U.S. patent application number 14/250668 was filed with the patent office on 2014-10-23 for deazapurines useful as inhibitors of janus 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 Jingrong Cao, John Duffy, Luc Farmer, Cornelia Forster, Huai Gao, Mark Ledeboer, Francois Maltais, Valerie Marone, Gabriel Martinez-Botella, David Messersmith, Albert Pierce, Francesco Salituro, Tiansheng Wang, Marion Wannamaker.
Application Number | 20140315931 14/250668 |
Document ID | / |
Family ID | 38377244 |
Filed Date | 2014-10-23 |
United States Patent
Application |
20140315931 |
Kind Code |
A1 |
Ledeboer; Mark ; et
al. |
October 23, 2014 |
DEAZAPURINES USEFUL AS INHIBITORS OF JANUS KINASES
Abstract
The present invention relates to compounds useful as inhibitors
of protein kinases, particularly of JAK family 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) ; Messersmith; David; (Somerville, MA) ;
Maltais; Francois; (Tewksbury, MA) ; Gao; Huai;
(Arlington, MA) ; Wang; Tiansheng; (Concord,
MA) ; Cao; Jingrong; (Newton, MA) ; Duffy;
John; (Northborough, MA) ; Martinez-Botella;
Gabriel; (Wayland, MA) ; Forster; Cornelia;
(Pellham, NH) ; Wannamaker; Marion; (Bolton,
MA) ; Salituro; Francesco; (Marlborough, MA) ;
Pierce; Albert; (Cambridge, MA) ; Farmer; Luc;
(Montreal, CA) ; Marone; Valerie; (Norton,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Boston |
MA |
US |
|
|
Assignee: |
Vertex Pharmaceuticals
Incorporated
Boston
MA
|
Family ID: |
38377244 |
Appl. No.: |
14/250668 |
Filed: |
April 11, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11732845 |
Apr 5, 2007 |
8741912 |
|
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14250668 |
|
|
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60789441 |
Apr 5, 2006 |
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Current U.S.
Class: |
514/265.1 ;
435/184; 544/280 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
25/00 20180101; A61P 25/18 20180101; A61P 25/16 20180101; A61P
35/00 20180101; A61P 43/00 20180101; A61P 17/14 20180101; A61P 9/10
20180101; C07D 487/04 20130101; A61P 11/06 20180101; A61P 9/00
20180101; A61P 21/00 20180101; A61P 19/02 20180101; A61P 35/02
20180101; A61P 37/08 20180101; A61P 25/14 20180101; A61P 31/18
20180101; A61P 29/00 20180101; A61P 37/00 20180101; A61P 17/06
20180101; A61P 41/00 20180101; A61P 25/28 20180101; A61P 37/06
20180101; A61P 21/02 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 ##STR00302## or a pharmaceutically
acceptable salt thereof, wherein: Ring A is a 5-membered monocyclic
heteroaryl selected from ##STR00303## wherein Ring A is optionally
substituted with up to 1-3 occurrences of R.sup.8; R.sup.1 is H,
halogen or C.sub.1-4 aliphatic; R.sup.2 is H, halogen or C.sub.1-4
aliphatic; R.sup.5 is H, halogen, CN, NH.sub.2, NO.sub.2, CF.sub.3,
C.sub.1-4 aliphatic, cyclopropyl, NCH.sub.3, OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)CH.sub.3, --NC(.dbd.O)CH.sub.3, or
OH; R.sup.3 is --(U).sub.m--X; U is a C.sub.1-6 aliphatic, wherein
up to two methylene units are optionally and independently replaced
by G.sup.U and wherein U is optionally substituted with 1-4
J.sup.U; G.sup.U is --NH--, --NR.sup.6--, --O--, --S--,
--CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--,
--C(O)NR.sup.6--, --NC(.dbd.N--CN)N--, --NHCO--, --NR.sup.6CO--,
--NHC(O)O--, --NR.sup.6C(O)O--, --SO.sub.2NH--,
--SO.sub.2NR.sup.6--, --NHSO.sub.2--, --NR.sup.6SO.sub.2--,
--NHC(O)NH--, --NR.sup.6C(O)NH--, --NHC(O)NR.sup.6--,
--NR.sup.6C(O)NR.sup.6, --OC(O)NH--, --OC(O)NR.sup.6--,
--NHSO.sub.2NH--, --NR.sup.6SO.sub.2NH--, --NHSO.sub.2NR.sup.6--,
--NR.sup.6SO.sub.2NR.sup.6--, --SO--, or --SO.sub.2--; R.sup.6 is
C.sub.1-6 aliphatic or a C.sub.3-10cycloaliphatic; or two R.sup.6
groups, together with the atom to which they are attached,
optionally form a 3-7 membered cycloaliphatic or heterocyclyl,
wherein said aliphatic, cycloaliphatic or heterocyclyl is
optionally substituted with R'', --OR'', --SR'', --NO.sub.2,
--CF.sub.3, --CN, --CO.sub.2R'', --COR'', OCOR'', CONHR'', or
NHCOR'', wherein R'' is H or an unsubstituted C.sub.1-6 aliphatic;
m is 0 or 1; X is H, halogen, CN, NO.sub.2, S(O)R, SO.sub.2R, or a
group selected from a C.sub.1-6aliphatic, a C.sub.3-10
cycloaliphatic, a C.sub.6-10 aryl, a 5-10 membered heteroaryl, or a
5-10 membered heterocyclyl, wherein said group is optionally
substituted with 1-4 J.sup.X; R is an optionally substituted group
selected from a C.sub.1-6 aliphatic, a C.sub.3-10 cycloaliphatic, a
C.sub.6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered
heterocyclyl, wherein R is independently and optionally substituted
with 1-6 occurrences of J.sup.R; each J.sup.R is independently
selected from halogen, L, -(L.sub.n)-R', -(L.sub.n)-N(R').sub.2,
-(L.sub.n)-SR', -(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-10
cycloaliphatic), -(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10
membered heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R',
--CO.sub.2H, --COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2,
--NHC(O)R', or NR'C(O)R'; or two J.sup.R groups, on the same
substituent or different substituents, together with the atom(s) to
which each J.sup.R group is bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; each J.sup.U is
independently selected from halogen, L, -(L.sub.n)-R',
-(L.sub.n)-N(R').sub.2, -(L.sub.n)-SR', -(L.sub.n)-OR',
-(L.sub.n)-(C.sub.3-10 cycloaliphatic), -(L.sub.n)-(C.sub.6-10
aryl), -(L.sub.n)-(5-10 membered heteroaryl), -(L.sub.n)-(5-10
membered heterocyclyl), oxo, C.sub.1-4haloalkoxy,
C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2, -(L.sub.n)-CN,
-(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R', --CO.sub.2H,
--COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2, --NHC(O)R',
or NR'C(O)R'; or two J.sup.U groups, on the same substituent or
different substituents, together with the atom(s) to which each
J.sup.U group is bound, form a 5-7 membered saturated, unsaturated,
or partially saturated ring; each J.sup.X is independently selected
from halogen, L, -(L.sub.n)-R', -(L.sub.n)-N(R').sub.2,
-(L.sub.n)-SR', -(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-10
cycloaliphatic), -(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10
membered heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R',
--CO.sub.2H, --COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2,
--NHC(O)R'; each L is independently a C.sub.1-6 aliphatic wherein
up to three methylene units are replaced by --NH--, --NR.sup.7--,
--O--, --S--, --CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--,
--C(O)NH--, --C(O)NR.sup.7--, --NC(.dbd.N--CN)N, --NHCO--,
--NR.sup.7CO--, --NHC(O)O--, --NR.sup.7C(O)O--, --SO.sub.2NH--,
--SO.sub.2NR.sup.7--, --NHSO.sub.2--, --NR.sup.7SO.sub.2--,
--NHC(O)NH--, --NR.sup.7C(O)NH--, --NHC(O)NR.sup.7--,
--NR.sup.7C(O)NR.sup.7, --OC(O)NH--, --OC(O)NR.sup.7--,
--NHSO.sub.2NH--, --NR.sup.7SO.sub.2NH--, --NHSO.sub.2NR.sup.7--,
--NR.sup.7SO.sub.2NR.sup.7--, --SO--, or --SO.sub.2--; each n is
independently 0 or 1; each R' is independently H or C.sub.1-6
aliphatic; or two R' groups, together with the atom to which they
are attached, optionally form a 3-6 membered cycloaliphatic or
heterocyclyl, wherein said aliphatic, cycloaliphatic or
heterocyclyl is optionally substituted with R*, --OR*, --SR*,
--NO.sub.2, --CF.sub.3, --CN, --CO.sub.2R*, --COR*, OCOR*, NHCOR*,
wherein R* is H or C.sub.1-6 aliphatic; R.sup.7 is selected from
C.sub.1-6 aliphatic, C.sub.3-10 cycloaliphatic, C.sub.6-10 aryl,
5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two
R.sup.7 groups, on the same substituent or different substituents,
together with the atom(s) to which each R.sup.6 group is bound,
form a 3-8 membered heterocyclyl; each R.sup.8 is independently
--(C.sub.1-3 aliphatic).sub.y-R.sup.9, wherein R.sup.8 is
optionally substituted with 1-5 occurrences of J.sup.R8; each y is
independently 0 or 1; R.sup.9 is halogen, CN, NH.sub.2, NO.sub.2,
CF.sub.3, C.sub.1-4 aliphatic, cyclopropyl, NHR.sup.10,
N(R.sup.10).sub.2, OR.sup.10, C(O)OR.sup.10, --C(O)NH.sub.2,
--C(O)R.sup.10, --NC(O)R.sup.10, or OH; R.sup.10 is C.sub.1-4
aliphatic; each J.sup.R8 is independently selected from halogen,
OCH.sub.3, OH, NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN, or
unsubstituted C.sub.1-2aliphatic; or two J.sup.R8, together with
the carbon to which they are attached, form a cyclopropyl ring or
C.dbd.O.
2. (canceled)
3. The compound according to claim 1, wherein R.sup.1 is H or
halogen.
4. The compound according to claim 3, wherein R.sup.1 is H.
5. (canceled)
6. The compound according to claim 1, wherein R.sup.2 is H, Cl, F
or CH.sub.3.
7. The compound according to claim 6, wherein R.sup.2 is H.
8. (canceled)
9. The compound according to claim 1, wherein Ring A is selected
from the following: ##STR00304## ##STR00305## wherein Ring A is
optionally substituted with 1-3 occurrences of R.sup.8.
10. The compound according to claim 9, wherein Ring A is selected
from ##STR00306## wherein Ring A is optionally substituted with 1-3
occurrences of R.sup.8.
11. (canceled)
12. The compound according to claim 1, wherein Ring A is selected
from ##STR00307## wherein Ring A is optionally substituted with 1-3
occurrences of R.sup.8.
13. (canceled)
14. (canceled)
15. The compound according to claim 1, wherein Ring A is
unsubstituted by R.sup.8 or substituted by one occurrence of
R.sup.8 and R.sup.8 is halogen.
16. (canceled)
17. The compound according to claim 1, wherein R.sup.3 is not
H.
18. (canceled)
19. (canceled)
20. The compound according to claim 17, wherein m is 1 and U is
selected from C(O)NH, C(O)NR.sup.6, NHC(O), NR.sup.6C(O), C(O),
C(O)NHCH.sub.2, C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2 or
NR.sup.6C(O)CH.sub.2.
21. (canceled)
22. The compound according to claim 20, wherein R.sup.6 is
C.sub.1-3 aliphatic optionally substituted with --OH, --CF.sub.3 or
--CN.
23. The compound according to claim 17, wherein m is 0.
24. (canceled)
25. (canceled)
26. The compound according to claim 1, wherein X is C.sub.1-4
straight or branched alkyl, C.sub.2-4 straight or branched alkenyl,
C.sub.2-4 straight or branched alkynyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl,
piperindinyl, pyrrolidinyl, dihydro-1H-pyrrolyl,
tetrohydro-1H-pyranyl, tetrohydrofuranyl, wherein said group is
optionally substituted with 1-4 J.sup.X.
27. (canceled)
28. (canceled)
29. The compound according to claim 26, wherein each J.sup.X is
independently selected from C.sub.1-4 straight or branched alkyl,
C.sub.2-4 straight or branched alkenyl, C.sub.2-4 straight or
branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
chloro, fluoro, --OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2OH, oxo, --CH.sub.2CN, --CH.sub.2CF.sub.3, --CN, or
--CF.sub.3, CO.sub.2H, --CO.sub.2CH.sub.3, or --COCH.sub.3.
30. The compound according to claim 1, having formula II
##STR00308## or a pharmaceutically acceptable salt thereof.
31-50. (canceled)
51. A compound according to claim 1, selected from Compounds 2,
31-33, 57-72, 96-105, 117-129, 131 and 141-157 in Table 1 or a
pharmaceutically acceptable salt thereof.
52. A compound according to claim 1, selected from Compound 159,
168-183, 191-197, 210-212, 215-222, 229-231 and 245-253 in Table 2
or a pharmaceutically acceptable salt thereof.
53. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier, adjuvant, or
vehicle.
54. (canceled)
55. A method of inhibiting JAK kinase activity in a biological
sample, comprising contacting said biological sample with a
compound according to claim 1 or with a composition comprising said
compound and a pharmaceutically acceptable carrier, adjuvant, or
vehicle.
56. A method of inhibiting JAK kinase activity in a patient,
comprising administering to said patient a compound according to
claim 1 or with a composition comprising said compound and a
pharmaceutically acceptable carrier, adjuvant, or vehicle.
57. 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 in a patient,
comprising the step of administering to said patient a compound
according to claim 1 or with a composition comprising said
compound.
58-64. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
11/732,845 filed Apr. 5, 2007 which claims priority to U.S.
Provisional Application No. 60/789,441 filed Apr. 5, 2006. The
entire teachings of these applications are incorporated herein.
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. JAK3 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 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] Accordingly, there is a great need to develop compounds
useful as inhibitors of protein kinases. In particular, it would be
desirable to develop compounds that are useful as inhibitors of JAK
family kinases.
SUMMARY OF THE INVENTION
[0005] 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.
These compounds have the general formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein Ring A,
R.sup.1, R.sup.2 and R.sup.3 are as defined herein.
[0006] These compounds, and pharmaceutically acceptable
compositions thereof, are useful for treating or lessening the
severity of a variety of disorders, including proliferative
disorders, cardiac disorders, neurodegenerative disorders,
autoimmune disorders, conditions associated with organ
transplantation, inflammatory disorders, or immunologically
mediated disorders in a patient.
[0007] The compounds and compositions provided by this invention
are also useful for the study of JAK kinases in biological and
pathological phenomena; the study of intracellular signal
transduction pathways mediated by such kinases; and the comparative
evaluation of new kinase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Terminology
[0008] 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, and the Handbook of Chemistry and
Physics, 75.sup.th Ed. 1994. Additionally, general principles of
organic chemistry are described in "Organic Chemistry", Thomas
Sorrell, University Science Books, Sausalito: 1999, and "March's
Advanced Organic Chemistry", 5th Ed., Smith, M. B. and March, J.,
eds. John Wiley & Sons, New York: 2001, the entire contents of
which are hereby incorporated by reference.
[0009] 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 one or more
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. When more than one position in a given
structure can be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at each position.
[0010] As described herein, when the term "optionally substituted"
precedes a list, said term refers to all of the subsequent
substitutable groups in that list. If a substituent radical or
structure is not identified or defined as "optionally substituted",
the substituent radical or structure is unsubstituted. 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.
[0011] 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.
[0012] 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.
[0013] The term "cycloaliphatic" (or "carbocycle" or "cycloalkyl")
refers to a 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, and wherein any individual ring in said bicyclic ring
system has 3-7 members. Unless otherwise specified, the term
"cycloaliphatic" refers to a monocyclic C.sub.3-C.sub.8 hydrocarbon
or bicyclic C.sub.8-C.sub.12 hydrocarbon. Suitable cycloaliphatic
groups include, but are not limited to, cycloalkyl, cycloalkenyl,
and cycloalkynyl. Further examples of aliphatic groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, and cycloheptenyl.
[0014] The term "heterocycle", "heterocyclyl" or "heterocyclic" as
used herein refers to a monocyclic, bicyclic, or tricyclic ring
system in which one or more ring members are an independently
selected heteroatom and 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. In some embodiments, the "heterocycle", "heterocyclyl" 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.
