 mg, yield: 17%) m/z 522.10 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 8.68 (d, J=4.8 Hz, 1H), 7.98 (t, J=7.8
Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.64 (t, J=6.4 Hz, 1H), 7.56-7.49
(m, 1H), 6.95 (d, J=3.8 Hz, 2H), 5.36 (s, 1H), 4.39 (d, J=6.2 Hz,
2H), 3.21 (t, J=14.8 Hz, 2H), 2.81 (d, J=11.5 Hz, 2H), 2.33 (t,
J=11.5 Hz, 4H), 1.72 (d, J=12.2 Hz, 2H), 1.51-1.40 (m, 2H), 1.38
(s, 9H) ppm.
Example 196--Preparation of Compound 145
[0666] The synthesis of Compound 145 followed the procedure of
General Procedure 5a following:
##STR00213##
[0667] To a cooled solution (0.degree. C.) of hydroxypivalic acid
(89 mg, 0.76 mmol, 1.1 eq) in THF (10 mL) was added DIPEA (221 mg,
1.7 mmol, 2.5 eq), HOBt (46 mg, 0.34 mmol, 0.5 eq) and then
EDCI.HCl (197 mg, 1.0 mmol, 1.5 eq). After stirring at 0.degree. C.
for 30 minutes, to the mixture was added
N-((5-chlorothiophen-2-yl)methyl)-3-(1-(2,2-difluoro-2-(pyridin-
-2-yl)ethyl)piperidin-4-yl)-1H-pyrazol-5-amine (Compound 143, 300
mg, 0.68 mmol, 1.0 eq) and the mixture stirred at room temperature
for another 12 hours. After completion, the reaction mixture was
concentrated, poured into ice-cold water and extracted with ethyl
acetate (3.times.50 mL). The combined organic layers were
concentrated under reduced pressure. The residue was purified by
preparative HPLC using 100% acetonitrile and 100% water to give
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(1-(2,2-difluoro-2-(pyridin-
-2-yl)ethyl)piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan--
1-one (Compound 145, 76 mg, yield: 21%) m/z 540.63 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO) .delta. 8.68 (d, J=4.4 Hz, 1H), 7.97
(td, J=7.8, 1.7 Hz, 1H), 7.71 (s, 1H), 7.63 (d, J=6.3 Hz, 1H), 7.54
(dd, J=7.4, 4.8 Hz, 1H), 7.03-6.89 (m, 2H), 5.35 (s, 1H), 4.81 (t,
J=5.4 Hz, 1H), 4.39 (d, J=6.2 Hz, 2H), 3.84 (d, J=5.4 Hz, 2H), 3.21
(t, J=14.8 Hz, 2H), 2.82 (d, J=11.5 Hz, 2H), 2.34 (dd, J=23.2, 11.6
Hz, 4H), 1.72 (d, J=11.4 Hz, 2H), 1.50-1.35 (m, 2H), 1.29 (s, 6H)
ppm.
Example 197--Preparation of Compound 146
[0668] The synthesis of Compound 146 followed the procedure of
General Procedure 5 following:
##STR00214##
[0669] To a cooled (0.degree. C.) solution of cyclohexanecarboxylic
acid (181 mg, 1.51 mmol) in dichloromethane (10 mL) under nitrogen
was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 361 mg, 1.89 mmol), followed by
hydroxybenzotriazole (HOBt, 511 mg, 3.78 mmol). The reaction
mixture was stirred for 10 minutes, then to the mixture was added
diisopropylethylamine (DIEA, 0.64 mL, 3.78 mmol), followed by
tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(cyclohexanecarbonyl)-1H-py-
razol-3-yl)piperidine-1-carboxylate (Compound 146, 487 mg, yield:
60%) m/z 508.16 [M+1].sup.+; TLC System: 50% Ethyl acetate in
hexane. R.sub.f-0.7.
Example 198--Preparation of Compound 147
[0670] The synthesis of Compound 147 followed the procedure of
General Procedure 5 following:
##STR00215##
[0671] To a cooled (0.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(cyclohexanecarbonyl)-1H-py-
razol-3-yl)piperidine-1-carboxylate (200 mg, 0.39 mmol) in diethyl
ether (2 mL) was added a solution of hydrogen chloride (1M) in
diethyl ether (2 mL). The reaction mixture was stirred for 2 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-p-
yrazol-1-yl)(cyclohexyl)methanone hydrochloride (Compound 147, 100
mg, yield: 64%) as an off white solid. m/z 407.27
[(M-HCl)+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70
(br s, 1H), 8.35 (br s, 1H), 7.65-7.63 (m, 1H), 6.95 (s, 2H), 5.39
(s, 1H), 4.43-4.41 (m, 2H), 3.40-3.26 (m, 3H), 2.98-2.77 (m, 3H),
2.01-1.67 (m, 8H), 1.41-1.24 (n, 4H); TLC System: 10% Methanol in
dichloromethane. R.sub.f-0.15.
Example 199--Preparation of Compound 148
[0672] The synthesis of Compound 148 followed the procedure of
General Procedure 5 following:
##STR00216##
[0673] To a cooled (0.degree. C.) solution of
cyclopentanecarboxylic acid (172 mg, 1.51 mmol) in dichloromethane
(10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 361 mg, 1.89 mmol), followed by hydroxybenzotriazole
(HOBt, 511 mg, 3.78 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.64 mL, 3.78 mmol), followed by tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(cyclopentanecarbonyl)-1H-p-
yrazol-3-yl)piperidine-1-carboxylate (Compound 148, 323 mg, yield:
52%) m/z 494.16 [M+1].sup.+; TLC System: 50% Ethyl acetate in
hexane. R.sub.f-0.7.
Example 200--Preparation of Compound 149
[0674] The synthesis of Compound 149 followed the procedure of
General Procedure 5 following:
##STR00217##
[0675] To a cooled (0.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(cyclopentanecarbonyl)-1H-p-
yrazol-3-yl)piperidine-1-carboxylate (200 mg, 0.40 mmol) in diethyl
ether (2 mL) was added a solution of hydrogen chloride (1M) in
diethyl ether (2 mL). The reaction mixture was stirred for 2 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-p-
yrazol-1-yl)(cyclopentyl)methanone (Compound 149, 60 mg, yield:
38%) as an off white solid. m/z 393.25 [(M-HCl)+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70 (br s, 1H), 8.35 (br s,
1H), 7.65-7.63 (m, 1H), 6.95 (s, 2H), 5.39 (s, 1H), 4.43-4.41 (m,
2H), 3.40-3.26 (m, 3H), 2.98-2.77 (m, 3H), 2.01-1.67 (m, 8H),
1.41-1.24 (m, 4H); TLC System: 10% Methanol in dichloromethane.
R.sub.f-0.15.
Example 201--Preparation of Compound 150
[0676] The synthesis of Compound 150 followed the procedure of
General Procedure 5 following:
##STR00218##
[0677] To a cooled (0.degree. C.) solution of benzoic acid (184 mg,
1.51 mmol) in dichloromethane (10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 361 mg, 1.89 mmol), followed by hydroxybenzotriazole
(HOBt, 511 mg, 3.78 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.64 mL, 3.78 mmol), followed by tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(1-benzoyl-5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pip-
eridine-1-carboxylate (Compound 150, 487 mg, yield: 60%) m/z 502.16
[M+1].sup.+; TLC System: 50% Ethyl acetate in hexane.
R.sub.f-0.6.
Example 202--Preparation of Compound 151
[0678] The synthesis of Compound 151 followed the procedure of
General Procedure 5 following:
##STR00219##
[0679] To a cooled (0.degree. C.) solution of tert-butyl
4-(1-benzoyl-5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pip-
eridine-1-carboxylate (200 mg, 0.40 mmol) in ethyl acetate (3 mL)
was added a solution of hydrogen chloride (1M) in ethyl acetate (3
mL). The reaction mixture was stirred for 6 hr, and then evaporated
under reduced pressure, triturated with diethyl ether and acetone.
The residue was recrystallized in isopropyl alcohol to afford
product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-1-
-yl)(phenyl)methanone hydrochloride (Compound 151, 40 mg, yield:
25%) as an off white solid. m/z 401.26 [(M-HCl)+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.79 (br s, 1H), 8.48 (br s,
1H), 7.97-7.94 (m, 2H), 7.81-7.79 (m, 1H), 7.64-6.97 (s, 3H), 5.51
(s, 1H), 4.51-4.49 (m, 2H), 3.31-3.23 (m, 2H), 2.99-2.77 (m, 3H),
2.02-1.96 (m, 2H), 1.78-1.66 (m, 2H); TLC System: 10% Methanol in
dichloromethane. R.sub.f-0.15.
Example 203--Preparation of Compound 152
[0680] The synthesis of Compound 152 followed the procedure of
General Procedure 5 following:
##STR00220##
[0681] To a cooled (0.degree. C.) solution of
2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (273 mg, 1.51
mmol) in dichloromethane (10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 361 mg, 1.89 mmol), followed by hydroxybenzotriazole
(HOBt, 511 mg, 3.78 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.64 mL, 3.78 mmol), followed by tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,3-dihydrobenzo[b][1,4]di-
oxine-5-carbonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate
(Compound 152, 318 mg, yield: 45%) m/z 560.16 [M+1].sup.+; TLC
System: 50% Ethyl acetate in hexane. R.sub.f-0.6.
Example 204--Preparation of Compound 153
[0682] The synthesis of Compound 153 followed the procedure of
General Procedure 5 following:
##STR00221##
[0683] To a cooled (0.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,3-dihydrobenzo[b][1,4]di-
oxine-5-carbonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (250 mg,
0.45 mmol) in ethyl acetate (3 mL) was added a solution of hydrogen
chloride (1M) in ethyl acetate (3 mL). The reaction mixture was
stirred for 7 hr, and then evaporated under reduced pressure,
triturated with diethyl ether and acetone. The residue was
recrystallized in isopropyl alcohol to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-1-
-yl)(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone hydrochloride
(Compound 153, 150 mg, yield: 67%) as an off white solid. m/z
401.26 [(M-HCl)+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.79 (br s, 1H), 8.48 (br s, 1H), 7.97-7.94 (m, 2H),
7.81-7.79 (m, 1H), 7.04-6.97 (m, 5H), 5.51 (s, 1H), 4.51-4.49 (m,
2H), 3.31-3.23 (m, 2H), 2.99-2.77 (m, 3H), 2.02-1.96 (m, 2H),
1.78-1.66 (m, 2H); TLC System: 5% Methanol in dichloromethane.
R.sub.f-0.1.
Example 205--Preparation of Compound 154
[0684] The synthesis of Compound 154 followed the procedure of
General Procedure 5 following:
##STR00222##
[0685] To a cooled (0.degree. C.) solution of furan-3-carboxylic
acid (169 mg, 1.51 mmol) in dichloromethane (10 mL) under nitrogen
was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 361 mg, 1.89 mmol), followed by
hydroxybenzotriazole (HOBt, 511 mg, 3.78 mmol). The reaction
mixture was stirred for 10 minutes, then to the mixture was added
diisopropylethylamine (DIEA, 0.64 mL, 3.78 mmol), followed by
tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyraz-
ol-3-yl)piperidine-1-carboxylate (Compound 154, 235 mg, yield: 38%)
m/z 492.16 [M+1].sup.+; TLC System: 50% Ethyl acetate in hexane.
