U.S. patent application number 15/578623 was filed with the patent office on 2018-06-14 for tyrosine kinase inhibitors.
This patent application is currently assigned to PRINCIPIA BIOPHARMA INC.. The applicant listed for this patent is PRINCIPIA BIOPHARMA INC.. Invention is credited to David M. GOLDSTEIN, Timothy D. OWENS.
Application Number | 20180162861 15/578623 |
Document ID | / |
Family ID | 56118090 |
Filed Date | 2018-06-14 |
United States Patent
Application |
20180162861 |
Kind Code |
A1 |
GOLDSTEIN; David M. ; et
al. |
June 14, 2018 |
TYROSINE KINASE INHIBITORS
Abstract
The present disclosure provides compounds that are tyrosine
kinase inhibitors, in particular Bruton tyrosine kinase ("BTK")
inhibitors, and are therefore useful for the treatment of diseases
treatable by inhibition of BTK such as cancer, autoimmune,
inflammatory, and thromboembolic diseases. Also provided are
pharmaceutical compositions containing such compounds and processes
for preparing such compounds.
Inventors: |
GOLDSTEIN; David M.;
(Redwood City, CA) ; OWENS; Timothy D.; (Redwood
City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PRINCIPIA BIOPHARMA INC. |
South San Francisco |
CA |
US |
|
|
Assignee: |
PRINCIPIA BIOPHARMA INC.
South San Francisco
CA
|
Family ID: |
56118090 |
Appl. No.: |
15/578623 |
Filed: |
June 2, 2016 |
PCT Filed: |
June 2, 2016 |
PCT NO: |
PCT/US2016/035588 |
371 Date: |
November 30, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62170547 |
Jun 3, 2015 |
|
|
|
62271689 |
Dec 28, 2015 |
|
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 29/00 20180101; C07D 473/34 20130101; A61P 35/00 20180101;
A61P 37/00 20180101 |
International
Class: |
C07D 473/34 20060101
C07D473/34; C07D 471/04 20060101 C07D471/04; A61P 35/00 20060101
A61P035/00; A61P 37/00 20060101 A61P037/00; A61P 29/00 20060101
A61P029/00 |
Claims
1. A compound of Formula (I): ##STR00056## wherein: R.sup.1 and
R.sup.2 are independently hydrogen, alkyl, alkoxy, halolakyl, or
halo; X is --O--, --CONR--, --NRCO--, or --NR--CO--NR' where R and
R' are independently hydrogen or alkyl; Ar is heteroaryl or phenyl
where heteroaryl and phenyl are optionally substituted with one,
two, or three substituents independently selected from alkyl, halo,
haloalkyl, alkoxy, and hydroxy; A is --N-- or --CR.sup.3-- wherein
R.sup.3 is hydrogen, alkyl, cyclopropyl, halo, haloalkyl,
haloalkoxy, alkoxy, or cyano; Y is bond or alkylene; ring Z is
heterocycloamino optionally substituted with one or two
substituents independently selected from alkyl, hydroxy, alkoxy,
and fluoro; R.sup.5 is a group of formula (i), (ii), (iii) or (iv):
##STR00057## wherein: R.sup.a is hydrogen, fluoro, or cyano;
provided that when R.sup.a is cyano then R.sup.b is hydrogen and
R.sup.c is not hydrogen; R.sup.b is hydrogen or alkyl; and R.sup.c
is hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl (optionally
substituted with one or two substituents independently selected
from hydroxy, hydoxyalkyl, heteroaryl (optionally substituted with
one or two substituents independently selected from alkyl and
heterocyclyl wherein heterocyclyl is optionally substituted with
one or two substituents independently selected from halo and
alkyl), and --CONR.sup.9R.sup.10 (where R.sup.9 and R.sup.10 are
independently hydrogen or alkyl, or R.sup.9 and R.sup.10 together
with the nitrogen atom to which they are attached form a
heterocyclyl optionally substituted with one or two substituents
selected from alkyl and heterocyclyl)), cycloalkyl (optionally
substituted with one or two substituents independently selected
from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent
substituents of the cycloalkyl together with the carbon atoms to
which they are attached form a heterocyclyl group),
heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and
heterocyclyl in heterocyclylalkyl are optionally substituted with
one, two, or three substituents where two of the optional
substituents are independently selected from alkyl, alkoxy,
hydroxy, halo, amino, and oxo, and one of the optional substituent
is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl, haloalkyl,
alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the
heterocyclyl is substituted with one or two substitutents
independently selected from hydrogen, alkyl, halo, hydroxy, and
alkoxy), or -(alkylene)-NR.sup.6R.sup.7 (where R.sup.6 and R.sup.7
are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl
is optionally substituted with one or two substituents
independently selected from alkyl, halo, hydroxy, hydroxyalkyl,
alkoxyalkyl, acyl, and alkoxycarbonyl; or R.sup.6 and R.sup.7
together with the nitrogen atom to which they are attached form
##STR00058## where one or two of X.sup.1, X.sup.2 and X.sup.3 are
nitrogen and the rest are carbon and the ring is optionally
substituted with one or two substituents independently selected
from alkyl, haloalkyl, and halo); and/or a pharmaceutically
acceptable salt thereof provided that: when A is --N--, then
R.sup.a is cyano and R.sup.c is heterocycloaminolalkyl wherein the
heterocycloamino in heterocycloaminoalkyl is optionally substituted
with one or two substituents independently selected from alkyl,
alkoxy, hydroxy, halo, amino, and oxo, and the nitrogen atom of
heterocycloamino is substituted with heterocyclyl wherein the
heterocyclyl is substituted with one or two substituents
independently selected from hydrogen, alkyl, halo, hydroxy, and
alkoxy.
2. The compound of claim 1 and/or a pharmaceutically acceptable
salt thereof wherein A is --CR.sup.3--.
3. The compound of claim 2 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.3 is hydrogen, methyl, ethyl, isopropyl,
fluoro, or chloro.
4. The compound of claim 3 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.3 is hydrogen.
5. The compound of claim 1 and/or a pharmaceutically acceptable
salt thereof wherein A is --N--.
6. The compound of any of claims 1 to 5 and/or a pharmaceutically
acceptable salt thereof wherein --X--Ar is attached to carbon at
the 4-position of the phenyl ring, the carbon of the phenyl ring
attached to N of the cyclic urea ring being position 1.
7. The compound of any of claims 1 to 6 and/or a pharmaceutically
acceptable salt thereof wherein X is --O--.
8. The compound of claim 7 and/or a pharmaceutically acceptable
salt thereof wherein Ar is pyridinyl, pyrimidinyl, thienyl, or
pyrazinyl optionally substituted with one, two, or three
substituents independently selected from alkyl, halo, haloalkyl,
alkoxy, and hydroxy.
9. The compound of claim 7 and/or a pharmaceutically acceptable
salt thereof wherein Ar is phenyl where phenyl is optionally
substituted with one, two, or three substituents independently
selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy.
10. The compound of any of claims 1 to 9 and/or a pharmaceutically
acceptable salt thereof wherein R.sup.1 and R.sup.2 are
independently hydrogen or halo, preferably hydrogen or fluoro.
11. The compound of claim 10 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.1 and R.sup.2 are hydrogen or R.sup.1 is
hydrogen and R.sup.2 is fluoro.
12. The compound of any of claims 1 to 11 and/or a pharmaceutically
acceptable salt thereof wherein Y is a bond and ring Z is
piperidinyl wherein the carbon atom at the 3-position of the
piperidinyl ring is attached to the nitrogen atom of the cyclic
urea ring,
13. The compound of claim 12 and/or a pharmaceutically acceptable
salt thereof wherein the stereochemistry at carbon of the
piperidinyl attached to the cyclic urea nitrogen is (R).
14. The compound of any of claims 1-4 and 6 to 13 and/or a
pharmaceutically acceptable salt thereof wherein R.sup.a is
hydrogen.
15. The compound of claim 13 or 14 and/or a pharmaceutically
acceptable salt thereof wherein R.sup.5 is a group of formula
(i).
16. The compound of claim 13 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.5 is a group of formula (iv).
17. The compound of claim 14 or 15 and/or a pharmaceutically
acceptable salt thereof wherein R.sup.b and R.sup.c are
hydrogen.
18. The compound of claim 14 or a pharmaceutically acceptable salt
thereof wherein R.sup.b is hydrogen and R.sup.c is alkyl or
-(alkylene)-NR.sup.6R.sup.7 (where R.sup.6 and R.sup.7 are
independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl
is optionally substituted with one or two substituents
independently selected from alkyl, halo, hydroxy, hydroxyalkyl,
alkoxyalkyl, acyl, and alkoxycarbonyl), preferably R.sup.6 and
R.sup.7 are independently hydrogen or alkyl.
19. The compound of any of claims 1-13 and/or a pharmaceutically
acceptable salt thereof wherein R.sup.a is cyano.
20. The compound of claim 19 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.5 is a group of formula (i).
21. The compound of 20 and/or a pharmaceutically acceptable salt
thereof wherein R.sup.c is heterocyclylalkyl wherein the
heterocyclyl in heterocyclylalkyl is optionally substituted with
one, two, or three substituents where two of the optional
substituents are independently selected from alkyl, alkoxy,
hydroxy, halo, amino, and oxo, and one of the optional substituent
is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl,
alkylsulfonyl, alkoxycarbonyl, or another heterocyclyl wherein the
another heterocyclyl is optionally substituted with one or two
substitutents independently selected from alkyl, halo, hydroxy, and
alkoxy.
22. The compound of claim 21 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is --C(CH.sub.3).sub.2morpholine-4-yl,
--C(CH.sub.3).sub.2-4-(2,2,2-trifluoroethyl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-(1-methyl)piperidin-1-yl, ##STR00059##
--C(CH.sub.3).sub.2-4-ethyl-3-oxopiperazin-1-yl,
C(CH.sub.3).sub.2tetrahydropyran-4-yl,
--C(CH.sub.3).sub.2-4-methoxycarbonylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(oxetan-4-yl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3-methyloxetan-4-yl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-t-butoxycarbonylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-acetylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-methoxycarbonylpiperazin-1-yl,
--C(CH.sub.3).sub.2-piperazin-1-yl,
--C(CH.sub.3).sub.2-3,3-difluoropyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(S)-3-methoxypyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(R)-3-methoxypyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(S)-2-(methoxymethyl)pyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(R)-2-(methoxymethyl)pyrrolidin-1-yl,
##STR00060## --C(CH.sub.3).sub.2-4-methylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-ethylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-isopropylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(2-methoxyethyl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-acetylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3R,5S)-3,4,5-trimethylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3R,5S)-3,5-dimethylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3R,5S)-dimethylmorpholin-4-yl,
--C(CH.sub.3).sub.2-piperidin-1-yl,
--C(CH.sub.3).sub.2-pyrrolidin-1-yl,
--C(CH.sub.3).sub.2-3-oxo-piperazin-1-yl, or
--C(CH.sub.3).sub.2-(3-oxo-4-methylpiperazin-1-yl).
23. The compound of claim 20 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is unsubstituted alkyl.
24. The compound of claim 23 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is tert-butyl.
25. The compound of claim 20 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is cycloalkyl, which is optionally
substituted with one or two substituents independently selected
from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent
substituents of the cycloalkyl together with the carbon atoms to
which they are attached form a heterocyclyl group.
26. The compound of claim 25 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is 1-methylcyclobutyl,
1-phenylcyclopropyl, 1-methylcyclopropyl, 2,2-difluorocyclopropyl,
##STR00061##
27. The compound of claim 20 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is heterocyclyl which is optionally
substituted with one, two, or three substituents where two of the
optional substituents are independently selected from alkyl,
alkoxy, hydroxy, halo, amino, and oxo, and one of the optional
substituent is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl,
haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein
the heterocyclyl is substituted with one or two substitutents
independently selected from hydrogen, alkyl, halo, hydroxy, and
alkoxy.
28. The compound of claim 27 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is ##STR00062##
29. The compound of claim 20 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is alkyl which is optionally
substituted with one or two substituents independently selected
from hydroxy, hydoxyalkyl, and heteroaryl which is substituted with
one or two substituents independently selected from alkyl and
heterocyclyl wherein heterocyclyl is optionally substituted with
one or two substituents independently selected from halo and
alkyl.
30. The compound of claim 29 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is alkyl which is substituted with one
or two hydroxy substituents.
31. The compound of claim 30 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is ##STR00063##
32. The compound of claim 20 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is alkyl which is substituted with a
heteroaryl that is optionally substituted with one or two
substituents independently selected from alkyl and heterocyclyl
wherein heterocyclyl is optionally substituted with one or two
substituents independently selected from halo and alkyl.
33. The compound of claim 32 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is ##STR00064##
34. The compound of claim 20 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is alkyl that is substituted with
--CONR.sup.9R.sup.10, where R.sup.9 and R.sup.10 are independently
hydrogen or alkyl, or R.sup.9 and R.sup.10 together with the
nitrogen atom to which they are attached form a heterocyclyl
optionally substituted with one or two substituents selected from
alkyl and heterocyclyl.
35. The compound of claim 34 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.9 and R.sup.10 are both hydrogen or
alkyl.
36. The compound of claim 35 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is --C(CH.sub.3).sub.2--CONH.sub.2 or
--C(CH.sub.3).sub.2--CON(CH.sub.3).sub.2.
37. The compound of claim 34 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.9 and R.sup.10 together with the
nitrogen atom to which they are attached form a heterocyclyl
optionally substituted with one or two substituents selected from
alkyl and heterocyclyl.
38. The compound of of claim 37 and/or a pharmaceutically
acceptable salt thereof wherein the heterocyclyl formed by R.sup.9
and R.sup.10 together with the nitrogen atom to which they are
attached is 4-methylpiperazinyl, or
4-(oxetan-3-yl)piperazin-1-yl.
39. The compound of any of claims 1-11 and/or a pharmaceutically
acceptable salt thereof wherein Y is alkylene and ring Z is
pyrrolidinyl.
40. The compound of claim 39 and/or a pharmaceutically acceptable
salt thereof wherein Y is methylene and ring Z is
2-pyrrolidinyl.
41. The compound of claim 40 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.5 is a group of formula (i) or (iv).
42. The compound of any of claims 1, 5, and 6-13, and/or a
pharmaceutically acceptable salt thereof wherein R.sup.5 is a group
of formula (i), R.sup.a is cyano, R.sup.b is hydrogen and R.sup.c
is heterocyclylalkyl, wherein heterocyclyl in heterocyclylalkyl is
optionally substituted with one, two, or three substituents where
two of the optional substituents are independently selected from
alkyl, alkoxy, hydroxy, halo, amino, and oxo, and one of the
optional substituent is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,
acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl
wherein the heterocyclyl is substituted with one or two
substitutents independently selected from hydrogen, alkyl, halo,
hydroxy, and alkoxy.
43. The compound of claim 42 and/or a pharmaceutically acceptable
salt thereof wherein R.sup.c is ##STR00065##
44. A compound selected from the group consisting of:
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitr-
ile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,-
5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(1-methylcyclobutyl)acrylonitril-
e;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5--
c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitri-
le;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-
-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazi-
n-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(2,2,2-trifluoroethyl)pi-
perazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1-methylpiperidin-4-yl)pen-
t-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-cyclobutylacrylonitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)-4-
-methylpent-2-enenitrile; (R)-methyl
4-(5-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]p-
yridin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazin-
e-1-carboxylate;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-6-hydroxy-4-(2-hydroxyethyl)hex-2-enen-
itrile;
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidaz-
o[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-ene-
nitrile;
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imida-
zo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-
-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-e-
nenitrile; (S)-methyl
4-(5-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)-
piperazine-1-carboxylate;
(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4-
,5-c]pyridin-2(3H)-one;
(R)-4-amino-1-(1-(but-2-ynoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imid-
azo[4,5-c]pyridin-2(3H)-one;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1--
yl)pent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-
-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-thiopyran-4-yl)acrylo-
nitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidaz-
o[4,5-c]pyridin-1H-yl)piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1--
yl)pent-2-enenitrile;
(S)-1-((1-acryloylpyrrolidin-2-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1H--
imidazo[4,5-c]pyridin-2(3H)-one;
(S)-4-amino-1-((1-(but-2-ynoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl-
)-1H-imidazo[4,5-c]pyridin-2(3H)-one;
(R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H--
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3--
yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H--
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3--
yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imida-
zo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imida-
zo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(3-methyl-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imida-
zo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-(5,6-dihydro-[1,2,4]triazolo[4,3-a]p-
yrazin-7(8H)-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)pip-
erazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine--
1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine--
1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)acrylonitrile;
(R)-2-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine--
1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-eneni-
trile;
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo-
[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methylpip-
erazin-1-yl)pent-2-enenitrile;
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopip-
erazin-1-yl)pent-2-enenitrile;
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methyl(oxetan-3-y-
l)amino)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)ac-
rylonitrile;
(R)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imid-
azo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)p-
iperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(I-oxidotetrahydro-2H-thiopyran-4-yl-
)acrylonitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-meth-
ylpent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-
-yl)acrylonitrile; (R)-tert-butyl
4-(5-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]p-
yridin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazin-
e-1-carboxylate;
(R)-4-(4-acetylpiperazin-1-yl)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,-
3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methylpen-
t-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]oc-
tan-8-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(1-phenylcyclopropyl)acrylonitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enen-
itrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo-
[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(1-methylcyclopropyl)acryloni-
trile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[-
4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethyl-5-(4-methylpiperazi-
n-1-yl)-5-oxopent-2-enenitrile;
(R)-5-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidin-1-yl)-4-cyano-N,N,
2,2-tetramethyl-5-oxopent-3-enamide;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethyl-5-(4-(oxetan-3-yl)piperaz-
in-1-yl)-5-oxopent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(2,2-difluorocyclopropyl)acrylonitri-
le;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-
-c]pyridin-1-yl)piperidine-1-carbonyl)-3-((1R,5S)-3-oxabicyclo[3.1.0]hexan-
-6-yl)acrylonitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(6-(4-methylpiperazin-1-yl)-
pyridin-2-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(pyridin-2-yl)pent-2-enenit-
rile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4-
,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(4-methylpiperazin--
1-yl)pyrimidin-2-yl)pent-2-enenitrile;
(R)-4-amino-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidaz-
o[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-(3,3-difluoropyrrolidin-1-yl)-4-meth-
ylpent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-((S)-3-methoxypyrrolidin-1-yl)-4-met-
hylpent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-((R)-3-methoxypyrrolidin-1-yl)-4-met-
hylpent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-6-oxohexahydropyrrolo[-
1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-((R)-2-(methoxymethyl)pyrrolidin-1-y-
l)-4-methylpent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-y-
l)-4-methylpent-2-enenitrile;
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((S)-6-oxohexahydropyrrolo[-
1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(4-ethyltetrahydro-2H-pyran-4-yl)acr-
ylonitrile;
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-3-(4-(methoxymethyl)tetrahydro-2H-pyra-
n-4-yl)acrylonitrile; and
(R)-4-amino-1-(1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-
-imidazo[4,5-c]pyridin-2(3H)-one; an E or Z isomer, and/or a
pharmaceutically acceptable salt of any of the foregoing
compounds.