[0015] 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.
[0016] 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).
[0017] The term "unsaturated", as used herein, means that a moiety
has one or more units of unsaturation.
[0018] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic,
bicyclic, and tricyclic carbocyclic ring systems having a total of
six to fourteen ring members, wherein at least one ring in the
system is aromatic, wherein each ring in the system contains 3 to 7
ring members and that has a single point of attachment to the rest
of the molecule. The term "aryl" may be used interchangeably with
the term "aryl ring". Examples of aryl rings would include phenyl,
naphthyl, and anthracene.
[0019] 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, wherein each ring in the system contains 3 to 7
ring members and that has a single point of attachment to the rest
of the molecule. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic".
[0020] 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).
[0021] In some embodiments, 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 definitions of R.sup.2 and R.sup.4 below. Other suitable
substituents include: 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.1-6 aliphatic, an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, --O(Ph), or
--CH.sub.2(Ph), or, 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, wherein said heteroaryl or heterocyclyl ring has 1-3
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.1-4 aliphatic), 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.
[0022] In some embodiments, 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.1-6 aliphatic. 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.1-4 aliphatic, 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.1-4 aliphatic), or halo(C.sub.1-4
aliphatic), wherein each of the foregoing C.sub.1-4aliphatic groups
of R* is unsubstituted.
[0023] In some embodiments, optional substituents on the nitrogen
of a non-aromatic heterocyclic ring include --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, 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, wherein said
heteroaryl or heterocyclyl ring has 1-3 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.1-4 aliphatic), NO.sub.2,
CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), 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.
[0024] As detailed above, in some embodiments, two independent
occurrences of R.sup.o (or R.sup.+, or any other variable similarly
defined herein), may be 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. 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
##STR00002##
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:
##STR00003##
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.
[0025] In some embodiments, 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 end of the chain; i.e. both at the point of
attachment and/or also at the terminal end. Two optional
replacements can also be adjacent to each other within a chain so
long as it results in a chemically stable compound. 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.
[0026] 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.
##STR00004##
[0027] 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.
##STR00005##
[0028] 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.
##STR00006##
[0029] 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.
[0030] 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.
Description of Compounds of the Invention
[0031] The present invention relates to a compound of formula
I:
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein: [0032] Ring
A is a 5-membered monocyclic heteroaryl having 1-4 heteroatoms
selected from nitrogen, oxygen, or sulfur linked via a carbon atom
to the deazapurine, provided that there is no more than one oxygen
or sulfur heteroatom in Ring A, and if there is an oxygen or sulfur
heteroatom, then there are no more than two nitrogen heteroatoms in
Ring A, wherein Ring A is optionally substituted with up to 1-3
occurrences of R.sup.8; [0033] R.sup.1 is --(C.sub.1-2
aliphatic).sub.p-R.sup.4, wherein R.sup.1 is optionally substituted
with 1-3 occurrences of J.sup.R1; [0034] R.sup.2 is --(C.sub.1-2
aliphatic).sub.d-R.sup.5, wherein R.sup.2 is optionally substituted
with 1-3 occurrences of J.sup.R2; [0035] p and d are each
independently 0 or 1; [0036] R.sup.4 is H, halogen, CN, NH.sub.2,
NO.sub.2, CF.sub.3, C.sub.1-4 aliphatic, cyclopropyl, NCH.sub.3,
OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)CH.sub.3,
--NC(.dbd.O)CH.sub.3, or OH; [0037] R.sup.5 is H, halogen, CN,
NH.sub.2, NO.sub.2, CF.sub.3, C.sub.1-4 aliphatic, cyclopropyl,
NCH.sub.3, OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)CH.sub.3,
--NC(.dbd.O)CH.sub.3, or OH; [0038] each J.sup.R1 is independently
selected from halogen, OCH.sub.3, OH, NO.sub.2, NH.sub.2,
SCH.sub.3, NCH.sub.3, CN, or unsubstituted C.sub.1-2aliphatic; or
two J.sup.R1, together with the carbon to which they are attached,
form a cyclopropyl ring or C.dbd.O; [0039] each J.sup.R2 is
independently selected from halogen, OCH.sub.3, OH, NO.sub.2,
NH.sub.2, SCH.sub.3, NCH.sub.3, CN, or unsubstituted
C.sub.1-2aliphatic; or two J.sup.R2, together with the carbon to
which they are attached, form a cyclopropyl ring or C.dbd.O; [0040]
R.sup.3 is --(U).sub.m--X; [0041] U is a C.sub.1-6 aliphatic,
wherein up to two methylene units are optionally and independently
replaced by G.sup.U and wherein U is optionally substituted with
1-4 J.sup.U; [0042] G.sup.U is --NH--, --NR.sup.6, --O--, --S--,
--CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--,
--C(O)NR.sup.6--, --NC(.dbd.N--CN)N--, --NHCO--, --NR.sup.6CO--,
--NHC(O)O--, --NR.sup.6C(O)O--, --SO.sub.2NH--,
--SO.sub.2NR.sup.6--, --NHSO.sub.2--, --NR.sup.6SO.sub.2--,
--NHC(O)NH--, --NR.sup.6C(O)NH--, --NHC(O)NR.sup.6--,
--NR.sup.6C(O)NR.sup.6, --OC(O)NH--, --OC(O)NR.sup.6--,
--NHSO.sub.2NH--, --NR.sup.6SO.sub.2NH--, --NHSO.sub.2NR.sup.6--,
--NR.sup.6SO.sub.2NR.sup.6--, --SO--, or --SO.sub.2--; [0043]
R.sup.6 is C.sub.1-6 aliphatic or a C.sub.3-10 cycloaliphatic; or
two R.sup.6 groups, together with the atom to which they are
attached, optionally form a 3-7 membered cycloaliphatic or
heterocyclyl, wherein said aliphatic, cycloaliphatic or
heterocyclyl is optionally substituted with R'', --OR'', --SR'',
--NO.sub.2, --CF.sub.3, --CN, --CO.sub.2R'', --COR'', OCOR'',
CONHR'', or NHCOR'', wherein R'' is H or an unsubstituted C.sub.1-6
aliphatic; [0044] m is 0 or 1; [0045] X is H, halogen, CN,
NO.sub.2, S(O)R, SO.sub.2R, or a group selected from a C.sub.1-6
aliphatic, a C.sub.3-10 cycloaliphatic, a C.sub.6-10 aryl, a 5-10
membered heteroaryl, or a 5-10 membered heterocyclyl, wherein said
group is optionally substituted with 1-4 J.sup.X; [0046] R is an
optionally substituted group selected from a C.sub.1-6 aliphatic, a
C.sub.3-10 cycloaliphatic, a C.sub.6-10 aryl, a 5-10 membered
heteroaryl, or a 5-10 membered heterocyclyl, wherein R is
independently and optionally substituted with 1-6 occurrences of
J.sup.R; [0047] each J.sup.R is independently selected from
halogen, L, -(L.sub.n)-R', -(L.sub.n)-N(R').sub.2, -(L.sub.n)-SR',
-(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-10 cycloaliphatic),
-(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10 membered
heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R',
--CO.sub.2H, --COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2,
--NHC(O)R', or NR'C(O)R'; or two J.sup.R groups, on the same
substituent or different substituents, together with the atom(s) to
which each J.sup.R group is bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; [0048] each J.sup.U is
independently selected from halogen, L, -(L.sub.n)-R',
-(L.sub.n)-N(R').sub.2, -(L.sub.n)-SR', -(L.sub.n)-OR',
-(L.sub.n)-(C.sub.3-10 cycloaliphatic), -(L.sub.n)-(C.sub.6-10
aryl), -(L.sub.n)-(5-10 membered heteroaryl), -(L.sub.n)-(5-10
membered heterocyclyl), oxo, C.sub.1-4haloalkoxy,
C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2, -(L.sub.n)-CN,
-(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R', --CO.sub.2H,
--COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2, --NHC(O)R',
or NR'C(O)R'; or two J.sup.X groups, on the same substituent or
different substituents, together with the atom(s) to which each
J.sup.U group is bound, form a 5-7 membered saturated, unsaturated,
or partially saturated ring; [0049] each J.sup.X is independently
selected from halogen, L, -(L.sub.n)-R', -(L.sub.n)-N(R').sub.2,
-(L.sub.n)-SR', -(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-10
cycloaliphatic), -(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10
membered heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R',
--CO.sub.2H, --COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2,
--NHC(O)R', or NR'C(O)R'; or two J.sup.X groups, on the same
substituent or different substituents, together with the atom(s) to
which each J.sup.X group is bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; [0050] each L is
independently a C.sub.1-6 aliphatic wherein up to three methylene
units are replaced by --NH--, --NR.sup.7--, --O--, --S--,
--CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--,
--C(O)NR.sup.7--, --NC(.dbd.N--CN)N, --NHCO--, --NR.sup.7CO--,
--NHC(O)O--, --NR.sup.7C(O)O--, --SO.sub.2NH--,
--SO.sub.2NR.sup.7--, --NHSO.sub.2--, --NR.sup.7SO.sub.2--,
--NHC(O)NH--, --NR.sup.7C(O)NH--, --NHC(O)NR.sup.7--,
--NR.sup.7C(O)NR.sup.7, --OC(O)NH--, --OC(O)NR.sup.7--,
--NHSO.sub.2NH--, --NR.sup.7SO.sub.2NH--, --NHSO.sub.2NR.sup.7--,
--NR.sup.7SO.sub.2NR.sup.7--, --SO--, or --SO.sub.2--; [0051] each
n is independently 0 or 1; [0052] each R' is independently H or
C.sub.1-6 aliphatic; or two R' groups, together with the atom to
which they are attached, optionally form a 3-6 membered
cycloaliphatic or heterocyclyl, wherein said aliphatic,
cycloaliphatic or heterocyclyl is optionally substituted with R*,
--OR*, --SR*, --NO.sub.2, --CF.sub.3, --CN, --CO.sub.2R*, --COR*,
OCOR*, NHCOR*, wherein R* is H or C.sub.1-6 aliphatic; [0053]
R.sup.7 is selected from C.sub.1-6 aliphatic, C.sub.3-10
cycloaliphatic, C.sub.6-10 aryl, 5-10 membered heteroaryl, or 5-10
membered heterocyclyl; or two R.sup.7 groups, on the same
substituent or different substituents, together with the atom(s) to
which each R.sup.6 group is bound, form a 3-8 membered
heterocyclyl; [0054] each R.sup.8 is independently --(C.sub.1-3
aliphatic).sub.y-R.sup.9, wherein R.sup.8 is optionally substituted
with 1-5 occurrences of J.sup.R8; [0055] each y is independently 0
or 1; [0056] R.sup.9 is halogen, CN, NH.sub.2, NO.sub.2, CF.sub.3,
C.sub.1-4 aliphatic, cyclopropyl, NHR.sup.10, N(R.sup.10).sub.2,
OR.sup.10, C(O)OR.sup.10, --C(O)NH.sub.2, --C(O)R.sup.10,
--NC(O)R.sup.10, or OH; [0057] R.sup.10 is C.sub.1-4 aliphatic;
[0058] each J.sup.R8 is independently selected from halogen,
OCH.sub.3, OH, NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN, or
unsubstituted C.sub.1-2aliphatic; or two J.sup.R8, together with
the carbon to which they are attached, form a cyclopropyl ring or
C.dbd.O; [0059] provided that said compound is not
##STR00008##
[0060] In one embodiment, R.sup.1 is H, halogen or C.sub.1-4
aliphatic. In a further embodiment, R.sup.1 is H or halogen. In yet
a further embodiment, R.sup.1 is H.
[0061] In one embodiment, R.sup.2 is H, halogen or C.sub.1-4
aliphatic. In a further embodiment, R.sup.2 is H, Cl, F or
CH.sub.3. In yet a further embodiment, R.sup.2 is H.
[0062] In another embodiment, both R.sup.1 and R.sup.2 are H.
[0063] In one embodiment, Ring A is selected from the
following:
##STR00009##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0064] In a further embodiment, Ring A is selected from the
following:
##STR00010##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0065] In yet a further embodiment, Ring A is selected from the
following:
##STR00011##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0066] In another embodiment, Ring A is selected from the
following:
##STR00012##
[0067] In another embodiment, Ring A is selected from the
following:
##STR00013##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0068] In another embodiment, Ring A is selected from the
following:
##STR00014##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8, and R.sup.1 and R.sup.2 are both H.
[0069] In another embodiment, Ring A is selected from the
following:
##STR00015##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0070] In another embodiment, Ring A is selected from the
following:
##STR00016##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8, and R.sup.1 and R.sup.2 are both H.
[0071] In another embodiment, Ring A is selected from the
following:
##STR00017##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0072] In another embodiment, Ring A is selected from the
following:
##STR00018##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0073] In one embodiment, Ring A is unsubstituted by R.sup.8. In
another embodiment, Ring A is substituted by one occurrence of
R.sup.8 and R.sup.8 is halogen.
[0074] In one embodiment, R.sup.3 is not H.
[0075] In another embodiment, m is 1 and U is selected from C(O)NH,
C(O)NR.sup.6, NHC(O), NR.sup.6C(O), C(O), C(O)O,
C(O)NH(CH.sub.2).sub.1-3, C(O)NR.sup.6(CH.sub.2).sub.1-3,
NHC(O)(CH.sub.2).sub.1-3, NR.sup.6C(O)(CH.sub.2).sub.1-3,
C(O)(CH.sub.2).sub.1-3, C(O)O(CH.sub.2).sub.1-3,
(CH.sub.2).sub.1-3C(O)NH, (CH.sub.2).sub.1-3C(O)NR.sup.6,
(CH.sub.2).sub.1-3NHC(O), (CH.sub.2).sub.1-3NR.sup.6C(O),
(CH.sub.2).sub.1-3C(O) or (CH.sub.2).sub.1-3C(O)O. In a further
embodiment, m is 1 and U is selected from C(O)NH, C(O)NR.sup.6,
NHC(O), NR.sup.6C(O), C(O), C(O)O, C(O)NHCH.sub.2,
C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2, NR.sup.6C(O)CH.sub.2,
C(O)CH.sub.2, C(O)OCH.sub.2, CH.sub.2C(O)NH, CH.sub.2C(O)NR.sup.6,
CH.sub.2NHC(O), CH.sub.2NR.sup.6C(O), CH.sub.2C(O) or
CH.sub.2C(O)O. In yet a further embodiment, m is 1 and U is
selected from C(O)NH, C(O)NR.sup.6, NHC(O), NR.sup.6C(O), C(O),
C(O)O, C(O)NHCH.sub.2, C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2,
NR.sup.6C(O)CH.sub.2, C(O)CH.sub.2, C(O)OCH.sub.2, CH.sub.2C(O)NH,
CH.sub.2C(O)NR.sup.6, CH.sub.2NHC(O), CH.sub.2NR.sup.6C(O),
CH.sub.2C(O) or CH.sub.2C(O)O. In yet a further embodiment, m is 1
and U is selected from C(O)NH, C(O)NR.sup.6, NHC(O), NR.sup.6C(O),
C(O), C(O)NHCH.sub.2, C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2 or
NR.sup.6C(O)CH.sub.2.
[0076] In another embodiment, R.sup.6 is C.sub.1-4 aliphatic
optionally substituted with --OH, --OCH.sub.3, --SH, --SCH.sub.3,
--CF.sub.3, --CN, --CO.sub.2H, --CO.sub.2CH.sub.3, NHCOH,
NHCOCH.sub.3, CONH.sub.2 or CONHCH.sub.3. In a further embodiment,
R.sup.6 is C.sub.1-3 aliphatic optionally substituted with --OH,
--CF.sub.3 or --CN.
[0077] In another embodiment, m is 0 and U is absent.
[0078] In another embodiment, X is a group selected from a
C.sub.1-6 aliphatic, a C.sub.3-7 cycloaliphatic, a C.sub.6-10 aryl,
a 5-8 membered heteroaryl, or a 5-8 membered heterocyclyl, wherein
said group is optionally substituted with 1-4 J.sup.X. In a further
embodiment, X is a group selected from a C.sub.1-6 aliphatic, a
C.sub.3-6 cycloaliphatic, phenyl, a 5-6 membered heteroaryl, or a
5-7 membered heterocyclyl, wherein said group is optionally
substituted with 1-4 J.sup.X. In yet a further embodiment, X is
C.sub.1-4 straight or branched alkyl, C.sub.2-4 straight or
branched alkenyl, C.sub.2-4 straight or branched alkynyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,
pyrimidinyl, pyrrolyl, piperindinyl, pyrrolidinyl,
dihydro-1H-pyrrolyl, tetrohydro-1H-pyranyl, tetrohydrofuranyl,
wherein said group is optionally substituted with 1-4 J.sup.X. In
another embodiment, X is not an optionally substituted C.sub.6-10
aryl. In a further embodiment, X is not an optionally substituted
phenyl.