R.sub.f-0.6.
Example 206--Preparation of Compound 155
[0686] The synthesis of Compound 155 followed the procedure of
General Procedure 5 following:
##STR00223##
[0687] To a cooled (0.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyraz-
ol-3-yl)piperidine-1-carboxylate (100 mg, 0.20 mmol) in ethyl
acetate (3 mL) was added a solution of hydrogen chloride (1M) in
ethyl acetate (4 mL). The reaction mixture was stirred for 6 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone. The residue was recrystallized in isopropyl
alcohol to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-1-
-yl)(furan-3-yl)methanone hydrochloride (Compound 155, 30 mg,
yield: 34%) as an off white solid. m/z 391.28 [(M-HCl)+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.82 (br s, 1H), 8.75
(s, 1H), 8.52 (br s, 1H), 7.86-7.84 (m, 1H), 7.82-7.77 (m, 1H),
7.04-6.95 (m, 3H), 5.50 (s, 1H), 4.50-4.48 (m, 2H), 3.33-3.27 (m,
2H), 2.99-2.85 (m, 3H), 2.11-2.07 (m, 2H), 1.81-1.77 (m, 2H); TLC
System: 5% Methanol in dichloromethane. R.sub.f-0.1.
Example 207--Preparation of Compound 156
[0688] The synthesis of Compound 156 followed the procedure of
General Procedure 5 following:
##STR00224##
[0689] To a cooled (0.degree. C.) solution of 2,4-dimethoxybenzoic
acid (274 mg, 1.51 mmol) in dichloromethane (10 mL) under nitrogen
was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 361 mg, 1.89 mmol), followed by
hydroxybenzotriazole (HOBt, 511 mg, 3.78 mmol). The reaction
mixture was stirred for 10 minutes, then to the mixture was added
diisopropylethylamine (DIEA, 0.64 mL, 3.78 mmol), followed by
tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,4-dimethoxybenzoyl)-1H-p-
yrazol-3-yl)piperidine-1-carboxylate (Compound 156, 324 mg, yield:
45%) m/z 562.16 [M+1].sup.+; TLC System: 50% Ethyl acetate in
hexane. R.sub.f-0.6.
Example 208--Preparation of Compound 157
[0690] The synthesis of Compound 157 followed the procedure of
General Procedure 5 following:
##STR00225##
[0691] To a cooled (-78.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,4-dimethoxybenzoyl)-1H-p-
yrazol-3-yl)piperidine-1-carboxylate (250 mg, 0.45 mmol) in diethyl
ether (3 mL) was added a solution of hydrogen chloride (1M) in
diethyl ether (3 mL). The reaction mixture was stirred for 1 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone. The residue was recrystallized in isopropyl
alcohol to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-1-
-yl)(2,4-dimethoxyphenyl)methanone hydrochloride (Compound 157, 10
mg, yield: 4%) as an off white solid. m/z 461.26 [(M-HCl)+1].sup.+;
.sup.1H NMR (400 MHzCDCl.sub.3) .delta. 7.45-7.43 (m, 2H),
6.81-6.76 (m, 2H), 6.53-6.50 (m, 2H), 5.23 (s, 1H), 4.42-4.41 (m,
2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.37-3.33 (m, 2H), 2.99-2.75 (m,
3H), 2.07-2.05 (m, 2H), 1.95-1.92 (m, 2H); TLC System: 5% Methanol
in dichloromethane. R.sub.f-0.1.
Example 209--Preparation of Compound 158
[0692] The synthesis of Compound 158 followed the procedure of
General Procedure 5 following:
##STR00226##
[0693] To a cooled (0.degree. C.) solution of
2,6-dimethylcyclohexane-1-carboxylic acid (235 mg, 1.51 mmol) in
dichloromethane (10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 361 mg, 1.89 mmol), followed by hydroxybenzotriazole
(HOBt, 511 mg, 3.78 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.64 mL, 3.78 mmol), followed by tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 15, 500 mg, 1.26 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford product tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,6-dimethylcyclohexane-1--
carbonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 158,
371 mg, yield: 55%) m/z 536.16 [M+1].sup.+; TLC System: 50% Ethyl
acetate in hexane. R.sub.f-0.8.
Example 210--Preparation of Compound 159
[0694] The synthesis of Compound 159 followed the procedure of
General Procedure 5 following:
##STR00227##
[0695] To a cooled (-60.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,6-dimethylcyclohexane-1--
carbonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (15 mg, 0.03
mmol) in diethyl ether (3 mL) was added a solution of hydrogen
chloride (1M) in diethyl ether (0.5 mL). The reaction mixture was
stirred for 1 hr, and then evaporated under reduced pressure,
triturated with diethyl ether and acetone to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-pyrazol-1-
-yl)(2,6-dimethylcyclohexyl)methanone hydrochloride (Compound 159,
10 mg, yield: 71%) as an off white solid. m/z 435.34
[(M-HCl)+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.66
(br s, 1H), 8.38 (br s, 1H), 7.72-7.69 (m, 1H), 6.96-6.94 (m, 2H),
5.40 (s, 1H), 4.44-4.43 (m, 2H), 3.40-3.26 (m, 3H), 3.00-2.77 (m,
3H), 2.32-2.28 (m, 1H), 2.01-1.87 (m, 3H), 1.75-1.65 (m, 3H),
1.61-1.42 (m, 4H), 0.82 (s, 3H), 0.81 (s, 3H); TLC System: 10%
Methanol in dichloromethane. R.sub.f-0.15.
Example 211--Preparation of Compound 160
[0696] The synthesis of Compound 160 followed the procedure of
General Procedure 5 following:
##STR00228##
[0697] To a cooled (0.degree. C.) solution of tert-butyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (3 g, 7.5 mmol) in diethyl ether (20 mL) was added a
solution of hydrogen chloride (1M) in diethyl ether (20 mL). The
reaction mixture was stirred for 2 hr, and then evaporated under
reduced pressure, triturated with diethyl ether and acetone to
afford product
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
hydrochloride (Compound 160, 2.8 g, yield: 91%) as an off white
solid. m/z 297.21 ((M-HCl)+1].sup.+; TLC System: 10% Methanol in
chloroform. R.sub.f-0.1.
Example 212--Preparation of Compound 161
[0698] The synthesis of Compound 161 followed the procedure of
General Procedure 5 following:
##STR00229##
[0699] To a cooled (0.degree. C.) solution of
N-((5-chlorothiophen-2-yl)methyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine
hydrochloride (2.8 g, 3.01 mmol) in dioxane (70 mL) was added a
solution of sodium carbonate (0.63 g, 6.02 mmol) in water (42 mL),
followed by Fmoc succinimide (0.81 g, 2.4 mmol). The reaction
mixture was stirred for 2 hr and allowed to reach room temperature,
then poured into water (100 mL) and extracted with ethyl acetate
(2.times.50 mL). The combined organic phases were dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with ethyl acetate, to
afford product
(9H-fluoren-9-yl)methyl4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyr-
azol-3-yl)piperidine-1-carboxylate (Compound 161, 1.2 g, yield:
76%) as an off white fluffy solid. m/z 505.3 [M+1].sup.+; TLC
System: 10% Methanol in dichloromethane. R.sub.f-0.5.
Example 213--Preparation of Compound 162
[0700] The synthesis of Compound 162 followed the procedure of
General Procedure 5 following:
##STR00230##
[0701] To a solution of (9H-fluoren-9-yl)methyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 161, 300 mg, 0.48 mmol) and
3-methoxy-2,2-dimethylpropanoic acid (76 mg, 0.58 mmol) in
chloroform (5 mL) under nitrogen at room temperature, was added
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU, 171 mg, 0.53 mmol), followed by
triethylamine (TEA, 0.1 mL, 0.72 mmol). The reaction mixture was
stirred at room temperature for 4 hr, diluted with water (50 mL)
and extracted with dichloromethane (2.times.25 mL). The combined
organic phases were dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 20%
ethyl acetate/petroleum ether, to afford (9H-fluoren-9-yl)methyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 162, 300
mg, yield: 82%). m/z 605.19 [M+1].sup.+; TLC System: 10% Methanol
in dichloromethane. R.sub.f-0.9.
Example 214--Preparation of Compound 163
[0702] The synthesis of Compound 163 followed the procedure of
General Procedure 5 following:
##STR00231##
[0703] To a solution of (9H-fluoren-9-yl)methyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (200 mg, 0.31 mmol)
in tetrahydrofurane (2 mL) was added piperidine (0.8 mL). The
reaction mixture was stirred for 30 min, and then evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10%
methanol/dichloromethane, to afford product
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-
-pyrazol-1-yl)-3-methoxy-2,2-dimethylpropan-1-one (Compound 163, 40
mg, yield: 31%) as an off white solid. m/z 411.22 [(M+1].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.80 (br s, 1H), 8.38 (br
s, 1H), 7.49 (s, 1H), 6.75 (s, 2H), 5.14 (s, 1H), 4.35-4.34 (m,
2H), 3.50-3.47 (m, 2H), 3.27 (s, 3H), 3.10-3.07 (m, 2H), 2.86 (br
s, 1H), 2.21-2.00 (m, 4H), 1.41 (s, 6H); TLC System: 10% Methanol
in dichloromethane. R.sub.f-0.15.
Example 215--Preparation of Compound 164
[0704] The synthesis of Compound 164 followed the procedure of
General Procedure 5 following:
##STR00232##
[0705] To a solution of (9H-fluoren-9-yl)methyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1--
carboxylate (Compound 161, 300 mg, 0.48 mmol) and
3-hydroxy-2,2-dimethylpropanoic acid (59 mg, 0.58 mmol) in
chloroform (5 mL) under nitrogen at room temperature, was added
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU, 171 mg, 0.53 mmol), followed by
triethylamine (TEA, 0.1 mL, 0.72 mmol). The reaction mixture was
stirred at room temperature for 4 hr, diluted with water (50 mL)
and extracted with dichloromethane (2.times.25 mL). The combined
organic phases were dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 20%
ethyl acetate/petroleum ether, to afford (9H-fluoren-9-yl)methyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 164, 250
mg, yield: 71%). m/z 620.19 [M+1].sup.+; TLC System: 10% Methanol
in dichloromethane. R.sub.f-0.85.