45. A pharmaceutical composition comprising a compound and/or a
pharmaceutically acceptable salt of any one of claims 1 to 44 and a
pharmaceutically acceptable excipient.
46. A method of inhibiting BTK in a mammal in need thereof which
method comprises administering to the mammal (such as a human) in
need of such treatment, a pharmaceutical composition comprising a
therapeutically effective amount of a compound of any one of claims
1 to 44, or an (E) or (Z) isomer thereof, and/or a pharmaceutically
acceptable salt of any of the foregoing compounds and a
pharmaceutically acceptable excipient.
47. A method of treating an autoimmune disease, inflammatory
disease, or cancer in a mammal in need thereof comprising
administering to the mammal (such as a human) in need of such
treatment, a pharmaceutical composition comprising a
therapeutically effective amount of a compound of any one of claims
1 to 44, or an (E) or (Z) isomer thereof, and/or a pharmaceutically
acceptable salt of any of the foregoing compounds and a
pharmaceutically acceptable excipient.
48. The method of claim 47 wherein the disease is acute necrotizing
hemorrhagic leukoencephalitis, acute disseminated
encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune
retinopathy, axonal & neuronal neuropathies, chronic
inflammatory demyelinating polyneuropathy (CIDP), demyelinating
neuropathies, Devic's disease (neuromyelitis optica), experimental
allergic encephalomyelitis, giant cell arteritis (temporal
arteritis), Guillain-Barre syndrome, Lambert-Eaton syndrome,
chronic Meniere's disease, myasthenia gravis, neuromyotonia,
opsoclonus-myoclonus syndrome, optic neuritis, paraneoplastic
cerebellar degeneration, peripheral neuropathy, perivenous
encephalomyelitis, restless legs syndrome, stiff person syndrome,
sympathetic ophthalmia, Takayasu's arteritis, temporal
arteritis/Giant cell arteritis, transverse myelitis, multiple
sclerosis, dysautonomia, age-related macular degeneration (wet and
dry), corneal transplantation, encephalitis, meningitis,
vasculitis, and systemic lupus erythematosus (SLE).
49. The method of claim 47 wherein the disease is rheumatoid
arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis,
warm autoimmune hemolytic anemia, Wegener's granulomatosis,
Sjogren's disease, Sjogren's dry eye, non-Sjogren's dry eye
disease, psoriasis, pemphigus, urticaria or asthma.
50. The method of claim 47 wherein the disease is diffuse large B
cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma,
chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, small
lymphocytic lymphoma (SLL), multiple myeloma, B-cell non-Hodgkin
lymphoma, lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia,
splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid
granulomatosis.
51. The method of any of claims 46-50 wherein the compound and/or a
pharmaceutically acceptable salt thereof is administered in
combination with one or more anti-cancer or anti-inflammatory
agents.
Description
[0001] The present application claims the benefit of U.S.
Provisional Application Ser. No. 62/170,547 filed Jun. 3, 2015 and
U.S. Provisional Application Ser. No. 62/271,689 filed Dec. 28,
2015, each of which is incorporated herein by reference in its
entirety.
FIELD OF INVENTION
[0002] The present disclosure provides compounds that are tyrosine
kinase inhibitors, in particular Bruton tyrosine kinase ("BTK")
inhibitors, and are therefore useful for the treatment of diseases
such as cancer, autoimmune, inflammatory, and thromboembolic
diseases. Also provided are pharmaceutical compositions containing
such compounds and processes for preparing such compounds.
BACKGROUND
[0003] BTK, a member of the Tec family non-receptor tyrosine
kinases, is essential for B cell signaling downstream from the
B-cell receptor. It is expressed in B cells and other hematopoietic
cells such as monocytes, macrophages and mast cells. It functions
in various aspects of B cell function that maintain the B cell
repertoire (see Gauld S. B. et al., B cell antigen receptor
signaling: roles in cell development and disease. Science,
296:1641-2. 2002.) B cells pay a role in rheumatoid arthritis (see
Perosa F., et al., CD20-depleting therapy in autoimmune diseases:
from basic research to the clinic. J Intern Med. 267:260-77. 2010
and Dorner T, et al. Targeting B cells in immune-mediated
inflammatory disease: a comprehensive review of mechanisms of
action and identification of biomarkers. Pharmacol Ther.
125:464-75. 2010 and Honigberg, L., et. al., The selective BTK
inhibitor PCI-32765 blocks B cell and mast cell activation and
prevents mouse collagen indiced arthritis. Clin. Immunol. 127
S1:S111. 2008) and in other autoimmune diseases such as systemic
lupus erythematosus and cancers (see Shlomchik M. J., et. al., The
role of B cells in lpr/lpr-induced autoimmunity. J. Exp Med.
180:1295-1306. 1994; Honigberg L. A., The Bruton tyrosine kinase
inhibitor PCI-32765 blocks B-cell activation and is efficacious in
models of autoimmune disease and B-cell malignancy. Proc. Natl.
Acad. Sci. 107:13075-80. 2010; and Mina-Osorio P, et al.,
Suppression of glomerulonephritis in lupus-prone NZB.times.NZW mice
by RN486, a selective inhibitor of Bruton's tyrosine kinase.
Arthritis Rheum. 65: 2380-91. 2013).
[0004] There is also potential for BTK inhibitors for treating
allergic diseases (see Honigberg, L., et. al., The selective BTK
inhibitor PCI-32765 blocks B cell and mast cell activation and
prevents mouse collagen indiced arthritis. Clin. Immunol. 127
S1:S111. 2008). It was noted that the irreversible inhibitor
suppresses passive cutaneous anaphylaxis (PCA) induced by IgE
antigen complex in mice. These findings are in agreement with those
noted with BTK-mutant mast cells and knockout mice and suggest that
BTK inhibitors may be useful for the treatment of asthma, an
IgE-dependent allergic disease of the airway.
[0005] Accordingly, compounds that inhibit BTK would be useful in
treatment for diseases such as autoimmune diseases, inflammatory
diseases, and cancer.
SUMMARY
[0006] In a first aspect, this disclosure is directed to a compound
of Formula (I):
##STR00001##
wherein:
[0007] R.sup.1 and R.sup.2 are independently hydrogen, alkyl,
alkoxy, halolakyl, or halo;
[0008] X is --O--, --CONR--, --NRCO--, or --NR--CO--NR' where R and
R' are independently hydrogen or alkyl;
[0009] Ar is heteroaryl or phenyl where heteroaryl and phenyl are
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, alkoxy, and
hydroxy;
[0010] A is --N-- or --CR.sup.3-- wherein R.sup.3 is hydrogen,
alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or
cyano;
[0011] Y is bond or alkylene;
[0012] ring Z is heterocycloamino optionally substituted with one
or two substituents independently selected from alkyl, hydroxy,
alkoxy, and fluoro;
[0013] R.sup.5 is a group of formula (i), (ii), (iii) or (iv):
##STR00002##
wherein:
[0014] R.sup.a is hydrogen, fluoro, or cyano; provided that when
R.sup.a is cyano then R.sup.b is hydrogen and R.sup.c is not
hydrogen;
[0015] R.sup.b is hydrogen or alkyl; and
[0016] R.sup.c is hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl
(optionally substituted with one or two substituents independently
selected from hydroxy, hydoxyalkyl, heteroaryl (optionally
substituted with one or two substituents independently selected
from alkyl and heterocyclyl wherein heterocyclyl is optionally
substituted with one or two substituents independently selected
from halo and alkyl), and --CONR.sup.9R.sup.10 (where R.sup.9 and
R.sup.10 are independently hydrogen or alkyl, or R.sup.9 and
R.sup.10 together with the nitrogen atom to which they are attached
form a heterocyclyl optionally substituted with one or two
substituents selected from alkyl and heterocyclyl)), cycloalkyl
(optionally substituted with one or two substituents independently
selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two
adjacent substituents of the cycloalkyl together with the carbon
atoms to which they are attached form a heterocyclyl group),
heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and
heterocyclyl in heterocyclylalkyl are optionally substituted with
one, two, or three substituents where two of the optional
substituents are independently selected from alkyl, alkoxy,
hydroxy, halo, amino, and oxo, and one of the optional substituent
is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl, haloalkyl,
alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the
heterocyclyl is substituted with one or two substitutents
independently selected from hydrogen, alkyl, halo, hydroxy, and
alkoxy), or -(alkylene)-NR.sup.6R.sup.7 (where R.sup.6 and R.sup.7
are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl
is optionally substituted with one or two substituents
independently selected from alkyl, halo, hydroxy, hydroxyalkyl,
alkoxyalkyl, acyl, and alkoxycarbonyl; or R.sup.6 and R.sup.7
together with the nitrogen atom to which they are attached form
##STR00003##
where one or two of X.sup.1, X.sup.2 and X.sup.3 are nitrogen and
the rest are carbon and the ring is optionally substituted with one
or two substituents independently selected from alkyl, haloalkyl,
and halo); and/or
[0017] a pharmaceutically acceptable salt thereof provided
that:
[0018] when A is --N--, then R.sup.a is cyano and R.sup.c is
heterocycloaminolalkyl wherein the heterocycloamino in
heterocycloaminoalkyl is optionally substituted with one or two
substituents independently selected from alkyl, alkoxy, hydroxy,
halo, amino, and oxo, and the nitrogen atom of heterocycloamino is
substituted with heterocyclyl wherein the heterocyclyl is
substituted with one or two substituents independently selected
from hydrogen, alkyl, halo, hydroxy, and alkoxy.
[0019] In one embodiment, when R.sup.5 in the compounds of Formula
(I) and/or a pharmaceutically acceptable salt thereof (and any
embodiments thereof disclosed herein) is a group of formula (i),
(ii), or (iii) wherein R.sup.a is cyano, the compounds of the
disclosure are reversible covalent inhibitors of BTK, i.e., they
can form a reversible covalent bond with a thiol group of a
cysteine residue, in particular with Cys481 of BTK.
[0020] In another embodiment, when R.sup.5 in the compounds of
Formula (I) and/or a pharmaceutically acceptable salt thereof (and
any embodiments thereof disclosed herein) is a group of formula
(i), (ii), or (iii) where R.sup.a is hydrogen or fluoro, or R.sup.5
is a group of formula (iv), the compounds of the disclosure are
irreversible covalent inhibitors of BTK, i.e., they can form an
irreversible covalent bond with a thiol group of a cysteine
residue, in particular with Cys481 of BTK.
[0021] In a second aspect, this disclosure is directed to a
pharmaceutical composition comprising a compound of Formula (I) (or
any of the embodiments thereof described herein), and/or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable excipient.
[0022] (a) In embodiment (a) of the second aspect, the formulation
is a solid oral formulation comprising:
[0023] (i) a compound of Formula (I) and/or a pharmaceutically
acceptable salt thereof (or any embodiment thereof disclosed
herein): and
[0024] (ii) means for release of said compound and/or a
pharmaceutically acceptable salt thereof in the intestine.
[0025] (b) In embodiment (b) of the second aspect, the formulation
is a solid oral formulation comprising means for release of a
therapeutically effective amount of a compound of Formula (I)
and/or a pharmaceutically acceptable salt thereof (or any
embodiment thereof disclosed herein) from said oral formulation in
the intestine.
[0026] Within embodiment (a) or (b), in one embodiment the compound
of Formula (I) and/or a pharmaceutically acceptable salt thereof
(or any embodiment thereof disclosed herein) is released in the
small intestine.
[0027] In yet another embodiment of embodiment (a) or (b) and
embodiments contained therein, wherein (i) the compound of Formula
(I) and/or a pharmaceutically acceptable salt thereof (or
embodiments thereof disclosed herein); and/or (ii) the dosage form
comprising a compound of Formula (I) (or embodiments thereof
disclosed herein); and/or a pharmaceutically acceptable salt
thereof; is coated with at least one coating wherein the said
coating is independently chosen from (when more than one coating is
present) enteric coating and a non-enteric time-delayed release
coating, preferably the coating is one or more enteric coating.
[0028] In one embodiment, when the compound of Formula (I) and/or a
pharmaceutically acceptable salt thereof (or embodiments thereof
disclosed herein) and/or the dosage form comprising the compound of
Formula (I) and/or a pharmaceutically acceptable salt thereof (or
embodiments thereof disclosed herein) is coated with an enteric
coating, the enteric coating is a polymer. In another embodiment,
when the compound of Formula (I) and/or a pharmaceutically
acceptable salt thereof and/or the dosage form comprising the
compound of Formula (I) and/or a pharmaceutically acceptable salt
thereof is coated with an enteric coating, the enteric coating is
an anionic polymer selected from polymethacrylates (e.g.,
methacrylic acid ethacrylate poly, methacrylic acid methyl
methacrylate poly); cellulose-based polymers (e.g., cellulose
acetate phthalate CAP, cellulose acetate trimellitate CAT,
cellulose acetate succinate CAS, hydroxypropylmethylcellulose
phthalate HPMCP, hydroxypropylmethylcellulose acetate succinate
HPMCAS), and polyvinyl derivatives such as polyvinyl acetate
phthalate PVAP. In yet another embodiment, the enteric coating
erodes in the gastrointestinal track having a pH from about 4.5 to
about 7 or from about 5 or 5.5 to about 7 to release the compound
of Formula (I) and/or a pharmaceutically acceptable salt thereof
(or embodiments thereof disclosed herein).
[0029] When a non-enteric coating is employed, the non-enteric
time-delayed release dosage forms can be administered in fasted
state and the time-delayed release coating can be designed to
erode, burst, or become hightly permeable in about 0.3 to about 3
hours or in about 0.5 to about 2 hours after administration to
release the compound of Formula (I) (or embodiments thereof
disclosed herein) and/or a pharmaceutically acceptable salt
thereof.
[0030] In a third aspect, this disclosure is directed to a method
of treating a disease treatable by inhibition of BTK in a mammal in
need thereof which method comprises administering to the mammal in
need thereof, a pharmaceutical composition comprising a
therapeutically effective amount of a compound of Formula (I) (or
any of the embodiments thereof described herein) and/or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient. In one embodiment the disease is cancer,
autoimmune, inflammatory, or thromboembolic diseases. In one
embodiment, the disease is acute necrotizing hemorrhagic
leukoencephalitis, acute disseminated encephalomyelitis, Addison's
disease, agammaglobulinemia, alopecia areata, alopecia universalis,
amyloidosis, ankylosing spondylitis, anti-GBM/Anti-TBM nephritis,
antiphospholipid syndrome (APS), antiphospholipid antibody
syndrome, aplastic anemia, arthritis, autoimmune angioedema,
autoimmune dysautonomia, autoimmune hepatitis, autoimmune
hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear
disease (AIED), autoimmune myocarditis, autoimmune oophoritis,
autoimmune pancreatitis, autoimmune retinopathy, autoimmune
thrombocytopenic purpura (ATP), autoimmune thyroid disease,
autoimmune urticaria, autoimmune hemolytic anemia, axonal &
neuronal neuropathies, Balo disease, Behcet's disease, bullous
pemphigoid, cardiomyopathy, Castleman disease, celiac disease,
Chagas disease, chronic fatigue syndrome, chronic inflammatory
demyelinating polyneuropathy (CIDP), chronic recurrent multifocal
ostomyelitis (CRMO), Churg-Strauss syndrome, cicatricial
pemphigoid/benign mucosal pemphigoid, coeliac disease, Cogans
syndrome, cold agglutinin disease, congenital heart block,
coxsackie myocarditis, CREST disease, Crohn's disease,
demyelinating neuropathies, dermatitis herpetiformis,
dermatomyositis, Devic's disease (neuromyelitis optica), diabetes,
discoid lupus, Dressler's syndrome, dry eye, dysautonomia,
endometriosis, eosinophilic esophagitis, eosinophilic fasciitis,
erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome,
experimental allergic encephalomyelitis, fibromyalgia, fibrosing
alveolitis, giant cell arteritis (temporal arteritis), giant cell
myocarditis, glomerulonephritis, Goodpasture's syndrome,
granulomatosis with polyangiitis (GPA) (formerly called Wegener's
Granulomatosis), Graves' disease, Guillain-Barre syndrome,
Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein
purpura, herpes gestationis, hypogammaglobulinemia, idiopathic
pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA
nephropathy, IgG4-related sclerosing disease, immunoregulatory
lipoproteins, inclusion body myositis, inflammatory bowel disease,
interstitial cystitis, juvenile arthritis, juvenile diabetes (Type
I diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton
syndrome, leukocytoclastic vasculitis, lichen planus, lichen
sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus
(SLE), lupus including lupus nephritis, lyme disease, chronic,
Meniere's disease, microscopic polyangiitis, mixed connective
tissue disease (MCTD), mooren's ulcer, Mucha-Habermann disease,
mucous membrane pemphigoid, multiple sclerosis, myasthenia gravis,
myositis, narcolepsy, neuromyotonia, neutropenia, ocular
cicatricial pemphigoid, opsoclonus-myoclonus syndrome, optic
neuritis, Ord's thyroiditis, osteoarthritis, palindromic
rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Streptococcus), paraneoplastic cerebellar
degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry
Romberg syndrome, pars planitis (peripheral uveitis),
Parsonnage-Turner syndrome, peripheral neuropathy, perivenous
encephalomyelitis, pernicious anemia, pemphigus such as pemphigus
vulgaris, pemphigus foliaceus, POEMS syndrome, polyarteritis
nodosa, polymyalgia rheumatica, polymyositis, postmyocardial
infarction syndrome, postpericardiotomy syndrome, primary biliary
cirrhosis, primary sclerosing cholangitis, primary biliary
cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis,
psoriaticarthritis, pure red cell aplasia, pyoderma gangrenosum,
raynauds phenomenon, reactive arthritis, reflex sympathetic
dystrophy, Reiter's syndrome, relapsing polychondritis, restless
legs syndrome, retroperitoneal fibrosis, rheumatic fever,
rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis,
scleroderma, Sjogren's syndrome, sperm & testicular
autoimmunity, stiff person syndrome, Still's disease, subacute
bacterial endocarditis (SBE), Susac's syndrome, sympathetic
ophthalmia, Takayasu's arteritis, temporal arteritis/Giant cell
arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,
transverse myelitis, Type I, II, & III autoimmune polyglandular
syndromes, ulcerative colitis, undifferentiated connective tissue
disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis,
vitiligo, vulvodynia, or lupus.
