U.S. patent application number 14/101543 was filed with the patent office on 2014-06-19 for substituted pyrrolo[2,3-d]pyrimidines as inhibitors of protein kinases.
This patent application is currently assigned to Vertex Pharmaceuticals Incorporated. The applicant listed for this patent is Vertex Pharmaceuticals Incorporated. Invention is credited to Guy Bemis, John Duffy, Luc Farmer, Mark Ledeboer, David Messersmith, Albert Pierce, Francesco Salituro, Jian Wang, Tiansheng Wang.
Application Number | 20140171454 14/101543 |
Document ID | / |
Family ID | 36498734 |
Filed Date | 2014-06-19 |
United States Patent
Application |
20140171454 |
Kind Code |
A1 |
Ledeboer; Mark ; et
al. |
June 19, 2014 |
Substituted Pyrrolo[2,3-d]pyrimidines as Inhibitors of Protein
Kinases
Abstract
The present invention relates to compounds useful as inhibitors
of protein kinases. The invention also provides pharmaceutically
acceptable compositions comprising said compounds and methods of
using the compositions in the treatment of various disease,
conditions, or disorders.
Inventors: |
Ledeboer; Mark; (Acton,
MA) ; Pierce; Albert; (Cambridge, MA) ; Bemis;
Guy; (Arlington, MA) ; Farmer; Luc; (Montreal,
CA) ; Wang; Tiansheng; (Concord, MA) ;
Messersmith; David; (Somerville, MA) ; Duffy;
John; (Northborough, MA) ; Salituro; Francesco;
(Marlborough, MA) ; Wang; Jian; (Newton,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Cambridge |
MA |
US |
|
|
Assignee: |
Vertex Pharmaceuticals
Incorporated
Cambridge
MA
|
Family ID: |
36498734 |
Appl. No.: |
14/101543 |
Filed: |
December 10, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11346048 |
Feb 2, 2006 |
8633205 |
|
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14101543 |
|
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60649781 |
Feb 3, 2005 |
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Current U.S.
Class: |
514/265.1 ;
435/184; 544/280 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
35/02 20180101; A61P 43/00 20180101; A61P 25/08 20180101; A61P
27/06 20180101; A61P 19/00 20180101; A61P 25/28 20180101; A61P
19/02 20180101; A61P 19/08 20180101; A61P 9/00 20180101; A61P 11/00
20180101; A61P 1/04 20180101; A61P 9/14 20180101; A61P 11/06
20180101; A61P 13/08 20180101; A61P 25/00 20180101; A61P 25/16
20180101; A61P 37/06 20180101; A61P 9/04 20180101; A61P 25/18
20180101; A61P 17/14 20180101; A61P 25/14 20180101; A61P 37/08
20180101; A61P 19/10 20180101; A61P 37/00 20180101; A61P 3/10
20180101; A61P 31/12 20180101; A61P 15/06 20180101; A61P 31/18
20180101; A61P 7/00 20180101; A61P 21/02 20180101; A61P 29/00
20180101; A61P 35/00 20180101; A61P 9/12 20180101; A61P 27/02
20180101; A61P 15/10 20180101; C07D 487/04 20130101; A61P 9/08
20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/265.1 ;
544/280; 435/184 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A compound of formula (I): ##STR00127## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is H, --NO.sub.2, --CN,
--OCF.sub.3, halogen, or amino; or C.sub.1-6aliphatic,
C.sub.3-7cycloaliphatic, C.sub.1-6alkoxy, or C.sub.1-4haloalkyl
optionally substituted with 0-10 J.sup.R groups; R.sup.2 is H,
--NO.sub.2, --CN, --OCF.sub.3, halogen, or amino; or
C.sub.1-6aliphatic, C.sub.3-7cycloaliphatic, C.sub.1-6alkoxy, or
C.sub.1-4haloalkyl optionally substituted with 0-10 J.sup.R groups;
Z.sup.1 is C.sub.1-6aliphatic or C.sub.3-10cycloaliphatic
optionally substituted with 0-10 J.sup.Z groups; if the bond
between Z.sup.1 and C is a double bond, then Z.sup.1 may also be
.dbd.O, .dbd.NR, or .dbd.C(R).sub.2; Z.sup.2 is H or halogen; or
C.sub.1-10haloalkyl, C.sub.1-4haloalkoxy, Y, --(V.sub.n)--CN,
--(V.sub.n)--NO.sub.2, --(V.sub.n)--OH,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), or --(V.sub.n)--(C.sub.3-10cycloaliphatic) optionally
substituted with 0-10 J.sup.Z groups; or Z.sup.1 and Z.sup.2,
together with the carbon atom to which they are attached, form ring
Q; Z.sup.3 is H or C.sub.1-6alkyl optionally substituted with 0-3
J.sup.Z groups; or Z.sup.1, Z.sup.2, and Z.sup.3, together with the
carbon atom to which they are attached, form an 6-14 membered
saturated, partially saturated, or unsaturated bicyclic ring having
0-3 heteroatoms; if the bond between Z.sup.1 and C is a triple
bond, then Z.sup.2 is absent; if the bond between Z.sup.1 and C is
a double bond or a triple bond, then Z.sup.3 is absent; Q is a 3-8
membered saturated or partially saturated monocyclic ring having
0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein
said Q is optionally and independently fused to Q.sup.1 or Q.sup.2;
or to both Q.sup.1 and Q.sup.2; wherein said Q is optionally
substituted with 0-4 J.sup.Q groups; Q.sup.1 is a 3-8 membered
saturated, partially saturated, or unsaturated monocyclic ring
having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur,
wherein said Q.sup.1 group is optionally substituted with 0-4
J.sup.Q groups; Q.sup.2 is a 3-8 membered saturated, partially
saturated, or unsaturated monocyclic ring having 0-3 heteroatoms
selected from nitrogen, oxygen, or sulfur wherein said Q.sup.2
group is optionally substituted with 0-4 J.sup.Q groups; R is H,
optionally substituted C.sub.1-6 aliphatic, C.sub.3-10
cycloaliphatic, C.sub.6-10 aryl, 5-14 membered heteroaryl, or 5-14
membered heterocyclyl; or two R groups, on the same substituent or
different substituents, together with the atom(s) to which each R
group is bound, form an optionally substituted 3-14 membered
saturated, partially unsaturated, or fully unsaturated monocyclic,
bicyclic, or tricyclic ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur wherein each R is
optionally substituted with 0-10 J.sup.R groups; each J.sup.Q and
J.sup.Z substituent on an unsaturated carbon atom is independently
selected from hydrogen, --OCF.sub.3, C.sub.1-6haloalkyl,
N(R).sub.2, OR, halogen, Y, --(V.sub.n)--CN, --(V.sub.n)--NO.sub.2,
--(V.sub.n)--OH, --(V.sub.n)--(C.sub.1-6aliphatic),
--(C.sub.3-10cycloaliphatic)-C(O)R,
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl);
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), --(V.sub.n)--(C.sub.3-10cycloaliphatic); wherein each
J.sup.Q and J.sup.Z is optionally substituted with up to 10 J.sup.R
groups; each J.sup.Q and J.sup.Z substituent on a saturated carbon
atom is selected from those listed above for an unsaturated carbon
and also the following: .dbd.O, .dbd.NN(R.sup.a).sub.2,
.dbd.NNHC(O)R.sup.a, .dbd.NNHCO.sub.2(C.sub.1-4alkyl),
.dbd.NNHSO.sub.2(C.sub.1-4alkyl), and .dbd.NR.sup.a wherein each
J.sup.Q and J.sup.Z is optionally substituted with up to 10 J.sup.R
groups; each J.sup.Q and J.sup.Z substituent on a nitrogen atom is
independently selected from hydrogen, Y, --(V.sub.n)--CN,
--(V.sub.n)--NO.sub.2, --(V.sub.n)--OH,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(C.sub.3-10cycloaliphatic)-C(O)R,
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), --(V.sub.n)--(C.sub.3-10cycloaliphatic); wherein two
J.sup.Z groups, on the same substituent or different substituents,
together with the atom(s) to which each J.sup.Z group is bound, can
optionally form an optionally substituted 3-14 membered saturated,
partially unsaturated, or fully unsaturated monocyclic, bicyclic,
or tricyclic ring having 0-4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur; wherein each J.sup.Q and J.sup.Z
is optionally substituted with up to 10 J.sup.R groups; J.sup.R is
selected from halogen, --N(R.sup.b).sub.2, SR.sup.b, OR.sup.b, oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, L,
-(L.sub.n)-(C.sub.1-6alkyl), -(L.sub.n)-(C.sub.3-12heterocyclyl),
-(L.sub.n)-(C.sub.6-10aryl), -(L.sub.n)-(5-10 membered heteroaryl),
-(L.sub.n)-(C.sub.3-10cycloalipahtic), -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, --CO.sub.2R.sup.b, --COR.sup.b,
--OC(O)R.sup.b, --NC(O)R.sup.b; L is C.sub.1-10alkyl wherein up to
three methylene units are replaced by --NR.sup.b--, --O--, --S--,
--CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NR.sup.b--,
--C(.dbd.N--CN), --NR.sup.bCO--, --NR.sup.bC(O)O--,
--SO.sub.2NR.sup.b--NR.sup.bSO.sub.2--, --NR.sup.bC(O)NR--,
--OC(O)NR.sup.b--, --NR.sup.bSO.sub.2NR.sup.b--, --SO--, or
--SO.sub.2--; V is C.sub.1-10aliphatic wherein up to three
methylene units are replaced by G.sup.V, wherein G.sup.V is
selected from --NR--, --O--, --S--, --CO.sub.2--, --OC(O)--,
--C(O)CO--, --C(O)--, --C(O)NR--, --C(.dbd.N--CN), --NRCO--,
--NRC(O)O--, --SO.sub.2NR--, --NRSO.sub.2--, --NRC(O)NR--,
--OC(O)NR--, --NRSO.sub.2NR--, --SO--, or --SO.sub.2--; Y is
C.sub.1-10aliphatic, wherein up to three methylene units are
replaced by G.sup.Y wherein G.sup.Y is selected from --NR--, --O--,
--S--, --CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NR--,
--C(.dbd.N--CN), --NRCO--, --NRC(O)O--, --SO.sub.2NR--,
--NRSO.sub.2--, --NRC(O)NR--, --OC(O)NR--, --NRSO.sub.2NR--,
--SO--, or --SO.sub.2--; R.sup.a is hydrogen or C.sub.1-6 aliphatic
group optionally substituted with 0-3 J.sup.R groups; R.sup.b is
hydrogen or an unsubstituted C.sub.1-6 aliphatic group; n is 0 or
1; provided that: when R.sup.1 and R.sup.2 are H, and Z.sup.2 and
Z.sup.3 are H, then Z.sup.1 is not methyl; when R.sup.1 is CH.sub.3
and R.sup.2 is H, then Z.sup.1, Z.sup.2, and Z.sup.3 are not all H;
when R.sup.1 and R.sup.2 are H, and Z.sup.2 and Z.sup.3 are H, then
Z.sup.1 is not unsubstituted phenyl, 4-pyridyl, or one of the
structures shown below: ##STR00128## and when R.sup.1 and R.sup.2
are H, Z.sup.1 and Z.sup.2 taken together are not
--C.ident.C--CH.sub.2CH.sub.2COOH.
2. The compound according to claim 1 wherein Z.sup.1, Z.sup.2, and
Z.sup.3, together with the carbon atom to which they are attached,
form the bicyclic ring shown in Formula II: ##STR00129## wherein
Q.sup.3 is 3-8 membered saturated, unsaturated, or partially
saturated monocyclic ring; Q and Q.sup.3 are each optionally and
independently substituted with 0-4 J.sup.Q groups.
3. The compound according claim 2 wherein Q.sup.3 is a cyclopropyl
group and both Q and Q.sup.3 are each optionally substituted with
0-2 J.sup.Q groups as shown in formula III: ##STR00130##
4. The compound according to claim 1, wherein Z.sup.1 and Z.sup.2,
together with the carbon atom to which they are attached, form a
compound as shown in Formula IV: ##STR00131## wherein Z.sup.11 is
selected from C, N, O, or S; Z.sup.12 is selected from C, N, O, or
S; Q is a 3-8 membered saturated or partially saturated monocyclic
ring, optionally fused to Q.sup.1 or Q.sup.2; Q.sup.1 and Q.sup.2
are each independently a 3-8 membered saturated, unsaturated, or
partially saturated monocyclic ring; Q, Q.sup.1 and Q.sup.2 each
independently contain up to three heteroatoms selected from O, N,
or S; m is 0-4; and is independently selected for Q, Q.sup.1 and
Q.sup.2; and Z.sup.3 is H; or if the bond between C and Z.sup.11 is
a double bond, then Z.sup.3 is absent.
5-8. (canceled)
9. The compound according to claim 1, wherein Z.sup.12 is carbon
and the fused ring of Q, Q.sup.1, and optionally Q.sup.2 is as
shown in Formula V: ##STR00132## wherein Q, Q.sup.1, and Q.sup.2
each independently and optionally contain a) 0-2 heteroatoms
selected from O, N, or S; and b) 0-4 J.sup.Q substituents.