[0079] In one embodiment, each J.sup.X is independently selected
from halogen, R', -(L.sub.n)-N(R').sub.2, -(L.sub.n)-SR',
-(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-6 cycloaliphatic), oxo,
C.sub.1-4haloalkyl, -(L.sub.n)-CN, -(L.sub.n)-OH,
-(L.sub.n)-CF.sub.3, --CO.sub.2R', --CO.sub.2H, --COR', --COH,
--OC(O)R', --C(O)NHR', or --NC(O)R'; or two J.sup.X groups, on the
same substituent or different substituents, together with the
atom(s) to which each J.sup.X group is bound, form a 5-7 membered
saturated, unsaturated, or partially saturated ring. In a further
embodiment, each J.sup.X is independently selected from C.sub.1-4
aliphatic, C.sub.3-7 cycloaliphatic, halogen, (CH.sub.2).sub.0-3OH,
(CH.sub.2).sub.0-3OCH.sub.3, (CH.sub.2).sub.0-3OCH.sub.2CH.sub.3,
oxo, (CH.sub.2).sub.0-3NH.sub.2, (CH.sub.2).sub.0-3NHCH.sub.3,
(CH.sub.2).sub.0-3N(CH.sub.3).sub.2, (CH.sub.2).sub.0-3SH,
(CH.sub.2).sub.0-3SCH.sub.3, (CH.sub.2).sub.0-3SCH.sub.2CH.sub.3,
(CH.sub.2).sub.0-3CN, (CH.sub.2).sub.0-3CF.sub.3, CO.sub.2H,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, --COCH.sub.3,
--COCH.sub.2CH.sub.3, --COH, --OC(O)CH.sub.3, --C(O)NHCH.sub.3, or
--NC(O)CH.sub.3. In yet a further embodiment, each J.sup.X is
independently selected from C.sub.1-4 straight or branched alkyl,
C.sub.2-4 straight or branched alkenyl, C.sub.2-4 straight or
branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
chloro, fluoro, --OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2OH, oxo, --CH.sub.2CN, --CH.sub.2CF.sub.3, --CN, or
--CF.sub.3, CO.sub.2H, --CO.sub.2CH.sub.3, or --COCH.sub.3. In
another embodiment, J.sup.X is not phenyl.
[0080] In another embodiment, the invention provides a compound of
formula II:
##STR00019##
or a pharmaceutically acceptable salt thereof, wherein Ring A and
R.sup.3 are as defined above.
[0081] In one embodiment of formula II, Ring A is selected from the
following:
##STR00020##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0082] In a further embodiment of formula II, Ring A is selected
from the following:
##STR00021##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0083] In yet another embodiment of formula II, Ring A is selected
from the following:
##STR00022##
[0084] In yet a further embodiment of formula II, Ring A is
selected from the following:
##STR00023##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0085] In yet a further embodiment of formula II, Ring A is
selected from the following:
##STR00024##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0086] In another embodiment of formula II, Ring A is selected from
the following:
##STR00025##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0087] In another embodiment of formula II, Ring A is selected from
the following:
##STR00026##
wherein Ring A is optionally substituted with 1-3 occurrences of
R.sup.8.
[0088] In one embodiment of formula II, Ring A is unsubstituted by
R.sup.8.
[0089] In another embodiment of formula II, R.sup.3 is not H.
[0090] In another embodiment of formula II, m is 1 and U is
selected from C(O)NH, C(O)NR.sup.6, NHC(O), NR.sup.6C(O), C(O),
C(O)O, C(O)NH(CH.sub.2).sub.1-3, C(O)NR.sup.6(CH.sub.2).sub.1-3,
NHC(O)(CH.sub.2).sub.1-3, NR.sup.6C(O)(CH.sub.2).sub.1-3,
C(O)(CH.sub.2).sub.1-3, C(O)O(CH.sub.2).sub.1-3,
(CH.sub.2).sub.1-3C(O)NH, (CH.sub.2).sub.1-3C(O)NR.sup.6,
(CH.sub.2).sub.1-3NHC(O), (CH.sub.2).sub.1-3NR.sup.6C(O),
(CH.sub.2).sub.1-3C(O) or (CH.sub.2).sub.1-3C(O)O. In a further
embodiment, m is 1 and U is selected from C(O)NH, C(O)NR.sup.6,
NHC(O), NR.sup.6C(O), C(O), C(O)O, C(O)NHCH.sub.2,
C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2, NR.sup.6C(O)CH.sub.2,
C(O)CH.sub.2, C(O)OCH.sub.2, CH.sub.2C(O)NH, CH.sub.2C(O)NR.sup.6,
CH.sub.2NHC(O), CH.sub.2NR.sup.6C(O), CH.sub.2C(O) or
CH.sub.2C(O)O. In yet a further embodiment, m is 1 and U is
selected from C(O)NH, C(O)NR.sup.6, NHC(O), NR.sup.6C(O), C(O),
C(O)O, C(O)NHCH.sub.2, C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2,
NR.sup.6C(O)CH.sub.2, C(O)CH.sub.2, C(O)OCH.sub.2, CH.sub.2C(O)NH,
CH.sub.2C(O)NR.sup.6, CH.sub.2NHC(O), CH.sub.2NR.sup.6C(O),
CH.sub.2C(O) or CH.sub.2C(O)O. In yet a further embodiment, m is 1
and U is selected from C(O)NH, C(O)NR.sup.6, NHC(O), NR.sup.6C(O),
C(O), C(O)NHCH.sub.2, C(O)NR.sup.6CH.sub.2, NHC(O)CH.sub.2 or
NR.sup.6C(O)CH.sub.2.
[0091] In another embodiment of formula II, R.sup.6 is C.sub.1-4
aliphatic optionally substituted with --OH, --OCH.sub.3, --SH,
--SCH.sub.3, --CF.sub.3, --CN, --CO.sub.2H, --CO.sub.2CH.sub.3,
NHCOH, NHCOCH.sub.3, CONH.sub.2 or CONHCH.sub.3. In a further
embodiment, R.sup.6 is C.sub.1-3 aliphatic optionally substituted
with --OH, --CF.sub.3 or --CN.
[0092] In another embodiment of formula II, m is 0 and U is
absent.
[0093] In another embodiment of formula II, X is a group selected
from a C.sub.1-6 aliphatic, a C.sub.3-7 cycloaliphatic, a
C.sub.6-10 aryl, a 5-8 membered heteroaryl, or a 5-8 membered
heterocyclyl, wherein said group is optionally substituted with 1-4
J.sup.X. In a further embodiment, X is a group selected from a
C.sub.1-6 aliphatic, a C.sub.3-6 cycloaliphatic, phenyl, a 5-6
membered heteroaryl, or a 5-7 membered heterocyclyl, wherein said
group is optionally substituted with 1-4 J.sup.X. In yet a further
embodiment, X is C.sub.1-4 straight or branched alkyl, C.sub.2-4
straight or branched alkenyl, C.sub.2-4 straight or branched
alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
pyridyl, pyrimidinyl, pyrrolyl, piperindinyl, pyrrolidinyl,
dihydro-1H-pyrrolyl, tetrahydro-1H-pyranyl, tetrohydrofuranyl,
wherein said group is optionally substituted with 1-4 J.sup.X. In
another embodiment, X is not an optionally substituted C.sub.6-10
aryl. In a further embodiment, X is not an optionally substituted
phenyl.
[0094] In one embodiment of formula II, each J.sup.X is
independently selected from halogen, R', -(L.sub.n)-N(R').sub.2,
-(L.sub.n)-SR', -(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-6
cycloaliphatic), oxo, C.sub.1-4haloalkyl, -(L.sub.n)-CN,
-(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R', --CO.sub.2H,
--COR', --COH, --OC(O)R', --C(O)NHR', or --NC(O)R'; or two J.sup.X
groups, on the same substituent or different substituents, together
with the atom(s) to which each J.sup.X group is bound, form a 5-7
membered saturated, unsaturated, or partially saturated ring. In a
further embodiment, each J.sup.X is independently selected from
C.sub.1-4 aliphatic, C.sub.3-7 cycloaliphatic, halogen,
(CH.sub.2).sub.0-3OH, (CH.sub.2).sub.0-3OCH.sub.3,
(CH.sub.2).sub.0-3OCH.sub.2CH.sub.3, oxo,
(CH.sub.2).sub.0-3NH.sub.2, (CH.sub.2).sub.0-3NHCH.sub.3,
(CH.sub.2).sub.0-3N(CH.sub.3).sub.2, (CH.sub.2).sub.0-3SH,
(CH.sub.2).sub.0-3SCH.sub.3, (CH.sub.2).sub.0-3SCH.sub.2CH.sub.3,
(CH.sub.2).sub.0-3CN, (CH.sub.2).sub.0-3CF.sub.3, CO.sub.2H,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, --COCH.sub.3,
--COCH.sub.2CH.sub.3, --COH, --OC(O)CH.sub.3, --C(O)NHCH.sub.3, or
--NC(O)CH.sub.3. In yet a further embodiment, each J.sup.X is
independently selected from C.sub.1-4 straight or branched alkyl,
C.sub.2-4 straight or branched alkenyl, C.sub.2-4 straight or
branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
chloro, fluoro, --OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2OH, oxo, --CH.sub.2CN, --CH.sub.2CF.sub.3, --CN, or
--CF.sub.3, CO.sub.2H, --CO.sub.2CH.sub.3, or --COCH.sub.3. In
another embodiment, J.sup.X is not phenyl.
[0095] In another embodiment, the invention provides a compound of
formulae I or II, wherein said compound inhibits a JAK kinase with
a lower K.sub.i (i.e., is more potent) than said compound inhibits
one or more kinases selected from Aurora-2 (AUR-A), Src, CDK2 or
Flt-3. In another embodiment, the invention provides a compound of
formulae I or II, wherein said compound inhibits JAK2 with a lower
K.sub.i than said compound inhibits one or more kinases selected
from JAK3, Aurora-2, Src, CDK2 or Flt-3. In another embodiment, the
invention provides a compound of formulae I or II, wherein said
compound inhibits a JAK kinase with a lower K.sub.i than said
compound inhibits ERK2.
[0096] In another embodiment, the invention provides a compound of
Table 1:
TABLE-US-00001 TABLE 1 ##STR00027## 1 ##STR00028## 2 ##STR00029## 3
##STR00030## 4 ##STR00031## 5 ##STR00032## 6 ##STR00033## 7
##STR00034## 8 ##STR00035## 9 ##STR00036## 10 ##STR00037## 11
##STR00038## 12 ##STR00039## 13 ##STR00040## 14 ##STR00041## 15
##STR00042## 16 ##STR00043## 17 ##STR00044## 18 ##STR00045## 19
##STR00046## 20 ##STR00047## 21 ##STR00048## 22 ##STR00049## 23
##STR00050## 24 ##STR00051## 25 ##STR00052## 26 ##STR00053## 27
##STR00054## 28 ##STR00055## 29 ##STR00056## 30 ##STR00057## 31
##STR00058## 32 ##STR00059## 33 ##STR00060## 34 ##STR00061## 35
##STR00062## 36 ##STR00063## 37 ##STR00064## 38 ##STR00065## 39
##STR00066## 40 ##STR00067## 41 ##STR00068## 42 ##STR00069## 43
##STR00070## 44 ##STR00071## 45 ##STR00072## 46 ##STR00073## 47
##STR00074## 48 ##STR00075## 49 ##STR00076## 50 ##STR00077## 51
##STR00078## 52 ##STR00079## 53 ##STR00080## 54 ##STR00081## 55
##STR00082## 56 ##STR00083## 57 ##STR00084## 58 ##STR00085## 59
##STR00086## 60 ##STR00087## 61 ##STR00088## 62 ##STR00089## 63
##STR00090## 64 ##STR00091## 65 ##STR00092## 66 ##STR00093## 67
##STR00094## 68 ##STR00095## 69 ##STR00096## 70 ##STR00097## 71
##STR00098## 72 ##STR00099## 73 ##STR00100## 74 ##STR00101## 75
##STR00102## 76 ##STR00103## 77 ##STR00104## 78 ##STR00105## 79
##STR00106## 80 ##STR00107## 81 ##STR00108## 82 ##STR00109## 83
##STR00110## 84 ##STR00111## 85 ##STR00112## 86 ##STR00113## 87
##STR00114## 88 ##STR00115## 89 ##STR00116## 90 ##STR00117## 91
##STR00118## 92 ##STR00119## 93 ##STR00120## 94 ##STR00121## 95
##STR00122## 96 ##STR00123## 97 ##STR00124## 98 ##STR00125## 99
##STR00126## 100 ##STR00127## 101 ##STR00128## 102 ##STR00129## 103
##STR00130## 104 ##STR00131## 105 ##STR00132## 106 ##STR00133## 107
##STR00134## 108 ##STR00135## 109 ##STR00136## 110 ##STR00137## 111
##STR00138## 112 ##STR00139## 113 ##STR00140## 114 ##STR00141## 115
##STR00142## 116 ##STR00143## 117 ##STR00144## 118 ##STR00145## 119
##STR00146## 120 ##STR00147## 121 ##STR00148## 122 ##STR00149## 123
##STR00150## 124
##STR00151## 125 ##STR00152## 126 ##STR00153## 127 ##STR00154## 128
##STR00155## 129 ##STR00156## 130 ##STR00157## 131 ##STR00158## 132
##STR00159## 133 ##STR00160## 134 ##STR00161## 135 ##STR00162## 136
##STR00163## 137 ##STR00164## 138 ##STR00165## 139 ##STR00166## 140
##STR00167## 141 ##STR00168## 142 ##STR00169## 143 ##STR00170## 144
##STR00171## 145 ##STR00172## 146 ##STR00173## 147 ##STR00174## 148
##STR00175## 149 ##STR00176## 150 ##STR00177## 151 ##STR00178## 152
##STR00179## 153 ##STR00180## 154 ##STR00181## 155 ##STR00182## 156
##STR00183## 157 ##STR00184## 158
[0097] In another embodiment, the invention provides a compound of
Table 2:
TABLE-US-00002 TABLE 2 ##STR00185## 159 ##STR00186## 160
##STR00187## 161 ##STR00188## 162 ##STR00189## 163 ##STR00190## 164
##STR00191## 165 ##STR00192## 166 ##STR00193## 167 ##STR00194## 168
##STR00195## 169 ##STR00196## 170 ##STR00197## 171 ##STR00198## 172
##STR00199## 173 ##STR00200## 174 ##STR00201## 175 ##STR00202## 176
##STR00203## 177 ##STR00204## 178 ##STR00205## 179 ##STR00206## 180
##STR00207## 181 ##STR00208## 182 ##STR00209## 183 ##STR00210## 184
##STR00211## 185 ##STR00212## 186 ##STR00213## 187 ##STR00214## 188
##STR00215## 189 ##STR00216## 190 ##STR00217## 191 ##STR00218## 192
##STR00219## 193 ##STR00220## 194 ##STR00221## 195 ##STR00222## 196
##STR00223## 197 ##STR00224## 198 ##STR00225## 199 ##STR00226## 200
##STR00227## 201 ##STR00228## 202 ##STR00229## 203 ##STR00230## 204
##STR00231## 205 ##STR00232## 206 ##STR00233## 207 ##STR00234## 208
##STR00235## 209 ##STR00236## 210 ##STR00237## 211 ##STR00238## 212
##STR00239## 213 ##STR00240## 214 ##STR00241## 215 ##STR00242## 216
##STR00243## 217 ##STR00244## 218 ##STR00245## 219 ##STR00246## 220
##STR00247## 221 ##STR00248## 222 ##STR00249## 223 ##STR00250## 224
##STR00251## 225 ##STR00252## 226 ##STR00253## 227 ##STR00254## 228
##STR00255## 229 ##STR00256## 230 ##STR00257## 231 ##STR00258## 232
##STR00259## 233 ##STR00260## 234 ##STR00261## 235 ##STR00262## 236
##STR00263## 237 ##STR00264## 238 ##STR00265## 239 ##STR00266## 240
##STR00267## 241 ##STR00268## 242 ##STR00269## 243 ##STR00270## 244
##STR00271## 245 ##STR00272## 246 ##STR00273## 247 ##STR00274## 248
##STR00275## 249 ##STR00276## 250 ##STR00277## 251 ##STR00278## 252
##STR00279## 253 ##STR00280## 254
Uses, Formulation and Administration
Pharmaceutically Acceptable Compositions
[0098] In another embodiment, the invention provides a
pharmaceutical composition comprising a compound of formulae I or
II.