[0031] In one embodiment of the third aspect, the mammal is
suffering from an autoimmune disease, e.g., inflammatory bowel
disease, arthritis, lupus including Lupus Nephritis, rheumatoid
arthritis, psoriatic arthritis, osteoarthritis, Still's disease,
juvenile arthritis, diabetes, myasthenia gravis, granulomatosis
with polyangiitis, Hashimoto's thyroiditis, Ord's thyroiditis,
Graves' disease, Sjogren's syndrome, dry eye (including Sjogren's
dry eye and non-Sjogren's dry eye), multiple sclerosis,
Guillain-Barre syndrome, acute disseminated encephalomyelitis,
Addison's disease, opsoclonus-myoclonus syndrome, ankylosing
spondylitisis, antiphospholipid antibody syndrome, aplastic anemia,
autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,
idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,
primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,
temporal arteritis, autoimmune hemolytic anemia, Wegener's
granulomatosis, psoriasis, alopecia universalis, Behcet's disease,
chronic fatigue, dysautonomia, endometriosis, interstitial
cystitis, neuromyotonia, scleroderma, pemphigus such as pemphigus
vulgaris and/or foliaceus, bullous pemphigoid, age-related macular
degeneration (wet and dry), diabetic macular edema, corneal
transplantation, abdominal aortic aneurysm, mucous membrane
pemphigoid, or vulvodynia.
[0032] In another embodiment, the autoimmune disease is lupus,
pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye,
multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic
anemia, idiopathic thrombocytopenic purpura, Granulomatosis with
Polyangiitis, or rheumatoid arthritis.
[0033] In another embodiment of the third aspect, the mammal is
suffering from a heteroimmune condition or disease, e.g., graft
versus host disease, transplantation, transfusion, anaphylaxis,
allergy, type I hypersensitivity, allergic conjunctivitis, allergic
rhinitis, or atopic dermatitis. In another embodiment, the disease
is atopic dermatitis.
[0034] In yet another embodiment of the third aspect, the mammal is
suffering from an inflammatory disease, e.g., asthma, appendicitis,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or
vulvitis. In another embodiment of this aspect, the mammal is
suffering from inflammatory skin disease which includes, by way of
example, dermatitis, contact dermatitis, eczema, urticaria,
rosacea, and scarring psoriatic lesions in the skin, joints, or
other tissues or organs. In another embodiment, the inflammatory
disease is asthma or dermatitis.
[0035] In yet another embodiment of the third aspect, the mammal is
suffering from inflammatory and/or autoimmune disease, including
acute inflammatory and/or autoimmune disease, where corticosteroid
therapy is used as the first or second line therapy or first or
second line maintenance therapy. In one embodiment, the compound of
Formula (I) (or any embodiments thereof disclosed herein) is used
for the treatment of:
[0036] Endocrine Disorders: Primary or secondary adrenocortical
insufficiency (hydrocortisone or cortisone is the first choice:
synthetic analogs may be used in conjunction with
mineralocorticoids where applicable; in infancy mineralocorticoid
supplementation is of particular importance); congenital adrenal
hyperplasia; nonsuppurative thyroiditis; hypercalcemia associated
with cancer.
[0037] Rheumatic Disorders: As adjunctive therapy for short-term
administration (to tide the patient over an acute episode or
exacerbation) in: psoriatic arthritis, rheumatoid arthritis,
including juvenile rheumatoid arthritis (selected cases may require
low-dose maintenance therapy), ankylosing spondylitis, acute and
subacute bursitis, acute nonspecific tenosynovitis, gout, acute
gouty arthritis, post-traumatic osteoarthritis, synovitis of
osteoarthritis, epicondylitis.
[0038] Collagen Diseases: During an exacerbation or as maintenance
therapy in selected cases of: systemic lupus erythematosus,
systemic dermatomyositis (polymyositis), acute rheumatic
carditis.
[0039] Dermatologic Diseases: Pemphigus; bullous dermatitis
herpetiformis; severe erythema multiforme (Stevens-Johnson
syndrome); exfoliative dermatitis; mycosis fungoides; severe
psoriasis; severe seborrheic dermatitis.
[0040] Allergic States: Control of severe or incapacitating
allergic conditions intractable to adequate trials of conventional
treatment: seasonal or perennial allergic rhinitis; bronchial
asthma; contact dermatitis; atopic dermatitis; serum sickness; drug
hypersensitivity reactions.
[0041] Ophthalmic Diseases: Severe acute and chronic allergic and
inflammatory processes involving the eye and its adnexa such as:
allergic corneal marginal ulcers, herpes zoster ophthalmicus,
anterior segment inflammation, diffuse posterior uveitis and
choroiditis, sympathetic ophthalmia, allergic conjunctivitis,
keratitis, chorioretinitis, optic neuritis, iritis and
iridocyclitis.
[0042] Respiratory Diseases: Symptomatic sarcoidosis; Loeffler's
syndrome not manageable by other means; berylliosis; aspiration
pneumonitis, fulminating or disseminated pulmonary tuberculosis
when used concurrently with appropriate antituberculous
chemotherapy
[0043] Hematologic Disorders: Idiopathic thrombocytopenic purpura
in adults; secondary thrombocytopenia in adults; acquired
(autoimmune) hemolytic anemia; erythroblastopenia (RBC anemia);
congenital (erythroid) hypoplastic anemia.
[0044] Neoplastic Diseases: For palliative management of: leukemias
and lymphomas in adults, acute leukemia of childhood.
[0045] Edematous States: To induce a diuresis or remission of
proteinuria in the nephrotic syndrome, without uremia, of the
idiopathic type or that due to lupus erythematosus.
[0046] Gastrointestinal Diseases: To tide the patient over a
critical period of the disease in: ulcerative colitis, regional
enteritis.
[0047] Miscellaneous: Tuberculous meningitis with subarachnoid
block or impending block when used concurrently with appropriate
antituberculous chemotherapy; trichinosis with neurologic or
myocardial involvement.
[0048] The compound of Formula (I) and/or a pharmaceutically
acceptable salt thereof can be used for the treatment of above
listed diseases optionally in combination with a corticosteroid,
noncorticosteroidal, immunosupressive, and/or antiinflammatory
agents. In one embodiment, the immunosuppressive agent is selected
from interferon alpha, interferon gamma, cyclophosphamide,
tacrolimus, mycophenolate mofetil, methotrexate, dapsone,
sulfasalazine, azathioprine, an anti-CD20 agent (such as rituximab,
ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version
thereof), anti-TNFalpha agent (such as entanercept, infliximab,
golilumab, adalimumab, or certolizumab pegol or a biosimilar
version thereof), anti-IL6 agent toward ligand or its receptors
(such as tocilizumab, sarilumab, olokizumab, elsililumab, or
siltuximab), anti-IL17 agent to ligand or its receptors (such as
secukinumab, ustekinumab, brodalumab, or ixekizumab), anti-IL1
agent to ligand or its receptors (such as with rilonacept,
canakinumab, or anakinra), anti-IL2 agent to ligand or its
receptors (such as basiliximab or daclizumab), anti-CD2 agent such
as alefacept, anti-CD3 agent such as muromonab-cd3, anti-CD80/86
agent such as abatacept or belatacept, anti-sphingosine-1-phosphate
receptor agent such as fingolimod, anti-C5 agent such as
eculizumab, anti-integrin alpha4 agent such as natalizumab,
anti-.alpha..sub.4.beta..sub.7 agent such as vedolizumab, anti-mTOR
agent such as sirolimus or everolimus, anti-calcineurin agent such
as tacrolimus, and anti-BAFF/BlyS agent (such as belimumab, VAY736,
or blisibimod), leflunomide and teriflunomide. Preferably, the
immunosuppressive agent is rituximab, ofatumumab, obinutuzumab, or
veltuzumab, or a biosimilar version thereof.
[0049] In yet another embodiment of tht third aspect, the mammal is
suffering from a cancer. In one embodiment, the cancer is a B-cell
proliferative disorder, e.g., diffuse large B cell lymphoma,
follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic
lymphocytic leukemia, chromic myleogenous leukemia, B-cell acute
lymphoblastic leukemia (B-ALL), Philadelphia chromosome positive
B-ALL, B-cell prolymphocytic leukemia, small lymphocytic lymphoma
(SLL), multiple myeloma, B-cell non-Hodgkin lymphoma,
lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia, splenic
marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid
granulomatosis.
[0050] In yet another embodiment of the third aspect, the mammal is
suffering from a thromboembolic disorder, e.g., myocardial infarct,
angina pectoris, reocclusion after angioplasty, restenosis after
angioplasty, reocclusion after aortocoronary bypass, restenosis
after aortocoronary bypass, stroke, transitory ischemia, a
peripheral arterial occlusive disorder, pulmonary embolism, or deep
venous thrombosis.
[0051] In a fourth aspect, the disclosure is directed a compound of
Formula (I) (and any embodiments thereof described herein) and/or a
pharmaceutically acceptable salt thereof for use as a medicament.
In one embodiment, the use of the compound of Formula (I) and/or a
pharmaceutically acceptable salt thereof is for treating a disease
mediated by BTK, for example, the disease is an inflammatory
disease, autoimmune disease, cancer, or thromboembolic diseases
described in the third aspect and embodiments therein.
[0052] In a fifth aspect is the use of a compound of Formula (I)
(or any of the embodiments thereof described herein) and/or a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for treating a disease in a mammal in which BTK
contributes to the pathology and/or symptoms of the disease. In one
embodiment of this aspect, the disease is cancer, autoimmune,
inflammatory, or thromboembolic disease described in the third
aspect and embodiments therein.
[0053] In any of the aforementioned aspects involving the treatment
of cancer, are further embodiments comprising administering the
compound of Formula (I) (or any of the embodiments thereof
described herein) and/or a pharmaceutically acceptable salt
thereof, in combination with an anticancer agent. When combination
therapy is used, the agents can be administered simultaneously
(such as a fixed combination drug product) or sequentially.
[0054] In a sixth aspect, this disclosure is directed to an
intermediate of Formula (II):
##STR00004##
wherein:
[0055] R.sup.1, R.sup.2, R.sup.3, X, Ar, Y, and ring Z are as
defined in the first aspect above; or a salt thereof.
[0056] In a seventh aspect, provided is a process of preparing:
[0057] (1). a compound of Formula (I) where R.sup.a is cyano, A is
--CR.sup.3-- and other groups are as defined above: or
[0058] a pharmaceutically acceptable salt thereof;
[0059] comprising:
[0060] (a) reacting a compound of Formula (II):
##STR00005##
wherein:
[0061] R.sup.1, R.sup.2, R.sup.3, X, Ar, Y, and ring Z are as
defined in the first aspect above; with an aldehyde of formula
R.sup.cCHO where R.sup.c is as defined in the first aspect above;
or
[0062] (b) reacting a compound of formula (III):
##STR00006##
wherein:
[0063] R.sup.1, R.sup.2, R.sup.3, X, Ar, Y, and Z are as defined in
the first aspect above;
[0064] with a compound of formula R.sup.cCH.dbd.C(CN)COL where L is
a leaving group under acylation reaction conditions where R.sup.c
is as defined in the first aspect above; or
[0065] (2). a compound of Formula (I) where R.sup.a is hydrogen, A
is --CR.sup.3-- and other groups are as defined in the first aspect
above: or a pharmaceutical salt thereof; comprising reacting a
compound of formula (III):
##STR00007##
wherein:
[0066] R.sup.1, R.sup.2, R.sup.3, X, Ar, Y, and ring Z are as
defined in the first aspect above; with a compound of formula
R.sup.cR.sup.bC.dbd.CHCOL where L is a leaving group under
acylation reaction conditions where R.sup.b and R.sup.c are as
defined in the first aspect above;
[0067] (c) optionally making an acid addition salt of a compound
obtained from Step (1) or (2) above;
[0068] (d) optionally making a free base of a compound obtained
from Step (1) or (2) above.
Definitions
[0069] Unless otherwise stated, the following terms used in the
specification and claims are defined for the purposes of this
disclosure and have the following meaning:
[0070] "Alkyl" means a linear saturated monovalent hydrocarbon
radical of one to six carbon atoms or a branched saturated
monovalent hydrocarbon radical of three to six carbon atoms, e.g.,
methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric
forms), pentyl (including all isomeric forms), and the like.
[0071] "Alkylene" means a linear saturated divalent hydrocarbon
radical of one to six carbon atoms or a branched saturated divalent
hydrocarbon radical of three to six carbon atoms unless otherwise
stated e.g., methylene, ethylene, propylene, 1-methylpropylene,
2-methylpropylene, butylene, pentylene, and the like.
[0072] "Alkylsulfonyl" means a --SO.sub.2R radical where R is alkyl
as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the
like.
[0073] "Amino" means a --NH.sub.2.
[0074] "Alkoxy" means a --OR radical where R is alkyl as defined
above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or
tert-butoxy, and the like.
[0075] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical
of one to six carbon atoms or a branched monovalent hydrocarbon
radical of three to six carbons substituted with an alkoxy group,
(in one embodiment one or two alkoxy groups), as defined above,
e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl,
and the like.
[0076] "Alkoxycarbonyl" means a --C(O)OR radical where R is alkyl
as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the
like.
[0077] "Acyl" means a --COR radical where R is alkyl, haloalkyl, or
cycloalkyl, e.g., acetyl, propionyl, cyclopropylcarbonyl, and the
like. When R is alkyl, the radical is also referred to herein as
alkylcarbonyl.
[0078] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon
radical of three to ten carbon atoms wherein one or two carbon
atoms may be replaced by an oxo group, e.g., cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
[0079] "Carboxy" means --COOH.
[0080] "Halo" means fluoro, chloro, bromo, or iodo; in one
embodiment fluoro or chloro.
[0081] "Haloalkyl" means alkyl radical as defined above, which is
substituted with one or one to five halogen atoms (in one
embodiment fluorine or chlorine,) including those substituted with
different halogens, e.g., --CH.sub.2Cl, --CF.sub.3, --CHF.sub.2,
--CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3, --CF(CH.sub.3).sub.2, and
the like. When the alkyl is substituted with only fluoro, it can
referred to in this disclosure as fluoroalkyl.
[0082] "Haloalkoxy" means a --OR radical where R is haloalkyl as
defined above e.g., --OCF.sub.3, --OCHF.sub.2, and the like. When R
is haloalkyl where the alkyl is substituted with only fluoro, it
can referred to in this disclosure as fluoroalkoxy.
[0083] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical
of one to six carbon atoms or a branched monovalent hydrocarbon
radical of three to six carbons substituted with one or two hydroxy
groups, provided that if two hydroxy groups are present they are
not both on the same carbon atom. Representative examples include,
but are not limited to, hydroxymethyl, 2-hydroxyethyl,
2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl,
2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,
2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,
2,3-dihydroxybutyl, 3,4-dihydroxybutyl and
2-(hydroxymethyl)-3-hydroxypropyl. Further examples include, but
are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl, and
1-(hydroxymethyl)-2-hydroxyethyl.
[0084] "Heterocyclyl" means a saturated or unsaturated monovalent
monocyclic or bi-cyclic group (fused bi-cyclic or bridged
bi-cyclic) of 4 to 10 ring atoms in which one or two ring atoms are
heteroatom selected from N, O, and S(O).sub.n, where n is an
integer from 0 to 2, the remaining ring atoms being C.
Additionally, one or two ring carbon atoms in the heterocyclyl ring
can optionally be replaced by a --CO-- group. More specifically the
term heterocyclyl includes, but is not limited to, oxetanyl,
pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl,
2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl,
thiomorpholino, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl,
tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one-yl,
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-yl,
3-oxa-8-azabicyclo[3.2.1]octane-yl, and the like. When the
heterocyclyl ring is unsaturated it can contain one or two ring
double bonds provided that the ring is not aromatic
[0085] "Heterocyclylalkyl" means a -(alkylene)-R radical where R is
heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl,
piperazinylmethyl, morpholinylethyl, and the like.
[0086] "Heterocycloamino" means a saturated or unsaturated
monovalent monocyclic group of 4 to 8 ring atoms in which one or
two ring atoms are heteroatom selected from N, O, or S(O).sub.n,
where n is an integer from 0 to 2, the remaining ring atoms being C
provided that at least one of the ring atoms is N. Additionally,
one or two ring carbon atoms in the heterocycloamino ring can
optionally be replaced by a --CO-- group. When the heterocycloamino
ring is unsaturated it can contain one or two ring double bonds
provided that the ring is not aromatic.