10. The compound according to claim 9, wherein the hydrogen atoms
at the point of fusion between ring Q and ring Q.sup.1 is in the
cis conformation as shown in Formula VI: ##STR00133##
11-19. (canceled)
20. The compound according to claim 10, wherein ring Q is a 5-7
membered cycloaliphatic.
21. The compound according to claim 10, wherein Q.sup.1 is a
6-membered aryl or 5-6 membered heteroaryl ring.
22. The compound according to claim 10, wherein Q.sup.1 is a 5-8
membered cycloaliphatic ring.
23. The compound according to claim 10, wherein Q.sup.1 is a 5-8
membered heterocyclic ring.
24. The compound according to claim 1, wherein Q or Q-Q.sup.1 is
represented is selected from ##STR00134## ##STR00135## wherein both
R.sup.7 and J.sup.Q are each independently selected from hydrogen,
Y, --(V.sub.n)--CN, --(V.sub.n)--NO.sub.2, --(V.sub.n)--OH,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), --(V.sub.n)--(C.sub.3-10cycloaliphatic), and
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl); each Q and
Q.sup.1, m is independently 0-3; and each R.sup.7 and J.sup.Q is
optionally and independently substituted with 0-10 J.sup.R
groups.
25-36. (canceled)
37. The compound according to claim 1, wherein Z.sup.1 and Z.sup.2
do not join to form a ring and Z.sup.3 is H or is absent.
38. The compound according to claim 37, wherein Z.sup.1 is H or
C.sub.1-6aliphatic optionally substituted with 0-3 J.sup.Z
groups.
39-59. (canceled)
60. A compound of formula VIII: ##STR00136## wherein A is selected
from: ##STR00137##
61. A compound selected from Table 3.
62. (canceled)
63. A method of inhibiting JAK 2 or JAK3 kinase activity in a
patient comprising administering to said patient a compound
according to claim 1 or a composition comprising said compound.
64. A method of inhibiting JAK2 or JAK3 kinase activity in a
biological sample comprising administering to contacting said
biological sample with a compound according to claim 1 or a
composition comprising said compound.
65. A method of treating or lessening the severity of a disease of
condition selected from a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a
condition associated with organ transplant, an inflammatory
disorder, or an immunologically mediated disorder, comprising the
step of administering to said patient a compound of claim 1 or a
composition comprising said compound.
66-73. (canceled)
74. A method of treating or lessening the severity of a
myeloproliferative disorder in a patient in need thereof,
comprising the step of administering to said patient a compound
according to claim 1 or a composition comprising said compound.
75-76. (canceled)
77. A method of inhibiting ROCK kinase activity in a patient or
biological sample comprising administering to said patient a
compound according to claim 1 or a composition comprising said
compound.
78-86. (canceled)
87. A composition comprising an effective amount of compound of
claim 1 and a pharmaceutically acceptable carrier, adjuvant, or
vehicle.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 11/346,048, filed Feb. 2, 2006, which claims priority to U.S.
Provisional Application 60/649,781, filed Feb. 3, 2005, the entire
contents of which are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as
inhibitors of Janus kinases (JAK). The invention also provides
pharmaceutically acceptable compositions comprising the compounds
of the invention and methods of using the compositions in the
treatment of various disorders.
BACKGROUND OF THE INVENTION
[0003] The Janus kinases (JAK) are a family of tyrosine kinases
consisting of JAK1, JAK2, JAK3 and TYK2. The JAKs play a critical
role in cytokine signaling. The down-stream substrates of the JAK
family of kinases include the signal transducer and activator of
transcription (STAT) proteins. JAK/STAT signaling has been
implicated in the mediation of many abnormal immune responses such
as allergies, asthma, autoimmune diseases such as transplant
rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and
multiple sclerosis as well as in solid and hematologic malignancies
such as leukemias and lymphomas. JAK2 has also been implicated in
myeloproliferative disorders, which include polycythemia vera,
essential thrombocythemia, chronic idiopathic myelofibrosis,
myeloid metaplasia with myelofibrosis, chronic myeloid leukemia,
chronic myelomonocytic leukemia, chronic eosinophilic leukemia,
hypereosinophilic syndrome and systematic mast cell disease.
[0004] The Rho-associated coiled-coil forming protein
serine/threonine kinase (ROCK) family are effectors of Ras-related
small GTPase Rho. The ROCK family includes p160ROCK (ROCK-1),
ROKa/Rho-kinase/ROCK-II, protein kinase PKN, and citron and citron
kinase. ROCK has been implicated in various diseases and disorders
including hypertension, chronic obstructive pulmonary disease,
cerebral vasospasm, coronary vasospasm, bronchial asthma, erectile
dysfunction, glaucoma, vascular smooth muscle cell proliferation,
myocardial hypertrophy, malignoma, ischemia/reperfusion-induced
injury, endothelial dysfunction, Crohn's Disease and colitis,
neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease,
atherosclerosis, and cardiac hypertrophy and perivascular
fibrosis.
[0005] Protein kinase A (PKA; also known as cAMP-dependent protein
kinase) is a tetrameric holoenzyme, which contains two catalytic
subunits bound to a homo-dimeric regulatory subunit (which acts to
inhibit the catalytic sub-units). On binding of cAMP (enzyme
activation), the catalytic subunits dissociate from the regulatory
subunits to yield the active serine/threonine kinase. Three
isoforms of the catalytic subunit (C-.alpha., C-.beta. and
C-.gamma.) have been reported to date, with the C-.alpha. subunit
being the most extensively studied, primarily because of its
elevated expression in primary and metastatic melanomas. PKA has
been shown to regulate many vital functions including energy
metabolism, gene transcription, proliferation, differentiation,
reproductive function, secretion, neuronal activity, memory,
contractility and motility.
[0006] Accordingly, there is a great need to develop compounds
useful as inhibitors of protein kinases, including JAK family, ROCK
and PKA kinases. In particular, it would be desirable to develop
compounds that are useful as inhibitors of JAK2 and JAK3.
SUMMARY OF THE INVENTION
[0007] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are effective as
inhibitors of protein kinases, particularly the JAK family kinases.
In certain embodiments, these compounds are effective as inhibitors
of JAK3 protein kinases. These compounds have the general formula
I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein R.sup.1,
R.sup.2, Z.sup.1, Z.sup.2, and Z.sup.3 are as defined below.
[0008] These compounds, and pharmaceutically acceptable
compositions thereof, are useful for treating or lessening the
severity of a variety of disorders, including allergic disorders
such as asthma and atopic dermatitis, autoimmune diseases such as
SLE lupus and psoriasis, conditions associated with organ
transplantation, myeloproliferative disorders, hypertension,
chronic obstructive pulmonary disease and proliferative disorders
such as melanoma.
DETAILED DESCRIPTION OF THE INVENTION
Compounds and Definitions
[0009] Compounds of this invention include those described
generally above, and are further illustrated by the classes,
subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For
purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 75.sup.th Ed. Additionally,
general principles of organic chemistry are described in "Organic
Chemistry", Thomas Sorrell, University Science Books, Sausalito:
1999, and "March's Advanced Organic Chemistry", 5.sup.th Ed., Ed.:
Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,
the entire contents of which are hereby incorporated by
reference.
[0010] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, refers to the replacement of hydrogen radicals
in a given structure with the radical of a specified substituent.
Unless otherwise indicated, an optionally substituted group may
have a substituent at each substitutable position of the group, and
when more than one position in any given structure may be
substituted with more than one substituent selected from a
specified group, the substituent may be either the same or
different at every position.
[0011] As described herein, when the term "optionally substituted"
precedes a list, said term refers to all of the subsequent
substitutable groups in that list. For example, if X is halogen;
optionally substituted C.sub.1-3alkyl or phenyl; X may be either
optionally substituted alkyl or optionally substituted phenyl.
Likewise, if the term "optionally substituted" follows a list, said
term also refers to all of the substitutable groups in the prior
list unless otherwise indicated. For example: if X is halogen,
C.sub.1-3alkyl or phenyl wherein X is optionally substituted by
J.sup.X, then both C.sub.1-3alkyl and phenyl may be optionally
substituted by J.sup.x. As is apparent to one having ordinary skill
in the art, groups such as H, halogen, NO.sub.2, CN, NH.sub.2, OH,
or OCF.sub.3 would not be included because they are not
substitutable groups.
[0012] Combinations of substituents envisioned by this invention
are preferably those that result in the formation of stable or
chemically feasible compounds. The term "stable", as used herein,
refers to compounds that are not substantially altered when
subjected to conditions to allow for their production, detection,
and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a
stable compound or chemically feasible compound is one that is not
substantially altered when kept at a temperature of 40.degree. C.
or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0013] As described herein, a bond drawn from a substituent to the
center of one ring within a multiple-ring system (as shown below),
represents substitution of the substituent at any substitutable
position in any of the rings within the multiple ring system. For
example, Figure a represents possible substitution in any of the
positions shown in Figure b.
##STR00002##
[0014] This also applies to multiple ring systems fused to optional
ring systems (which would be represented by dotted lines). For
example, in Figure c, X is an optional substituent both for ring A
and ring B.
##STR00003##
[0015] If, however, two rings in a multiple ring system each have
different substituents drawn from the center of each ring, then,
unless otherwise specified, each substituent only represents
substitution on the ring to which it is attached. For example, in
Figure d, Y is an optionally substituent for ring A only, and X is
an optional substituent for ring B only.
##STR00004##
[0016] The term "aliphatic" or "aliphatic group", as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation. Unless otherwise
specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In
some embodiments, aliphatic groups contain 1-10 aliphatic carbon
atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic
carbon atoms. In still other embodiments, aliphatic groups contain
1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic
groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic
groups include, but are not limited to, linear or branched,
substituted or unsubstituted alkyl, alkenyl, or alkynyl groups.
Further examples of aliphatic groups include methyl, ethyl, propyl,
butyl, isopropyl, isobutyl, vinyl, and sec-butyl.
[0017] The term "cycloaliphatic" (or "carbocycle" or "cycloalkyl")
refers to a monocyclic C.sub.3-C.sub.8 hydrocarbon or bicyclic
C.sub.8-C.sub.12 hydrocarbon that is completely saturated or that
contains one or more units of unsaturation, but which is not
aromatic, that has a single point of attachment to the rest of the
molecule wherein any individual ring in said bicyclic ring system
has 3-7 members. Suitable cycloaliphatic groups include, but are
not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further
examples of aliphatic groups include cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl.
[0018] The term "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" as used herein means
non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in
which one or more ring members are an independently selected
heteroatom. In some embodiments, the "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" group has three to
fourteen ring members in which one or more ring members is a
heteroatom independently selected from oxygen, sulfur, nitrogen, or
phosphorus, and each ring in the system contains 3 to 7 ring
members.
[0019] Further examples of heterocyclic rings include, but are not
limited to, the following monocycles: 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,
2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,
3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,
5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl,
1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
5-imidazolidinyl, and the following bicycles:
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,
benzodithiane, and 1,3-dihydro-imidazol-2-one.
[0020] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon (including, any oxidized form of
nitrogen, sulfur, phosphorus, or silicon; the quaternized form of
any basic nitrogen or; a substitutable nitrogen of a heterocyclic
ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl)).
[0021] The term "unsaturated", as used herein, means that a moiety
has one or more units of unsaturation.
[0022] The term "alkoxy", or "thioalkyl", as used herein, refers to
an alkyl group, as previously defined, attached to the principal
carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl")
atom.
[0023] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means
alkyl, alkenyl or alkoxy, as the case may be, substituted with one
or more halogen atoms. The term "halogen" means F, Cl, Br, or
I.
[0024] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic,
bicyclic, and tricyclic ring systems having a total of five to
fourteen ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3 to 7 ring
members. The term "aryl" may be used interchangeably with the term
"aryl ring". The term "aryl" also refers to heteroaryl ring systems
as defined herein below. Examples of aryl rings would include
phenyl, naphthyl, and the heteroaryl group listed below.
[0025] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
monocyclic, bicyclic, and tricyclic ring systems having a total of
five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or
more heteroatoms, and wherein each ring in the system contains 3 to
7 ring members. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic".
