U.S. patent application number 16/374430 was filed with the patent office on 2019-07-25 for pyridinyl and fused pyridinyl triazolone derivatives.
The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to John David Lawson, Mark Sabat, Nicholas Scorah, Christopher Smith, Phong H. Vu, Haixia Wang.
Application Number | 20190224190 16/374430 |
Document ID | / |
Family ID | 50543655 |
Filed Date | 2019-07-25 |
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United States Patent
Application |
20190224190 |
Kind Code |
A1 |
Lawson; John David ; et
al. |
July 25, 2019 |
PYRIDINYL AND FUSED PYRIDINYL TRIAZOLONE DERIVATIVES
Abstract
Disclosed are compounds of Formula 1, ##STR00001## or
pharmaceutically acceptable salts thereof, wherein R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are defined in the specification.
This disclosure also relates to materials and methods for preparing
compounds of Formula 1, to pharmaceutical compositions which
contain them, and to their use for treating Type I hypersensitivity
reactions, autoimmune diseases, inflammatory disorders, cancer,
non-malignant proliferative disorders, and other conditions
associated with BTK.
Inventors: |
Lawson; John David;
(Carlsbad, CA) ; Sabat; Mark; (San Diego, CA)
; Scorah; Nicholas; (San Diego, CA) ; Smith;
Christopher; (San Diego, CA) ; Vu; Phong H.;
(San Diego, CA) ; Wang; Haixia; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka |
|
JP |
|
|
Family ID: |
50543655 |
Appl. No.: |
16/374430 |
Filed: |
April 3, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15717624 |
Sep 27, 2017 |
10307414 |
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16374430 |
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15197051 |
Jun 29, 2016 |
9801872 |
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15717624 |
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14203366 |
Mar 10, 2014 |
9402841 |
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15197051 |
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61776445 |
Mar 11, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4439 20130101;
C07D 471/04 20130101; C07D 401/04 20130101; A61K 31/519 20130101;
C07D 403/14 20130101; A61K 31/4725 20130101; C07D 401/14 20130101;
A61K 31/4375 20130101; A61P 35/02 20180101 |
International
Class: |
A61K 31/4725 20060101
A61K031/4725; C07D 401/04 20060101 C07D401/04; C07D 403/14 20060101
C07D403/14; A61P 35/02 20060101 A61P035/02; A61K 31/4375 20060101
A61K031/4375; C07D 401/14 20060101 C07D401/14; A61K 31/519 20060101
A61K031/519; A61K 31/4439 20060101 A61K031/4439; C07D 471/04
20060101 C07D471/04 |
Claims
1. A method of treating a disease, disorder or condition in a
subject, the method comprising administering to the subject a
compound of Formula 1, ##STR00165## a tautomer thereof or a
pharmaceutically acceptable salt of the compound or tautomer,
wherein: R.sup.1 is selected from hydrogen, halo, and C.sub.1-4
alkyl; R.sup.2 and R.sup.3 are each independently selected from
hydrogen, halo, and C.sub.1-6 alkyl, or R.sup.2 and R.sup.3,
together with carbon atoms to which they are attached, form a
benzene ring or a pyridine ring in which the benzene ring is
optionally substituted with from one to four substituents
independently selected from halo, --CN, --OR.sup.8, and C.sub.1-6
alkyl, and the pyridine ring is optionally substituted with from
one to three substituents independently selected from halo, --CN,
--OR.sup.8, and C.sub.1-6 alkyl; R.sup.4 has the formula
##STR00166## in which indicates a point of attachment; L is
selected from --O--, --CH.sub.2O--, and N(R.sup.4e)--; R.sup.4a is
selected from --CH.sub.2R.sup.5 and ethenyl optionally substituted
with from one to three substituents independently selected from
halo, cyano, and C.sub.1-6 alkyl optionally substituted with
--N(R.sup.11)R.sup.12; and (a) R.sup.4c is hydrogen, R.sup.4e is
selected from hydrogen and C.sub.1-4 alkyl when L is
--N(R.sup.4e)--, and R.sup.4b and R.sup.4d, together with a
nitrogen atom and carbon atoms to which R.sup.4b, R.sup.4c, and
R.sup.4d are respectively attached, form a pyrrolidine ring or a
piperidine ring, each ring optionally substituted with from one to
six substituents independently selected from halo, C.sub.1-4 alkyl,
and C.sub.1-4 haloalkyl; or (b) R.sup.4b is selected from hydrogen
and C.sub.1-4 alkyl, R.sup.4d is hydrogen, L is --N(R.sup.4e)--,
and R.sup.4c and R.sup.4e, together with the carbon atoms and a
nitrogen atom to which R.sup.4c, R.sup.4d, and R.sup.4e are
respectively attached, form a pyrrolidine ring or a piperidine
ring, each ring optionally substituted with from one to six
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; or (c) R.sup.4d is hydrogen, R.sup.4e is
selected from hydrogen and C.sub.1-4 alkyl when L is
--N(R.sup.4e)--, and R.sup.4b and R.sup.4c, together with the
nitrogen and carbon atoms to which R.sup.4b and R.sup.4c are
respectively attached, form pyrrolidine ring or a piperidine ring,
each ring optionally substituted with from one to six substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; R.sup.5 is selected from hydrogen, halo, and C.sub.1-4
alkyl; each R.sup.8 is independently selected from hydrogen and
C.sub.1-6 alkyl; and each R.sup.11 and R.sup.12 is independently
selected from hydrogen and C.sub.1-6 alkyl; wherein the disease,
disorder or condition is selected from allergic rhinitis, asthma,
atopic dermatitis, rheumatoid arthritis, multiple sclerosis,
systemic lupus erythematosus, lupus nephritis, psoriasis, immune
thrombocytopenic purpura, inflammatory bowel disease, chronic
obstructive pulmonary disease, Sjogren's syndrome, ankylosing
spondylitis, Behcet's disease, graft versus host disease, pemphigus
vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis,
myocardial infarction, and thrombosis.
2-24. (canceled)
25. The method according to claim 1, wherein the compound is
selected from the following compounds:
(R)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one;
(R)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triaz-
ol-5(4H)-one;
(R,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,-
4-triazol-5(4H)-one;
N-(1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)pyrroli-
din-3-yl)acrylamide;
(S)-3-(1-(1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one;
(S)-3-(14(1-acryloylpyrrolidin-2-yl)methyl)amino)isoquinolin-3-yl)-1H-1,2-
,4-triazol-5(4H)-one;
(S)-3-(1-(((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H-1,2,4--
triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-tri-
azol-5(4H)-one;
(R)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one;
(S)-3-(1-((1-methacryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)(methyl)amino)isoquinolin-3-yl)-1H-1-
,2,4-triazol-5(4H)-one;
(S)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)methyl)isoquinolin-3-yl)-1H-1,2,-
4-triazol-5(4H)-one;
(S,E)-5-(1-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)isoquino-
lin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one;
(S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-
-triazol-5(4H)-one;
(S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2-
,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-fluoroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one;
3-(1-((trans-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one;
3-(1-(((3R,4S)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one;
3-(1-(((3S,4R)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-fluoroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one;
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-methoxyisoquinolin-3-yl)-1H-
-1,2,4-triazol-5(4H)-one;
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-4-methylpyridin-2-yl)-1H-1,2,4--
triazol-5(4H)-one;
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5
(4H)-one;
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-5-methylpyridin-2-yl)-
-1H-1,2,4-triazol-5(4H)-one;
(S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-di-
hydro-3H-1,2,4-triazol-3-one;
(S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-2,4--
dihydro-3H-1,2,4-triazol-3-one;
(S)-5-(1-((1-acryloylpiperidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H--
1,2,4-triazol-3-one;
(S)-5-(14(1-acetylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,-
2,4-triazol-3-one;
(S)-5-(1-((1-propionylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3-
H-1,2,4-triazol-3-one; a tautomer of any one of the aforementioned
compounds; a stereoisomer of any one of the aforementioned
compounds or tautomers; and a pharmaceutically acceptable salt of
any one of the aforementioned compounds, tautomers or
stereoisomers.
26-32. (canceled)
33. The method according to claim 1, further comprising
administering to the subject at least one additional
pharmacologically active agent.
34-35. (canceled)
36. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triaz-
ol-5 (4H)-one, a tautomer thereof, or a pharmaceutically acceptable
salt of the compound or tautomer.
37. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-tri-
azol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
38. The method according to claim 1, wherein the compound is
(S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-
-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
39. The method according to claim 1, wherein the compound is
(S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2-
,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
40. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
41. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
42. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
43. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
44. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
45. The method according to claim 1, wherein the compound is
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically
acceptable salt of the compound or tautomer.
Description
FIELD OF THE INVENTION
[0001] This invention relates to pyridinyl and fused pyridinyl
triazolone derivatives, which are inhibitors of Bruton's tyrosine
kinase (BTK), to pharmaceutical compositions which contain them,
and to the use of the inhibitors to treat diseases, disorders, and
conditions associated with BTK.
BACKGROUND OF THE INVENTION
[0002] BTK is a member of the TEC family of non-receptor protein
tyrosine kinases, and it is involved in the regulation of B-cell
development, activation, and survival through B-cell antigen
receptor (BCR) signaling. See W. N. Khan et al., Immunity 3:283-299
(1995); and A. B. Satterthwaite and O. N. Witte, Immunol. Rev.
175:120-127 (2000). Mutation of the gene encoding BTK in humans
leads to a condition known as X-linked agammaglobulinemia (XLA),
which is characterized by reduced immune function, including
impaired maturation of B cells, decreased levels of immunoglobulin
and peripheral B cells, diminished T-cell independent immune
response, and attenuated calcium mobilization following BCR
stimulation. See F. S. Rosen et al., N. Engl. J. Med.
333(7):431-440 (1995); and J. M. Lindvall et al., Immunol. Rev.
203:200-215 (2005).
[0003] BTK's key role in B-cell development and the BCR signaling
pathway suggests that inhibition of BTK may provide therapeutic
benefit for the treatment of lymphoma, inflammatory disorders, and
autoimmune diseases, among others. Clinical studies involving the
depletion of mature B cells via treatment with rituximab indicate
that rheumatoid arthritis, systemic lupus erythematosus (SLE), and
multiple sclerosis may result from the over expression of B cells.
See J. C. Edwards et al., N. Engl. J. Med. 350:2572-81 (2004); C.
Favas and D. A. Isenberg Nat. Rev. Rheumatol. 5:711-16 (2009); and
S. L. Hauser et al. N. Engl. J. Med. 358:676-88 (2008). Other
studies suggest that the BCR pathway may be involved in the
survival of tumor cells in non-Hodgkin lymphoma and diffuse large
B-cell lymphoma. See R. Kuppers, Nat. Rev. Cancer 5:251-62 (2005);
and R. E. Davis et al., Nature 463:88-92 (2010). In preclinical
studies, BTK-deficient mice have demonstrated decreased disease
progression in murine models of SLE and resistance to
collagen-induced arthritis. See M. J. Shlomchik et al., J. Exp.
Med. 180:1295-1306 (1994); and L. Jansson and R. Holmdahl, Clin.
Exp. Immunol. 94(3):459-65 (1993). Furthermore, a selective
irreversible BTK inhibitor has been shown to completely suppress
collagen-induced arthritis in mice, to inhibit autoantibody
production and the development of kidney disease in a mouse model
for SLE, and to induce objective clinical responses in dogs with
spontaneous B-cell non-Hodgkin lymphoma. See L. A. Honigberg et
al., Proc. Natl. Acad. Sci. USA 107(29):13075-80 (2010).
[0004] Certain inhibitors of Bruton's tyrosine kinase are described
in WO 99/54286 A2, WO 2002/50071 A1, WO 2007/087068 A2, WO
2008/039218 A2, WO 2008/121742 A2, WO 2007/147771 A2, WO
2009/077334 A1, WO 2009/098144 A1, WO 2009/156284 A1, WO
2010/000633 A1, WO 2010/006947 A1, WO 2008/033834 A1, WO
2010/056875 A1, WO 2010/068788 A1, and WO 2010/068810 A2.
SUMMARY OF THE INVENTION
[0005] This invention provides pyridinyl and fused pyridinyl
triazolone derivatives and pharmaceutically acceptable salts
thereof. This invention also provides pharmaceutical compositions
which contain the triazolone derivatives and provides for their use
to treat diseases, disorders and conditions associated with
BTK.
[0006] One aspect of the invention provides compounds of Formula
1:
##STR00002## [0007] a tautomer thereof or a pharmaceutically
acceptable salt of the compound or tautomer, wherein: [0008]
R.sup.1 is selected from hydrogen, halo, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, and --OR.sup.14; [0009] R.sup.2 and R.sup.3
are each independently selected from hydrogen, halo, --CN, R.sup.6,
and R.sup.7, or R.sup.2 and R.sup.3, together with carbon atoms to
which they are attached, form a benzene ring or a pyridine ring in
which the benzene ring is optionally substituted with from one to
four substituents independently selected from halo, --CN, R.sup.6,
and R.sup.7, and the pyridine ring is optionally substituted with
from one to three substituents independently selected from halo,
--CN, R.sup.6, and R.sup.7; [0010] R.sup.4 has the formula
[0010] ##STR00003## [0011] in which indicates a point of
attachment; [0012] L is selected from --O--, --CH.sub.2O--, and
N(R.sup.4e)--; [0013] R.sup.4a is selected from CH.sub.2R.sup.5 and
ethenyl optionally substituted with from one to three substituents
independently selected from halo, cyano, and R.sup.7; and [0014]
(a) R.sup.4c is hydrogen, R.sup.4e is selected from hydrogen and
C.sub.1-4 alkyl when L is --N(R.sup.4e)--, and R.sup.4b and
R.sup.4d, together with a nitrogen atom and carbon atoms to which
R.sup.4b, R.sup.4c, and R.sup.4d are respectively attached, form a
pyrrolidine ring or a piperidine ring, each ring optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or
[0015] (b) R.sup.4b is selected from hydrogen and C.sub.1-4 alkyl,
R.sup.4d is hydrogen, L is N(R.sup.4e)--, and R.sup.4c and
R.sup.4e, together with the carbon atoms and a nitrogen atom to
which R.sup.4c, R.sup.4d, and R.sup.4e are respectively attached,
form a pyrrolidine ring or a piperidine ring, each ring optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or
[0016] (c) R.sup.4d is hydrogen, R.sup.4e is selected from hydrogen
and C.sub.1-4 alkyl when L is --N(R.sup.4e)--, and R.sup.4b and
R.sup.4c, together with the nitrogen and carbon atoms to which
R.sup.4b and R.sup.4c are respectively attached, form pyrrolidine
ring or a piperidine ring, each ring optionally substituted with
from one to six substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; [0017] R.sup.5 is
selected from hydrogen, halo, and C.sub.1-4 alkyl; [0018] each
R.sup.6 is independently selected from --OR.sup.8,
--N(R.sup.8)R.sup.9, --NR.sup.8C(O)R.sup.9,
--NHC(O)NR.sup.8R.sup.9, --NR.sup.8C(O)NHR.sup.9, --C(O)R.sup.8,
--C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9, --C(O)N(R.sup.8)OR.sup.9,
--C(O)N(R.sup.8)S(O).sub.2R.sup.7, --N(R.sup.8)S(O).sub.2R.sup.7,
--SR.sup.8, --S(O)R.sup.7, --S(O).sub.2R.sup.7, and
--S(O).sub.2N(R.sup.8)R.sup.9; [0019] each R.sup.7 is independently
selected from [0020] (a) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl, each optionally substituted with from one to
five substituents independently selected from halo, oxo, --CN, and
R.sup.10; and [0021] (b) C.sub.3-10 cycloalkyl-(CH.sub.2).sub.m--,
C.sub.6-14 aryl-(CH.sub.2).sub.m--, C.sub.2-6
heterocyclyl-(CH.sub.2).sub.m--, and C.sub.1-9
heteroaryl-(CH.sub.2).sub.m--, each optionally substituted with
from one to five substituents independently selected from halo,
oxo, --CN, R.sup.10, and C.sub.1-6 alkyl optionally substituted
with from one to five substituents independently selected from
halo, oxo, --CN, and R.sup.10; [0022] each R.sup.8 and R.sup.9 is
independently selected from [0023] (a) hydrogen; [0024] (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, each
optionally substituted with from one to five substituents
independently selected from halo, oxo, --CN, and R.sup.10; and
[0025] (c) C.sub.3-10 cycloalkyl-(CH.sub.2).sub.m--, C.sub.6-14
aryl-(CH.sub.2).sub.m--, C.sub.2-6 heterocyclyl-(CH.sub.2).sub.m--,
and C.sub.1-9 heteroaryl-(CH.sub.2).sub.m--, each optionally
substituted with from one to five substituents independently
selected from halo, oxo, --CN, R.sup.10, and C.sub.1-6 alkyl
optionally substituted with from one to five substituents
independently selected from halo, oxo, --CN, and R.sup.10; [0026]
each R.sup.10 is independently selected from --OR.sup.11,
--N(R.sup.11)R.sup.12, --N(R.sup.11)C(O)R.sup.12,
--NHC(O)NR.sup.11R.sup.12, --NR.sup.11C(O)NHR.sup.12,
--C(O)R.sup.11, --C(O)OR.sup.11, --C(O)N(R.sup.11)R.sup.12,
--C(O)N(R.sup.11)OR.sup.12, --C(O)N(R.sup.11)S(O).sub.2R.sup.13,
--NR.sup.11S(O).sub.2R.sup.13, --SR.sup.11, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, and --S(O).sub.2N(R.sup.11)R.sup.12, [0027]
each R.sup.11 and R.sup.12 is independently selected from [0028]
(a) hydrogen; and [0029] (b) C.sub.1-6 alkyl and C.sub.3-10
cycloalkyl-(CH.sub.2).sub.m--, each optionally substituted with
from one to five substituents independently selected from halo,
oxo, --CN, --OH, and --NH.sub.2; [0030] each R.sup.13 is
independently selected from C.sub.1-6 alkyl and C.sub.3-10
cycloalkyl-(CH.sub.2).sub.m--, each optionally substituted with
from one to five substituents independently selected from halo,
oxo, --CN, --OH, and --NH.sub.2; [0031] each R.sup.14 is
independently selected from hydrogen, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; and [0032] each m is independently selected
from 0, 1, 2, 3, and 4; [0033] wherein each heteroaryl and
heterocyclyl of R.sup.7, R.sup.8, and R.sup.9 independently has one
to four heteroatoms, each of the heteroatoms independently selected
from N, O, and S.
[0034] Another aspect of the invention provides a compound which is
selected from the group of compounds described in the examples,
tautomers thereof, stereoisomers of the example compounds and their
tautomers, and pharmaceutically acceptable salts of any of the
aforementioned example compounds, tautomers, and stereoisomers.
[0035] A further aspect of the invention provides a pharmaceutical
composition which includes a compound of Formula 1, a tautomer
thereof or a pharmaceutically acceptable salt of the compound or
tautomer as defined above, or a compound as defined in the
immediately preceding paragraph; and a pharmaceutically acceptable
excipient.
[0036] An additional aspect of the invention provides a compound of
Formula 1, a tautomer thereof or a pharmaceutically acceptable salt
of the compound or tautomer as defined above, or a compound
selected from the group of compounds as defined above, for use as a
medicament.
[0037] Another aspect of the invention provides a use of a compound
of Formula 1, a tautomer thereof or a pharmaceutically acceptable
salt of the compound or tautomer as defined above, or a compound
selected from the group of compounds as defined above, for the
manufacture of a medicament for the treatment of a condition
associated with BTK.
[0038] An additional aspect of the invention provides a method for
inhibiting BTK in a subject, the method comprising administering to
the subject a compound of Formula 1, a tautomer thereof or a
pharmaceutically acceptable salt of the compound or tautomer as
defined above, or a compound selected from the group of compounds
as defined above.
[0039] A further aspect of the invention provides a method of
treating a disease, disorder or condition associated with BTK in a
subject, the method comprising administering to the subject an
effective amount of a compound of Formula 1, a tautomer thereof or
a pharmaceutically acceptable salt of the compound or tautomer as
defined above, or a compound selected from the group of compounds
as defined above.
[0040] An additional aspect of the invention provides a method of
treating a disease, disorder or condition in a subject, the method
comprising administering to the subject an effective amount of a
compound of Formula 1, a tautomer thereof or a pharmaceutically
acceptable salt of the compound or tautomer as defined above, or a
compound selected from the group of compounds as defined above,
wherein the disease, disorder or condition is selected from Type I
hypersensitivity reactions, autoimmune diseases, inflammatory
disorders, cancer, and non-malignant proliferative disorders.
[0041] Another aspect of the invention provides a method of
treating a disease, disorder or condition in a subject, the method
comprising administering to the subject an effective amount of a
compound of Formula 1, a tautomer thereof or a pharmaceutically
acceptable salt of the compound or tautomer as defined above, or a
compound selected from the group of compounds as defined above,
wherein the disease, disorder or condition is selected from
allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis,
multiple sclerosis, systemic lupus erythematosus, lupus nephritis,
psoriasis, immune thrombocytopenic purpura, inflammatory bowel
disease, chronic obstructive pulmonary disease, Sjogren's syndrome,
ankylosing spondylitis, Behcet's disease, pemphigus vulgaris,
idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial
infarction, and thrombosis.
[0042] Another aspect of the invention provides a method of
treating a disease, disorder or condition in a subject, the method
comprising administering to the subject an effective amount of a
compound of Formula 1, a tautomer thereof or a pharmaceutically
acceptable salt of the compound or tautomer as defined above, or a
compound selected from the group of compounds as defined above,
wherein the disease, disorder or condition is selected from B-cell
lymphoma, chronic lymphocytic leukemia, and multiple myeloma.
[0043] A further aspect of the invention provides a combination of
an effective amount of a compound of Formula 1, a tautomer thereof
or a pharmaceutically acceptable salt of the compound or tautomer
as defined above, or a compound selected from the group of
compounds as defined above, and at least one additional
pharmacologically active agent.
DETAILED DESCRIPTION OF THE INVENTION
[0044] Unless otherwise indicated, this disclosure uses definitions
provided below.
[0045] "Substituted," when used in connection with a chemical
substituent or moiety (e.g., a C.sub.1-6 alkyl group), means that
one or more hydrogen atoms of the substituent or moiety have been
replaced with one or more non-hydrogen atoms or groups, provided
that valence requirements are met and that a chemically stable
compound results from the substitution.
[0046] "About" or "approximately," when used in connection with a
measurable numerical variable, refers to the indicated value of the
variable and to all values of the variable that are within the
experimental error of the indicated value or within .+-.10 percent
of the indicated value, whichever is greater.
[0047] "Alkyl" refers to straight chain and branched saturated
hydrocarbon groups, generally having a specified number of carbon
atoms (e.g., C.sub.1-4 alkyl refers to an alkyl group having 1 to 4
(i.e., 1, 2, 3 or 4) carbon atoms, C.sub.1-6 alkyl refers to an
alkyl group having 1 to 6 carbon atoms, and so on). Examples of
alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl,
3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl,
2,2,2-trimethyleth-1-yl, n-hexyl, and the like.
[0048] "Alkenyl" refers to straight chain and branched hydrocarbon
groups having one or more carbon-carbon double bonds, and generally
having a specified number of carbon atoms. Examples of alkenyl
groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl,
2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl,
3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl,
2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and
the like.
[0049] "Alkynyl" refers to straight chain or branched hydrocarbon
groups having one or more triple carbon-carbon bonds, and generally
having a specified number of carbon atoms. Examples of alkynyl
groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl,
3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.
[0050] "Halo," "halogen" and "halogeno" may be used interchangeably
and refer to fluoro, chloro, bromo, and iodo.
[0051] "Haloalkyl," "haloalkenyl," and "haloalkynyl," refer,
respectively, to alkyl, alkenyl, and alkynyl groups substituted
with one or more halogen atoms, where alkyl, alkenyl, and alkynyl
are defined above, and generally having a specified number of
carbon atoms. Examples of haloalkyl groups include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, and the like.
[0052] "Cycloalkyl" refers to saturated monocyclic and bicyclic
hydrocarbon groups, generally having a specified number of carbon
atoms that comprise the ring or rings (e.g., C.sub.3-10 cycloalkyl
refers to a cycloalkyl group having 3 to 10 carbon atoms as ring
members). Bicyclic hydrocarbon groups may include spiro rings (two
rings sharing one carbon atom), fused rings (two rings sharing two
carbon atoms and the bond between the two common carbon atoms), and
bridged rings (two rings sharing two carbon atoms, but not a common
bond). The cycloalkyl group may be attached through any ring atom
unless such attachment would violate valence requirements.
[0053] Examples of monocyclic cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Examples of fused bicyclic cycloalkyl groups include
bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl,
bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl),
bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl,
bicyclo[4.1.1]heptanyl, bicyclo[3.3.1]octanyl,
bicyclo[4.2.1]octanyl, bicyclo[4.3.0]nonanyl,
bicyclo[4.4.0]decanyl, and the like. Examples of bridged cycloalkyl
groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl,
bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl,
bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl,
bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl,
bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl,
bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like.
Examples of spiro cycloalkyl groups include spiro[3.3]heptanyl,
spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl,
spiro[3.5]nonanyl, and the like.
[0054] "Cycloalkylidene" refers to divalent monocyclic cycloalkyl
groups, where cycloalkyl is defined above, which are attached
through a single carbon atom of the group, and generally having a
specified number of carbon atoms that comprise the ring (e.g.,
C.sub.3-6 cycloalkylidene refers to a cycloalkylidene group having
3 to 6 carbon atoms as ring members). Examples include
cyclopropylidene, cyclobutylidene, cyclopentylidene, and
cyclohexylidene.
[0055] "Cycloalkenyl" refers to partially unsaturated monocyclic
and bicyclic hydrocarbon groups, generally having a specified
number of carbon atoms that comprise the ring or rings. As with
cycloalkyl groups, the bicyclic cycloalkenyl groups may include
spiro, fused, or bridged rings. Similarly, the cycloalkenyl group
may be attached through any ring atom, and when stated, may include
one or more non-hydrogen substituents unless such attachment or
substitution would violate valence requirements. Examples of
cycloalkenyl groups include the partially unsaturated analogs of
the cycloalkyl groups described above, such as cyclobutenyl (i.e.,
cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl,
bicyclo[2.2.1]hept-2-enyl, and the like.
[0056] "Aryl" refers to fully unsaturated monocyclic aromatic
hydrocarbons and to polycyclic hydrocarbons having at least one
aromatic ring, both monocyclic and polycyclic aryl groups generally
having a specified number of carbon atoms that comprise their ring
members (e.g., C.sub.6-14 aryl refers to an aryl group having 6 to
14 carbon atoms as ring members). The group may be attached through
any ring atom unless such attachment would violate valence
requirements. Examples of aryl groups include phenyl,
cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl,
biphenylenyl, fluorenyl, groups derived from cycloheptatriene
cation, and the like.
[0057] "Arylene" refers to divalent aryl groups, where aryl is
defined above. Examples of arylene groups include phenylene (i.e.,
benzene-1,2-diyl).
[0058] "Heterocycle" and "heterocyclyl" may be used interchangeably
and refer to saturated or partially unsaturated monocyclic or
bicyclic groups having ring atoms composed of carbon atoms and 1 to
4 heteroatoms independently selected from nitrogen, oxygen, and
sulfur. Both the monocyclic and bicyclic groups generally have a
specified number of carbon atoms in their ring or rings (e.g.,
C.sub.2-6 heterocyclyl refers to a heterocyclyl group having 2 to 6
carbon atoms and 1 to 4 heteroatoms as ring members). As with
bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may
include spiro rings, fused rings, and bridged rings. The
heterocyclyl group may be attached through any ring atom unless
such attachment would violate valence requirements or result in a
chemically unstable compound. Examples of monocyclic heterocyclyl
groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl
and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl,
tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidinyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,
1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl,
piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl,
1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl,
1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl,
3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridine,
1,2,3,4-tetrahydropyridinyl, and 1,2,5,6-tetrahydropyridinyl.
[0059] "Heterocycle-diyl" refers to heterocyclyl groups which are
attached through two ring atoms of the group, where heterocyclyl is
defined above. They generally have a specified number of carbon
atoms in their ring or rings (e.g., C.sub.2-6 heterocycle-diyl
refers to a heterocycle-diyl group having 2 to 6 carbon atoms and 1
to 4 heteroatoms as ring members). Examples of heterocycle-diyl
groups include the multivalent analogs of the heterocycle groups
described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl,
1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene,
1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene,
3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene,
1-piperazinyl-6-ylidene, and the like.
[0060] "Heteroaromatic" and "heteroaryl" may be used
interchangeably and refer to unsaturated monocyclic aromatic groups
and to polycyclic groups having at least one aromatic ring, each of
the groups having ring atoms composed of carbon atoms and 1 to 4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. Both the monocyclic and polycyclic groups generally have a
specified number of carbon atoms as ring members (e.g., C.sub.1-9
heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms
and 1 to 4 heteroatoms as ring members) and may include any
bicyclic group in which any of the above-listed monocyclic
heterocycles are fused to a benzene ring. The heteroaryl group may
be attached through any ring atom unless such attachment would
violate valence requirements or result in a chemically unstable
compound. Examples of heteroaryl groups include monocyclic groups
such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl),
furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,
isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,
1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,
1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,
1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
[0061] Examples of heteroaryl groups also include bicyclic groups
such as benzofuranyl, isobenzofuranyl, benzothiophenyl,
benzo[c]thiophenyl, indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl,
indolinyl, isoindolinyl, benzimidazolyl, indazolyl, benzotriazolyl,
1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,
1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,
3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl,
1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl,
1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl,
7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl,
imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,
pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl,
isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl,
1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl,
2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,
pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl,
pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl,
pyrazino[2,3-b]pyrazinyl, and pyrimido[4,5-d]pyrimidinyl.
[0062] "Heteroarylene" refers to heteroaryl groups which are
attached through two ring atoms of the group, where heteroaryl is
defined above. They generally have a specified number of carbon
atoms in their ring or rings (e.g., C.sub.3-5 heteroarylene refers
to a heteroarylene group having 3 to 5 carbon atoms and 1 to 4
heteroatoms as ring members). Examples of heteroarylene groups
include the multivalent analogs of the heteroaryl groups described
above, such as pyridine-2,3-diyl, pyridine-3,4-diyl,
pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.
[0063] "Oxo" refers to a double bonded oxygen (.dbd.O).