[0099] In a further embodiment, the composition additionally
comprising a therapeutic agent selected from a chemotherapeutic or
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, a neurotrophic factor,
an agent for treating cardiovascular disease, an agent for treating
destructive bone disorders, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, or an agent for treating immunodeficiency
disorders.
[0100] According to another embodiment, the invention provides a
composition comprising a compound of this invention or a
pharmaceutically acceptable derivative thereof and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. The
amount of compound in the compositions of this invention is such
that is effective to measurably inhibit a protein kinase,
particularly a JAK family kinase, in a biological sample or in a
patient. Preferably the composition of this invention is formulated
for administration to a patient in need of such composition. Most
preferably, the composition of this invention is formulated for
oral administration to a patient.
[0101] The term "patient", as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0102] 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.
[0103] 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 prodrugs, 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.
As used herein, the term "inhibitorily active metabolite or residue
thereof" means that a metabolite or residue thereof is also an
inhibitor of a JAK family kinase.
[0104] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like.
[0105] 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 dispersable 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.
[0106] 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.
[0107] 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.
[0108] The term "measurably inhibit", as used herein means a
measurable change in kinase activity, particularly JAK kinase
activity, between a sample comprising a compound of this invention
and a JAK kinase and an equivalent sample comprising JAK kinase in
the absence of said compound.
[0109] The compositions of the present invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intraocular,
intrahepatic, intralesional and intracranial injection or infusion
techniques. Preferably, the compositions are administered orally,
intraperitoneally or intravenously. Sterile injectable forms of the
compositions of this invention may be aqueous or oleaginous
suspension. These suspensions may be formulated according to
techniques known in the art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium.
[0110] For this purpose, any bland fixed oil may be employed
including synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0111] The pharmaceutically acceptable compositions of this
invention may be orally administered in any orally acceptable
dosage form including, but not limited to, capsules, tablets,
aqueous suspensions or solutions. In the case of tablets for oral
use, carriers commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful diluents
include lactose and dried cornstarch. When aqueous suspensions are
required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents may also be added.
[0112] Alternatively, the pharmaceutically acceptable compositions
of this invention may be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0113] The pharmaceutically acceptable compositions of this
invention may also be administered topically, especially when the
target of treatment includes areas or organs readily accessible by
topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0114] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0115] For topical applications, the pharmaceutically acceptable
compositions may be formulated in a suitable ointment containing
the active component suspended or dissolved in one or more
carriers. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutically acceptable compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0116] For ophthalmic use, the pharmaceutically acceptable
compositions may be formulated, e.g., as micronized suspensions in
isotonic, pH adjusted sterile saline or other aqueous solution, or,
preferably, as solutions in isotonic, pH adjusted sterile saline or
other aqueous solution, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutically acceptable compositions may be formulated in an
ointment such as petrolatum. The pharmaceutically acceptable
compositions of this invention may also be administered by nasal
aerosol or inhalation. Such compositions are prepared according to
techniques well-known in the art of pharmaceutical formulation and
may be prepared as solutions in saline, employing benzyl alcohol or
other suitable preservatives, absorption promoters to enhance
bioavailability, fluorocarbons, and/or other conventional
solubilizing or dispersing agents.
[0117] Most preferably, the pharmaceutically acceptable
compositions of this invention are formulated for oral
administration.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] The amount of the compounds of the present invention that
may be combined with the carrier materials to produce a composition
in a single dosage form will vary depending upon the host treated,
the particular mode of administration. Preferably, the compositions
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of the inhibitor can be administered to a patient
receiving these compositions.
[0129] Depending upon the particular condition, or disease, to be
treated or prevented, additional therapeutic agents, which are
normally administered to treat or prevent that condition, may also
be present in the compositions of this invention. 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".
[0130] For example, chemotherapeutic agents or other
anti-proliferative agents may be combined with the compounds of
this invention to treat proliferative diseases and cancer. Examples
of known chemotherapeutic agents include, but are not limited to,
Gleevec.TM., adriamycin, dexamethasone, vincristine,
cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and
platinum derivatives.
[0131] Other examples of agents the inhibitors of this invention
may also be combined with include, without limitation: treatments
for Alzheimer's Disease such as Aricept.RTM. and Excelon.RTM.;
treatments for Parkinson's Disease such as L-DOPA/carbidopa,
entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating Multiple
Sclerosis (MS) such as beta interferon (e.g., Avonex.RTM. and
Rebif.RTM.), Copaxone.RTM., and mitoxantrone; treatments for asthma
such as albuterol and Singulair.RTM.; agents for treating
schizophrenia such as zyprexa, risperdal, seroquel, and
haloperidol; anti-inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive agents such
as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil,
interferons, corticosteroids, cyclophophamide, azathioprine, and
sulfasalazine; neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion
channel blockers, riluzole, and anti-Parkinsonian agents; agents
for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth factors; and agents for treating
immunodeficiency disorders such as gamma globulin.
[0132] 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.
Uses of the Compounds and Compositions
[0133] In one embodiment, the invention provides a method of
inhibiting JAK kinase activity in a patient, comprising
administering to said patient a compound or composition of the
invention.
[0134] In another embodiment, the invention comprises a method of
treating or lessening the severity of a JAK-mediated condition or
disease in a patient. The term "JAK-mediated disease", as used
herein means any disease or other deleterious condition in which a
JAK family kinase, in particular JAK2 or JAK3, is known to play a
role. In a further embodiment, the invention comprises a method of
treating a JAK3-mediated disease. 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. In another embodiment, the
invention comprises a method for treating a JAK2-mediated disease,
such as, for example, a myeloproliferative disease.
[0135] In another embodiment, the invention provides 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, an
immune disorder or an immunologically mediated disorder, comprising
administering to said patient a compound or composition of the
invention.
[0136] In a further embodiment, the method comprises the additional
step of administering to said patient an additional therapeutic
agent selected from a chemotherapeutic or anti-proliferative agent,
an anti-inflammatory agent, an immunomodulatory or
immunosuppressive agent, a neurotrophic factor, an agent for
treating cardiovascular disease, an agent for treating diabetes, or
an agent for treating immunodeficiency disorders, wherein said
additional therapeutic agent is appropriate for the disease being
treated and said additional therapeutic agent is administered
together with said composition as a single dosage form or
separately from said composition as part of a multiple dosage
form.
[0137] In one embodiment, the disease or disorder is allergic or
type I hypersensitivity reactions, asthma, diabetes, Alzheimer's
disease, Huntington's disease, Parkinson's disease, AIDS-associated
dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's
disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte
hypertrophy, reperfusion/ischemia, stroke, baldness, transplant
rejection, graft versus host disease, rheumatoid arthritis,
amyotrophic lateral sclerosis, and multiple sclerosis, and solid
and hematologic malignancies such as leukemias and lymphomas. In a
further embodiment, said disease or disorder is asthma. In another
embodiment, said disease or disorder is transplant rejection.
[0138] In another embodiment, a compound or composition of this
invention may be used to treat a myeloproliferative disorder. In
one embodiment, the myeloproliferative disorder is polycythemia
vera, essential thrombocythemia, or chronic idiopathic
myelofibrosis. In another embodiment, the myeloproliferative
disorder is myeloid metaplasia with myelofibrosis, chronic myeloid
leukemia (CML), chronic myelomonocytic leukemia, chronic
eosinophilic leukemia, hypereosinophilic syndrome, systematic mast
cell disease, atypical CML or juvenile myelomonocytic leukemia.
[0139] In another embodiment, the invention provides a method of
inhibiting JAK kinase activity in a biological sample, comprising
contacting said biological sample with a compound or composition of
the invention.
[0140] The term "biological sample", as used herein, means an ex
vivo sample, and includes, without limitation, cell cultures or
extracts thereof; tissue or organ samples 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.
[0141] Inhibition of kinase activity, particularly JAK 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.
[0142] 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 one or more of the aforementioned disorders. 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
the disorder or disease. 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.
[0143] In an alternate embodiment, the methods of this invention
comprise the additional step of separately administering to said
patient an additional therapeutic agent. When these additional
therapeutic agents are administered separately they may be
administered to the patient prior to, sequentially with or
following administration of the compositions of this invention.
[0144] The compounds of this invention or pharmaceutical
compositions thereof may also be used for coating an implantable
medical device, such as prostheses, artificial valves, vascular
grafts, stents and catheters. 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
compound of this invention.
[0145] 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. Implantable devices coated with
a compound of this invention are another embodiment of the present
invention. The compounds may also be coated on implantable medical
devices, such as beads, or co-formulated with a polymer or other
molecule, to provide a "drug depot", thus permitting the drug to be
released over a longer time period than administration of an
aqueous solution of the drug.
Methodology for Synthesis and Characterization of Compounds
[0146] 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. See,
e.g., the examples described in WO 2005/095400 and WO 2006/127587,
which are herein incorporated by reference in its entirety.
[0147] All references provided in the 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.
##STR00281##
[0148] Compounds of the invention may be synthesized following the
general approach outlined above. Starting with the appropriately
protected 4-iododeazapurine, palladium-mediated cross coupling can
be effected with heteroaryl boronic acids, or pinnacoleborane
esters. Alternatively, heteroarylstannanes or arylzincates derived
from the corresponding aryl halides can be used in cross coupling
reactions. Deprotection of the deazapurine followed by further
elaboration of the R group provides the desired compounds.
[0149] Exemplary heteroaryl precursors that may be used in the
above-described synthetic scheme are described in the following
publications: WO 2004/081008; WO 2005/063755; WO 2003/053925; Wendt
et al., Bioorg. Med. Chem. Lett. 14(12): 3063-3068 (2004); Hocek et
al., J. Med. Chem. 48 (18): 5869-5873 (2005); Malamas et al., J.
Med. Chem. 47 (21): 5021-5040 (2004); Xu et al., Bioorg. Med. Chem.
Lett. 15 (10): 2533-2536 (2005); and Advanced Synthesis &
Catalysis 345 (9, 10): 1103-(2003). In addition, a number of
heteroaryl precursors are available commercially.
EXAMPLES
Example 1
Preparation of Thiazolyl-Pyrrolo[2,3-d]Pyrimidines of the
Invention
##STR00282##
##STR00283##
[0150]
4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine
[0151] To a solution of [10 g, 65.1 mmol] of
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine in 250 mL of dry THF was
cautiously added portionwise over 5 minutes time [2.86 g, 71.6
mmol] sodium hydride (60% oil dispersion). Reaction was then
allowed to stir for 30 minutes at ambient temperature under a
blanket of nitrogen gas. [12.96 g, 68.0 mmol] of solid toluene
sulphonyl chloride was then added, in one portion and the reaction
mixture was allowed to stir for one hour additional at ambient
temperature. Ten mL of water was then cautiously added to the
reaction (a quench for the excess hydride) and the solvent was
removed under reduced pressure to 1/4 the original volume. The
residue was then suspended in 300 mL of water, stirred at ambient
temperature for 30 minutes and isolated as a white solid via
suction filtration. The material was washed with additional water
and the damp cake was suspended in a minimum of acetonitrile and
stirred overnight at ambient temperature. The precipitate was
isolated via suction filtration and washed cautiously with cold
acetonitrile and washed with hexanes; material air dried. Yield:
17.2 g of an off white solid (85%).
[0152] NMR: 500 MHz in CDCL3 .delta.8.75 (s, 1H), 8.09 (d, 2H J=8.5
Hz), 7.78 (d, 1H J=4.1 Hz), 7.36 (d, 2H J=8.5 Hz), 6.70 (d, 1H
J=4.1 Hz), 2.4 (s, 3H)
##STR00284##
4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine
[0153] [5 g. 16.2 mmol] of
4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine 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 twice with saturated sodium hydrogen
carbonate solution, 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%).
[0154] 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)
##STR00285##
4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine
[0155] [10 g, 25 mmol] of
4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine 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.
[0156] 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).
##STR00286##
1-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethanone
[0157] [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.
[0158] 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).
##STR00287##
2-Bromo-1-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethano-
ne
[0159] [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
saturated 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.
[0160] 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).
##STR00288##
4-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-thiazol-2-ylam-
ine
[0161] Into 75 mL of acetone was successively added [4.2 g, 10.65
mmol] of
2-Bromo-1-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethano-
ne followed by [0.81 g, 10.65 mmol] of thiourea. The reaction was
then stirred for 4.0 hours at ambient temperature. The pale yellow
precipitate was collected via suction filtration and washed with
more acetone. The crude cake was suspended into 20 mL of
triethylamine and stirred for one hour. The material was then
diluted with water and suction filtered to isolate the solid. The
damp cake was triturated with acetonitrile, the solid isolated
again via suction filtration and airdried. The beige solid, 2.6 g,
represents a 72% yield of the free base.
[0162] NMR: 500 MHz in CDCL3 .delta.8.92 (s, 1H), 8.08 (d, 2H,
J=8.5 Hz), 7.73 (d, 1H, J=4.1 Hz), 7.70 (s, 1H), 7.42 (d, 1H, J=4.1
Hz), 7.28 (d, 2H, J=8.5 Hz), 5.1 (br m, 2H, exch), 2.4 (s, 3H).
##STR00289##
3-Methyl-N-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-thiazol-2-yl]-butyramide
(Compound 31)
[0163] To a solution of [60 mg, 0.1615 mmols] of
4-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-thiazol-2-ylam-
ine in 1 mL of dry pyridine contained in a microwave vial, was
added successively; [46 mg, 0.242 mmol] of EDCI, and [27 uL, 25 mg,
0.242 mmol] of isovaleric acid. The reaction was heated via
microwave to 150.degree. C. (150 W) for 10 minutes. The vial was
opened and the pyridine was removed under a nitrogen stream before
the residue was re-dissolved in a mixture of THF/methanol (2:1). To
this solution was added, 3 drops of 50% sodium hydroxide and the
reaction was stirred for approx one hour at ambient temperature.
The hydrolysis was determined to be complete by HPLC and reaction
was brought to low pH by addition of conc. Hydrochloric acid
(11.0M). The solvents were removed via a stream of nitrogen gas and
residue was dissolved in DMSO and particulates allowed to settle
before purifying the crude material via C.sub.18 HPLC utilizing
water/acetonitrile/trifluoroacetic acid as the eluent. This yielded
14 mg of the final product as the TFA salt after lyophilization of
the aqueous HPLC fractions; a 20.8% yield.
[0164] All other amide derivatives synthesized from
4-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-thiazol-2-ylam-
ine were accomplished in an analogous manner.
##STR00290##
3-Methyl-N-propyl-N-{4-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-thiazol-2-yl}-butyramide
[0165] [100 mg; 0.22 mmol] of
3-Methyl-N-{4-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-thia-
zol-2-yl}-butyramide was dissolved in 1 mL of dry DMF and to this
solution was added [13.0 mg; 0.27 mmol] of sodium hydride (60% in
oil dispersion) and the reaction was stirred at 40.degree. C. for
10 minutes before addition of [21.5 uL; 37.37 mg; 0.22 mmol] of
n-propyliodide, in one portion. The reaction was stirred for one
hour more at 40.degree. C. After reaction was determined to be
complete, the solvent was removed under reduced pressure and
residue triturated with methyl t-butyl ether and filtrate decanted
away from oil. The trituration was performed again and the crude
reaction mixture stirred overnight at ambient temperature, the
material solidifies. The material was isolated via suction
filtration and washed with more ether, again with petroleum ether
and air dried. This provides a dark beige powder; 83 mg
representing a 76% yield.