[0026] Further examples of heteroaryl rings include the following
monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,
4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,
3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl
(e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and
5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl),
isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl,
and the following bicycles: benzimidazolyl, benzofuryl,
benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl
(e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl
(e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
[0027] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy
and the like) group may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl or
heteroaryl group are selected from those listed in the definition
of J.sup.X, J.sup.Q, J.sup.R above; halogen; --R.sup.o; --OR.sup.o;
--SR.sup.o; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph)
optionally substituted with R.sup.o; --O(Ph) optionally substituted
with R.sup.o; --(CH.sub.2).sub.1-2(Ph), optionally substituted with
R.sup.o; --CH.dbd.CH(Ph), optionally substituted with R.sup.o;
--NO.sub.2; --CN; --N(R.sup.o).sub.2; --NR.sup.oC(O)R.sup.o;
--NR.sup.oC(S)R.sup.o; --NR.sup.oC(O)N(R.sup.o).sub.2;
--NR.sup.oC(S)N(R.sup.o).sub.2; --NR.sup.oCO.sub.2R.sup.o;
--NR.sup.oNR.sup.oC(O)R.sup.o;
--NR.sup.oNR.sup.oC(O)N(R.sup.o).sub.2;
--NR.sup.oNR.sup.oCO.sub.2R.sup.o; --C(O)C(O)R.sup.o;
--C(O)CH.sub.2C(O)R.sup.o; --CO.sub.2R.sup.o; --C(O)R.sup.o;
--C(S)R.sup.o; --C(O)N(R.sup.o).sub.2; --C(S)N(R.sup.o).sub.2;
--OC(O)N(R.sup.o).sub.2; --OC(O)R.sup.o; --C(O)N(OR.sup.o)R.sup.o;
--C(NOR.sup.o)R.sup.o; --S(O).sub.2R.sup.o; --S(O).sub.3R.sup.o;
--SO.sub.2N(R.sup.o).sub.2; --S(O)R.sup.o;
--NR.sup.oSO.sub.2N(R.sup.o).sub.2; --NR.sup.oSO.sub.2R.sup.o;
--N(OR.sup.o)R.sup.o; --C(.dbd.NH)--N(R.sup.o).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.sup.o wherein each independent
occurrence of R.sup.o is selected from hydrogen, optionally
substituted C.sub.1-6aliphatic, an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, --O(Ph), or
--CH.sub.2(Ph), or, notwithstanding the definition above, two
independent occurrences of R.sup.o, on the same substituent or
different substituents, taken together with the atom(s) to which
each R.sup.o group is bound, form a 5-8-membered heterocyclyl,
aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Optional substituents on the aliphatic group of R.sup.o are
selected from NH.sub.2, NH(C.sub.1-4aliphatic),
N(C.sub.1-4aliphatic).sub.2, halogen, C.sub.1-4aliphatic, OH,
O(C.sub.1-4aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4aliphatic), O(haloC.sub.1-4 aliphatic), or
haloC.sub.1-4aliphatic, wherein each of the foregoing
C.sub.1-4aliphatic groups of R.sup.o is unsubstituted.
[0028] An aliphatic or heteroaliphatic group, or a non-aromatic
heterocyclic ring may contain one or more substituents. Suitable
substituents on the saturated carbon of an aliphatic or
heteroaliphatic group, or of a non-aromatic heterocyclic ring are
selected from those listed above for the unsaturated carbon of an
aryl or heteroaryl group and additionally include the following:
.dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2, .dbd.NNHC(O)R*,
.dbd.NNHCO.sub.2(alkyl), .dbd.NNHSO.sub.2(alkyl), or .dbd.NR*,
where each R* is independently selected from hydrogen or an
optionally substituted C.sub.1-6aliphatic. Optional substituents on
the aliphatic group of R* are selected from NH.sub.2, NH(C.sub.1-4
aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen,
C.sub.1-4aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN,
CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo
C.sub.1-4aliphatic), or halo(C.sub.1-4 aliphatic), wherein each of
the foregoing C.sub.1-4aliphatic groups of R* is unsubstituted.
[0029] Optional substituents on the nitrogen of a non-aromatic
heterocyclic ring include those listed in the definition of J.sup.Q
and R.sup.7 herein; --R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+,
--CO.sub.2R.sup.+, --C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+,
--SO.sub.2R.sup.+, --SO.sub.2N(R.sup.+).sub.2,
--C(.dbd.S)N(R.sup.+).sub.2, --C(.dbd.NH)--N(R.sup.+).sub.2, or
--NR.sup.+SO.sub.2R.sup.+; wherein R.sup.+is hydrogen, an
optionally substituted C.sub.1-6 aliphatic, optionally substituted
phenyl, optionally substituted --O(Ph), optionally substituted
--CH.sub.2(Ph), optionally substituted --(CH.sub.2).sub.1-2(Ph);
optionally substituted --CH.dbd.CH(Ph); or an unsubstituted 5-6
membered heteroaryl or heterocyclic ring having one to four
heteroatoms independently selected from oxygen, nitrogen, or
sulfur, or, notwithstanding the definition above, two independent
occurrences of R.sup.+, on the same substituent or different
substituents, taken together with the atom(s) to which each
R.sup.+group is bound, form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Optional substituents on the aliphatic group or the phenyl
ring of R.sup.+are selected from NH.sub.2, NH(C.sub.1-4 aliphatic),
N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH,
O(C.sub.1-4aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4aliphatic), O(halo C.sub.1-4 aliphatic), or
halo(C.sub.1-4 aliphatic), wherein each of the foregoing
C.sub.1-4aliphatic groups of R.sup.+ is unsubstituted.
[0030] As detailed above, in some embodiments, two independent
occurrences of R.sup.o (or R.sup.+, or any other variable similarly
defined herein), are taken together with the atom(s) to which each
variable is bound to form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Exemplary rings that are formed when two independent
occurrences of R.sup.o (or R.sup.+, or any other variable similarly
defined herein) are taken together with the atom(s) to which each
variable is bound include, but are not limited to the following: a)
two independent occurrences of R.sup.o (or R.sup.+, or any other
variable similarly defined herein) that are bound to the same atom
and are taken together with that atom to form a ring, for example,
N(R.sup.o).sub.2, where both occurrences of R.sup.o are taken
together with the nitrogen atom to form a piperidin-1-yl,
piperazin-1-yl, or morpholin-4-yl group; and b) two independent
occurrences of R.sup.o (or R.sup.+, or any other variable similarly
defined herein) that are bound to different atoms and are taken
together with both of those atoms to form a ring, for example where
a phenyl group is substituted with two occurrences of OR.sup.o
##STR00005##
these two occurrences of R.sup.o are taken together with the oxygen
atoms to which they are bound to form a fused 6-membered oxygen
containing ring:
##STR00006##
It will be appreciated that a variety of other rings can be formed
when two independent occurrences of R.sup.o (or R.sup.+, or any
other variable similarly defined herein) are taken together with
the atom(s) to which each variable is bound and that the examples
detailed above are not intended to be limiting.
[0031] An alkyl or aliphatic chain can be optionally interrupted
with another atom or group. This means that a methylene unit of the
alkyl or aliphatic chain is optionally replaced with said other
atom or group. Examples of such atoms or groups would include, but
are not limited to, --NR--, --O--, --S--, --CO.sub.2--, --OC(O)--,
--C(O)CO--, --C(O)--, --C(O)NR--, --C(.dbd.N--CN), --NRCO--,
--NRC(O)O--, --SO.sub.2NR--, --NRSO.sub.2--, --NRC(O)NR--,
--OC(O)NR--, --NRSO.sub.2NR--, --SO--, or --SO.sub.2--, wherein R
is defined herein. Unless otherwise specified, the optional
replacements form a chemically stable compound. Optional
interruptions can occur both within the chain and at either ends of
the chain; both at the point of attachment and also at the terminal
end. Two optional replacements can also be adjacent to each other
within a chain. Unless otherwise specified, if the replacement or
interruption occurs at the terminal end, the replacement atom is
bound to an H on the terminal end. For example, if
--CH.sub.2CH.sub.2CH.sub.3 were optionally interrupted with --O--,
the resulting compound could be --OCH.sub.2CH.sub.3,
--CH.sub.2OCH.sub.3, or --CH.sub.2CH.sub.2OH.
[0032] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention.
[0033] Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
[0034] The present invention relates to a compound of formula
I:
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein: wherein
[0035] R.sup.1 is H, --NO.sub.2, --CN, --OCF.sub.3, halogen, or
amino; or C.sub.1-6aliphatic, C.sub.3-7cycloaliphatic,
C.sub.1-6alkoxy, or C.sub.1-4haloalkyl optionally substituted with
0-10 J.sup.R groups; [0036] R.sup.2 is H, --NO.sub.2, --CN,
--OCF.sub.3, halogen, or amino; or C.sub.1-6aliphatic,
C.sub.3-7cycloaliphatic, C.sub.1-6alkoxy, or C.sub.1-4haloalkyl
optionally substituted with 0-10 J.sup.R groups; [0037] Z.sup.1 is
C.sub.1-6aliphatic or C.sub.3-10cycloaliphatic optionally
substituted with 0-10 J.sup.Z groups; if the bond between Z.sup.1
and C is a double bond, then Z.sup.1 may also be .dbd.O, .dbd.NR,
or .dbd.C(R).sub.2; [0038] Z.sup.2 is H or halogen; or
C.sub.1-10haloalkyl, C.sub.1-4haloalkoxy, Y, --(V.sub.n)--CN,
--(V.sub.n)--NO.sub.2, --(V.sub.n)--OH,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), or --(V.sub.n)--(C.sub.3-10cycloaliphatic) optionally
substituted with 0-10 J.sup.Z groups; or [0039] Z.sup.1 and
Z.sup.2, together with the carbon atom to which they are attached,
form ring Q; [0040] Z.sup.3 is H or C.sub.1-6alkyl optionally
substituted with 0-3 J.sup.Z groups; or [0041] Z.sup.1, Z.sup.2,
and Z.sup.3, together with the carbon atom to which they are
attached, form an 6-14 membered saturated, partially saturated, or
unsaturated bicyclic ring having 0-3 heteroatoms; wherein [0042] if
the bond between Z.sup.1 and C is a triple bond, then Z.sup.2 is
absent; and [0043] if the bond between Z.sup.1 and C is a double
bond or a triple bond, then Z.sup.3 is absent; [0044] Q is a 3-8
membered saturated or partially saturated monocyclic ring having
0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein
said Q is optionally and independently fused to Q.sup.1 or Q.sup.2;
or to both Q.sup.1 and Q.sup.2; wherein said Q is optionally
substituted with 0-4 J.sup.Q groups; [0045] Q.sup.1 is a 3-8
membered saturated, partially saturated, or unsaturated monocyclic
ring having 0-3 heteroatoms selected from nitrogen, oxygen, or
sulfur, wherein said Q.sup.1 group is optionally substituted with
0-4 J.sup.Q groups; [0046] Q.sup.2 is a 3-8 membered saturated,
partially saturated, or unsaturated monocyclic ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur wherein said
Q.sup.2 group is optionally substituted with 0-4 J.sup.Q groups;
[0047] R is H, optionally substituted C.sub.1-6 aliphatic,
C.sub.3-10 cycloaliphatic, C.sub.6-10 aryl, 5-14 membered
heteroaryl, or 5-14 membered heterocyclyl; or two R groups, on the
same substituent or different substituents, together with the
atom(s) to which each R group is bound, form an optionally
substituted 3-14 membered saturated, partially unsaturated, or
fully unsaturated monocyclic, bicyclic, or tricyclic ring having
0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur wherein said R is optionally substituted with 0-10 J.sup.R
groups; [0048] each J.sup.Q and J.sup.Z substituent on an
unsaturated carbon atom is independently selected from hydrogen,
--OCF.sub.3, C.sub.1-6haloalkyl, N(R).sub.2, OR, halogen, Y,
--(V.sub.n)--CN, --(V.sub.n)--NO.sub.2, --(V.sub.n)--OH,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(C.sub.3-10cycloaliphatic)-C(O)R,
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl);
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), --(V.sub.n)--(C.sub.3-10cycloaliphatic); wherein each
J.sup.Q and J.sup.Z is optionally substituted with up to 10 J.sup.R
groups; [0049] each J.sup.Q and J.sup.Z substituent on a saturated
carbon atom is selected from those listed above for an unsaturated
carbon and also the following: .dbd.O, .dbd.NN(R.sup.a).sub.2,
.dbd.NNHC(O)R.sup.a, .dbd.NNHCO.sub.2(C.sub.1-4alkyl),
.dbd.NNHSO.sub.2(C.sub.1-4alkyl), and .dbd.NR.sup.a wherein each
J.sup.Q and J.sup.Z is optionally substituted with up to 10 J.sup.R
groups; each J.sup.Q and J.sup.Z substituent on a nitrogen atom is
independently selected from hydrogen, Y, --(V.sub.n)--CN,
--(V.sub.n)--NO.sub.2, --(V.sub.n)--OH,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(C.sub.3-10cycloaliphatic)-C(O)R,
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), --(V.sub.n)--(C.sub.3-10cycloaliphatic); wherein two
J.sup.Z groups, on the same substituent or different substituents,
together with the atom(s) to which each J.sup.Z group is bound, can
optionally form an optionally substituted 3-14 membered saturated,
partially unsaturated, or fully unsaturated monocyclic, bicyclic,
or tricyclic ring having 0-4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur; wherein each J.sup.Q and J.sup.Z
is optionally substituted with up to 10 J.sup.R groups; [0050]
J.sup.R is selected from halogen, --N(R.sup.b).sub.2, SR.sup.b,
OR.sup.b, oxo, C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, L,
-(L.sub.n)-(C.sub.1-6alkyl), -(L.sub.n)-(C.sub.3-12heterocyclyl),
-(L.sub.n)-(C.sub.6-10aryl), -(L.sub.n)-(5-10 membered heteroaryl),
-(L.sub.n)-(C.sub.3-10cycloalipahtic), -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, --CO.sub.2R.sup.b, --COR.sup.b,
--OC(O)R.sup.b, --NC(O)R.sup.b; [0051] L is C.sub.1-10alkyl wherein
up to three methylene units are replaced by --NR.sup.b--, --O--,
--S--, --CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--,
--C(O)NR.sup.b--, --C(.dbd.N--CN), --NR.sup.bCO--,
--NR.sup.bC(O)--, --SO.sub.2NR.sup.b--, --NR.sup.bSO.sub.2--,
--NR.sup.bC(O)NR--, --OC(O)NR.sup.b--,
--NR.sup.bSO.sub.2NR.sup.b--, --SO--, or --SO.sub.2--; [0052] V is
C.sub.1-10aliphatic wherein up to three methylene units are
replaced by G.sup.V, wherein G.sup.V is selected from --NR--,
--O--, --S--, --CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--,
--C(O)NR--, --C(.dbd.N--CN), --NRCO--, --NRC(O)O--, --SO.sub.2NR--,
--NRSO.sub.2--, --NRC(O)NR--, --OC(O)NR--, --NRSO.sub.2NR--,
--SO--, or --SO.sub.2--; [0053] Y is C.sub.1-10aliphatic, wherein
up to three methylene units are replaced by G.sup.Y wherein G.sup.Y
is selected from --NR--, --O--, --S--, --CO.sub.2--, --OC(O)--,
--C(O)CO--, --C(O)--, --C(O)NR--, --C(.dbd.N--CN), --NRCO--,
--NRC(O)O--, --SO.sub.2NR--, --NRSO.sub.2--, --NRC(O)NR--,
--OC(O)NR--, --NRSO.sub.2NR--, --SO--, or --SO.sub.2--; [0054]
R.sup.a is hydrogen or C.sub.1-6aliphatic group optionally
substituted with 0-3 J.sup.R groups; [0055] R.sup.b is hydrogen or
an unsubstituted C.sub.1-6 aliphatic group; [0056] n is 0 or 1;
[0057] provided that: [0058] when R.sup.1 and R.sup.2 are H, and
Z.sup.2 and Z.sup.3 are H, then Z.sup.1 is not methyl; [0059] when
R.sup.1 is CH.sub.3 and R.sup.2 is H, then Z.sup.1, Z.sup.2, and
Z.sup.3 are not all H; [0060] when R.sup.1 and R.sup.2 are H, and
Z.sup.2 and Z.sup.3 are H, then Z.sup.1 is not unsubstituted
phenyl, 4-pyridyl, or one of the structures shown below:
##STR00008##
[0060] and [0061] when R.sup.1 and R.sup.2 are H, Z.sup.1 and
Z.sup.2 taken together are not
--C.ident.C--CH.sub.2CH.sub.2COOH.