[0064] "Leaving group" refers to any group that leaves a molecule
during a fragmentation process, including substitution reactions,
elimination reactions, and addition-elimination reactions. Leaving
groups may be nucleofugal, in which the group leaves with a pair of
electrons that formerly served as the bond between the leaving
group and the molecule, or may be electrofugal, in which the group
leaves without the pair of electrons. The ability of a nucleofugal
leaving group to leave depends on its base strength, with the
strongest bases being the poorest leaving groups. Common
nucleofugal leaving groups include nitrogen (e.g., from diazonium
salts); sulfonates, including alkylsulfonates (e.g., mesylate),
fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and
tresylate), and arylsulfonates (e.g., tosylate, brosylate,
closylate, and nosylate). Others include carbonates, halide ions,
carboxylate anions, phenolate ions, and alkoxides. Some stronger
bases, such as NH.sub.2.sup.- and OH.sup.- can be made better
leaving groups by treatment with an acid. Common electrofugal
leaving groups include the proton, CO.sub.2, and metals.
[0065] "Opposite enantiomer" refers to a molecule that is a
non-superimposable mirror image of a reference molecule, which may
be obtained by inverting all of the stereogenic centers of the
reference molecule. For example, if the reference molecule has S
absolute stereochemical configuration, then the opposite enantiomer
has R absolute stereochemical configuration. Likewise, if the
reference molecule has S,S absolute stereochemical configuration,
then the opposite enantiomer has R,R stereochemical configuration,
and so on.
[0066] "Stereoisomer" and "stereoisomers" of a compound with given
stereochemical configuration refer to the opposite enantiomer of
the compound and to any diastereoisomers, including geometrical
isomers (Z/E) of the compound. For example, if a compound has S,R,Z
stereochemical configuration, its stereoisomers would include its
opposite enantiomer having R,S,Z configuration, and its
diastereomers having S,S,Z configuration, R,R,Z configuration,
S,R,E configuration, R,S,E configuration, S,S,E configuration, and
R,R,E configuration. If the stereochemical configuration of a
compound is not specified, then "stereoisomer" refers to any one of
the possible stereochemical configurations of the compound.
[0067] "Substantially pure stereoisomer" and variants thereof refer
to a sample containing a compound having a specific stereochemical
configuration and which comprises at least about 95% of the
sample.
[0068] "Pure stereoisomer" and variants thereof refer to a sample
containing a compound having a specific stereochemical
configuration and which comprises at least about 99.5% of the
sample.
[0069] "Subject" refers to a mammal, including a human.
[0070] "Pharmaceutically acceptable" substances refer to those
substances which are suitable for administration to subjects.
[0071] "Treating" refers to reversing, alleviating, inhibiting the
progress of, or preventing a disease, disorder or condition to
which such term applies, or to reversing, alleviating, inhibiting
the progress of, or preventing one or more symptoms of such
disorder, disease or condition.
[0072] "Treatment" refers to the act of "treating," as defined
immediately above.
[0073] "Drug," "drug substance," "active pharmaceutical
ingredient," and the like, refer to a compound (e.g., compounds of
Formula 1, including subgeneric compounds and compounds
specifically named in the specification) that may be used for
treating a subject in need of treatment.
[0074] "Effective amount" of a drug, "therapeutically effective
amount" of a drug, and the like, refer to the quantity of the drug
that may be used for treating a subject and may depend on the
weight and age of the subject and the route of administration,
among other things.
[0075] "Excipient" refers to any diluent or vehicle for a drug.
[0076] "Pharmaceutical composition" refers to the combination of
one or more drug substances and one or more excipients.
[0077] "Drug product," "pharmaceutical dosage form," "dosage form,"
"final dosage form" and the like, refer to a pharmaceutical
composition suitable for treating a subject in need of treatment
and generally may be in the form of tablets, capsules, sachets
containing powder or granules, liquid solutions or suspensions,
patches, films, and the like.
[0078] "Condition associated with BTK" and similar phrases relate
to a disease, disorder or condition in a subject for which
inhibition of BTK may provide a therapeutic or prophylactic
benefit.
[0079] The following abbreviations are used throughout the
specification: Ac (acetyl); ACN (acetonitrile); AIBN
(azo-bis-isobutyronitrile); API (active pharmaceutical ingredient);
aq (aqueous); Boc (tert-butoxycarbonyl); Cbz (carbobenzyloxy); CDI
(1,1'-carbonyldiimidazole); dba (dibenzylideneacetone); DBU
(1,8-diazabicyclo[5.4.0]undec-1(7)-ene); DCC
(1,3-dicyclohexylcarbodiimide); DCM (dichloromethane); DIPEA
(N,N-diisopropylethylamine, Htinig's Base); DMA
(N,N-dimethylacetamide); DMAP (4-dimethylaminopyridine); DMARD
(disease modifying antirheumatic drug); DME (1,2-dimethoxyethane);
DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); DPPA
(diphenylphosphoryl azide); dppf
(1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EDA
ethoxylated dodecyl alcohol, Brj.RTM.35); EDC
(N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA
(ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq
(equivalents); Et (ethyl); Et.sub.3N (triethyl-amine); EtOAc (ethyl
acetate); EtOH (ethanol); 5-FAM (5-carboxyfluorescein); HATU
(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate(V)); HEPES
(4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); HOAc (acetic
acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC.sub.50
(concentration at 50% inhibition); IPA (isopropanol); IPAc
(isopropyl acetate); IPE (isopropylether); LDA (lithium
diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); mCPBA
(m-chloroperoxybenzoic acid); Me (methyl); MeOH (methanol); MTBE
(methyl tert-butyl ether); mp (melting point); NaOt-Bu (sodium
tertiary butoxide); NMM (N-methylmorpholine); NMP
(1-methyl-2-pyrrolidinone); PE (petroleum ether); Ph (phenyl);
pIC.sub.50 (-log.sub.10(IC.sub.50), where IC.sub.50 is given in
molar (M) units); Pr (propyl); i-Pr (isopropyl); PTFE
(polytetrafluoroethylene); RT (room temperature, approximately
20.degree. C. to 25.degree. C.); TCEP
(tris(2-carboxyethyl)phosphine); Tf (trifluoromethylsulfonyl); TFA
(trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF
(tetrahydrofuran); TMS (trimethylsilyl); and Tris buffer
(2-amino-2-hydroxymethyl-propane-1,3-diol buffer).
[0080] As described, below, this disclosure concerns compounds of
Formula 1, tautomers thereof, and pharmaceutically acceptable salts
thereof. This disclosure also concerns materials and methods for
preparing compounds of Formula 1, pharmaceutical compositions which
contain them, and the use of compounds of Formula 1 and their
pharmaceutically acceptable salts (optionally in combination with
other pharmacologically active agents) for treating Type I
hypersensitivity reactions, autoimmune diseases, inflammatory
disorders, cancer, non-malignant proliferative disorders, and other
diseases, disorders or conditions associated with BTK.
[0081] In addition to the specific compounds in the examples,
compounds of Formula 1 include those in which: (i) R.sup.1 is
selected from hydrogen, halo, methyl, and OCH.sub.3; (ii) R.sup.1
is selected from hydrogen, halo, and methyl; (iv) R.sup.1 is
selected from hydrogen and methyl; or (v) R.sup.1 is hydrogen.
[0082] In addition, or as an alternative, to one of embodiments
(i)-(v) in the immediately preceding paragraph, compounds of
Formula 1 include those in which: (vi) R.sup.2 and R.sup.3 are each
independently selected from hydrogen, halo, and methyl; (vii)
R.sup.2 and R.sup.3 are each independently selected from hydrogen,
fluoro, chloro, and methyl; (viii) R.sup.2 is methyl and R.sup.3 is
hydrogen; (ix) R.sup.2 is hydrogen and R.sup.3 is methyl; or (x)
R.sup.2 and R.sup.3 are each hydrogen.
[0083] In addition, or as an alternative, to one of embodiments
(i)-(v) above, compounds of Formula 1 include those in which
R.sup.2 and R.sup.3, together with the carbon atoms to which they
are attached, form a benzene ring, and: (xi) the benzene ring is
optionally substituted with from one to four substituents
independently selected from halo, --CN, R.sup.6, and R.sup.7; (xii)
the benzene ring is optionally substituted with from one to four
substituents independently selected from halo and C.sub.1-6 alkyl;
(xiii) the benzene ring is optionally substituted with from one to
four substituents independently selected from fluoro, chloro, and
methyl; (xiv) the benzene ring is optionally substituted with one
to two substituents independently selected from fluoro, chloro, and
methyl; or (xv) the benzene ring is unsubstituted.
[0084] In addition, or as an alternative, to one of embodiments
(i)-(v) above, compounds of Formula 1 include those in which
R.sup.2 and R.sup.3, together with the carbon atoms to which they
are attached, form a pyridine ring, and: (xvi) the pyridine ring is
optionally substituted with from one to three substituents
independently selected from halo, --CN, R.sup.6, and R.sup.7;
(xvii) the pyridine ring is optionally substituted with from one to
three substituents independently selected from halo and C.sub.1-6
alkyl; (xviii) the pyridine ring is optionally substituted with
from one to three substituents independently selected from fluoro,
chloro, and methyl; (xix) the pyridine ring is optionally
substituted with one or two substituents independently selected
from fluoro, chloro, and methyl; or (xx) the pyridine ring is
unsubstituted.
[0085] In addition, or as an alternative, to one of embodiments
(i)-(v) above, compounds of Formula 1 include those in which
R.sup.2 and R.sup.3, together with the carbon atoms to which they
are attached, form a pyridine ring having a nitrogen ring atom that
is directly bonded to the carbon atom attached to R.sup.3, and:
(xxi) the pyridine ring is optionally substituted with from one to
three substituents independently selected from halo, --CN, R.sup.6,
and R.sup.7; (xxii) the pyridine ring is optionally substituted
with from one to three substituents independently selected from
halo and C.sub.1-6 alkyl; (xxiii) the pyridine ring is optionally
substituted with from one to three substituents independently
selected from fluoro, chloro, and methyl; (xxiv) the pyridine ring
is optionally substituted with one or two substituents
independently selected from fluoro, chloro, and methyl; or (xxv)
the pyridine ring is unsubstituted.
[0086] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--N(R.sup.4e)--, R.sup.4c is hydrogen, and R.sup.4b and R.sup.4d,
together with the nitrogen atom and the carbon atoms to which
R.sup.4b, R.sup.4c, and R.sup.4d are respectively attached, form a
pyrrolidine ring, and: (xxvi) R.sup.4e is selected from hydrogen
and C.sub.1-4 alkyl, and the pyrrolidine ring is optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(xxvii) R.sup.4e is selected from hydrogen and C.sub.1-4 alkyl, and
the pyrrolidine ring is optionally substituted with from one to
four substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (xxviii) R.sup.4e is hydrogen and
the pyrrolidine ring is optionally substituted with from one to
four substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (xxix) R.sup.4e is hydrogen and the
pyrrolidine ring is optionally substituted with one or two
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; or (xxx) R.sup.4e is hydrogen and the
pyrrolidine ring is unsubstituted.
[0087] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--N(R.sup.4e)--, R.sup.4c is hydrogen, and R.sup.4b and R.sup.4d,
together with the nitrogen atom and the carbon atoms to which
R.sup.4b, R.sup.4c, and R.sup.4d are respectively attached, form a
piperidine ring, and: (xxxi) R.sup.4e is selected from hydrogen and
C.sub.1-4 alkyl, and the piperidine ring is optionally substituted
with from one to six substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (xxxii) R.sup.4e is
selected from hydrogen and C.sub.1-4 alkyl, and the piperidine ring
is optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (xxxiii) R.sup.4e is hydrogen and the piperidine ring is
optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (xxxiv) R.sup.4e is hydrogen and the piperidine ring is
optionally substituted with one or two substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or
(xxxv) R.sup.4e is hydrogen and the piperidine ring is
unsubstituted.
[0088] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--N(R.sup.4e)--, R.sup.4d is hydrogen, and R.sup.4c and R.sup.4e,
together with the carbon atoms and the nitrogen atom to which
R.sup.4c, R.sup.4d, and R.sup.4e are respectively attached, form a
pyrrolidine ring, and: (xxxvi) R.sup.4b is selected from hydrogen
and C.sub.1-4 alkyl, and the pyrrolidine ring is optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(xxxvii) R.sup.4b is selected from hydrogen and C.sub.1-4 alkyl,
and the pyrrolidine ring is optionally substituted with from one to
four substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (xxxviii) R.sup.4b is hydrogen and
the pyrrolidine ring is optionally substituted with from one to
four substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (xxxix) R.sup.4b is hydrogen and
the pyrrolidine ring is optionally substituted with one or two
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; or (xl) R.sup.4b is hydrogen and the
pyrrolidine ring is unsubstituted.
[0089] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
N(R.sup.4e)--, R.sup.4d is hydrogen, and R.sup.4c and R.sup.4e,
together with the carbon atoms and the nitrogen atom to which
R.sup.4c, R.sup.4d, and R.sup.4e are respectively attached, form a
piperidine ring, and: (xli) R.sup.4b is selected from hydrogen and
C.sub.1-4 alkyl, and the piperidine ring is optionally substituted
with from one to six substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (xlii) R.sup.4b is
selected from hydrogen and C.sub.1-4 alkyl, and the piperidine ring
is optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (xliii) R.sup.4b is hydrogen and the piperidine ring is
optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (xliv) R.sup.4b is hydrogen and the piperidine ring is
optionally substituted with one or two substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or
(xlv) R.sup.4b is hydrogen and the piperidine ring is
unsubstituted.
[0090] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--N(R.sup.4e)--, R.sup.4d is hydrogen, and R.sup.4b and R.sup.4c,
together with the nitrogen and carbon atoms to which R.sup.4b and
R.sup.4c are respectively attached, form a pyrrolidine ring, and:
(xlvi) R.sup.4e is selected from hydrogen and C.sub.1-4 alkyl, and
the pyrrolidine ring is optionally substituted with from one to six
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; (xlvii) R.sup.4e is selected from hydrogen and
C.sub.1-4 alkyl, and the pyrrolidine ring is optionally substituted
with from one to four substituents independently selected from
halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (xlviii) R.sup.4e
is hydrogen and the pyrrolidine ring is optionally substituted with
from one to four substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (xlix) R.sup.4e is
hydrogen and the pyrrolidine ring is optionally substituted with
one or two substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; or (l) R.sup.4e is hydrogen and the
pyrrolidine ring is unsubstituted.
[0091] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--N(R.sup.4e)--, R.sup.4d is hydrogen, and R.sup.4b and R.sup.4c,
together with the nitrogen and carbon atoms to which R.sup.4b and
R.sup.4c are respectively attached, form a piperidine ring, and:
(li) R.sup.4e is selected from hydrogen and C.sub.1-4 alkyl, and
the piperidine ring is optionally substituted with from one to six
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; (lii) R.sup.4e is selected from hydrogen and
C.sub.1-4 alkyl, and the piperidine ring is optionally substituted
with from one to four substituents independently selected from
halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (liii) R.sup.4e is
hydrogen and the piperidine ring is optionally substituted with
from one to four substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (liv) R.sup.4e is
hydrogen and the piperidine ring is optionally substituted with one
or two substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; or (lv) R.sup.4e is hydrogen and
the piperidine ring is unsubstituted.
[0092] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--O--, R.sup.4c is hydrogen, and R.sup.4b and R.sup.4d, together
with the nitrogen atom and the carbon atoms to which R.sup.4b,
R.sup.4c, and R.sup.4d are respectively attached, form a
pyrrolidine ring, and: (lvi) the pyrrolidine ring is optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(lvii) the pyrrolidine ring is optionally substituted with from one
to four substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (lviii) the pyrrolidine ring is
optionally substituted with from one to three substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (lix) the pyrrolidine ring is optionally substituted
with one or two substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or (lx) the pyrrolidine
ring is unsubstituted.
[0093] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--O--, R.sup.4c is hydrogen, and R.sup.4b and R.sup.4d, together
with the nitrogen atom and the carbon atoms to which R.sup.4b,
R.sup.4c, and R.sup.4d are respectively attached, form a piperidine
ring, and: (lxi) the piperidine ring is optionally substituted with
from one to six substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (lxii) the piperidine
ring is optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (lxiii) the piperidine ring is optionally substituted
with from one to three substituents independently selected from
halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (lxiv) the
piperidine ring is optionally substituted with one or two
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; or (lxv) the piperidine ring is
unsubstituted.
[0094] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--O--, R.sup.4d is hydrogen, and R.sup.4b and R.sup.4c, together
with the nitrogen and carbon atoms to which R.sup.4b and R.sup.4c
are respectively attached, form a pyrrolidine ring, and: (lxvi) the
pyrrolidine ring is optionally substituted with from one to six
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; (lxvii) the pyrrolidine ring is optionally
substituted with from one to four substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(lxviii) the pyrrolidine ring is optionally substituted with from
one to three substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (lxix) the pyrrolidine
ring is optionally substituted with one or two substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; or (lxx) the pyrrolidine ring is unsubstituted.
[0095] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--O--, R.sup.4d is hydrogen, and R.sup.4b and R.sup.4c, together
with the nitrogen and carbon atoms to which R.sup.4b and R.sup.4c
are respectively attached, form a piperidine ring, and: (lxxi) the
piperidine ring is optionally substituted with from one to six
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; (lxxii) the piperidine ring is optionally
substituted with from one to four substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(lxxiii) the piperidine ring is optionally substituted with from
one to three substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (lxxiv) the piperidine
ring is optionally substituted with one or two substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; or (lxxv) the piperidine ring is unsubstituted.
[0096] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--CH.sub.2O--, R.sup.4c is hydrogen, and R.sup.4b and R.sup.4d,
together with the nitrogen atom and the carbon atoms to which
R.sup.4b, R.sup.4c, and R.sup.4d are respectively attached, form a
pyrrolidine ring, and: (lxxvi) the pyrrolidine ring is optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(lxxvii) the pyrrolidine ring is optionally substituted with from
one to four substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (lxxviii) the pyrrolidine
ring is optionally substituted with from one to three substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (lxxix) the pyrrolidine ring is optionally substituted
with one or two substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or (lxxx) the pyrrolidine
ring is unsubstituted; wherein in embodiments (lxxvi)-(lxxx), the O
atom of L is directly bonded to the carbon atom attached to
R.sup.4d.
[0097] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--CH.sub.2O--, R.sup.4c is hydrogen, and R.sup.4b and R.sup.4d,
together with the nitrogen atom and the carbon atoms to which
R.sup.4b, R.sup.4c, and R.sup.4d are respectively attached, form a
piperidine ring, and: (lxxxi) the piperidine ring is optionally
substituted with from one to six substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(lxxxii) the piperidine ring is optionally substituted with from
one to four substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (lxxxiii) the piperidine
ring is optionally substituted with from one to three substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (lxxxiv) the piperidine ring is optionally substituted
with one or two substituents independently selected from halo,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or (lxxxv) the piperidine
ring is unsubstituted; wherein in embodiments (lxxxi)-(lxxxv), the
O atom of L is directly bonded to the carbon atom attached to
R.sup.4d.
[0098] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--CH.sub.2O--, R.sup.4d is hydrogen, and R.sup.4b and R.sup.4c,
together with the nitrogen and carbon atoms to which R.sup.4b and
R.sup.4c are respectively attached, form a pyrrolidine ring, and:
(lxxxvi) the pyrrolidine ring is optionally substituted with from
one to six substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (lxxxvii) the pyrrolidine ring is
optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (lxxxviii) the pyrrolidine ring is optionally
substituted with from one to three substituents independently
selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
(lxxxix) the pyrrolidine ring is optionally substituted with one or
two substituents independently selected from halo, C.sub.1-4 alkyl,
and C.sub.1-4 haloalkyl; or (xc) the pyrrolidine ring is
unsubstituted; wherein in embodiments (lxxxvi)-(xc), the O atom of
L is directly bonded to the carbon atom attached to R.sup.4d.
[0099] In addition, or as an alternative, to one of embodiments
(i)-(v) above, or to one of embodiments (vi)-(xxv) in the preceding
paragraphs, compounds of Formula 1 include those in which L is
--CH.sub.2O--, R.sup.4d is hydrogen, and R.sup.4b and R.sup.4c,
together with the nitrogen and carbon atoms to which R.sup.4b and
R.sup.4c are respectively attached, form a piperidine ring, and:
(xci) the piperidine ring is optionally substituted with from one
to six substituents independently selected from halo, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl; (xcii) the piperidine ring is
optionally substituted with from one to four substituents
independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; (xciii) the piperidine ring is optionally substituted
with from one to three substituents independently selected from
halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; (xciv) the
piperidine ring is optionally substituted with one or two
substituents independently selected from halo, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl; or (xcv) the piperidine ring is unsubstituted;
wherein in embodiments (xci)-(xcv), the O atom of L is directly
bonded to the carbon atom attached to R.sup.4d.
[0100] In addition, or as an alternative, to one of embodiments
(i)-(v) above, to one of embodiments (vi)-(xxv) above, or to one of
embodiments (xxvi)-(xcv) in the preceding paragraphs, compounds of
Formula 1 include those in which: (xcvi) R.sup.4a is ethenyl
optionally substituted with from one to three substituents
independently selected from halo, cyano, and R.sup.7; (xcvii)
R.sup.4a is ethenyl optionally substituted with from one to three
methyl groups; (xcviii) R.sup.4a is ethenyl optionally substituted
with one or two substituents independently selected from halo,
cyano, and R.sup.7; (xcix) R.sup.4a is ethenyl optionally
substituted with one or two methyl groups; or (c) R.sup.4a is
ethenyl.
[0101] In addition, or as an alternative, to one of embodiments
(i)-(v) above, to one of embodiments (vi)-(xxv) above, to one of
embodiments (xxvi)-(xcv) above, and to one of embodiments
(xcvi)-(c) in the immediately preceding paragraph, compounds of
Formula 1 include those in which: (ci) each m is independently
selected from 0, 1, 2, and 3; (cii) each m is independently
selected from 0, 1, and 2; (ciii) each m is independently selected
from 0 and 1; or (civ) each m is 0.
[0102] Compounds of Formula 1, including embodiments (i) through
(civ) described in the preceding paragraphs and all compounds
specifically named in the examples, may exist as salts, complexes,
solvates, hydrates, and liquid crystals. Likewise, compounds of
Formula 1 that are salts may exist as complexes, solvates,
hydrates, and liquid crystals.
[0103] Compounds of Formula 1 may form pharmaceutically acceptable
complexes, salts, solvates and hydrates. These salts include acid
addition salts (including di-acids) and base salts.
Pharmaceutically acceptable acid addition salts include salts
derived from inorganic acids such as hydrochloric acid, nitric
acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic
acid, hydrofluoric acid, and phosphorous acids, as well nontoxic
salts derived from organic acids, such as aliphatic mono- and
dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy
alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and
aromatic sulfonic acids, etc. Such salts include acetate, adipate,
aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate,
sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate,
formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate,
malate, maleate, malonate, mesylate, methylsulfate, naphthylate,
2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate,
pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate,
pyroglutamate, saccharate, stearate, succinate, tannate, tartrate,
tosylate, trifluoroacetate and xinofoate salts.
[0104] Pharmaceutically acceptable base salts include salts derived
from bases, including metal cations, such as an alkali or alkaline
earth metal cation, as well as amines. Examples of suitable metal
cations include sodium, potassium, magnesium, calcium, zinc, and
aluminum. Examples of suitable amines include arginine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine,
glycine, lysine, N-methylglucamine, olamine,
2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a
discussion of useful acid addition and base salts, see S. M. Berge
et al., J. Pharm. Sci. (1977) 66:1-19; see also Stahl and Wermuth,
Handbook of Pharmaceutical Salts: Properties, Selection, and Use
(2002).
[0105] Pharmaceutically acceptable salts may be prepared using
various methods. For example, a compound of Formula 1 may be
reacted with an appropriate acid or base to give the desired salt.
Alternatively, a precursor of the compound of Formula 1 may be
reacted with an acid or base to remove an acid- or base-labile
protecting group or to open a lactone or lactam group of the
precursor. Additionally, a salt of the compound of Formula 1 may be
converted to another salt (or free form) through treatment with an
appropriate acid or base or through contact with an ion exchange
resin. Following reaction, the salt may be isolated by filtration
if it precipitates from solution, or by evaporation to recover the
salt. The degree of ionization of the salt may vary from completely
ionized to almost non-ionized.
[0106] Compounds of Formula 1 may exist in a continuum of solid
states ranging from fully amorphous to fully crystalline. The term
"amorphous" refers to a state in which the material lacks long
range order at the molecular level and, depending upon temperature,
may exhibit the physical properties of a solid or a liquid.
Typically such materials do not give distinctive X-ray diffraction
patterns and, while exhibiting the properties of a solid, are more
formally described as a liquid. Upon heating, a change from solid
to liquid properties occurs which is characterized by a change of
state, typically second order ("glass transition"). The term
"crystalline" refers to a solid phase in which the material has a
regular ordered internal structure at the molecular level and gives
a distinctive X-ray diffraction pattern with defined peaks. Such
materials when heated sufficiently will also exhibit the properties
of a liquid, but the change from solid to liquid is characterized
by a phase change, typically first order ("melting point").
[0107] Compounds of Formula 1 may also exist in unsolvated and
solvated forms. The term "solvate" describes a molecular complex
comprising the compound and one or more pharmaceutically acceptable
solvent molecules (e.g., ethanol). The term "hydrate" is a solvate
in which the solvent is water. Pharmaceutically acceptable solvates
include those in which the solvent may be isotopically substituted
(e.g., D.sub.2O, acetone-d.sub.6, DMSO-d.sub.6).
[0108] A currently accepted classification system for solvates and
hydrates of organic compounds is one that distinguishes between
isolated site, channel, and metal-ion coordinated solvates and
hydrates. See, e.g., K. R. Morris (H. G. Brittain ed.) Polymorphism
in Pharmaceutical Solids (1995). Isolated site solvates and
hydrates are ones in which the solvent (e.g., water) molecules are
isolated from direct contact with each other by intervening
molecules of the organic compound. In channel solvates, the solvent
molecules lie in lattice channels where they are next to other
solvent molecules. In metal-ion coordinated solvates, the solvent
molecules are bonded to the metal ion.
[0109] When the solvent or water is tightly bound, the complex will
have a well-defined stoichiometry independent of humidity. When,
however, the solvent or water is weakly bound, as in channel
solvates and in hygroscopic compounds, the water or solvent content
will depend on humidity and drying conditions. In such cases,
non-stoichiometry will typically be observed.
[0110] Compounds of Formula 1 may also exist as multi-component
complexes (other than salts and solvates) in which the compound
(drug) and at least one other component are present in
stoichiometric or non-stoichiometric amounts. Complexes of this
type include clathrates (drug-host inclusion complexes) and
co-crystals. The latter are typically defined as crystalline
complexes of neutral molecular constituents which are bound
together through non-covalent interactions, but could also be a
complex of a neutral molecule with a salt. Co-crystals may be
prepared by melt crystallization, by recrystallization from
solvents, or by physically grinding the components together. See,
e.g., O. Almarsson and M. J. Zaworotko, Chem. Commun. (2004)
17:1889-1896. For a general review of multi-component complexes,
see J. K. Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.
[0111] When subjected to suitable conditions, compounds of Formula
1 may exist in a mesomorphic state (mesophase or liquid crystal).
The mesomorphic state lies between the true crystalline state and
the true liquid state (either melt or solution). Mesomorphism
arising as the result of a change in temperature is described as
"thermotropic" and mesomorphism resulting from the addition of a
second component, such as water or another solvent, is described as
"lyotropic." Compounds that have the potential to form lyotropic
mesophases are described as "amphiphilic" and include molecules
which possess a polar ionic moiety (e.g., --COO.sup.-Na.sup.+,
--COO.sup.-K.sup.+, --SO.sub.3.sup.-Na.sup.+) or polar non-ionic
moiety (such as --N.sup.-N.sup.+(CH.sub.3).sub.3). See, e.g., N. H.
Hartshorne and A. Stuart, Crystals and the Polarizing Microscope
(4th ed, 1970).
[0112] Each compound of Formula 1 may exist as polymorphs,
stereoisomers, tautomers, or some combination thereof, may be
isotopically-labeled, may result from the administration of a
prodrug, or form a metabolite following administration.
[0113] "Prodrugs" refer to compounds having little or no
pharmacological activity that can, when metabolized in vivo,
undergo conversion to compounds having desired pharmacological
activity. Prodrugs may be prepared by replacing appropriate
functionalities present in pharmacologically active compounds with
"pro-moieties" as described, for example, in H. Bundgaar, Design of
Prodrugs (1985). Examples of prodrugs include ester, ether or amide
derivatives of compounds of Formula 1 having carboxylic acid,
hydroxy, or amino functional groups, respectively. For further
discussions of prodrugs, see e.g., T. Higuchi and V. Stella
"Pro-drugs as Novel Delivery Systems," ACS Symposium Series 14
(1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design
(1987).
[0114] "Metabolites" refer to compounds formed in vivo upon
administration of pharmacologically active compounds. Examples
include hydroxymethyl, hydroxy, secondary amino, primary amino,
phenol, and carboxylic acid derivatives of compounds of Formula 1
having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and
amide groups, respectively.
[0115] Compounds of Formula 1 may exist as stereoisomers that
result from the presence of one or more stereogenic centers, one or
more double bonds, or both. The stereoisomers may be pure,
substantially pure, or mixtures. Such stereoisomers may also result
from acid addition or base salts in which the counter-ion is
optically active, for example, when the counter-ion is D-lactate or
L-lysine.
[0116] Compounds of Formula 1 may exist as tautomers, which are
isomers resulting from tautomerization. Examples of tautomeric
isomerism include imine-enamine, keto-enol, oxime-nitroso, and
amide-imidic acid tautomerism. The triazolone moiety of Formula 1
may exist, for example, in the following tautomeric forms:
##STR00004##
[0117] Compounds of Formula 1 may exhibit more than one type of
isomerism.
[0118] Geometrical (cis/trans) isomers may be separated by
conventional techniques such as chromatography and fractional
crystallization.
[0119] Conventional techniques for preparing or isolating a
compound having a specific stereochemical configuration include
chiral synthesis from a suitable optically pure precursor or
resolution of the racemate (or the racemate of a salt or
derivative) using, for example, chiral high pressure liquid
chromatography (HPLC). Alternatively, the racemate (or a racemic
precursor) may be reacted with a suitable optically active
compound, for example, an alcohol, or, in the case where the
compound of Formula 1 contains an acidic or basic moiety, an acid
or base such as tartaric acid or 1-phenylethylamine. The resulting
diastereomeric mixture may be separated by chromatography,
fractional crystallization, etc., and the appropriate
diastereoisomer converted to the compound having the requisite
stereochemical configuration. For a further discussion of
techniques for separating stereoisomers, see E. L. Eliel and S. H.