Example 216--Preparation of Compound 165
[0706] The synthesis of Compound 165 followed the procedure of
General Procedure 5 following:
##STR00233##
[0707] To a solution of (9H-fluoren-9-yl)methyl
4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (250 mg, 0.31 mmol)
in tetrahydrofurane (10 mL) was added piperidine (1 mL). The
reaction mixture was stirred for 30 min, and then evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10%
methanol/dichloromethane, to afford product
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(piperidin-4-yl)-1H-
-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 165, 60
mg, yield: 48%) as an off white solid. m/z 397.31 [(M+1].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.82 (br s, 1H),
7.49-7.47 (m, 1H), 6.77-6.76 (m, 2H), 5.21 (s, 1H), 4.38-4.36 (m,
2H), 4.00 (br s, 1H), 3.78 (s, 2H), 3.51-3.48 (m, 2H), 3.07-3.02
(m, 2H), 2.87-2.82 (m, 1H), 2.23-2.12 (m, 4H), 1.43 (s, 6H); TLC
System: 10% Methanol in dichloromethane. R.sub.f-0.15.
Example 217--Characterization of Compound 166
[0708] The synthesis of Compound 166 followed the procedure of
General Procedure 5.
##STR00234##
[0709] m/z 531.30 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.4 (m, 3H), 7.0 (m, 2H), 6.8 (m, 2H), 5.2 (s, 1H), 4.4 (m,
2H), 4.1 (m, 2H), 3.8 (s, 3H), 2.8 (m, 2H), 2.6 (m, 2H), 1.8 (m,
2H), 1.4 (s, 9H).
Example 218--Characterization of Compound 167
[0710] The synthesis of Compound 167 followed the procedure of
General Procedure 6c.
##STR00235##
[0711] m/z 431.25 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.2-8.8 (br m, 3H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H),
7.1 (m, 1H), 7.0 (m, 3H), 5.4 (s, 1H), 4.5 (m, 2H), 3.7 (s, 3H),
3.2 (m, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 1.9 (m, 2H), 1.6 (m,
2H).
Example 219--Characterization of Compound 168
[0712] The synthesis of Compound 168 followed the procedure of
General Procedure 7.
##STR00236##
[0713] m/z 473.27 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.4 (m, 3H), 7.0 (m, 2H), 6.8 (m, 2H), 5.2 (s, 1H), 4.5 (m,
1H), 4.4 (m, 2H), 3.8 (s, 3H), 3.8 (m, 1H), 3.1 (m, 1H), 2.7 (m,
2H), 2.1 (s, 3H), 1.8 (m, 2H), 1.5 (m, 1H).
Example 220--Characterization of Compound 169
[0714] The synthesis of Compound 169 followed the procedure of
General Procedure 7.
##STR00237##
[0715] m/z 515.24 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.5 (m, 3H), 7.0 (m, 2H), 6.8 (m, 2H), 5.2 (s, 1H), 4.4 (m,
1H), 4.3 (m, 2H), 3.8 (s, 3H), 2.9 (m, 2H), 2.7 (m, 1H), 1.9 (m,
2H), 1.6 (m, 1H), 1.5 (m, 1H), 1.3 (s, 9H).
Example 221--Characterization of Compound 170
[0716] The synthesis of Compound 170 followed the procedure of
General Procedure 5.
##STR00238##
[0717] m/z 507.24 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.9 (s, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 6.8 (m,
2H), 5.3 (s, 1H), 4.4 (m, 2H), 4.2 (br s, 2H), 2.9 (m, 2H), 2.7 (m,
1H), 1.9 (m, 2H), 1.6 (m, 2H), 1.4 (s, 9H).
Example 222--Characterization of Compound 171
[0718] The synthesis of Compound 171 followed the procedure of
General Procedure 6c.
##STR00239##
[0719] m/z 407.14 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.9 (s, 1H), 8.6 (br s, 1H), 8.3 (br s, 1H), 7.9 (m, 1H),
7.8 (m, 1H), 7.6 (m, 1H), 7.0 (m, 2H), 5.5 (s, 1H), 4.5 (m, 2H),
3.2 (m, 2H), 3.0 (m, 2H), 2.8 (m, 1H), 2.1 (m, 2H), 1.8 (m,
2H).
Example 223--Characterization of Compound 172
[0720] The synthesis of Compound 172 followed the procedure of
General Procedure 7.
##STR00240##
[0721] m/z 449.16 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.9 (s, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 6.8 (m,
2H), 5.2 (s, 1H), 4.6 (m, 1H), 4.4 (m, 2H), 3.9 (m, 1H), 3.2 (m,
1H), 2.7-2.9 (m, 2H), 2.1 (s, 3H), 2.0 (m, 2H), 1.7 (m, 3H).
Example 224--Characterization of Compound 173
[0722] The synthesis of Compound 173 followed the procedure of
General Procedure 7.
##STR00241##
[0723] m/z 491.18 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.9 (s, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 6.8 (m,
2H), 5.2 (s, 1H), 4.4-4.5 (m, 4H), 3.0 (m, 2H), 2.8 (m, 1H), 2.0
(m, 2H), 1.7 (m, 2H), 1.3 (s, 9H).
Example 225--Characterization of Compound 174
[0724] The synthesis of Compound 174 followed the procedure of
General Procedure 5.
##STR00242##
[0725] m/z 481.33 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.7 (m, 1H), 7.0 (m, 2H), 5.4 (s, 1H), 4.4 (m, 2H), 3.9 (m,
2H), 2.8-2.9 (br s, 2H), 2.7 (m, 1H), 1.8 (m, 2H), 1.4 (m,
18H).
Example 226--Characterization of Compound 175
[0726] The synthesis of Compound 175 followed the procedure of
General Procedures 6c and 7.
##STR00243##
[0727] m/z 423.26 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.5 (m, 1H), 6.8 (m, 2H), 5.1 (s, 1H), 4.5 (m, 1H), 4.4 (m,
2H), 3.8 (m, 1H), 3.2 (m, 1H), 2.7-2.9 (m, 2H), 2.1 (s, 3H), 2.0
(m, 2H), 1.6 (m, 2H), 1.4 (s, 9H).
Example 227--Characterization of Compound 176
[0728] The synthesis of Compound 176 followed the procedure of
General Procedures 6c and 7.
##STR00244##
[0729] m/z 465.34 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.5 (m, 1H), 6.8 (m, 2H), 5.1 (s, 1H), 4.3-4.4 (m, 4H), 3.0
(m, 2H), 2.8 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H), 1.5 (s, 9H), 1.3
(s, 9H).
Example 228--Preparation of Intermediate 55
[0730] The synthesis of Intermediate 55 followed the procedure of
General Procedure 7 following:
##STR00245##
[0731] To a cooled solution (0.degree. C.) of
tetrahydrofuran-2-carboxylic acid (5.8 g, 43 mmol) in Ethanol (40
mL) was added thionyl chloride (9.6 mL, 129 mmol). After stirring
at this temperature for 2 hours, the mixture was concentrated under
reduced pressure. The mixture was diluted with water (20 mL) and
extracted into Diethyl ether (3.times.100 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
under reduced pressure to give ethyl tetrahydrofuran-2-carboxylate
(Intermediate 55, 6 g, yield: 96%) as an oily residue that was used
without further purification into the next step. m/z 145.03
[M+H].sup.+; TLC System: 10% Methanol-dichloromethane;
R.sub.f-0.6.
Example 229--Preparation of Intermediate 56
[0732] The synthesis of Intermediate 56 followed the procedure of
General Procedure 2 following:
##STR00246##
[0733] To a cooled (0.degree. C.) solution of ethyl
tetrahydrofuran-2-carboxylate (Intermediate 55, 6 g, 41.66 mmol in
THF (100 mL), dry acetonitrile (3.4 mL, 83.33 mmol) was added.
After 10 min, LHDMS (1M in THF, 13.9 g, 83.3 mmol) was added. After
stirring at 0.degree. C. for 2 hours, the mixture was quenched with
saturated citric acid solution until pH=5 and extracted into Ethyl
acetate (3.times.200 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated under reduced
pressure to give 3-oxo-3-(tetrahydrofuran-2-yl)propanenitrile
(Intermediate 56, 7.5 g, yield: 99%) as an oily residue that was
used without further purification into the next step. m/z 140.02
[M+H].sup.+; TLC System: 10% Methanol-dichloromethane;
R.sub.f-0.4.
Example 230--Preparation of Compound 177
[0734] The synthesis of Compound 177 followed the procedure of
General Procedure 3 following:
##STR00247##
[0735] To a solution of
3-oxo-3-(tetrahydrofuran-2-yl)propanenitrile (Intermediate 56, 7.5
g, 53.95 mmol) in ethanol (90 mL) was added hydrazine hydrate
(N.sub.2H.sub.4.H.sub.2O, 4.04 mL, 24 mmol) and the reaction
mixture was then heated to 90.degree. C. for 5 hours. The reaction
mixture was cooled to room temperature and the volatiles were
evaporated. The residue was purified by neutral alumina column
chromatography (100-300 mesh), eluting with 2%
MeOH-dichloromethane, to afford
3-(tetrahydrofuran-2-yl)-1H-pyrazol-5-amine (Compound 177, 2 g,
24%) as an orange liquid; m/z 154.13 [M+H].sup.+; TLC System: 5%
Methanol-dichloromethane. R.sub.f-0.5.
Example 231--Preparation of Compound 178
[0736] The synthesis of Compound 178 followed the procedure of
General Procedure 4 following:
##STR00248##
[0737] To a cooled solution (0.degree. C.) of
3-(tetrahydrofuran-2-yl)-1H-pyrazol-5-amine (Compound 177, 2 g,
13.1 mmol) in dry DMF (20 mL) was added
5-chlorothiophene-2-carbaldehyde (1.97 mL, 19.6 mmol) and acetic
acid (2 mL). The reaction mixture was stirred at room temperature
for 2 hours. (Formation of imine was observed as a less polar spot
on TLC). The reaction mixture was cooled (0.degree. C.) and sodium
cyanoborohydride (1.64 g, 26.1 mmol) was added portionwise and a
catalytic amount of acetic acid. After 2 hours, the reaction
mixture was quenched with ice-cold water (50 mL), and extracted
into Ethyl acetate (3.times.100 mL). The combined organic layers
were washed with saturated NaHCO.sub.3(2.times.50 mL), water
(2.times.50 mL) and brine (2.times.50 mL) and dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 10% diethyl ether/dichloromethane, to afford
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydrofuran-2-yl)-1H-pyrazol-5-a-
mine (Compound 178, 650 mg, 6.2%) as a light yellow gummy liquid;
m/z 284.13 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.50 (br s, 1H), 6.91-6.84 (m, 2H), 5.74 (br s, 1H), 5.37 (s, 1H),
4.70 (s, 2H), 4.29 (br s, 2H), 3.84-3.79 (m, 1H), 3.71-3.66 (m,
1H), 2.13-2.11 (m, 1H), 1.91-1.79 (m, 3H) ppm; TLC System: 50%
Ethyl acetate in hexane R.sub.f-0.5.
Example 232--Preparation of Compound 179
[0738] The synthesis of Compound 179 followed the procedure of
General Procedure 5 following:
##STR00249##
[0739] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydrofuran-2-yl)-1H-pyrazol-5-a-
mine (Compound 178, 200 mg, 0.70 mmol) in dry dichloromethane (8
mL) was added triethylamine (TEA, 0.10 mL, 0.7 mmol), followed by
trimethylacetyl chloride (0.06 mL, 0.56 mmol). After stirring at
room temperature for 2 hours, the reaction mixture was diluted with
water (50 mL) and extracted into dichloromethane (2.times.25 mL).