[0062] According to one embodiment of this invention, Z.sup.1,
Z.sup.2, and Z.sup.3, together with the carbon atom to which they
are attached, form the bicyclic ring shown in Formula I:
##STR00009##
wherein [0063] Q.sup.3 is 3-8 membered saturated, unsaturated, or
partially saturated monocyclic ring; [0064] Q and Q.sup.3 are each
optionally and independently substituted with 0-4 J.sup.Q
groups.
[0065] In one embodiment, Q.sup.3 is a cyclopropyl group optionally
substituted with 0-2 J.sup.Q groups as shown in formula II:
##STR00010##
[0066] According to another embodiment of this invention, Z.sup.1
and Z.sup.2, together with the carbon atom to which they are
attached, form a monocyclic, bicyclic, or tricyclic ring as shown
in formula III:
##STR00011##
wherein [0067] Z.sup.11 is selected from C, N, O, or S; [0068]
Z.sup.12 is selected from C, N, O, or S; [0069] Q is a 3-8 membered
saturated or partially saturated monocyclic ring, optionally fused
to Q1 or Q2; [0070] Q.sup.1 and Q.sup.2 are each independently a
3-8 membered saturated, unsaturated, or partially saturated
monocyclic ring; [0071] Q, Q.sup.1 and Q.sup.2 each independently
contain up to three heteroatoms selected from O, N, or S; [0072] m
is 0-4; and is independently selected for Q, Q.sup.1 and Q.sup.2;
and [0073] Z.sup.3 is H; or if the bond between C and Z.sup.11 is a
double bond, then Z.sup.3 is absent.
[0074] In some embodiments, Z.sup.11 and Z.sup.12 are each
independently carbon.
[0075] In one embodiment, Q is C.sub.3-7 monocycle and Q.sup.1 and
Q.sup.2 are absent.
[0076] In another embodiment, Q and Q.sup.1 together form a fused
6-14 membered bicyclic ring and Q.sup.2 is absent.
[0077] In yet another embodiment, Q, Q.sup.1, and Q.sup.2 together
form a fused 8-20 membered tricyclic ring.
[0078] In one embodiment, of the invention Z.sup.12 is carbon and
the fused ring of Q, Q.sup.1, and optionally Q.sup.2 is as shown in
Formula IV:
##STR00012##
wherein Q, Q.sup.1, and Q.sup.2 each independently and optionally
contain [0079] a) 0-2 heteroatoms selected from O, N, or S; and
[0080] b) 0-4 J.sup.Q substituents.
[0081] In one embodiment, the hydrogen atoms at the point of fusion
between ring Q and ring Q.sup.1 is in the cis conformation as shown
in Formula V:
##STR00013##
[0082] In another embodiment, the hydrogen atoms at the point of
fusion between ring Q and ring Q.sup.1 are in the trans
conformation.
[0083] In one embodiment, C--Z.sup.11 is a single bond.
[0084] In another embodiment, C.dbd.Z.sup.11 is a double bond.
[0085] In certain embodiments, ring Q contains up to two
heteroatoms. In other embodiments, ring Q contains one heteroatom;
and in yet other embodiments, ring Q contains zero heteroatoms.
[0086] In one embodiment, Q contains two heteroatoms and each of
said heteroatoms are independently selected from nitrogen, sulfur,
or oxygen; preferably nitrogen and sulfur; more preferably,
nitrogen. In some embodiments, both heteroatoms are nitrogen. In
other embodiments, one is nitrogen and the other is sulfur. In some
embodiments, one heteroatom is nitrogen and the other is oxygen. In
yet other embodiments, one heteroatom is nitrogen and the other is
sulfur.
[0087] In another embodiment, Q contains one heteroatom selected
from O, N, or S. In some embodiments, the heteroatom is oxygen; in
other embodiments, the heteroatom is nitrogen; in yet other
embodiments, the heteroatom is sulfur. In some embodiments, the
sulfur is optionally substituted with 0, 1, or 2 oxo groups.
[0088] Examples of heterocyclic groups include piperidine,
piperazine, morpholine, thiomorpholine, and pyrrolidine.
[0089] In some embodiments, ring Q is a 5-7 membered
cycloaliphatic. Examples of cycloaliphatic groups include
cyclohexane, cyclopentane, cyclohexene, and cyclopentene.
[0090] In other embodiments, Q.sup.1 is a 6-membered aryl or 5-6
membered heteroaryl ring. Examples of aryl or heteroaryl rings
include phenyl, pyridine, pyrimidine, thiophene, thiazole,
tetrazole, triazole, pyrrole, furan, and pyrazole.
[0091] In some embodiments, Q.sup.1 is a 3-7 membered
cycloaliphatic ring. Examples of cycloaliphatic rings include
cyclohexane, cyclopentane, cyclohexene, cyclopentene, cycloheptene,
cycloheptane, cyclopropane, cyclobutane, cyclopropene, and
cyclobutene.
[0092] In other embodiment, Q.sup.1 is a 3-7 membered heterocyclic
ring. Examples of heterocyclic groups include piperidine,
piperazine, morpholine, thiomorpholine, pyrrolidine,
homopiperidine, and homopiperazine.
[0093] In one embodiment, Q or Q-Q.sup.1 is represented by the
following structures:
##STR00014## ##STR00015##
wherein both R.sup.7 and J.sup.Q are each independently selected
from hydrogen, Y, --(V.sub.n)--CN, --(V.sub.n)--NO.sub.2,
--(V.sub.n)--OH, --(V.sub.n)--(C.sub.1-6aliphatic),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), --(V.sub.n)--(C.sub.3-10cycloaliphatic), and
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl); [0094]
wherein for each Q and Q.sup.1, m is independently 0-3; and [0095]
each R.sup.7 and J.sup.Q is optionally and independently
substituted with 0-10 J.sup.R groups.
[0096] In one embodiment m is 0, 1, or 2. In another embodiment, m
is 1 or 2. In some embodiments, m is 0; in other embodiments, m is
1; in yet other embodiments, m is 2.
[0097] In some embodiments, J.sup.Q is Y, --(V.sup.1.sub.n)--CN,
--(V.sup.1.sub.n)--NO.sub.2, --(V.sup.1.sub.n)--OH,
--(V.sup.1.sub.n)--(C.sub.1-6aliphatic),
--(V.sup.1.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sup.1.sub.n)--C.sub.6-10aryl), --(V.sup.1.sub.n)-(5-10
membered heteroaryl),
--(V.sup.1.sub.n)--(C.sub.3-10cycloaliphatic), or
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl); wherein
[0098] V.sup.1 is -G.sup.V-(X).sub.p, wherein X is a
C.sub.1-9aliphatic wherein up to two methylene units are replaced
by --NR--, --O--, --S--, --CO.sub.2--, --OC(O)--, --C(O)CO--,
--C(O)--, --C(O)NR--, --C(.dbd.N--CN), --NRCO--, --NRC(O)O--,
--SO.sub.2NR--, --NRSO.sub.2--, --NRC(O)NR--, --OC(O)NR--,
--NRSO.sub.2NR--, --SO--, or --SO.sub.2--; [0099] p is 0 or 1;
[0100] n is 0 or 1; [0101] G.sup.V is selected from C.dbd.O,
C(.dbd.O)NR, S(O).sub.2 or S(O); and [0102] said J.sup.Q is
optionally substituted with 0-10 J.sup.R groups.
[0103] In one embodiment, X is optionally substituted
C.sub.1-4aliphatic. In some embodiments, X is optionally
substituted C.sub.1-4alkyl. In some embodiments, X is optionally
substituted C.sub.1-2alkyl.
[0104] In some embodiments, n is 0. In other embodiments, n is 1.
In certain embodiments, p is 0. In other embodiments, p is 1.
[0105] In some embodiments, J.sup.Q is optionally substituted with
0-10 J.sup.R groups. In some embodiments, 0-5 J.sup.R groups; in
other embodiments, 0-3 J.sup.R groups; and in yet other
embodiments, 0-2 J.sup.R groups; In some embodiments, one J.sup.R
group, and in certain embodiments, 0 J.sup.R groups.
[0106] In one embodiment, G.sup.V is C.dbd.O.
[0107] In another embodiment of this invention, R.sup.1 and R.sup.2
are each independently H, halogen, C.sub.1-4alkyl, or
C.sub.1-4alkoxy. In one embodiment, R.sup.1 and R.sup.2 are each
independently H.
[0108] In some embodiments, R.sup.7 is independently selected from
Y, --(V.sup.1.sub.n)--CN, --(V.sup.1.sub.n)--NO.sub.2,
--(V.sup.1.sub.n---OH, --(V.sup.1.sub.n)--(C.sub.1-6aliphatic),
--(V.sup.1.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sup.1.sub.n)--(C.sub.6-10aryl), --(V.sup.1.sub.n)-(5-10
membered heteroaryl),
--(V.sup.1.sub.n)--(C.sub.3-10cycloaliphatic), or
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl); wherein
[0109] V.sup.1 is -G.sup.V-(X).sub.p wherein X is a
C.sub.1-9aliphatic wherein up to two methylene units are replaced
by --NR--, --O--, --S--, --CO.sub.2--, --OC(O)--, --C(O)CO--,
--C(O)--, --C(O)NR--, --C(.dbd.N--CN), --NRCO--, --NRC(O)O--,
--SO.sub.2NR--, --NRSO.sub.2--, --NRC(O)NR--, --OC(O)NR--,
--NRSO.sub.2NR--, --SO--, or --SO.sub.2--; [0110] p is 0 or 1;
[0111] n is 0 or 1; and [0112] G.sup.V is selected from C.dbd.O,
C(.dbd.O)NR, S(O).sub.2 or S(O). [0113] Representative examples of
compounds of formula I are set forth in Table 1.
TABLE-US-00001 [0113] TABLE 1 Formula VI ##STR00016## wherein A is
selected from: ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##
##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##
##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055##
##STR00056## or ##STR00057##
[0114] In another embodiment of this invention, Z.sup.1 and Z.sup.2
do not join to form a ring and Z.sup.3 is H or is absent.
[0115] In one embodiment, Z.sup.1 is H or C.sub.1-6aliphatic
optionally substituted with 0-3 J.sup.Z groups. In some
embodiments, Z.sup.1 is H.
[0116] In certain embodiments, C.ident.Z.sup.1 is a triple bond,
and Z.sup.2 and Z.sup.3 are absent.
[0117] In other embodiments, C.dbd.Z.sup.1 is a double bond and
Z.sup.3 is absent.
[0118] In certain embodiments, Z.sup.1 is O; in other embodiments,
Z.sup.1 is CH.sub.2.
[0119] In certain embodiments, Z.sup.2 is optionally substituted Y,
--(V.sub.n)--(C.sub.1-6aliphatic),
--(V.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sub.n)--(C.sub.6-10aryl), --(V.sub.n)-(5-10 membered
heteroaryl), or --(V.sub.n)--(C.sub.3-10cycloaliphatic). In some
embodiments, is 0; In other embodiments, n is 1.