Wilen, Stereochemistry of Organic Compounds (1994).
[0120] Compounds of Formula 1 may possess isotopic variations, in
which at least one atom is replaced by an atom having the same
atomic number, but an atomic mass different from the atomic mass
usually found in nature. Isotopes suitable for inclusion in
compounds of Formula 1 include, for example, isotopes of hydrogen,
such as .sup.2H and .sup.3H; isotopes of carbon, such as .sup.11C,
.sup.13C and .sup.14C; isotopes of nitrogen, such as .sup.13N and
.sup.15N; isotopes of oxygen, such as .sup.15O, .sup.17O and
.sup.18O; isotopes of sulfur, such as .sup.35S; isotopes of
fluorine, such as .sup.18F; isotopes of chlorine, such as
.sup.36Cl, and isotopes of iodine, such as .sup.123I and .sup.125I.
Use of isotopic variations (e.g., deuterium, .sup.2H) may afford
certain therapeutic advantages resulting from greater metabolic
stability, for example, increased in vivo half-life or reduced
dosage requirements. Additionally, certain isotopic variations of
the disclosed compounds may incorporate a radioactive isotope
(e.g., tritium, .sup.3H, or .sup.14C), which may be useful in drug
and/or substrate tissue distribution studies. Substitution with
positron emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O
and .sup.13N, may be useful in Positron Emission Topography (PET)
studies for examining substrate receptor occupancy.
Isotopically-labeled compounds may be prepared by processes
analogous to those described elsewhere in the disclosure using an
appropriate isotopically-labeled reagent in place of a non-labeled
reagent.
[0121] The compounds of Formula 1 may be prepared using the
techniques described below. Some of the schemes and examples may
omit details of common reactions, including oxidations, reductions,
and so on, separation techniques (extraction, evaporation,
precipitation, chromatography, filtration, trituration,
crystallization, and the like), and analytical procedures, which
are known to persons of ordinary skill in the art of organic
chemistry. The details of such reactions and techniques can be
found in a number of treatises, including Richard Larock,
Comprehensive Organic Transformations (1999), and the multi-volume
series edited by Michael B. Smith and others, Compendium of Organic
Synthetic Methods (1974 et seq.). Starting materials and reagents
may be obtained from commercial sources or may be prepared using
literature methods. Some of the reaction schemes may omit minor
products resulting from chemical transformations (e.g., an alcohol
from the hydrolysis of an ester, CO.sub.2 from the decarboxylation
of a di-acid, etc.). In addition, in some instances, reaction
intermediates may be used in subsequent steps without isolation or
purification (i.e., in situ).
[0122] In some of the reaction schemes and examples below, certain
compounds may be prepared using protecting groups, which prevent
undesirable chemical reaction at otherwise reactive sites.
Protecting groups may also be used to enhance solubility or
otherwise modify physical properties of a compound. For a
discussion of protecting group strategies, a description of
materials and methods for installing and removing protecting
groups, and a compilation of useful protecting groups for common
functional groups, including amines, carboxylic acids, alcohols,
ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts,
Protecting Groups in Organic Chemistry (1999) and P. Kocienski,
Protective Groups (2000).
[0123] Generally, the chemical transformations described throughout
the specification may be carried out using substantially
stoichiometric amounts of reactants, though certain reactions may
benefit from using an excess of one or more of the reactants.
Additionally, many of the reactions disclosed throughout the
specification may be carried out at about room temperature (RT) and
ambient pressure, but depending on reaction kinetics, yields, and
so on, some reactions may be run at elevated pressures or employ
higher temperatures (e.g., reflux conditions) or lower temperatures
(e.g., -78.degree. C. to 0.degree. C.). Any reference in the
disclosure to a stoichiometric range, a temperature range, a pH
range, etc., whether or not expressly using the word "range," also
includes the indicated endpoints.
[0124] Many of the chemical transformations may also employ one or
more compatible solvents, which may influence the reaction rate and
yield. Depending on the nature of the reactants, the one or more
solvents may be polar protic solvents (including water), polar
aprotic solvents, non-polar solvents, or some combination.
Representative solvents include saturated aliphatic hydrocarbons
(e.g., n-pentane, n-hexane, n-heptane, n-octane); aromatic
hydrocarbons (e.g., benzene, toluene, xylenes); halogenated
hydrocarbons (e.g., methylene chloride, chloroform, carbon
tetrachloride); aliphatic alcohols (e.g., methanol, ethanol,
propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol,
butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol,
hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol,
2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol,
2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether,
di-isopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane,
1,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane,
1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane);
ketones (e.g., acetone, methyl ethyl ketone); esters (methyl
acetate, ethyl acetate); nitrogen-containing solvents (e.g.,
formamide, N,N-dimethylformamide, acetonitrile,
N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene);
sulfur-containing solvents (e.g., carbon disulfide, dimethyl
sulfoxide, tetrahydro-thiophene-1,1,-dioxide); and
phosphorus-containing solvents (e.g., hexamethylphosphoric
triamide).
[0125] In the schemes, below, substituent identifiers (e.g.,
R.sup.1, R.sup.2, R.sup.3, etc.) are as defined above for Formula
1. As mentioned earlier, however, some of the starting materials
and intermediates may include protecting groups, which are removed
prior to the final product. In such cases, the substituent
identifier refers to moieties defined in Formula 1 and to those
moieties with appropriate protecting groups. For example, a
starting material or intermediate in the schemes may include a
substituent identifier that is a moiety having a potentially
reactive amine. In such cases, the substituent identifier would
include the moiety with or without, say, a Boc or Cbz group
attached to the amine.
[0126] Schemes A and B depict general methods for preparing
compounds of Formula 1 in which L is --O-- or --N(R.sup.4e)--. As
shown in Scheme A, a dihalopyridine derivative (A1) is reacted with
an alcohol (A2) or an amine (A3) in the presence of a
nonnucleophilic or inorganic base (e.g., NaH, Et.sub.3N,
Cs.sub.2CO.sub.3, etc.). In Formula A1, X is halo (typically Cl or
Br), and in Formula A2 and A3, PG is an amine protective group,
such as Boc. The reaction is carried out in a compatible solvent
(e.g., NMP, DMF, THF, etc.) and at a temperature which may range
from RT to about 140.degree. C. The resulting intermediate (A4, in
which L.sup.1 is --O-- or --N(R.sup.4e)--) is reacted with zinc
cyanide in the presence of a palladium catalyst (e.g.,
Pd(PPh.sub.3).sub.4) and solvent (e.g., DMF, DMA, etc.) and at
elevated temperature (e.g., about 150-165.degree. C.). The
resulting nitrile (A5) is combined with ethyl hydrazinecarboxylate
in a compatible solvent (e.g., NMP) and is heated (e.g., at about
175.degree. C.) to give a triazolone intermediate (A6). Subsequent
removal of the amine protective group (e.g., via treatment with an
acid when PG is Boc) and reaction with an acyl chloride (A7) in the
presence of a nonnucleophilic base (e.g., 2,6-dimethylpyridine) and
a compatible solvent (e.g., DCM, NMP, DMSO, etc.) give the desired
compound of Formula 1A.
##STR00005##
[0127] Scheme B provides an alternative method for installing the
triazolone moiety. As in Scheme A, a dihalopyridine derivative (A1)
is reacted with an alcohol (A2) or an amine (A3) in the presence of
a nonnucleophilic or inorganic base, and the resulting intermediate
(A4) is reacted with zinc cyanide in the presence of a palladium
catalyst and solvent. In contrast to Scheme A, the resulting
nitrile (A5) is combined with hydrazine hydrate in a compatible
solvent (e.g., MeOH) and is heated at elevated temperature (e.g.,
reflux) to give a picolinimidohydrazide intermediate (B1). The
picolinimidohydrazide derivative (B1) is subsequently reacted with
1,1'-carbonyldiimidazole (CDI) in a compatible solvent (e.g.,
dioxane) and at elevated temperature (e.g., reflux) to give a
triazolone intermediate (A6). As in Scheme A, the protective group
(PG) is removed and the resulting amine (not shown) is reacted with
an acyl chloride (A7) in the presence of a nonnucleophilic base and
a compatible solvent to give the desired compound of Formula
1A.
##STR00006##
[0128] Scheme C depicts a general method for preparing compounds of
Formula 1 in which L is --CH.sub.2O--. As shown in Scheme C, a
picolinic acid derivative (C1) is reacted with methanol and
sulfuric acid at elevated temperature (e.g., about 65.degree. C.).
The resulting methyl picolinate derivative (C2) is activated via
treatment with m-chloroperoxybenzoic acid in a compatible solvent
(e.g., DCM) to give and N-oxide intermediate (C3) which is
subsequently reacted with phosphoryl trichloride at elevated
temperature (e.g., about 100.degree. C.). The resulting methyl
6-chloropicolinate derivative (C4) is treated with sodium
borohydride and methanol to give a (6-chloropyridin-2-yl)methanol
derivative (C5) which is reacted with zinc cyanide in the presence
of a palladium catalyst (e.g. Pd.sub.2(dba).sub.3), an optional
ligand (e.g., XPhos) and solvent (e.g., DMF, DMA, etc.) at elevated
temperature (e.g., about 150-165.degree. C.). The resulting
6-(hydroxymethyl)picolinonitrile derivative (C6) is reacted with
tribromophosphine in a compatible solvent (e.g., THF) to give a
brominated intermediate (C7) which is reacted with an alcohol (A2)
in the presence of a base to give a nitrile (C8) in which L.sup.2
is --CH.sub.2O--. As in Scheme A, the nitrile (C8) is combined with
ethyl hydrazinecarboxylate in a compatible solvent and is heated to
give a triazolone intermediate (C9). Subsequent removal of the
amine protective group and reaction with an acyl chloride (A7) in
the presence of a nonnucleophilic base and a compatible solvent
gives the desired compound of Formula 1B.
##STR00007##
[0129] The methods depicted in Schemes A, B, and C may be varied as
desired. For example, additional protecting groups may be added or
removed at various steps in the routes. The intermediates may be
further elaborated via, for example, alkylation, acylation,
hydrolysis, oxidation, reduction, amidation, sulfonation,
alkynation, and the like to give the desired final product.
Furthermore, any racemic intermediate may be optionally purified by
chiral column chromatography (e.g., supercritical fluid
chromatography) or by derivatization with optically-pure reagents
as described above, to give a desired stereoisomer.
[0130] Compounds of Formula 1, which include compounds named in the
examples, and their pharmaceutically acceptable complexes, salts,
solvates and hydrates, should be assessed for their
biopharmaceutical properties, such as solubility and solution
stability across pH, permeability, and the like, to select an
appropriate dosage form and route of administration. Compounds that
are intended for pharmaceutical use may be administered as
crystalline or amorphous products, and may be obtained, for
example, as solid plugs, powders, or films by methods such as
precipitation, crystallization, freeze drying, spray drying,
evaporative drying, microwave drying, or radio frequency
drying.
[0131] Compounds of Formula 1 may be administered alone or in
combination with one another or with one or more pharmacologically
active compounds which are different than the compounds of Formula
1. Generally, one or more these compounds are administered as a
pharmaceutical composition (a formulation) in association with one
or more pharmaceutically acceptable excipients. The choice of
excipients depends on the particular mode of administration, the
effect of the excipient on solubility and stability, and the nature
of the dosage form, among other things. Useful pharmaceutical
compositions and methods for their preparation may be found, for
example, in A. R. Gennaro (ed.), Remington: The Science and
Practice of Pharmacy (20th ed., 2000).
[0132] Compounds of Formula 1 may be administered orally. Oral
administration may involve swallowing in which case the compound
enters the bloodstream via the gastrointestinal tract.
Alternatively or additionally, oral administration may involve
mucosal administration (e.g., buccal, sublingual, supralingual
administration) such that the compound enters the bloodstream
through the oral mucosa.
[0133] Formulations suitable for oral administration include solid,
semi-solid and liquid systems such as tablets; soft or hard
capsules containing multi- or nano-particulates, liquids, or
powders; lozenges which may be liquid-filled; chews; gels; fast
dispersing dosage forms; films; ovules; sprays; and buccal or
mucoadhesive patches. Liquid formulations include suspensions,
solutions, syrups and elixirs. Such formulations may be employed as
fillers in soft or hard capsules (made, e.g., from gelatin or
hydroxypropylmethylcellulose) and typically comprise a carrier
(e.g., water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil) and one or more emulsifying
agents, suspending agents or both. Liquid formulations may also be
prepared by the reconstitution of a solid (e.g., from a
sachet).
[0134] Compounds of Formula 1 may also be used in fast-dissolving,
fast-disintegrating dosage forms such as those described in Liang
and Chen, Expert Opinion in Therapeutic Patents (2001)
11(6):981-986.
[0135] For tablet dosage forms, depending on dose, the active
pharmaceutical ingredient (API) may comprise from about 1 wt % to
about 80 wt % of the dosage form or more typically from about 5 wt
% to about 60 wt % of the dosage form. In addition to the API,
tablets may include one or more disintegrants, binders, diluents,
surfactants, glidants, lubricants, anti-oxidants, colorants,
flavoring agents, preservatives, and taste-masking agents. Examples
of disintegrants include sodium starch glycolate, sodium
carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl
cellulose, microcrystalline cellulose, C.sub.1-6 alkyl-substituted
hydroxypropylcellulose, starch, pregelatinized starch, and sodium
alginate. Generally, the disintegrant will comprise from about 1 wt
% to about 25 wt % or from about 5 wt % to about 20 wt % of the
dosage form.
[0136] Binders are generally used to impart cohesive qualities to a
tablet formulation. Suitable binders include microcrystalline
cellulose, gelatin, sugars, polyethylene glycol, natural and
synthetic gums, polyvinylpyrrolidone, pregelatinized starch,
hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets
may also contain diluents, such as lactose (monohydrate,
spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose,
sucrose, sorbitol, microcrystalline cellulose, starch and dibasic
calcium phosphate dihydrate.
[0137] Tablets may also include surface active agents, such as
sodium lauryl sulfate and polysorbate 80, and glidants such as
silicon dioxide and talc. When present, surface active agents may
comprise from about 0.2 wt % to about 5 wt % of the tablet, and
glidants may comprise from about 0.2 wt % to about 1 wt % of the
tablet.
[0138] Tablets may also contain lubricants such as magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
and mixtures of magnesium stearate with sodium lauryl sulfate.
Lubricants may comprise from about 0.25 wt % to about 10 wt % or
from about 0.5 wt % to about 3 wt % of the tablet.
[0139] Tablet blends may be compressed directly or by roller
compaction to form tablets. Tablet blends or portions of blends may
alternatively be wet-, dry-, or melt-granulated, melt congealed, or
extruded before tableting. If desired, prior to blending one or
more of the components may be sized by screening or milling or
both. The final dosage form may comprise one or more layers and may
be coated, uncoated, or encapsulated. Exemplary tablets may contain
up to about 80 wt % of API, from about 10 wt % to about 90 wt % of
binder, from about 0 wt % to about 85 wt % of diluent, from about 2
wt % to about 10 wt % of disintegrant, and from about 0.25 wt % to
about 10 wt % of lubricant. For a discussion of blending,
granulation, milling, screening, tableting, coating, as well as a
description of alternative techniques for preparing drug products,
see A. R. Gennaro (ed.), Remington: The Science and Practice of
Pharmacy (20th ed., 2000); H. A. Lieberman et al. (ed.),
Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2d ed., 1990); and
D. K. Parikh & C. K. Parikh, Handbook of Pharmaceutical
Granulation Technology, Vol. 81 (1997).
[0140] Consumable oral films for human or veterinary use are
pliable water-soluble or water-swellable thin film dosage forms
which may be rapidly dissolving or mucoadhesive. In addition to the
API, a typical film includes one or more film-forming polymers,
binders, solvents, humectants, plasticizers, stabilizers or
emulsifiers, viscosity-modifying agents, and solvents. Other film
ingredients may include anti-oxidants, colorants, flavorants and
flavor enhancers, preservatives, salivary stimulating agents,
cooling agents, co-solvents (including oils), emollients, bulking
agents, anti-foaming agents, surfactants, and taste-masking agents.
Some components of the formulation may perform more than one
function.
[0141] In addition to dosing requirements, the amount of API in the
film may depend on its solubility. If water soluble, the API would
typically comprise from about 1 wt % to about 80 wt % of the
non-solvent components (solutes) in the film or from about 20 wt %
to about 50 wt % of the solutes in the film. A less soluble API may
comprise a greater proportion of the composition, typically up to
about 88 wt % of the non-solvent components in the film.
[0142] The film-forming polymer may be selected from natural
polysaccharides, proteins, or synthetic hydrocolloids and typically
comprises from about 0.01 wt % to about 99 wt % or from about 30 wt
% to about 80 wt % of the film.
[0143] Film dosage forms are typically prepared by evaporative
drying of thin aqueous films coated onto a peelable backing support
or paper, which may carried out in a drying oven or tunnel (e.g.,
in a combined coating-drying apparatus), in lyophilization
equipment, or in a vacuum oven.
[0144] Useful solid formulations for oral administration may
include immediate release formulations and modified release
formulations. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted-, and
programmed-release. For a general description of suitable modified
release formulations, see U.S. Pat. No. 6,106,864. For details of
other useful release technologies, such as high energy dispersions
and osmotic and coated particles, see Verma et al, Pharmaceutical
Technology On-line (2001) 25(2):1-14.
[0145] Compounds of Formula 1 may also be administered directly
into the blood stream, muscle, or an internal organ of the subject.
Suitable techniques for parenteral administration include
intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial,
intramuscular, intrasynovial, and subcutaneous administration.
Suitable devices for parenteral administration include needle
injectors, including microneedle injectors, needle-free injectors,
and infusion devices.
[0146] Parenteral formulations are typically aqueous solutions
which may contain excipients such as salts, carbohydrates and
buffering agents (e.g., pH of from about 3 to about 9). For some
applications, however, compounds of Formula 1 may be more suitably
formulated as a sterile non-aqueous solution or as a dried form to
be used in conjunction with a suitable vehicle such as sterile,
pyrogen-free water. The preparation of parenteral formulations
under sterile conditions (e.g., by lyophilization) may be readily
accomplished using standard pharmaceutical techniques.
[0147] The solubility of compounds which are used in the
preparation of parenteral solutions may be increased through
appropriate formulation techniques, such as the incorporation of
solubility-enhancing agents. Formulations for parenteral
administration may be formulated to be immediate or modified
release. Modified release formulations include delayed, sustained,
pulsed, controlled, targeted, and programmed release. Thus,
compounds of Formula 1 may be formulated as a suspension, a solid,
a semi-solid, or a thixotropic liquid for administration as an
implanted depot providing modified release of the active compound.
Examples of such formulations include drug-coated stents and
semi-solids and suspensions comprising drug-loaded
poly(DL-lactic-coglycolic)acid (PGLA) microspheres.
[0148] Compounds of Formula 1 may also be administered topically,
intradermally, or transdermally to the skin or mucosa. Typical
formulations for this purpose include gels, hydrogels, lotions,
solutions, creams, ointments, dusting powders, dressings, foams,
films, skin patches, wafers, implants, sponges, fibers, bandages
and microemulsions. Liposomes may also be used. Typical carriers
may include alcohol, water, mineral oil, liquid petrolatum, white
petrolatum, glycerin, polyethylene glycol and propylene glycol.
Topical formulations may also include penetration enhancers. See,
e.g., Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).
[0149] Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and
microneedle or needle-free (e.g. Powderject.TM. and Bioject.TM.)
injection. Formulations for topical administration may be
formulated to be immediate or modified release as described
above.
[0150] Compounds of Formula 1 may also be administered intranasally
or by inhalation, typically in the form of a dry powder, an aerosol
spray, or nasal drops. An inhaler may be used to administer the dry
powder, which comprises the API alone, a powder blend of the API
and a diluent, such as lactose, or a mixed component particle that
includes the API and a phospholipid, such as phosphatidylcholine.
For intranasal use, the powder may include a bioadhesive agent,
e.g., chitosan or cyclodextrin. A pressurized container, pump,
sprayer, atomizer, or nebulizer, may be used to generate the
aerosol spray from a solution or suspension comprising the API, one
or more agents for dispersing, solubilizing, or extending the
release of the API (e.g., EtOH with or without water), one or more
solvents (e.g., 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane) which serve as a propellant, and
an optional surfactant, such as sorbitan trioleate, oleic acid, or
an oligolactic acid. An atomizer using electrohydrodynamics may be
used to produce a fine mist.
[0151] Prior to use in a dry powder or suspension formulation, the
drug product is usually comminuted to a particle size suitable for
delivery by inhalation (typically 90% of the particles, based on
volume, having a largest dimension less than 5 microns). This may
be achieved by any appropriate size reduction method, such as
spiral jet milling, fluid bed jet milling, supercritical fluid
processing, high pressure homogenization, or spray drying.
[0152] Capsules, blisters and cartridges (made, for example, from
gelatin or hydroxypropylmethyl cellulose) for use in an inhaler or
insufflator may be formulated to contain a powder mixture of the
active compound, a suitable powder base such as lactose or starch,
and a performance modifier such as L-leucine, mannitol, or
magnesium stearate. The lactose may be anhydrous or monohydrated.
Other suitable excipients include dextran, glucose, maltose,
sorbitol, xylitol, fructose, sucrose, and trehalose.
[0153] A suitable solution formulation for use in an atomizer using
electrohydrodynamics to produce a fine mist may contain from about
1 .mu.g to about 20 mg of the API per actuation and the actuation
volume may vary from about 1 .mu.L to about 100 .mu.L. A typical
formulation may comprise one or more compounds of Formula 1,
propylene glycol, sterile water, EtOH, and NaCl. Alternative
solvents, which may be used instead of propylene glycol, include
glycerol and polyethylene glycol.
[0154] Formulations for inhaled administration, intranasal
administration, or both, may be formulated to be immediate or
modified release using, for example, PGLA. Suitable flavors, such
as menthol and levomenthol, or sweeteners, such as saccharin or
sodium saccharin, may be added to formulations intended for
inhaled/intranasal administration.
[0155] In the case of dry powder inhalers and aerosols, the dosage
unit is determined by means of a valve that delivers a metered
amount. Units are typically arranged to administer a metered dose
or "puff" containing from about 10 .mu.g to about 1000 .mu.g of the
API. The overall daily dose will typically range from about 100
.mu.g to about 10 mg which may be administered in a single dose or,
more usually, as divided doses throughout the day.
[0156] The active compounds may be administered rectally or
vaginally, e.g., in the form of a suppository, pessary, or enema.
Cocoa butter is a traditional suppository base, but various
alternatives may be used as appropriate. Formulations for rectal or
vaginal administration may be formulated to be immediate or
modified release as described above.
[0157] Compounds of Formula 1 may also be administered directly to
the eye or ear, typically in the form of drops of a micronized
suspension or solution in isotonic, pH-adjusted, sterile saline.
Other formulations suitable for ocular and aural administration
include ointments, gels, biodegradable implants (e.g. absorbable
gel sponges, collagen), non-biodegradable implants (e.g. silicone),
wafers, lenses, and particulate or vesicular systems, such as
niosomes or liposomes. The formulation may include one or more
polymers and a preservative, such as benzalkonium chloride. Typical
polymers include crossed-linked polyacrylic acid, polyvinylalcohol,
hyaluronic acid, cellulosic polymers (e.g.,
hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl
cellulose), and heteropolysaccharide polymers (e.g., gelan gum).
Such formulations may also be delivered by iontophoresis.
Formulations for ocular or aural administration may be formulated
to be immediate or modified release as described above.
[0158] To improve their solubility, dissolution rate,
taste-masking, bioavailability, or stability, compounds of Formula
1 may be combined with soluble macromolecular entities, including
cyclodextrin and its derivatives and polyethylene glycol-containing
polymers. For example, API-cyclodextrin complexes are generally
useful for most dosage forms and routes of administration. Both
inclusion and non-inclusion complexes may be used. As an
alternative to direct complexation with the API, the cyclodextrin
may be used as an auxiliary additive, i.e. as a carrier, diluent,
or solubilizer. Alpha-, beta- and gamma-cyclodextrins are commonly
used for these purposes. See, e.g., WO 91/11172, WO 94/02518, and
WO 98/55148.
[0159] As noted above, one or more compounds of Formula 1,
including compounds specifically named in the examples, and their
pharmaceutically active complexes, salts, solvates and hydrates,
may be combined with each other or with one or more other active
pharmaceutically active compounds to treat various diseases,
disorders or conditions. In such cases, the active compounds may be
combined in a single dosage form as described above or may be
provided in the form of a kit which is suitable for
coadministration of the compositions. The kit comprises (1) two or
more different pharmaceutical compositions, at least one of which
contains a compound of Formula 1; and (2) a device for separately
retaining the two pharmaceutical compositions, such as a divided
bottle or a divided foil packet. An example of such a kit is the
familiar blister pack used for the packaging of tablets or
capsules. The kit is suitable for administering different types of
dosage forms (e.g., oral and parenteral) or for administering
different pharmaceutical compositions at separate dosing intervals,
or for titrating the different pharmaceutical compositions against
one another. To assist with patient compliance, the kit typically
comprises directions for administration and may be provided with a
memory aid.
[0160] For administration to human patients, the total daily dose
of the claimed and disclosed compounds is typically in the range of
about 0.1 mg to about 3000 mg depending on the route of
administration. For example, oral administration may require a
total daily dose of from about 1 mg to about 3000 mg, while an
intravenous dose may only require a total daily dose of from about
0.1 mg to about 300 mg. The total daily dose may be administered in
single or divided doses and, at the physician's discretion, may
fall outside of the typical ranges given above. Although these
dosages are based on an average human subject having a mass of
about 60 kg to about 70 kg, the physician will be able to determine
the appropriate dose for a patient (e.g., an infant) whose mass
falls outside of this weight range.
[0161] As noted above, the compounds of Formula 1 may be used to
treat diseases, disorders or conditions for which inhibition of BTK
is indicated. Such diseases, disorders or conditions generally
relate to any unhealthy or abnormal state in a subject for which
the inhibition of BTK provides a therapeutic benefit. More
particularly, such diseases, disorders or conditions may involve
the immune system and inflammation, including Type I
hypersensitivity (allergic) reactions (allergic rhinitis, allergic
asthma, and atopic dermatitis); autoimmune diseases (rheumatoid
arthritis, multiple sclerosis, systemic lupus erythematosus,
psoriasis, lupus nephritis, immune thrombocytopenic purpura,
Sjogren's syndrome, ankylosing spondylitis, and Behcet's disease);
inflammatory bowel disease; inflammation of the lung (chronic
obstructive pulmonary disease), atherosclerosis, thrombosis, and
myocardial infarction. The compounds of Formula 1 may also be used
to treat diseases, disorders or conditions related to abnormal cell
growth, including hematological malignancies, such as acute myeloid
leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma
(e.g., mantle cell lymphoma), T-cell lymphoma (e.g., peripheral
T-cell lymphoma), and multiple myeloma, as well as epithelial
cancers (i.e., carcinomas), such as lung cancer (small cell lung
cancer and non-small cell lung cancer), pancreatic cancer, and
colon cancer.
[0162] In addition to the hematological malignancies and epithelial
cancers noted above, the compounds of Formula 1 may also be used to
treat other types of cancer, including leukemia (chronic
myelogenous leukemia and chronic lymphocytic leukemia); breast
cancer, genitourinary cancer, skin cancer, bone cancer, prostate
cancer, and liver cancer; brain cancer; cancer of the larynx, gall
bladder, rectum, parathyroid, thyroid, adrenal, neural tissue,
bladder, head, neck, stomach, bronchi, and kidneys; basal cell
carcinoma, squamous cell carcinoma, metastatic skin carcinoma,
osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's
sarcoma; myeloma, giant cell tumor, islet cell tumor, acute and
chronic lymphocytic and granulocytic tumors, hairy-cell tumor,
adenoma, medullary carcinoma, pheochromocytoma, mucosal neuromas,
intestinal ganglioneuromas, hyperplastic corneal nerve tumor,
marfanoid habitus tumor, Wilms' tumor, seminoma, ovarian tumor,
leiomyomater tumor, cervical dysplasia, neuroblastoma,
retinoblastoma, myelodysplastic syndrome, rhabdomyosarcoma,
astrocytoma, non-Hodgkin's lymphoma, malignant hypercalcemia,
polycythermia vera, adenocarcinoma, glioblastoma multiforma,
glioma, lymphomas, and malignant melanomas, among others.
[0163] In addition to cancer, the compounds of Formula 1 may also
be used to treat other diseases, disorders or conditions related to
abnormal cell growth, including non-malignant proliferative
diseases such as benign prostatic hypertrophy, restinosis,
hyperplasia, synovial proliferation disorder, idiopathic
plasmacytic lymphadenopathy, retinopathy or other neovascular
disorders of the eye, among others.
[0164] The compounds of Formula 1 may also be used to treat
autoimmune diseases, disorders or conditions in addition to those
listed above. Such diseases, disorders or conditions include Crohns
disease, dermatomyositis, diabetes mellitus type 1, Goodpasture's
syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's
disease, mixed connective tissue damage, myasthenia gravis,
narcolepsy, pemphigus vulgaris, pernicious anemia, polymyositis,
primary biliary cirrhosis, temporal arteritis, ulcerative colitis,
vasculitis, and Wegener's granulomatosis, among others.
[0165] The compounds of Formula 1 may be used to treat inflammatory
diseases, disorders or conditions including asthma, chronic
inflammation, chronic prostatitis, glomerulonephritis,
hypersensitivities, inflammatory bowel diseases (ulcerative colitis
in addition to Crohn's disease), pelvic inflammatory disease,
reperfusion injury, transplant rejection, vasculitis, and systemic
inflammatory response syndrome.
[0166] The compounds of Formula 1 may also be used to treat
specific diseases or conditions that may fall within one or more
general disorders described above, including arthritis. In addition
to rheumatoid arthritis, Sjogren's syndrome, systemic lupus
erythematosus, SLE in children and adolescents, compounds of
Formula 1 may also be used to treat other arthritis diseases,
including ankylosing spondylitis, avascular necrosis, Behcet's
disease, bursitis, calcium pyrophosphate dihyrate crystal
deposition disease (pseudo gout), carpal tunnel syndrome,
Ehlers-Danlos syndrome, fibromyalgia, Fifth disease, giant cell
arteritis, gout, juvenile dermatomyositis, juvenile rheumatoid
arthritis, juvenile spondyloarthopathy, Lyme disease, Marfan
syndrome, myositis, osteoarthritis, osteogenesis imperfect,
osteoporosis, Paget's disease, psoriatic arthritis, Raynaud's
phenomenon, reactive arthritis, reflex sympathetic dystrophy
syndrome, scleroderma, spinal stenosis, Still's disease, and
tendinitis, among others.