##STR00291##
3-Methyl-N-propyl-N-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-thiazol-2-yl]-bu-
tyramide (Compound 103)
[0166] To 55 mg [0.11 mmol] of
3-Methyl-N-propyl-N-{4-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-thiazol-2-yl}-butyramide dissolved in 2 mL of dry THF was
added 5 drops of a 1M tetra n-butylammonium fluoride solution in
THF, the vial was capped and heated/stirred at 80.degree. C. for 4
hours. Reaction determined to be complete via HPLC and reaction was
cooled. The solvent was removed under an N.sub.2 stream and residue
was partitioned between DCM and water. The organic layer was brined
and dried with anhydrous sodium sulphate and the solvent removed
under vacuum. The crude product was purified on C.sub.18 silica
with water/acetonitrile/TFA as the eluent, isolating 15 mg of a
yellow solid which constituted a 39% yield.
Example 2
Preparation of Pyrrolyl-Pyrrolo[2,3-d]Pyrimidines of the
Invention
##STR00292##
[0167]
4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrro-
le-2-carboxylic acid methyl ester (3')
[0168] Under N.sub.2, Compound 1' (1.3 g, 8.49 mmol) and compound
2' (1.1 equivalent, 9.34 mmol) and K.sub.2CO.sub.3 (3.3 equivalent,
28 mmol) were dissolved into 9 mL of dioxane and 3 mL of H.sub.2O
in a microwave. To this reaction mixture, catalytic amount of
Pd(PPh.sub.3).sub.4 was added and the tube was under microwave
irradiation at 170.degree. C. for 10 min. After cooled down the
reaction mixture, the product crashed out and filtered off the
solid, washed with H.sub.2O and CH.sub.3CN respectively to obtain
title compound 3' quantatively. MS+1=397.2.
4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid
(4')
[0169] To a microwave tube with compound 3' from previous step,
LiOH (4 equivalent, 33.96 mmol) was added, followed by THF (8 mL)
and H.sub.2O (4 mL). The reaction mixture was microwave irradiated
at 150.degree. C. for 10 min. Poured reaction mixture into a
beaker, and 2N HCl was added to the reaction mixture drop wise to
adjust the pH of the solution to 4-5. In the process of acidifying
the solution, precipitation was formed, filtered off the solid and
washed with H.sub.2O extensively and then small amount of
CH.sub.3CN. Dried to give title compound 4' quantatively.
MS+1=229.1
4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid
amide (5')
[0170] To a vial with Compound 4' (0.1 mmol) in DMF (1 mL), EDC (2
equivalent, 0.2 mmol) and HOBt (0.5 equivalent, 0.05 mmol) were
added and the reaction mixture was stirred at room temperature for
half an hour. Amine (1.2 equivalent, 0.12 mmol) was added and the
reaction mixture was stirred at room temperature for 2-3 hour.
Reverse phase HPLC was used to purify the final compound.
Example 3
Preparation of Furanyl-Pyrrolo[2,3-d]Pyrimidines of the
Invention
##STR00293##
[0171] 5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-furan-2-carbaldehyde
(8')
[0172] Under N.sub.2, Compound 1' (0.875 g, 5.7 mmol) and compound
7' (1.01 g, 7.2 mmol) and KF (3.3 equivalent, 18.8 mmol) were
dissolved into 10 mL of dioxane in a microwave. To this reaction
mixture, catalytic amount of Pd.sub.2(dba).sub.3 (0.015% mol) and
P(t-Bu).sub.3 (0.045% mol) were added, and the tube was microwave
irradiated at 160.degree. C. for 15 min. After it was concentrated
down, CH.sub.3CN was added to the reaction mixture. The product
precipitated out and the solid was filtered off, washed with
H.sub.2O and CH.sub.3CN respectively to obtain title compound 8'.
MS+1=214.1.
5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-furan-2-carboxylic acid
(9')
[0173] Sodium dihydrogen phosphate (210 mg, 1.75 mmol),
2-methyl-2-butene (0.742 mL, 7.0 mmol) and sodium chlorite (127 mg,
1.4 mmol) were consecutively added to a solution of compound 8'
(74.5 mg, 0.35 mmol) in t-BuOH (6 mL) and H.sub.2O (2.4 mL) at
0.degree. C. under N.sub.2, and the solution was stirred at room
temperature over night. Water was added to the solution and the
aqueous layer was adjusted to pH 2 with 20% aqueous solution of
phosphoric acid. A precipitate was formed, was filtered off, washed
with H.sub.2O, and dried to give the title compound 9' (32 mg,
40%).
5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-furan-2-carboxylic acid amide
(10')
[0174] To a vial with Compound 9' (0.1 mmol) in DMF (1 mL), EDC (2
equivalent, 0.2 mmol) and HOBt (0.5 equivalent, 0.05 mmol) were
added and the reaction mixture was stirred at room temperature for
half an hour. Amine (1.2 equivalent, 0.12 mmol) was added and the
reaction mixture was stirred at room temperature for 2-3 hour.
Reverse phase HPLC was used to purify the final compound.
Example 4
Preparation of Pyrazolyl-Pyrrolo[2,3-d]Pyrimidines of the
Invention
##STR00294##
[0175] 4-(1H-pyrazo-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine
(13')
[0176] The reaction mixture of
4-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (12', 0.800 g, 2 mmol),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-H-pyrazole-1-carboxylat-
e, 3.5 ml 2M KOAc, 0.12 g (0.1 mmol) Palladium
tetrakistriphenylphosphine and 10 ml 1,4-dioxane was deoxygenated
by bubbling N.sub.2 for 20 min. The reaction mixture was heated at
140.degree. C. on microwave synthesizer for 10 min. Work up: The
reaction mixture was cooled to room temperature and filtered. The
filtration cake is 2.0 g 95% pure title product, yield 50%.
4-(1-(Hexan-3-yl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo-[2,3-d]pyrimidine
(example of 14')
[0177] The DMF suspension of
4-(1H-pyrazo-4-yl)-7-tosyl-7H-pyrrolo-[2,3-d]pyrimidine,
3-bromohexane and CsCO.sub.3 was stirred at 80.degree. C. for
overnight. LC/MS indicated the product peak and some starting
material. No work up and the reaction material was carried on for
next step. No yield was calculated.
4-(1-(hexan-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
(example of 15', Compound 94)
[0178] To the crude product mixture of
4-(1-(hexan-3-yl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo-[2,3-d]pyrimidine
was added 1 mL 1M NaOH solution, the reaction mixture was stirred
at 80.degree. C. for 3 h. LC/MS indicated no starting material.
Work up: The reaction mixture was filtered through syring filter
and injected on to prep HPLC, the product fraction was collected
and dried on EZ 2-plus. No yield was calculated.
Example 5
Preparation of Thiazolyl-Pyrrolo[2,3-d]Pyrimidines of the
Invention
##STR00295##
##STR00296##
[0179] 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbaldehyde
[0180] 1 g [4.5 mMols] of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carbaldehyde,
550 mg [3.6 mMols] 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 1.52 g
[6.7 mMols] of tripotassium phosphate were placed in 20 mL DMF and
10 mL water and purged with nitrogen gas while stirring for 10
minutes at ambient temperature. To this stirring suspension, 400
mg, 0.45 mMols] of tetrakistriphenylphosphine palladium (0) was
added in one portion, and reaction vessel was placed in a preheated
bath at 110.degree. C. The reaction was stirred and heated under a
nitrogen atmosphere for 30 minutes (deemed complete by analytical
liquid chromatography). The reaction mixture was cooled and suction
filtered to remove the ligand present as a precipitate, which was
washed with a little DMF/H.sub.2O 2:1. The combined filtrates were
reduced in volume to one quarter of the original under reduced
pressure and diluted slowly with water with stirring. The resulting
fine precipitate was centrifuged down and the pellet was washed
with more water, re-centrifuged and transferred to a RB with
acetonitrile. This solvent was reduced to dryness under reduced
pressure. The material, 670 mg (yield 87%) of a light beige powder
was carried on without further purification. LC/ms m+1=214.
##STR00297##
4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carboxylic acid
[0181] 600 mg [2.82 mMols] of
4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbaldehyde was
dissolved in 5.0 mL of DMSO/2.0 mL of water and stirred with 210 mg
[1.75 mMols] of sodium dihydrogen phosphate, reducing the
temperature as cold as possible so as not to effect
crystallization. 532 mg sodium chlorite [5.88 mMols] in 4.0 mL of
water was slowly added dropwise to this stirring solution. Solution
was allowed to warm to ambient temperature and diluted with water
to effect precipitation. The fine flocculent material was
centrifuged down and washed with water and re-centrifuged. The oily
pellet was transferred to a RB with acetonitrile and the solvents
were removed under reduced pressure. The residue was stirred with a
mixture of MTBE/acetonitrile (4:1) overnight and the powder
isolated in the morning via suction filtration, washed with the
same mixture and air dried. The material, (yield 64.6%) a beige
powder, was utilized without further purification. LC/MS m+1
230/m-1 228.
##STR00298##
N-(cyclopropylmethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(2,2,2-triflu-
oroethyl)furan-2-carboxamide (Compound 231)
[0182] 35 mg [0.153 mMols] of
4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carboxylic acid was
dissolved in 1.5 mL of DMF and stirred with 120 mg [0.22 mMols] of
PyBOP, 50 .mu.L [46 mg, 0.46 mMols] of N-methylmorpholine, and 50
mg [0.26 mMols] of
N-(2,2,2-trifluoroethyl)N-2-cyclopropylethylamine overnight at
ambient temperature. The solvent was removed under a nitrogen
stream at 30.degree. C. and residue dissolved in methanol with
several drops of TFA to protonate the amines present. The crude
material was purified via C.sub.18 silica utilizing a gradient of
water/acetonitrile/TFA as an eluent 5%-95%. The product, 4 mg of a
beige powder (after lyophilization of filtrates) was obtained;
yield 9.5%.
##STR00299##
N-(2-cyanoethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3,3,3-trifluoropr-
opyl)furan-2-carboxamide (Compound 230)
[0183] In an analogous fashion,
N-(2-cyanoethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3,3,3-trifluoropr-
opyl)furan-2-carboxamide was prepared and purified to yield 6.0 mg
of a beige powder, yield 7.9%.
##STR00300##
N-(cyclopropylmethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3,3,3-triflu-
oropropyl)furan-2-carboxamide (Compound 229)
[0184] In an analogous fashion,
N-(cyclopropylmethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3,3,3-triflu-
oropropyl)furan-2-carboxamide was prepared and purified to yield
4.0 mg of a beige powder, yield 5.2%.
Example 6
Preparation of Furanyl-Pyrrolo[2,3-d]Pyrimidines of the
Invention
##STR00301##
[0185] 5-boronofuran-3-carboxylic acid (17')
[0186] 139 mg compound 16' [1 mmol] was dissolved into 3 mL acetone
at 0.degree. C., to which 5 equivalent of Jones Reagent was added
slowly during the course of 5 min. The reaction mixture was stirred
at room temperature for 1 hour, the reaction mixture was poured
into 10 mL of ether and the solid filtered off. The ether was
removed to give the crude compound 2. MS-1=155.0.
5-(1H-pyrrolo[2,3-b]pyridin-4-yl)furan-3-carboxylic acid (18')
[0187] To a microwave tube with 50 mg compound 17' [0.32 mmol], 2
mL of dioxane was added, followed by compound 1' (1.1 equiv), KF
(3.3 equiv.), Pd.sub.2(dba).sub.3 (10% mol equiv.) and
P(t-Bu).sub.3 (30% mol equiv) and the reaction tube was subjected
to microwave irradiation for 15 min. at 160.degree. C. After the
reaction cooled down, the solid was filtered off, washed with small
amount of CH.sub.3CN to give the title compound 18'.
MS+1=229.9.
[0188] 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)furan-3-carboxamide (19'):
To a vial with compound 18' (0.1 mmol) in DMF (1 mL), PyBOP (2
equivalent, 0.2 mmol) and NMM (2 equivalent, 0.2 mmol) were added
and the reaction mixture was stirred at room temperature for half
an hour. The desired amine (1.2 equivalent, 0.12 mmol) was added
and the reaction mixture was stirred at room temperature for 2-3
hour. Reverse phase HPLC was used to purify the final compound
19'.
[0189] Other compounds of the invention may be synthesized in
analogous fashion to those examples presented herein.
Example 7
Analytical Results
[0190] Tables 3 and 4 below depict 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 Tables 3 and 4 correspond to the compounds
depicted in Tables 1 and 2 respectively (empty cells in the NMR
column indicate that results were not available). If multiple lots
were made and tested, only the results from the first lot tested
are depicted.