[0120] In other embodiments, Z.sup.2 is an optionally substituted
5-7 membered monocycle selected from heterocyclyl, cycloaliphatic,
aryl, or heteroaryl; preferably a 5-7 membered fully or partially
saturated monocycle selected from heterocyclyl or cycloaliphatic;
more preferably, a 6-membered monocycle with 0-2 nitrogen atoms. In
one preferred embodiment of this invention, Z.sup.2 is piperidine
optionally substituted with 0-3 J.sup.Z groups.
[0121] In some embodiments, Z.sup.2 is optionally substituted
--(V.sub.n)--(C.sub.3-10cycloaliphatic) wherein n is 0. In one
embodiment, Z.sup.2 is a bicyclo-octane ring. In another
embodiment, Z.sup.2 is a C.sub.5-7cycloaliphatic. In yet another
embodiment, Z.sup.2 is a C.sub.5-7cycloalkyl.
[0122] In one embodiment, J.sup.Z is halogen, CF.sub.3, optionally
substituted C.sub.1-4haloalkyl, --(V.sup.1.sub.n)--CN,
--(V.sup.1.sub.n)--NO.sub.2, --(V.sup.1.sub.n)--OH, Y,
--(V.sup.1.sub.n)--(C.sub.3-12heterocyclyl),
--(V.sup.1.sub.n)--(C.sub.6-10aryl), --(V.sup.1.sub.n)-(5-10
membered heteroaryl),
--(V.sup.1.sub.n)--(C.sub.3-10cycloaliphatic), or
--(C.sub.3-10cycloaliphatic)-(C.sub.3-12heterocyclyl); wherein
[0123] V.sup.1 is -G.sup.V-(X).sub.p wherein X is a
C.sub.1-9aliphatic wherein up to two methylene units are replaced
by --NR--, --O--, --S--, --CO.sub.2--, --OC(O)--, --C(O)CO--,
--C(O)--, --C(O)NR--, --C(.dbd.N--CN), --NRCO--, --NRC(O)O--,
--SO.sub.2NR--, --NRSO.sub.2--, --NRC(O)NR--, --OC(O)NR--,
--NRSO.sub.2NR--, --SO--, or --SO.sub.2; [0124] p is 0 or 1; and
[0125] G.sup.V is selected from C.dbd.O, C(.dbd.O)NR, S(O).sub.2 or
S(O).
[0126] In some embodiments, X is C.sub.1-5aliphatic. In certain
preferred embodiments, X is C.sub.1-5alkyl. In other preferred
embodiments, X is C.sub.1-2alkyl.
[0127] In some embodiments, G.sup.V is selected from C.dbd.O,
C(.dbd.O)NR, S(O).sub.2 or S(O). In certain embodiments, G.sub.V is
C.dbd.O. In other embodiments, G.sub.V is C(.dbd.O)NR. In yet other
embodiments, G.sup.V is S(O).sub.2 or S(O).
[0128] In some embodiments, J.sup.Z is halogen, CF.sub.3, CN,
optionally substituted C.sub.1-6aliphatic, C.sub.1-4haloalkyl,
--(C.sub.1-6alkyl)-R.sup.J,
--(C.sub.1-6alkyl).sub.n-C(.dbd.O)R.sup.J,
--(C.sub.1-6alkyl).sub.n-CON(R.sup.b)R.sup.J,
--(C.sub.1-6alkyl).sub.n-N(R.sup.b)R.sup.J,
--(C.sub.1-6alkyl).sub.n-OR.sup.J,
--(C.sub.1-6alkyl).sub.n-OCON(R.sup.b)R.sup.J,
--(C.sub.1-6aliphatic).sub.n-S(O)N(R.sup.b)R.sup.J,
--(C.sub.1-6aliphatic).sub.n-S(O)R.sup.J, or
--(C.sub.1-6aliphatic).sub.n-NHC(O)R.sup.J; wherein [0129] R.sup.J
is C.sub.1-6aliphatic, C.sub.3-12heterocyclyl, C.sub.6-10aryl, 5-10
membered heteroaryl, or C.sub.3-10cycloaliphatic; and [0130] n is 0
or 1.
[0131] In other embodiments, J.sup.Z is halogen, OR.sup.J,
N(R.sup.b).sub.2, CF.sub.3, CN, optionally substituted
C.sub.1-6alkyl, --(C.sub.1-6alkyl)-R.sup.J,
--C(.dbd.O)(C.sub.1-6alkyl), --CON(R.sup.b)(C.sub.1-6alkyl),
--OCON(R.sup.b)(C.sub.1-6alkyl), --S(O)N(R.sup.b)(C.sub.1-6alkyl),
--S(O)(C.sub.1-6alkyl), --NHC(O)C.sub.1-6alkyl,
--(C.sub.1-6alkyl)-CONH, --(C.sub.1-6alkyl)-N(R.sup.b).sub.2,
--(C.sub.1-6alkyl)-OCON(R.sup.b)R.sup.J,
--(C.sub.1-6aliphatic)-S(O)N(R.sup.b)(C.sub.6-10aryl),
--N(R.sup.b)C(O)N(R.sup.b)R.sup.J, or --N(R.sup.b)C(O)R.sup.b.
[0132] In other embodiments, J.sup.Z is halogen, OR,
N(R.sup.b).sub.2, CF.sub.3, CN, optionally substituted
C.sub.1-6alkyl, --(C.sub.1-6alkyl)-R.sup.J,
C(.dbd.O)(C.sub.1-6alkyl), CONH, --(C.sub.1-6alkyl)-CONH,
--(C.sub.1-6alkyl)-N(R.sup.b).sub.2,
--(C.sub.1-6alkyl)-OCON(R.sup.b)R.sup.J,
--(C.sub.1-6aliphatic)-S(O)N(R.sup.b)(C.sub.6-10aryl),
--N(R.sup.b)C(O)N(R.sup.b).sub.2, or --N(R.sup.b)C(O)R.sup.b.
[0133] In certain embodiments, R.sup.J is C.sub.6-10aryl or 5-10
membered heteroaryl. In other embodiments, R.sup.J is
C.sub.1-6aliphatic or C.sub.3-10cycloaliphatic. In some
embodiments, R.sup.J is C.sub.1-6aliphatic. In other embodiments,
R.sup.J is C.sub.3-10cycloaliphatic.
[0134] In some embodiments, n is 1. In other embodiments, n is
0.
[0135] In certain embodiments, J.sup.Z is optionally substituted
--C(.dbd.O)(C.sub.1-6alkyl), --C(.dbd.O)CH.sub.2CN, or
C.sub.1-6alkyl.
[0136] Representative examples of compounds of formula I are set
forth in Table 2.
TABLE-US-00002 TABLE 2 Formula VII ##STR00058## wherein A is
selected from: ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067##
##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072##
##STR00073## ##STR00074## ##STR00075## or ##STR00076##
[0137] Representative examples of compounds of Formula I are set
forth below in Table 3:
TABLE-US-00003 1 ##STR00077## 2 ##STR00078## 3 ##STR00079## 4
##STR00080## 5 ##STR00081## 6 ##STR00082## 7 ##STR00083## 8
##STR00084## 9 ##STR00085## 10 ##STR00086## 11 ##STR00087## 12
##STR00088## 13 ##STR00089## 14 ##STR00090## 15 ##STR00091## 16
##STR00092## 17 ##STR00093## 18 ##STR00094## 19 ##STR00095## 20
##STR00096## 21 ##STR00097## 22 ##STR00098## 23 ##STR00099## 24
##STR00100## 25 ##STR00101## 26 ##STR00102## 27 ##STR00103## 28
##STR00104## 29 ##STR00105## 30 ##STR00106## 31 ##STR00107##
General Synthetic Methodology:
[0138] The compounds of this invention may be prepared in general
by methods known to those skilled in the art for analogous
compounds or by those methods depicted in the Examples below. In
general, Example 1 depicts several methods for the preparation of
functionalized quinoxalines.
[0139] Although certain exemplary embodiments are depicted and
described herein, it will be appreciated that a compounds of the
invention can be prepared according to the methods described
generally above using appropriate starting materials by methods
generally available to one of ordinary skill in the art.
[0140] All references provided in the synthetic schemes and
examples are herein incorporated by reference. As used herein, all
abbreviations, symbols and conventions are consistent with those
used in the contemporary scientific literature. See, e.g., Janet S.
Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors,
2nd Ed., Washington, D.C.: American Chemical Society, 1997, herein
incorporated in its entirety by reference. In addition, the
following definitions describe terms and abbreviations used herein:
[0141] Ts--Cl--p-toluenesulfonyl chloride (tosyl chloride) [0142]
DMF--dimethylformamide [0143] Tf--triflate [0144] LiHMDS--lithium
hexamethyldisilazide [0145]
dppf--1,1'-bis(diphenylphosphino)-ferrocene [0146] Ac--acetyl
[0147] DME--1,2-Dimethoxyethane [0148] atm--atmospheres [0149]
EDCI--1-Ethyl-3-(3-dimethylaminopropy)carbodiimide Hydrochloride
[0150] DIEA--diisopropylethylamine [0151] LiHMDS--Lithium
Hexamethyldisilazane [0152] THF--tetrahydrofuran [0153]
HEPES--4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [0154]
Glu--glutamate [0155] Tyr--tyrosine [0156] ATP--adenosine
triphosphate [0157] Ph--phenyl [0158] Me--methyl [0159] BSA--bovine
serum albumin [0160] DTT--dithiothreitol
##STR00108##
[0161] Scheme 1 is a representative scheme for the preparation of
compounds of this invention. Compound 1, which is commercially
available, can be protected by a suitable protecting group (e.g.
Tosyl) as described in T. W. Greene & P. G. M Wutz, "Protective
Groups in Organic Synthesis", 3.sup.rd Edition, John Wiley &
Sons, Inc. (1999)) to form compound 2. Boronic acids/esters (5) can
be prepared from the corresponding vinyl halides (4b) or vinyl
triflates (4a) as described in Comins, D. L.; Dehghani, A.
Tetrahedron Lett. 1992, 33, 6299-6302; McMurry, J. E.; Scott, W. J.
Tetrahedron Lett., 1983, 24, 979; Stang, P. J.; Fisk, P. J.
Synthesis, 1980, 283; Stang, P. J.; Fisk, P. J. Synthesis, 1979,
438; Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am.
Chem. Soc., 2002, 124, 8001 and references therein. The Pd-mediated
cross coupling of the N-protected halide (e.g. chloride) (2) and
the boronic acid (3) in the presence of an appropriate base such as
KOAc or Na.sub.2CO.sub.3 provides compounds of type (6) as
described in A. Suzuki, H. C. Brown "Organic Synthesis Via Boranes;
Volume 3: Suzuki Coupling" Aldrich Chemical Company: Milwaukee,
Wis., 2003 and references therein. Deprotection under basic
conditions (e.g. LiOH.sub.(aq) or NaOMe) then delivers (7).
Hydrogenation with Pd--C under H2 atmosphere gives (8).
Cyclopropanation of (7), as described in Reiser, Oliver
"Cyclopropanation and other reactions of palladium-carbene (and
carbyne) complexes" Handbook of Organopalladium Chemistry for
Organic Synthesis (2002), 1 1561-1577, gives (9).
##STR00109##
[0162] Scheme 2 shows additional methods for the preparation of
compounds of this invention. In addition to acid chlorides,
isocyanates, and oxalyl chlorides, other compounds that react with
amines can be used to form P.sub.1 substitutions. Examples include,
but are not limited to, R'-halogen, R'-tosyl, R'-mesylate,
R'S(O).sub.2Cl, R'NS(O).sub.2Cl, R'OH, R'COOH, and
R'CH.sub.2-halogen. --C.dbd.CH.sub.2 compounds can optionally be
converted into --C.dbd.O compounds with ozonolysis (g).
##STR00110##
[0163] Scheme III shows an additional method for preparing
compounds of this invention. The aryl bromide or iodide can be
coupled with substituted terminal alkynes in the presence of
palladium, base, and CuI under Sonogashira coupling conditions
(Sonogashira, Kenkichi. "Palladium-catalyzed alkynylation"
Editor(s): Negishi, Ei-ichi. Handbook of Organopalladium Chemistry
for Organic Synthesis (2002), 1: 493-529. Publisher: John Wiley
& Sons, Inc., Hoboken, N.J.) to form the product as shown. HR'
refers to suitable terminal alkynes which are either commercially
available or can be made from commercially available starting
materials.
[0164] Although certain exemplary embodiments are depicted and
described above and herein, it will be appreciated that a compounds
of the invention can be prepared according to the methods described
generally above using appropriate starting materials by methods
generally available to one of ordinary skill in the art.
Uses, Formulations and Administration
[0165] As discussed above, the present invention provides compounds
that are inhibitors of protein kinases, including JAK family, ROCK
and PKA kinases, particularly JAK2 and JAK3 kinases, and thus the
present compounds are useful for the treatment of diseases,
disorders, and conditions including, but not limited to,
immunodeficiency disorders, inflammatory diseases, allergic
diseases, autoimmune diseases, proliferative disorders,
immunologically-mediated diseases, respiratory disorders.
Accordingly, in another aspect of the present invention,
pharmaceutically acceptable compositions are provided, wherein
these compositions comprise any of the compounds as described
herein, and optionally comprise a pharmaceutically acceptable
carrier, adjuvant or vehicle. In certain embodiments, these
compositions optionally further comprise one or more additional
therapeutic agents.