[0167] The claimed and disclosed compounds may be combined with one
or more other pharmacologically active compounds or therapies for
the treatment of one or more diseases, disorders or conditions for
which BTK is indicated, including those involving the immune
system, inflammation, and abnormal cell growth. For example,
compounds of Formula 1, which include compounds specifically named
in the examples, and their pharmaceutically acceptable complexes,
salts, solvates and hydrates, may be administered simultaneously,
sequentially or separately in combination with one or more
compounds or therapies for treating arthritis, including rheumatoid
arthritis and osteoarthritis, or for treating cancer, including
hematological malignancies, such as acute myeloid leukemia, B-cell
chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma,
multiple myeloma, and carcinomas, such as lung cancer, pancreatic
cancer, and colon cancer. Such combinations may offer significant
therapeutic advantages, including fewer side effects, improved
ability to treat underserved patient populations, or synergistic
activity.
[0168] For example, when used to treat arthritis, the compounds of
Formula 1 may be combined with one or more nonsteroidal
anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids,
biological response modifiers, and protein-A immunoadsorption
therapy. Alternatively or additionally, when treating rheumatoid
arthritis, the compounds of Formula 1 may be combined with one or
more disease modifying antirheumatic drugs (DMARDs), and when
treating osteoarthritis, the compounds of Formula 1 may be combined
with one or more osteoporosis agents.
[0169] Representative NSAIDs include apazone, aspirin, celecoxib,
diclofenac (with and without misoprostol), diflunisal, etodolac,
fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
meclofenamate sodium, mefenamic acid, meloxicam, nabumetone,
naproxen, oxaprozin, phenylbutazone, piroxicam, choline and
magnesium salicylates, salsalate, and sulindac. Representative
analgesics include acetaminophen and morphine sulfate, as well as
codeine, hydrocodone, oxycodone, propoxyphene, and tramadol, all
with or without acetaminophen. Representative corticosteroids
include betamethasone, cortisone acetate, dexamethasone,
hydrocortisone, methylprednisolone, prednisolone, and prednisone.
Representative biological response modifiers include TNF-.alpha.
inhibitors, such as adalimumab, etanercept, and infliximab;
selective B-cell inhibitors, such as rituximab; IL-1 inhibitors,
such as anakinra, and selective costimulation modulators, such as
abatacept.
[0170] Representative DMARDs include auranofin (oral gold),
azathioprine, chlorambucil, cyclophosamide, cyclosporine, gold
sodium thiomalate (injectable gold), hydroxychloroquine,
leflunomide, methotrexate, minocycline, myophenolate mofetil,
penicillamine, sulfasalazine, and JAK3 inhibitor (e.g.,
tofacitinib). Representative osteoporosis agents include
bisphosphonates, such as alendronate, ibandronate, risedronate, and
zoledronic acid; selective estrogen receptor modulators, such as
droloxifene, lasofoxifene, and raloxifene; hormones, such as
calcitonin, estrogens, and parathyroid hormone; and
immunosuppressant agents such as azathioprine, cyclosporine, and
rapamycin.
[0171] Particularly useful combinations for treating rheumatoid
arthritis include a compound of Formula 1 and methotrexate; a
compound of Formula 1 and one or more biological response
modifiers, such as lefluonomide, etanercept, adalimumab, and
infliximab; or a compound of Formula 1, methotrexate, and one or
more biological response modifiers, such as lefluonomide,
etanercept, adalimumab, and infliximab.
[0172] For the treatment of thrombis and restensosis, the compounds
of Formula 1 may be combined with one or more cardiovascular agents
such as calcium channel blockers, statins, fibrates, beta-blockers,
ACE inhibitors, and platelet aggregation inhibitors.
[0173] The compounds of Formula 1 may also be combined with one or
more compounds or therapies for treating cancer. These include
chemotherapeutic agents (i.e., cytotoxic or antineoplastic agents)
such as alkylating agents, antibiotics, antimetabolic agents,
plant-derived agents, and topoisomerase inhibitors, as well as
molecularly targeted drugs which block the growth and spread of
cancer by interfering with specific molecules involved in tumor
growth and progression. Molecularly targeted drugs include both
small molecules and biologics.
[0174] Representative alkylating agents include
bischloroethylamines (nitrogen mustards, e.g., chlorambucil,
cyclophosphamide, ifosfamide, mechlorethamine, melphalan, and
uracil mustard); aziridines (e.g., thiotepa); alkyl alkone
sulfonates (e.g., busulfan); nitrosoureas (e.g., carmustine,
lomustine, and streptozocin); nonclassical alkylating agents (e.g.,
altretamine, dacarbazine, and procarbazine); and platinum compounds
(e.g., carboplatin, cisplatin, nedaplatin, oxaliplatin,
satraplatin, and triplatin tetranitrate).
[0175] Representative antibiotic agents include anthracyclines
(e.g., aclarubicin, amrubicin, daunorubicin, doxorubicin,
epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin);
anthracenediones (e.g., mitoxantrone and pixantrone); and
streptomyces (e.g., actinomycin, bleomycin, dactinomycin, mitomycin
C, and plicamycin).
[0176] Representative antimetabolic agents include dihydrofolate
reductase inhibitors (e.g., aminopterin, methotrexate, and
pemetrexed); hymidylate synthase inhibitors (e.g., raltitrexed and
pemetrexed); folinic acid (e.g., leucovorin); adenosine deaminase
inhibitors (e.g., pentostatin); halogenated/ribonucleotide
reductase inhibitors (e.g., cladribine, clofarabine, and
fludarabine); thiopurines (e.g., thioguanine and mercaptopurine);
thymidylate synthase inhibitors (e.g., fluorouracil, capecitabine,
tegafur, carmofur, and floxuridine); DNA polymerase inhibitors
(e.g., cytarabine); ribonucleotide reductase inhibitors (e.g.,
gemcitabine); hypomethylating agent (e.g., azacitidine and
decitabine); and ribonucleotide reductase inhibitor (e.g.,
hydroxyurea); and an asparagine depleter (e.g., asparaginase)
[0177] Representative plant-derived agents include vinca alkaloids
(e.g., vincristine, vinblastine, vindesine, vinzolidine, and
vinorelbine), podophyllotoxins (e.g., etoposide and teniposide),
and taxanes (e.g., docetaxel, larotaxel, ortataxel, paclitaxel, and
tesetaxel).
[0178] Representative type I topoisomerase inhibitors include
camptothecins, such as belotecan, irinotecan, rubitecan, and
topotecan. Representative type II topoisomerase inhibitors include
amsacrine, etoposide, etoposide phosphate, and teniposide, which
are derivatives of epipodophyllotoxins.
[0179] Molecularly targeted therapies include biologic agents such
as cytokines and other immune-regulating agents. Useful cytokines
include interleukin-2 (IL-2, aldesleukin), interleukin 4 (IL-4),
interleukin 12 (IL-12), and interferon, which includes more than 23
related subtypes. Other cytokines include granulocyte colony
stimulating factor (CSF) (e.g., filgrastim) and granulocyte
macrophage colony stimulating factor (GM-CSF or CSF2) (e.g.,
sargramostim, namimulab). Other immuno-modulating agents include
bacillus Calmette-Guerin, levamisole, and octreotide; monoclonal
antibodies against tumor antigens, such as trastruzumab and
rituximab; and cancer vaccines, which induce an immune response to
tumors.
[0180] In addition, molecularly targeted drugs that interfere with
specific molecules involved in tumor growth and progression include
inhibitors of epidermal growth factor (EGF), transforming growth
factor-alpha (TGF.sub..alpha.), TGF.sub..beta., heregulin,
insulin-like growth factor (IGF), fibroblast growth factor (FGF),
keratinocyte growth factor (KGF), colony stimulating factor (CSF),
erythropoietin (EPO), interleukin-2 (IL-2), nerve growth factor
(NGF), platelet-derived growth factor (PDGF), hepatocyte growth
factor (HGF), vascular endothelial growth factor (VEGF),
angiopoietin, epidermal growth factor receptor (EGFR), human
epidermal growth factor receptor 2 (HER2), HER4, insulin-like
growth factor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1
receptor (FGF1R), FGF2R, FGF3R, FGF4R, vascular endothelial growth
factor receptor (VEGFR), tyrosine kinase with immunoglobulin-like
and epidermal growth factor-like domains 2 (Tie-2),
platelet-derived growth factor receptor (PDGFR), Abl, Bcr-Abl, Raf,
FMS-like tyrosine kinase 3 (FLT3), c-Kit, Src, protein kinase c
(PKC), tropomyosin receptor kinase (Trk), Ret, mammalian target of
rapamycin (mTOR), Aurora kinase, polo-like kinase (PLK), mitogen
activated protein kinase (MAPK), mesenchymal-epithelial transition
factor (c-MET), cyclin-dependant kinase (CDK), Akt, extracellular
signal-regulated kinases (ERK), poly(ADP) ribose polymerase (PARP),
and the like.
[0181] Specific molecularly targeted drugs include selective
estrogen receptor modulators, such as tamoxifen, toremifene,
fulvestrant, and raloxifene; antiandrogens, such as bicalutamide,
nilutamide, megestrol, and flutamide; and aromatase inhibitors,
such as exemestane, anastrozole, and letrozole. Other specific
molecularly targeted drugs include agents which inhibit signal
transduction, such as imatinib, dasatinib, nilotinib, trastuzumab,
gefitinib, erlotinib, cetuximab, lapatinib, panitumumab, and
temsirolimus; agents that induce apoptosis, such as bortezomib;
agents that block angiogenesis, such as bevacizumab, sorafenib, and
sunitinib; agents that help the immune system destroy cancel cells,
such as rituximab and alemtuzumab; and monoclonal antibodies which
deliver toxic molecules to cancer cells, such as gemtuzumab
ozogamicin, tositumomab, 131I-tositumoab, and ibritumomab
tiuxetan.
[0182] Biological Activity
[0183] The activity of compounds as BTK inhibitors may be
determined by a variety of methods, including in vitro and in vivo
methods. The following in vitro assay measures a test compound's
ability to inhibit BTK-mediated phosphorylation of a FAM-labeled
substrate, 5-FAM-EEPLYWSFPAKKK-NH.sub.2.
[0184] Purified BTK may be obtained as follows (Clone SBVC-1603_9P
is used). A cDNA sequence encoding residues 382 to 659 of human BTK
is cloned into the vector pSXB4. This construct engineers an
in-frame translational fusion with the Glutathione-S-Transferase
(GST) protein for use in affinity purification. The fusion protein
derived from this construct contains a protease recognition
sequence to liberate the BTK from the GST affinity tag. High-titer
baculoviral stocks, generated using the Bac-to-Bac.RTM. system
(Invitrogen), are used to express the recombinant protein in
Spodoptera frugiperda Sf9 cells in 10 L Wave bags. Recombinant
proteins are isolated from cellular extracts by passage over
Glutathione Sepharose 4B (GE Healthcare) and the BTK moiety is
released from the GST affinity tag by treatment with PreScission
protease. The BTK recombinant protein is further purified by size
exclusion chromatography (HiLoad 16/60 Superdex 200, GE Healthcare)
in a buffer containing 20 mM Hepes (pH 7.4), 50 mM NaCl, 10 mM
MgCl.sub.2, 0.25 mM TCEP and 0.1 mM EDTA. The purity of the
fractions is assessed by SDS PAGE and the peak protein fractions
are pooled and concentrated using Amicon Ultra-15 Centrifugal
Filter Devices (Millipore).
[0185] The inhibitory properties of compounds relative to BTK is
determined using a black 384-well-plate format in a buffer which
contains 50 mM Hepes, 10 mM NaCl, 10 mM MgCl.sub.2, 0.2 mM EDTA,
0.1% Brij35.RTM., 1 mM DTT, and 0.1 mg/mL BSA at pH 7.3. The test
compound is prepared in DMSO using 2-fold serial dilutions for 11
data points, which are added to the buffer so that each dilution
contains 3% DMSO. To initiate the assay, 5 .mu.L of 3 .mu.M
5FAM-EEPLYWSFPAKKK-NH.sub.2 (in buffer), 5 .mu.L of diluted test
compound (3% DMSO in buffer), and 5 .mu.L of 9 nM BTK and 150 .mu.M
ATP in buffer are combined in each well. The reaction mixtures are
incubated at room temperature for 60 minutes and then quenched by
adding 25 .mu.L of 50 mM EDTA. To quantify the fluorescent-labeled
substrate and product following reaction, the test plate is loaded
on a Caliper LC-3000, which measures percent of conversion by
microfluidic-based separation. Corresponding IC.sub.50 values are
calculated by non-linear curve fitting of the compound
concentrations and percent of inhibition to the standard IC.sub.50
equation and reported as pIC.sub.50, i.e., -log(IC.sub.50), where
IC.sub.50 is molar concentration at 50% inhibition.
EXAMPLES
[0186] The following examples are intended to be illustrative and
non-limiting, and represent specific embodiments of the present
invention.
[0187] .sup.1H Nuclear magnetic resonance (NMR) spectra were
obtained for many of the compounds in the following examples.
Characteristic chemical shifts (.delta.) are given in
parts-per-million downfield from tetramethylsilane using
conventional abbreviations for designation of major peaks,
including s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). The following abbreviations are used
for common solvents: CDCl.sub.3 (deuterochloroform), DMSO-d.sub.6
(deuterodimethylsulfoxide), CD.sub.3OD (deuteromethanol),
CD.sub.3CN (deuteroacetonitrile), and THF-d.sub.8
(deuterotetrahydrofuran). The mass spectra (M+H) were recorded
using either electrospray ionization (ESI-MS) or atmospheric
pressure chemical ionization (APCI-MS).
[0188] Where indicated, products of certain preparations and
examples are purified by mass-triggered HPLC (Pump: Waters.TM.
2525; MS: ZQ.TM.; Software: MassLynx.TM.), flash chromatography or
preparative thin layer chromatography (TLC). Reverse phase
chromatography is typically carried out on a column (e.g.,
Gemini.TM. 5 .mu.m C18 110 .ANG., Axia.TM., 30.times.75 mm, 5
.mu.m) under acidic conditions ("acid mode") eluting with ACN and
water mobile phases containing 0.035% and 0.05% trifluoroacetic
acid (TFA), respectively, or under basic conditions ("basic mode")
eluting with water and 20/80 (v/v) water/acetonitrile mobile
phases, both containing 10 mM NH.sub.4HCO.sub.3. Preparative TLC is
typically carried out on silica gel 60 F.sub.254 plates. After
isolation by chromatography, the solvent is removed and the product
is obtained by drying in a centrifugal evaporator (e.g.,
GeneVac.TM.), rotary evaporator, evacuated flask, etc. Reactions in
an inert (e.g., nitrogen) or reactive (e.g., H.sub.2) atmosphere
are typically carried out at a pressure of about 1 atmosphere (14.7
psi).
Preparation x1:
(R)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
##STR00008##
[0189] Step A: (R)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00009##
[0191] A mixture of (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (496 mg, 2.65 mmol) in NMP (4
mL) at 0.degree. C. was treated with NaH (106 mg, 2.65 mmol) and
stirred for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (500
mg, 2.65 mmol) was added and the reaction mixture was stirred at RT
for 15 minutes and then heated at 140.degree. C. for 15 minutes in
a microwave reactor. The crude reaction mixture, which contained
the title compound, was used directly in the next step.
Step B: (R)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrro-
lidine-1-carboxylate
##STR00010##
[0193] To crude (R)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate was added
ethyl hydrazinecarboxylate (1.104 g, 10.60 mmol). The reaction
mixture was heated at 175.degree. C. overnight and was subsequently
cooled and diluted with EtOAc. The organic phase was washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated to give the
title compound, which was used directly in the next step.
Step C:
(R)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(-
4H)-one
[0194] To crude (R)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrro-
lidine-1-carboxylate was added a minimal amount of NMP and TFA (2
mL). The solution was stirred at RT for 10 minutes and
concentrated. The crude product was purified by preparative HPLC
eluting with a gradient of 15-22% ACN in water (acid mode) to give
the title compound (229 mg, 29% over 3 steps).
Preparation x2: (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00011##
[0196] A mixture of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate
(434 mg, 2.333 mmol) in NMP (2.5 mL) at 0.degree. C. was treated
with NaH (93 mg, 2.333 mmol) and stirred for 1 hour. Next,
1-chloroisoquinoline-3-carbonitrile (400 mg, 2.121 mmol) was added
and the reaction mixture was stirred at RT for 15 minutes and then
heated at 140.degree. C. for 15 minutes in a microwave reactor. The
crude reaction mixture, which contained the title compound, was
used without further purification. ESI-MS m/z [M+H].sup.+
339.4.
Preparation x3:
(S)-3-(1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-o-
ne
##STR00012##
[0198] STEP A: (S)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyr-
rolidine-1-carboxylate
##STR00013##
[0199] To a crude reaction mixture containing (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (717
mg) was added NMP (2 mL) and ethyl hydrazinecarboxylate (883 mg,
8.484 mmol). The reaction mixture was heated at 175.degree. C.
overnight and was subsequently cooled, diluted with EtOAc, and
washed with aqueous NH.sub.4Cl. The organic layer was separated and
concentrated to give the title compound, which was used directly in
the next step.
Step B:
(S)-3-(1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol--
5(4H)-one
[0200] To crude (S)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyr-
rolidine-1-carboxylate was added DCM (3 mL) and TFA (1 mL). The
mixture was stirred for 1 hour and concentrated. The crude product
was purified by preparative HPLC eluting with a gradient of 5-30%
ACN in water (acid mode) to give the title compound (8 mg).
Preparation x4: 1-(bromomethyl)isoquinoline-3-carbonitrile
##STR00014##
[0201] Step A: Methyl isoquinoline-1-carboxylate
##STR00015##
[0203] To a solution of isoquinoline-1-carboxylic acid (10 g, 57.74
mmol) in MeOH (150 mL) was added concentrated sulfuric acid (15 mL)
at 0.degree. C. The mixture was warmed to 65.degree. C. and stirred
at 65.degree. C. for 24 hours. After cooling to RT, the reaction
mixture was partitioned between DCM and saturated aqueous
NaHCO.sub.3. The organic layer was separated and dried over
Na.sub.2SO.sub.4, and the solvent was evaporated under reduced
pressure to give the title compound as a yellow oil (11.2 g, 100%).
ESI-MS m/z [M+H].sup.+ 188.
Step B: 1-(methoxycarbonyl)isoquinoline 2-oxide
##STR00016##
[0205] To a suspension of methyl isoquinoline-1-carboxylate (11.2
g, 59.8 mmol) in DCM (150 mL) was added 3-chloroperoxybenzoic acid
(15.5 g, 89.7 mmol) at 0.degree. C. The mixture was warmed to RT
and was stirred at RT for 24 hours. The reaction was quenched with
saturated aqueous NaHCO.sub.3 and the mixture was extracted with
DCM. The organic layer was separated and dried over
Na.sub.2SO.sub.4, and the solvent was evaporated under reduced
pressure. The crude product was purified by silica gel
chromatography eluting with petroleum ether and EtOAc (1:1) to give
the title compound as a white solid (9.5 g, 78%). ESI-MS m/z
[M+H].sup.+ 204.
Step C: Methyl 3-chloroisoquinoline-1-carboxylate
##STR00017##
[0207] A mixture of 1-(methoxycarbonyl)isoquinoline 2-oxide (9.5 g,
46.75 mmol) and POCl.sub.3 (50 mL) was heated at 100.degree. C. for
4 hours. The reaction mixture was subsequently cooled and
concentrated, and the crude product was purified by silica gel
chromatography eluting with petroleum ether and EtOAc (15:1) to
give the title compound as a white solid (5.1 g, 49%). ESI-MS m/z
[M+H].sup.+ 222.
Step D: (3-chloroisoquinolin-1-yl)methanol
##STR00018##
[0209] To a solution of methyl 3-chloroisoquinoline-1-carboxylate
(5.1 g, 23.0 mmol) in MeOH (50 mL) was added NaBH.sub.4 (2.17 g,
57.5 mmol). The reaction mixture was stirred at RT for 2 hours. The
reaction was quenched with saturated aqueous NH.sub.4Cl and the
mixture was extracted with EtOAc. The organic layer was separated
and dried over Na.sub.2SO.sub.4, and the solvent was evaporated
under reduced pressure to give the title compound as a yellow solid
(3.94 g, 88%). ESI-MS m/z [M+H].sup.+ 194.
Step E: 1-(hydroxymethyl)isoquinoline-3-carbonitrile
##STR00019##
[0211] A suspension of (3-chloroisoquinolin-1-yl)methanol (1.0 g,
5.17 mmol), zinc cyanide (672 mg, 5.68 mmol), Pd.sub.2(dba).sub.3
(190 mg, 0.21 mmol), XPhos (241 mg, 0.52 mmol) in DMF (15 mL) was
heated at 150.degree. C. for 1 hour under a nitrogen atmosphere in
a microwave reactor. The reaction mixture was subsequently diluted
with water and extracted with EtOAc. The organic layer was
separated and dried over Na.sub.2SO.sub.4, and the solvent was
evaporated under reduced pressure. The crude product was purified
by silica gel chromatography eluting with petroleum ether and EtOAc
(4:1) to give the title compound as a yellow solid (330 mg, 34%).
ESI-MS m/z [M+H].sup.+ 185.1.
Step F: 1-(bromomethyl)isoquinoline-3-carbonitrile
[0212] A suspension of 1-(hydroxymethyl)isoquinoline-3-carbonitrile
(0.150 g, 0.814 mmol) in THF (0.8 mL) and treated with PBr.sub.3
(0.814 mL, 0.814 mmol). The reaction mixture was stirred at RT for
2 hours, then poured over ice and neutralized with saturated
aqueous NaHCO.sub.3. The mixture was warmed to RT and extracted
with EtOAc (20 mL). The organic phase was separated, dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give the title
compound as a yellow solid. The crude product was dried under high
vacuum and used without further purification (0.15 g, 75%). ESI-MS
m/z [M+H].sup.+ 247.5.
Preparation x5: 1-chloro-8-fluoroisoquinoline-3-carbonitrile
##STR00020##
[0213] Step A: methyl 2-bromo-6-fluorobenzoate
##STR00021##
[0215] To a solution 2-bromo-6-fluorobenzoic acid (50 g, 0.229 mol)
and potassium carbonate (31.6 g, 0.229 mol) in
N,N-dimethylformamide (250 mL) was added dropwise methyl iodide
(51.83 g, 0.365 mol) over a 30 minute period. The reaction mixture
was stirred at RT for 3.5 hours. The resulting mixture was diluted
with water (500 mL) and extracted with EtOAc (3.times.300 mL). The
combined organic layers were washed with 1M aqueous HCl (100 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure to give the title compound (53 g,
99.7%).
Step B: methyl 2-fluoro-6-vinylbenzoate
##STR00022##
[0217] To a solution of methyl 2-bromo-6-fluorobenzoate (53 g,
0.228 mol) and potassium trifluoro(vinyl)borate (33.63 g, 0.251
mol) in dioxane and H.sub.2O (3:1, 600 mL) was added
Pd(dppf)Cl.sub.2 (5 g, 6.84 mmol) and sodium carbonate (69 g, 0.684
mol) at RT. The reaction mixture was heated at 100.degree. C. for
12 hours under a nitrogen atmosphere. The mixture was concentrated
in vacuo, diluted with water, and extracted with EtOAc (3.times.200
mL). The combined organic layers were washed with brine, dried over
anhydrous Na.sub.2CO.sub.3, filtered, and concentrated. The crude
product was purified by column chromatography eluting with a
gradient of EtOAc (1-100%) and PE to give the title compound (31.4
g, 76.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.45-7.36
(m, 2H), 7.03-7.02 (m, 1H), 6.88-6.81 (m, 1H), 5.77-5.73 (m, 1H),
5.41-5.39 (d, J=10.8 Hz, 1H), 3.95 (s, 3H).
Step C: methyl 2-fluoro-6-formylbenzoate
##STR00023##
[0219] Into a solution of methyl 2-fluoro-6-vinylbenzoate (31 g,
0.172 mol) in dry dichloromethane (300 mL) was bubbled O.sub.3 at
-78.degree. C. over a 30 minute period. Next, nitrogen gas was
bubbled into the solution until it turned colorless.
Dimethylsulfane (84.13 g, 1.36 mol) was added dropwise to the
solution, which was subsequently warmed to RT and stirred for 2
hours. The mixture was then washed with water (30 mL) and extracted
with DCM (3.times.300 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified by column chromatography eluting with a gradient of EtOAc
(10-100%) and PE to give the title compound (21 g, 67%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 10.01 (s, 1H), 7.65-7.63 (d,
J=7.6 Hz, 1H), 7.56-7.53 (dd, J.sub.1=5.2 Hz, J.sub.2=8.0 Hz, 1H),
7.35-7.30 (t, J=8.4 Hz, 1H), 3.94 (s, 3H).
Step D: (Z)-methyl
2-fluoro-6-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)
benzoate
##STR00024##
[0221] This step was performed in five separate batches. For each
batch, a solution of methyl 2-fluoro-6-formylbenzoate (3 g, 16.5
mmol), 2-benzamidoacetic acid (3.6, 20 mmol) and sodium acetate
(1.62 g, 19.7 mmol) in acetic anhydride (30 mL) was heated at
100.degree. C. in a microwave reactor (100 W, 150 psi) under
nitrogen atmosphere for 2 hours. The reaction mixtures were diluted
with EtOAc (100 mL) and washed with saturated aqueous
Na.sub.2CO.sub.3. The combined organic layers were concentrated in
vacuo to give the title compound as a brown solid, which was used
without further purification (15 g). ESI-MS m/z [M+H].sup.+
326.2.
Step E: methyl
8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate
##STR00025##
[0223] A solution of crude (Z)-methyl
2-fluoro-6-((5-oxo-2-phenyloxazol-4(5R)-ylidene)methyl) benzoate
(15 g) and potassium hydroxide (2.58 g, 46 mmol) in acetic
anhydride (150 mL) was heated at 100.degree. C. for 2 hours. The
solvent was removed in vacuo, and the residue was diluted with
water (30 mL). The resulting mixture was neutralized with 1M
aqueous HCl (100 mL) and filtered. The solids were dried in vacuo
to give 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4
g, ESI-MS m/z [M+H].sup.+ 208.0) which was converted to the methyl
ester as described, below. The filtrate was concentrated under
reduced pressure to give crude product which was purified by column
chromatography eluting with a gradient of EtOAc (30-100%) and PE to
give a first batch of the title compound (2 g, 19.6%). ESI-MS m/z
[M+H].sup.+ =222.1.
[0224] To a solution of
8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4 g, 19.3
mmol) in MeOH (100 mL) was added SOCl.sub.2 (20 mL) at 0.degree. C.
The reaction mixture was stirred at RT for 30 minutes and then
heated to reflux for 5 hours. The reaction mixture was subsequently
concentrated in vacuo. The crude product was purified by column
chromatography eluting with petroleum ether and ethyl acetate
(PE/EtOAc=1:1-1:2 gradient) to give a second batch of the title
compound (3 g, 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 11.19 (s, 1H), 7.79-7.71 (m, 2H), 7.42-7.38 (m, 2H), 3.89 (s,
3H).
Step F: 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide
##STR00026##
[0226] To a vessel containing NH.sub.3/MeOH (140 mL) was added
methyl 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (5 g,
15 mmol). The vessel was sealed and the solution was stirred at RT
for 30 minutes and then heated to reflux for 2 hours. The reaction
mixture was concentrated in vacuo to give the title compound, which
was used without further purification (5 g, 85%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 10.26 (s, 1H), 8.32 (s, 1H), 7.92
(s, 1H), 7.82-7.81 (m, 1H), 7.61-7.59 (d, J=8.0 Hz, 1H), 7.41-7.35
(m, 1H).
Step G: 1-chloro-8-fluoroisoquinoline-3-carbonitrile
[0227] A solution of
8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (5 g, 5.5
mmol) in POCl.sub.3(46.23 g) was heated to reflux for 4 hours and
was subsequently concentrated in vacuo. The crude product was
purified by column chromatography eluting with petroleum ether and
ethyl acetate (PE/EtOAc=5:1-2:1 gradient) to give the title
compound (3.2 g, 35%). ESI-MS m/z [M+H].sup.+ 207.1.
Preparation x6: 1,7-dichloroisoquinoline-3-carbonitrile
##STR00027##
[0228] Step A: methyl 5-chloro-2-vinylbenzoate
##STR00028##
[0230] A stirred suspension of methyl 2-bromo-5-chlorobenzoate (10
g, 40.08 mmol), potassium trifluoro(vinyl)borate (8.05 g, 60.12
mmol), Pd(dppf)Cl.sub.2 (1.64 g, 2.0 mmol) and sodium carbonate
(8.5 g, 80.16 mmol) in dioxane (150 mL) and water (15 mL) was
refluxed for 8 hours under a nitrogen atmosphere. After cooling to
RT, the mixture was filtered, concentrated, and the crude product
was purified by column chromatography eluting with petroleum ether
and ethyl acetate (PE/EtOAc=100:1-50:1 gradient) to give the title
compound (31.4 g, 76.4%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 7.80 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.31-7.39 (m,
2H), 5.57 (d, J=17.6 Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 3.83 (s,
3H).
Step B: methyl 5-chloro-2-formylbenzoate
##STR00029##
[0232] Into a solution of methyl 5-chloro-2-vinylbenzoate (16.3 g,
82.89 mmol) in dry DCM (250 mL) was bubbled O.sub.3 at -78.degree.
C. over a 30 minute period. Next, nitrogen gas was bubbled into the
solution until it turned colorless. Dimethylsulfane (10.3 g, 165.79
mmol) was added dropwise. The resulting mixture was warmed to RT,
stirred for 2 hours, and concentrated. The crude product was
purified by silica gel column chromatography eluting with petroleum
ether and ethyl acetate (PE/EtOAc=40:1) to give the title compound
as a white solid (10 g, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 10.52 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.0
Hz, 1H), 7.55 (dd, J=8.0 Hz and 2.0 Hz, 1H), 3.93 (s, 3H).