TABLE-US-00003 TABLE 3 Cpd # M + H RT NMR 1 382.00 2.00 (CD3OD)
3.85 (m, 2H), 5.15 (t, 1H), 7.2 (m, 1H), 7.3 (m, 3H), 7.4 (s, 1H),
7.8 (m, 2H), 8.1 (s, 1H), 8.8 (s, 1H) 2 202.10 1.60 (500 MHz,
dmso-d6) 12.3 (s, 1H), 8.81 (s, 1H), 8.55 (d, 1H), 7.96 (dd, 1H),
7.70 (d, 1H), 7.05 (d, 1H) ppm 3 200.20 1.30 (500 MHz, dmso-d6)
12.7 (s, 1H), 8.88 (s, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 7.77 (s,
1H), 7.14 (s, 1H), 3.99 (s, 3H) ppm 4 186.20 2.20 (500 MHz,
dmso-d6) 12.3 (s, 1H), 8.82 (d, 1H), 8.64 (s, 1H), 8.00 (m, 1H),
7.60 (m, 1H), 7.12 (m, 1H), 6.66 (m, 1H) ppm 5 186.20 2.20 6 296.10
1.50 (500 MHz, DMSO-d6) 12.51 (s, 1H), 8.80 (d, J = 10.7 Hz, 2H),
8.40 (s, 1H), 7.72 (s, 1H), 7.11 (s, 1H), 4.39-4.33 (m, 2H),
2.36-2.26 (m, 2H), 2.14-2.06 (m, 2H) 7 310.30 1.59 8 270.30 1.49 9
284.30 1.63 10 292.30 1.44 11 298.40 1.74 12 268.30 1.40 13 296.30
1.67 14 266.30 1.37 15 267.30 1.30 16 308.80; 1.37; (500 MHz, MeOD)
8.82 (s, H), 8.14 (d, J = 1.4 Hz, 1H), 7.80 309.20 1.45 (d, J = 3.7
Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.25 (d, J = 3.7 Hz, 1H), 3.87
(s, 4H), 3.34 (s, H), 2.91 (t, J = 6.7 Hz, 2H), 1.41 (t, J = 6.8
Hz, 3H), 17 308.20 1.70 18 372.30 1.13 19 323.30 1.70 20 324.30
1.85 21 323.30 1.60 22 337.30 1.70 23 295.20 1.30 24 280.20 1.40 25
344.30 1.38 26 312.30 1.80 27 298.30 1.70 28 340.30 2.00 29 371.30
1.80 30 346.30 1.90 31 302.00 2.00 500 MHz/DMSO-d6: 12.3(br s, 1H),
12.17(s, 1H), 8.8(s, 1H), 8.25(s, 1H), 7.7(m, 1H), 7.35(m, 1H),
2.4(d, 2H), 2.1(sept, 1H), 097(d, 6H) 32 328.00 2.20 500
MHz/DMSO-d6: 12.3(br s, 1H), 12.17(s, 1H), 8.8(s, 1H), 8.2(s, 1H)
7.7(m, 1H), 7.3(m, 1H), 2.57(d, 2H under DMSO peak), 2.27(quint,
1H)1.78(m, 2H), 1.6(m, 2H), 1.53(m, 2H), 1.2(m, 2H) 33 358.00 2.70
500 MHz/DMSO-d6: 12.3(br s, 1H), 12.17(s, 1H), 8.8(s, 1H), 8.2(s,
1H) 7.73(m, 1H), 7.33(m, 1H), 2.57(dd, 1H under DMSO peak),
2.37(dd, 1H), 2.1(m, 1H), 1.33(dd, 1H), 1.15(dd, 1H), 0.97(d, 3H),
0.9(s, 9H) 34 228.20 1.39 (500 MHz, Methanol-d4) 8.85 (s, 1H), 8.77
(s, 1H), 8.43 (s, 1H), 7.83 (d, J = 3.7 Hz, 1H), 7.30 (d, J = 3.7
Hz, 1H), 4.74 (qn, J = 6.7 Hz, 1H), 1.61 (d, J = 6.7 Hz, 6H), 0.00
(TMS) 35 242.30 1.56 (500 MHz, Methanol-d4) 8.86 (s, 1H), 8.79 (s,
1H), 8.45 (s, 1H), 7.84 (d, J = 3.7 Hz, 1H), 7.31 (d, J = 3.7 Hz,
1H), 4.51- 4.47 (m, 1H), 2.05-1.98 (m, 1H), 1.95-1.89 (m, 1H), 1.59
(d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.00 (TMS) 36 253.30
1.69 (500 MHz, Methanol-d4) 8.86 (s, 1H), 8.78 (s, 1H), 8.44 (s,
1H), 7.85 (d, J = 3.7 Hz, 1H), 7.31 (d, J = 3.7 Hz, 1H), 4.94- 4.90
(m, 1H), 2.29-2.24 (m, 2H), 2.16-2.09 (m, 2H), 1.98- 1.93 (m, 2H),
1.83-1.79 (m, 2H), 0.00 (TMS) 37 284.30 2.17 (500 MHz, Methanol-d4)
8.85 (s, 1H), 8.78 (s, 1H), 8.46 (s, 1H), 7.84 (d, J = 3.7 Hz, 1H),
7.29 (d, J = 3.6 Hz, 1H), 4.44- 4.40 (m, 1H), 2.03-1.96 (m, 2H),
1.87-1.80 (m, 2H), 1.31- 1.24 (m, 2H), 1.17-1.12 (m, 2H), 0.94 (t,
3H), 0.00 (TMS)- 0.04 (s, H), 38 256.30 1.78 (500 MHz, Methanol-d4)
8.86 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 7.85 (d, J = 3.7 Hz, 1H),
7.31 (d, J = 3.7 Hz, 1H), 4.61- 4.57 (m, 1H), 2.05-1.97 (m, 2H),
1.87-1.80 (m, 2H), 1.59 (d, J = 4.2, 6.6 Hz, 3H), 1.34-1.28 (m,
2H), 1.23-1.17 (m, 2H), 0.92 (t, J = 7.3, 12.5 Hz, 3H), 0.00 (TMS)
39 256.30 1.74 (500 MHz, Methanol-d4) 8.85 (s, 1H), 8.79 (s, 1H),
8.47 (s, 1H), 7.84 (d, J = 3.7 Hz, 1H), 7.31 (d, J = 3.7 Hz, 1H),
4.21 (dd, J = 4.6, 9.5 Hz, 1H), 2.04-1.92 (m, 4H), 0.84 (t, J = 7.4
Hz, 3H), 0.00 (d, J = 3.1 Hz, H), 40 300.40 1.40 41 312.40 1.50 42
326.40 1.40 43 368.40 1.80 44 327.40 1.20 45 298.30 1.30 46 347.10
1.20 47 325.30 1.40 48 347.40 1.30 49 333.00 1.10 50 325.40 1.10 51
312.40 1.40 52 307.30 1.50 53 350.30 1.90 54 310.40 1.80 CD3OD(H)
8.8 s (1H), 8.1 s (1H), 7.8 d (1H), 7.5 s (1H), 7.2 d (1H), 4.7 bs
(1H), 4.5 bs (1H), 2.5 bs (1H), 2.2 bs (1H), 1.8 bs (1H), 1.6 bs
(1H), 1.2 d (6H) 55 324.30 1.70 56 298.30 1.30 57 300.00 1.90 500
MHz DMSO-d6: 12.4(br s, 1H), 12.15(s, 1H), 8.83(s, 1H), 8.25 (s,
1H), 7.8(s, 1H), 7.35(s, 1H), 3.4(quin, 1H), 2.3(m, 2H), 2.2(m,
2H), 2.0(dd, 1H), 1.9(m, 1H) 58 300.00 1.90 500 MHz DMSO-d6:
12.4(br s, 1H), 12.15(s, 1H), 8.83(s, 1H), 8.25 (s, 1H), 7.8(s,
1H), 7.35(s, 1H), 1.77(m, 1H), 1.43(m, 1H), 1.15(m, 4H) 0.86(m, 1H)
59 312.00 1.90 500 MHz DMSO-d6: 12.4(br s, 1H), 12.15(s, 1H),
8.83(s, 1H), 8.25 (s, 1H), 7.8(s, 1H), 7.35(s, 1H), 5.7(s, 2H),
3.4(quin, 1H), 2.6(m, 4H) 60 330.00 1.90 61 330.00 1.90 500 MHz
DMSO-d6: 12.4(br s, 1H), 12.15(s, 1H), 8.83(s, 1H), 8.25 (s, 1H),
7.8(s, 1H), 7.35(s, 1H), 3.93(d, 2H), 3.35(t, 2H), 2.85(m, 1H),
1.8(m, 2H), 1.7(m, 2H) 62 342.00 2.40 500 MHz DMSO-d6: 12.4(br s,
1H), 12.15(s, 1H), 8.83(s, 1H), 8.25 (s, 1H), 7.8(s, 1H), 7.35(s,
1H), 1.95(d, 2H), 1.78(d, 2H), 1.5(quar, 2H), 1.43(m, 1H),
0.98(quart, 2H), 0.89(d, 3H) 63 358.00 1.80 500 MHz DMSO-d6:
12.4(br s, 1H), 12.15(s, 1H), 8.83(s, 1H), 8.25 (s, 1H), 7.8(s,
1H), 7.35(s, 1H), 3.39(s, 3H), 3.2(m, 1H), 2.6(, t, 1H), 2.25(d,
1H), 2.05(d, 1H), 1.83(m, 2H), 1.3(m, 2H), 1.07(m, 1H) 64 328.00
1.90 500 MHz DMSO-d6: 12.4(br s, 1H), 12.15(s, 1H), 8.83(s, 1H),
8.25 (s, 1H), 7.8(s, 1H), 7.35(s, 1H), 3.7(m, 2H) 65 342.00 1.60
500 MHz DMSO-d6: 12.4(br s, 1H), 12.15(s, 1H), 8.83(s, 1H), 8.25
(s, 1H), 7.8(s, 1H), 7.35(s, 1H), 3.05(m, 1H), 2.55(m, 2H), 2.37(m,
2H), 2.18(m, 2H). 1.9(m, 2H) 66 316.00 2.10 500H MHz: DMSO-d6:
12.35(br s, 1H), 12.15(s, 1H), 8.(s, 1H), 8.2 (s, 1H), 7.68(s, 1H),
7.43(s, 1H), 2.33(s, 2H), 1.07(s, 9H) 67 342.00 2.50 500H MHz:
DMSO-d6: 12.35(br s, 1H), 12.15(s, 1H), 8.(s, 1H), 8.2 (s, 1H),
7.68(s, 1H), 7.43(s, 1H), 2.55(m, 1H), 2.17(m, 1H), 1.4-1.7 (cplx
m, 8H), 1.1(m, 3H) 68 350.00 2.20 69 300.00 1.80 500 MHz DMSO-d6:
12.27(br s, 1H), 12.23(s, 1H), 8.78(s, 1H), 8.2(s, 1H), 7.65(m,
1H), 7.34(m, 1H), 5.85(m, 1H), 5.07(dd, 1H), 5.0(dd, 1H). 2.6(t,
2H), 2.4(t, 2H) 70 300.00 1.70 500 MHz DMSO-d6: 12.27(br s, 1H),
12.23(s, 1H), 8.78(s, 1H), 8.2(s, 1H), 7.65(m, 1H), 7.34(m, 1H),
2.47(d, 2H), 1.06(m, 1H), 0.5(m, 2H), 0.23(m, 2H) 71 316.00 1.40
500 MHz DMSO-d6: 12.27(br s, 1H), 12.23(s, 1H), 8.8(s, 1H), 8.2(s,
1H), 7.65(m, 1H), 7.34(m, 1H), 2.81(t, 2H), 2.7(t, 2H), 2.15(s, 3H)
72 316.00 2.10 500 MHz DMSO-d6: 12.27(br s, 1H), 12.23(s, 1H),
8.8(s, 1H), 8.2(s, 1H) 7.65(m, 1H), 7.34(m, 1H), 2.5(t, 1H), 1.5(m,
4H), 0.9(d, 6H) 73 297.30 1.61 (500 MHz, DMSO-d6) 8.82 (s, 2 H),
8.45 (s, 2H), 8.39 (d, J = 3.5 Hz, 1H), 7.77 (s, 1H), 7.19 (s, 1H),
5.07 (q, J = 7.2 Hz, 1H), 2.68-2.63 (m, 1H), 1.68 (d, 3H),
0.67-0.61 (m, 2H), 0.47-0.41 (m, 2H), 0.00 (TMS) 74 313.30 2.30
(500 MHz, DMSO-d6) 8.82 (d, J = 12.6 Hz, 2H), 8.43 (s, 1H), 8.22
(t, J = 5.7 Hz, 1H), 7.77 (s, 1H), 7.19 (s, 1H), 5.18 (q, J = 7.1
Hz, 1H), 3.02 (td, J = 6.6, 4.0 Hz, 1H), 2.98-2.88 (m, 2H),
1.77-1.67 (m, 2H), 0.88-0.79 (m, 6H) 75 325.30 2.39 (500 MHz,
DMSO-d6) 8.87 (s, 1H), 8.83 (d, J = 6.5 Hz, 1H), 8.43 (s, 1H), 8.26
(d, J = 7.2 Hz, 1H), 7.77 (s, 1H), 7.19 (s, 1H), 5.12 (q, J = 7.1
Hz, 1H), 4.02-3.95 (m, 1H), 1.85-1.69 (m, 5H), 1.65-1.60 (m, 2H),
1.57-1.35 (m, 4H), -0.00 (d, J = 3.3 Hz, H), 76 341.30 1.89 (500
MHz, DMSO-d6) 8.88 (d, J = 6.1 Hz, 2H), 8.48 (s, 1H), 8.36-8.32 (m,
1H), 7.83 (s, 1H), 7.25 (s, 1H), 5.23 (td, J = 7.1, 5.5 Hz, 1H),
3.88-3.82 (m, 1H), 3.77-3.72 (m, 1H), 3.64- 3.59 (m, 1H), 3.23-3.13
(m, 2H), 1.90-1.71 (m, 6H), 1.52- 1.43 (m, 1H), -0.00 (d, J = 3.2
Hz, H), 77 285.30 1.48 (500 MHz, DMSO-d6) 8.88 (d, J = 6.1 Hz, 2H),
8.48 (s, 1H), 8.36-8.32 (m, 1H), 7.83 (s, 1H), 7.25 (s, 1H), 5.23
(td, J = 7.1, 5.5 Hz, 1H), 3.88-3.82 (m, 1H), 3.77-3.72 (m, 1H),
3.64- 3.59 (m, 1H), 3.23-3.13 (m, 2H), 1.90-1.71 (m, 6H), 1.52-
1.43 (m, 1H), -0.00 (d, J = 3.2 Hz, H), 78 299.30 1.39 (500 MHz,
DMSO-d6) 8.84 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H), 8.16 (d, J = 7.5
Hz, 1H), 7.78 (s, 1H), 7.20 (s, 1H), 5.11 (q, J = 7.1 Hz, 1H),
3.86-3.80 (m, 1H), 1.75-1.69 (m, 3H), 1.08 (dd, J = 6.6, 11.6 Hz,
6H), -0.00 (d, J = 3.3 Hz, H), 79 315.30 1.40 80 315.30 1.57 (500
MHz, DMSO-d6) 8.79 (s, 1H), 8.75 (s, 1 H), 8.39 (s, 1H), 8.30 (s,
1H), 7.72 (s, 1H), 7.13 (s, 1H), 5.18 (q, J = 7.1 Hz, 1H),
3.38-3.35 (m, 2H), 3.28-3.25 (m, 1 H), 1.70 (d, J = 7.1 Hz, 2H),
-0.00 (d, J = 3.2 Hz, H), 81 315.30 1.59 82 329.30 1.63 83 329.30
1.69 84 331.30 2.02 (500 MHz, DMSO-d6) 8.83 (s, 1H), 8.80 (s, 1H),
8.43 (s, 1H), 8.36 (t, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.19 (s, 1H),
5.17 (q, J = 7.1 Hz, 1H), 3.34-3.24 (m, 2H), 2.56-2.50 (m, 2 H),
2.06 (s, 3H), 175-1.72 (m, 3H), 0.00 (TMS) 85 343.30 2.21 (500 MHz,
DMSO-d6) 8.82 (s, 1H), 8.79 (s, 1H), 8.42 (s, 1H), 8.21 (t, J = 5.4
Hz, 1H), 7.75 (s, 1H), 7.17 (s, H), 5.20 (q, J = 7.1 Hz, 1H), 3.56
(m, 1H), 3.41-3.35 (m, 2H), 3.27-3.17 (m, 2H), 1.76-1.70 (m, 4H),
1.02 (d, 6H), -0.00 (d, J = 3.3 Hz, H) 86 347.30 2.69 87 311.30
1.95 (500 MHz, DMSO-d6) 8.85 (d, J = 11.1 Hz, 2H), 8.46 (s, 1H),
7.81 (s, 1H), 7.23 (d, J = 1.8 Hz, 1H), 5.51 (q, J = 7.0 Hz, 1H),
3.64-3.60 (m, 1H), 3.46-3.42 (m, 1H), 1.95-1.69 (m, 4H), 1.63 (d, J
= 6.8 Hz, 3H), 0.04 (s, H), 0.00 (s, H), 88 313.30 2.28 (500 MHz,
DMSO-d6) 8.87 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 7.82 (s, 1H),
7.25 (s, 1H), 5.65 (q, J = 6.9 Hz, 1H), 3.57-3.49 (m, 1H),
3.46-3.33 (m, 2H), 3.26-3.20 (m, 1H), 1.69 (d, J = 6.9 Hz, 3H),
1.13 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H), 0.00 (TMS) 0.00
(s, H), 89 350.30 2.28 (500 MHz, DMSO-d6) 8.87 (s, 1H), 8.81 (s, 1
H), 8.55 (t, J = 5.2 Hz, 1H), 8.43 (s, 1H), 7.77 (s, 1H), 7.19 (s,
1H), 6.67 (s, 1H), 5.95 (s, 1H), 5.89-5.88 (m, 1H), 5.20 (q, J =
7.1 Hz, 1H), 4.32-4.24 (m, 2H), 3.59 (s, 3H), 1.68 (d, J = 6.9 Hz,
3H), 0.00 (s, H), 90 299.30 1.89 (500 MHz, DMSO-d6) 8.81 (s, 1H),
8.77 (s, 1H), 8.41 (s, 1H), 8.29 (d, J = 9.4 Hz, 1H), 7.74 (s, 1H),