[0166] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or any other adduct
or derivative which upon administration to a patient in need is
capable of providing, directly or indirectly, a compound as
otherwise described herein, or a metabolite or residue thereof.
[0167] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt of a compound of this invention.
[0168] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0169] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0170] In yet another aspect, a method for the treatment or
lessening the severity of a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a
condition associated with organ transplant, an inflammatory
disorder, or an immunologically mediated disorder is provided
comprising administering an effective amount of a compound, or a
pharmaceutically acceptable composition comprising a compound to a
subject in need thereof. In certain embodiments of the present
invention an "effective amount" of the compound or pharmaceutically
acceptable composition is that amount effective for treating or
lessening the severity of a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a
condition associated with organ transplant, an inflammatory
disorder, a psychotic disorder, a viral disease, a bone disorder or
an immunologically mediated disorder. The compounds and
compositions, according to the method of the present invention, may
be administered using any amount and any route of administration
effective for treating or lessening the severity of a proliferative
disorder, a cardiac disorder, a neurodegenerative disorder, an
autoimmune disorder, a condition associated with organ transplant,
an inflammatory disorder, a psychotic disorder, a viral disease, a
bone disorder or an immunologically mediated disorder. The exact
amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the infection, the particular agent, its mode of administration,
and the like. The compounds of the invention are preferably
formulated in dosage unit form for ease of administration and
uniformity of dosage. The expression "dosage unit form" as used
herein refers to a physically discrete unit of agent appropriate
for the patient to be treated. It will be understood, however, that
the total daily usage of the compounds and compositions of the
present invention will be decided by the attending physician within
the scope of sound medical judgment. The specific effective dose
level for any particular patient or organism will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed, and like factors well known in the medical arts.
The term "patient", as used herein, means an animal, preferably a
mammal, and most preferably a human.
[0171] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0172] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0173] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
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 are used in the preparation of injectables.
[0174] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0175] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0176] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0177] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0178] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0179] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0180] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0181] As described generally above, the compounds of the invention
are useful as inhibitors of protein kinases, particularly for the
JAK family kinases, ROCK and PKA. In a specific embodiment, the
compounds and compositions of the invention are inhibitors of JAK2
and JAK3. The compounds and compositions are useful for treating or
lessening the severity of a disease, condition, or disorder where
activation of a JAK family kinase, ROCK and/or PKA is implicated in
the disease, condition, or disorder. In a particular embodiment,
the compounds and compositions are useful for treating or lessening
the severity of a disease, condition, or disorder where activation
of JAK2 or JAK3 is implicated in the disease, condition, or
disorder. When activation of JAK2, JAK3, ROCK or PKA is implicated
in a particular disease, condition, or disorder, the disease,
condition, or disorder may also be referred to as "JAK2-mediated
disease", "JAK3-mediated disease", "ROCK-mediated disease" or
"PKA-mediated disease", respectively. Accordingly, in another
aspect, the present invention provides a method for treating or
lessening the severity of a disease, condition, or disorder where
activation of a JAK family kinase, ROCK or PKA, particularly JAK2
or JAK3, is implicated in the disease state.
[0182] The activity of a compound utilized in this invention as an
inhibitor of a JAK family kinase, ROCK or PKA, particularly JAK2 or
JAK3, may be assayed in vitro, in vivo or in a cell line. In vitro
assays include assays that determine inhibition of either the
phosphorylation activity or ATPase activity of activated JAK2,
JAK3, ROCK or PKA. Alternate in vitro assays quantitate the ability
of the inhibitor to bind to JAK2, JAK3, ROCK or PKA. Inhibitor
binding may be measured by radiolabelling the inhibitor prior to
binding, isolating the inhibitor/kinase complex and determining the
amount of radiolabel bound. Alternatively, inhibitor binding may be
determined by running a competition experiment where new inhibitors
are incubated with the kinase of interest bound to known
radioligands.
[0183] The term "detectably inhibit", as used herein means a
detectable change in JAK2, JAK3, ROCK or PKA activity between a
sample comprising said composition and JAK2, JAK3, ROCK or PKA and
an equivalent sample comprising JAK2, JAK3, ROCK or PKA,
respectively, in the absence of said composition.
[0184] The term "JAK3-mediated disease" or "JAK3-mediated
condition", as used herein means any disease or other deleterious
condition in which JAK3 is known to play a role. A JAK3-mediated
condition or disease also means those diseases or conditions that
are alleviated by treatment with a JAK3 inhibitor. Such conditions
include, without limitation, immune responses such as allergic or
type I hypersensitivity reactions, asthma, autoimmune diseases such
as transplant rejection, graft versus host disease, rheumatoid
arthritis, amyotrophic lateral sclerosis, and multiple sclerosis,
neurodegenerative disorders such as Familial amyotrophic lateral
sclerosis (FALS), as well as in solid and hematologic malignancies
such as leukemias and lymphomas.
[0185] The term "JAK2-mediated disease" or "JAK2-mediated
condition", as used herein means any disease or other deleterious
condition in which JAK2 is known to play a role. A JAK2-mediated
condition or disease also means those diseases or conditions that
are alleviated by treatment with a JAK2 inhibitor. Such conditions
include, without limitation, myeloproliferative disorders,
including polycythemia vera, essential thrombocythemia, chronic
idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis,
chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic
eosinophilic leukemia, hypereosinophilic syndrome and systematic
mast cell disease.
[0186] The term "ROCK-mediated disease" or "ROCK-mediated
condition", as used herein, means any disease or other deleterious
condition in which ROCK is known to play a role. A ROCK-mediated
condition or disease also means those diseases or conditions that
are alleviated by treatment with a ROCK inhibitor. Such conditions
include, without limitation, hypertension, angina, angina pectoris,
cerebrovascular contraction, asthma, peripheral circulation
disorder, premature birth, cancer, erectile dysfunction,
arteriosclerosis, spasm (cerebral vasospasm and coronary
vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders,
autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy,
ischemia/reperfusion-induced injury, endothelial dysfunction,
Alzheimer's disease, or benign prostatic hyperplasia. In other
embodiments, such conditions in which ROCK is known to play a role
include, without limitation, hypertension, cerebral vasospasm,
coronary vasospasm, bronchial asthma, preterm labor, erectile
dysfunction, glaucoma, vascular smooth muscle cell proliferation,
myocardial hypertrophy, malignoma, ischemia/reperfusion-induced
injury, endothelial dysfunction, Crohn's Disease and colitis,
neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease,
benign prostatic hyperplasia, or atherosclerosis.
[0187] The term "PKA-mediated disease" or "PKA-mediated condition",
as used herein, means any disease or other deleterious condition in
which PKA is known to play a role. The term PKA-mediated condition
or disease also means those diseases or conditions that are
alleviated by treatment with a PKA inhibitor. PKA-mediated diseases
or conditions include, but are not limited to, proliferative
disorders and cancer.
[0188] It will also be appreciated that the compounds and
pharmaceutically acceptable compositions of the present invention
can be employed in combination therapies, that is, the compounds
and pharmaceutically acceptable compositions can be administered
concurrently with, prior to, or subsequent to, one or more other
desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in
a combination regimen will take into account compatibility of the
desired therapeutics and/or procedures and the desired therapeutic
effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered
concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse
effects). As used herein, additional therapeutic agents that are
normally administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated".
[0189] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0190] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating implantable medical devices, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Accordingly, the present invention, in another aspect,
includes a composition for coating an implantable device comprising
a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device. In still another aspect, the
present invention includes an implantable device coated with a
composition comprising a compound of the present invention as
described generally above, and in classes and subclasses herein,
and a carrier suitable for coating said implantable device.
[0191] Vascular stents, for example, have been used to overcome
restenosis (re-narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk clot
formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a
pharmaceutically acceptable composition comprising a kinase
inhibitor. Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics in the composition.
[0192] Another aspect of the invention relates to inhibiting JAK2,
JAK3, ROCK or PKA activity in a biological sample, which method
comprises contacting said biological sample with a compound of
formula I or a composition comprising said compound. The term
"biological sample", as used herein, is an ex vivo or in vitro
sample, and includes, without limitation, cell cultures or extracts
thereof; biopsied material obtained from a mammal or extracts
thereof; and blood, saliva, urine, feces, semen, tears, or other
body fluids or extracts thereof.
[0193] Inhibition of JAK2, JAK3, ROCK or PKA kinase activity in a
biological sample is useful for a variety of purposes that are
known to one of skill in the art. Examples of such purposes
include, but are not limited to, blood transfusion,
organ-transplantation, biological specimen storage, and biological
assays.
EXAMPLES
[0194] For Examples 1-7, 1H-NMR spectra were recorded at 500 MHz
using a Bruker AMX 500 instrument. Mass spectrometry samples were
analyzed on a MicroMass ZQ or Quattro II mass spectrometer operated
in single MS mode with electrospray ionization. Samples were
introduced into the mass spectrometer using flow injection (FIA) or
chromatography. Mobile phase for all mass spectrometric analyses
consisted of acetonitrile-water mixtures with 0.2% formic acid as a
modifier. As used herein, the term "R.sub.tt" refers to the HPLC
retention time, in minutes, associated with the compound.
Example 1
##STR00111##
[0195] 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine
[0196] A slurry of 1 (307 mg, 2.00 mmol), Tosyl-chloride (418 mg,
2.20 mmol) and freshly ground K.sub.2CO.sub.3 (1.1 g, 8.0 mmol) in
DMF (5.0 mL) was stirred at R.T. for 2 h. The mixture was
partitioned between water and EtOAc and the organic phase was
washed with brine (2.times.), dried (Na.sub.2SO.sub.4), filtered,
and concentrated to provide the title compound (583 mg, 1.89 mmol,
95% yield) as a white solid.
##STR00112##
4-cyclopentenyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine
[0197] A mixture of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine
(62 mg, 0.20 mmol), cyclopenteneboronic acid (27 mg, 0.24 mmol),
KOAc (78 mg, 0.80 mmol), and Pd(PPh3).sub.4 (11 mg, 0.010 mmol), in
dioxane (0.6 mL) was heated to 150.degree. C. (MW, 600s) in a
sealed tube. The reaction mixture was subjected to flash
chromatography (SiO.sub.2, 0-50% EtOAc-hexanes, gradient elution)
to provide the title compound (55 mg, 0.16 mmol, 81% yield) as a
white solid.
##STR00113##
4-cyclopentenyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1)
[0198] A mixture of
4-cyclopentenyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (55 mg, 0.16
mmol) in methanol (0.5 mL) was treated with NaOMe (0.5 N, 0.25 mL)
and warmed to 60.degree. C. for 25 min. the reaction was diluted,
quenched with TFA, concentrated and subjected to flash
chromatography to provide the title compound (19 mg) as a white
solid.
[0199] LC-MS R.sub.tt=1.57 min, (M+H.sup.+) 186.00
[0200] .sup.1H NMR (500 MHz, CDCl3) 9.30 (br s, 1H), 8.86 (s, 1H),
7.33 (dd, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 3.06 (m, 2H), 2.70 (m,
2H), 2.13 (q, 2H)
Example 2
##STR00114##
[0201] 4-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 3)
[0202] A mixture of 4-cyclopentenyl-7H-pyrrolo[2,3-d]pyrimidine (11
mg, 0.060 mmol) and Pd--C (10% on carbon, 22 mg) in EtOAc (1 mL)
was stirred under H.sub.2 atmosphere (balloon) for 5 h. The mixture
was filtered and concentrated to provide the title compound (10 mg)
as a white solid.
[0203] LC-MS R.sub.tt=1.37 min, (M+H.sup.+) 188.10
[0204] .sup.1H NMR (500 MHz, CDCl3) 9.00 (br s, 1H), 8.80 (s, 1H),
7.24 (buried dd, 1H), 6.63 (dd, 1H), 3.56 (q, 2H), 2.13 (m, 2H),
2.05 (m, 2H), 1.92 (m, 2H), 1.75 (m, 2H)
[0205] The compounds in Examples 3-7 were made according to Scheme
II.