Step C: ethyl
7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate
##STR00030##
[0234] To a stirred mixture of NaH (1.81 g, 30.3 mmol) in DMF (20
mL) was added a solution of methyl 5-chloro-2-formylbenzoate (5.0
g, 25 mmol) and ethyl 2-isocyanoacetate (2.85 g, 25 mmol) in DMF
(60 mL) at 40.degree. C. over a 20 minute period. The reaction
mixture was stirred at 20.degree. C. for 2 hours. Its pH was
adjusted to 7.0 with acetic acid (10%) and the mixture was
extracted with DCM (3.times.200 mL). The organic layers were
combined, washed with brine (200 mL), dried over Na.sub.2SO.sub.4,
and concentrated. The crude product was purified by silica gel
column chromatography eluting with petroleum ether and ethyl
acetate (PE/EtOAc=15:1-5:1 gradient) to give the title compound
(2.0 g, 31%). ESI-MS m/z [M+H].sup.+ 252.1.
Step D: 7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide
##STR00031##
[0236] Ethyl 7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate
(580 mg, 2.30 mmol) was dissolved in NH.sub.3/MeOH (4.0M, 15 mL)
and the reaction mixture was stirred at RT overnight. The solvent
was removed in vacuo. The resulting residue was washed with
petroleum ether and dried to give the title compound (200 mg, 38%).
ESI-MS m/z [M+1-1].sup.+223.1.
Step E: 1,7-dichloroisoquinoline-3-carbonitrile
[0237] A solution of
7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (550 mg, 2.46
mmol) in POCl.sub.3(10 mL) was heated to reflux for 6 hours. The
solvent was subsequently removed in vacuo and the crude product was
purified by column chromatography eluting with petroleum ether and
ethyl acetate (PE/EA=30:1) to give the title compound (450 mg,
81.8%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.35 (d,
J=1.6 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.80 (dd,
J=1.6 Hz and 8.0 Hz, 1H).
Preparation x7: 1,8-dichloroisoquinoline-3-carbonitrile
##STR00032##
[0238] Step A: methyl 2-bromo-6-chlorobenzoate
##STR00033##
[0240] To a solution 2-bromo-6-chlorobenzoic acid (9.5 g, 0.041
mol) and potassium carbonate (8.6 g, 0.061 mol) in
N,N-dimethylformamide (50 mL) was added methyl iodide (11.2 g,
0.081 mol) dropwise over a 10 minute period. The reaction mixture
was stirred at RT for 3.5 hours and was subsequently diluted with
water (500 mL). The aqueous phase was back-extracted with EtOAc
(3.times.300 mL). The organic layers were combined, washed with 1M
HCl aq (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure to give the title compound
(10.0 g, 99.4%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.413 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.137 (t, J=8 Hz, 1H),
3.9 (s, 3H).
Step B: methyl 2-chloro-6-vinylbenzoate
##STR00034##
[0242] To a solution of methyl 2-bromo-6-chlorobenzoate (7.5 g,
0.03 mol) and potassium trifluoro(vinyl)borate (6.07 g, 0.045 mol)
in dioxane and H.sub.2O (10:1, 100 mL) was added Pd(dppf)Cl.sub.2
(739 mg, 0.906 mmol), and sodium carbonate (6.4 g, 0.06 mol) at RT.
The reaction mixture was heated at 100.degree. C. for 12 hours
under a nitrogen atmosphere. The mixture was subsequently
concentrated in vacuo and diluted with water. The aqueous phase was
extracted with EtOAc (3.times.100 mL). The organic layers were
combined, washed with brine, dried over anhydrous Na.sub.2CO.sub.3,
filtered, and concentrated. The crude product was purified by
column chromatography eluting with a gradient of EtOAc (0-90%) and
PE to give the title compound (6.7 g, 85%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.39-7.41 (m, 1H), 7.22-7.26 (m, 2H),
6.55-6.62 (m, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.31 (d, J=11.2 Hz,
1H).
Step C: methyl 2-chloro-6-formylbenzoate
##STR00035##
[0244] Into a solution of methyl 2-chloro-6-vinylbenzoate (6.7 g,
34 mmol) in dry DCM (100 mL) was bubbled O.sub.3 at -78.degree. C.
over a 30 minute period. Next, nitrogen gas was bubbled into the
solution until the solution was colorless. Dimethylsulfane (4.3 g,
68 mmol) was added dropwise and the resulting mixture was warmed to
RT and stirred for 2 hours. The reaction mixture was subsequently
washed with water (30 mL) and extracted with DCM (3.times.100 mL).
The organic layers were combined, dried over Na.sub.2SO.sub.4, and
concentrated. The crude product was purified by column
chromatography eluting with a gradient of EtOAc (0-90%) and PE to
give the title compound (3.8 g, 56%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 9.89 (s, 1H), 7.728 (d, J=7.2 Hz, 1H),
7.606 (d, J=8.0 Hz, 1H), 7.489 (t, J=8.0 Hz, 1H), 3.95 (s, 3H).
Step D: ethyl
8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate
##STR00036##
[0246] To a solution of NaH (652.8 mg, 16.32 mmol) in DMF (20 mL)
was added methyl 2-chloro-6-formylbenzoate (2.7 g, 13.6 mmol) and
ethyl 2-isocyanoacetate (1.55 g, 13.6 mmol) in DMF (5 mL) at
40.degree. C. over a 20 minute period. The reaction mixture was
stirred at 20.degree. C. for an additional 30 minutes. The reaction
mixture was subsequently diluted with EtOAc (100 mL) and washed
with saturated aqueous Na.sub.2CO.sub.3. The organic phase was
concentrated in vacuo. The crude product was purified by column
chromatography eluting with a gradient of EtOAc (0-90%) and PE to
give the title compound (0.5 g, 15.6%). ESI-MS m/z [M+H].sup.+
252.1.
Step E: 8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide
##STR00037##
[0248] To a vessel containing NH.sub.3/MeOH (10 mL) was added ethyl
8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (500 mg, 1.99
mmol). The vessel was sealed and the resulting solution was stirred
at RT for 1 hour. The reaction mixture was subsequently
concentrated in vacuo to give the title compound, which was used
without further purification (0.5 g, 98%). ESI-MS m/z [M+H].sup.+
223.1.
Step F: 1,8-dichloroisoquinoline-3-carbonitrile
[0249] A solution of
8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (0.5 g, 1.99
mmol) in POCl.sub.3 (10 mL) was heated to reflux for 4 hours. The
reaction mixture was subsequently concentrated in vacuo and the
crude product was purified by column chromatography eluting with
petroleum ether and ethyl acetate (PE/EtOAc=5:1-2:1 gradient) to
give the title compound (200 mg, 40%). ESI-MS m/z [M+H].sup.+
223.1.
Preparation x8: 1-chloro-8-methoxyisoquinoline-3-carbonitrile
##STR00038##
[0250] Step A: methyl 2-bromo-6-methoxybenzoate
##STR00039##
[0252] To a mixture of 2-bromo-6-methoxybenzoic acid (40 g, 0.176
mol) in DMF (300 mL) was added K.sub.2CO.sub.3 (24.8 g, 0.176 mol)
and CH.sub.3I (37 g, 0.264 mol). The mixture was stirred at RT
overnight. The reaction was quenched with 1M HCl aq and the mixture
was extracted with EtOAc (3.times.300 mL). The organic phase was
dried over MgSO.sub.4 and concentrated in vacuo to give the title
compound (41 g, 99%).
Step B: methyl 2-methoxy-6-vinylbenzoate
##STR00040##
[0254] To a mixture of methyl 2-bromo-6-methoxybenzoate (30 g, 0.12
mol) and potassium trifluoro(vinyl)borate (18 g, 0.13 mol) in
dioxane and H.sub.2O (5:1, 360 mL) was added Pd(dppf)Cl.sub.2 (2.63
g, 0.0036 mol) and Na.sub.2CO.sub.3 (25.4 g, 0.24 mol) at RT. The
reaction mixture was heated at 100.degree. C. for 12 hours under a
nitrogen atmosphere. The mixture was subsequently concentrated in
vacuo, diluted with water, and extracted with EtOAc (3.times.100
mL). The organic layers were combined, washed with brine, dried
over anhydrous Na.sub.2CO.sub.3, filtered, and concentrated. The
crude product was purified by column chromatography eluting with a
gradient of petroleum ether (1-2%) and EtOAc to give the title
compound (22 g, 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.33 (t, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz,
1H), 6.67 (dd, J=11.0, 17.4 Hz, 1H), 5.75 (d, J=17.4 Hz, 1H), 5.35
(d, J=11.0 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H); ESI-MS m/z
[M+H].sup.+ 193.
Step C: methyl 2-formyl-6-methoxybenzoate
##STR00041##
[0256] Into a solution of methyl 2-methoxy-6-vinylbenzoate (22 g,
0.11 mol) in anhydrous DCM (400 mL) was bubbled O.sub.3 at
-78.degree. C. over a 30 minute period. Next, nitrogen gas was
bubbled into the solution until it turned colorless.
Dimethylsulfane (20 mL) was added dropwise and the resulting
mixture was warmed to RT and stirred for 2 hours. The mixture was
washed with water (30 mL) and the aqueous layer was extracted with
DCM (3.times.100 mL). The organic layers were combined, dried over
Na.sub.2SO.sub.4, and concentrated. The crude product was purified
by column chromatography eluting with a gradient of EtOAc (0-90%)
and PE to give the title compound (11.8 g, 53.6%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 9.97 (s, 1H), 7.56 (t, J=8.0 Hz, 1H),
7.47 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.98 (s, 3H), 3.90
(s, 3H).
Step D: (Z)-methyl
2-methoxy-6-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)benzoate
##STR00042##
[0258] To a solution of methyl 2-formyl-6-methoxybenzoate (1.6 g,
8.24 mmol) in acetic anhydride (10 mL) was added 2-benzamidoacetic
acid (1.77 g, 9.88 mmol) and NaOAc (810 mg, 9.88 mmol). The mixture
was heated at 100.degree. C. in a microwave reactor. The reactant
mixture was partitioned between EtOAc (30 mL) and H.sub.2O (50 mL).
The organic layer was washed with saturated aqueous
Na.sub.2CO.sub.3 (5.times.30 mL), dried over Na.sub.2SO.sub.4, and
concentrated to give the title compound (7 g). ESI-MS m/z
[M+H].sup.+ 338.1.
Step E: methyl
8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylate
##STR00043##
[0260] To a solution of (Z)-methyl
2-methoxy-6-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)benzoate
(4.2 g, 12.45 mmol) in MeOH (50 mL) was added KOH (2.1 g, 37.35
mmol). The reaction mixture was heated to reflux for 1 hour. The
solvent was subsequently removed and the residue was partitioned
between water (30 mL) and EtOAc (20 mL). The aqueous layer was
extracted with EtOAc (3.times.20 mL). The organic layers were
combined, concentrated in vacuo, adjusted to pH=3 with a 4M
solution of HCl in MeOH, and concentrated. The resulting brown
solid which was purified by column chromatography eluting with
petroleum ether and ethyl acetate (PE/EtOAc=5:1-1:1 gradient) to
give the title compound (1 g, 26.3% over 2 steps). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.55 (s, 1H), 7.58 (t, 1H, J=8.0 Hz),
7.12 (d, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.0 Hz), 6.67 (s, 1H), 4.01
(s, 3H).
Step F: 8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxamide
##STR00044##
[0262] To a vessel containing NH.sub.3/MeOH (20 mL) was added
methyl 8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (800
mg, 3.43 mmol). The vessel was sealed and the solution was stirred
at 50.degree. C. for 16 hours. The reaction mixture was
subsequently concentrated in vacuo to give the title compound,
which was used without further purification (800 mg). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.22 (s, 1H), 7.80 (s, 1H),
7.66 (t, 1H, J=8.0 Hz), 7.19-7.22 (m, 2H), 7.09 (d, J=8.0 Hz, 1H),
3.85 (s, 3H); ESI-MS m/z [M+H].sup.+ 219.
Step G: 1-chloro-8-methoxyisoquinoline-3-carbonitrile
[0263] A solution of
8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (800 mg, 3.66
mmol) in POCl.sub.3 (40 mL) was heated to reflux for 1 hour. The
reaction mixture was subsequently concentrated in vacuo to give the
title compound (660 mg, 82%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.98 (s, 1H), 7.78 (t, 1H, J=8.0 Hz), 7.48 (d, 1H,
J=8.0 Hz), 7.20 (d, 1H, J=8.0 Hz), 4.05 (s, 3H); ESI-MS m/z
[M+H].sup.+ 219.
Example 1:
(R)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)--
1H-1,2,4-triazol-5(4H)-one
##STR00045##
[0265] To a solution of
(R)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(30 mg, 0.101 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(0.023 mL, 0.202 mmol) at 0.degree. C. followed by methacryloyl
chloride (21.10 mg, 0.202 mmol). The reaction mixture was stirred
at RT overnight, which resulted in little conversion of the
starting material. The reaction mixture was subsequently treated
with excess 2,6-dimethylpyridine and methacryloyl chloride, stirred
for 30 minutes, and concentrated. The residue was treated with MeOH
and the crude product purified by preparative HPLC eluting with a
gradient of 25-45% ACN in water (acid mode) to give a TFA salt of
the title compound (6 mg, 16%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
(rotamers were observed) .delta. ppm 1.83 (s, 1.5H), 1.89 (s,
1.5H), 2.10-2.75 (m, 2H), 3.50-4.24 (m, 4H), 5.10-5.40 (m, 2H),
6.14 (d, J=12.38 Hz, 1H), 7.62-7.70 (m, 1H), 7.81 (t, J=7.58 Hz,
1H), 7.98 (s, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.11-8.22 (m, 1H),
11.80 (s, 1H), 12.04 (d, J=14.40 Hz, 1H); ESI-MS m/z [M+H].sup.+
366.5.
Example 2:
(R)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1-
,2,4-triazol-5(4H)-one
##STR00046##
[0267] To a solution of
(R)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(11 mg, 0.037 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(5.80 .mu.L, 0.050 mmol) at 0.degree. C. followed by acryloyl
chloride (8.08 .mu.L, 0.100 mmol). The reaction mixture was stirred
at RT overnight, forming a white solid. The solids were filtered
and dried to give the title compound (4 mg, 23%). .sup.1H NMR (400
MHz, CD.sub.3CN) .delta. ppm 2.22-2.51 (m, 2H), 3.09-3.17 (m, 1H),
3.68-3.91 (m, 2H), 3.94 (br s, 1H), 4.06 (d, J=12.13 Hz, 1H),
5.60-5.76 (m, 1H), 5.98 (br s, 1H), 6.06 (br s, 1H), 7.47-7.62 (m,
1H), 7.62-7.74 (m, 1H), 7.79 (d, J=7.58 Hz, 1H), 7.92 (d, J=3.79
Hz, 1H), 8.15 (d, J=8.08 Hz, 1H); ESI-MS m/z
[M+1-1].sup.+352.0.
Example 3:
(R,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)oxy)isoquinolin-3-y-
l)-1H-1,2,4-triazol-5(4H)-one
##STR00047##
[0269] To a solution of
(R)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(30 mg, 0.101 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(0.016 mL, 0.136 mmol) at 0.degree. C. followed by (E)-but-2-enoyl
chloride (28.5 mg, 0.273 mmol). The reaction mixture was stirred at
RT overnight, which resulted in little conversion of the starting
material. The reaction mixture was subsequently treated with excess
2,6-dimethylpyridine and (E)-but-2-enoyl chloride, stirred for 30
minutes, and concentrated. The reaction was quenched with MeOH and
the crude product purified by preparative HPLC eluting with a
gradient of 25-45% ACN in water (acid mode) to give a TFA salt of
the title compound (10 mg, 20%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (rotamers were observed) .delta. ppm 1.81 (d, J=1.52
Hz, 1.5H), 1.86 (d, J=1.52 Hz, 1.5H), 2.19-2.70 (m, 2H), 3.59-4.11
(m, 4H), 6.14 (m, 0.5H), 6.22 (m, 0.5H), 6.27 (dd, J=15.16 Hz, 1.77
Hz, 0.5H), 6.37 (dd, J=15.16, 1.77 Hz, 0.5H), 6.63-6.77 (m, 1H),
7.61-7.70 (m, 1H), 7.77-7.84 (m, 1H), 7.99 (d, J=3.03 Hz, 1H), 8.02
(d, J=9.09 Hz, 1H), 8.16 (d, J=8.34 Hz, 1H), 11.80 (br s, 1H),
12.05 (d, J=4.04 Hz, 1H); ESI-MS m/z [M+H].sup.+ 366.5.
Example 4:
N-(1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1--
yl)pyrrolidin-3-yl)acrylamide
##STR00048##
[0270] Step A: tert-butyl
(1-(3-cyanoisoquinolin-1-yl)pyrrolidin-3-yl)carbamate
##STR00049##
[0272] A mixture of 1-chloroisoquinoline-3-carbonitrile (438 mg,
2.322 mmol), tert-butyl pyrrolidin-3-ylcarbamate (519 mg, 2.79
mmol) and Et.sub.3N (0.653 mL, 4.64 mmol) in NMP (3 mL) was heated
at 160.degree. C. for 30 minutes in a microwave reactor. The crude
reaction mixture, which contained the title compound, was used
directly in the next step.
Step B:
3-(1-(3-aminopyrrolidin-1-yl)isoquinolin-3-yl)-1H-1,2,4-triazol-5(-
4H)-one
##STR00050##
[0274] To a crude reaction mixture containing tert-butyl
(1-(3-cyanoisoquinolin-1-yl)pyrrolidin-3-yl)carbamate (786 mg) was
added ethyl hydrazinecarboxylate (242 mg, 2.323 mmol) in NMP (5
mL). The resulting suspension was heated at 175.degree. C.
overnight and was subsequently cooled, diluted with MeOH, and
filtered. The crude product was purified using mass-triggered HPLC
eluting with a gradient of 20-45% ACN in water (acid mode). The
product-containing fractions were concentrated to give the title
compound (117 mg, 17.0% over 2 steps). ESI-MS m/z [M+H].sup.+
297.5.
Step C:
N-(1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
pyrrolidin-3-yl)acrylamide
[0275] To a solution of tert-butyl
(1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)pyrrolidi-
n-3-yl)carbamate (80 mg, 0.202 mmol) in DCM (3 mL) was added
2,6-dimethylpyridine (0.023 mL, 0.202 mmol) at 0.degree. C.
followed by acryloyl chloride (0.033 mL, 0.404 mmol). The reaction
mixture was stirred at RT overnight and was subsequently
concentrated and partition between EtOAc and water. The organic
phase was dried over Na.sub.2SO.sub.4, concentrated, and filtered.
The crude product was purified using mass-triggered HPLC eluting
with a gradient of 15-40% ACN in water (acid mode). The
product-containing fractions were concentrated to give a TFA salt
of the title compound (1 mg, 1.4%). .sup.1H NMR (400 MHz, CD3OD)
.delta. ppm 3.45 (br s, 1H), 3.61 (br s, 1H), 3.85 (br s, 1H), 4.03
(br s, 1H), 4.13 (br s, 1H), 4.28 (br s, 1H), 4.58 (br s, 1H), 5.67
(br s, 1H), 6.27 (br s, 2H), 7.56 (br s, 1H), 7.66 (br s, 2H), 7.82
(br s, 1H), 8.33 (br s, 1H); ESI-MS m/z [M+H].sup.+ 351.4.
Example 5:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1-
,2,4-triazol-5 (4H)-one
##STR00051##
[0276] Step A: (S)-tert-butyl
3-((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00052##
[0278] To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.134
g, 6.06 mmol) in NMP (10 mL) at 0.degree. C. was added NaH (60%)
(202 mg, 5.05 mmol). The mixture was stirred for 5 minutes and
1,3-dichloroisoquinoline (1.000 g, 5.05 mmol) was added. The
reaction mixture was stirred at RT for 5 minutes and then heated at
135.degree. C. for 30 minutes in a microwave reactor. The mixture
was diluted with water (400 mL) and extracted with EtOAc
(3.times.125 mL). The organic layers were combined, washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The crude product was purified by silica column
chromatography eluting with a gradient of 25-50% EtOAc in hexane to
give the title compound (5.29 g, 75%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 1.40 (d, J=14.16 Hz, 9H), 2.12-2.34 (m,
2H), 3.42-3.58 (m, 3H), 3.69 (td, J=12.33, 4.64 Hz, 1H), 5.63-5.76
(m, 1H), 7.59 (s, 1H), 7.64 (ddd, J=8.30, 7.08, 1.22 Hz, 1H), 7.81
(td, J=7.57, 1.46 Hz, 1H), 7.87-7.92 (m, 1H), 8.11-8.19 (m, 1H);
ESI-MS m/z [M+H-tert-butyl].sup.+ 293.5.
Step B: (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00053##
[0280] A solution of (S)-tert-butyl
3-((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (4.430
g, 12.70 mmol), zinc cyanide (2.980 g, 25.40 mmol) and
Pd(PPh.sub.3).sub.4 (1.468 g, 1.27 mmol) in DMF (36.3 mL) was
heated at 160.degree. C. for 20 minutes in a microwave reactor. The
reaction mixture was filtered, diluted with water (400 mL) and
extracted with EtOAc (2.times.100 mL). The organic layers were
combined, washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. The crude product was purified by silica
column chromatography to give the title compound as a
white-to-pale-yellow solid (3.570 g, 83%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 1.40 (d, J=13.18 Hz, 9H), 2.23 (d,
J=11.23 Hz, 2H), 3.42-3.59 (m, 3H), 3.65-3.75 (m, 1H), 5.68-5.80
(m, 1H), 7.82-7.89 (m, 1H), 7.91-7.98 (m, 1H), 8.06 (d, J=8.79 Hz,
1H), 8.21-8.30 (m, 2H); ESI-MS m/z [M+H-tert-butyl].sup.+
284.6.
Step C: (S)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrro-
lidine-1-carboxylate
##STR00054##
[0282] (S)-tert-Butyl
3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (4.670 g,
13.76 mmol), ethyl hydrazinecarboxylate (7.160 g, 68.80 mmol), DBU
(1.037 mL, 6.88 mmol) and NMP (34.6 mL) were mixed in a 200 mL high
pressure reaction vessel. The resulting suspension was heated at
170.degree. C. overnight and was then cooled to room temperature.
Crushed ice was added and the mixture was stirred. A yellow
precipitate was collected by vacuum filtration, washed with
additional water, and dried in a vacuum oven at 45.degree. C.
overnight to give the title compound, which was used in the next
step without further purification (5.47 g). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 1.33-1.51 (m, 9H), 2.09-2.38 (m, 2H),
3.39-3.60 (m, 3H), 3.75 (dd, J=12.20, 4.88 Hz, 1H), 6.03-6.22 (m,
1H), 7.62-7.71 (m, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.95-8.05
(m, 1H), 8.11-8.29 (m, 2H), 11.78 (s, 1H), 12.03 (br s, 1H).
Step D:
(S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(-
4H)-one
##STR00055##
[0284] To a 200 mL round-bottom flask charged with crude
(S)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrro-
lidine-1-carboxylate (5.47 g) and dioxane (27.5 mL) was added 4M
HCl in dioxane (13.76 mL, 55.1 mmol). The suspension was stirred at
RT with periodic monitoring by HPLC. Upon completion, the reaction
mixture was concentrated in vacuo to give an HCl salt of the title
compound as a light tan powder that was dried and used without
further purification. ESI-MS m/z [M+H].sup.+ 298.6.
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,-
4-triazol-5(4H)-one
[0285] To a suspension of
(S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
hydrochloride (4.29 g) in DCM (48.1 mL) was added
2,6-dimethylpyridine (3.19 mL, 27.4 mmol). Upon cooling the
suspension to 0.degree. C., acryloyl chloride (1.3 mL, 15.9 mmol)
was added drop-wise. The reaction mixture was stirred for 15
minutes and warmed to RT over a period of 90 minutes. Additional
2,6-dimethylpyridine (1.68 mL, 14.43 mmol) and acryloyl chloride
(0.469 mL, 5.77 mmol) were added and the mixture was stirred until
HPLC indicated the reaction was completed. The product was
collected by vacuum filtration, washed with DCM, and dried to give
title compound as a pale yellow solid (1.929 g, 39.9% over 3
steps). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 2.16-2.43
(m, 2H), 3.58-3.73 (m, 1H), 3.74-3.91 (m, 2H), 4.10 (dd, J=11.72,
4.88 Hz, 1H), 5.60-5.74 (m, 1H), 6.10-6.25 (m, 2H), 6.53-6.73 (m,
1H), 7.62-7.69 (m, 1H), 7.77-7.85 (m, 1H), 7.95-8.05 (m, 2H), 8.17
(d, J=8.30 Hz, 1H), 11.78 (s, 1H), 12.03 (d, J=13.18 Hz, 1H);
ESI-MS m/z [M+H].sup.+ 352.6.
Example 6:
(S)-3-(1-(((1-acryloylpyrrolidin-2-yl)methyl)amino)isoquinolin--
3-yl)-1H-1,2,4-triazol-5(4H)-one
##STR00056##
[0286] Step A: (S)-tert-butyl
2-(((3-cyanoisoquinolin-1-yl)amino)methyl)pyrrolidine-1-carboxylate
##STR00057##
[0288] A mixture of (S)-tert-butyl
2-(aminomethyl)pyrrolidine-1-carboxylate (350 mg, 1.750 mmol) in
NMP (4 mL) at 0.degree. C. was treated with NaH (70.0 mg, 1.750
mmol) and stirred for 1 hour. Next,
1-chloroisoquinoline-3-carbonitrile (300 mg, 1.591 mmol) was added
and the reaction mixture was stirred at RT for 15 minutes and then
heated at 140.degree. C. for 15 minutes in a microwave reactor. The
crude reaction mixture, which contained the title compound, was
used directly in the next step.
Step B: (S)-tert-butyl
2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)me-
thyl)pyrrolidine-1-carboxylate
##STR00058##
[0290] To a crude reaction mixture containing (S)-tert-butyl
2-(((3-cyanoisoquinolin-1-yl)amino)methyl)pyrrolidine-1-carboxylate
(0.561 g) was added ethyl hydrazinecarboxylate (0.663 g, 6.36
mmol). The reaction mixture was heated at 175.degree. C. overnight
and was subsequently cooled, diluted with EtOAc, and washed with
saturated aqueous NH.sub.4Cl. The aqueous and organic layers were
separated. The organic layer was concentrated to give the title
compound, which was used directly in the next step.
Step C:
(S)-3-(1-((pyrrolidin-2-ylmethyl)amino)isoquinolin-3-yl)-1H-1,2,4--
triazol-5(4H)-one
##STR00059##
[0292] To crude
(S)-tert-butyl-2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinoli-
n-1-yl)amino)methyl)pyrrolidine-1-carboxylate (653 mg) suspended in
DCM (3 mL) was added TFA (2 mL). The mixture was stirred for 2
hours and then concentrated. The product was purified by
preparative HPLC eluting with a gradient of 5-30% ACN in water
(acid mode) to give the title compound.
Step D:
(S)-3-(1-(((1-acryloylpyrrolidin-2-yl)methyl)amino)isoquinolin-3-y-
l)-1H-1,2,4-triazol-5(4H)-one
[0293] To a solution of
(S)-3-(1-((pyrrolidin-2-ylmethyl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-
-5(4H)-one (50 mg, 0.161 mmol) in DCM (3 mL) was added
2,6-dimethylpyridine (0.056 mL, 0.483 mmol) at 0.degree. C.
followed by acryloyl chloride (0.026 mL, 0.322 mmol). The reaction
mixture was stirred at RT for 30 minutes and then concentrated in
vacuo. The residue was taken up in MeOH and the product purified by
preparative HPLC eluting with a gradient of 15-40% ACN in water
(acid mode) to give a TFA salt of the title compound (10 mg, 17%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.08-2.25 (m, 4H),
3.53 (dd, J=13.64, 8.34 Hz, 1H), 3.58-3.71 (m, 1H), 3.79 (t, J=8.34
Hz, 1H), 4.12 (dd, J=13.39, 3.79 Hz, 1H), 4.68 (br s, 1H), 5.84 (d,
J=9.85 Hz, 1H), 6.50-6.61 (m, 1H), 6.61-6.72 (m, 1H), 7.60-7.73 (m,
2H), 7.78 (t, J=7.20 Hz, 1H), 7.86 (d, J=7.83 Hz, 1H), 8.20 (d,
J=8.08 Hz, 1H); ESI-MS m/z [M+H].sup.+ 365.5.
Example 7:
(S)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)--
1H-1,2,4-triazol-5(4H)-one
##STR00060##
[0294] Step A: (S)-tert-butyl
2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate
##STR00061##
[0296] A mixture of (S)-tert-butyl
2-(hydroxymethyl)pyrrolidine-1-carboxylate (222 mg, 1.103 mmol) in
NMP (4 mL) at 0.degree. C. was treated with Cs.sub.2CO.sub.3 (345
mg, 1.060 mmol) and stirred for 1 hour. Next,
1-chloroisoquinoline-3-carbonitrile (200 mg, 1.060 mmol) was added
and the reaction mixture was stirred at RT for 15 minutes and then
heated at 140.degree. C. for 15 minutes in a microwave reactor. The
crude reaction mixture, which contained the title compound, was
used directly in the next step.
Step B: (S)-tert-butyl
2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)meth-
yl)pyrrolidine-1-carboxylate
##STR00062##
[0298] To a crude reaction mixture containing (S)-tert-butyl
2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate
(0.562 g) was added NMP (2 mL) followed by ethyl
hydrazinecarboxylate (0.663 g, 6.36 mmol). The reaction mixture was
heated at 175.degree. C. overnight and was subsequently cooled,
diluted with EtOAc, and washed with brine. The organic layer was
separated, dried over Na.sub.2SO.sub.4, and concentrated to give
the title compound, which was used directly in the next step.
Step C:
(S)-3-(1-(pyrrolidin-2-ylmethoxy)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one
##STR00063##
[0300] To crude (S)-tert-butyl
2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)meth-
yl)pyrrolidine-1-carboxylate suspended in DCM (1 mL) was added TFA
(1 mL). The mixture was stirred for 10 minutes and then
concentrated. The product was purified by preparative HPLC eluting
with a gradient of 15-22% ACN in water (acid mode) to give the
title compound.
Step D:
(S)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one
[0301] To a solution of
(S)-3-(1-(pyrrolidin-2-ylmethoxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-
-one (50 mg, 0.161 mmol) in DCM (3 mL) was added
2,6-dimethylpyridine (0.056 mL, 0.482 mmol) at 0.degree. C.
followed by acryloyl chloride (0.026 mL, 0.321 mmol). The reaction
mixture was stirred at RT for 30 minutes and then concentrated. The
residue was taken up in MeOH and water and the product purified by
preparative HPLC eluting with a gradient of 30-50% ACN in water
(acid mode) to give a TFA salt of the title compound (14 mg, 24%);
ESI-MS m/z [M+H].sup.+ 366.5.