[0087] "Heterocycloaminoalkyl" means a -(alkylene)-R radical where
R is heterocycloamino as described above.
[0088] "Heteroaryl" means a monovalent monocyclic or bicyclic
aromatic radical of 5 to 10 ring atoms where one or more, (in one
embodiment one, two, or three), ring atoms are heteroatom selected
from N, O, and S, the remaining ring atoms being carbon.
Representative examples include, but are not limited to, pyrrolyl,
thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl,
oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl,
isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazolyl, tetrazolyl, and the like.
[0089] "Mammal" as used herein means domesticated animals (such as
dogs, cats, and horses), and humans. In one embodiment, mammal is a
human.
[0090] The present disclosure also includes the prodrugs of
compounds of Formula (I) (or any of the embodiments thereof
described herein) and/or a pharmaceutically acceptable salt
thereof. The term prodrug is intended to represent covalently
bonded carriers, which are capable of releasing the active
ingredient of Formula (I) (or any of the embodiments thereof
described herein) when the prodrug is administered to a mammalian
subject. Release of the active ingredient occurs in vivo. Prodrugs
can be prepared by techniques known to one skilled in the art.
These techniques generally modify appropriate functional groups in
a given compound. These modified functional groups however
regenerate original functional groups in vivo or by routine
manipulation. Prodrugs of compounds of Formula (I) (or any of the
embodiments thereof described herein) include compounds wherein a
hydroxy, amino, carboxylic, or a similar group is modified.
Examples of prodrugs include, but are not limited to esters (e.g.,
acetate, formate, and benzoate derivatives), carbamates (e.g.,
N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in
compounds of Formula (I)), amides (e.g., trifluoroacetylamino,
acetylamino, and the like), and the like. Prodrugs of compounds of
Formula (I) (or any of the embodiments thereof described herein)
and/or a pharmaceutically acceptable salt thereof are also within
the scope of this disclosure.
[0091] The present disclosure also includes polymorphic forms
(amorphous as well as crystalline) and deuterated forms of
compounds of Formula (I) (or any of the embodiments thereof
described herein) and/or a pharmaceutically acceptable salt
thereof.
[0092] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include:
[0093] acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
formic acid, acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like; or
[0094] salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like. It
is understood that the pharmaceutically acceptable salts are
non-toxic. Additional information on suitable pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985,
which is incorporated herein by reference.
[0095] The compounds of the present disclosure may have asymmetric
centers. Compounds of the present disclosure containing an
asymmetrically substituted atom may be isolated in optically active
or racemic forms. It is well known in the art how to prepare
optically active forms, such as by resolution of materials. All
chiral, diastereomeric, racemic forms, as individual forms and
mixtures thereof, are within the scope of this disclosure, unless
the specific stereochemistry or isomeric form is specifically
indicated.
[0096] Certain compounds of Formula (I) (or any of the embodiments
thereof described herein) and/or a pharmaceutically acceptable salt
thereof can exist as tautomers and/or geometric isomers. All
possible tautomers and cis and trans isomers, as individual forms
and mixtures thereof, are within the scope of this disclosure.
Additionally, as used herein the term alkyl includes all the
possible isomeric forms of said alkyl group albeit only a few
examples are set forth. Furthermore, when the cyclic groups such as
heteroaryl, heterocyclyl are substituted, they include all the
positional isomers albeit only a few examples are set forth.
Furthermore, all hydrate forms of a compound of Formula (I) (or any
of the embodiments thereof described herein) and/or a
pharmaceutically acceptable salt thereof are within the scope of
this disclosure.
[0097] "Oxo" or "carbonyl" means=(O) group.
[0098] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example,
"heterocyclyl group optionally substituted with an alkyl group"
means that the alkyl may but need not be present, and the
description includes situations where the heterocyclyl group is
substituted with an alkyl group and situations where the
heterocyclyl group is not substituted with alkyl.
[0099] A "pharmaceutically acceptable carrier or excipient" means a
carrier or an excipient that is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and
neither biologically nor otherwise undesirable, and includes a
carrier or an excipient that is acceptable for veterinary use as
well as human pharmaceutical use. "A pharmaceutically acceptable
carrier/excipient" as used in the specification and claims includes
both one and more than one such excipient.
[0100] The phrase "where two of the optional substituents are
independently selected from alkyl, alkoxy, hydroxy, halo, and oxo,
and one of the optional substituent is alkyl, cycloalkyl,
hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl,
alkoxycarbonyl, or heterocyclyl" in the definition of heterocyclyl
for R.sup.c in Formula (I) (and similar phrases elsewhere in the
claim and/or specification) means that when heterocyclyl is
substituted with one substituent, the substituent can be any of the
optional substituents listed. When heterocyclyl ring is substituted
with two substituents, then either both substituents can be
selected from alkyl, alkoxy, hydroxy, halo, and oxo or one of the
two substituent is selected from alkyl, alkoxy, hydroxy, halo, and
oxo and the other substituent is selected from alkyl, cycloalkyl,
hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl,
alkoxycarbonyl, and heterocyclyl. And when heterocyclyl ring is
substituted with three substituents, then two substituents are
selected from alkyl, alkoxy, hydroxy, halo, and oxo and the third
substituent is selected from alkyl, cycloalkyl, hydroxyalkyl,
alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, and
heterocyclyl.
[0101] "Treating" or "treatment" of a disease includes:
[0102] (1) preventing the disease, i.e. causing the clinical
symptoms of the disease not to develop in a mammal that may be
exposed to or predisposed to the disease but does not yet
experience or display symptoms of the disease;
[0103] (2) inhibiting the disease, i.e., arresting or reducing the
development of the disease or its clinical symptoms; or
[0104] (3) relieving the disease, i.e., causing regression of the
disease or its clinical symptoms.
[0105] A "therapeutically effective amount" means the amount of a
compound of Formula (I) (or any of the embodiments thereof
described herein), that, when administered to a mammal for treating
a disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
EMBODIMENTS
[0106] In embodiments 1-24 below and embodiments or subembodiments
contained therin, the present disclosure includes:
[0107] 1. A compound of Formula (I) as defined in the first
embodiment of the first aspect above, including an E or Z isomer
thereof, and/or a pharmaceutically acceptable salt thereof.
[0108] 2. The compound of embodiment 1 and/or a pharmaceutically
acceptable salt thereof wherein: R.sup.1 and R.sup.2 are
independently hydrogen, alkyl, alkoxy, halolakyl, or halo;
[0109] X is --O--, --CONR--, --NRCO--, or --NR--CO--NR' where R and
R' are independently hydrogen or alkyl;
[0110] Ar is heteroaryl or phenyl where heteroaryl and phenyl are
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, alkoxy, and
hydroxy;
[0111] A is --N-- or --CR.sup.3-- wherein R.sup.3 is hydrogen,
alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or
cyano;
[0112] Y is bond or alkylene;
[0113] ring Z is heterocycloamino optionally substituted with one
or two substituents independently selected from alkyl, hydroxy,
alkoxy, and fluoro;
[0114] R.sup.5 is a group of formula (i), (ii), (iii) or (iv):
##STR00008##
wherein:
[0115] R.sup.a is hydrogen, fluoro, or cyano; provided that when
R.sup.a is cyano then R.sup.b is hydrogen and R.sup.c is not
hydrogen;
[0116] R.sup.b is hydrogen or alkyl; and
[0117] R.sup.c is hydrogen, alkyl optionally substituted with one
or two substituents independently selected from OH, heteroaryl
(optionally substituted with one or two substituents independently
selected from alkyl and heterocyclyl wherein heterocyclyl is
optionally substituted with one or two substituents independently
selected from halo and alkyl), and --CONR.sup.9R.sup.10 (where
R.sup.9 and R.sup.10 are independently hydrogen or alkyl, or
R.sup.9 and R.sup.10 together with the nitrogen atom to which they
are attached form a heterocyclyl optionally substituted with one or
two substituents selected from alkyl and heterocyclyl),
[0118] cycloalkyl optionally substituted with one or two
substituents independently selected from halo, alkyl and aryl,
[0119] hydroxyalkyl,
[0120] alkoxyalkyl,
[0121] heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and
heterocyclyl in heterocyclylalkyl are optionally substituted with
one, two, or three substituents where two of the optional
substituents are independently selected from alkyl, alkoxy,
hydroxy, halo, amino, and oxo, and one of the optional substituent
is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl, haloalkyl,
alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the
heterocyclyl is substituted with one or two substitutents
independently selected from hydrogen, alkyl, halo, hydroxy, and
alkoxy), or
[0122] -(alkylene)-NR.sup.6R.sup.7 (where R.sup.6 and R.sup.7 are
independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl
is optionally substituted with one or two substituents
independently selected from alkyl, halo, hydroxy, hydroxyalkyl,
alkoxyalkyl, acyl, and alkoxycarbonyl; or R.sup.6 and R.sup.7
together with the nitrogen atom to which they are attached form
##STR00009##
where one or two of X.sup.1, X.sup.2 and X.sup.3 are nitrogen and
the rest are carbon and the ring is optionally substituted with one
or two substituents independently selected from alkyl, haloalkyl,
and halo); and/or a pharmaceutically acceptable salt thereof
provided that:
[0123] when A is --N--, then R.sup.a is cyano and R.sup.c is
heterocycloaminolalkyl wherein the heterocycloamino in
heterocycloaminoalkyl is optionally substituted with one or two
substituents independently selected from alkyl, alkoxy, hydroxy,
halo, amino, and oxo, and the nitrogen atom of heterocycloamino is
substituted with heterocyclyl wherein the heterocyclyl is
substituted with one or two substituents independently selected
from hydrogen, alkyl, halo, hydroxy, and alkoxy.
[0124] 3. The compound of embodiments 1 to 2 and/or a
pharmaceutically acceptable salt thereof wherein A is --N--.
[0125] 4. The compound of embodiments 1 to 2 and/or a
pharmaceutically acceptable salt thereof wherein A is --CR.sup.3--.
In one embodiment of embodiment 4, R.sup.3 is hydrogen, methyl,
ethyl, isopropyl, fluoro, or chloro. In a second embodiment of
embodiment 3, R.sup.3 is hydrogen.
[0126] 5. The compound of any of embodiments 1 to 4 and embodiments
contained therein and/or a pharmaceutically acceptable salt thereof
wherein --X--Ar is attached to carbon at the 4-position of the
phenyl ring, the carbon of the phenyl ring attached to N of the
cyclic urea ring being position 1.
[0127] 6. The compound of any of embodiments 1 to 5 and embodiments
contained therein and/or a pharmaceutically acceptable salt thereof
wherein X is --O--. Within embodiment 6, in a fourth embodiment, Ar
is heteroaryl or phenyl where heteroaryl and phenyl are optionally
substituted with one, two, or three substituents independently
selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy. Within
embodiment 6, in a fifth embodiment, Ar is pyridinyl, pyrimidinyl,
thienyl, or pyrazinyl, optionally substituted with one, two, or
three substituents independently selected from alkyl, halo,
haloalkyl, alkoxy, and hydroxy. Within embodiment 6, in a sixth
embodiment, Ar is phenyl where phenyl is optionally substituted
with one, two, or three substituents independently selected from
alkyl, halo, haloalkyl, alkoxy, and hydroxy, preferably substituted
with one or two fluoro.
[0128] 7. The compound of any of embodiments 1 to 6 and embodiments
contained therein and/or a pharmaceutically acceptable salt thereof
wherein X is --CONR-- or --NRCO--. Within embodiment 6, in a fourth
embodiment, Ar is heteroaryl or phenyl where heteroaryl and phenyl
are optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, alkoxy, and
hydroxy. Within embodiment 7, in a fifth embodiment, Ar is
pyridinyl, pyrimidinyl, thienyl, or pyrazinyl, optionally
substituted with one, two, or three substituents independently
selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy. Within
embodiment 7, in a sixth embodiment, Ar is phenyl where phenyl is
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, alkoxy, and
hydroxy, preferably one or two fluoro.
[0129] 8. The compound of any of embodiments 1 to 7 and embodiments
contained therein and/or a pharmaceutically acceptable salt thereof
wherein R.sup.1 and R.sup.2 are independently hydrogen or halo,
preferably hydrogen or fluoro, more preferably R.sup.1 and R.sup.2
are hydrogen or R.sup.1 is hydrogen and R.sup.2 is fluoro.
[0130] 9. The compound of any of embodiments 1 to 8 and embodiments
contained therein and/or a pharmaceutically acceptable salt thereof
wherein Y is alkylene and ring Z is pyrrolidinyl, and in one
embodiment, pyrrolidin-2-yl or azetidin-3-yl. Within embodiment 9,
in one embodiment, Y is methylene. Within embodiment 9, in a second
embodiment, the pyrrolidinyl ring ring attached at C2 and the
stereochemistry at carbon of the pyrrolidinyl ring attached to Y is
(R) or (S). Within embodiment 9, is another embodiment, wherein
R.sup.5 is a group of formula (i) or (iv).
[0131] 10. The compound of any of embodiments 1 to 9 and
embodiments contained therein and/or a pharmaceutically acceptable
salt thereof wherein Y is a bond and ring Z is pyrrolidinyl or
piperidinyl and is attached to the cyclic urea nitrogen at the C-3
carbon, the nitrogen atom of pyrrolidinyl or piperidinyl being
position C-1. In one embodiment, the stereochemistry at carbon of
the pyrrolidinyl or piperidinyl attached to the cyclic urea
nitrogen is (R).
[0132] 11. The compound of any of embodiments 1 to 10 and
embodiments contained therein and/or a pharmaceutically acceptable
salt thereof wherein R.sup.a is hydrogen. Within embodiment 11, in
one embodiment, R.sup.5 is a group of formula (i). Within
embodiment 11, in a second embodiment, R.sup.5 is a group of
formula (ii) or (iii). Within embodiment 11, in a third embodiment,
R.sup.5 is a group of formula (iv). Within the embodiments one to
three in embodiment 11, in one subembodiment R.sup.b and R.sup.c
are hydrogen. Within the embodiments one to three in embodiment 11,
in another subembodiment R.sup.b is hydrogen and R.sup.c is alkyl
or or -(alkylene)-NR.sup.6R.sup.7 (where R.sup.6 and R.sup.7 are
independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl
ring is optionally substituted with one or two substituents
independently selected from alkyl, halo, hydroxy, hydroxyalkyl,
alkoxyalkyl, acyl, and alkoxycarbonyl), preferably R.sup.6 and
R.sup.7 are independently hydrogen or alkyl.
[0133] 12. The compound of any of embodiments 1 to 11 and
embodiments contained therein or a pharmaceutically acceptable salt
thereof wherein R.sup.a is cyano. Within embodiment 12, in one
embodiment, R.sup.5 is a group of formula (i). Within embodiment
12, in a second embodiment, R.sup.5 is a group of formula (ii) or
(iii).
[0134] (a) Within the embodiments one and two in embodiment 12, in
one subembodiment R.sup.c is cycloalkyl, which is optionally
substituted with one or two substituents independently selected
from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent
substituents of the cycloalkyl together with the carbon atoms to
which they are attached form a heterocyclyl group. In one
embodiment R.sup.c is cyclopropyl, 1-methylcyclobutyl,
1-phenylcyclopropyl, 1-methylcyclopropyl,
2,2-difluorocyclopropyl,
##STR00010##
[0135] (b). Within the embodiments one and two in embodiment 12, in
a second subembodiment R.sup.c is unsubstituted alkyl. In one
embodiment R.sup.c is isopropyl or tert-butyl.
[0136] (c). Within the embodiments one and two in embodiment 11, in
one subembodiment R.sup.c is -(alkylene)-NR.sup.6R.sup.7 (where
R.sup.6 and R.sup.7 are independently hydrogen, alkyl, haloalkyl,
hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl. In another
subembodiment R.sup.c is-C(CH.sub.3).sub.2NH.sub.2,
--C(CH.sub.3).sub.2NHCH.sub.3,
--C(CH.sub.3).sub.2N(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2NHCH.sub.2CH.sub.3,
--C(CH.sub.3).sub.2NHCH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2NHcyclopropyl,
--C(CH.sub.3).sub.2NH(CH.sub.2).sub.2OCH.sub.3,
--C(CH.sub.3).sub.2OCH.sub.2CH.sub.3,
--C(CH.sub.3).sub.2N(CH.sub.2CH.sub.3)(oxetan-3-yl),
--C(CH.sub.3).sub.2N(CH.sub.3)(oxetan-3-yl), or
--C(CH.sub.3).sub.2NH(oxetan-3-yl).
[0137] (d) Within the embodiments one and two in embodiment 12, in
another subembodiment R.sup.c is heterocyclylalkyl wherein the
heterocyclyl in heterocyclylalkyl is optionally substituted with
one, two, or three substituents where two of the optional
substituents are independently selected from alkyl, alkoxy,
hydroxy, halo, amino, and oxo, and one of the optional substituent
is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl,
alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the
heterocyclyl is optionally substituted with one or two
substitutents independently selected from alkyl, halo, hydroxy, and
alkoxy.