The combined organic layers were washed with saturated
NaHCO.sub.3(2.times.10 mL) and water (2.times.10 mL) and dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by preparative silica gel TLC (100-200
mesh), eluting with 15% Ethyl acetate/hexanes, to afford
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(tetrahydrofuran-2-yl)-1H-p-
yrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 179, 35 mg, 14%) as
a colorless liquid. MS (ESI): m/z 368.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.71 (s, 1H), 6.96 (s, 2H), 5.41
(s, 1H), 4.66 (s, 1H), 4.43 (s, 3H), 3.82-3.80 (m, 1H), 3.73-3.71
(m, 1H), 2.12-2.11 (m, 1H), 1.94-1.89 (m, 3H) ppm; TLC System: 30%
Ethyl acetate in hexane. R.sub.f-0.6.
Example 233--Preparation of Compound 180
[0740] The synthesis of Compound 180 followed the procedure of
General Procedure 5 following:
##STR00250##
[0741] To a cooled (0.degree. C.) solution of
thiophene-3-carboxylic acid (95 mg, 0.84 mmol) in dichloromethane
(10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 201 mg, 1.05 mmol), followed by hydroxybenzotriazole
(HOBt, 283 mg, 2.1 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.48 mL, 2.8 mmol), followed by
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydrofuran-2-yl)-1H-pyrazol-5-a-
mine (Compound 178, 200 mg, 0.7 mmol). The reaction was monitored
by LC-MS, and after 16 hr at room temperature the reaction mixture
was poured into water (50 mL) and extracted with dichloromethane
(2.times.25 mL). The combined organic phases were dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by preparative HPLC using
acetonitrile-water as mobile phase to give product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(tetrahydrofuran-2-yl)-1H-pyr-
azol-1-yl)(thiophen-3-yl)methanone (Compound 180, 38 mg, yield:
15%) m/z 394.16 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
8.87 (s, 1H), 7.84-7.83 (m, 1H), 7.81-7.77 (m, 1H), 7.66-7.64 (m,
1H), 7.00-6.96 (m, 2H), 5.54 (s, 1H), 4.73-4.70 (m, 1H), 4.51 (s,
2H), 3.88-3.83 (m, 1H), 3.77-3.72 (m, 1H), 2.21-2.14 (m, 1H),
1.99-1.87 (m, 3H) ppm; TLC System: 50% Ethyl acetate in hexane.
R.sub.f-0.6.
Example 234--Preparation of Compound 181
[0742] The synthesis of Compound 181 followed the procedure of
General Procedure 5 following:
##STR00251##
[0743] To a cooled (0.degree. C.) solution of 2-methoxybenzoic acid
(127 mg, 0.84 mmol) in dichloromethane (10 mL) under nitrogen was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 201 mg, 1.05 mmol), followed by hydroxybenzotriazole
(HOBt, 283 mg, 2.1 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.48 mL, 2.8 mmol), followed by
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydrofuran-2-yl)-1H-pyrazol-5-a-
mine (Compound 178, 200 mg, 0.7 mmol). The reaction was monitored
by LC-MS, and after 16 hr at room temperature the reaction mixture
was poured into water (50 mL) and extracted with dichloromethane
(2.times.25 mL). The combined organic phases were dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by preparative HPLC using
acetonitrile-water as mobile phase to give product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(tetrahydrofuran-2-yl)-1H-pyr-
azol-1-yl)(2-methoxyphenyl)methanone (Compound 181, 32 mg, yield:
11%) m/z 394.16 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
7.71-7.68 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.34 (m, 1H), 7.14-7.12
(m, 2H), 7.03-6.98 (m, 3H), 5.49 (s, 1H), 4.50-4.46 (m, 3H),
3.83-3.77 (m, 1H), 3.73 (s, 3H), 3.69-3.64 (m, 1H), 2.06-2.02 (m,
1H), 1.88-1.68 (m, 3H); TLC System: 50% Ethyl acetate in hexane.
R.sub.f-0.6.
Example 235--Preparation of Intermediate 57
[0744] The synthesis of Intermediate 57 followed the procedure of
General Procedure 7 following:
##STR00252##
[0745] To a cooled solution (0.degree. C.) of
tetrahydro-2H-pyran-4-carboxylic acid (10 g, 76 mmol) in Ethanol
(100 mL) was added thionyl chloride (17.1 mL, 230 mmol). After
stirring at this temperature for 3 hours, the mixture was
concentrated under reduced pressure. The mixture was diluted with
saturated NaHCO.sub.3(20 mL) and extracted into Diethyl ether
(3.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure to
give ethyl tetrahydro-2H-pyran-4-carboxylate (Intermediate 57, 11
g, yield: 91%) as an oily residue that was used without further
purification into the next step. m/z 145.03 [M+H].sup.+; TLC
System: 30% Ethyl acetate in hexane; R.sub.f-0.7.
Example 236--Preparation of Intermediate 58
[0746] The synthesis of Intermediate 58 followed the procedure of
General Procedure 2 following:
##STR00253##
[0747] To a cooled (0.degree. C.) solution of ethyl
tetrahydro-2H-pyran-4-carboxylate (Intermediate 57, 3 g, 18.98
mmol) in THF (50 mL), dry acetonitrile (1.5 mL, 37.97 mmol) was
added. After 10 min, LHDMS (1M in THF, 63.4 g, 37.9 mmol) was
added. After stirring at 0.degree. C. for 2 hours, the mixture was
quenched with saturated citric acid solution until pH=5 and
extracted into Ethyl acetate (3.times.100 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
under reduced pressure to give
3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (Intermediate 58,
3.3 g, yield: 99%) as an oily residue that was used without further
purification into the next step. m/z 153.12 [M+H].sup.+; TLC
System: 50% Ethyl acetate in hexane; R.sub.f-0.2.
Example 237--Preparation of Compound 182
[0748] The synthesis of Compound 182 followed the procedure of
General Procedure 3 following:
##STR00254##
[0749] To a solution of
3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (Intermediate 58,
3.3 g, 21.5 mmol) in ethanol (90 mL) was added hydrazine hydrate
(N.sub.2H.sub.4.H.sub.2O, 1.56 mL, 32.3 mmol) and the reaction
mixture was then heated to 90.degree. C. for 5 hours. The reaction
mixture was cooled to room temperature and the volatiles were
evaporated. The residue was purified by neutral alumina column
chromatography (100-300 mesh), eluting with 2%
MeOH-dichloromethane, to afford
3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (Compound 182, 1.7
g, 47%) as an orange liquid; m/z 168.15 [M+H].sup.+; TLC System:
10% Methanol-dichloromethane. R.sub.f-0.3.
Example 238--Preparation of Compound 183
[0750] The synthesis of Compound 183 followed the procedure of
General Procedure 4 following:
##STR00255##
[0751] To a cooled solution (0.degree. C.) of
3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (Compound 182, 2.1
g, 12.5 mmol) in dry DMF (20 mL) was added
5-chlorothiophene-2-carbaldehyde (1.96 mL, 18.8 mmol) and acetic
acid (2 mL). The reaction mixture was stirred at room temperature
for 2 hours. (Formation of imine was observed as a less polar spot
on TLC). The reaction mixture was cooled (0.degree. C.) and sodium
cyanoborohydride (2.58 g, 25.1 mmol) was added portionwise and a
catalytic amount of acetic acid. After 2 hours, the reaction
mixture was quenched with ice-cold water (25 mL), and extracted
into Ethyl acetate (3.times.50 mL). The combined organic layers
were washed with saturated NaHCO.sub.3(2.times.50 mL), water
(2.times.50 mL) and brine (2.times.50 mL) and dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 10% diethyl ether/dichloromethane, to afford
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-
-5-amine (Compound 183, 600 mg, 16%) as a light yellow gummy
liquid; m/z 298.19 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.50 (br s, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 5.69 (br s,
1H), 5.29 (s, 1H), 4.28 (s, 2H), 3.88-3.84 (m, 2H), 3.39-3.34 (m,
3H), 2.76-2.68 (m, 1H), 1.76-1.72 (m, 2H), 1.60-1.50 (m, 2H) ppm;
TLC System: 50% Ethyl acetate in hexane R.sub.f-0.5.
Example 239--Preparation of Compound 184
[0752] The synthesis of Compound 184 followed the procedure of
General Procedure 5 following:
##STR00256##
[0753] To a cooled solution (0.degree. C.) of
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-
-5-amine (Compound 183, 100 mg, 0.33 mmol) in dry dichloromethane
(8 mL) was added triethylamine (TEA, 0.06 mL, 0.7 mmol), followed
by trimethylacetyl chloride (0.03 mL, 0.26 mmol). After stirring at
room temperature for 3 hours, the reaction mixture was diluted with
water (50 mL) and extracted into dichloromethane (2.times.25 mL).
The combined organic layers were washed with saturated
NaHCO.sub.3(2.times.10 mL) and water (2.times.10 mL) and dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by preparative silica gel TLC (100-200
mesh), eluting with 15% Ethyl acetate/hexanes, to afford
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(tetrahydrofuran-2-yl)-1H-p-
yrazol-1-yl)-2,2-dimethylpropan-1-one (Compound 184, 15 mg, 11%) as
a colorless liquid. MS (ESI): m/z 382.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.69-7.66 (m, 1H), 6.96 (s, 2H),
5.40 (s, 1H), 4.41 (s, 1H), 4.43 (s, 3H), 3.88-3.85 (m, 2H),
3.43-3.34 (m, 2H), 2.74-2.67 (m, 1H), 1.79-1.76 (m, 2H), 1.64-1.54
(m, 2H), 1.40 (s, 9H) ppm; TLC System: 50% Ethyl acetate in hexane.
R.sub.f-0.7.
Example 240--Preparation of Compound 185
[0754] The synthesis of Compound 185 followed the procedure of
General Procedure 5 following:
##STR00257##
[0755] To a cooled (0.degree. C.) solution of
thiophene-3-carboxylic acid (103 mg, 0.80 mmol) in dichloromethane
(10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 192 mg, 1.00 mmol), followed by hydroxybenzotriazole
(HOBt, 271 mg, 2.01 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.46 mL, 2.68 mmol), followed by
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-
-5-amine (Compound 183, 200 mg, 0.67 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by preparative HPLC
using acetonitrile-water as mobile phase to give product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(tetrahydrofuran-2-yl)-1H-pyr-
azol-1-yl)(thiophen-3-yl)methanone (Compound 185, 30 mg, yield:
11%) m/z 408.23 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
8.90 (s, 1H), 7.81-7.78 (m, 2H), 7.65-7.63 (m, 1H), 7.01-6.96 (m,
2H), 5.54 (s, 1H), 4.49-4.47 (m, 2H), 3.91-3.88 (m, 2H), 3.44-3.41
(m, 2H), 2.80-2.67 (m, 1H), 1.83-1.79 (m, 2H), 1.68-1.58 (m, 2H)
ppm; TLC System: 50% Ethyl acetate in hexane. R.sub.f-0.5.