Example 8:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-
-1,2,4-triazol-5 (4H)-one
##STR00064##
[0303] To a solution of
(S)-3-(1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-o-
ne (8 mg, 0.027 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(9.40 .mu.L, 0.081 mmol) at 0.degree. C. followed by acryloyl
chloride (4.39 .mu.L, 0.054 mmol). The mixture was stirred for 30
minutes and concentrated. The residue was dispersed in water and
the product purified by preparative HPLC eluting with a gradient of
5-30% ACN in water (acid mode) to give a TFA salt of the title
compound (2 mg, 21%). ESI-MS m/z [M+H].sup.+ 351.4.
Example 9:
(R)-3-(1-((l-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)--
1H-1,2,4-triazol-5(4H)-one
##STR00065##
[0304] Step A: (R)-tert-butyl
2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate
##STR00066##
[0306] A mixture of (R)-tert-butyl
2-(hydroxymethyl)pyrrolidine-1-carboxylate (444 mg, 2.206 mmol) and
Cs.sub.2CO.sub.3 (719 mg, 2.206 mmol) in NMP (4 mL) were stirred at
0.degree. C. for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile
(400 mg, 2.121 mmol) was added and the reaction mixture was heated
at 140.degree. C. for 15 minutes in a microwave reactor. Additional
Cs.sub.2CO.sub.3 (719 mg, 2.206 mmol) was added. The reaction
mixture heated at 140.degree. C. for 1 hour to give the title
compound, which was used directly in the next step.
Step B: (R)-tert-butyl
2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)meth-
yl)pyrrolidine-1-carboxylate
##STR00067##
[0308] To a crude reaction mixture containing (R)-tert-butyl
2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate
(0.749 g) was added NMP (2 mL) and ethyl hydrazinecarboxylate
(0.883 g, 8.48 mmol). The reaction mixture was heated at
175.degree. C. overnight and was subsequently cooled, diluted with
EtOAc, and washed with saturated aqueous NH.sub.4Cl followed by
water. The organic layer was separated and concentrated to give the
title compound, which was used without further purification.
Step C:
(R)-3-(1-(pyrrolidin-2-ylmethoxy)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one
##STR00068##
[0310] To crude (R)-tert-butyl
2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)meth-
yl)pyrrolidine-1-carboxylate was added DCM (3 mL) followed by TFA
(2 mL). The mixture was stirred at RT for 2 hours and the solvent
was removed in vacuo. The crude product was purified by preparative
HPLC eluting with a gradient of 10-25% ACN in water (acid mode) to
give the title compound (10 mg, 1.5% over 3 steps). ESI-MS m/z
[M+H].sup.+ 312.4.
Step D:
(R)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H--
1,2,4-triazol-5 (4H)-one
[0311] To a solution of
(R)-3-(1-(pyrrolidin-2-ylmethoxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-
-one (10 mg, 0.032 mmol) in DCM (3 mL) was added
2,6-dimethylpyridine (0.011 mL, 0.096 mmol) at 0.degree. C.
followed by acryloyl chloride (5.22 .mu.L, 0.064 mmol). The
reaction mixture was stirred for 30 minutes. The solvent was
subsequently removed in vacuo and the residue was taken up in MeOH
and the product purified by preparative HPLC eluting with a
gradient of 35-60% ACN in water (acid mode) to give a TFA salt of
the title compound (1.8 mg, 15%). ESI-MS m/z [M+H].sup.+ 366.4.
Example 10:
(S)-3-(1-((1-methacryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5(4H)-one
##STR00069##
[0313] To a solution of
(S)-3-(1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-o-
ne (13 mg, 0.044 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(0.015 mL, 0.132 mmol) at 0.degree. C. followed by methacryloyl
chloride (6.88 mg, 0.066 mmol). The reaction mixture was stirred at
RT overnight and was subsequently partitioned between water and
DCM. The organic phase was separated and concentrated in vacuo. The
crude product was purified by preparative HPLC eluting with a
gradient of 20-45% ACN in water (acid mode) to give a TFA salt of
the title compound (0.5 mg, 2%). ESI-MS m/z [M+H].sup.+ 365.4.
Example 11:
(S)-3-(1-((l-acryloylpyrrolidin-3-yl)(methyl)amino)isoquinolin-3-yl)-1H-1-
,2,4-triazol-5(4H)-one
##STR00070##
[0314] Step A: (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)(methyl)amino)pyrrolidine-1-carboxylate
##STR00071##
[0316] To (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (235
mg, 0.694 mmol) in DMF (6 mL) was added NaH (27.8 mg, 0.694 mmol)
and methyl iodide (0.052 mL, 0.833 mmol) at 0.degree. C. The
reaction mixture was allowed to warm to RT with stirring over a 2
hour period and was subsequently diluted with EtOAc and washed with
aqueous NH.sub.4Cl, water, and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Toluene
(2.times.5 mL) was added and removed in vacuo to give the title
compound as a crude residue.
Step B: (S)-tert-butyl
3-(methyl(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)ami-
no)pyrrolidine-1-carboxylate
##STR00072##
[0318] To crude (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)(methyl)amino)pyrrolidine-1-carboxylate
(0.245 g) in NMP (1 mL) was added ethyl hydrazinecarboxylate (0.289
g, 2.78 mmol). The reaction mixture was heated at 175.degree. C.
for 2 days and was subsequently cooled, diluted with EtOAc, and
washed with aqueous NH.sub.4Cl. The organic phase was separated,
dried, and concentrated. The crude product was purified by HPLC to
give the title compound (91 mg, 32% over 2 steps).
Step C:
(S)-3-(1-(methyl(pyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4--
triazol-5(4H)-one
##STR00073##
[0320] To (S)-tert-butyl
3-(methyl(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)ami-
no)pyrrolidine-1-carboxylate (91 mg, 0.222 mmol) in DCM was added
TFA (1.5 mL). After 2 hours the solvent was removed in vacuo to
give the title compound, which was used without further
purification.
Step D:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)(methyl)amino)isoquinolin-3-y-
l)-1H-1,2,4-triazol-5(4H)-one
[0321] To a solution of crude
(S)-3-(1-(methyl(pyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-
-5(4H)-one (69 mg) in DCM (10 mL) was added 2,6-dimethylpyridine
(0.077 mL, 0.667 mmol) at 0.degree. C. followed by acryloyl
chloride (0.023 mL, 0.278 mmol). The reaction mixture was stirred
at RT overnight and then quenched with water. The solvent was
removed in vacuo and the crude product was purified by preparative
HPLC to give a TFA salt of the title compound (19 mg, 24% over 2
steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) (rotamers were
observed) .delta. ppm 1.99-2.20 (m, 1H), 2.20-2.40 (m, 1H), 3.06
(s, 1.5H), 3.04 (s, 1.5H), 3.15-3.25 (m, 0.5H), 3.30-3.47 (m, 1H),
3.50-3.64 (m, 0.5H), 3.65-3.75 (m, 0.5H), 3.80-3.90 (m, 0.5H),
3.98-4.06 (m 0.5H), 4.22 (dd, J=9.85, 7.58 Hz, 0.5H), 4.63-4.92 (m,
1H), 5.66 (ddd, J=19.58, 10.23, 2.53 Hz, 1H), 6.15 (ddd, J=16.67,
5.81, 2.53 Hz, 1H), 6.49-6.72 (m, 1H), 7.47-7.68 (m, 1H), 7.68-7.81
(m, 1H), 7.89-8.03 (m, 2H), 8.16 (d, J=8.59 Hz, 1H), 11.75 (s, 1H),
11.93 (d, J=3.79 Hz, 1H); ESI-MS m/z [M+H].sup.+ 365.4.
Example 12:
(S)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one
##STR00074##
[0323] To a solution of
(S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(17 mg, 0.057 mmol) in NMP (3 mL) was added 2,6-dimethylpyridine
(8.97 .mu.L, 0.077 mmol) at 0.degree. C. followed by methacryloyl
chloride (10.57 .mu.L, 0.108 mmol). The reaction mixture was
stirred at RT overnight and was subsequently diluted with MeOH, and
filtered. The crude product was purified by mass-triggered HPLC
eluting with a gradient of 25-50% ACN in water (acid mode). The
product-containing fractions were concentrated to give a TFA salt
of the title compound (10 mg, 35%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.15-1.24 (m, 4H), 3.59-3.83 (m, 3H),
3.84-3.98 (m, 1H), 5.08 (s, 1H), 5.19 (d, J=5.81 Hz, 1H), 5.28 (s,
1H), 6.02 (d, J=15.16 Hz, 1H), 7.52-7.59 (m, 1H), 7.68 (td, J=7.58,
1.26 Hz, 1H), 7.78-7.93 (m, 2H), 8.06-8.20 (m, 1H); ESI-MS m/z
[M+H].sup.+ 366.4.
Example 13:
(S)-3-(1-(((1-acryloylpyrrolidin-3-yl)oxy)methyl)isoquinolin-3-yl)-1H-1,2-
,4-triazol-5(4H)-one
##STR00075##
[0324] Step A: (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)methoxy)pyrrolidine-1-carboxylate
##STR00076##
[0326] To 1-(bromomethyl)isoquinoline-3-carbonitrile (0.150 g,
0.607 mmol) in DCM (6 mL) was added (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (0.114 g, 0.607 mmol) and AgOTf
(0.016 g, 0.061 mmol). The suspension was stirred for 15 minutes at
RT and then heated at 45.degree. C. overnight. The reaction mixture
was subsequently cooled, absorbed onto silica and eluted with a
gradient of 0-5% MeOH in DCM. The enriched fractions were
concentrated in vacuo to give the title compound as a yellow
residue which was used without further purification (54.6 mg,
25.4%). ESI-MS m/z [M+H-tert butyl].sup.+ 298.6.
Step B:
(S)-3-(1-((pyrrolidin-3-yloxy)methyl)isoquinolin-3-yl)-1H-1,2,4-tr-
iazol-5(4H)-one
##STR00077##
[0328] A mixture of (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)methoxy)pyrrolidine-1-carboxylate (54.6
mg, 0.154 mmol) in NMP (0.4 mL), ethyl hydrazinecarboxylate (80 mg,
0.772 mmol) and DBU (0.012 mL, 0.077 mmol) was heated at
170.degree. C. overnight and then filtered. The product in the
filtrate was purified by mass-triggered HPLC eluting with a
gradient of 35-60% ACN in water (acid mode). The product-containing
fractions were concentrated in vacuo, treated with neat TFA (1 mL)
for 5 minutes, and again concentrated in vacuo. The concentrate was
dispersed in ACN/water (1:1) and lyophilized to give the title
compound (7.5 mg, 16%). ESI-MS m/z [M+H].sup.+ 312.6.
Step C:
(S)-3-(1-(((1-acryloylpyrrolidin-3-yl)oxy)methyl)isoquinolin-3-yl)-
-1H-1,2,4-triazol-5(4H)-one
[0329] A suspension of
(S)-3-(1-((pyrrolidin-3-yloxy)methyl)isoquinolin-3-yl)-1H-1,2,4-triazol-5-
(4H)-one (7.5 mg, 0.024 mmol) in DCM (134 .mu.L) and
2,6-dimethylpyridine (5.61 .mu.L, 0.048 mmol) was cooled to
0.degree. C. Acryloyl chloride (3.91 .mu.L, 0.048 mmol) was added
drop-wise. The reaction mixture was slowly warmed to RT overnight
with stirring. The reaction mixture was subsequently concentrated
in vacuo, reconstituted in DMSO, and the product isolated by
mass-triggered HPLC eluting with a gradient of 20-35% ACN in water
(acid mode). The product-containing fractions were combined,
concentrated in vacuo, and lyophilized to give a TFA salt of the
title compound (0.9 mg, 10%). .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. ppm 1.22-1.39 (m, 2H), 1.96-2.31 (m, 1H), 3.51 (d, J=9.28
Hz, 1H), 3.57-3.88 (m, 2H), 5.15-5.29 (m, 3H), 5.70 (ddd, J=16.96,
10.62, 1.71 Hz, 1H), 6.23 (td, J=17.09, 1.95 Hz, 1H), 6.45-6.63 (m,
1H), 7.74 (d, J=7.32 Hz, 1H), 7.81 (t, J=7.57 Hz, 1H), 7.85-7.96
(m, 1H), 7.97-8.12 (m, 1H), 8.30-8.47 (m, 3H); ESI-MS m/z
[M+H].sup.+ 366.5.
Example 14:
(S,E)-5-(1-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)isoquino-
lin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one
##STR00078##
[0330] Step A: (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00079##
[0332] To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.906
g, 10.18 mmol) in NMP (10 mL) at 0.degree. C. was added NaH (0.339
g, 8.48 mmol). The mixture was stirred for 5 minutes and then
1-chloroisoquinoline-3-carbonitrile (1.6 g, 8.48 mmol) was added.
The reaction mixture was heated at 160.degree. C. for 30 minutes in
a microwave reactor and was subsequently diluted with water and
extracted with EtOAc (2.times.). The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by silica column chromatography eluting with a gradient of 0-75%
EtOAc in hexane to give the title compound as a yellow solid (1.61
g, 55.9%). ESI-MS m/z [M+H-tert-butyl].sup.+ 284.2.
Step B: (S)-tert-butyl
3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrro-
lidine-1-carboxylate
##STR00080##
[0334] A mixture of (S)-tert-butyl
3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1.61 g,
4.74 mmol) and ethyl hydrazinecarboxylate (1.482 g, 14.23 mmol) in
NMP (8 mL) was heated at 160.degree. C. overnight. The reaction
mixture was diluted with EtOAc and washed with water (2.times.).
The aqueous layer was back-extracted with EtOAc. The organic layers
were combined, dried over MgSO.sub.4, filtered, and evaporated in
vacuo to give the title compound as a pale oil, which was used
without further purification. ESI-MS m/z [M+H-tert-butyl].sup.+
342.3.
Step C:
(S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5
(4H)-one
##STR00081##
[0336] Crude
(S)-tert-butyl-3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-
-1-yl)oxy)-pyrrolidine-1-carboxylate (1 g, 1.258 mmol) was
dissolved in a solution of 4N HCl in dioxane (0.315 mL, 1.258 mmol)
and stirred at RT for 30 minutes. The solvent was removed in vacuo
and the resulting oil was dried under high vacuum to give the title
compound, which used without further purification. ESI-MS m/z
[M+H].sup.+ 298.3.
Step D:
(S,E)-5-(1-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)i-
soquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one
[0337] To a mixture of (E)-4-(dimethylamino)but-2-enoic acid
hydrochloride (23.40 mg, 0.141 mmol),
(S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(100 mg, 0.135 mmol) and HATU (61.4 mg, 0.161 mmol) in DCM (3 mL)
was added Htinig's Base (0.070 mL, 0.404 mmol). The reaction
mixture was stirred at RT overnight and was subsequently diluted
with EtOAc and washed with water. The product remained in the
aqueous layer, which was concentrated to afford a residue. The
crude product was purified by preparative HPLC eluting with a
gradient of 25-50% ACN in water (basic mode). The solvent was
removed by lyophilization to give the title compound (26 mg, 47%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.33-2.44 (m, 1H),
2.44-2.53 (m, 1H), 2.55 (s, 3H), 2.60 (s, 3H), 3.53 (d, J=6.06 Hz,
1H), 3.59 (d, J=6.57 Hz, 1H), 3.72-3.91 (m, 1H), 3.91-4.00 (m, 2H),
4.14-4.18 (m, 1H), 6.15 (d, J=18.44 Hz, 1H), 6.65-6.89 (m, 2H),
7.58-7.69 (m, 1H), 7.73-7.83 (m, 1H), 7.90 (d, J=3.03 Hz, 1H), 7.96
(d, J=5.31 Hz, 1H), 8.21 (d, J=7.33 Hz, 1H); ESI-MS m/z [M+H].sup.+
409.5.
Example 15:
(S,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one
##STR00082##
[0339] To a solution of
(S)-3-(1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-o-
ne (70 mg, 0.236 mmol) in DCM (10 mL) was added
2,6-dimethylpyridine (0.082 mL, 0.709 mmol) at 0.degree. C.
followed by (E)-but-2-enoyl chloride (0.027 mL, 0.283 mmol). The
reaction mixture was stirred at RT overnight. The reaction was
subsequently quenched with water and the solvent was removed in
vacuo to afford a residue. The crude product was purified by
preparative HPLC eluting with a gradient of 20-45% ACN in water
(acid mode) to give a TFA salt of the title compound (10 mg, 12%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) (rotamers were observed)
.delta. ppm 1.82 (dd, J=6.82, 1.52 Hz, 1.5H), 1.86 (dd, J=6.82,
1.52 Hz, 1.5H), 1.93-2.14 (m, 1H), 2.15-2.39 (m, 1H), 3.22-3.77 (m,
1H), 3.75-3.95 (m, 2.5H), 4.13 (dd, J=9.98, 7.20 Hz, 0.5H),
5.10-5.34 (m, 1H), 6.22-6.41 (m, 1H), 6.64-6.78 (m, 1H), 7.48-7.63
(m, 3H), 7.63-7.73 (m, 1H), 7.83 (dd, J=7.83, 3.03 Hz, 1H), 8.34
(d, J=8.34 Hz, 1H), 11.67 (d, J=1.77 Hz, 1H), 11.81 (d, J=3.28 Hz,
1H); ESI-MS m/z [M+H].sup.+ 365.4.
Example 16:
(S)-3-(8-((l-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-
-triazol-5(4H)-one
##STR00083##
[0340] Step A: (S)-tert-butyl
3-((6-bromo-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate
##STR00084##
[0342] To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (890
mg, 4.75 mmol) in N-methyl-2-pyrrolidinone (16 mL) at 0.degree. C.
was added NaH (60%) (158.4 mg, 3.96 mmol). The mixture was stirred
for 5 minutes. Next, 1,3-dibromoisoquinoline (1139 mg, 3.96 mmol)
was added and the reaction mixture was stirred at RT for 5 minutes
and then heated in a microwave reactor at 135.degree. C. for 30
minutes and at 160.degree. C. at for another 30 minutes. The
mixture was subsequently diluted with water and extracted with
EtOAc (2.times.). The organic phase was separated, dried over
Na.sub.2SO.sub.4, and concentrated. The crude product was purified
by silica column chromatography eluting with a gradient of 0-75%
EtOAc in hexane over a 45 minute period to give the title compound
(1.3 g, 70% from two batches).
Step B: (S)-tert-butyl
3-((6-cyano-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate
##STR00085##
[0344] A solution of (S)-tert-butyl
3-((6-bromo-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate
(1400 mg, 3.55 mmol), zinc cyanide (834 mg, 7.1 mmol) and
N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.106 mL, 0.71 mmol) in
DMSO (9 mL) was degassed with nitrogen for 5 minutes. Xantphos (206
mg, 0.355 mmol) and Pd.sub.2(dba).sub.3 (325 mg, 0.355 mmol) were
added and the mixture was heated in a microwave reactor at
160.degree. C. for 15 minutes. The reaction mixture was diluted
with EtOAc and washed with water (2.times.). The organic layer was
separated and concentrated in vacuo. The crude product was purified
by silica column chromatography to give the title compound as a
yellow solid (181 mg, 15%).
Step C: (S)-tert-butyl
3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)oxy-
)pyrrolidine-1-carboxylate
##STR00086##
[0346] A suspension of (S)-tert-butyl
3-((6-cyano-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate
(181 mg, 0.532 mmol) and ethyl hydrazinecarboxylate (277 mg, 2.66
mmol) in NMP (5 mL) was heated at 175.degree. C. overnight. The
reaction mixture was subsequently diluted with MeOH and filtered.
The crude product was purified using mass-triggered HPLC eluting
with a gradient of 25-50% ACN in water (acid mode). The
product-containing fractions were collected and concentrated to
give a TFA salt of the title compound as a yellow film (100 mg,
47.2%).
Step D:
(S)-3-(8-(pyrrolidin-3-yloxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-tria-
zol-5(4H)-one
##STR00087##
[0348] To (S)-tert-butyl
3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)oxy-
)pyrrolidine-1-carboxylate (100 mg, 0.251 mmol) suspended in
dioxane (10 mL) was added 4M HCl in dioxane (0.251 mL, 1.004 mmol).
The reaction mixture was stirred for 30 minutes and concentrated to
give an HCl salt of the title compound (74 mg, 88%). This material
was used directly in next step.
Step E:
(S)-3-(8-((l-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1-
H-1,2,4-triazol-5(4H)-one
[0349] To a solution of
(S)-3-(8-(pyrrolidin-3-yloxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4-
H)-one (74.0 mg, 0.248 mmol) in DMSO (3 mL) was added
2,6-dimethylpyridine (0.030 mL, 0.258 mmol) at 0.degree. C.
followed by acryloyl chloride (65.4 mg, 0.724 mmol). The reaction
mixture was stirred at RT overnight and was subsequently diluted
with MeOH and filtered through a PTFE membrane. The product, which
was contained in the filtrate, was isolated using mass-triggered
HPLC eluting with a gradient of 15-30% ACN in water (acid mode).
The product-containing fractions were concentrated to give a TFA
salt of the title compound (14 mg, 12% from two batches). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.34-2.58 (m, 2H), 3.76-3.99
(m, 2H), 3.99-4.11 (m, 1H), 4.16 (dd, J=12.25, 4.42 Hz, 1H),
5.64-5.85 (m, 1H), 6.19 (br s, 1H), 6.29 (ddd, J=16.80, 3.66, 2.02
Hz, 1H), 6.52-6.76 (m, 1H), 7.82 (dd, J=8.21, 4.17 Hz, 1H),
8.00-8.15 (m, 1H), 8.44 (d, J=8.59 Hz, 1H), 8.95 (br s, 1H); ESI-MS
m/z [M+H].sup.+ 353.3.
Example 17:
(S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2-
,4-triazol-5(4H)-one
##STR00088##
[0350] Step A: (S)-tert-butyl
3-((6-bromo-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate
##STR00089##
[0352] To (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.776 g,
4.17 mmol) in N-methyl-2-pyrrolidinone (12 mL) at 0.degree. C. was
added NaH (0.139 g, 3.47 mmol). The mixture was stirred for 5
minutes. Next, 6,8-dibromo-1,7-naphthyridine (1 g, 3.47 mmol) was
added and the reaction mixture was stirred at RT for 5 minutes and
then heated at 135.degree. C. for 30 minutes in a microwave
reactor. The reaction mixture was diluted with water and extracted
with EtOAc (2.times.). The organic layers were combined, dried over
Na.sub.2SO.sub.4, and concentrated. The crude product was purified
using silica column chromatography eluting with a gradient of 0-75%
EtOAc in hexane over a 45 minute period to give the title compound
as a yellow solid (1.3 g, 95%).
Step B: (S)-tert-butyl
3-((6-cyano-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate
##STR00090##
[0354] A solution of (S)-tert-butyl
3-((6-bromo-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate
(1141 mg, 2.9 mmol), zinc cyanide (681 mg, 5.80 mmol) and
N1,N1,N2,N2-tetramethylethane-1,2-diamine (87 .mu.L, 0.580 mmol) in
NMP was degassed with nitrogen for 5 minutes. Xantphos (168 mg,
0.290 mmol) and Pd.sub.2dba.sub.3 (266 mg, 0.290 mmol) were added
and the mixture was heated in a microwave reactor at 160.degree. C.
for 10 minutes. The reaction mixture was subsequently diluted with
EtOAc. The organic phase was washed with water (2.times.), dried,
and concentrated in vacuo. The crude product was purified by
preparative HPLC eluting with a gradient of 45-70% ACN in water
(acid mode) to give the title compound as a yellow solid (175 mg,
17.8%).
Step C: (S)-tert-butyl
3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)ami-
no)pyrrolidine-1-carboxylate
##STR00091##
[0356] To (S)-tert-butyl
3-((6-cyano-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate
(210 mg, 0.619 mmol) in NMP (1.5 mL) was added ethyl
hydrazinecarboxylate (258 mg, 2.475 mmol). The reaction mixture was
heated at 175.degree. C. for 2 days and was then cooled, diluted
with EtOAc, and washed with aqueous NH.sub.4Cl. The organic phase
was dried and concentrated. The crude product was purified by
preparative HPLC eluting with a gradient of 35-60% ACN in water
(acid mode) to give the title compound (80 mg, 33%).
Step D:
(S)-3-(8-(pyrrolidin-3-ylamino)-1,7-naphthyridin-6-yl)-1H-1,2,4-tr-
iazol-5(4H)-one
##STR00092##
[0358] A mixture of (S)-tert-butyl
3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)ami-
no)pyrrolidine-1-carboxylate (80 mg, 0.201 mmol) in DCM (3 mL) was
treated with TFA (1.5 mL) for 2 hours. The solvent was removed in
vacuo to give the title compound, which was used in the next step
without further purification.
Step E:
(S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-
-1H-1,2,4-triazol-5(4H)-one
[0359] To a solution of
(S)-3-(8-(pyrrolidin-3-ylamino)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5-
(4H)-one (36 mg, 0.121 mmol) in DCM (3 mL) was added
2,6-dimethylpyridine (0.042 mL, 0.363 mmol) at 0.degree. C.
followed by acryloyl chloride (0.015 mL, 0.182 mmol). The reaction
mixture was stirred at RT overnight. The reaction was subsequently
quenched with water and the mixture was concentrated in vacuo. The
crude product was purified by preparative HPLC eluting with a
gradient of 15-40% ACN in water (acid mode) to give a TFA salt of
the title compound (16 mg, 38%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (rotamers were observed) .delta. ppm 1.94-2.30 (m,
2H), 3.20-3.50 (m, 1.5H), 3.51-3.67 (m, 1H), 3.72-3.91 (m, 1H),
4.05 (dd, J=9.85, 7.07 Hz, 0.5H), 4.99-5.25 (m, 1H), 5.60 (ddd,
J=16.11, 10.29, 2.40 Hz, 1H), 6.00-6.16 (m, 1H), 6.43-6.65 (m, 1H),
7.47 (d, J=3.79 Hz, 1H), 7.65 (ddd, J=8.27, 4.23, 1.39 Hz, 1H),
7.73-7.88 (m, 1H), 8.23 (dt, J=8.34, 1.77 Hz, 1H), 8.74 (dt,
J=4.29, 1.52 Hz, 1H), 11.66 (s, 1H), 11.83 (s, 1H); ESI-MS m/z
[M+H].sup.+ 352.4.
Example 18:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-fluoroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one
##STR00093##
[0360] Step A: (S)-tert-butyl
3-((3-chloro-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00094##
[0362] To a solution of (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (1.56 g, 8.3 mmol) in THF (20
mL) was added NaH (0.33 g, 8.3 mmol) under nitrogen at 0.degree. C.
The mixture was warmed to RT over a 30 minute period and
1,3-dichloro-7-fluoroisoquinoline (0.9 g, 4.17 mmol) was added. The
resulting mixture was stirred for 10 hours at RT. The mixture was
subsequently diluted with EtOAc (100 mL), quenched with saturated
aqueous NH.sub.4Cl (100 mL), and extracted with EtOAc (3.times.100
mL). The combined organic layers were dried over Na.sub.2SO.sub.4
and concentrated. The crude product was purified by column
chromatography eluting with petroleum ether and ethyl acetate
(PE/EtOAc=50:1-10:1 gradient) to give the title compound (1.1 g,
72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.00-7.98 (m,
1H), 7.82-7.80 (m, 2H), 7.62 (s, 1H), 5.67-5.63 (d, J=16 Hz, 1H),
3.69-3.66 (m, 1H), 3.53-3.487 (m, 3H), 2.30-2.22 (m, 2H), 1.41-1.39
(d, J=10.8 Hz, 2H).
Step B: (S)-tert-butyl
3-((3-cyano-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00095##
[0364] To a solution of (S)-tert-butyl
3-((3-chloro-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
(1 g, 2.73 mmol) in DMF (10 mL) was added Zn(CN).sub.2 (0.64 g,
5.46 mmol) and Pd(PPh.sub.3).sub.4 (0.316 g, 0.273 mmol) under
N.sub.2. The mixture was heated at 160.degree. C. for 30 minutes in
a microwave reactor and was subsequently partition between EtOAc
(50 mL) and water (50 mL). The aqueous phase was back-extracted
with EtOAc (3.times.50 mL) and the organic layers were combined and
washed with saturated aqueous NaCl (3.times.50 mL) and concentrated
in vacuo. The crude product was purified by column chromatography
eluting with petroleum ether and ethyl acetate (PE/EtOAc=20:1-5:1
gradient) to give the title compound (0.65 g, 65%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.28 (s, 1H), 8.19-8.16 (dd,
J.sub.1=5.2 Hz, J.sub.2=3.6 Hz, 1H), 7.97-7.95 (m, 2H), 5.73-5.69
(d, J=16 Hz, 1H), 3.71-3.67 (m, 1H), 3.58-3.50 (m, 3H), 2.25-2.24
(d, J=4 Hz, 2H), 1.42-1.39 (d, J=12 Hz, 9H).
Step C: (S)-tert-butyl
3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate
##STR00096##
[0366] To a mixture of (S)-tert-butyl
3-((3-cyano-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
(400 mg, 1.12 mmol) in MeOH (5 mL) was added
NH.sub.2NH.sub.2H.sub.2O (5 mL). The reaction mixture was heated to
reflux for 2 hours. The solvent was subsequently removed to give
the title compound as a white solid, which was used in next step
without purification (450 mg, 100%). ESI-MS m/z [M+H].sup.+
390.
Step D: (S)-tert-butyl
3-((7-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate
##STR00097##
[0368] To a solution of (S)-tert-butyl
3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate (0.45 g, 1.12 mmol) in dioxane (10 mL) was added CDI
(0.72 g, 2.24 mmol) under N.sub.2. The mixture was heated to reflux
for 2 hours and was subsequently concentrated in vacuo. The crude
product was purified by preparative HPLC to give the title compound
(70 mg, 40%). ESI-MS m/z [M+H-Boc].sup.+ 316.
Step E:
(S)-3-(7-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one
##STR00098##
[0370] A solution of (S)-tert-butyl
3-((7-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in HCl/EtOAc (5
mL) was stirred at RT for 30 minutes. The mixture was subsequently
concentrated in vacuo to give the title compound, which was used in
the next step without further purification (60 mg, 100%). ESI-MS
m/z [M+H].sup.+ 316.