Example 3
##STR00115##
[0206] 4-(1-phenylvinyl)-7H-pyrrolo[2,3-d]pyrimidine (Compound
8)
[0207] LC-MS R.sub.tt=2 min, (M+H.sup.+) 221
[0208] .sup.1H NMR 500 MHz; DMSO-d6: 12.6 (br m, 1H), 8.85 (s, 1),
7.53 (m, 1H), 7.4 (m, 5H), 6.03 (m, 3H)
Example 4
##STR00116##
[0209] 4-(4-fluorostyryl)-7H-pyrrolo[2,3-d]pyrimidine (Compound
5)
[0210] LC-MS R.sub.tt=2 min, (M+H.sup.+) 239
[0211] .sup.1H NMR: 500 MHz; DMSO-d6: 13.8 (br m, 1H), 8.93 (s, 1),
8.14 (d, 1H), 7.92 (dd, 2H), 7.83 (m, 1H), 7.71 (d, 1H), 7.35 (dd,
2H), 7.27 (m, 1H)
Example 5
##STR00117##
[0212] 4-(4-chlorostyryl)-7H-pyrrolo[2,3-d]pyrimidine (Compound
6)
[0213] LC-MS R.sub.tt=2.3 min, (M+H.sup.+) 255
[0214] .sup.1H NMR: 500 MHz; DMSO-d6: 12.7 (br m, 1H), 8.90 (s, 1),
8.10 (d, 1H), 7.90 (d, 2H), 7.79 (m, 2H), 7.54 (d, 2H), 7.22 (m,
1H)
Example 6
##STR00118##
[0215] 4-(4-(trifluoromethyl)styryl)-7H-pyrrolo[2,3-d]pyrimidine
(Compound 7)
[0216] LC-MS R.sub.tt=2.7 min, (M+H.sup.+) 289
[0217] .sup.1H NMR: 500 MHz; DMSO-d6: 12.5 (br m, 1H), 8.88 (s, 1),
8.15 (d, 1H), 8.07 (d, 2H), 7.90 (d, 1H), 7.85 (d, 2H), 7.75 (m,
1H), 7.45 (m, 1H), 7.17 (m, 1H)
Example 7
##STR00119##
[0218] 4-styryl-7H-pyrrolo[2,3-d]pyrimidine (Compound 4)
[0219] LC-MS R.sub.tt=2 min, (M+H.sup.+) 221
[0220] .sup.1H NMR: 500 MHz; DMSO-d6: 12.8 (br m, 1H), 8.93 (s, 1),
8.14 (d, 2H), 7.85 (d, 2H), 7.83 (m, 1H), 7.75 (d, 1H), 7.51 (d,
2H), 7.47 (m, 1H), 7.28 (m, 1H)
Example 8
##STR00120##
[0221] Step 1
[0222] Compound A (1-(tert Butoxycarbonyl)-3-piperidine carboxylic
acid) (4.60 g, 20.0 mMol) was suspended in 40 ml of
CH.sub.2Cl.sub.2. Added was EDCI (4.60 g, 24.0 mMol), followed by
N,O-Dimethylamine (HCl) (2.34 g (24.0 mMol) and catalytic DMAP. The
resulting mixture was allowed to stir at room temperature
overnight. All volatiles were removed at reduced pressure. The
residue was dissolved in saturated aqueous NaHCO.sub.3 solution and
EtOAc. The layers were separated and the organic was washed with
brine, dried over MgSO.sub.4, filtered and evaporated to dryness.
No further purification, material used as is. Yield: 4.7 g,
approximately 86%. H NMR (500 MHz, CDCl3) 3.73 (s, 3H), 3.18 (s,
3H), 2.87-2.81 (m, 4H), 1.94 (s, H), 1.73-1.65 (m, 4H), 1.49-1.46
(m, 9H).
Step 2
[0223] To a solution of compound B (4.7 g, 17.2 mMol) in 70 ml of
THF at 0.degree. C. (under N.sub.2) was added a 3.0 M (11.5 ml,
34.5 mMol) solution of Methyl Magnesium Bromide in THF. After the
addition was complete, the cooling bath was removed and the
resulting mixture was allowed to rise to room temperature where it
was allowed to stir overnight. The resulting mixture was quenched
with a saturated aqueous KHSO.sub.4 solution and diluted with
EtOAc. The organic phase was washed with brine, dried over
MgSO.sub.4, filtered and evaporated to dryness. The crude residue
was passed through a plug of silica gel and eluted with 5-20%
EtOAc/Hexane. Yield: 2.37 g, approximately 60%. H NMR (500 MHz,
CDCl3) 4.10 (d, J=12.0 Hz, H), 3.92 (s, H), 2.94 (dd, J=10.3, 13.3
Hz, H), 2.82-2.77 (m, H), 2.52-2.48 (m, H), 2.18 (s, 3H), 1.98 (dd,
J=3.6, 12.9 Hz, H), 1.73-1.69 (m, H), 1.56-1.44 (m, 11H).
Step 3
[0224] Compound C (2.37 g, 10.4 mMol) was dissolved in 5.0 ml of
THF and added (under N.sub.2) to a solution of LiHMDS (13.0 ml,
13.0 mMol) at -78.degree. C. (IPA-dry ice bath). After 30 min.,
added was 2-[N,N-bis(trifluoromethylsulfonyl)amino]pyridine (4.11
g, 11.5 mMol) and after 10 min. the cooling bath was removed. The
resulting mixture gradually rose to room temperature where it was
allowed to stir overnight. The resulting mixture was quenched with
saturated aqueous KHSO.sub.4 solution and diluted with EtOAc. The
layers were separated and the organic was washed with brine, dried
over MgSO.sub.4, filtered and evaporated to dryness. The crude was
passed through a plug of silica gel and eluted with 10%
EtOAc/Hexane. Yield: 2.93 g, approximately 79%. HNMR (500 MHz,
CDCl3) 5.19 (d, J=4.1 Hz, H), 5.01 (dd, J=1.0, 4.1 Hz, H),
4.14-4.11 (m, H), 2.84 (dd, J=9.7, 13.2 Hz, 3H), 2.41 (s, H),
2.04-2.00 (m, H), 1.72 (t, J=3.4 Hz, H), 1.52-1.46 (m, 11H).
Step 4
[0225] Compound D (2.93 g, 8.2 mMol) was dissolved in 30 ml of
toluene. Added was Bis(Pinacoloto)diboron (2.07 g, 8.2 mMol)
followed by Triphenyl phosphine (117.3 mg, 0.44 mMol) and Potassium
phenoxide (1.48 g, 11.2 mMol). The RM was degassed with Ar for 5
min. Added was trans-Dichlorobis(triphenylphosphine)palladium (II)
(157.0 mg, 0.22 mMol) and the resulting mixture was allowed stir at
55.degree. C. for 3 hours. The resulting mixture was allowed to
cool to room temperature where it was stirred overnight. The
resulting mixture was diluted with saturated aqueous NaHCO.sub.3
solution and EtOAc. The layers were separated and the organic was
washed with brine, dried over MgSO.sub.4, filtered and evaporated
to dryness. The crude was passed through a plug of silica gel
eluting with 5-15% EtOAc/Hexane. Phenol was still present, so
material was dissolved in Et.sub.2O and washed with 1N NaOH
solution. The organic phase was dried over MgSO.sub.4, filtered and
evaporated to dryness. Yield: 2.01 g, approximately 73%. H NMR (500
MHz, CDCl3) 5.83 (d, J=2.6 Hz, H), 5.65 (s, H), 4.07 (dd, J=1.6,
12.8 Hz, 2H), 2.64-2.58 (m, 2H), 2.26 (t, J=11.2 Hz, H), 1.82-1.79
(m, H), 1.67-1.64 (m, H), 1.50 (t, J=3.7 Hz, 11H), 1.29-1.19 (m,
12H).
Step 5
[0226] Compound E (45.7 mg, 0.14 mMol) was dissolved in 1.0 ml of
DME. Added was 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (20.8 mg, 0.14
mMol) followed by a 2.0 M solution of Na.sub.2CO.sub.3 (200 uL, 0.4
mMol). The resulting mixture was degassed with Ar for 5 minutes and
added was catalytic tetrakis triphenylphosphine palladium (0). The
resulting mixture was warmed to 160.degree. C. via microwave
irradiation. After 10 minutes, the resulting mixture was cooled to
room temperature. The resulting mixture was diluted with H.sub.2O
and EtOAc. The layers were separated and the organic washed with
brine, dried over MgSO.sub.4, filtered and evaporated to dryness.
The crude residue was chromatographed on a plug of silica gel and
eluted with 10-30% EtOAc/Hexane. Yield: 7.1 mg of Compound 22.
Example 9
##STR00121##
##STR00122##
[0227]
4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine
[0228] [5 g. 16.2 mmol] of
4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (as
described in Example 1) was added in small portions, to 100 mL of
cold stirring 47% stabilized hydriodic acid at 0.degree. C. and
stirred for one hour cold; the temperature was then allowed to warm
to ambient temperature and stirred an additional 5 hrs. The
reaction mixture was diluted with water and the solid was isolated
via suction filtration, the solid being washed with additional
water. The crude solid was dissolved in dichloromethane and washed
with saturated sodium hydrogen carbonate solution twice, brined,
dried (Na.sub.2SO.sub.4) and the solvent was removed under reduced
pressure and triturated with a 2:1 mixture of hexanes/MTBE to yield
5.7 g of a white material (88%). .sup.1H NMR: 500 Mhz in CDCL3
.delta.8.61 (s, 1H), 8.06 (d, 2H J=8.5 Hz), 7.75 (d, 1H J=4.1 Hz),
7.32 (d, 2H J=8.5 Hz), 6.45 (d, 1H J=4.1 Hz), 2.4 (s, 3H).
##STR00123##
Step a:
4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimi-
dine
[0229] [10 g, 25 mmol] of
4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (as
described above) was dissolved/suspended in 200 mL of dry toluene
along with [2.0 g, 2.85 mmol] of palladium (II)
bis-triphenylphosphine dichloride. The mixture was purged with
nitrogen gas for .about.5 minutes before mixture was heated to
90.degree. C. in an oil bath under an atmosphere of nitrogen gas.
Added slowly dropwise over 2 hours, was [12.66 mL, 13.54 g, 37.5
mmol] of tri-n-butyl(1-ethoxyvinyl) tin in 100 mL of dry toluene.
After completing the addition, the mixture was heated for an
additional 6 hours under nitrogen. The reaction was cooled to
ambient temperature and the solvent was removed under reduced
pressure until the remaining volume was 1/5 the original. Added to
this slurry was 160 mL of petroleum ether and the mixture was
stirred for 1 hour, the solid being isolated via suction filtration
and washed with petroleum ether. The damp solid was slurried in
acetonitrile, stirred for one hour and the solid re-isolated via
suction filtration and airdried. The resulting pale yellow solid,
7.2 g representing an 82% yield was utilized without further
treatment. .sup.1H NMR: 500 Mhz in CDCL3 .delta.8.9 (s, 1H), 8.07
(d, 2H, J=8.5 Hz), 7.7 (d, 1H, J=4.1 Hz), 7.28 (d, 2H, J=8.5 Hz),
7.04 (d, 1H, J=4.1 Hz), 5.7 (d, 1H, J=2 Hz), 4.58 (d, 1H, J=2 Hz),
4.0 (quart, 2H), 2.4 (s, 3H), 1.5 (t, 3H).
##STR00124##
Step b:
1-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethano-
ne
[0230] [7.25 g, 21.12 mmol] of
4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine
was dissolved in 50 mL each of methanol and THF and stirred with 10
mL of 6N HCL for 4.0 hours at ambient temperature. The solvents
were removed under reduced pressure and the residue was partitioned
between dichloromethane and saturated sodium hydrogen carbonate
solution. The organic fraction was brined and dried with anhydrous
sodium sulphate and the solvent was removed under reduced pressure.
The crude material was triturated with a mixture of MTBE and
petroleum ether (1:4) for several hours and the solid finally
isolated via suction filtration and air dried. The 5.95 g of pale
yellow material, representing a 89% yield was used without further
purification. .sup.1H NMR: 500 Mhz CDCL3 .delta.9.0 (s, 1H), 8.08
(d, 2H, J=8.4 Hz), 7.87 (d, 1H, J=4.1 Hz), 7.3 (m, 3H), 2.8 (s,
3H), 2.4 (s, 3H).
##STR00125##
Step c:
2-Bromo-1-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
]-ethanone
[0231] [5.95 g, 18.88 mmol] of
1-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethanone
was dissolved/suspended in 90 mL of glacial acetic acid and [7.53
mL, 10.197 g, 37.76 mmol] of 30% hydrogen bromide in acetic acid.
Added dropwise to this stirring mixture at ambient temperature, was
[0.970 mL, 3.02 g, 18.88 mmol] of bromine in 10 mL of glacial
acetic acid over 1.0 hour. The reaction was stirred an additional
4.0 hours at ambient temperature during which time a yellow
precipitate forms. The solvent was removed under reduced pressure
and the residue was partitioned between dichloromethane and sat'ed
sodium hydrogen carbonate solution. The organic phase was washed
with water, brine, and dried with anhydrous sodium sulphate and the
solvent was removed under reduce pressure. The crude solid was
triturated/stirred with MTBE overnight and the solid isolated via
suction filtration and airdried to yield 4.2 g of pale yellow
solid, a 56.6% yield. .sup.1H NMR: 500 Mhz in CDCL3 .delta.9.1 (s,
1H), 8.09 (d, 2H, J=8.5 Hz), 7.93 (d, 1H, J=4.0 Hz), 7.33 (d, 2H,
J=8.5 Hz). 7.29 (d, 1H, J=4.0 Hz), 4.83 (s, 2H), 2.4 (s, 3H).
Steps d, e
[0232] Conversion of the bromide may be accomplished upon
nucleophilic displacement with primary or secondary amines (i.e.,
step d) or upon treatment with an alcohol (i.e., step e) under
basic conditions.
Step f
[0233] The compound is deprotected as described for Compound 1.
Example 10
##STR00126##
[0234] Steps a,b:
4-Bicyclo[2.2.1]hept-2-yl-7H-pyrrolo[2,3-d]pyrimidine
[0235] To a solution of N-tosyl-4-chlorodeazapurine (40 mg, 0.13
mmol) in anhydrous THF (0.5 mL) was added an appropriate alkylzinc
halide (e.g., exo-2-norbornylzinc bromide [0.40 mL, 0.5 M]) and the
mixture is stirred overnight at room temperature. Then the mixture
is heated to 80.degree. C. for an additional 1.5 h and cooled to
room temperature. The reaction mixture is treated with NaOMe (200
uL, 0.5 M) in MeOH at 50.degree. C. for 1.5 h before work up.