Example 241--Preparation of Compound 186
[0756] The synthesis of Compound 186 followed the procedure of
General Procedure 5 following:
##STR00258##
[0757] To a cooled (0.degree. C.) solution of 2-methoxybenzoic acid
(91 mg, 0.60 mmol) in dichloromethane (10 mL) under nitrogen was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 144 mg, 0.75 mmol), followed by hydroxybenzotriazole
(HOBt, 202 mg, 1.5 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.34 mL, 1.5 mmol), followed by
N-((5-chlorothiophen-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-
-5-amine (Compound 183, 150 mg, 0.50 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by preparative HPLC
using acetonitrile-water as mobile phase to give product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(tetrahydrofuran-2-yl)-1H-pyr-
azol-1-yl)(2-methoxyphenyl)methanone (Compound 186, 25 mg, yield:
12%) m/z 432.27 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO) .delta.
7.67-7.64 (m, 1H), 7.49-7.44 (m, 1H), 7.36-7.33 (m, 1H), 7.13-7.11
(m, 2H), 7.03-6.98 (m, 3H), 5.50 (s, 1H), 4.48-4.47 (m, 2H),
3.82-3.74 (m, 2H), 3.73 (s, 3H), 3.34-3.28 (m, 1H), 2.55-2.49 (m,
1H), 1.61-1.44 (m, 4H); TLC System: 30% Ethyl acetate in hexane.
R.sub.f-0.5.
Example 242--Preparation of Intermediate 59
[0758] The synthesis of Intermediate 59 followed the procedure of
General Procedure 2 following:
##STR00259##
[0759] To a cooled (-20.degree. C.) solution of 1-(tert-butyl)
2-ethyl pyrrolidine-1,2-dicarboxylate (15 g, 61.7 mmol) in THF (150
mL), dry acetonitrile (2.5 mL, 61.7 mmol) was added. After 10 min,
LHDMS (1M in THF, 15 g, 92.5 mmol) was added. After stirring at
0.degree. C. for 2 hours, the mixture was quenched with saturated
citric acid solution until pH=5 and extracted into Ethyl acetate
(3.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated under reduced pressure to
give tert-butyl 2-(2-cyanoacetyl)pyrrolidine-1-carboxylate
(Intermediate 59, 15 g, yield: 99%) as an oily residue that was
used without further purification into the next step. m/z 238.12
[M+H].sup.+; TLC System: 50% Ethyl acetate in petroleum ether;
R.sub.f-0.3.
Example 243--Preparation of Compound 187
[0760] The synthesis of Compound 187 followed the procedure of
General Procedure 3 following:
##STR00260##
[0761] To a solution of tert-butyl
2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (Intermediate 59, 15 g,
61.7 mmol) in ethanol (300 mL) was added hydrazine hydrate
(N.sub.2H.sub.4.H.sub.2O, 4.68 mL, 32.3 mmol) and the reaction
mixture was then heated to 80.degree. C. for 16 hours. The reaction
mixture was cooled to room temperature and the volatiles were
evaporated. The residue was purified by neutral alumina column
chromatography (100-300 mesh), eluting with 3%
MeOH-dichloromethane, to afford tert-butyl
2-(5-amino-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound 187,
5 g, 32%) as a light brown solid; m/z 252.15 [M+H].sup.+; TLC
System: 5% Methanol-dichloromethane. R.sub.f-0.2.
Example 244--Preparation of Compound 188
[0762] The synthesis of Compound 188 followed the procedure of
General Procedure 4 following:
##STR00261##
[0763] To a cooled solution (0.degree. C.) of tert-butyl
2-(5-amino-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound 187,
5 g, 19.8 mmol) in dry DMF (10 mL) was added
5-chlorothiophene-2-carbaldehyde (2.75 mL, 25.8 mmol) and acetic
acid (1 mL). The reaction mixture was stirred at room temperature
for 2 hours. (Formation of imine was observed as a less polar spot
on TLC). The reaction mixture was cooled (0.degree. C.) and sodium
cyanoborohydride (2.58 g, 25.1 mmol) was added portionwise and a
catalytic amount of acetic acid. After 2 hours, the reaction
mixture was quenched with ice-cold water (25 mL), and extracted
into Ethyl acetate (3.times.50 mL). The combined organic layers
were washed with brine (2.times.50 mL) and dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 1% dichloromethane/MeOH, to afford tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 188, 2.2 g, 27%) as a reddish brown solid;
m/z 383.29 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.34 (br s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 5.63 (br s, 1H), 5.24
(s, 1H), 4.29-4.27 (m, 2H), 3.38-3.24 (m, 2H), 2.1 (br s, 1H), 1.84
(br s, 3H), 1.38-1.22 (br m, 9H) ppm; TLC System: 5%
Methanol-dichloromethane R.sub.f-0.5.
Example 245--Preparation of Compound 189
[0764] The synthesis of Compound 189 followed the procedure of
General Procedure 5 following:
##STR00262##
[0765] To a cooled (0.degree. C.) solution of 2-methoxybenzoic acid
(1 g, 6.59 mmol) in dichloromethane (20 mL) under nitrogen was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 2.1 g, 10.99 mmol), followed by hydroxybenzotriazole
(HOBt, 742 mg, 5.49 mmol). The reaction mixture was stirred for 10
minutes, cooled (0.degree. C.) and then to the mixture was added
diisopropylethylamine (DIEA, 2.8 mL, 16.49 mmol), followed by
tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 188, 2.1 g, 5.49 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 30% ethyl
acetate/petroleum ether, to afford tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)pyrrolidine-1-carboxylate (Compound 189, 1.5 g, yield: 53%)
as an off white solid. m/z 417.37 [M+1].sup.+; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.47-7.40 (m, 3H), 7.02-6.96 (m, 2H),
6.82-6.77 (m, 2H), 5.34 (s, 1H), 4.45-4.43 (m, 2H), 4.03-3.99 (m,
1H), 3.81 (s, 3H), 3.06-3.02 (m, 1H), 2.93-2.87 (m, 1H), 2.08-2.03
(m, 1H), 1.87-1.72 (m, 3H); TLC System: 70% Ethyl acetate in
petroleum ether. R.sub.f-0.8.
Example 246--Preparation of Compound 190
[0766] The synthesis of Compound 190 followed the procedure of
General Procedure 5 following:
##STR00263##
[0767] To a cooled (-10.degree. C.) solution of tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)pyrrolidine-1-carboxylate (500 mg, 0.96 mmol) in ethyl
acetate (10 mL) was added a solution of hydrogen chloride (1M) in
ethyl acetate (2 mL). The reaction mixture was stirred for 1 hr,
and then evaporated under reduced pressure to give product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(2-methoxyphenyl)methanone hydrochloride (Compound 190, 350
mg, yield: 74%) as an off white solid. m/z 417.37
[(M-HCl)+1].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.47-7.40 (m, 3H), 7.02-6.96 (m, 2H), 6.82-6.77 (m, 2H), 5.34 (s,
1H), 4.45-4.43 (m, 2H), 4.03-3.99 (m, 1H), 3.81 (s, 3H), 3.06-3.02
(m, 1H), 2.93-2.87 (m, 1H), 2.08-2.03 (m, 1H), 1.87-1.72 (m, 3H);
TLC System: 70% Ethyl acetate in petroleum ether. R.sub.f-0.8.
Example 247--Preparation of Compound 191
[0768] The synthesis of Compound 191 followed the procedure of
General Procedure 5 following:
##STR00264##
[0769] To a cooled (0.degree. C.) solution of
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(2-methoxyphenyl)methanone hydrochloride (170 mg, 0.39 mmol)
in dichloromethane (10 mL) was added triethylamine (0.1 mL, 0.74
mmol) followed by pivaloyl chloride (36 mg, 0.29 mmol). The
reaction mixture was stirred for 4 hr at room temperature, and then
was poured into water (50 mL) and extracted with dichloromethane
(2.times.25 mL). The combined organic phases were washed with brine
(2.times.25 mL), dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 50%
ethyl acetate/petroleum ether, to afford product
1-(2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-py-
razol-3-yl)pyrrolidin-1-yl)-2,2-dimethylpropan-1-one (Compound 191,
80 mg, yield: 43%) as an off white solid. m/z 501.29 [M+1].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.32 (m, 3H),
6.99-6.93 (m, 2H), 6.80-6.76 (m, 2H), 5.18 (s, 1H), 5.17-5.13 (m,
1H), 4.42-4.40 (m, 2H), 3.80 (s, 3H), 3.62 (s, 2H), 1.96-1.87 (m,
4H), 1.56 (s, 9H); TLC System: 5% Methanol in chloroform.
R.sub.f-0.6.
Example 248--Preparation of Compound 192
[0770] The synthesis of Compound 192 followed the procedure of
General Procedure 5 following:
##STR00265##
[0771] To a cooled (0.degree. C.) solution of
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(2-methoxyphenyl)methanone hydrochloride (150 mg, 0.33 mmol)
in dichloromethane (15 mL) was added triethylamine (0.09 mL, 0.66
mmol) followed by isobutyryl chloride (35 mg, 0.33 mmol). The
reaction mixture was stirred for 4 hr at room temperature, and then
was poured into water (50 mL) and extracted with dichloromethane
(2.times.25 mL). The combined organic phases were washed with brine
(2.times.25 mL), dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 60%
ethyl acetate/petroleum ether, to afford product
1-(2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-py-
razol-3-yl)pyrrolidin-1-yl)-2-methylpropan-1-one (Compound 192, 90
mg, yield: 56%) as an off white solid. m/z 487.35 [M+1].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. rotamers 7.49-7.32 (m,
3H), 7.04-6.91 (m, 2H), 6.79-6.75 (m, 2H), 5.16 (s, 1H), 4.80-4.78
(m, 1H), 4.42-4.39 (m, 2H), 3.80 (s, 3H), 3.62-3.48 (m, 2H),
2.63-2.53 (m, 1H), 2.02-1.86 (m, 4H), 1.09-0.86 (m, 6H); TLC
System: 5% Methanol in chloroform. R.sub.f-0.5.
Example 249--Preparation of Compound 193
[0772] The synthesis of Compound 193 followed the procedure of
General Procedure 5 following:
##STR00266##
[0773] To a cooled (0.degree. C.) solution of
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(2-methoxyphenyl)methanone hydrochloride (130 mg, 0.28 mmol)
in dichloromethane (15 mL) was added triethylamine (0.08 mL, 0.57
mmol) followed by acetyl chloride (22 mg, 0.28 mmol). The reaction
mixture was stirred for 4 hr at room temperature, and then was
poured into water (50 mL) and extracted with dichloromethane
(2.times.25 mL). The combined organic phases were washed with brine
(2.times.25 mL), dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 1%
Methanol/dichloromethane, to afford product
1-(2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-py-
razol-3-yl)pyrrolidin-1-yl)ethan-1-one (Compound 193, 15 mg, yield:
12%) as a colorless gummy liquid. m/z 459.27 [M+1].sup.+; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. rotamers 7.52-7.28 (m, 3H),
7.04-6.94 (m, 2H), 6.82-6.77 (m, 2H), 5.31-5.06 (m, 2H), 4.79-4.76
(m, 1H), 4.48-4.38 (m, 2H), 3.81 (s, 3H), 3.62-3.48 (m, 2H),
2.29-2.01 (m, 1H), 1.99-1.86 (m, 6H); TLC System: 5% Methanol in
chloroform. R.sub.f-0.2.