[0138] In one subembodiment of subembodiment (d), R.sup.c is
--C(CH.sub.3).sub.2morpholine-4-yl,
--C(CH.sub.3).sub.2-4-(2,2,2-trifluoroethyl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-(1-methyl)piperidin-1-yl,
##STR00011##
--C(CH.sub.3).sub.2-4-ethyl-3-oxopiperazin-1-yl,
C(CH.sub.3).sub.2tetrahydropyran-4-yl,
--C(CH.sub.3).sub.2-4-methoxycarbonylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(oxetan-4-yl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3-methyloxetan-4-yl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-t-butoxycarbonylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-acetylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-methoxycarbonylpiperazin-1-yl,
--C(CH.sub.3).sub.2-piperazin-1-yl,
--C(CH.sub.3).sub.2-3,3-difluoropyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(S)-3-methoxypyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(R)-3-methoxypyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(S)-2-(methoxymethyl)pyrrolidin-1-yl,
--C(CH.sub.3).sub.2--(R)-2-(methoxymethyl)pyrrolidin-1-yl,
##STR00012##
--C(CH.sub.3).sub.2-4-methylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-ethylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-isopropylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(2-methoxyethyl)piperazin-1-yl,
--C(CH.sub.3).sub.2-4-acetylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3R,5S)-3,4,5-trimethylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3R,5S)-3,5-dimethylpiperazin-1-yl,
--C(CH.sub.3).sub.2-4-(3R,5S)-dimethylmorpholin-4-yl,
--C(CH.sub.3).sub.2-piperidin-1-yl,
--C(CH.sub.3).sub.2-pyrrolidin-1-yl,
--C(CH.sub.3).sub.2-3-oxo-piperazin-1-yl, or
--C(CH.sub.3).sub.2-(3-oxo-4-methylpiperazin-1-yl). In a second
subembodiment of subembodiment (d), R.sup.c is heterocyclylalkyl
wherein the heterocyclyl in heterocyclylalkyl is substituted with
another heterocyclyl wherein the another heterocyclyl is
substituted with alkyl on a carbon of the another heterocyclyl.
[0139] (e). Within the embodiments one and two in embodiment 12, in
yet another subembodiment R.sup.c is heterocyclyl optionally
substituted with one, two, or three substituents where two of the
optional substituents are independently selected from alkyl,
alkoxy, hydroxy, halo, amino, and oxo, and one of the optional
substituent is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, or
heterocyclyl. In one subembodiment of subembodiment (e), R.sup.c is
3-methyloxetan-3-yl, 3-ethyloxetan-3-yl, 3-fluorooxetan-3-yl,
3-aminooxetan-3-yl, 4-methylpiperidin-4-yl, 3-methylazetidin-3-yl,
1-methylazetidin-3-yl, 4-methyl-4-tetrahydropyranyl or
1,3-dimethylazetidin-3-yl. In another subembodiment (f), R is
##STR00013##
[0140] (g) In another subembodiment of embodiment 12, R.sup.c is
alkyl which is optionally substituted with one or two substituents
independently selected from hydroxy, hydoxyalkyl, and heteroaryl
which is substituted with one or two substituents independently
selected from alkyl and heterocyclyl wherein heterocyclyl is
optionally substituted with one or two substituents independently
selected from halo and alkyl. In another embodiment, R.sup.c is
alkyl which is substituted with one or two hydroxy substituents. In
another embodiment, R.sup.c is
##STR00014##
[0141] In a subembodiment, R.sup.c is alkyl which is substituted
with a heteroaryl that is optionally substituted with one or two
substituents independently selected from alkyl and heterocyclyl
wherein heterocyclyl is optionally substituted with one or two
substituents independently selected from halo and alkyl. Within
this subembodiment, in another embodiment, R.sup.c is
##STR00015##
[0142] In another subembodiment, R.sup.c is alkyl that is
substituted with --CONR.sup.9R.sup.10, where R.sup.9 and R.sup.10
are independently hydrogen or alkyl, or R.sup.9 and R.sup.0
together with the nitrogen atom to which they are attached form a
heterocyclyl optionally substituted with one or two substituents
selected from alkyl and heterocyclyl. Within this subembodiment is
an embodiment wherein R.sup.9 and R.sup.10 are both hydrogen or
alkyl. In another embodiment, R.sup.c is
--C(CH.sub.3).sub.2--CONH.sub.2 or
--C(CH.sub.3).sub.2--CON(CH.sub.3).sub.2.
[0143] In another subembodiment, Re is alkyl that is substituted
with --CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 together
with the nitrogen atom to which they are attached form a
heterocyclyl optionally substituted with one or two substituents
selected from alkyl and heterocyclyl. Within this subembodiment is
an embodiment wherein the heterocyclyl formed by R.sup.9 and
R.sup.10 together with the nitrogen atom to which they are attached
is 4-methylpiperazinyl, or 4-(oxetan-3-yl)piperazin-1-yl.
[0144] 13. The compounds of any of the embodiments 3, 5, 6, and
8-10 (i.e., A is --N--; --X--Ar is attached to carbon at the
4-position of the phenyl ring, the carbon of the phenyl ring
attached to N of the cyclic urea ring being position 1; X is O; Y
is a bond; ring Z is pyrrolidinyl or piperidinyl and is attached to
the cyclic urea nitrogen at the C-3 carbon, the nitrogen atom of
pyrrolidinyl or piperidinyl ring being C-1; the stereochemistry at
carbon of the pyrrolidinyl or piperidinyl attached to the cyclic
nitrogen being (R)), wherein R.sup.5 is a group of formula (i),
R.sup.a is cyano, R.sup.b is hydrogen and R.sup.c is
heterocyclylalkyl, wherein heterocyclyl in heterocyclylalkyl is
optionally substituted with one, two, or three substituents where
two of the optional substituents are independently selected from
alkyl, alkoxy, hydroxy, halo, amino, and oxo, and one of the
optional substituent is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,
acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl
wherein the heterocyclyl is substituted with one or two
substitutents independently selected from hydrogen, alkyl, halo,
hydroxy, and alkoxy.
[0145] In a subembodiment of this embodiment, R.sup.c is
##STR00016##
[0146] Representative compounds are listed in Table I below:
TABLE-US-00001 TABLE I Cpd Ms # Name M + 1 1
(R)-2-(3-(4-amino-2-oxo-3-(4- 537.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4,4-dimethylpent-2- enenitrile 2
(R)-2-(3-(4-amino-2-oxo-3-(4- 565.5 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-3-(tetrahydro-2H- pyran-4-yl)acrylonitrile 3
(R)-2-(3-(4-amino-2-oxo-3-(4- 549.4 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1- yl)piperidine-1-carbonyl)-3-(1-
methylcyclobutyl)acrylonitrile 4 (R)-2-(3-(4-amino-2-oxo-3-(4-
608.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-methyl-4-
morpholinopent-2-enenitrile 5 (R)-2-(3-(4-amino-2-oxo-3-(4- 663.3
phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(oxetan-
3-yl)piperazin-1-yl)pent-2-enenitrile 6
(R)-2-(3-(4-amino-2-oxo-3-(4- 689.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(2,2,2-
trifluoroethyl)piperazin-1-yl)pent-2-enenitrile 7
(R)-2-(3-(4-amino-2-oxo-3-(4- 620.4 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-methyl-4-(1-
methylpiperidin-4-yl)pent-2-enenitrile 8
(R)-2-(3-(4-amino-2-oxo-3-(4- 535.4 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-
carbonyl)-3-cyclobutylacrylonitrile 9 (R)-2-(3-(4-amino-2-oxo-3-(4-
665.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-
4-(4-(2-methoxyethyl)piperazin- 1-yl)-4-methylpent-2-enenitrile 10
(R)-methyl 4-(5-(3-(4-amino-2-oxo-3- 665.3
(4-phenoxyphenyl)-2,3-dihydro-
1H-imidazo[4,5-c]pyridin-1-yl)piperidin- 1-yl)-4-cyano-2-methyl-5-
oxopent-3-en-2-yl)piperazine-1-carboxylate 11
(R)-2-(3-(4-amino-2-oxo-3-(4- 583.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-6-hydroxy-4-(2-
hydroxyethyl)hex-2-enenitrile 12 (S)-2-(2-((4-amino-2-oxo-3- 537.0
(4-phenoxyphenyl)-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-
yl)methyl)pyrrolidine-1-carbonyl)-4,4- dimethylpent-2-enenitrile 13
(S)-2-(2-((4-amino-2-oxo-3-(4- 662.8 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-
yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-
(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile 14
(S)-2-(2-((4-amino-2-oxo-3-(4- 607.8 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-
yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-
morpholinopent-2-enenitrile 15 (S)-methyl
4-(5-(2-((4-amino-2-oxo-3- 665.7 (4-phenoxyphenyl)-2,3-dihydro-
1H-imidazo[4,5-c]pyridin-1- yl)methyl)pyrrolidin-1-yl)-4-cyano-2-
methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate 16
(R)-1-(1-acryloylpiperidin-3-yl)-4- 456.2
amino-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 17
(R)-4-amino-1-(1-(but-2-ynoyl)piperidin- 468.2
3-yl)-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 18
(R)-2-(3-(4-amino-2-oxo-3-(4- 635.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-methyl-
3-oxopiperazin-1-yl)pent-2-enenitrile 19
2-((R)-3-(4-amino-2-oxo-3-(4- 635.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-((3R,5S)-3,5-
dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile 20
(R)-2-(3-(4-amino-2-oxo-3-(4- 581.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo [4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-3-(tetrahydro-2H- thiopyran-4-yl)acrylonitrile 21
(R)-2-(3-(4-amino-2-oxo-3-(4- 621.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-methyl-4-(3-
oxopiperazin-1-yl)pent-2-enenitrile 22
(S)-1-((1-acryloylpyrrolidin-2-yl)methyl)- 455.9
4-amino-3-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 23
(S)-4-amino-1-((1-(but-2- 467.9 ynoyl)pyrrolidin-2-yl)methyl)-3-(4-
phenoxyphenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 24
(R)-2-(3-(4-amino-3-(4-(2,6- 699.3
difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-
1H-imidazo[4,5-c]pyridin-1-
yl)piperidine-1-carbonyl)-4-methyl-4-(4-
(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile 25
(R)-2-(3-(4-amino-3-(4-(2,3- 699.2
difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-
1H-imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-
(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile 26
(R)-2-(3-(4-amino-3-(3-fluoro-4- 681.4
phenoxyphenyl)-2-oxo-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(oxetan-
3-yl)piperazin-1-yl)pent-2-enenitrile 27
(R)-2-(3-(4-amino-3-(2-fluoro-4- 681.3
phenoxyphenyl)-2-oxo-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(oxetan-
3-yl)piperazin-1-yl)pent-2-enenitrile 28
(R)-2-(3-(4-amino-3-(3-methyl-4- 677.3
phenoxyphenyl)-2-oxo-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(oxetan-
3-yl)piperazin-1-yl)pent-2-enenitrile 29
(R)-2-(3-(4-amino-2-oxo-3-(4- 645.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-(5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)-4-methylpent-2-enenitrile
30 (R)-2-(3-(4-amino-2-oxo-3-(4- 677.3
phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(3- methyloxetan-3-yl)piperazin-1-
yl)pent-2-enenitrile 31 (R)-2-(3-(6-amino-8-oxo-7-(4- 663.8
phenoxyphenyl)-7H-purin-9(8H)-
yl)piperidine-1-carbonyl)-4-methyl-4-
(4-(oxetan-3-yl)piperazin-1-yl)pent- 2-enenitrile 32
(R)-2-(3-(6-amino-8-oxo-7-(4- 635.0 phenoxyphenyl)-7H-purin-9(8H)-
yl)piperidine-1-carbonyl)-3-(4-methyl- 1-(oxetan-3-yl)piperidin-4-
yl)acrylonitrile 33 (R)-2-(3-(6-amino-8-oxo-7-(4-
phenoxyphenyl)-7H-purin-9(8H)-
yl)piperidine-1-carbonyl)-4-methyl-4-
(4-(3-methyloxetan-3-yl)piperazin- 1-yl)pent-2-enenitrile 34
(S)-2-(2-((4-amino-2-oxo-3-(4- 620.9 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-
yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-
(4-methylpiperazin-1-yl)pent-2-enenitrile 35
(S)-2-(2-((4-amino-2-oxo-3-(4- 635.0 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-
yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-
(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile 36
(S)-2-(2-((4-amino-2-oxo-3-(4- 607.9 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-
yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-
(methyl(oxetan-3-yl)amino)pent-2-enenitrile 37
(R)-2-(3-(4-amino-2-oxo-3-(4- 579.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-
carbonyl)-3-(4-methyltetrahydro- 2H-pyran-4-yl)acrylonitrile 38
(R)-2-(3-(4-amino-3-(4-(2- 681.3
fluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(oxetan-
3-yl)piperazin-1-yl)pent-2-enenitrile 39
(R)-2-(3-(4-amino-2-oxo-3-(4- 597.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-3-(1-oxidotetrahydro- 2H-thiopyran-4-yl)acrylonitrile
40 (R)-2-(3-(4-amino-2-oxo-3-(4- 649.3
phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-(4-ethyl-3-oxopiperazin-
1-yl)-4-methylpent-2-enenitrile 41 (R)-2-(3-(4-amino-2-oxo-3-(4-
521.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-
carbonyl)-3-cyclopropylacrylonitrile 42
(R)-2-(3-(4-amino-2-oxo-3-(4- 635.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-3-(4-methyl-1-(oxetan-
3-yl)piperidin-4-yl)acrylonitrile 43 (R)-tert-butyl
4-(5-(3-(4-amino-2-oxo- 707.5 3-(4-phenoxyphenyl)-2,3-dihydro-
1H-imidazo[4,5-c]pyridin-1- yl)piperidin-1-yl)-4-cyano-2-methyl-5-
oxopent-3-en-2-yl)piperazine-1-carboxylate 44
(R)-4-(4-acetylpiperazin-1-yl)- 649.3 2-(3-(4-amino-2-oxo-3-(4-
phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-
carbonyl)-4-methylpent-2-enenitrile 45
2-((R)-3-(4-amino-2-oxo-3-(4- 634.5 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-((
1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-
4-methylpent-2-enenitrile 46 (R)-2-(3-(4-amino-2-oxo-3-(4- 597.4
phenoxyphenyl)-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-
yl)piperidine-1-carbonyl)-3-(1- phenylcyclopropyl)acrylonitrile 47
(R)-2-(3-(4-amino-2-oxo-3-(4- 607.4 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(piperazin- 1-yl)pent-2-enenitrile 48
(R)-2-(3-(4-amino-2-oxo-3-(4- 535.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-
3-(1-methylcyclopropyl)acrylonitrile 49
(R)-2-(3-(4-amino-2-oxo-3-(4- 648.7 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4,4-dimethyl-5-(4-
methylpiperazin-1-yl)-5-oxopent-2-enenitrile 50
(R)-5-(3-(4-amino-2-oxo-3-(4- 593.9 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidin-
1-yl)-4-cyano-N,N,2,2-tetramethyl- 5-oxopent-3-enamide 51
(R)-2-(3-(4-amino-2-oxo-3-(4- 690.7
phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4,4-dimethyl-5-(4-(oxetan-
3-yl)piperazin-1-yl)-5-oxopent-2-enenitrile 52
(R)-2-(3-(4-amino-2-oxo-3-(4- 557.2 phenoxyphenyl)-2,3-dihydro-IH-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-
3-(2,2-difluorocyclopropyl)acrylonitrile 53
2-((R)-3-(4-amino-2-oxo-3-(4- 563.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-3-((1R,5S)-3-
oxabicyclo[3.1.0]hexan-6-yl)acrylonitrile 54
(R)-2-(3-(4-amino-2-oxo-3-(4- 698.0 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(6-(4-
methylpiperazin-1-yl)pyridin-2-yl)pent- 2-enenitrile 55
(R)-2-(3-(4-amino-2-oxo-3-(4- 599.7 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(pyridin-2- yl)pent-2-enenitrile 56
(R)-2-(3-(4-amino-2-oxo-3-(4- 698.9 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-(4-(4- methylpiperazin-1-yl)pyrimidin-
2-yl)pent-2-enenitrile 57 (R)-4-amino-2-(3-(4-amino-2-oxo-3- 538.3
(4-phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine- 1-carbonyl)-4-methylpent-2-
enenitrile 58 (R)-2-(3-(4-amino-2-oxo-3-(4- 628.3
phenoxyphenyl)-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-
yl)piperidine-1-carbonyl)-4-(3,3-
difluoropyrrolidin-1-yl)-4-methylpent- 2-enenitrile 59
2-((R)-3-(4-amino-2-oxo-3-(4- 622.2 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1- yl)piperidine-1-carbonyl)-4-((S)-3-
methoxypyrrolidin-1-yl)-4-methylpent- 2-enenitrile 60
2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)- 622.3
2,3-dihydro-1H-imidazo[4,5-c]pyridin-
1-yl)piperidine-1-carbonyl)-4-((R)-3-
methoxypyrrolidin-1-yl)-4-methylpent-2-enenitrile 61
2-((R)-3-(4-amino-2-oxo-3-(4- 661.4 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-((R)-6- oxohexahydropyrrolo[1,2-a]pyrazin-
2(1H)-yl)pent-2-enenitrile 62 2-((R)-3-(4-amino-2-oxo-3-(4- 636.4
phenoxyphenyl)-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-
yl)piperidine-1-carbonyl)-4-((R)-2- (methoxymethyl)pyrrolidin-1-
yl)-4-methylpent-2-enenitrile 63 2-((R)-3-(4-amino-2-oxo-3-(4-
636.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-((S)-2-(methoxymethyl)pyrrolidin-
1-yl)-4-methylpent-2-enenitrile 64 2-((R)-3-(4-amino-2-oxo-3-(4-
661.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-4-methyl-4-((S)-6- oxohexahydropyrrolo[1,2-a]pyrazin-
2(1H)-yl)pent-2-enenitrile 65 (R)-2-(3-(4-amino-2-oxo-3-(4- 593.2
phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-
1-carbonyl)-3-(4-ethyltetrahydro- 2H-pyran-4-yl)acrylonitrile 66
(R)-2-(3-(4-amino-2-oxo-3-(4- 609.3 phenoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-
3-(4-(methoxymethyl)tetrahydro- 2H-pyran-4-yl)acrylonitrile 67
(R)-4-amino-1-(1-(2-fluoroacryloyl)piperidin- 474.1
3-yl)-3-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one
[0147] E or Z isomer of any of the compounds of Table 1, and/or a
pharmaceutically acceptable salt of any of these compounds are also
included within the scope of the present invention
[0148] The present invention is also directed to the following
compounds: [0149]
4-amino-1-((3S)-1-(oxirane-2-carbonyl)piperidin-3-yl)-3-(4-phenoxy-
phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; [0150]
4-amino-1-((3S)-1-(2,3-dihydroxypropanoyl)piperidin-3-yl)-3-(4-phenoxyphe-
nyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; [0151]
4-amino-1-((3S)-1-(2-hydroxypropanoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-
-1H-imidazo[4,5-c]pyridin-2(3H)-one; [0152]
(S)-4-amino-1-(1-(3-hydroxypropanoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)--
1H-imidazo[4,5-c]pyridin-2(3H)-one; [0153]
4-amino-1-(((2R)-1-(oxirane-2-carbonyl)pyrrolidin-2-yl)methyl)-3-(4-pheno-
xyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; [0154]
4-amino-1-(((2R)-1-(2,3-dihydroxypropanoyl)pyrrolidin-2-yl)methyl)-3-(4-p-
henoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; [0155]
4-amino-1-(((2R)-1-(2-hydroxypropanoyl)pyrrolidin-2-yl)methyl)-3-(4-pheno-
xyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; and [0156]
(R)-4-amino-1-((1-(3-hydroxypropanoyl)pyrrolidin-2-yl)methyl)-3-(4-phenox-
yphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one;
[0157] and/or a pharmaceutically acceptable salt thereof.