7.16 (s, 1H), 5.14 (q, J = 7.1 Hz, 1H), 3.10-3.01 (m, 2H),
1.75-1.70 (m, 4H), 1.43 (qn, J = 7.2 Hz, 2H), 0.84 (t, J = 7.4 Hz,
3H), 0.00 (s, H), 91 339.30 1.98 (500 MHz, DMSO-d6) 8.94 (t, J =
6.3 Hz, 1H), 8.83 (d, J = 7.5 Hz, 2H), 8.44 (s, 1H), 7.78 (s, 1H),
7.20 (s, 1H), 5.28 (q, J = 7.2 Hz, 1H), 4.02-3.91 (m, 2H),
1.76-1.68 (d, 3H), 0.00 (TMS) 92 284.20 2.13 (500 MHz, CD3OD) 8.88
(s, 1H), 8.83 (s, 1H), 8.49 (s, 1H), 7.86 (d, J = 3.7 Hz, 1H), 7.34
(s, 1H), 4.33-4.27 (m, 1H), 2.06- 1.86 (m, 4H), 1.40-1.23 (m, 3H),
0.96-0.82 (m, 5H), 0.00 (TMS)
93 270.00 1.93 (500 MHz, CD3OD) 8.87 (s, 1H), 8.80 (s, 1H), 8.47
(s, 1H), 7.87 (d, 1H), 7.32 (d, 1H), 4.59-4.55 (m, 1H), 2.05-1.99
(m, 1H), 1.94-1.84 (m, 2H), 1.61-1.58 (d, 2H), 1.39-1.27 (m, 3H),
1.15-1.13 (m, 1H), 1.03 dt, J = 6.6 Hz, 2H), 0.94-0.82 (m, 3H). 94
270.00 1.93 (500 MHz, CD3OD) 8.86 (s, 1H), 8.80 (s, 1H), 8.47 (s,
1H), 7.85(d, 1H), 7.30 (d, 1H), 4.33(m, 1 H), 2.05-1.82(m, 7H),
1.3(m, 1H), 1.15(m, 1H), 0.92 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.4
Hz, 3H), 0.00 (m, H), 95 314.30 1.95 (500 MHz, DMSO-d6) 8.86 (d, J
= 8.1 Hz, 2H), 8.45 (s, 1H), 7.79 (s, 1H), 7.18 (s, 1H), 5.30 (m,
1H), 1.76 (d, J = 7.3 Hz, 3H), 1.40 (s, 9H), 0.00 (TMS) 96 314.00
2.00 500 MHz, DMSO-d6: 12.3br s, 1H), 12.2(s, 1H), 8.78(s, 1H),
8.18(s, 1H)7.65(m, 1H), 7.34(m, 1H), 2.5(t, 2H), 1.53(dt, 2H),
0.75(m, 1H), 0, 4 (dt, 2H), 0.09(dt, 2H) 97 304.00 1.50 500 MHz
DMSO-d6: 12.24(s, 1H), 8.78(s, 1H), 8.23(s, 1H), 7.65m, 1H),
7.42(m, 1H), 4.1(quart, 1H), 3.3(s, 3H), 1.32(D, 3H) 98 316.00 2.00
500 MHz DMSO-d6: 12.24(s, 1H), 8.78(s, 1H), 8.23(s, 1H), 7.65m,
1H), 7.32(m, 1H), 2.3(dd, 1H), 1.9(sext, 1H), 1.39(sept, 1H),
1.25(m, 1H), 0.93(d, 3H), 0.9(t, 3H) 99 342.00 1.90 500 MHz
DMSO-d6: 12.24(s, 1H), 8.78(s, 1H), 8.23(s, 1H), 7.65m, 1H),
7.32(m, 1H), 2.83(m, 2H), 2.68(m, 2H) 100 344.00 1.70 500 MHz
DMSO-d6: 12.6(s, 1H), 12.24(s, 1H), 8.78(s, 1H), 8.23(s, 1H),
7.65m, 1H), 7.32(m, 1H), 5.0(quat, 1H), 4.4(br m, 1H), 101 352.00
1.70 500 MHz DMSO-d6: 12.25(s, 1H), 12.20(s, 1H), 8.78(s, 1H),
8.23(s, 1H), 7.65m, 1H), 7.55(d, 2H), 7.45(m, 1H), 7.36(m, 2H),
7.31(m, 1H), 5.35(s, 1H) 102 356.00 1.90 500 MHz DMSO-d6: 12.46(s,
1H), 12.20(s, 1H), 8.78(s, 1H), 8.23(s, 1H), 7.65m, 1H), 7.30(m,
1H), 3.09(m, 1H), 2.8(m, 1H), 2.5(m, 1H) 103 344.00 2.30 500 MHz
DMSO-d6: 12.4(br m, 1H), 8.8(s, 1H), 8.32(s, 1H), 7.72 (m, 1H)
7.25(m, 1H), 4.3(t, 2H), 2.68(d, 2H), 2.2(sept, 1H), 1.83 (quin,
2H), 1.03(t, 3H), 0.99(d, 6H) 104 330.00 1.98 500 MHz DMSO-d6:
12.55(br m, 1H), 8.88(s, 1H), 8.4(s, 1H), 7.75 (m, 1H) 7.25(m, 1H),
4.4(quart, 2H), 2.68(d, 2H), 2.2(sept, 1H), 1.4 (t, 3H), 1.0(d, 6H)
105 316.00 1.70 500 MHz DSMO-d6: 12.5(br m, 1H), 8.85(s, 1H),
8.36(s, 1H), 7.7(m, 1H), 7.30(m, 1H), 3.82(s, 3H), 2.68(d, 2H),
2.17(sept, 1H), 0.98(d, 6H) 106 228.20 1.43 (500 MHz, DMSO-d6)
12.79 (s, 1H), 8.86 (d, J = 2.4 Hz, 2H), 8.44 (s, 1H), 7.81 (s,
1H), 7.20 (s, 1 H), 4.23 (t, J = 7.0 Hz, 2H), 2.50 (qn, J = 1.7 Hz,
DMSO-d6), 1.88 (qn, J = 7.2 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H), 0.00
(TMS) 107 256.30 1.82 (500 MHz, DMSO-d6) 12.68 (s, 1H), 8.84 (d, J
= 7.5 Hz, 2H), 8.40 (s, 1H), 7.78 (s, 1H), 7.17 (d, J = 2.0 Hz,
1H), 4.28 (t, J = 7.3 Hz, 2H), 2.50 (qn, J = 1.8 Hz, DMSO-d6),
1.79-1.75 (m, 2H), 1.53 (qn, J = 6.7 Hz, 1H), 0.93 (d, J = 6.6 Hz,
6H), 0.00 (TMS) 108 414.10 2.08 109 364.10 1.90 CD3CN (H) 10.4 s
(1H), 9.9 s (1H), 8.7 s (1H), 7.9 s (1H0, 7.5 s (1H), 7.45 s(1H),
4.4 q (2H), 3.8 d (2H), 1.3 m (1H), 0.6 m (2H), 0.3 m (2H) 110
378.10 1.90 CD3CN (H) 10.4 s (1H), 9.9 s (1H), 8.7 s (1H), 7.9 s
(1H0, 7.45 d(2H), 3.9 m (2H), 3.7 m (2H), 2.7 m (2H), 1.2 m (1H),
0.6 m (2H), 0.3 m (2H) 111 357.10 1.70 112 375.10 1.80 113 391.10
1.90 114 372.10 2.00 115 335.10 1.60 116 372.10 2.00 117 357.20
1.95 118 347.10 2.20 119 296.00 1.40 120 365.10 2.30 121 353.10
2.21 122 379.10; 2.30; 379.30 2.60 123 415.10 2.50 124 358.10 2.10
125 336.10 1.80 CD3CN (H) 11.0 s (1H), 8.9 S (1H), 7.9 d (1H), 7.7
d (1H), 7.3 d (1H), 7.2 d (1H), 4.0 m (2H), 3.7 m (2H), 2.8 t (2H),
1.2 m (1H), 0.6 m (2H), 0.4 m (2H) 126 311.10 1.90 CD3CN (H) 11.8 s
(1H), 8.9 S (1H), 7.9 d (1H), 7.7 d (1H), 7.3 d (1H), 7.2 d (1H),
4.8 m (1H), 4.5 m (1H), 2.4 m (1H), 2.2 (1H), 1.8 m (1H), 1.7 m
(1H), 1.3 m (3H), 1.1 m (3H) 127 325.00 1.90 128 342.00 2.60 500
MHz DMSO-d6: 13.8(br m, 1H), 8.97(s, 1H), 8.6(s, 1H), 7.82(s,
1H)7.3(s, 1H), 6.1(m, 1H), 5.2(d, J = 10, 1H), 5.1(d, J = 17, 1H),
5.04(br s, 1H) 3.6(pair of m, 1H), 2.6(d, 2H), 2.15 (sept, 1H),
0.98(d, 6H) 129 412.00 2.90 130 201.10 0.87 (500 MHz, DMSO-d6)
12.14 (s, 1H), 8.64 (s, 1H), 8.32 (s, 1H), 7.53 (d, 1H), 6.97(d,
1H), 2.50 (t, J = 1.7 Hz, H), 0.00 (s, H), 131 351.22 2.80 CD3CN
(H) 11.8 s (1H), 8.9 S (1H), 7.9 S (1H), 7.7 S (1H), 7.6 D (1H),
7.2 D (1H), 3.9 S (2H), 3.3 (2H), 2.6 d (2H), 1.0 m (1H), 0.5 m
(2H), 0.2 m (2H) 132 310.40 2.60 CD3OD(H) 8.8 s (1H), 8.1 s (1H),
7.8 d (1H), 7.5 s (1H), 7.2 d (1H), 4.5 bs (2H), 2.2 bs (2H), 1.8 m
(2H), 1.4 d (6H) 133 286.20 1.20 134 334.20 1.30 135 361.40 1.60
136 365.50 1.50 137 348.30 2.00 138 312.40 1.90 139 348.20 1.70 140
286.20 1.20 141 216.90 0.39 (500 MHz, Methanol-d4) 8.17 (d, J = 5.1
Hz, 1 H), 7.48 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 3.5 Hz, H1), 6.93
(d, J = 3.5 Hz, 1 H) 142 329.20 1.50 (d6-DMSO) 12.54 (s, 1H), 11.87
(s, 1H), 8.29 (d, 1H), 7.97 (d, 1H), 7.62 (d, 1H), 7.59 (dd, 1H),
2.36 (dd, 1H), 2.14 (ddd, 1H), 1.51 (ddd, 1H), 1.27 (ddd, 1H) 143
385.10 2.00 144 371.50 1.90 145 359.50 1.80 146 317.20 1.50 147
365.40 1.80 (d6-DMSO) 12.71 (s, 1H), 11.79 (s, 1H), 8.28 (d, 1H),
8.03 (s, 1H), 7.94 (d, 1H), 7.69 (dd, 1H), 7.62 (m, 3H), 7.56 (dd,
1H), 7.13 (s, 1H) 148 343.30 1.70 149 383.40 2.00 150 399.50 2.30
(d6-DMSO) 12.24 (s, 1H), 11.89 (s, 1H), 8.30 (d, 1H), 7.99 (s, 1H),
7.63 (d, 1H), 7.60 (dd, 1H), 7.12 (s, 1H), 5.58 (s, 3H), 2.68 (s,
2H), 2.57 (s, 2H), 1.62 (br s, 8H) 151 385.50 2.10 (d6-DMSO) 12.21
(s, 1H), 11.91 (s, 1H), 8.30 (d, 1H), 7.99 (s, 1H), 7.64 (d, 1H),
7.60 (dd, 1H), 7.14 (s, 1H), 3.55 (s, 3H), 3.14 (q, 1H), 2.85 (q,
1H), 2.10-1.35 (m, 8H) 152 385.50 2.10 (d6-DMSO) 12.35 and 12.21
(2s, 1H), 11.90 (s, 1H), 8.30 (d, 1H), 7.98 (s, 1H), 7.64 (d, 1H),
7.60 (dd, 1H), 7.13 (s, 1H), 3.13 (q, 1H), 2.85 (q, 1H), 2.09-1.36
(m, 8H) 153 331.20 1.70 (d6-DMSO) 12.35 and 12.21 (2s, 1H), 11.90
(s, 1H), 8.30 (d, 1H), 7.98 (s, 1H), 7.64 (d, 1H), 7.60 (dd, 1H),
7.13 (s, 1H), 3.13 (q, 1H), 2.85 (q, 1H), 2.09-1.36 (m, 8H) 154
379.40 2.00 (d6-DMSO) 12.79 (s, 1H), 11.84 (s, 1H), 8.30 (d, 1H),
8.06 (s, 1H), 7.93 (d, 1H), 7.76-7.65 (m, 3H), 7.63 (d, 1H), 7.57
(dd, 1H), 7.14 (s, 1H), 3.78 (s, 3H) 155 395.50 2.00 156 353.40
2.10 157 373.50 2.10 158 185.10 1.40 (500 MHz, MeOD) 8.56 (s, H),
7.70 (t, J = 1.6 Hz, H), 7.40 (d, J = 3.6 Hz, H), 6.94-6.90 (m,
3H).
TABLE-US-00004 TABLE 4 Cpd # M + H RT NMR 159 342.00 0.94 160
214.20 1.37 (500 MHz, Methanol-d4) 8.87 (s, 1H), 8.39 (s, 1 H),
8.09 (s, 1H), 7.64 (s, 1H), 4.08(s, 3H), 3.31 (qn, J = 1.5 Hz,
Methanol-d4), 2.38 (s, 3H), 0.00 (s, H) 161 242.30 1.78 (500 MHz,
Methanol-d4) 8.87 (s, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.64 (s,
1H), 4.30 (t, J = 6.9 Hz, 2H), 3.31 (qn, J = 1.6 Hz, Methanol-d4),
2.37 (s, 3H), 1.98 (qn, J = 7.2 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H),
0.00 (s, H) 162 256.30 2.19 (500 MHz, Methanol-d4) 8.88 (s, 1H),
8.44 (s, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 4.16 (d, 2H), 2.38(s,
3H), 2.37-2.26 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H), 0.00 (s, H) 163
270.30 2.83 (500 MHz, Methanol-d4) 8.87 (s, 1H), 8.45 (s, 1H), 8.10
(s, 1H), 7.64 (s, 1H), 4.19 (t, J = 7.4 Hz, 2H), 3.31 (q, J = 1.4
Hz, H), 1.89-1.84 (m, 2H), 1.64-1.56 (m, 1H), 1.00 (dd, J = 2.7,
6.6 Hz, 6H), 0.00 (d, J = 2.8 Hz, H) 164 290.30 2.26 (500 MHz,
Methanol-d4) 8.86 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.82 (s,
1H), 4.34 (t, J = 7.3 Hz, 2H), 3.31 (qn, J = 1.6 Hz, Methanol-d4),
1.87-1.83 (m, 2H), 1.60 (qn, J = 6.7 Hz, 1H), 1.03 (d, J = 6.6 Hz,
6H), 0.00 (s, H), 165 262.20 1.78 (500 MHz, Methanol-d4) 8.87 (s,
1H), 8.51 (s, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 4.28 (t, J = 6.9 Hz,
2H), 3.31 (t, J = 1.5 Hz, H), 1.97 (qn, J = 7.2 Hz, 2H), 0.97 (t, J
= 7.4 Hz, 3H), 0.00 (s, H) 166 276.20 2.03 (500 MHz, Methanol-d4)
8.90 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 4.13 (d, J
= 7.3 Hz, 2H), 3.31 (q, J = 1.5 Hz, H), 2.33-2.25 (m, 1H), 0.97 (d,
J = 6.6 Hz, 6H), 0.00 (s, H), 167 328.30 1.50 168 345.30 1.40 169
371.50 1.50 170 342.30 1.70 171 387.50 1.70 172 343.30 1.40 173
433.50 1.80 174 331.30 1.30 175 352.50 2.00 176 329.30 1.20 (500
MHz, Methanol-d4) 8.95 (s, 1 H), 8.54 (s, 1 H), 7.87 (d, J = 3.6
Hz, 1 H), 7.52 (d, J = 3.6 Hz, 1 H), 3.49-3.40 (m, 2 H), 3.17 (dd,
J = 3.7, 8.5 Hz, 2 H), 2.24-2.21 (m, 1 H), 2.03- 1.92 (m, 4 H) 177
429.50 2.10 178 429.50 2.10 179 407.30 1.60 (500 MHz, DMSO-d6)
12.28 (s, 1 H), 12.08 (s, 1 H), 8.74 (d, J = 3.4 Hz, 1H), 8.14 (d,
J = 3.0 Hz, H1), 7.60 (s, 1 H), 7.30 (dd, J = 1.8, 3.3 Hz, 1 H),
3.65-3.63 (m, 2 H), 3.29 (s, 4 H), 2.91 (s, 3 H), 2.81 (t, J = 11.8
Hz, 2 H), 2.73-2.68 (m, 1 H), 2.02-2.00 (m, 2 H), 1.76-1.68 (m, 2
H) 180 353.50 2.00 181 353.50 2.00 182 371.50 1.90 183 336.10 2.07
CD3CN10.9 s (1H), 8.9 s (1H), 8.2 s (1H), 7.9 s (1H), 7.7 s (1H),
7.2 s (1H), 3.9 t (2H), 3.5 d (2H), 2.9 m (2H), 1.1-1.2 bs (1H),
0.6 m (2H), 0.4 s (2H) 184 338.10 1.86 H-DMSO-d6 (150C) 11.7 bs
(1H), 11.3 bs (1H), 8.7 s (1H), 7.8 s (1H), 7.5 s (1H), 7.3 s (1H),
6.9 s (1H), 4.3 m (2H), 2.1 m (2H), 1.9 m (2H), 1.8 m (2H), 1.6 m
(2H), 1.0 t (6H) 185 338.00 1.90 300 MHz; DMSO-d6: 12.4(br s, 1H),
12.2(br s, 1H), 8.7(s, 1H), 7.9(s, 1H) 7.7(s, 1H), 7.4(s, 1H),