Example 250--Preparation of Compound 194
[0774] The synthesis of Compound 194 followed the procedure of
General Procedure 5 following:
##STR00267##
[0775] To a cooled (0.degree. C.) solution of
2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (282 mg, 1.57
mmol) in dichloromethane (15 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 191 mg, 3.91 mmol), followed by hydroxybenzotriazole
(HOBt, 135 mg, 1.3 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.69 mL, 3.91 mmol), followed by tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 188, 500 mg, 1.30 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 25% Ethyl
acetate/Petroleum ether, to afford product tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,3-dihydrobenzo[b][1,4]di-
oxine-5-carbonyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate
(Compound 194, 200 mg, yield: 32%) m/z 545.16 [M+1].sup.+; TLC
System: 70% Ethyl acetate in petroleum ether. R.sub.f-0.7.
Example 251--Preparation of Compound 195
[0776] The synthesis of Compound 195 followed the procedure of
General Procedure 5 following:
##STR00268##
[0777] To a cooled (0.degree. C.) solution of tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,3-dihydrobenzo[b][1,4]di-
oxine-5-carbonyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (200
mg, 0.96 mmol) in diethyl ether (2 mL) was added a solution of
hydrogen chloride (1M) in diethyl ether (2 mL). The reaction
mixture was stirred for 2 hr, and then evaporated under reduced
pressure, triturated with diethyl ether and acetone to afford
product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone hydrochloride
(Compound 195, 50 mg, yield: 15%) as an off white solid. m/z 445.19
[(M-HCl)+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.85
(br s, 1H), 8.95 (br s, 1H), 7.86 (s, 1H), 7.03-6.88 (m, 5H),
5.78-5.74 (m, 1H), 4.51-4.49 (m, 1H), 4.41 (s, 1H), 4.27-4.21 (m,
4H), 3.17 (s, 1H), 2.24-2.18 (m, 1H), 1.98-1.88 (m, 3H); TLC
System: 10% Methanol in dichloromethane. R.sub.f-0.25.
Example 252--Preparation of Compound 196
[0778] The synthesis of Compound 196 followed the procedure of
General Procedure 5 following:
##STR00269##
[0779] To a cooled (0.degree. C.) solution of furane-3-carboxylic
acid (175 mg, 1.57 mmol) in dichloromethane (15 mL) under nitrogen
was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 191 mg, 3.91 mmol), followed by
hydroxybenzotriazole (HOBt, 135 mg, 1.3 mmol). The reaction mixture
was stirred for 10 minutes, then to the mixture was added
diisopropylethylamine (DIEA, 0.69 mL, 3.91 mmol), followed by
tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate Compound 188, 500 mg, 1.30 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature at room
temperature the reaction mixture was poured into water (50 mL) and
extracted with dichloromethane (2.times.25 mL). The combined
organic phases were dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (100-200 mesh), eluting with 15%
Ethyl acetate/Petroleum ether, to afford product tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyraz-
ol-3-yl)pyrrolidine-1-carboxylate (Compound 196, 280 mg, yield:
45%) m/z 477.16 [M+1].sup.+; TLC System: 70% Ethyl acetate in
petroleum ether. R.sub.f-0.75.
Example 253--Preparation of Compound 197
[0780] The synthesis of Compound 197 followed the procedure of
General Procedure 5 following:
##STR00270##
[0781] To a cooled (-30.degree. C.) solution of tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyraz-
ol-3-yl)pyrrolidine-1-carboxylate (100 mg, 0.20 mmol) in dioxane (3
mL) was added a solution of hydrogen chloride (1M) in diethyl ether
(2 mL). The reaction mixture was stirred for 2 hr, and then
evaporated under reduced pressure. The mixture was washed with
n-pentane, diethyl ether and n-pentane to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(furan-3-yl)methanone hydrochloride (Compound 197, 30 mg,
yield: 38%) as an off white solid. m/z 377.21 [(M-HCl)+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.64 (br s, 1H), 8.95
(br s, 1H), 9.01 (s, 1H), 8.99 (s, 1H), 8.00-7.98 (m, 1H), 7.88 (s,
1H), 7.06 (s, 1H), 6.99-6.97 (m, 2H), 5.69 (s, 1H), 4.69-4.51 (m,
3H), 3.32-3.29 (m, 2H), 2.39-2.33 (m, 1H), 1.96-1.92 (m, 3H); TLC
System: 10% Methanol in chloroform. R.sub.f-0.1.
Example 254--Preparation of Compound 198
[0782] The synthesis of Compound 198 followed the procedure of
General Procedure 5 following:
##STR00271##
[0783] To a cooled (0.degree. C.) solution of tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (200 mg, 0.52 mmol) in dioxane (5 mL) was added a
solution of hydrogen chloride (1M) in dioxane (5 mL). The reaction
mixture was stirred for 8 hr at room temperature, and then
evaporated under reduced pressure. The mixture was diluted with
saturated NaHCO.sub.3(20 mL) and extracted into ethyl acetate
(3.times.50 mL). The combined organic layers were washed with brine
(50 mL), dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 5%
Methanol/dichloromethane, to afford product
N-((5-chlorothiophen-2-yl)methyl)-3-(pyrrolidin-2-yl)-1H-pyrazol-5-amine
(Compound 198, 130 mg, yield: 91%) as an off white solid. m/z
283.21 (M+1].sup.+; TLC System: 10% Methanol in chloroform.
R.sub.f-0.2.
Example 255--Preparation of Compound 199
[0784] The synthesis of Compound 199 followed the procedure of
General Procedure 5 following:
##STR00272##
[0785] To a cooled (0.degree. C.) solution of
N-((5-chlorothiophen-2-yl)methyl)-3-(pyrrolidin-2-yl)-1H-pyrazol-5-amine
hydrochloride (3.5 g, 11.0 mmol) in dichloromethane (20 mL) was
added triethylamine (0.72 mL, 16.5 mmol) followed by Fmoc chloride
(3.13 g, 12.1 mmol). The reaction mixture was stirred for 2 hr, and
then was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 5%
Methanol/dichloromethane, to afford product
(9H-fluoren-9-yl)methyl-2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-py-
razol-3-yl)pyrrolidine-1-carboxylate (Compound 199, 3.5 g, yield:
63%) as an off white fluffy solid. m/z 505.3 [M+1].sup.+; TLC
System: 10% Methanol in chloroform. R.sub.f-0.4.
Example 256--Preparation of Compound 200
[0786] The synthesis of Compound 200 followed the procedure of
General Procedure 5 following:
##STR00273##
[0787] To a solution of tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 199, 500 mg, 0.99 mmol) and
3-methoxy-2,2-dimethylpropanoic acid (180 mg, 1.18 mmol) in
dichloromethane (5 mL) under nitrogen at room temperature, was
added
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU, 564 mg, 1.48 mmol), followed by
diisopropylethylamine (DIEA, 0.32 mL, 1.48 mmol). The reaction
mixture was stirred at room temperature for 16 hr, diluted with
water (50 mL) and extracted with dichloromethane (2.times.25 mL).
The combined organic phases were dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by preparative HPLC using acetonitrile-water
as mobile phase to give product (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,4-dimethoxybenzoyl)-1H-p-
yrazol-3-yl)pyrrolidine-1-carboxylate (Compound 200, 140 mg, yield:
21%). m/z 669.19 [M+1].sup.+; TLC System: 10% Acetone in
dichloromethane. R.sub.f-0.85.
Example 257--Preparation of Compound 201
[0788] The synthesis of Compound 201 followed the procedure of
General Procedure 5 following:
##STR00274##
[0789] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2,4-dimethoxybenzoyl)-1H-p-
yrazol-3-yl)pyrrolidine-1-carboxylate (140 mg, 0.20 mmol) in
dimethylformamide (2 mL) was added diisopropylethylamine (DIEA, 142
mg, 1.70 mmol). The reaction mixture was stirred for 2 hr, and then
evaporated under reduced pressure. The mixture was diluted with
water and extracted with ethyl acetate. The combined organic phases
were dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (100-200 mesh), eluting with 5%
Methanol/dichloromethane, to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(2,4-dimethoxyphenyl)methanone (Compound 201, 45 mg, yield:
48%) as gummy liquid. m/z 447.24 [(M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.64 (br s, 1H), 8.95 (br s, 1H), 9.11
(s, 1H), 7.84-7.81 (m, 1H), 7.39-7.37 (m, 1H), 7.02-6.98 (m, 2H),
6.67 (s, 1H), 6.60-6.57 (m, 1H), 5.72 (s, 1H), 4.50-4.37 (m, 3H),
3.83 (s, 3H), 3.74 (m, 3H), 3.19-3.14 (m, 2H), 2.22-2.17 (m, 1H),
1.96-1.88 (m, 3H); TLC System: 10% Methanol in chloroform.
R.sub.f-0.3.
Example 258--Preparation of Compound 202
[0790] The synthesis of Compound 202 followed the procedure of
General Procedure 5 following:
##STR00275##
[0791] To a solution of tert-butyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 199, 500 mg, 0.99 mmol) and pivalic acid
(121 mg, 1.18 mmol) in dichloromethane (5 mL) under nitrogen at
room temperature, was added
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-
ium 3-oxid hexafluorophosphate (HATU, 564 mg, 1.48 mmol), followed
by diisopropylethylamine (DIEA, 0.32 mL, 1.48 mmol). The reaction
mixture was stirred at room temperature for 16 hr, diluted with
water (50 mL) and extracted with dichloromethane (2.times.25 mL).
The combined organic phases were dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by preparative HPLC using acetonitrile-water
as mobile phase to give product (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)py-
rrolidine-1-carboxylate (Compound 202, 200 mg, yield: 35%). m/z
590.19 [M+1].sup.+; TLC System: 10% Acetone in dichloromethane.
R.sub.f-0.8.
Example 259--Preparation of Compound 203
[0792] The synthesis of Compound 203 followed the procedure of
General Procedure 5 following:
##STR00276##
[0793] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)py-
rrolidine-1-carboxylate (100 mg, 0.17 mmol) in methanol (2 mL) was
added sodium bicarbonate (142 mg, 1.70 mmol). The reaction mixture
was stirred for 16 hr, and then evaporated under reduced pressure.