Step F:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-fluoroisoquinolin-3-yl-
)-1H-1,2,4-triazol-5(4H)-one
[0371] To
(S)-3-(7-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5 (4H)-one (60 mg, 1.61 mmol) in DCM (10 mL) was added
2,6-dimethylpyridine (51 mg, 0.475 mmol). The mixture was cooled to
-40.degree. C. Acryloyl chloride (17 mg, 0.20 mmol) was added and
the mixture was warmed to 0.degree. C. over a 30 minute period. The
reaction was subsequently quenched with MeOH (5 mL) and the mixture
concentrated in vacuo. The crude product was purified by
preparative HPLC to give the title compound (16.4 mg, 27%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.06 (s, 1H), 11.82 (s,
1H), 8.17-8.13 (t, J=8 Hz, 1H), 8.05 (s, 1H), 7.88-7.85 (d, J=12
Hz, 1H), 7.78-7.76 (t, J=8 Hz, 1H), 6.50-6.70 (m, 1H), 6.19-6.13
(m, 2H), 5.73-5.67 (dd, J.sub.1=12 Hz, J.sub.2=4 Hz, 1H), 4.11-4.08
(m, 0.5H), 3.87-3.82 (m, 2H), 3.69-3.65 (m, 1.5H), 2.38-2.25 (m,
2H); ESI-MS m/z [M+H].sup.+ 370.
Example 19:
3-(1-(((3R,4S)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one and
3-(1-(((3S,4R)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one (Mixture of Enantiomers)
##STR00099##
[0372] Step A: tert-butyl
trans-3-((3-chloroisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate
##STR00100##
[0374] To a 25 mL microwave vial was added N-methyl-2-pyrrolidinone
(10.00 mL) and tert-butyl
trans-3-hydroxy-4-methylpyrrolidine-1-carboxylate (1.118 g, 5.55
mmol). The mixture was cooled to 0.degree. C. under a nitrogen
atmosphere. To this mixture was added portion-wise NaH (60%
suspension in mineral oil, 0.202 g, 5.05 mmol). After 5 minutes the
mixture was allowed to warm to RT and was stirred for 10 minutes.
Next, 1,3-dichloroisoquinoline (1 g, 5.05 mmol) was added and the
reaction mixture was heated in a microwave reactor at 135.degree.
C. for 30 minutes. The reaction mixture was subsequently diluted
with water (100 mL) and extracted with EtOAc (3.times.100 mL). The
organic layers were combined, washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated onto silica. The crude product
was purified by flash column chromatography (SiO.sub.2) eluting
with a gradient of 5-50% heptane in EtOAc to give the title
compound as a white solid (1.066 g, 58.2%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 1.16 (d, 3H), 1.48 (s, 9H), 2.60 (br s,
1H), 3.23 (br s, 1H), 3.49 (br s, 1H), 3.74 (br s, 1H), 3.94 (br s,
1H), 5.38 (br s, 1H), 7.23-7.32 (m, 1H), 7.51 (ddd, 1H), 7.61-7.71
(m, 2H), 8.17 (d, 1H); ESI-MS m/z [M+H].sup.+ 307.6.
Step B: tert-butyl
trans-3-((3-cyanoisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate
##STR00101##
[0376] A mixture of tert-butyl
trans-3-((3-chloroisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate
(1 g, 2.76 mmol), zinc cyanide (0.647 g, 5.51 mmol),
Pd(PPh.sub.3).sub.4 (0.318 g, 0.276 mmol) and DMF (7.83 mL) was
heated in a microwave reactor at 160.degree. C. for 20 minutes. The
reaction mixture was subsequently taken up in EtOAc (100 mL),
washed with brine (50 mL) and water (50 mL), dried over
Na.sub.2SO.sub.4, and concentrated onto silica gel. The crude
product was purified by flash column chromatography (SiO.sub.2)
eluting with a 5-50% gradient of heptane in EtOAc to give title
compound as a white solid (0.796 g, 82%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 1.17 (d, 3H), 1.41-1.54 (m, 9H), 2.60 (br
s, 1H), 3.26 (br s, 1H), 3.45-3.65 (br s, 1H), 3.74 (br s, 1H),
3.93 (dd, 1H), 5.40 (dt, 1H), 7.67-7.87 (m, 4H), 8.27 (d, 1H);
ESI-MS m/z [M+H-tert-butyl].sup.+298.6.
Step C: tert-butyl
trans-3-methyl-4-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-
-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00102##
[0378] A mixture of tert-butyl
trans-3-((3-cyanoisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate
(790 mg, 2.235 mmol), ethyl hydrazinecarboxylate (1164 mg, 11.18
mmol) and DBU (168 .mu.L, 1.118 mmol) in N-methyl-2-pyrrolidinone
(5.6 mL) and under a nitrogen atmosphere was heated at 170.degree.
C. in a sealed vial for 16 hours. The reaction mixture was allowed
to cool to RT and was poured onto ice water, forming a pale yellow
precipitate. After the ice melted (total volume was 100 mL) the
solid was filtered and dried to give the title compound as a pale
yellow solid (647 mg, 70.3%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 1.12 (d, 3H), 1.40 (d, 9H), 3.11 (d, 1H), 3.70 (dd,
2H), 3.86-4.04 (m, 2H), 5.70-5.80 (1H, m), 7.68 (t, 1H), 7.81 (t,
1H), 7.98 (s, 1H), 8.02 (d, 1H), 8.18 (d, 1H), 11.79 (s, 1H), 12.03
(d, 1H); ESI-MS m/z [M+H-Boc].sup.+ 312.7.
Step D:
3-(1-((trans-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,-
4-triazol-5(4H)-one
##STR00103##
[0380] A mixture of ter t-butyl
trans-3-methyl-4-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-
-1-yl)oxy)pyrrolidine-1-carboxylate (0.640 g, 1.555 mmol) and HCl
in 1,4-dioxane (3.8 mL, 15.55 mmol) was stirred for 30 minutes,
forming a mustard colored precipitate. The precipitate was
filtered, washed with diethyl ether, and dried to give an HCl salt
of the title compound (0.550 g, quantitative yield). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 1.19 (d, 3H), 2.68-2.74 (m,
1H), 3.03 (dd, 1H), 3.27-3.60 (m, 3H), 3.86 (dd, 1H), 5.73-5.85 (m,
1H), 7.69 (t, 1H), 7.78-7.90 (m, 1H), 8.02 (s, 1H), 8.04 (d, 1H),
8.21-8.30 (m, 1H), 9.48 (br s, 1H), 9.67 (br s, 1H), 11.8 (s,
0.5H), 12.01 (s, 0.5H); ESI-MS m/z [M+H].sup.+ 312.6.
Step E:
3-(1-(((3R,4S)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin--
3-yl)-1H-1,2,4-triazol-5(4H)-one and
3-(1-(((3S,4R)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one (Mixture of Enantiomers)
[0381] A suspension of
3-(1-((trans-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triaz-
ol-5(4H)-one, HCl (0.55 g, 1.58 mmol) and 2,6-dimethylpyridine
(0.37 mL, 3.16 mmol) in DCM (13 mL) was cooled to 0.degree. C.
Acryloyl chloride (0.26 mL, 3.16 mmol) was added and the reaction
mixture was stirred for 10 minutes, forming a pale yellow
precipitate. The reaction was quenched with aqueous NaHCO.sub.3 (15
mL) and the mixture was filtered. The precipitate was collected,
washed with DCM (2.times.5 mL) and water (2.times.5 mL) and dried
to give the title compounds (a mixture of enantiomers) as a white
solid (300 mg, 52%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 1.15 (d, J=6.83 Hz, 3H), 2.53-2.65 (m, 1H), 3.25-3.45 (1H, m),
3.55 (ddd, 1H), 3.81-4.03 (m, 1H), 4.20 (1H, ddd), 5.65 (ddd, 1H),
5.73-5.88 (m, 1H), 6.15 (ddd, J=16.84, 9.76, 2.20 Hz, 1H), 6.60
(1H, ddd), 7.67 (td, J=7.32, 3.42 Hz, 1H), 7.81 (t, J=7.57 Hz, 1H),
7.93-8.08 (m, 2H), 8.19 (d, J=8.30 Hz, 1H), 11.79 (br s, 1H), 12.03
(br s, 1H); ESI-MS m/z [M+H].sup.+ 366.
Example 20:
3-(1-(((3R,4S)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one
##STR00104##
[0383] The enantiomers of EXAMPLE 19 were separated using chiral
supercritical fluid chromatography (SFC) eluting with CO.sub.2,
IPA, and 0.1% diethyl amine. During the SFC separation a
diethylamine adduct was formed in a 1:1 ratio with title compound.
Further purification via preparative HPLC gave the title compound
as a white solid (22 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 1.10 (d, 3H), 2.45-2.58 (m, 1H), 3.20 (dd, 1H), 3.54
(dd, 1H), 3.76 (dd, 1H), 3.89-4.08 (m, 1H), 5.51-5.67 (m, 1H),
5.67-5.78 (m, 1H), 6.08 (ddd, 1H), 6.50 (dd, 1H), 7.60 (td, 1H),
7.74 (t, 1H), 7.88-8.01 (m, 2H), 8.12 (d, 1H), 11.73 (s, 1H), 11.96
(d, 1H); ESI-MS m/z [M+H].sup.+ 366.6.
Example 21:
3-(1-(((3S,4R)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1-
H-1,2,4-triazol-5(4H)-one
##STR00105##
[0385] The enantiomers of EXAMPLE 19 were separated using chiral
SFC eluting with CO.sub.2, IPA, and 0.1% diethyl amine. During the
SFC separation a diethylamine adduct was formed in a 1:1 ratio with
title compound. Further purification via preparative HPLC gave the
title compound as a white solid (24 mg). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 1.08 (3H, d), 2.55-2.65 (m, 1H), 3.20
(dd, 1H), 3.54 (dd, 1H), 3.76 (dd, 1H), 3.89-4.08 (m, 1H),
5.54-5.76 (m, 2H), 6.09 (ddd, 1H), 6.50 (dd, 1H), 7.60 (td, 1H),
7.74 (t, 1H), 7.87-8.01 (m, 2H), 8.12 (d, 1H), 11.73 (s, 1H), 11.96
(d, 1H); ESI-MS m/z [M+H].sup.+ 366.6.
Example 22:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one
##STR00106##
[0386] Step A: (S)-tert-butyl
3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00107##
[0388] To a solution of (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (2.18 g, 12 mmol) in THF (50 mL)
was added NaH (0.464 g, 12 mmol) at 0.degree. C. The mixture was
stirred at RT for 30 minutes. Next,
1-chloro-8-fluoroisoquinoline-3-carbonitrile (1.6 g, 8 mmol) was
added and the reaction mixture was warmed to RT and stirred for 4
hours. The reaction was subsequently quenched with H.sub.2O (20 mL)
and the mixture was extracted with EtOAc (3.times.50 mL). The
organic layers were combined and concentrated in vacuo. The crude
product was purified by preparative HPLC to give the title compound
(1 g, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.72 (s,
2H), 7.61-7.59 (d, J=8 Hz, 1H), 7.38-7.32 (t, J=12 Hz, 1H), 5.8 (s,
1H), 3.75-3.59 (m, 4H), 2.29-2.28 (d, J=4 Hz, 2H).
Step B: (S)-tert-butyl
3-((8-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate
##STR00108##
[0390] To a mixture of (S)-tert-butyl
3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
(600 mg, 1.61 mmol) in MeOH (15 mL) was added
NH.sub.2NH.sub.2H.sub.2O (10 mL) and the resulting mixture was
heated to reflux for 2 hours. The solvent was removed in vacuo to
afford the title compound as a white solid, which was used without
further purification (500 mg).
Step C: (S)-tert-butyl
3-((8-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate
##STR00109##
##STR00110##
[0392] To a mixture of (S)-tert-butyl
3-((8-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate (500 mg, 1.12 mmol) in dioxane (10 mL) was added CDI
(362 mg, 2.24 mmol) and the resulting mixture was heated to reflux
for 2 hours. The reaction mixture was concentrated in vacuo to give
crude product, which was purified by preparative HPLC to give the
title compound (220 mg, 47.4%). ESI-MS m/z [M+H-Boc].sup.+ 316.
Step D:
(S)-3-(8-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one
[0393] A solution of (S)-tert-butyl
3-((8-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate (90 mg, 0.224 mmol) in HCl/EtOAc (4M,
10 mL) was stirred at RT for 2 hours. The mixture was subsequently
concentrated in vacuo to give an HCl salt of title compound (80 mg,
100%).
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl-
)-1H-1,2,4-triazol-5(4H)-one
[0394] To a mixture of
(S)-3-(8-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol--
5(4H)-one hydrochloride (80 mg, 0.22 mmol) in DCM (5 mL) was added
2,6-dimethylpyridine (70 mg, 0.6 mmol). The mixture was cooled to
-40.degree. C. Acryloyl chloride (25 mg, 0.28 mmol) was added and
the reaction mixture was warmed to 0.degree. C. over a 30 minute
period. The reaction was quenched with MeOH (5 mL) and the mixture
concentrated in vacuo. The crude product was purified by
preparative HPLC to give the title compound (43 mg, 54%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.07 (s, 1H), 11.88 (s,
1H), 8.01 (s, 1H), 7.85-7.83 (d, J=8 Hz, 1H), 7.78-7.76 (t, J=4 Hz,
1H), 7.39 (m, 1H), 6.67-6.64 (m, 1H), 6.19-6.14 (m, 2H), 5.72-5.66
(m, 1H), 4.06 (m, 0.5H), 3.85-3.58 (m, 3.5H), 2.29-2.25 (m,
2H).
Example 23:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one
##STR00111##
[0395] Step A: (S)-tert-butyl
3-((3-cyano-8-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00112##
[0397] To a suspension of
1-chloro-8-fluoroisoquinoline-3-carbonitrile (0.8 g, 3.88 mmol) and
Et.sub.3N (0.78 g, 7.76 mmol) in NMP (5 mL) was added
(S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.87 g, 4.66 mmol)
at RT. The resulting mixture was heated at 160.degree. C. for 30
minutes in a microwave reactor. The reaction was quenched with
water and the mixture was extracted with EtOAc (3.times.30 mL). The
organic phase was dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The crude product was purified by column chromatography
eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:50-1:9
gradient) on silica gel to give the title compound (1.12 g, 81%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.56-7.52 (m, 1H),
7.44-7.42 (d, 1H, J=8.0 Hz), 7.29 (s, 1H), 7.21-7.18 (m, 1H),
6.47-6.43 (m, 1H), 4.73 (br s, 1H), 3.77-3.72 (dd, J.sub.1=6.4 Hz,
J.sub.2=11.6 Hz, 1H), 3.48-3.19 (m, 3H), 2.26 (br s, 1H), 1.90 (br
s, 1H), 1.41 (s, 9H); ESI-MS m/z [M+H-tert-butyl].sup.+ 301.2.
Step B: 0-tert-butyl
3-((8-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate
##STR00113##
[0399] To a mixture of (S)-tert-butyl
3-((3-cyano-8-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
(1.0 g, 2.81 mmol), ethyl hydrazinecarboxylate (7.74 g, 74.40 mmol)
and 2,3,4,5,7,8,9,10-octahydropyrido[1,2-a][1,3]diazepine (1.13 g,
7.44 mmol) was added a catalytic amount of NaH (10 mg, 0.25 mmol).
The reaction mixture was heated to 170.degree. C. for 30 minutes.
The crude product was purified by preparative HPLC to give the
title compound as pale yellow solid (300 mg, 25.7%). ESI-MS m/z
[M+H].sup.+ 415.2.
Step C:
(S)-3-(8-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5(4H)-one
##STR00114##
[0401] To a mixture of (S)-tert-butyl
3-((8-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate (300 mg, 0.72 mmol) in EtOAc (5 mL)
was added a 4M solution of HCl in EtOAc (5 mL). The reaction
mixture was stirred at RT for 45 minutes. The solvent was removed
in vacuo to give an HCl salt of the title compound (250 mg, 99.2%).
ESI-MS m/z [M+H].sup.+ 315.2.
Step D:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3--
yl)-1H-1,2,4-triazol-5(4H)-one
[0402] To a mixture of
(S)-3-(8-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one hydrochloride (250 mg, 0.71 mmol) in DCM (15 mL) was
added a solution of 2,6-dimethylpyridine (192 mg, 1.8 mmol) in DCM
(1 mL). Acryloyl chloride (135 mg, 1.5 mmol) in DCM (1.35 mL) was
added dropwise via syringe at -78.degree. C. The reaction mixture
was stirred at -78.degree. C. for 30 minutes. Additional
2,6-dimethylpyridine (32 mg, 0.3 mmol) in DCM (0.32 mL) was added
followed by acryloyl chloride (45 mg, 0.50 mmol) in DCM (0.45 mL).
The reaction mixture was stirred at -10.degree. C. for 20 minutes.
The reaction was quenched with MeOH (1 mL) and the mixture was
concentrated under vacuum. The crude product was purified by
preparative HPLC to give the title compound as a white solid (40.58
mg, 15.5%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.91
(s, 1H), 11.78 (s, 1H), 7.69-7.63 (m, 3H), 7.60-7.58 (m, 1H),
6.61-6.55 (m, 2H), 6.18-6.13 (m, 1H), 5.67-5.64 (m, 1H), 5.30-5.10
(m, 1H), 4.17-4.15 (m, 1H), 3.66-3.63 (m, 2H), 3.28-3.25 (m, 1H),
2.25-2.03 (m, 2H); ESI-MS m/z [M+H].sup.+ 369.1.
Example 24:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one
##STR00115##
[0403] Step A: (S)-tert-butyl
3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00116##
[0405] To a solution of (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (201 mg, 1.076 mmol) in THF (5
mL) at 0.degree. C. was added NaH (81 mg, 1.35 mmol). The reaction
mixture was stirred at RT for 30 minutes. Next,
1,7-dichloroisoquinoline-3-carbonitrile (200 mg, 0.897 mmol) was
added and the reaction mixture was warmed to RT over a 1 hour
period. The reaction was quenched with saturated aqueous NH.sub.4Cl
(10 mL) and the resulting mixture was extracted with EtOAc
(3.times.50 mL). The organic layers were combined, washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated. The crude
product was purified by preparative TLC eluting with petroleum
ether and ethyl acetate (PE/EtOAc=3:1) to give the title compound
(200 mg, 59%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.15
(s, 1H), 7.65-7.71 (m, 3H), 5.74 (br, 1H), 3.46-3.69 (m, 4H), 2.23
(s, 1H), 1.49 (s, 9H).
Step B: (S)-tert-butyl
3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate
##STR00117##
[0407] To a mixture of (S)-tert-butyl
3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
(300 mg, 1.61 mmol) in MeOH (4 mL) was added
NH.sub.2NH.sub.2.H.sub.2O (5 mL). The resulting mixture was heated
to reflux for 2 hours. The solvents were removed in vacuo to give
the title compound, which was used without further purification.
ESI-MS m/z [M+H].sup.+ 406.1.
Step C: (S)-tert-butyl
3-((7-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate
##STR00118##
[0409] To a mixture of (S)-tert-butyl
3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate (350 mg, 0.862 mmol) in dioxane (8 mL) was added CDI
(210 mg, 1.293 mmol). The reaction mixture was heated to reflux for
2 hours and was subsequently concentrated in vacuo. The crude
product was purified by preparative HPLC to give the title compound
(200 mg, 57%).
Step D:
(S)-3-(7-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one
##STR00119##
[0411] A solution of (5)-tert-butyl
3-((7-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate (200 mg, 0.463 mmol) in 4M HCl/EtOAc
(5 mL) was stirred at RT for 2 hours. The reaction mixture was
subsequently concentrated in vacuo to give the title compound (180
mg, 100%).
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl-
)-1H-1,2,4-triazol-5(4H)-one
[0412] To a mixture of
(S)-3-(7-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol--
5(4H)-one (180 mg, 0.489 mmol) in DCM (10 mL) was added
2,6-dimethylpyridine (157 mg, 1.467 mmol) at -20.degree. C.
followed by the dropwise addition of acryloyl chloride (88 mg,
0.978 mmol, 10 mg/mL in dry DCM). The reaction mixture was warmed
to 0.degree. C. over a 30 minute period. The reaction was quenched
with MeOH (5 mL) and the mixture concentrated in vacuo. The crude
product was purified by preparative HPLC to give the title compound
(35 mg, 18%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.06
(br, 1H), 11.84 (s, 1H), 8.16 (s, 1H), 8.09 (dd, J=1.8 Hz and 8.9
Hz, 1H), 8.03 (s, 1H), 7.83-7.86 (m, 1H), 6.55-6.72 (m, 1H),
6.12-6.19 (m, 2H), 5.63-5.72 (m, 1H), 4.65-4.12 (m, 4H), 2.25-2.42
(m, 2H).
Example 25:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-fluoroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one
##STR00120##
[0413] Step A: (S)-tert-butyl
3-((3-chloro-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00121##
[0415] To a solution of 1,3-dichloro-7-fluoroisoquinoline (1 g, 4.6
mmol) in NMP (15 mL) was added (S)-tert-butyl
3-aminopyrrolidine-1-carboxylate (1.72 g, 9.3 mmol) and Et.sub.3N
(1.4 g, 14 mmol). The reaction mixture was heated at 160.degree. C.
for 2 hours. The mixture was subsequently partition between
H.sub.2O (20 mL) and EtOAc (20 mL). The aqueous phase was extracted
with EtOAc (3.times.20 mL). The organic layers were combined, dried
over Na.sub.2SO.sub.4, and concentrated. The crude product was
purified by column chromatography eluting with petroleum ether and
ethyl acetate (PE/EA=10:1-5:1 gradient) to give the title compound
(1.2 g, 70%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.26-8.23 (d, J=10.8 Hz, 1H), 7.82-7.80 (dd, J.sub.1=8.8 Hz,
J.sub.2=5.2 Hz, 1H), 7.68-7.67 (d, J=5.6 Hz 1H), 7.63-7.60 (t,
J=8.8 Hz, 1H), 7.10 (s, 1H), 4.63-4.53 (m, 1H), 3.70-3.66 (m, 1H),
3.48-3.45 (m, 1H), 3.29-3.26 (m, 1H), 2.23-2.18 (m, 1H), 2.03-1.97
(m, 1H), 1.40 (s, 9H).
Step B: (S)-tert-butyl
3-((3-cyano-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00122##
[0417] To a solution of (S)-tert-butyl
3-((3-chloro-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
(0.5 g, 1.37 mmol) in DMF (15 mL) was added Zn(CN).sub.2 (0.48 g,
4.1 mmol), and Pd(PPh.sub.3).sub.4 (0.16 g, 0.14 mmol) under a
nitrogen atmosphere. The mixture was heated to 160.degree. C. for
30 minutes in a microwave reactor. The mixture was partition
between EtOAc (50 mL) and water (50 mL). The aqueous layer was
extracted with EtOAc (3.times.50 mL). The organic layers were
combined, washed with saturated aqueous NaCl (3.times.50 mL) and
concentrated in vacuo. The crude product was purified by column
chromatography eluting with petroleum ether and ethyl acetate
(PE/EtOAc=10:1-5:1 gradient) to give the title compound (0.36 g,
72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.38-8.35 (d,
J=10.8 Hz, 1H), 8.11-7.97 (m, 1H), 7.77-7.72 (m, 3H), 4.66-4.58 (m,
1H), 3.69-3.67 (m, 1H), 3.48-3.46 (m, 1H), 3.39-3.37 (m, 1H),
3.28-3.27 (m, 1H), 2.2 (s, 1H), 1.97-1.91 (m, 1H), 1.40 (s,
9H).
Step C: (S)-tert-butyl
3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidin-
e-1-carboxylate
##STR00123##
[0419] To a mixture of (S)-tert-butyl
3-((3-cyano-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
(350 mg, 1 mmol) in MeOH (10 mL) was added NH.sub.2NH.sub.2H.sub.2O
(10 mL). The reaction mixture was heated to reflux for 2 hours. The
solvent was removed to give the title compound as white solid,
which was used without further purification (350 mg, 92%). ESI-MS
m/z [M+H].sup.+ 389.2.
Step D: (S)-tert-butyl
3-((7-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate
##STR00124##
[0421] To a solution of (S)-tert-butyl
3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidin-
e-1-carboxylate (0.35 g, 1 mmol) in dioxane (10 mL) was added CDI
(0.36 g, 2 mmol) under a nitrogen atmosphere. The mixture was
heated to reflux for 2 hours and was subsequently concentrated in
vacuo. The crude product was purified by preparative HPLC to give
the title compound (120 mg, 34%). ESI-MS m/z [M+H].sup.+ 415.2.
Step E:
(S)-3-(7-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5(4H)-one
##STR00125##
[0423] A solution of (S)-tert-butyl
3-((7-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate (120 mg, 0.29 mmol) in 4M HCl/EtOAc
(10 mL) was stirred at RT for 30 minutes. The reaction mixture was
concentrated in vacuo to give the title compound, which was used
without further purification (100 mg, 100%). ESI-MS m/z [M+H].sup.+
315.2.
Step F:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-fluoroisoquinolin-3--
yl)-1H-1,2,4-triazol-5(4H)-one
[0424] To a mixture of
(S)-3-(7-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one (100 mg, 0.35 mmol) in DCM (10 mL) was added
2,6-dimethylpyridine (122 mg, 1.15 mmol). The resulting mixture was
cooled to -40.degree. C. Acryloyl chloride (45 mg, 0.49 mmol) was
added dropwise and the reaction mixture was stirred at -40.degree.
C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and
the mixture concentrated in vacuo. The crude product was purified
by preparative HPLC to give the title compound (79 mg, 75%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.84 (s, 1H),
11.70 (s, 1H), 8.25-8.22 (d, J=10.8 Hz, 1H), 7.97-7.96 (m, 1H),
7.63-7.60 (m, 2H), 7.55-7.54 (m, 1H), 6.59-6.57 (m, 1H), 6.21-6.15
(m, 1H), 5.68-5.65 (dd, J.sub.1=10.4 Hz, J.sub.2=2.4 Hz, 1H),
5.20-5.18 (m, 1H), 4.19-4.15 (m, 0.5H), 3.70-3.67 (m, 2H),
3.69-3.45 (m, 1.5H), 3.25 (m, 0.5H), 2.26-2.24 (m, 1H), 2.08-2.03
(m, 1H).
Example 26:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H--
1,2,4-triazol-5 (4H)-one
##STR00126##
[0425] Step A: (S)-tert-butyl
3-((7-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00127##
[0427] To a solution of 1,7-dichloroisoquinoline-3-carbonitrile
(500 mg, 2.24 mmol) in NMP (5 mL) was added (S)-tert-butyl
3-aminopyrrolidine-1-carboxylate (460 mg, 2.46 mmol) and Et.sub.3N
(453 mg, 4.48 mmol). The solution was heated to 160.degree. C. for
30 minutes in a microwave reactor. The reaction was quenched with
H.sub.2O (20 mL) and extracted with EtOAc (3.times.10 mL). The
organic layers were combined and concentrated in vacuo. The crude
product was purified by column chromatography eluting with ethyl
acetate and petroleum ether (EtOAc/PE=1:10 to 1:5 gradient) to give
the title compound (660 mg, 79%). ESI-MS m/z [M+H-tert-butyl].sup.+
317.
Step B: (S)-tert-butyl
3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidin-
e-1-carboxylate
##STR00128##
[0429] To a mixture of (S)-tert-butyl
3-((7-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
(660 mg, 1.77 mmol) in MeOH (5 mL) was added
NH.sub.2NH.sub.2H.sub.2O (5 mL) and the resulting mixture was
heated to reflux for 2 hours. The solvent was subsequently removed
to give the title compound as a yellow solid, which was used
without further purification (710 mg). ESI-MS m/z [M+H].sup.+
405.
Step C: (S)-tert-butyl
3-((7-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate
##STR00129##
[0431] To a mixture of (S)-tert-butyl
3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidin-
e-1-carboxylate (710 mg) in dioxane (10 mL) was added CDI (42.6 mg,
2.63 mmol). The resulting mixture was heated to reflux for 2 hours.
The reaction mixture was concentrated in vacuo. The crude product
was purified by preparative HPLC to give the title compound (130
mg, 17% over 2 steps). ESI-MS m/z [M+H].sup.+ 431.
Step D:
(S)-3-(7-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5 (4H)-one
##STR00130##
[0433] A solution of (S)-tert-butyl
3-((7-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate (130 mg, 0.30 mmol) in 4M HCl/EtOAc
(4 mL) was stirred at RT for 50 minutes. The reaction mixture was
subsequently concentrated in vacuo to give an HCl salt of the title
compound (120 mg). ESI-MS m/z [M+H].sup.+ 331.
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3--
yl)-1H-1,2,4-triazol-5(4H)-one
[0434] To a mixture of
(S)-3-(7-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one hydrochloride (120 mg) in DCM (8 mL) was added
2,6-dimethylpyridine (105 mg, 0.978 mmol). The resulting mixture
was cooled to -78.degree. C. and acryloyl chloride (48 mg, 0.530
mmol, 10 mg/mL in dry DCM) was added dropwise. The reaction mixture
was stirred at -78.degree. C. for 30 minutes. The reaction was
quenched with MeOH (5 mL) and the mixture was concentrated in
vacuo. The crude product was purified by preparative HPLC to give
the title compound (22 mg, 18% over 2 steps). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 11.87 (s, 1H), 11.72 (s, 1H), 8.51 (S,
1H), 7.88 (m, 1H), 7.60-7.70 (m, 2H), 7.56 (d, 1H, J=4.0 Hz),
6.55-6.57 (m, 1H), 6.13-6.19 (m, 1H), 5.63-5.70 (m, 1H), 5.17-5.18
(m, 1H), 3.65-4.17 (m, 4H), 2.11-2.37 (m, 2H); ESI-MS m/z
[M+H].sup.+ 385.
Example 27:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,-
2,4-triazol-5(4H)-one
##STR00131##
[0435] Step A: (S)-tert-butyl
3-((8-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00132##
[0437] To a solution of (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (126 mg, 0.674 mmol) in THF (5
mL) was added NaH (26.8 mg, 0.677 mmol) at 0.degree. C. The mixture
was stirred for 30 minutes. Next,
1,8-dichloroisoquinoline-3-carbonitrile was added and the reaction
mixture was warmed to RT for 4 hours. The reaction was quenched
with H.sub.2O (2 mL) and the mixture was extracted with EtOAc
(3.times.10 mL). The organic layers were combined and concentrated
in vacuo. The crude product was purified by preparative TLC to give
the title compound (120 mg, 73.2%).