[0158] These compounds may be prepared according to Scheme 4 set
forth below and have the same utility as the compounds of formula
(I).
General Synthetic Scheme
[0159] Compounds of this disclosure can be made by the methods
depicted in the reaction schemes shown below.
[0160] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.),
or Sigma (St. Louis, Mo.) or are prepared by methods known to those
skilled in the art following procedures set forth in references
such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes
1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon
Compounds, Volumes 1-5 and Supplementals (Elsevier Science
Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and
Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and
Sons, 4th Edition) and Larock's Comprehensive Organic
Transformations (VCH Publishers Inc., 1989). These schemes are
merely illustrative of some methods by which the compounds of this
disclosure can be synthesized, and various modifications to these
schemes can be made and will be suggested to one skilled in the art
having referred to this disclosure. The starting materials and the
intermediates, and the final products of the reaction may be
isolated and purified if desired using conventional techniques,
including but not limited to filtration, distillation,
crystallization, chromatography and the like. Such materials may be
characterized using conventional means, including physical
constants and spectral data.
[0161] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure over a temperature range
from about -78.degree. C. to about 150.degree. C., or from about
0.degree. C. to about 125.degree. C. or at about room (or ambient)
temperature, e.g., about 20.degree. C.
[0162] Compounds of Formula (I) where R.sup.5 is a group of formula
(i) and other groups as 5 defined in the Summary can be prepared as
illustrated and described in Scheme 1 below.
##STR00017## ##STR00018##
[0163] Reaction of a dihaloheteroaryl compound such as
4,6-dichloro-5-nitropyrimidine with an amine of formula
NH(PG).sub.2 where PG is a suitable amino protecting group such as
benzyl provides a compound of formula 1. The reaction is carried
out in a suitable organic solvent such as dioxane, dichloromethane,
and the like. Displacement of the second halo group by an amino
compound of formula 2 where Y and ring Z are as defined in the
Summary and PG.sup.1 is a suitable amino protecting group such as
Boc, yields a compound of formula 3. The reaction is carried out in
dichloromethane, dioxane, tetrahydrofuran, and the like with
additional base such as triethylamine. Compounds of formula 2 such
as (R)-tert-butyl 3-aminopiperidine-1-carboxylate, (S)-tert-butyl
3-aminopiperidine-1-carboxylate, (R)-tert-butyl
3-(aminomethyl)pyrrolidine-1-carboxylate, (S)-tert-butyl
3-(aminomethyl)pyrrolidine-1-carboxylate, (R)-tert-butyl
2-(aminomethyl)azetidine-1-carboxylate, and (S)-tert-butyl
2-(aminomethyl)azetidine-1-carboxylate, are commercially available
or can be prepared by methods well known in the art. The nitro
group of compounds of formula 3 can be reduced with reagents such
as Zn and ammonium chloride in EtOAc or with Fe or SnCl in a
solvent such as acetic acid in EtOH to afford compounds of formula
4.
[0164] Compounds of formula 4 can be cyclized to form the
benzimidazolones of formula 5 by heating 4 in an organic solvent
such as dichloroethane and the like, with carbonyl diimidazole,
phosgene or a phosgene equivalent (e.g., diphosgene or
triphosgene), in the presence of a base such as triethyl amine,
diisopropylethyl amine, and the like. Removal of the amino
protecting group PG provides compound of formula 6. The reaction
conditions utilized are based on the nature of the amino protecting
group. For example, when PG is a benzyl group it can be removed via
hydrogenation using a Pd/C catalyst and the like with an additive
such as acetic acid to afford a compound of formula 6. Reaction of
6 with an aryl boronic acid of formula 7 where R.sup.1, R.sup.2,
Ar, and X are as defined in the Summary via a copper mediated
coupling (Chan-Lam coupling) using, for example, Cu(OAc).sub.2 as a
catalyst in a solvent such as DCM, with an additive such TEMP or
oxygen and a base such as pyridine or triethylamine affords a
compound of formula 8. Compounds of formula 7, e.g
(4-phenoxyphenyl)boronic acid,
2-[4-(3-fluorophenoxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
4-(4-fluorophenoxy)phenylboronic acid,
4-(3-fluorophenoxy)phenylboronic acid,
4-(3,5-difluorophenoxy)-phenylboronic acid,
4-(4-chloro-2-fluorophenoxy)phenyl-boronic acid, and
4-(3-(trifluoromethyl)phenoxy)phenyl boronic acid are either
commercially available or can be prepared from the phenyl halide by
lithium halogen exchange and quenching with triisopropyl
borate.
[0165] Alternatively, compound 8 can be prepared by reacting
compound 5 first with boronic acid 7, followed by removal of the
amino protecting group under conditions described above. Removal of
the amino protecting group PG.sup.1 in compound 8 provides compound
of formula 9. The reaction conditions utilized are based on the
nature of the amino protecting group. For example, when PG.sup.1 is
Boc it can be removed under acid hydrolysis reaction conditions
such as treatment with an acid such TFA, HCl, and the like.
[0166] Compound 9 can be then converted to a compound of Formula
(I) by methods well known in the art. For example, compounds of
Formula (I) can be prepared by coupling compound 9 with an acid of
formula 10 or an acid derivative of compound 10 such as acid
chloride, where R.sup.a, R.sup.b, and R.sup.c are as described in
the Summary to give a compound of Formula (I). When compound 10 is
used, the reaction is carried out under standard amide coupling
conditions such as in the presence of HATU, DCC, carbon diimidazole
(CDI) and the like. Compounds of formula 10 or acid chloride
derivatives thereof are commercially available (e.g. acryloyl
chloride) or they can be prepared by methods well known in the art,
such as the condensation product of cyanoacetic acid and an
aldehyde such as isobutyraldeyde or pivaldehyde.
[0167] Compound of Formula (I) where R.sup.a is cyano also be
prepared by first condensing compound 9 with 2-cyanoacetic acid
under standard amide coupling conditions such as carbon diimidazole
(CDI) and the like to give a compound of formula 11. Condensation
of a compound of formula 11 with an aldehyde of formula R.sup.cCHO
where R.sup.c is as defined in the Summary under standard
condensation reaction conditions such as using a base such as
piperidine and the like, in the presence or absence of acetic acid
and the like, in solvents such as ethanol and the like at
temperatures ranging from room temperature to reflux then provides
a compound of Formula (I). Compounds of formula R.sup.cCHO are
commercially available or they can be prepared by methods well
known in the art, e.g., acetaldehyde, cyclopropylaldehyde,
isobutyraldehyde, 3-methyloxetane-3-carbaldehyde,
2-(dimethylamino)-2-methylpropanal,
2-methyl-2-(1-piperidyl)propanal, tert-butyl
(2S)-2-formylpyrrolidine-1-carboxylate and
2-methyl-2-(morpholin-4-yl)propanal are commercially available.
Ethoxy-2-methylpropanal was prepared from isobutyraldehyde as
described in PCT Int. Appl., 2007142576. Compounds R.sup.cCHO where
R.sup.c is -(alkylene)-NR.sup.6R.sup.7 can be prepared by treatment
of isobutryaldhyde with bromine to form bromoisobutryaldehyde
followed displacement of the bromide by addition of
HNR.sup.6R.sup.7.
[0168] Alternatively, compound 11 can also be condensed with a
precursor group of R.sup.cCHO and then converted to a compound of
Formula (I). For example, compound 11 can be condensed with
tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate followed by removal
of the amino protecting group to give a compound of Formula (I)
where R.sup.c is 2-aminopropan-2-yl. The condensation reaction can
be also be carried out by adding the desired aldehyde R.sup.cCHO
with a base such as pyrrolidine or piperidine with or without
chlorotrimethylsilane in dichloromethane or other suitable solvent
(e.g. dioxane and ethanol). Compounds of Formula (I) where R.sup.5
is a group of formula (ii)-(iv) can be prepared as described in
scheme 2. By following the procedure described above and
substituting compound 9 with suitable starting materials, such as
2-butynoic acid, vinylsulfonyl chloride, (E)-prop-1-ene-1-sulfonyl
chloride, 1-propyne-1-sulfonyl chloride, compounds of formula (I)
can be obtained.
[0169] Alternatively, to prepare compounds of formula (I) where
R.sup.5 is a group of formula (ii), compounds of formula 11 can be
reacted with cyanomethanesulfonyl chloride, available commercially,
to afford a cyanomethylsulfonamide which can be condensed with
aldehydes of formula 12 with TMSCl and pyrrolidine to afford
structures of formula (I).
##STR00019##
[0170] Compounds of formula (I) where A=CH can be prepared as
described in scheme 3. 2,4-dichloro-3-nitropyridine can first be
reacted with an amino compound of formula 2 where Y and ring Z are
as defined in the Summary and PG.sup.1 is a suitable amino
protecting group such as Boc. Subsequent reaction with an amine of
formula NH(PG).sub.2 where PG is a suitable amino protecting group
such as 4-methoxybenzyl in a solvent such as DMF afford a compound
of formula 14. Reduction of the nitro group by hydrogenation with
Pd/C or by reduction with Zn, Fe, or SnCl under standard
conditions, affords a compound of formula 15. Condensation with
carbonyldiimidazole or a phosgene equivalent affords the cyclic
urea 16. Chan-Lam coupling can be performed at this stage and the
syntheses of compounds (I) completed as described in Scheme 1.
[0171] Alternatively, compound 17 can be prepared by treating first
with an acid such as TFA to remove both protecting groups and
subsequently installing the PG.sup.1 (e.g. Boc) group. Subsequent
treatment with dimethylformamide dimethyl acetal affords a compound
of formula 18. Reacting under Chan-Lam conditions as described
above then affords compound 19. Subsequent deprotection by
treatment of 19 with an acid such as HCl or TFA in solvents such as
Dichloromethane, dioxane, MeOH, or EtOH affords a compound of
formula 20. Preparation of compounds of formula (I) are then
prepared in analogous fashion to the methods described in Schemes 1
and 2.
##STR00020## ##STR00021##
scheme 4 below shows the preparation of the compounds of formula
21, 22, 24, and 25. Coupling of a commercially available acid such
as 3-hydroxypropanoic acid or 2-hydroxypropanoic acid (as a
racemate or as the (S) or (R) isomer) with compound 20 from scheme
2 using a reagent such as HATU in a solvent such as DMF affords
compounds of formula 21 and 22 respectively. Acryloyl chloride may
be added to compound 20 in a solvent such as DMF with a base such
as trimethylamine or diisopropylethylamine to afford a compound of
formula 23. Oxidation with reagents such as osmium tetroxide and
N-methyl morpholine oxide (NMO) in a mixture of acetone and water
affords diols of formula 24. Compound 25 can be prepared from a
compound of formula 23 by oxidation with an oxidant such as mCPBA
in a solvent such as toluene or dichloromethane or by tert-butyl
hydrogen peroxide (TBHP) and a cinchona alkaloid catalyst
(Sharpless epoxidation).
##STR00022##
General Method A
[0172] Some other compounds can be prepared using the general
method shown below.
##STR00023## ##STR00024##
Step 1
[0173] Into a 100-mL round-bottom flask purged and maintained with
an atmosphere of 02, was placed the aryl boronic acid (1.0 equiv),
TEA (4.0 equiv), Cu(OAc)2 (0.50 equiv), TEMPO (1.10 equiv) and mol
sieves (4 A) (500 mg) in dichloromethane (0.1 mM). The resulting
solution was stirred for 30 min and then the arylboronic acid (2.00
equiv) was added. The resulting solution was stirred overnight at
rt. The resulting mixture was concentrated under vacuum. The
residue was applied onto a silica gel column eluting with
dichloromethane/methanol to afford the desired product A.
Step 2
[0174] To a solution of A (1.0 equiv) in dioxane was added hydrogen
chloride (12M). The resulting solution was stirred for 3 h at
85.degree. C. in an oil bath. The reaction was then quenched by the
addition of sodium bicarbonate (sat.). The resulting solution was
extracted with DCM/MeOH (10:1) and the organic layers combined. The
resulting mixture was washed with saturated sodium chloride. The
mixture was dried over anhydrous sodium sulfate and concentrated
under vacuum. This resulted in 360 mg (100%) of B.
Step 3
[0175] Into a 50-mL round-bottom flask, was placed B (1.0 equiv),
2-cyanoacetic acid (1.0 equiv), HATU (1.5 equiv), TEA (3.0 equiv)
and N,N-dimethylformamide (0.1 mMol). The resulting solution was
stirred for 2 h at rt. The resulting solution was extracted with
dichloromethane and the organic layers combined. The resulting
mixture was washed with 6.times.100 mL of water. The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was applied onto a silica gel column with
dichloromethane/methanol to afford compound C.
Step 4
[0176] Into a round bottomed flask was placed C (1.0 equiv) which
was dissolved in DCM to a concentration of 0.2M. The solution was
cooled to 0.degree. C., and the aldehyde (3.0 equiv) was added
followed by pyrrolidine (6.0 equiv) and TMSCl (4.0 equiv). The
reaction was warmed to rt and stirred for 3 h or until the sm was
consumed. Water was added and the layers separated. The organic
layer was dried over sodium sulfate, filtered and the solvent
removed in vacuo. Purification by either silica gel chromatography
or preparative HPLC afforded the desired compounds D. Aldehydes
were either purchased commercially, by the method shown below or by
methods known in the literature (i.e. oxidation of an alcohol via
Swern conditions or with an oxidant such as PCC or Dess-Martin
periodinane).
General Method B
Preparation of Aldehydes from Isobutuyraldehyde
##STR00025##
[0177] To a solution of 2-methylpropanal (1.0 equiv) in DCM (0.2M)
cooled with an ice bath was added bromine (1.0 equiv) dropwise.
After 1 hr, most solvent was removed from the resulting
2-bromo-2-methylpropanal solution in vacuo. This material was
diluted in DCM (8 ml) at rt and amine (2.0 equiv) was added. After
stirring overnight, the mixture was diluted with brine (30 mL) and
the layers separated. The organic layer is dried (MgSO.sub.4),
filtered and concentrated to isolate the desired aldehyde which is
either used directly in the next step or purified by silica gel
chromatography prior to use.
Testing
[0178] The BTK inhibitory activity, residence time of the inhibitor
BTK bound complex, and the ability of the of the compounds of the
present disclosure to form an irreversible covalent bond or a
reversible covalent bond with Cys 481 (UniprotKB Sequence ID
Q06187) of BTK can be tested using the in vitro and/or in vivo
assays described in Biological Examples below.
[0179] The BTK inhibitory activity of the compound of Formula (I)
and/or a pharmaceutically acceptable salt thereof of the present
disclosure can be tested using the in vitro and/or in vivo assays
described in Biological Examples 1, 3, 4, and 5 below. A
determination of kinase inhibitory activity by any of those assays
is considered to be kinase inhibitory activity within the scope of
this disclosure even if any or all of the other assays do not
result in a determination of kinase inhibitory activity.
[0180] Without being bound to any specific mechanistic theory, in
those embodiments where the compound of the present disclosure is a
reversible covalent inhibitor, it is believed that the cysteine
sulfhydryl group and a carbon atom forming part of the
carbon-carbon double bond in the R.sup.5 group in a compound of
Formula (I) where R.sup.5 is a group of formula (i), (ii) or (iii)
where R.sup.a is cyano, (see Formula (I)) can form a reversible,
i.e., labile, covalent bond, such as wherein Cys 481 of BTK attacks
an electron deficient carbon atom of the carbon-carbon double bond
in the above listed R.sup.5 groups in the compound of present
disclosure to form a thiol adduct.
[0181] In some embodiments, the electron deficient carbon atom of
the olefin is distal to the carbon attached to the R.sup.a group
(where R.sup.a is cyano) i.e., the carbon atom attached to the
R.sup.b and R.sup.c group (see Formula (I) in the compounds of the
present disclosure). Therefore, the combination of the R.sup.a
group (where R.sup.a is cyano) and the "--N--CO--, --NSO.sub.2 or
--N--SO--" moieties and the olefinic moiety to which they are
bonded in the compounds of the present disclosure can increase the
reactivity of the olefin to form a thiol adduct with the active
site cysteine residue in BTK.
[0182] The compounds of the present disclosure which are reversible
covalent inhibitors can bind with BTK in two different manners. In
addition to the labile covalent binding, discussed above, they are
believed to also form non-covalent binding (e.g., via van der Waals
binding, hydrogen binding, hydrophobic binding, hydrophilic
binding, and/or electrostatic charge binding) with BTK, the
non-covalent binding sufficient to at least partially inhibit the
kinase activity of the BTK.
[0183] As disclosed herein, the labile covalent binding occurs
between the olefin in the inhibitor and the cysteine 481 residue
thiol side chain at or near the site where the inhibitor has the
aforementioned non-covalent binding with the BTK.