The mixture was diluted with water and extracted with ethyl
acetate. The combined organic phases were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 8% Methanol/dichloromethane, to afford product
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazo-
l-1-yl)-2,2-dimethylpropan-1-one (Compound 203, 35 mg, yield: 56%)
as a gummy liquid. m/z 367.23 [(M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.72-7.62 (m, 1H), 6.99 (s, 1H), 5.4 (s, 1H),
4.45-4.38 (m, 2H), 3.93-3.82 (m, 1H), 2.85-2.97 (m, 2H), 1.98-1.88
(m, 1H), 1.78-1.62 (m, 3H), 1.42 (s, 9H); TLC System: 10% Methanol
in chloroform. R.sub.f-0.35.
Example 260--Preparation of Compound 204
[0794] The synthesis of Compound 204 followed the procedure of
General Procedure 5 following:
##STR00277##
[0795] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 199, 500 mg, 0.99 mmol) and
3-hydroxy-2,2-dimethylpropanoic acid (146 mg, 1.2 mmol) in
chloroform (25 mL) under nitrogen at room temperature, was added
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU, 365 mg, 1.1 mmol), followed by
diisopropylethylamine (DIEA, 0.3 mL, 7.4 mmol). The reaction
mixture was stirred at room temperature for 4 hr, diluted with
water (50 mL) and extracted with chloroform (2.times.25 mL). The
combined organic phases were dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by preparative HPLC using acetonitrile-water as mobile
phase to give product (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound 204, 250
mg, yield: 42%). m/z 605.19 [M+1].sup.+; TLC System: 10% Methanol
in dichloromethane. R.sub.f-0.9.
Example 261--Preparation of Compound 205
[0796] The synthesis of Compound 205 followed the procedure of
General Procedure 5 following:
##STR00278##
[0797] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (100 mg, 0.16
mmol) in methanol (2 mL) was added sodium bicarbonate (139 mg, 1.65
mmol). The reaction mixture was stirred for 16 hr, and then
evaporated under reduced pressure. The mixture was diluted with
water and extracted with ethyl acetate. The combined organic phases
were dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (100-200 mesh), eluting with 5%
Methanol/dichloromethane, to afford product
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazo-
l-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 205, 15 mg,
yield: 24%) as a semi solid. m/z 383.23 [(M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.72-7.62 (m, 1H), 6.99 (s, 1H),
5.4 (s, 1H), 4.84-4.83 (m, 1H), 4.45-4.38 (m, 2H), 3.93-3.82 (m,
1H), 2.85-2.97 (m, 2H), 2.78-2.81 (m, 1H), 1.98-1.88 (m, 1H),
1.78-1.62 (m, 3H), 1.42 (s, 6H); TLC System: 5% Methanol in
chloroform. R.sub.f-0.3.
Example 262--Preparation of Compound 206
[0798] The synthesis of Compound 206 followed the procedure of
General Procedure 5 following:
##STR00279##
[0799] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 199, 500 mg, 0.99 mmol) and
4-methyltetrahydro-2H-pyran-4-carboxylic acid (143 mg, 0.99 mmol)
in dichloromethane (5 mL) under nitrogen at room temperature, was
added
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU, 564 mg, 1.48 mmol), followed by
diisopropylethylamine (DIEA, 0.32 mL, 1.48 mmol). The reaction
mixture was stirred at room temperature for 16 hr, diluted with
water (50 mL) and extracted with dichloromethane (2.times.25
mL).
[0800] The combined organic phases were dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by preparative HPLC using acetonitrile-water
as mobile phase to give product (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-methyltetrahydro-2H-pyra-
n-4-carbonyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound
206, 110 mg, yield: 18%). m/z 632.19 [M+1].sup.+; TLC System: 10%
Acetone in dichloromethane. R.sub.f-0.9.
Example 263--Preparation of Compound 207
[0801] The synthesis of Compound 207 followed the procedure of
General Procedure 5 following:
##STR00280##
[0802] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(4-methyltetrahydro-2H-pyra-
n-4-carbonyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (100 mg,
0.16 mmol) in methanol (2 mL) was added sodium bicarbonate (139 mg,
1.65 mmol). The reaction mixture was stirred for 16 hr, and then
evaporated under reduced pressure. The mixture was diluted with
water and extracted with ethyl acetate. The combined organic phases
were dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (100-200 mesh), eluting with 5%
Methanol/dichloromethane, to afford product
(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazol--
1-yl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (Compound 207, 15
mg, yield: 24%) as a semi solid. m/z 410.31 [(M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.81 (br s, 1H), 7.85 (br s,
1H), 6.96 (s, 2H), 5.60 (s, 1H), 4.54-4.43 (m, 2H), 3.78 (br s,
2H), 3.45 (br s, 2H), 3.22 (br s, 2H), 2.43-2.21 (br s, 3H),
1.98-1.89 (m, 3H), 1.75 (br s, 2H), 1.54-1.50 (m, 3H); TLC System:
10% Methanol in chloroform. R.sub.f-0.35.
Example 264--Preparation of Compound 208
[0803] The synthesis of Compound 208 followed the procedure of
General Procedure 5 following:
##STR00281##
[0804] To a cooled (0.degree. C.) solution of
3-methoxy-2,2-dimethylpropanoic acid (200 mg, 1.57 mmol) in
dichloromethane (15 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 191 mg, 3.91 mmol), followed by hydroxybenzotriazole
(HOBt, 135 mg, 1.3 mmol). The reaction mixture was stirred for 10
minutes, then to the mixture was added diisopropylethylamine (DIEA,
0.69 mL, 3.91 mmol), followed by (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate (Compound 199, 500 mg, 1.30 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (50 mL) and extracted with
dichloromethane (2.times.25 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 20% Ethyl
acetate/Petroleum ether, to afford product (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (Compound 208, 200
mg, yield: 31%) m/z 497.26 [M+1].sup.+; TLC System: 70% Ethyl
acetate in petroleum ether. R.sub.f-0.7.
Example 265--Preparation of Compound 209
[0805] The synthesis of Compound 209 followed the procedure of
General Procedure 5 following:
##STR00282##
[0806] To a solution of (9H-fluoren-9-yl)methyl
2-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(3-methoxy-2,2-dimethylprop-
anoyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (180 mg, 0.29
mmol) in methanol (2 m.) was added sodium bicarbonate (200 mg, 2.91
mmol). The reaction mixture was stirred for 16 hr, and then
evaporated under reduced pressure. The mixture was diluted with
water and extracted with ethyl acetate. The combined organic phases
were dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (100-200 mesh), eluting with 8%
Methanol/dichloromethane, to afford product
1-(5-(((5-chlorothiophen-2-yl)methyl)amino)-3-(pyrrolidin-2-yl)-1H-pyrazo-
l-1-yl)-3-methoxy-2,2-dimethylpropan-1-one (Compound 209.15 mg,
yield: 24%) as a semi solid. m/z 397.25 [(M+1].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.51-7.50 (i, 1H), 6.80-6.79 (i, 1H),
6.76-6.75 (i, 1H), 5.42 (s, 1H), 4.64-4.61 (i, 1H), 4.36-4.35 (i,
2H), 3.79 (s, 2H), 3.41-3.40 (i, 1H), 3.27 (s, 3H), 2.37-2.32 (i,
1H), 2.17-1.97 (m, 4H), 1.42 (s, 6H); TLC System: 10% Methanol in
chloroform. R.sub.f-0.2.
Example 266--Preparation of Intermediate 60
[0807] The synthesis of Intermediate 60 followed the procedure of
General Procedure 7 following:
##STR00283##
[0808] To a cooled solution (0.degree. C.) of
azetidine-3-carboxylic acid (50 g, 494 mmol) in Ethanol (500 mL)
was added thionyl chloride (110 mL, 1483 mmol) dropwise. After
stirring at this temperature for 2 hours, the mixture was
concentrated under reduced pressure. The mixture was co-distilled
with benzene (3.times.50 mL) and concentrated under reduced
pressure to give ethyl azetidine-3-carboxylate hydrochloride
(Intermediate 60, 70 g, yield: 96%) as a gummy liquid that was used
without further purification into the next step. m/z 130.03
[(M-HCl)+1].sup.+; TLC System: 10% Methanol-chloroform;
R.sub.f-0.6.
Example 267--Preparation of Intermediate 61
[0809] The synthesis of Intermediate 61 followed the procedure of
General Procedure 7 following:
##STR00284##
[0810] To a cooled solution (0.degree. C.) of ethyl
azetidine-3-carboxylate hydrochloride (70 g, 424 mmol) in
dichloromethane (700 mL) was added triethylamine (119 mL, 848 mmol)
dropwise over 30 min, followed by di-tert butyl dicarbonate (111 g,
509 mmol). After stirring at this temperature for 3 hours, the
mixture was concentrated under reduced pressure. The mixture was
diluted with water (20 mL) and extracted into dichloromethane
(3.times.100 mL). The combined organic layers were washed with
brine (2.times.10 mL), dried over sodium sulfate, filtered and
concentrated under reduced pressure to give 1-(tert-butyl) 3-ethyl
azetidine-1,3-dicarboxylate (Intermediate 61, 40 g, yield: 42%) as
an oily residue that was used without further purification into the
next step. m/z 230.23 [M+H].sup.+; TLC System: 10%
Methanol-dichloromethane; R.sub.f-0.7.
Example 268--Preparation of Intermediate 62
[0811] The synthesis of Intermediate 62 followed the procedure of
General Procedure 2 following:
##STR00285##
[0812] To a cooled (0.degree. C.) solution of 1-(tert-butyl)
3-ethyl azetidine-1,3-dicarboxylate (Intermediate 61, 1 g, 4.36
mmol in THF (50 mL), dry acetonitrile (0.32 mL, 8.7 mmol) was
added. After 10 min, LHDMS (1M in THF, 8.7 mL, 8.7 mmol) was added.
After stirring at 0.degree. C. for 2 hours, the mixture was
quenched with saturated citric acid solution until pH=5 and
extracted into Ethyl acetate (3.times.50 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
under reduced pressure to give tert-butyl
3-(2-cyanoacetyl)azetidine-1-carboxylate (Intermediate 62, 1.2 g,
yield: 99%) as an oily residue that was used without further
purification into the next step. m/z 225.02 [M+H].sup.+; TLC
System: 10% Methanol-dichloromethane; R.sub.f-0.5.
Example 269--Preparation of Compound 210
[0813] The synthesis of Compound 210 followed the procedure of
General Procedure 3 following:
##STR00286##
[0814] To a solution of tert-butyl
3-(2-cyanoacetyl)azetidine-1-carboxylate (Intermediate 62, 1.2 g,
5.35 mmol) in ethanol (12 mL) was added hydrazine hydrate
(N.sub.2H.sub.4.H.sub.2O, 1.34 mL, 8.0 mmol) and the reaction
mixture was then heated to 90.degree. C. for 5 hours. The reaction
mixture was cooled to room temperature and the volatiles were
evaporated. The residue was purified by neutral alumina column
chromatography (100-300 mesh), eluting with 2%
MeOH-dichloromethane, to afford tert-butyl
3-(5-amino-1H-pyrazol-3-yl)azetidine-1-carboxylate (Compound 210,
600 mg, 47%) as an off white solid; m/z 239.13 [M+H].sup.+; TLC
System: 10% Methanol-dichloromethane. R.sub.f-0.4.