Step B: (S)-tert-butyl
3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate
##STR00133##
[0439] To (S)-tert-butyl
3-((8-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
(120 mg, 0.32 mmol) in MeOH (50 mL) was added
NH.sub.2NH.sub.2H.sub.2O (5 mL). The resulting mixture was heated
to reflux for 2 hours and then cooled and concentrated in vacuo to
give the title compound as a yellow solid, which was used without
further purification (130.3 mg, 100%). ESI-MS m/z [M+H].sup.+
406.2.
Step C: (S)-tert-butyl
3-((8-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate
##STR00134##
[0441] To (S)-tert-butyl
3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine--
1-carboxylate (130 mg, 1.61 mmol) in dioxane (10 mL) was added CDI
(78 mg, 0.48 mmol). The resulting mixture was heated to reflux for
2 hours and was then cooled and concentrated in vacuo. The crude
product was purified by preparative HPLC to give the title compound
(50 mg, 35%). ESI-MS m/z [M+H-Boc].sup.+332.2.
Step D:
(S)-3-(8-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-t-
riazol-5(4H)-one
##STR00135##
[0443] A solution of (S)-tert-butyl
3-((8-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
oxy)pyrrolidine-1-carboxylate (50 mg, 0.116 mmol) in HCl/EtOAc (10
mL) was stirred at RT for 2 hours. The reaction mixture was
subsequently concentrated in vacuo to give an HCl salt of the title
compound (42.6 mg). ESI-MS m/z [M+H].sup.+ 332.2.
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl-
)-1H-1,2,4-triazol-5(4H)-one
[0444] To
(S)-3-(8-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5(4H)-one hydrochloride (42.6 mg, 0.116 mmol) in DCM (25
mL) was added 2,6-dimethylpyridine (37.24 mg, 0.35 mmol). The
resulting mixture was cooled to -20.degree. C. Acryloyl chloride
(26.1 mg, 0.29 mmol, 10 mg/mL in dry DCM) was added dropwise and
the reaction mixture was warmed to 0.degree. C. for 30 minutes. The
reaction was quenched with MeOH (5 mL) and the mixture was
concentrated in vacuo. The crude product was purified by
preparative HPLC to give the title compound (22.02 mg, 49.25%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.09 (s, 1H),
11.87 (s, 1H), 8.11-7.98 (m, 2H), 7.71-7.70 (d, J=4.0 Hz, 2H),
6.67-6.57 (m, 1H), 6.26-6.14 (m, 2H), 5.72-5.63 (m, 1H), 4.11-3.71
(m, 4H), 2.33-2.24 (m, 2H); ESI-MS m/z [M+H].sup.+ 386.1.
Example 28:
(S)-3-(1-((l-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H--
1,2,4-triazol-5(4H)-one
##STR00136##
[0445] Step A: (S)-tert-butyl
3-((8-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00137##
[0447] To a suspension of 1,8-dichloroisoquinoline-3-carbonitrile
(0.3 g, 1.35 mmol) and Et.sub.3N (0.27 g, 2.7 mmol) in NMP (5 mL)
was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.3 g,
1.62 mmol) at RT. The resulting mixture was stirred at 160.degree.
C. for 30 minutes in a microwave reactor. The reaction was
subsequently quenched with water and the mixture was extracted with
EtOAc (3.times.30 mL). The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was
purified by column chromatography eluting with ethyl acetate and
petroleum ether (EtOAc/PE=1:10-1:2 gradient) on silica gel to give
the title compound (0.45 g, 85%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.92-7.90 (d, J=8.0 Hz, 1H), 7.85-7.83
(m, 2H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 4.66-4.58 (m,
1H), 3.75-3.72 (t, J=8.0 Hz, 3H), 3.52-3.35 (m, 3H), 2.31-2.30 (br
s, 1H), 2.11-2.07 (br s, 1H), 1.47-1.45 (s, 9H).
Step B: (S)-tert-butyl
3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidin-
e-1-carboxylate
##STR00138##
[0449] To a mixture of (S)-tert-butyl
3-((8-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
(450 mg, 1.21 mmol) in MeOH (5 mL) was added
NH.sub.2NH.sub.2H.sub.2O (5 mL). The resulting mixture was heated
to reflux for 2 hours and the solvent was subsequently removed to
give the title compound as a yellow solid, which was used without
further purification (450 mg, 91%). ESI-MS m/z [M+H].sup.+
405.2.
Step C: (S)-tert-butyl
3-((8-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate
##STR00139##
[0451] To a mixture of (S)-tert-butyl
3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidin-
e-1-carboxylate (450 mg, 1.1 mmol) in dioxane (10 mL) was added CDI
(360 mg, 2.2 mmol). The resulting mixture was heated to reflux for
2 hours and was subsequently concentrated in vacuo. The crude
product was purified by preparative HPLC to give the title compound
(170 mg, 45%). ESI-MS m/z [M+H].sup.+ 431.1.
Step D:
(S)-3-(8-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-
-triazol-5(4H)-one hydrochloride
##STR00140##
[0453] A solution of (S)-tert-butyl
3-((8-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)-
amino)pyrrolidine-1-carboxylate (170 mg, 0.52 mmol) in HCl/EtOAc
(10 mL) was stirred at RT for 2 hours. The reaction mixture was
subsequently concentrated in vacuo to give an HCl salt of the title
compound (160 mg, 100%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 11.90 (s, 1H), 11.85 (s, 1H), 9.134 (s, 2H), 7.86-7.84
(dd, J.sub.1=2.8 Hz, J.sub.2=6.8 Hz, 1H), 7.64-7.62 (m, 3H),
7.57-7.56 (d, J=6.4 Hz, 1H), 5.0 (s, 1H), 3.65-3.60 (m, 1H),
3.24-3.21 (m, 2H), 2.40-2.36 (m, 1H), 2.11-2.07 (m, 1H).
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3--
yl)-1H-1,2,4-triazol-5(4H)-one
[0454] To a mixture of
(S)-3-(8-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazo-
l-5(4H)-one hydrochloride (100 mg, 0.3 mmol) in DCM (20 mL) was
added 2,6-dimethylpyridine (97 mg, 0.91 mmol). The resulting
mixture was cooled to -40.degree. C. Acryloyl chloride (51 mg, 0.6
mmol, 10 mg/mL in dry DCM) was added dropwise and the mixture was
stirred at -40.degree. C. for 30 minutes. The reaction was
subsequently quenched with MeOH (5 mL) and the mixture was
concentrated in vacuo. The crude product was purified by
preparative HPLC to give the title compound (57 mg, 52%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.91 (s, 1H), 11.80 (s,
1H), 7.85-7.83 (m, 1H), 7.61-7.59 (m, 3H), 7.49-7.47 (m, 1H),
6.6-6.5 (m, 1H), 6.17-6.13 (m, 1H), 5.67-5.63 (m, 1H), 5.18-5.16
(m, 1H), 4.18-4.17 (m, 0.5H), 3.69-3.65 (m, 0.5H), 3.42 (m, 0.5H),
3.32-3.31 (m, 1.5H), 2.31-2.29 (m, 1H), 2.04-2.01 (m, 1H); ESI-MS
m/z [M+H].sup.+ 385.1.
Example 29:
(S)-3-(1-((l-acryloylpyrrolidin-3-yl)amino)-8-methoxyisoquinolin-3-yl)-1H-
-1,2,4-triazol-5(4H)-one
##STR00141##
[0455] Step A: (S)-tert-butyl
3-((3-cyano-8-methoxyisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
##STR00142##
[0457] To a solution of
1-chloro-8-methoxyisoquinoline-3-carbonitrile (230 mg, 1.05 mmol)
in NMP (5 mL) was added (S)-tert-butyl
3-aminopyrrolidine-1-carboxylate (294 mg, 1.57 mmol) and Et.sub.3N
(212 mg, 2.1 mmol). The reaction mixture was heated to 130.degree.
C. for 45 minutes in a microwave reactor and was subsequently
quenched with H.sub.2O (20 mL). The aqueous phase was extracted
with EtOAc (3.times.10 mL). The organic layers were combined and
concentrated in vacuo. The crude product was purified by column
chromatography eluting with ethyl acetate and petroleum ether
(EtOAc/PE=1:20-1:2 gradient) to give the title compound (380 mg, 2
batches, 52%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.85
(s, 1H), 7.55 (t, 1H, J=8.0 Hz), 7.25 (s, 1H), 6.97 (d, 1H, J=8.0
Hz), 4.60-4.80 (m, 1H), 4.01 (s, 3H), 3.78-3.79 (m, 1H), 3.27-3.57
(m, 3H), 2.29-2.34 (m, 1H), 1.94-1.99 (m, 1H), 1.48 (s, 9H).
Step B: (S)-tert-butyl
3-((3-(hydrazinyl(imino)methyl)-8-methoxyisoquinolin-1-yl)amino)pyrrolidi-
ne-1-carboxylate
##STR00143##
[0459] To a mixture of (S)-tert-butyl
3-((3-cyano-8-methoxyisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate
(380 mg, 1.03 mmol) in MeOH (5 mL) was added
NH.sub.2NH.sub.2.H.sub.2O (5 mL). The resulting mixture was heated
to reflux for 2 hours. The solvent was removed to give the title
compound as a yellow solid, which was used without further
purification (660 mg). ESI-MS m/z [M+H].sup.+ 401.
Step C: (S)-tert-butyl
3-((8-methoxy-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl-
)amino)pyrrolidine-1-carboxylate
##STR00144##
[0461] To a mixture of (S)-tert-butyl
3-((3-(hydrazinyl(imino)methyl)-8-methoxyisoquinolin-1-yl)amino)pyrrolidi-
ne-1-carboxylate (400 mg, 1.0 mmol) in dioxane (10 mL) was added
CDI (245 mg, 1.5 mmol). The resulting mixture was heated to reflux
for 2 hours and then concentrated in vacuo. The crude product was
purified by preparative HPLC to give the title compound (80 mg, 18%
over 2 steps). ESI-MS m/z [M+H].sup.+ 427.
Step D:
(S)-3-(8-methoxy-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,-
4-triazol-5(4H)-one
##STR00145##
[0463] A solution of (5)-tert-butyl
3-((8-methoxy-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl-
)amino)pyrrolidine-1-carboxylate (80 mg, 0.187 mmol) in HCl/EtOAc
(5 mL) was stirred at RT for 1 hour. The reaction mixture was
subsequently concentrated in vacuo to give an HCl salt of the title
compound, which was used without further purification (120 mg).
ESI-MS m/z [M+H].sup.+ 327.
Step E:
(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-methoxyisoquinolin-3-
-yl)-1H-1,2,4-triazol-5(4H)-one
[0464] To a mixture of
(S)-3-(8-methoxy-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triaz-
ol-5(4H)-one hydrochloride (120 mg, 0.33 mmol) in DCM (8 mL) was
added 2,6-dimethylpyridine (106 mg, 0.99 mmol). The resulting
mixture was cooled to -78.degree. C. Acryloyl chloride (120 mg,
1.20 mmol, 10 mg/mL in dry DCM) was added dropwise and the reaction
mixture was stirred at -78.degree. C. for 1.5 hours. The reaction
was quenched with MeOH (5 mL) and the mixture was concentrated in
vacuo. The crude product was purified by preparative HPLC to give
the title compound (34 mg, 27%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 11.81 (s, 1H), 11.69 (s, 1H), 7.85 (dd,
14.5 Hz, 1H), 7.57-7.51 (m, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d,
J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.72-6.54 (m, 1H), 6.16 (m,
1H), 5.73-5.61 (m, 1H), 5.21-5.03 (m, 1H), 4.16 (m, 1H), 4.04-3.89
(m, 3H), 3.79 (m, 1H), 3.71-3.61 (m, 1H), 3.44 (m, 1H), 3.24 (m,
1H), 2.42-2.21 (m, 1H), 2.09-1.90 (m, 1H); ESI-MS m/z [M+H].sup.+
381.
Example 30:
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-4-methylpyridin-2-yl)-1H-1,2,4--
triazol-5(4H)-one
##STR00146##
[0465] Step A: 2-cyano-4-methylpyridine-1-oxide
##STR00147##
[0467] A solution of 4-methylpicolinonitrile (5 g, 42.3 mmol) in
DCM (25 mL) was cooled in an ice/brine bath. To this solution was
added mCPBA (14.61 g, 85 mmol). The reaction mixture was allowed to
warm to RT and was stirred overnight. The mixture was subsequently
diluted with DCM until all solids were dissolved and was washed
with 1N NaOH (2.times.200 mL) and with brine. The organic phase was
dried over MgSO.sub.4, filtered, and concentrated in vacuo to give
the title compound as a white solid (4.03 g, 71%). ESI-MS m/z
[M+H].sup.+ 135.1.
Step B: 6-chloro-4-methylpicolinonitrile
##STR00148##
[0469] A mixture of 2-cyano-4-methylpyridine-1-oxide (4.03 g, 30
mmol) in phosphoryl trichloride (80 mL, 858 mmol) was heated to
reflux overnight. The solvent was removed in vacuo. The residue was
treated with ice and its pH made basic using saturated NaOH
solution at 0.degree. C. The aqueous layer was extracted with DCM
(3.times.). The organic layers were combined, dried over
MgSO.sub.4, filtered, and evaporated in vacuo to give the title
compound (3.7 g, 81%). ESI-MS m/z [M+H].sup.+ 153.6.
Step C:
3-(6-chloro-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one
##STR00149##
[0471] A mixture of 6-chloro-4-methylpicolinonitrile (3 g, 19.66
mmol) and ethyl hydrazinecarboxylate (8.19 g, 79 mmol) in NMP (6
mL) was heated in a sealed tube at 160.degree. C. overnight. The
residue was purified by column chromatography eluting with a
gradient of 0-80% EtOAc in heptanes. The product-containing
fractions were collected and evaporated in vacuo to give the title
compound as a yellow semi-solid (428 mg). ESI-MS m/z [M+H].sup.+
211.6.
Step D: (S)-tert-butyl
3-((4-methyl-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)-
pyrrolidine-1-carboxylate
##STR00150##
[0473] A mixture of
3-(6-chloro-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (428
mg, 2.032 mmol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate
(457 mg, 2.439 mmol) and sodium hydride (81 mg, 2.032 mmol) in
N-methyl-2-pyrrolidinone (7 mL) was heated in a microwave reactor
at 140.degree. C. for 30 minutes. After cooling, water was added
and the mixture was extracted with EtOAc. The aqueous layer was
acidified with 1M HCl aq and extracted with EtOAc. The organic
layers were combined, dried over MgSO.sub.4, filtered, and
evaporated in vacuo to give the title compound, which was used
without further purification. ESI-MS [M+H-tert-butyl].sup.+
306.2.
Step E:
(S)-3-(4-methyl-6-(pyrrolidin-3-yloxy)pyridin-2-yl)-1H-1,2,4-triaz-
ol-5(4H)-one
##STR00151##
[0475] A mixture of (S)-tert-butyl
3-((4-methyl-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)-
pyrrolidine-1-carboxylate (700 mg, 1.937 mmol) and TFA (3 mL, 38.9
mmol) was stirred at RT for 1 hour. The solvent was removed in
vacuo and the crude product purified by preparative HPLC eluting
with a gradient 5-40% ACN in water (acid mode). The
product-containing fractions were collected and evaporated in vacuo
to give the title compound (12 mg, 2%).
Step F:
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-4-methylpyridin-2-yl)-1H-
-1,2,4-triazol-5(4H)-one
[0476] To
(S)-3-(4-methyl-6-(pyrrolidin-3-yloxy)pyridin-2-yl)-1H-1,2,4-tri-
azol-5(4H)-one (23 mg, 0.088 mmol), which was dissolved in a
minimal amount of DCM, was added 2,6-dimethylpyridine (20.44 .mu.L,
0.176 mmol) and acryloyl chloride (9.56 mg, 0.106 mmol). The
reaction mixture was stirred overnight at RT and was subsequently
diluted with water and extracted with EtOAc (2.times.). The organic
layers were combined, dried over MgSO.sub.4, filtered, and
evaporated in vacuo. The crude product was purified by preparative
HPLC eluting with a gradient of 20-45% ACN in water (acid mode).
The product-containing fractions were combined and evaporated in
vacuo to give a TFA salt of the title compound (12 mg). ESI-MS m/z
[M+H].sup.+ 316.3.
Example 31:
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5-
(4H)-one
##STR00152##
[0477] Step A: (S)-tert-butyl
3-((6-cyanopyridin-2-yl)oxy)pyrrolidine-1-carboxylate
##STR00153##
[0479] To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (676
mg, 3.61 mmol) in NMP (4 mL) at 0.degree. C. was added
Cs.sub.2CO.sub.3 (1176 mg, 3.61 mmol) followed by
6-chloropicolinonitrile (500 mg, 3.61 mmol). The mixture was heated
at 140.degree. C. for 15 minutes in a microwave reactor to give the
title compound. The crude product was used directly in the next
step.
Step B: (S)-tert-butyl
3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)pyrrolidi-
ne-1-carboxylate
##STR00154##
[0481] To crude (S)-tert-butyl
3-((6-cyanopyridin-2-yl)oxy)pyrrolidine-1-carboxylate (1.044 g) in
NMP (1.5 mL) was added ethyl hydrazinecarboxylate (0.752 g, 7.22
mmol). The reaction mixture was heated at 175.degree. C. overnight
and was subsequently cooled and diluted with EtOAc. The organic
phase was washed with saturated aqueous NH.sub.4Cl, dried, and
concentrated to give the title compound, which was used without
further purification.
Step C:
(S)-3-(6-(pyrrolidin-3-yloxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)--
one
##STR00155##
[0483] Crude (S)-tert-butyl
3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)pyrrolidi-
ne-1-carboxylate was treated with DCM (4 mL) and TFA (2 mL) for 2
hours at RT and then concentrated. The crude product was purified
by preparative HPLC eluting with a gradient of 1-25% ACN in water
(acid mode) to give the title compound (125 mg, 14.0% over 3
steps).
Step D:
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1H-1,2,4-tr-
iazol-5(4H)-one
[0484] To a solution of
(S)-3-(6-(pyrrolidin-3-yloxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one
(84 mg, 0.340 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine
(0.118 mL, 1.019 mmol) at 0.degree. C. followed by acryloyl
chloride (0.041 mL, 0.510 mmol). The mixture was stirred overnight.
The reaction was subsequently quenched with water and the solvent
was removed in a rotary evaporator. The crude product was purified
by preparative HPLC eluting with a gradient of 20-31% ACN in water
(acid mode) to give a TFA salt of the title compound (7 mg, 7%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) (rotamers were observed)
.delta. ppm 1.90-2.25 (m, 2H), 3.35-3.75 (m, 3.5H), 3.90-4.00 (m,
0.5H), 5.75-5.90 (m, 1H), 5.60 (ddd, J=18.57, 10.36, 2.40 Hz, 1H),
6.00-6.13 (m, 1H), 6.43-6.64 (m, 1H), 6.80 (dd, J=8.34, 4.55 Hz,
1H), 7.44 (d, J=7.58 Hz, 1H), 7.68-7.80 (m, 1H); ESI-MS m/z
[M+H].sup.+ 302.3.
Example 32:
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-5-methylpyridin-2-yl)-1H-1,2,4--
triazol-5(4H)-one
##STR00156##
[0485] Step A: (S)-tert-butyl
3-((6-cyano-3-methylpyridin-2-yl)oxy)pyrrolidine-1-carboxylate
##STR00157##
[0487] To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (491
mg, 2.62 mmol) in NMP (4 mL) was added Cs.sub.2CO.sub.3 (1025 mg,
3.15 mmol). The mixture was stirred at 0.degree. C. for 1 hour at
which time 6-chloro-5-methylpicolinonitrile (400 mg, 2.62 mmol) was
added. The reaction mixture was heated at 140.degree. C. for 1 hour
in a microwave reactor to give the title compound in a crude
reaction mixture that was used directly in the next step.
Step B: (S)-tert-butyl
3-((3-methyl-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)-
pyrrolidine-1-carboxylate
##STR00158##
[0489] To the reaction mixture containing (S)-tert-butyl
3-((6-cyano-3-methylpyridin-2-yl)oxy)pyrrolidine-1-carboxylate
(1.095 g) was added NMP (1.5 mL) and ethyl hydrazinecarboxylate
(0.752 g, 7.22 mmol). The mixture was heated at 175.degree. C. for
1.5 days and was subsequently cooled and diluted with EtOAc. The
organic phase was washed with aqueous NH.sub.4Cl, dried, and
concentrated. The crude product was purified by preparative HPLC
eluting with a gradient of 35-60% ACN in water (acid mode) to give
the title compound (0.042 g, 4.4% over 2 steps).
Step C:
(S)-3-(5-methyl-6-(pyrrolidin-3-yloxy)pyridin-2-yl)-1H-1,2,4-triaz-
ol-5(4H)-one
##STR00159##
[0491] To a solution of (S)-tert-butyl
3-((3-methyl-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)-
pyrrolidine-1-carboxylate (0.042 g, 0.115 mmol) in DCM (5 mL) was
added TFA (1 mL). The reaction mixture was stirred at RT overnight.
The solvent was removed in vacuo and the residue was dried under
high vacuum to give the title compound, which was used directly to
the next step.
Step D:
(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-5-methylpyridin-2-yl)-1H-
-1,2,4-triazol-5(4H)-one
[0492] To a solution of
(S)-3-(5-methyl-6-(pyrrolidin-3-yloxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H-
)-one (30 mg, 0.115 mmol) in DCM (10 mL) was added
2,6-dimethylpyridine (0.040 mL, 0.344 mmol) at 0.degree. C.
followed by acryloyl chloride (0.014 mL, 0.172 mmol). The mixture
was stirred overnight. The reaction was quenched with water and the
mixture concentrated in vacuo. The crude product was purified by
preparative HPLC eluting with a gradient of 20-37% ACN in water
(acid mode) to give a TFA salt of the title compound (6 mg, 17%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.14-2.29 (m, 1H),
2.32 (br s, 1H), 3.39 (s, 3H), 3.45-3.99 (m, 4H), 5.49-5.70 (m,
1H), 5.74 (br s, 1H), 6.09 (ddd, J=16.74, 8.53, 2.27 Hz, 1H),
6.47-6.68 (m, 1H), 7.56-7.68 (m, 1H), 7.76 (t, J=7.58 Hz, 1H),
7.93-8.05 (m, 1H), 8.13 (d, J=8.34 Hz, 1H); ESI-MS m/z [M+H].sup.+
316.3.
Example 33:
(S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-di-
hydro-3H-1,2,4-triazol-3-one
##STR00160##
[0494] To a solution of
(S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(10 mg, 0.034 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(5.28 .mu.L, 0.045 mmol) at 0.degree. C. followed by 2-chloroacetyl
chloride (5.06 .mu.L, 0.064 mmol). The reaction mixture was stirred
at room temperature overnight. A white solid formed, which was
filtered. This solid quickly gummed up and was treated with MeOH.
The resulting liquor was combined with the filtrate, passed through
a membrane, and purified by mass-triggered HPLC eluting with a
gradient of 25-45% ACN in water (acid mode). The product-containing
fractions were concentrated to give a TFA salt of the title
compound as a yellow film (5.9 mg, 35%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 2.35-2.57 (m, 2H), 3.71-3.99 (m, 3H), 4.12
(dd, J=12.38, 4.29 Hz, 1H), 4.22 (s, 1H), 4.31 (s, 1H), 6.16 (br s,
1H), 6.22 (br s, 1H), 7.63-7.71 (m, 1H), 7.76-7.84 (m, 1H),
7.90-8.03 (m, 2H), 8.26 (d, J=7.58 Hz, 1H); ESI-MS m/z [M+H].sup.+
374.4.
Example 34:
(S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-2,4--
dihydro-3H-1,2,4-triazol-3-one
##STR00161##
[0496] To a solution of
(S)-3-(1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-o-
ne (0.028 g, 0.093 mmol) in DCM (5 mL) was added
2,6-dimethylpyridine (0.054 mL, 0.465 mmol) at 0.degree. C.
followed by 2-chloroacetyl chloride (0.011 mL, 0.140 mmol). The
reaction mixture was allowed to warm to room temperature overnight,
then quenched with water, and concentrated to dryness. The crude
residue was purified by preparative HPLC to give a TFA salt of the
title compound as yellow a solid (1.9 mg). ESI-MS m/z [M+H].sup.+
373.4.
Example 35:
(S)-5-(1-((1-acryloylpiperidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H--
1,2,4-triazol-3-one
##STR00162##
[0498] To a solution of
(S)-3-(1-(piperidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one
(175 mg, 0.562 mmol) in DCM (3 mL) was added 2,6-dimethylpyridine
(0.131 mL, 1.124 mmol) at 0.degree. C. followed by acryloyl
chloride (0.091 mL, 1.124 mmol). The reaction mixture was stirred
at room temperature overnight. The crude reaction mixture was
filtered and purified by preparative HPLC eluting with 20-65% ACN
(acid mode) to give a TFA salt of the title compound. A related
compound,
(S)-1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)piperi-
din-3-yl acrylate, was also isolated during the chromatographic
separation. Peak 1: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.28 (s, 1H), 1.53-1.67 (m, 1H), 1.80 (dd, J=9.85, 3.79 Hz, 1H),
1.93-2.09 (m, 1H), 2.75 (s, 3H), 3.03-3.17 (m, 1H), 3.24 (t,
J=10.11 Hz, 1H), 3.63-3.77 (m, 1H), 3.86 (d, J=12.88 Hz, 1H), 4.03
(dt, J=8.46, 4.36 Hz, 1H), 6.09 (dd, J=10.48, 1.64 Hz, 1H), 6.70
(dd, J=17.18, 1.77 Hz, 1H), 7.94 (d, J=8.08 Hz, 1H), 8.11 (s, 1H),
8.19 (d, J=8.34 Hz, 1H), 8.33 (t, J=7.96 Hz, 1H); peak 2: .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.66-1.95 (m, 2H), 1.95-2.06
(m, 1H), 2.12 (d, J=4.29 Hz, 1H), 2.76 (s, 2H), 3.39-3.51 (m, 1H),
3.71-3.83 (m, 1H), 4.02 (d, J=9.09 Hz, 1H), 5.34 (dt, J=8.15, 4.39
Hz, 1H), 5.88-5.99 (m, 1H), 6.22 (dd, J=17.31, 10.48 Hz, 1H), 6.49
(dd, J=17.43, 1.52 Hz, 1H), 7.61 (ddd, J=8.27, 6.88, 1.26 Hz, 1H),
7.66-7.77 (m, 1H), 7.85-7.97 (m, 1H), 8.16 (d, J=7.83 Hz, 1H).
Example 36:
(S)-5-(1-((1-acetylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1-
,2,4-triazol-3-one
##STR00163##
[0500] A solution of
(S)-5-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-3H-1,2,4-triazol-3-one
(200 mg, 0.677 mmol) and 2,6-dimethylpyridine (0.079 mL, 0.677
mmol) in DCM (4 mL) was mixed for 30 minutes. A freshly prepared
mixture of acetyl chloride (80 mg, 1.016 mmol),
2,6-dimethylpyridine (0.079 mL, 0.677 mmol) in DCM (1 mL) was added
dropwise. The reaction mixture stirred for 20 minutes and then
concentrated. The product was purified using preparative HPLC
eluting with a gradient of 25-55% ACN in water (acid mode) to give
a TFA salt of the title compound (15 mg, 7%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.93-2.06 (m, 3H), 2.09-2.43 (m, 2H),
3.38 (br s, 4H), 3.48-3.86 (m, 4H), 3.93-4.18 (m, 1H), 6.04-6.31
(m, 1H), 7.63-7.74 (m, 1H), 7.76-7.87 (m, 1H), 7.94-8.08 (m, 2H),
8.18 (dd, J=8.21, 0.88 Hz, 1H), 11.80 (s, 1H), 12.04 (br s, 1H);
ESI-MS m/z [M+H].sup.+ 340.2.
Example 37:
(S)-5-(1-((1-propionylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3-
H-1,2,4-triazol-3-one
##STR00164##
[0502] A solution of
(S)-5-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-3H-1,2,4-triazol-3-one
(200 mg, 0.677 mmol) and 2,6-dimethylpyridine (0.079 mL, 0.677
mmol) in DCM (4 mL) was mixed for 30 minutes. A freshly prepared
mixture of propionyl chloride (94 mg, 1.016 mmol),
2,6-dimethylpyridine (0.079 mL, 0.677 mmol) in DCM (1 mL) was added
dropwise. The reaction mixture stirred for 20 minutes and then
concentrated. The product was purified using preparative HPLC
eluting with a gradient of 25-55% ACN in water (acid mode) to give
a TFA salt of the title compound (12 mg, 5%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.95-1.04 (m, 3H), 2.16-2.40 (m, 4H),
2.48-2.52 (m, 8H), 2.64 (s, 1H), 3.13 (dt, J=3.16, 1.71 Hz, 3H),
3.50-3.79 (m, 3H), 4.11 (s, 10H), 6.08-6.18 (m, 1H), 7.58-7.66 (m,
1H), 7.76 (t, J=7.19 Hz, 1H), 7.94 (d, J=5.13 Hz, 2H), 8.16 (d,
J=8.34 Hz, 1H); ESI-MS m/z [M+H].sup.+ 354.1.
[0503] TABLE 1, below, lists BTK inhibition data for many of the
compounds described in the examples, where larger pIC.sub.50 values
represent higher potency. The compounds were tested in accordance
with the assay described on page 42 of the specification.
[0504] As used in this specification and the appended claims,
singular articles such as "a," "an," and "the," may refer to a
single object or to a plurality of objects unless the context
clearly indicates otherwise. Thus, for example, reference to a
composition containing "a compound" may include a single compound
or two or more compounds. It is to be understood that the above
description is intended to be illustrative and not restrictive.
Many embodiments will be apparent to those of skill in the art upon
reading the above description. Therefore, the scope of the
invention should be determined with reference to the appended
claims and includes the full scope of equivalents to which such
claims are entitled. The disclosures of all articles and
references, including patents, patent applications and
publications, are herein incorporated by reference in their
entirety and for all purposes.
TABLE-US-00001 TABLE 1 BTK Inhibition (pIC.sub.50) for Example
Compounds Example No. pIC.sub.50 1 6.7 2 7.1 3 6.5 4 >8.1 5
>8.7 6 8.0 7 8.0 8 >8.6 9 >7.9 10 7.5 11 8.5 12 6.9 13
>8.0 14 8.2 15 7.6 16 >8.5 17 >8.6 18 >8.2 19 >8.2
20 >8.6 21 6.9 22 >8.9 23 >8.9 24 >8.9 25 >8.6 26
>8.6 27 >8.9 28 >8.6 29 >8.6 30 >8.6 31 7.2 32 8.3
33 >8.2 34 >8.6 35 7.5
* * * * *