7.1(s, 1H), 4.3m, 1H), 4.1(m, 1H), 1.8(m, 6H), 1.2(m, 2H), 1.0(m,
6H) 186 392.30 2.30 187 337.30 1.80 188 392.30 2.30 189 336.30 2.10
190 362.40 2.30 191 393.30 2.70 192 338.30 2.10 193 393.30 2.60 194
339.00 2.60 500 MHz DMSO-d6: 12.34(br s, 1H), 8.8(s, 1H), 7.75(s,
1H), 7.62(m, 1H), 7.21(m, 1H), 7.0(s, 1H), 4.6(m, 1H), 4.1(m, 1H),
2.2(m, 1H), 1.9(m, 1H), 1.8(m, 2H), 1.35(d of m, 3H), 1.24(m, 1H),
0.88(m, 3H), 0.7(m, 3H) 195 365.40 2.50 MeOD (H) 8.9 s (1H), 8.4 s
(1H), 7.8 s (1H), 7.2 s (1H), 4.4 q (2H), 3.6 d (2H), 1.1 bs (1H),
0.6 d (2H), 0.3 bs (2H) 196 379.50 2.50 MeOD(H) 8.8 s (1H), 8.2 s
(1H), 7.7 s (1H), 7.6 s (1H), 7.1 s (1H), 3.9 m (2H), 3.5 m (2H),
2.7 m (2H), 1.1 bs (1H), 0.6 m (2H), 0.3 m (2H) 197 311.40 2.10 198
346.50 1.95 (500 MHz, Methanol-d4) 8.84(s, 1H), 7.88(d, 1H),
7.85(s, 1H), 7.3(d, 1H), 3.85-3.55(m, 4H), 1.75(m, 2H), 1.45-
1.52(m, 5H), 1.0(t, 3H) 199 380.50 2.04 (500 MHz, Methanol-d4)
8.82(s, 1H), 7.9(s, 2H), 7.83(s, 1H), 7.40-7.28(m, 5H), 4.97(s,
2H), 3.65(s, 2H) 200 314.20 1.57 201 326.30 2.01 (500 MHz, DMSO-d6)
8.92 (s, 1H), 7.70 (s, 2H), 7.03 (s, 1H), 3.59-3.50 (m, 4H), 2.36 -
(s, 3H), 1.61 (m, 2H), 1.33 (q, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3
Hz, 3H), 0.01--0.00 (m, H) 202 360.30 2.05 (500 MHz, DMSO-d6) 12.50
(s, 1H), 8.88 (s, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.38 (t, J = 7.4
Hz, 2H), 7.33-7.28 (m, 3H), 4.84 (s, 2H), 3.56 (s, 2H), 2.36 (s,
3H), 1.21 (t, 3H), 0.00 (TMS) 203 360.30 1.97 204 322.20 1.84 (500
MHz, DMSO-d6) 8.89 (s, 1H), 7.69-7.65 (m, 2H), 7.24 (d, J = 12.7
Hz, 1H), 5.93 (s, 1H), 5.84 (s, 1H), 5.27(m, 1H), 4.92(m, 1H), 2.35
(s, 3H), 1.38 (d, J = 6.2 Hz, 6H), 0.0(TMS) 205 326.30 1.99 (500
MHz, DMSO-d6) 8.89 (s, 1H), 7.69-7.65 (m, 2H), 7.10(s, 1H), 3.25(m,
5H), 2.4(s, 3H), 1.65(m, 2H), 1.37- 1.25(m, 6H), 0.88(t, 3H),
0.00(TMS) 206 312.30 1.87 207 323.20 1.61 (500 MHz, DMSO-d6) 8.87
(s, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.10 (s, 1H), 3.82 (s, 2H),
3.58 (s, 2H), 2.90(t, 2H), 2.35 (s, 3H), 1.24 (t, 3H), 0.00 (TMS)
208 392.20 2.17 (500 MHz, DMSO-d6) 8.87 (s, 1H), 7.69 (s, 1H), 7.63
(s, 1H), 7.10 (s, 1H), 3.82 (s, 2H), 3.58 (s, 2H), 2.90 (t, 2H),
2.35 (s, 3H), 1.24 (m, 5H), 0.00 (TMS) 209 340.30 2.13 (500 MHz,
DMSO-d6) 8.94 (s, 1H), 7.71 (s, 2H), 7.00 (s, 1H), 3.85 (d, J =
12.4 Hz, 2H), 3.51 (s, 2H), 2.34 (s, 3H), 1.66- 1.60 (m, 4H), 1.32
(q, J = 7.5 Hz, 2H), 0.91 (t, 3H), 0.00 (TMS) 210 367.00 2.60 211
381.00 2.80 212 407.00 3.00 213 344.10 1.82 H DMSO-d6: 9.92(s, 1H),
8.10(s, 1H), 7.87(s, 1H), 7.45(s, 1H), 4.73-4.67(m, 1H),
4.43-4.28(m, 1H), 3.10-2.97(m, 2H), 1.84-1.7(m, 2H), 1.2(d, 6H) 214
318.00 2.20 215 393.00 1.90 300 MHz; DMSO-d6: 12.6(s, 1H), 8.8(s,
1H), 7.8(s, 1H), 7.7(s, 1H), 7.3(s, 1H), 7.0(1H), 3.6(m, 4H),
3.1(m, 1H), 2.6(m, 2H), 1.7(m, 6H), 216 379.00 1.90 217 309.00 2.30
300 MHz, DMSO-d6: 12.35(s, 1H), 8.79(s, 1H), 7.71(m, 1H), 7.53(d,
1H), 7.20(d, 1H), 6.98(m, 1H), 5.93(m, 2H), 5.25(m, 4H), 4.17(m,
4H) 218 297.00 2.40 219 283.00 2.20 300 MHz DMSO-d6: 12.3(s, 1H),
8.7(s, 1H), 7.7(s, 2H), 7.6(s, 1H), 7.35(s, 1H), 7.0s, 1H), 3.9(m,
2H) 1.97(m, 4H) 220 373.00 2.80 221 326.00 2.50 222 373.00 2.80 223
406.30 2.01 224 324.30 1.61 225 392.30 1.89 226 349.30 1.55 227
412.20 2.26 DMSO d-6: 8.82(s, 1H), 7.92(s, 1H), 7.73(s, 1H),
7.26(s, 1H), 3.82(m, 2H), 3.58(m, 2H), 2.78-2.62(m, 2H), 1.1(m,
1H), 0.60-0.54(m, 2H), 0.34-0.28(m, 2H) 228 378.30 1.88 (CD3CN)
11.2 s (1H), 9.0 s (1H), 8.2 s 91H), 7.9 s (1H), 7.6 s (1H), 7.2 s
(1H), 4.61 (2H), 3.9 s (3H), 37 d (2H), 1.1 m (1H), 0.6 m (2H), 0.2
m (2H) 229 379.00 2.60 300 MHz; DMSO-d6: 12.45(s, 1H), 8.9(s, 1H),
8.85(s, 1H), 7.75(m, 2H), 7.08(m, 1H), 3.83(m, 2H), 3.52(m, 2H),
2.72(m, 2H), 1.12(m, 1H), 0.55 (m, 2H), 0.3(m, 2H) 230 378.00 2.20
300 MHz; DMSO-d6: 12.45(s, 1H), 8.9(s, 1H), 8.85(s, 1H), 7.75(m,
2H), 7.08(m, 1H), 3.83(m, 4H), 3.0(m, 2H), 2.75(m, 2H) 231 365.00
2.60 300 MHz; DMSO-d6: 12.4(s, 1H), 8.93(s, 1H), 8.82(s, 1H),
7.82(s, 1H), 7.7(m, 1H), 7.04(m, 1H), 3.6(m, 2H), 1.1(m, 1H),
0.5(m, 2H). 0.3(m, 2H) 232 326.30 2.20 233 314.20 1.50 234 298.20
1.80 235 324.20 2.00 236 294.20 1.80 237 323.30 1.70 238 392.20
2.60 239 331.10 1.82 CDCl3: 9.0(s, 1H), 8.16(d, 1H), 7.62(s, 1H),
7.60(d, 1H), 4.8(m, 1H), 3.67(m, 1H), 1.3(m, 10H) 240 412.20 2.43
CDCl3: 8.94(s, 1H), 8.16(s, 1H), 7.55(s, 1H), 7.40(s, 1H), 4.27(m,
2H), 3.90(m, 2H), 2.76(m, 1H), 2.15(m, 2H), 1.95- 1.78(m, 4H). 241
426.20 2.47 CDCl3: 8.94(s, 1H), 8.21(s, 1H), 7.63(s, 1H), 7.52(s,
1H), 3.80(m, 4H), 2.80-2.65(m, 1H), 2.68-2.45(m, 2H), 2.20- 2.05(m,
2H), 1.95-1.78(m, 4H). 242 411.20 1.95 CDCl3: 8.94(s, 1H), 8.05(s,
1H), 7.66(s, 1H), 7.45(s, 1H), 4.0(m, 4H), 2.93(t, 2H),
2.75-2.65(m, 2H). 243 371.30 1.89 CDCl3: 9.05(s, 1H), 8.05(s, 1H),
7.60(s, 1H), 7.40(s, 1H), 3.9-3.7(m, 2H), 3.66-3.45(m, 2H),
2.67-2.48(m, 2H), , 2.20- 2.02(m, 1H), 1.0(d, 6H). 244 414.20 2.34
CDCl3: 9.02(s, 1H), 8.05(s, 1H), 7.60(s, 1H), 7.40(s, 1H),
3.88-3.7(m, 2H), 3.66-3.45(m, 2H), 2.67-2.50(m, 2H), , 2.18-
2.02(m, 1H), 0.95(d, 6H). 245 309.00 2.20 300 MHz, DMSO-d6: 12.4(s,
1H), 8.9(s, 1H), 8.8(s, 1H), 7.7(m, 1H), 7.66(s, 1H), 7.0(m, 1H),
5.93(m, 2H), 5.25(m, 4H), methylenes obscured by water peak 246
339.00 2.60 300 MHz, acetone-d6: 11.5(s, 1H), 8.8(s, 1H), 8.74(s,
1H), 7.84(s, 1H), 7.73(m, 1H), 7.08(m, 1H), 4.55(m, 1), 4.18(m,
1H), 3.1(m4H), 1.44(m, 4H), 0.9(m, 6H) 247 367.00 2.50 300 MHz,
DMCSO-d6: 12.4(s, 1H), 8.88(s, 1H), 8.78(s, 1H), 7.(m, 1H), 7.63(s,
1H), 7.07(m, 1H), 4.55(m, 1H), 3.6(m, 2H), 2.6(m, 2H) 248 373.00
2.70 249 311.00 2.10 300 MHz; DMSO-d6: 12.5(s, 1H), 8.92(m, 1H),
8.84(s, 1H), 7.75(m, 1H), 7.71(s, 1H), 7.01(m, 1H), 4.76(m, 1H),
2.27(m, 1H), 1.7(m, 2H), 1.56(m, 1H), 1.34(d, 3H), 1.28(d, 1.5H),
1.05(d, 1.5H) 250 393.00 2.80 251 379.00 2.80 252 381.00 2.70 300
MHz-DMSO-d6: 12.95(br s, 1H), 9.07(s, 1H), 8.94(s, 1H), 7.89 (m,
2H), 7.22(m, 1H), 3.7(m, 2H), 3.4(m, 2H), 2.6(m, 2H), 1.8(m, 1H),
0.89(d, 6H) 253 240.00 1.75 (CDCl3, 300 MHz) 10.19 (s, 1H), 8.99
(s, 1H), 8.15 (s, 1H), 8.02 (d, 1H), 7.80-7.44 (m, 3H), 6.92 (d,
1H) 254 328.0 2.50 (300 MHz, DMSO-d6) 12.37 (s, 1 H), 8.88 (s, 1
H), 8.75 (s, 1H), 8.38 (s, 1 H), 7.70-7.22 (m, 4 H), 7.05 (s, 1 H),
5.59 (s, 2 H)
Example 8
JAK3 Inhibition Assay
[0191] Compounds were screened for their ability to inhibit JAK3
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. Substrate concentrations in
the assay were 5 .mu.M ATP (200 uCi/.mu.mole ATP) and 1 .mu.M
poly(Glu).sub.4Tyr. Reactions were carried out at 25.degree. C. and
1 nM JAK3.
[0192] 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.degree. 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 9
JAK2 Inhibition Assay
[0193] The assays were as described above in Example 36 except that
JAK-2 enzyme was used, the final poly(Glu).sub.4Tyr concentration
was 15 .mu.M, and final ATP concentration was 12 .mu.M.
[0194] Tables 5 and 6 depict enzyme inhibition data (K.sub.i) for
certain exemplary compounds. Compound numbers in Tables 5 and 6
correspond to those compounds depicted in Tables 1 and 2,
respectively. In Tables 5 and 6, "A" represents a K.sub.i of less
than 0.1 .mu.M, "B" represents a K.sub.i of between 0.1 and
.ltoreq.0.5 "C" represents a K.sub.i of >0.5 .mu.M and less than
5.0 .mu.M and "D" represents a K.sub.i of >5.0 .mu.M.
TABLE-US-00005 TABLE 5 Cpd# JAK2 JAK3 1 A 2 B B 3 B B 4 C B 5 B B 6
A B 7 A A 8 A B 9 A A 10 A A 11 A B 12 A B 13 A A 14 A B 15 A A 16
A A 17 A A 18 A A 19 A A 20 A A 21 A A 22 A A 23 A A 24 A B 25 A B
26 A A 27 A B 28 A B 29 A A 30 A A 31 A A 32 A A 33 A B 34 A A 35 A
A 36 A A 37 A A 38 A A 39 A A 40 A B 41 B C 42 B C 43 C C 44 C C 45
C C 46 B B 47 B B 48 A A 49 A B 50 C C 51 B C 52 A B 53 A B 54 A A
55 A B 56 B C 57 A A 58 A A 59 A A 60 A A 61 A A 62 A B 63 A B 64 A
A 65 A A 66 A A 67 A A 68 A A 69 A A 70 A A 71 A B 72 A A 73 B B 74
B A 75 B A 76 C C 77 B C 78 B B 79 C B 80 C B 81 C C 82 B B 83 C B
84 B B 85 C C 86 B B 87 B B 88 B A 89 A B 90 B A 91 A A 92 A A 93 A
A 94 A A 95 B V 96 A A 97 A B 98 A A 99 A A 100 A A 101 A A 102 A A
103 A A 104 A A 105 A A 106 A B 107 A B 108 A A 109 A A 110 A A 111
A A 112 A A 113 A A 114 A A 115 A A 116 A A 117 A B 118 A A 119 A A
120 A A 121 A A 122 A A 123 A A 124 A B 125 A A 126 A A 127 A A 128
A A 129 A B 130 B B 131 A A 132 A B 133 A B 134 A A 135 A A 136 A B
137 A B 138 A A 139 A B 140 A B 141 C C 142 C C 143 B B 144 B B 145
B B 146 B B 147 B C 148 A B 149 A B 150 A B 151 A B 152 A B 153 B B
154 B B 155 A B 156 A B 157 A B 158
TABLE-US-00006 TABLE 6 Cpd# JAK2 JAK3 159 C D 160 B B 161 B B 162 A
B 163 A B 164 A B 165 A B 166 A B 167 A A 168 A B 169 A A 170 A B
171 A A 172 A B 173 A A 174 A B 175 A B 176 A A 177 B B 178 B B 179
A A 180 B B 181 B B 182 A B 183 A A 184 A B 185 A B 186 A B 187 A A
188 A B 189 A A 190 B C 191 A A 192 A A 193 A A 194 A A 195 A B 196
A B 197 A C 198 A A 199 A A 200 B C 201 A B 202 A B 203 A B 204 A B
205 A B 206 A B 207 A B 208 A A 209 A B 210 A A 211 A A 212 A A 213
A A 214 A A 215 A A 216 A A 217 A A 218 A B 219 B C 220 A B 221 C C
222 A A 223 A A 224 A B 225 A A 226 A A 227 A A 228 A A 229 A B 230
A B 231 A A 232 A B 233 A C 234 A C 235 A A 236 A B 237 A A 238 A B
239 A B 240 A A 241 A B 242 A A 243 A A 244 A B 245 A B 246 A B 247
B C 248 A B 249 250 A B 251 B B 252 B B 253 C B 254
[0195] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments which utilize the compounds and methods
of this invention. Therefore, it will be appreciated that the scope
of this invention is to be defined by the appended claims rather
than by the specific embodiments which have been represented by way
of example.
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