Example 270--Preparation of Compound 211
[0815] The synthesis of Compound 211 followed the procedure of
General Procedure 4 following:
##STR00287##
[0816] To a cooled solution (0.degree. C.) of tert-butyl
3-(5-amino-1H-pyrazol-3-yl)azetidine-1-carboxylate (Compound 210,
11 g, 46.2 mmol) in dry DMF (40 mL) was added
5-chlorothiophene-2-carbaldehyde (7.12 mL, 69.3 mmol) and acetic
acid (12 mL). The reaction mixture was stirred at room temperature
for 2 hours. (Formation of imine was observed as a less polar spot
on TLC). The reaction mixture was cooled (0.degree. C.) and sodium
cyanoborohydride (6.18 g, 92.4 mmol) was added portionwise and a
catalytic amount of acetic acid. After 2 hours, the reaction
mixture was quenched with ice-cold water (50 mL), and extracted
into Ethyl acetate (3.times.100 mL). The combined organic layers
were washed with saturated NaHCO.sub.3(2.times.50 mL), water
(2.times.50 mL) and brine (2.times.50 mL) and dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (100-200
mesh), eluting with 2% methanol/dichloromethane, to afford
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)azetidine-1-c-
arboxylate (Compound 211, 7 g, 41%); m/z 368.13 [M+H].sup.+; TLC
System: 10% Methanol in dichloromethane R.sub.f-0.5.
Example 271--Preparation of Compound 212
[0817] The synthesis of Compound 212 followed the procedure of
General Procedure 5 following:
##STR00288##
[0818] To a cooled (0.degree. C.) solution of furan-3-carboxylic
acid (182 mg, 1.63 mmol) in dichloromethane (10 mL) under nitrogen
was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HCl, 388 mg, 2.0 mmol), followed by
hydroxybenzotriazole (HOBt, 135 mg, 4 mmol). The reaction mixture
was stirred for 10 minutes, cooled (0.degree. C.) and then to the
mixture was added diisopropylethylamine (DIEA, 0.9 mL, 5.4 mmol),
followed by tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)azetidine-1-c-
arboxylate (Compound 211, 500 mg, 1.35 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (25 mL) and extracted with
dichloromethane (2.times.10 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10% ethyl
acetate/hexane, to afford tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyraz-
ol-3-yl)azetidine-1-carboxylate (Compound 212, 230 mg, yield: 35%)
as an off white solid. m/z 463.37 [M+1].sup.+; TLC System: 30%
Ethyl acetate in hexane. R.sub.f-0.5.
Example 272--Preparation of Compound 213
[0819] The synthesis of Compound 213 followed the procedure of
General Procedure 5 following:
##STR00289##
[0820] To a cooled (-10.degree. C.) solution of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyraz-
ol-3-yl)azetidine-1-carboxylate (230 mg, 0.49 mmol) in ethyl
acetate (5 mL) was added a solution of hydrogen chloride (1M) in
ethyl acetate (8 mL). The reaction mixture was stirred for 2 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone and the residue was purified by preparative HPLC
using acetonitrile-water-TFA as mobile phase to give product
(3-(azetidin-3-yl)-5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-1--
yl)(furan-3-yl)methanone 2,2,2-trifluoroacetate (Compound 213, 10
mg, yield: 8%) as an off white solid. m/z 363.14 [(M-TFA)+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.94 (s, 1H), 8.74 (br
s, 1H), 7.96-7.92 (m, 1H), 7.89-7.88 (m, 1H), 7.07 (s, 1H),
6.98-6.96 (m, 2H), 5.58 (s, 1H), 4.50-4.49 (m, 2H), 4.26-4.22 (m,
2H), 4.13-3.95 (m, 3H); TLC System: 10% Ethyl acetate in petroleum
ether. R.sub.f-0.1.
Example 273--Preparation of Compound 214
[0821] The synthesis of Compound 214 followed the procedure of
General Procedure 5 following:
##STR00290##
[0822] To a cooled (0.degree. C.) solution of
thiophene-3-carboxylic acid (208 mg, 1.63 mmol) in dichloromethane
(10 mL) under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 388 mg, 2.0 mmol), followed by hydroxybenzotriazole
(HOBt, 135 mg, 4 mmol). The reaction mixture was stirred for 10
minutes, cooled (0.degree. C.) and then to the mixture was added
diisopropylethylamine (DIEA, 0.9 mL, 5.4 mmol), followed by
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)azetidine-1-c-
arboxylate (Compound 211, 500 mg, 1.35 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (25 mL) and extracted with
dichloromethane (2.times.10 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10% ethyl
acetate/hexane, to afford tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-p-
yrazol-3-yl)azetidine-1-carboxylate (Compound 214, 230 mg, yield:
36%) as an off white solid. m/z 479.37 [M+1].sup.+; TLC System: 30%
Ethyl acetate in hexane. R.sub.f-0.5.
Example 274--Preparation of Compound 215
[0823] The synthesis of Compound 215 followed the procedure of
General Procedure 5 following:
##STR00291##
[0824] To a cooled (-10.degree. C.) solution of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-p-
yrazol-3-yl)azetidine-1-carboxylate (230 mg, 0.48 mmol) in ethyl
acetate (5 mL) was added a solution of hydrogen chloride (1M) in
ethyl acetate (8 mL). The reaction mixture was stirred for 2 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone and the residue was purified by preparative HPLC
using acetonitrile-water-TFA as mobile phase to give product
(3-(azetidin-3-yl)-5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-1--
yl)(thiophene-3-yl)methanone 2,2,2-trifluoroacetate (Compound 215,
10 mg, yield: 7%) as an off white solid. m/z 379.13
[(M-TFA)+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.01
(s, 1H), 9.00 (br s, 1H), 7.98-7.94 (m, 1H), 7.81-7.79 (m, 1H),
7.68-7.67 (m, 1H), 7.09-6.97 (m, 2H), 5.63 (s, 1H), 4.51-4.49 (m,
2H), 4.26-4.21 (m, 2H), 4.12-3.93 (m, 3H); TLC System: 10% Ethyl
acetate in petroleum ether. R.sub.f-0.1.
Example 275--Preparation of Compound 216
[0825] The synthesis of Compound 216 followed the procedure of
General Procedure 5 following:
##STR00292##
[0826] To a cooled (0.degree. C.) solution of 2-methoxybenzoic acid
(247 mg, 1.63 mmol) in dichloromethane (10 mL) under nitrogen was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 388 mg, 2.0 mmol), followed by hydroxybenzotriazole
(HOBt, 135 mg, 4 mmol). The reaction mixture was stirred for 10
minutes, cooled (0.degree. C.) and then to the mixture was added
diisopropylethylamine (DIEA, 0.9 mL, 5.4 mmol), followed by
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)azetidine-1-c-
arboxylate (Compound 211, 500 mg, 1.35 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (25 mL) and extracted with
dichloromethane (2.times.10 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10% ethyl
acetate/hexane, to afford tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)azetidine-1-carboxylate (Compound 216, 150 mg, yield: 25%)
as an off white solid. m/z 503.37 [M+1].sup.+; TLC System: 30%
Ethyl acetate in hexane. R.sub.f-0.5.
Example 276--Preparation of Compound 217
[0827] The synthesis of Compound 217 followed the procedure of
General Procedure 5 following:
##STR00293##
[0828] To a cooled (-10.degree. C.) solution of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)azetidine-1-carboxylate (150 mg, 0.29 mmol) in ethyl
acetate (5 mL) was added a solution of hydrogen chloride (1M) in
ethyl acetate (8 mL). The reaction mixture was stirred for 2 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone and the residue was purified by preparative HPLC
using acetonitrile-water as mobile phase to give product
(3-(azetidin-3-yl)-5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-1--
yl)(2-methoxyphenyl)methanone hydrochloride (Compound 217, 8 mg,
yield: 5%) as an off white solid. m/z 403.24 [(M-HCl)+1].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.51-7.38 (m, 3H),
7.06-6.94 (m, 2H), 6.86 (s, 1H), 6.78 (s, 1H), 5.51 (s, 1H),
4.46-4.43 (m, 2H), 4.25-4.16 (m, 4H), 3.82 (s, 3H), 3.81-3.76 (m,
1H); TLC System: 50% Ethyl acetate in petroleum ether.
R.sub.f-0.1.
Example 277--Preparation of Compound 218
[0829] The synthesis of Compound 218 followed the procedure of
General Procedure 5 following:
##STR00294##
[0830] To a cooled (0.degree. C.) solution of 2-methoxybenzoic acid
(293 mg, 1.63 mmol) in dichloromethane (10 mL) under nitrogen was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HCl, 388 mg, 2.0 mmol), followed by hydroxybenzotriazole
(HOBt, 135 mg, 4 mmol). The reaction mixture was stirred for 10
minutes, cooled (0.degree. C.) and then to the mixture was added
diisopropylethylamine (DIEA, 0.9 mL, 5.4 mmol), followed by
tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)azetidine-1-c-
arboxylate (Compound 211, 500 mg, 1.35 mmol). The reaction was
monitored by LC-MS, and after 16 hr at room temperature the
reaction mixture was poured into water (25 mL) and extracted with
dichloromethane (2.times.10 mL). The combined organic phases were
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (100-200 mesh), eluting with 10% ethyl
acetate/hexane, to afford tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)azetidine-1-carboxylate (Compound 218, 100 mg, yield: 18%)
as an off white solid. m/z 531.37 [M+1].sup.+; TLC System: 30%
Ethyl acetate in hexane. R.sub.f-0.5.
Example 278--Preparation of Compound 219
[0831] The synthesis of Compound 219 followed the procedure of
General Procedure 5 following:
##STR00295##
[0832] To a cooled (-10.degree. C.) solution of tert-butyl
3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyraz-
ol-3-yl)azetidine-1-carboxylate (100 mg, 0.19 mmol) in ethyl
acetate (5 mL) was added a solution of hydrogen chloride (1M) in
ethyl acetate (8 mL). The reaction mixture was stirred for 2 hr,
and then evaporated under reduced pressure, triturated with diethyl
ether and acetone and the residue was purified by preparative HPLC
using acetonitrile-water-TFA as mobile phase to give product
(3-(azetidin-3-yl)-5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-1--
yl)(2-methoxyphenyl)methanone 2,2,2-trifluoroacetate (Compound 219,
2 mg, yield: 2%) as an oily liquid. m/z 431.2 [(M-TFA)+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.84-7.81 (m, 1H),
7.02-6.87 (m, 5H), 5.63 (s, 1H), 4.50-4.49 (m, 4H), 4.14-4.09 (m,
2H), 3.94-3.85 (m, 2H); TLC System: 50% Ethyl acetate in petroleum
ether. R.sub.f-0.1.
[0833] The contents of all references, patents, and published
applications cited herein are hereby incorporated by reference in
their entirety and for all purposes.
[0834] While the invention has been described in detail with
reference to certain preferred embodiments thereof, it will be
understood that modifications and variations are within the spirit
and scope of that which is described and claimed.
* * * * *