[0184] As is evident, the compounds of the present disclosure which
are reversible covalent inhibitors have both a cysteine-mediated
covalent binding and a non-covalent binding with the BTK. This is
in contrast with non-covalent reversible inhibitors which inhibit
the BTK only via non-covalent binding and lack the
cysteine-mediated covalent binding.
[0185] The binding of the compounds of the present disclosure with
BTK in the two different manners mentioned above provides a
reversible covalent inhibitor having a slow off-rate and a
protracted duration of action, in some instances comparable to an
irreversible covalent inhibitor without forming permanent
irreversible protein adducts. The difference between irreversible
and reversible covalent inhibitors, particularly the compounds
disclosed herein, can be ascertained utilizing assays disclosed
herein.
[0186] In general, the binding involved an inhibitor that forms a
reversible covalent bond with BTK which is stable when the BTK is
in certain configurations and susceptible to being broken when the
BTK is in different configurations (in both cases under physiologic
conditions), whereas the interaction between an inhibitor that
forms an irreversible covalent bond with BTK is stable under
physiologic conditions even when the BTK is in different
configurations.
[0187] A reversible covalent bond often imparts unique properties
related to the residence time of the compound within the
cysteine-containing binding site. In this context, residence time
refers to the temporal duration of the compound-target complex
under different conditions (see Copeland R A, Pompliano D L, Meek T
D. Drug-target residence time and its implications for lead
optimization. Nat. Rev. Drug Discov. 5(9), 730-739 (2006).
[0188] The presence of a reversible covalent bond in a reversible
covalent inhibitor as disclosed herein can lead to an extended
residence time when compared to a compound that does not form a
covalent bond with BTK. In one embodiment disclosed herein the
compounds of the present disclosure that are reversible covalent
inhibitors have a residence time of at least about 1 h. Residence
time may be measured using an occupancy assay in a biochemical or
cellular environment (see Biological Example 2 and 9 below).
Additionally, residence time may be measured using a functional
assay following a defined wash-out period.
[0189] Compounds that form an irreversible covalent bond in an
irreversible covalent inhibitor share these extended residence time
properties but may nonetheless be differentiated from reversible
covalent inhibitor using a reversibility assay. The ability of the
compound of the disclosure to form reversible or irreversible
covalent bond with Cys481 of BTK, can be determined by the assays
described in Biological Examples 2, 6-8 below. A determination of
the binding reversibility of the covalent bond between the cysteine
residue and the olefinic bond of the compound of the disclosure by
any of Biological Examples 2, 6-8 below is considered to be
reversible binding within the scope of this disclosure even if one
or both of the other methods does not result in a determination of
binding reversibility.
Administration and Pharmaceutical Composition
[0190] In general, the compounds of this disclosure will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. Therapeutically effective amounts of compounds of
Formula (I) may range from about 0.01 to about 500 mg per kg
patient body weight per day, which can be administered in single or
multiple doses. In one embodiment, the dosage level will be about
0.1 to about 250 mg/kg per day. In another embodiment the dosage
level will be about 0.5 to about 100 mg/kg per day. A suitable
dosage level may be about 0.01 to about 250 mg/kg per day, about
0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per
day. Within this range the dosage can be about 0.05 to about 0.5,
about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral
administration, the compositions may be provided in the form of
tablets containing about 1.0 to about 1000 milligrams of the active
ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75,
100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000
milligrams of the active ingredient. The actual amount of the
compound of this disclosure, i.e., the active ingredient, will
depend upon numerous factors such as the severity of the disease to
be treated, the age and relative health of the subject, the potency
of the compound being utilized, the route and form of
administration, and other factors.
[0191] In general, compounds of this disclosure will be
administered as pharmaceutical compositions by any one of the
following routes: oral, systemic (e.g., transdermal, intranasal or
by suppository), or parenteral (e.g., intramuscular, intravenous or
subcutaneous) administration. The preferred manner of
administration is oral using a convenient daily dosage regimen,
which can be adjusted according to the degree of affliction.
Compositions can take the form of tablets, pills, capsules,
semisolids, powders, sustained release formulations, solutions,
suspensions, elixirs, aerosols, or any other appropriate
compositions.
[0192] The choice of formulation depends on various factors such as
the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills or capsules are
preferred) and the bioavailability of the drug substance. Recently,
pharmaceutical formulations have been developed especially for
drugs that show poor bioavailability based upon the principle that
bioavailability can be increased by increasing the surface area
i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles
in the size range from 10 to 1,000 nm in which the active material
is supported on a crosslinked matrix of macromolecules. U.S. Pat.
No. 5,145,684 describes the production of a pharmaceutical
formulation in which the drug substance is pulverized to
nanoparticles (average particle size of 400 nm) in the presence of
a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high
bioavailability. Bioavailablity of drugs that decompose at stomach
pH can be increased by administration of such drugs in a
formulation that releases the drug intraduodenally.
[0193] The compositions are comprised of in general, a compound of
Formula (I) and/or a pharmaceutically acceptable salt thereof in
combination with a pharmaceutically acceptable excipient such as
binders, surfactants, diluents, buffering agents, antiadherents,
glidants, hydrophilic or hydrophobic polymers, retardants,
stabilizing agents or stabilizers, disintegrants or
superdisintegrants, antioxidants, antifoaming agents, fillers,
flavors, colors, lubricants, sorbents, preservatives, plasticizers,
or sweeteners, or mixtures thereof, which facilitate processing of
the compound of Formula (I) (or embodiments thereof disclosed
herein) and/or a pharmaceutically acceptable salt thereof into
preparations which can be used pharmaceutically. Any of the
well-known techniques and excipients may be used as suitable and as
understood in the art, see for example, Remington: The Science and
Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press,
2005); Liberman, H. A., Lachman, L., and Schwartz, J. B. Eds.,
Pharmaceutical Dosage Forms, Vol. 1-2 Taylor & Francis 1990;
and R. I. Mahato, Ansel's Pharmaceutical Dosage Forms and Drug
Delivery Systems, Second Ed. (Taylor & Francis, 2012).
[0194] In certain embodiments, the formulations may include one or
more pH adjusting agents or buffering agents, for example, acids
such as acetic, boric, citric, fumaric, maleic, tartaric, malic,
lactic, phosphoric and hydrochloric acids; bases such as sodium
hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium
acetate, sodium lactate and tris-hydroxymethylaminomethane; and
buffers such as citrate/dextrose, sodium bicarbonate, ammonium
chloride, and the like. Such buffers used as bases may have other
counterions than sodium, for example, potassium, magnesium,
calcium, ammonium, or other counterions. Such acids, bases and
buffers are included in an amount required to maintain pH of the
composition in an acceptable range.
[0195] In certain embodiments, the formulations may also include
one or more salts in an amount required to bring osmolality of the
composition into an acceptable range. Such salts include those
having sodium, potassium or ammonium cations and chloride, citrate,
ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or
bisulfite anions; suitable salts include sodium chloride, potassium
chloride, sodium thiosulfate, sodium bisulfite and ammonium
sulfate.
[0196] In certain embodiments, the formulations may also include
one or more antifoaming agents to reduce foaming during processing
which can result in coagulation of aqueous dispersions, bubbles in
the finished film, or generally impair processing. Exemplary
anti-foaming agents include silicon emulsions or sorbitan
sesquoleate.
[0197] In certain embodiments, the formulations may also include
one or more antioxidants, such as non-thiol antioxidants, for
example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic
acid or its derivative, and tocopherol or its derivatives. In
certain embodiments, antioxidants enhance chemical stability where
required. Other agents such as citric acid or citrate salts or EDTA
may also be added to slow oxidation.
[0198] In certain embodiments, the formulations may also include
one or more preservatives to inhibit microbial activity. Suitable
preservatives include mercury-containing substances such as merfen
and thiomersal; stabilized chlorine dioxide; and quaternary
ammonium compounds such as benzalkonium chloride,
cetyltrimethylammonium bromide, and cetylpyridinium chloride.
[0199] In certain embodiments, the formulations may also include
one or more binders. Binders impart cohesive qualities and include,
e.g., alginic acid and salts thereof; cellulose derivatives such as
carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.),
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.);
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin;
polyvinyl-pyrrolidone/vinyl acetate copolymer; crosspovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), and
lactose; a natural or synthetic gum such as acacia, tragacanth,
ghatti gum mucilage of isapol husks, polyvinylpyrrolidone (e.g.,
Polyvidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10),
larch arabogalactan, Veegum.RTM., polyethylene glycol, polyethylene
oxide, waxes, sodium alginate, and the like.
[0200] In certain embodiments, the formulations may also include
dispersing agents and/or viscosity modulating agents. Dispersing
agents and/or viscosity modulating agents include materials that
control the diffusion and homogeneity of a drug through liquid
media or a granulation method or blend method. In some embodiments,
these agents also facilitate the effectiveness of a coating or
eroding matrix. Exemplary diffusion facilitators/dispersing agents
include, e.g., hydrophilic polymers, electrolytes, Tween.RTM.60 or
80, PEG, polyvinylpyrrolidone (PVP; commercially known as
Plasdone.RTM.), and the carbohydrate-based dispersing agents such
as, for example, hydroxypropyl celluloses (e.g., HPC, H-PC-SL, and
HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, RPMC K4M,
HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium,
methylcellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropyl-methylcellulose acetate stearate (HPMCAS),
noncrystalline cellulose, polyethylene oxides, magnesium aluminum
silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl
pyrrolidone/vinyl acetate copolymer (S630),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics
F680, F88.RTM.., and F10@8, which are block copolymers of ethylene
oxide and propylene oxide); and poloxamines (e.g., Tetronic
908.RTM., also known as Poloxamine 908.RTM., which is a
tetrafonctional block copolymer derived from sequential addition of
propylene oxide and ethylene oxide to ethylenediamine (BASF
Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate
copolymer (S-630), polyethylene glycol, e.g., the polyethylene
glycol can have a molecular weight of about 300 to about 6000, or
about 3350 to about 4000, or about 7000 to 5400, sodium
carboxymethylcellulose, methylcellulose, polysorbate-80, sodium
alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar
gum, xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone, carbomers, polyvinyl alcohol (PVA),
alginates, chitosans and combinations thereof. Plasticizcers such
as cellulose or triethyl cellulose can also be used as dispersing
agents. Dispersing agents particularly useful in liposomal
dispersions and self-emulsifying dispersions are dimyristoyl
phosphatidyl choline, natural phosphatidyl choline from eggs,
natural phosphatidyl glycerol from eggs, cholesterol and isopropyl
myristate. In general, binder levels of about 10 to about 70% are
used in powder-filled gelatin capsule formulations. Binder usage
level in tablet formulations varies whether direct compression, wet
granulation, roller compaction, or usage of other excipients such
as fillers which itself can act as moderate binder. Formulators
skilled in art can determine the binder level for the formulations,
but binder usage level of up to 90% and more typically up to 70% in
tablet formulations is common.
[0201] In certain embodiments, the formulations may also include
one or more diluents which refer to chemical compounds that are
used to dilute the compound of interest prior to delivery. Diluents
can also be used to stabilize compounds because they can provide a
more stable environment Salts dissolved in buffered solutions
(which also can provide pH control or maintenance) are utilized as
diluents in the art, including, but not limited to a phosphate
buffered saline solution. In certain embodiments, diluents increase
bulk of the composition to facilitate compression or create
sufficient bulk for homogenous blend for capsule filling. Such
compounds include e.g., lactose, starch, mannitol, sorbitol,
dextrose, microcrystalline cellulose such as Avicel.RTM.; dibasic
calcium phosphate, dicalcium phosphate dihydrate; tricalcium
phosphate, calcium phosphate; anhydrous lactose, spray-dried
lactose; pregelatinized starch, compressible sugar, such as
Di-Pac.RTM. (Amstar); hydroxypropyl-methylcellulose,
hydroxypropylmethylcellulose acetate stearate, sucrose-based
diluents, confectioner's sugar; monobasic calcium sulfate
monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate,
dextrates; hydrolyzed cereal solids, amylose; powdered cellulose,
calcium carbonate; glycine, kaolin; mannitol, sodium chloride;
inositol, bentonite, and the like.
[0202] In certain embodiments, the formulations may also include
one or more disintegrant which includes both the dissolution and
dispersion of the dosage form when contacted with gastrointestinal
fluid. Disintegration agents or disintegrants facilitate the
breakup or disintegration of a substance. Examples of
disintegration agents include a starch, e.g., a natural starch such
as corn starch or potato starch, a pregelatinized starch such as
National 1551 or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM., a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101,
Avicel.RTM. PH 102, Avicel.RTM. PH105, Elceme.RTM. P100,
Emcocel.RTM., Vivacel.RTM., and Solka-Floc.RTM., methylcellulose,
croscarmellose, or a cross-linked cellulose, such as cross-linked
sodium carboxymethyl-cellulose (Ac-Di-Sol.RTM.), cross-linked
carboxymethylcellulose, or cross-linked croscarmellose, a
cross-linked starch such as sodium starch glycolate, a cross-linked
polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone,
alginate such as alginic acid or a salt of alginic acid such as
sodium alginate, a clay such as Veegum.RTM. HV (magnesium aluminum
silicate), a gum such as agar, guar, locust bean, Karaya, pectin,
or tragacanth, sodium starch glycolate, bentonite, a natural
sponge, a surfactant, a resin such as a cation-exchange resin,
citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in
combination starch, and the like.
[0203] In certain embodiments, the formulations may also include
erosion facilitators. Erosion facilitators include materials that
control the erosion of a particular material in gastrointestinal
fluid. Erosion facilitators are generally known to those of
ordinary skill in the art. Exemplary erosion facilitators include,
e.g., hydrophilic polymers, electrolytes, proteins, peptides, and
amino acids.
[0204] In certain embodiments, the formulations may also include
one or more filling agents which include compounds such as lactose,
calcium carbonate, calcium phosphate, dibasic calcium phosphate,
calcium sulfate, microcrystalline cellulose, cellulose powder,
dextrose, dextrates, dextran, starches, pregelatinized starch,
sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like.
[0205] In certain embodiments, the formulations may also include
one or more flavoring agentsand/or sweeteners e.g., acacia syrup,
acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian
cream berry, black currant, butterscotch, calcium citrate, camphor,
caramel, cherry, cherry cream chocolate, cinnamon, bubble gum,
citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool
cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus,
eugenol, fructose, fruit punch, ginger, glycyrrhetinate,
glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt,
lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol,
mannitol, maple, marshmallow, menthol, mint cream, mixed berry,
neohesperidine DC, neotame, orange, pear, peach, peppermint,
peppermint cream, Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin, aspartame, acesulfame potassium, mannitol, talin,
sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,
thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof.
[0206] In certain embodiments, the formulations may also include
one or more lubricants and glidants which are compounds that
prevent, reduce or inhibit adhesion or friction of materials.
Exemplary lubricants include, e.g., stearic acid, calcium
hydroxide, talc, sodium stearyl lumerate, a hydrocarbon such as
mineral oil, or hydrogenated vegetable oil such as hydrogenated
soybean oil, higher fatty acids and their alkali-metal and alkaline
earth metal salts, such as aluminum, calcium, magnesium, zinc,
stearic acid, sodium stearates, glycerol, talc, waxes, boric acid,
sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol (e.g., PEG4000) or a methoxypolyethylene glycol
such as Carbowax.RTM., sodium oleate, sodium benzoate, glyceryl
behenate, polyethylene glycol, magnesium or sodium lauryl sulfate,
colloidal silica such as Syloid.RTM., Cab-O-Sil.RTM., a starch such
as corn starch, silicone oil, a surfactant, and the like.
[0207] In certain embodiments, the formulations may also include
one or more plasticizers which are compounds used to soften the
enteric or delayed release coatings to make them less brittle.
Suitable plasticizers include, e.g., polyethylene glycols such as
PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic
acid, propylene glycol, oleic acid, triethyl citrate, dibutyl
sebacate, triethyl cellulose and triacetin. In some embodiments,
plasticizers can also function as dispersing agents or wetting
agents.
[0208] In certain embodiments, the formulations may also include
one or more solubilizers which include compounds such as triacetin,
triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl
sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cyclodextrins for example Captisol.RTM., ethanol, n-butanol,
isopropyl alcohol, cholesterol, bile salts, polyethylene glycol
200-600, glycofurol, transcutol, propylene glycol, and dimethyl
isosorbide and the like. In one embodiment, the solubilizer is
vitamin E TPGS and/or Captisol.RTM. or
B-hydroxypropylcyclodextrin.
[0209] In certain embodiments, the formulations may also include
one or more suspending agents which include compounds such as
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K112,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer
(S630), polyethylene glycol, e.g., the polyethylene glycol can have
a molecular weight of about 300 to about 6000, or about 3350 to
about 4000, or about 7000 to about 5400, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, hydroxymethylcellulose acetate
stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate,
gums, such as, e.g., gum tragacanth and gum acacia, guar gum,
xanthans, including xanthan gun, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monoleate, povidone and the like.
[0210] In certain embodiments, the formulations may also include
one or more surfactants which include compounds such as sodium
lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin,
vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan
monooleate, polyoxyethylene sorbitan monolaurate, polysorbates,
polaxomers, bile salts, glyceryl monostearate, copolymers of
ethylene oxide and propylene oxide, e.g., Pluronic.RTM. (BASF), and
the like. Some other surfactants include polyoxyethylene fatty acid
glycerides and vegetable oils, e.g., polyoxyethylene (60)
hydrogenated castor oil; and polyoxyethylene alkylethers and
alkylphenyl ethers, e.g. octoxynol 10, octoxynol 40. In some
embodiments, surfactants may be included to enhance physical
stability or for other purposes.
[0211] In certain embodiments, the formulations may also include
one or more viscosity enhancing agents which include, e.g., methyl
cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulose acetate stearate, hydroxypropylmethyl cellulose
phthalate, carbomer, polyvinyl alcohol alginates, acacia, chitosans
and combinations thereof.