Rochelle's salt is added and the mixture is extracted repeatedly
with EtOAc. The organic layer is filtered and concentrated. The
crude residue is purified by HPLC to provide the Compound 26.
LC-MS: RT=1.86, (M+H)=214.2; .sup.1H NMR (DMSO) 12.42 (m, 2H), 8.78
(s, 1H), 8.74 (s, 1H), 7.62 (br s, 2H), 6.82 (s, 1H), 6.77 (s, 1H),
3.76 (m, 1H), 3.31 (s, 1H), 2.75 (m, 1H), 2.46 (m, 1H), 2.37 (m,
2H), 2.14 (m, 2H), 1.90 (m, 1H), 1.72 (m, 1H), 1.67 (d, 2H), 1.59
(m, 2H), 1.55-1.42 (complex m, 3H), 1.33 (m, 2H), 1.23 (m, 1H),
1.17 (d, 1H), 0.99 (m, 1H).
[0236] Compounds 23, 24, 25, 27, 28, 29, 30 and 31 were prepared by
the method described above.
[0237] Table 4 below depicts exemplary .sup.1H-NMR data (NMR) and
liquid chromatographic mass spectral data, reported as mass plus
proton (M+H), as determined by electrospray, and retention time
(RT) for certain compounds of the present invention, wherein
compound numbers in Table 4 correspond to the compounds depicted in
Table 3 (empty cells indicate that the test was not performed):
TABLE-US-00004 TABLE 4 Cmpd # M + H.sup.+ LC-MS R.sub.t .sup.1H NMR
2 Lot 1: Lot 1: 1.93 Lot 1: (500 MHz, CDCl3) 8.92 (br s, 1H), 8.81
(s, 200.00 1H), 7.26 (burried dd, 1H), 6.86 (m, 1H), 6.72 (dd, 1H),
2.70 (m, 2H), 2.34 (m, 2H), 1.84 (m, 2H), 1.76 (m, 2H) 9 301.00
2.05 (CDCl3) 10.07 (br s, 1H), 8.86 (s, 1H), 7.35 (d, 1H), 6.83 (d,
1H), 6.73 (br s, 1H), 4.24 (br s, 2H), 3.71 (br s, 2H), 2.86 (br s,
2H), 1.52 (s, 9H) 10 (d4-methanol) 8.71 (s, 1H), 7.52 (d, 1H), 6.86
(m, 1H), 6.84 (d, 1H), 4.01 (br s, 2H), 3.54 (dd, 2H), 3.08 (br s,
2H) 11 213.80 2.40 (500 MHz, CDCl3) 9.24 (s, 1H), 7.7 (brs, 1H),
7.56 (s, 1H), 7.02 (d, 1H), 6.93 (br s, 1H), 3.68 (m, 2H), 2.62 (m,
2H), 2.28 (m, 1H), 2.16 (m, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.29
(d, 3H) 12 228.19 2.17 (500 MHz, CD3OD) 8.90 (s, 1H), 7.81 (d, 1H),
6.95 (d, 1H), 5.83 (br s, 2H), 2.79 (m, 1H), 1.85 (complex m, 4H),
1.75 (br d, 1H), 1.47-1.24 (complex m, 5H) 13 218.00 1.50 500 Mhz;
DMSO-d6: 12.1 (br s, 1H), 8.7 (s, 1H), 7.5 (s, 1H), 7.0 (s, 1H),
6.73 (s, 1H), 3.45 (s, 2H), 2.9 (s, 4H) 14 146.00 0.60 (CDCl3)
10.70 (br s, 1H), 8.89 (s, 1H), 7.39 (d, 1H), 7.15 (dd, 1H), 6.73
(d, 1H), 6.66 (dd, 1H), 5.82 (dd, 1H) 15 242.90 0.52 16 310.90 1.61
17 268.20 0.60 (d4-methanol) 8.76 (s, 1H), 7.61 (d, 1), 6.93 (d,
1H), 6.90 and 6.86 (2m, 1H), 4.40 and 4.34 (2m, 2H), 4.01 and 3.97
(2s, 2H), 3.90 and 3.78 (2t, 2H), 2.94 (m, 2H) 18 214.23 1.97 (500
MHz, CD3OD) 8.81 (s, 1H), 7.66 (d, 1H), 6.85 (d, 1H), 5.78 and 5.77
(two s, 2H), 1.94 (m, 2H), 1.78 (m, 2H), 1.70 (m, 2H), 1.50 (m, 2H)
ppm. 19 214.21 1.75 (500 MHz, CD3OD) 8.86 (s, 1H), 7.83 (d, 1H),
7.08 (d, 1H), 7.05 (m, 1H), 3.16 (m, 1H), 2.99 (m, 1H), 2.33 (m,
1H), 2.20 (m, 1H), 1.23 (d, 3H), 1.18 (d, 3H) ppm. 20 214.20 2.60
1H NMR (500 MHz, CD3OD) 8.86 (s, 1H), 7.84 (m, 1H), 7.00 (m, 2H),
2.88 (m, 2H), 2.58 (m, 2H), 1.97 (m, 2H), 1.81 (m, 2H), 1.72 (m,
2H). 21 211.90 1.60 500 MHz, CDCl3: 12.3.0 (br m, 1H), 9.0 (s, 1H),
7.63 (s, 1H), 7.58 (s, 1H), 6.93 (s, 1H), 3.75 (s, 1H), 3.30 (s,
1H), 1.97 (m, 2H), 1.74 (d, 1H), 1.45 (d, 1H), 1.33 (m, 1H), 1.22
(m, 1H) 22 328.90 2.46 500 Mhz, CDCl3 10.16 (s, br, 1H), 8.87 (s,
1H), 7.34 (s, 1H), 6.67 (s, 1H), 5.59 (s, 1H), 4.11 (d, br, 2H),
3.18 (m, 1H), 2.79 (t, 2H), 2.00 (m, 1H), 1.71 (m, 2H), 1.64-1.48
(m, 2H), 1.43 (s, 9H). 23 224.20 1.91 24 220.20 1.52 12.47 (br s,
1H), 8.79 (s, 1H), 7.65 (s, 1H), 6.81 (s, 1H), 3.55 (s, 3H), 3.39
(q, 1H), 3.16 (m, 2H), 1.15 (d, 3H) 25 176.20 1.65 27 216.20 2.04
28 201.20 1.48 29 234.20 1.52 30 243.20 1.91 31 190.20 1.91
Example 11
JAK3 Inhibition Assay
[0238] Compounds were screened for their ability to inhibit JAK
using the assay shown below. Reactions were carried out in a kinase
buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM
MgCl.sub.2, 25 mM NaCl, and 0.01% BSA.
[0239] Substrate concentrations in the assay were 5 .mu.M ATP (200
uCi/pmole ATP) and 1 .mu.M poly(Glu).sub.4Tyr. Reactions were
carried out at 25.degree. C. and 1 nM JAK3.
[0240] To each well of a 96 well polycarbonate plate was added 1.5
.mu.l of a candidate JAK3 inhibitor along with 50 .mu.l of kinase
buffer containing 2 .mu.M poly(Glu).sub.4Tyr and 10 .mu.M ATP. This
was then mixed and 50 .mu.l of kinase buffer containing 2 nM JAK3
enzyme was added to start the reaction. After 20 minutes at room
temperature (25 C), the reaction was stopped with 50 .mu.l of 20%
trichloroacetic acid (TCA) that also contained 0.4 mM ATP. The
entire contents of each well were then transferred to a 96 well
glass fiber filter plate using a TomTek Cell Harvester. After
washing, 60 .mu.l of scintillation fluid was added and .sup.33P
incorporation detected on a Perkin Elmer TopCount.
Example 12
JAK2 Inhibition Assay
[0241] As described above in Example 11 except that JAK-2 enzyme is
used, the final poly(Glu).sub.4Tyr concentration is 15 .mu.M, and
final ATP concentration is 12 .mu.M.
Example 13
ROCK Inhibition Assays
[0242] Compounds are screened for their ability to inhibit ROCK I
(AA 6-553) activity using a standard coupled enzyme system (Fox et
al. Protein Sci. 7: 2249, 1998). Reactions are carried out in a
solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl.sub.2, 25 mM
NaCl, 2 mM DTT and 1.5% DMSO. Final substrate concentrations in the
assay are 45 .mu.M ATP (Sigma Chemicals, St Louis, Mo.) and 200
.mu.M peptide (American Peptide, Sunnyvale, Calif.). Reactions are
carried out at 30.degree. C. and 45 nM ROCK I. Final concentrations
of the components of the coupled enzyme system are 2.5 mM
phosphoenolpyruvate, 350 .mu.M NADH, 30 .mu.g/ml pyruvate kinase
and 10 .mu.g/ml lactate dehydrogenase.
[0243] Compounds are screened for their ability to inhibit ROCK
using a standard radioactive enzyme assay. Assays are carried out
in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl.sub.2,
25 mM NaCl, 2 mM DTT and 1.5% DMSO. Final substrate concentrations
in the assay are 13 .mu.M [.gamma.-.sup.33P] ATP (25 mCi .sup.33P
ATP/mmol ATP, Perkin Elmer, Cambridge, Mass./Sigma Chemicals, St
Louis, Mo.) and 27 .mu.M Myelin Basic Protein (MBP). Final enzyme
concentration in the assay is 5 nM ROCK. Assays are carried out at
room temperature. 1.5 .mu.l of DMSO stock containing serial
dilutions of the compound of the present invention (concentrations
ranging from 10 .mu.M to 2.6 nM) is placed in a 96 well plate. 50
.mu.l of Solution 1 (100 mM HEPES (pH 7.5), 10 mM MgCl.sub.2, 26 mM
[.gamma.-.sup.33P] ATP) is added to the plate. The reaction is
initiated by addition of 50 .mu.l of Solution 2 (100 mM HEPES (pH
7.5), 10 mM MgCl.sub.2, 4 mM DTT, 54 mM MBP and 10 nM ROCK). After
2 hours the reaction is quenched with 50 .mu.L of 30%
trichloroacetic acid (TCA, Fisher) containing 9 mM ATP. Transfer of
140 .mu.L of the quenched reaction to a glass fiber filter plate
(Corning, Cat. No. 3511) is followed by washing 3 times with 5%
TCA. 50 .mu.L of Optima Gold scintillation fluid (Perkin Elmer) is
added and the plates are counted on a Top Count (Perkin Elmer).
After removing mean background values for all of the data points
the data is fit using Prism software to obtain a K.sub.i(app).
Example 14
PKA Inhibition Assay
[0244] Compounds were screened for their ability to inhibit PKA
using a standard coupled enzyme assay (Fox et al., Protein Sci,
1998, 7, 2249). Assays were carried out in a mixture of 100 mM
HEPES (pH 7.5), 10 mM MgCl.sub.2, 25 mM NaCl, 1 mM DTT and 3% DMSO.
Final substrate concentrations in the assay were 50 M ATP (Sigma
Chemicals) and 80 M peptide (Kemptide, American Peptide, Sunnyvale,
Calif.). Assays were carried out at 30.degree. C. and 18 nM PKA.
Final concentrations of the components of the coupled enzyme system
were 2.5 mM phosphoenolpyruvate, 300 M NADH, 30 g/ml pyruvate
kinase and 10 g/ml lactate dehydrogenase.
[0245] An assay stock buffer solution was prepared containing all
of the reagents listed above, with the exception of ATP, and the
test compound of the present invention. 55 .mu.l of the stock
solution was placed in a 96 well plate followed by addition of 2
.mu.l of DMSO stock containing serial dilutions of the test
compound of the present invention (typically starting from a final
concentration of 5 .mu.M). The plate was preincubated for 10
minutes at 30.degree. C. and the reaction initiated by addition of
5 .mu.l of ATP (final concentration 50 M). Initial reaction rates
were determined with a Molecular Devices SpectraMax Plus plate
reader over a 15 minute time course. IC.sub.50 and K.sub.i data
were calculated from non-linear regression analysis using the Prism
software package (GraphPad Prism version 3.0a for Macintosh,
GraphPad Software, San Diego Calif., USA).
[0246] Table 5 depicts enzyme inhibition data (K.sub.i) for certain
exemplary compounds. Compound numbers in Table 5 correspond to
those compounds depicted in Table 3. In Table 5, "A" represents a
K.sub.i of less than 0.5 .mu.M, "B" represents a K.sub.i of between
0.5 and 5.0 .mu.M, and "C" represents a K.sub.i of greater than 5.0
.mu.M.
TABLE-US-00005 TABLE 5 Cmpd # JAK2 JAK3 PKA ROCK 1 A A B B 2 A A B
B 3 B B B B 4 A A B B 5 A A B B 6 A A B B 7 A A B B 8 C B B B 9 A A
B B 10 C C B B 11 B A B B 12 B B B B 13 A A B B 14 B B B B 15 C C B
B 16 B C B B 17 A B B B 18 A A B B 19 A A B B 20 A A B B 21 A A B B
22 B B B B 23 B B B B 24 C C B B 25 B B B B 26 A A B B 27 A A B B
28 B B B B 29 B B B B 30 B B B B 31 A A B B
* * * * *