[0212] In certain embodiments, the formulations may also include
one or more wetting agents which include compounds such as oleic
acid, glyceryl monostearate, sorbitan monooleate, sorbitan
monolaurate, triethanolamine oleate, polyoxyethylene sorbitan
monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate,
sodium oleate, sodium lauryl sulfate, sodium doccusate, triacetin,
Tween 80, vitamin E TPGS, ammonium salts and the like.
[0213] Pharmaceutical preparations disclosed herein can be obtained
by mixing one or more solid excipient such as carrier, binder,
filling agent, suspending agent, flavoring agent, sweetening agent,
disintegrating agent, dispersing agent, surfactant, lubricant,
colorant diluent, solubilizer, moistening agent, plasticizer,
stabilizer, penetration enhancer, wetting agent, anti-foaming
agent, antioxidant, preservative, or one or more combination
thereof with one or more of the compounds described herein,
optionally grinding the resulting mixture, and processing the
mixture of granules, after adding suitable excipients, if desired,
to obtain tablets.
[0214] Pharmaceutical preparations disclosed herein also include
capsules made of gelatin, as well as soft, sealed capsules made of
gelatin and a plasticizer, such as glycerol or sorbitol. Capsules
may also be made of polymers such as hypromellose. The capsules can
contain the active ingredients in admixture with filler such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds may be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, lipids,
solubilizers, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0215] These formulations can be manufactured by conventional
pharmacological techniques. Conventional pharmacological techniques
include, e.g., one or a combination of methods: (1) dry mixing, (2)
direct compression, (3) milling, (4) dry or non-aqueous
granulation, (5) wet granulation, (6) fusion, or (7) extrusion.
See, e.g., Lachman et al., The Theory and Practice of Industrial
Pharmacy, 3.sup.rd ed. (1986). Other methods include, e.g., spray
drying, pan coating, melt granulation, granulation, fluidized bed
spray drying or coating (e.g., wurster coating), tangential
coating, top spraying, tableting, extruding,
extrusion/spheronization, and the like.
[0216] It should be appreciated that there is considerable overlap
between excipients used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of excipient that can be
included in solid dosage forms described herein. The type and
amounts of such excipient can be readily determined by one skilled
in the art, according to the particular properties desired.
[0217] In some embodiments, the solid dosage forms described herein
are enteric coated oral dosage forms, i.e., as an oral dosage form
of a pharmaceutical composition as described herein which utilizes
an enteric coating to effect the release of the compound in the
intestine of the gastrointestinal tract. An "enterically coated"
drug and/or tablet refers to a drug and/or tablet that is coated
with a substance that remains intact in the stomach but dissolves
and releases the drug once the intestine (in one embodiment small
intestine) is reached. As used herein "enteric coating", is a
material, such as a polymer material or materials which encase the
therapeutically active agent core either as a dosage form or as
particles. Typically, a substantial amount or all of the enteric
coating material is dissolved before the therapeutically active
agent is released from the dosage form, so as to achieve delayed
dissolution of the therapeutically active agent core or particles
in the small and/or large intestine. Enteric coatings are
discussed, for example, Loyd, V. Allen, Remington: The Science and
Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press,
2005; and P. J. Tarcha, Polymers for Controlled Drug Delivery,
Chapter 3, CRC Press, 1991. Methods for applying enteric coatings
to pharmaceutical compositions are well known in the art, and
include for example, U.S. Patent Publication No. 2006/0045822.
[0218] The enteric coated dosage form may be a compressed or molded
or extruded tablet (coated or uncoated) containing granules,
powder, pellets, beads or particles of the compound of Formula (I)
(or any embodiments thereof) and/or a pharmaceutically acceptable
salt thereof and/or other excipients, which are themselves coated
or uncoated provided at least the tablet or the compound of Formula
(I) is coated. The enteric coated oral dosage form may also be a
capsule (coated or uncoated) containing pellets, beads or granules
of the compound of Formula (I) (or any embodiments thereof) and/or
a pharmaceutically acceptable salt thereof and/or other excipients,
which are themselves coated or uncoated provided at least one of
them is coated. Some examples of coatings that were originally used
as enteric coatings are beeswax and glyceryl monostearate; beeswax,
shellac and cellulose; and cetyl alcohol, mastic and shellac as
well as shellac and stearic acid (U.S. Pat. No. 2,809,918);
polyvinylacetate and ethyl cellulose (U.S. Pat. No. 3,835,221).
More recently, the coatings used are neutral copolymers of
polymethacrylic acid esters (Eudragit L30D). (F. W. Goodhart et al,
Pharm. Tech., p. 64-71, April, 1984); copolymers of methacrylic
acid and methacrylic acid methyl ester (Eudragit S), or a neutral
copolymer of polymethacrylic acid esters containing metallic
stearates (Mehta et al U.S. Pat. Nos. 4,728,512 and 4,794,001),
cellulose acetate succinate, and hypromellose phthalate.
[0219] Any anionic polymer exhibiting a pH-dependent solubility
profile can be used as an enteric coating in the methods and
compositions described herein to achieve delivery to the intestine.
In one embodiment, delivery to the small intestine. In another
embodiment, delivery to the duodenum. In some embodiments the
polymers described herein are anionic carboxylic polymers. In other
embodiments, the polymers and compatible mixtures thereof, and some
of their properties, include, but are not limited to:
Shellac:
[0220] Also called purified lac, it is a refined product obtained
from the resinous secretion of an insect. This coating dissolves in
media of pH>7;
Acrylic Polymers:
[0221] The performance of acrylic polymers (primarily their
solubility in biological fluids) can vary based on the degree and
type of substitution. Examples of suitable acrylic polymers include
methacrylic acid copolymers and ammonium methacrylate copolymers.
The Eudragit series L, S, and RS (manufactured Rohm Pharma and
known as Evonik.RTM.) are available as solubilized in organic
solvent, aqueous dispersion, or dry powders. The Eudragit series
RL, NE, and RS are insoluble in the gastrointestinal tract but are
permeable and are used primarily for colonic targeting. The
Eudragit series L, L-30D and S are insoluble in stomach and
dissolve in the intestine and may be selected and formulated to
dissolve at a value of pH greater than 5.5 or as low as greater
than 5 or as high as greater than 7.
Cellulose Derivatives:
[0222] Examples of suitable cellulose derivatives are: ethyl
cellulose; reaction mixtures of partial acetate esters of cellulose
with phthalic anhydride. The performance can vary based on the
degree and type of substitution. Cellulose acetate phthalate (CAP)
dissolves in pH>6. Aquateric (FMC) is an aqueous based system
and is a spray dried CAP pseudolatex with particles <1 .mu.m.
Other components in Aquateric can include pluronics, Tweens, and
acetylated monoglycerides. Other suitable cellulose derivatives
include; cellulose acetate tritnellitate (Eastman); methylcellulose
(Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate
(HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (HPMCAS e.g., AQOAT
(Shin Etsu)). The performance can vary based on the degree and type
of substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S,
HP-55F grades are suitable. The performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate include, but are not
limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which
dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
These polymers are offered as granules, or as fine powders for
aqueous dispersions;
Poly Vinyl Acetate Phthalate (PVAP):
[0223] PVAP dissolves in pH>5, and it is much less permeable to
water vapor and gastric fluids. Detailed description of above
polymers and their pH-dependent solubility can be found at in the
article titled "Enteric coated hard gelatin capsules" byProfessor
Karl Thoma and Karoline Bechtold at
http://pop.www.capsugel.com/mediallibrary/enteric-coated-hard-gelatin-cap-
sules.pdf. In some embodiments, the coating can, and usually does,
contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in
the art. Suitable plasticizers include triethyl citrate (Citroflex
2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl
phthalate, tributyl citrate, acetylated monoglycerides, glycerol,
fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers usually will
contain 10-25% by weight of a plasticizer, especially dibutyl
phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as fluid bed or Wurster
coaters, or spray or pan coating are employed to apply coatings.
The coating thickness must be sufficient to ensure that the oral
dosage form remains intact until the desired site of topical
delivery in the intestinal tract is reached.
[0224] Colorants, surfactants, anti-adhesion agents, antifoaming
agents, lubricants (e.g., carnuba wax or PEG) and other additives
may be added to the coatings besides plasticizers to solubilize or
disperse the coating material, and to improve coating performance
and the coated product.
[0225] To accelerate the dissolution of the enteric coat, a
half-thickness, double coat of enteric polymer (for instance,
Eudragit L30 D-55) may be applied, and the inner enteric coat may
have a buffer up to pH 6.0 in the presence of 10% citric acid,
followed by a final layer of standard Eudragit L 30 D-55. Applying
two layers of enteric coat, each half the thickness of a typical
enteric coat, Liu and Basit were able to accelerate enteric coating
dissolution compared to a similar coating system applied,
unbuffered, as a single layer (Liu, F. and Basit, A. Journal of
Controlled Release. 147 (2010) 242-245.)
[0226] The intactness of the enteric coating may be measured, for
example, by the degradation of the drug within the micropellets.
The enteric coated dosage forms or pellets may be tested in
dissolution testing first in gastric fluid and separately in
intestinal fluid as described in USP to determine its function.
[0227] The enteric coated tablets and capsules formulation
containing the disclosed compounds can be made by methods well
known in the art. For example, tablets containing a compound
disclosed herein can be enterically coated with a coating solution
containing Eudragit.RTM., diethylphthlate, isopropyl alcohol, talc,
and water using a side vented coating pan (Freund Hi-Coater).
[0228] Alternatively, a multi-unit dosage form comprising
enteric-coated pellets that can be incorporated into a tablet or
into a capsule can be prepared as follows.
Core Material:
[0229] The core material for the individually enteric coating
layered pellets can be constituted according to different
principles. Seeds layered with the active agent (i.e., the compound
of Formula (I) (including embodiments disclosed herein) and/or a
pharmaceutically acceptable sale thereof), optionally mixed with
alkaline substances or buffer, can be used as the core material for
the further processing. The seeds which are to be layered with the
active agent can be water insoluble seeds comprising different
oxides, celluloses, organic polymers and other materials, alone or
in mixtures or water-soluble seeds comprising different inorganic
salts, sugars, non-pareils and other materials, alone or in
mixtures. Further, the seeds may comprise the active agent in the
form of crystals, agglomerates, compacts etc. The size of the seeds
is not essential for the present invention but may vary between
approximately 0.1 and 2 mm. The seeds layered with the active agent
are produced either by powder or solution/suspension layering using
for instance granulation or spray coating layering equipment.
[0230] Before the seeds are layered, active agent may be mixed with
further components. Such components can be binders, surfactants,
fillers, disintegrating agents, alkaline additives or other and/or
pharmaceutically acceptable ingredients alone or in mixtures. The
binders are for example polymers such as hydroxypropyl
methylcellulose (HPMC), hydroxypropyl-cellulose (HPC),
carboxymethylcellulose sodium, polyvinyl pyrrolidone (PVP), or
sugars, starches or other pharmaceutically acceptable substances
with cohesive properties. Suitable surfactants are found in the
groups of pharmaceutically acceptable non-ionic or ionic
surfactants such as for instance sodium lauryl sulfate.
[0231] Alternatively, the active agent optionally mixed with
suitable constituents can be formulated into a core material. Said
core material may be produced by extrusion/spheronization, balling
or compression utilizing conventional process equipment. The size
of the formulated core material is approximately between 0.1 and 4
mm and for example, between 0.1 and 2 mm. The manufactured core
material can further be layered with additional ingredients
comprising the active agent and/or be used for further
processing.
[0232] The active agent is mixed with pharmaceutical constituents
to obtain preferred handling and processing properties and a
suitable concentration of the active agent in the final
preparation. Pharmaceutical constituents such as fillers, binders,
lubricants, disintegrating agents, surfactants and other
pharmaceutically acceptable additives may be used.
[0233] Alternatively, the aforementioned core material can be
prepared by using spray drying or spray congealing technique.
Enteric Coating Layer(s):
[0234] Before applying the enteric coating layer(s) onto the core
material in the form of individual pellets, the pellets may
optionally be covered with one or more separating layer(s)
comprising pharmaceutical excipients optionally including alkaline
compounds such as pH-buffering compounds. This/these separating
layer(s), separate(s) the core material from the outer layers being
enteric coating layer(s). This/these separating layer(s) protecting
the core material of active agent should be water soluble or
rapidly disintegrating in water.
[0235] A separating layer(s) can be optionally applied to the core
material by coating or layering procedures in suitable equipments
such as coating pan, coating granulatooror in a fluidized bed
apparatus using water and/or organic solvents for the coating
process. As an alternative the separating layer(s) can be applied
to the core material by using powder coating technique. The
materials for the separating layers are pharmaceutically acceptable
compounds such as, for instance, sugar, polyethylene glycol,
polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate,
hydroxypropyl cellulose, methylcellulose, ethylcellulose,
hydroxypropyl methyl cellulose, carboxymethylcellulose sodium,
water soluble salts of enteric coating polymers and others, used
alone or in mixtures. Additives such as plasticizers, colorants,
pigments, fillers anti-tacking and anti-static agents, such as for
instance magnesium stearate, titanium dioxide, talc and other
additives may also be included into the separating layer(s).
[0236] When the optional separating layer is applied to the core
material it may constitute a variable thickness. The maximum
thickness of the separating layer(s) is normally only limited by
processing conditions. The separating layer may serve as a
diffusion barrier and may act as a pH-buffering zone. The
optionally applied separating layer(s) is not essential for the
invention. However, the separating layer(s) may improve the
chemical stability of the active substance and/or the physical
properties of the novel multiple unit tableted dosage form.
[0237] Alternatively, the separating layer may be formed in situ by
a reaction between an enteric coating polymer layer applied on the
core material and an alkaline reacting compound in the core
material. Thus, the separating layer formed comprises a water
soluble salt formed between the enteric coating layer polymer(s)
and an alkaline reacting compound which is in the position to form
a salt
[0238] One or more enteric coating layers are applied onto the core
material or onto the core material covered with separating layer(s)
by using a suitable coating technique. The enteric coating layer
material may be dispersed or dissolved in either water or in
suitable organic solvents. As enteric coating layer polymers, one
or more, separately or in combination, of the following can be
used, e.g. solutions or dispersions of methacrylic acid copolymers,
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, hydroxypropyl methylcellulose acetate succinate,
polyvinyl acetate phthalate, cellulose acetate trimellitate,
carboxymethylethylcellulose, shellac or other suitable enteric
coating polymer(s).
[0239] The enteric coating layers contain pharmaceutically
acceptable plasticizers to obtain the desired mechanical
properties, such as flexibility and hardness of the enteric coating
layers. Such plasticizers are for instance, but not restricted to
triacetin, citric acid esters, phthalic acid esters, dibutyl
sebacate, cetyl alcohol, polyethylene glycols, polysorbates or
other plasticizers.
[0240] The amount of plasticizer is optimized for each enteric
coating layer formula, in relation to the selected enteric coating
layer polymer(s), selected plasticizer(s) and the applied amount of
said polymer(s), in such a way that the mechanical properties, i.e.
flexibility and hardness of the enteric coating layer(s), for
instance exemplified as Vickers hardness, are adjusted so that if a
tablet is desired the acid resistance of the pellets covered with
enteric coating layer(s) does not decrease significantly during
compression of pellets into tablets. The amount of plasticizer is
usually above 5% by weight of the enteric coating layer polymer(s),
such as 15-50% and further such as 20-50%. Additives such as
dispersants, colorants, pigments polymers e.g. poly(ethylacrylate,
methylmethacrylate), anti-tacking and anti-foaming agents may also
be included into the enteric coating layer(s). Other compounds may
be added to increase film thickness and to decrease diffusion of
acidic gastric juices into the acid susceptible material. The
maximum thickness of the applied enteric coating is normally only
limited by processing conditions and the desired dissolution
profile.
Over-Coating Layer:
[0241] Pellets covered with enteric coating layer(s) may optionally
further be covered with one or more over-coating layer(s). The
over-coating layer(s) should be water soluble or rapidly
disintegrating in water. The over-coating layer(s) can be applied
to the enteric coating layered pellets by coating or layering
procedures in suitable equipments such as coating pan, coating
granulator or in a fluidized bed apparatus using water and/or
organic solvents for the coating or layering process. The materials
for over-coating layers are chosen among pharmaceutically
acceptable compounds such as, for instance sugar, polyethylene
glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate,
hydroxypropyl cellulose, methylcellulose, ethylcellulose,
hydroxypropyl methyl cellulose, carboxymethylcellulose sodium and
others, used alone or in mixtures. Additives such as plasticizers,
colorants, pigments, fillers, anti-tacking and anti-static agents,
such for instance magnesium stearate, titanium dioxide, talc and
other additives may also be included into the over-coating
layer(s). The over-coating layer may further prevent potential
agglomeration of enteric coating layered pellets, further it may
protect the enteric coating layer towards cracking during the
compaction process and enhance the tableting process. The maximum
thickness of the applied over-coating layer(s) is normally limited
by processing conditions and the desired dissolution profile. The
over-coating layer may also be used as a tablet film coating
layer.
[0242] Enteric coating of soft gelatin capsules may contain an
emulsion, oil, microemulsion, self-emulsifying system, lipid,
triglycerides, polyethylene glycol, surfactants, other solubilizers
and the like, and combinations thereof, to solubilize the active
agent. The flexibility of the soft gelatin capsule is maintained by
residual water and plasticizer. Moreover, for gelatin capsules the
gelatin may be dissolved in water so that spraying must be
accomplished at a rate with relatively low relative humidity such
as can be accomplished in a fluid bed or Wurster. In addition,
drying should be accomplished without removing the residual water
or plasticizer causing cracking of the capsule shell. Commercially
available blends optimized for enteric coating of soft gelatin
capsules such as Instamodel EPD (Enteric Polymeric Dispersion),
available from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a
laboratory scale enteric coated capsules may be prepared by: a)
rotating capsules in a flask or dipping capsules in a solution of
the gently heated enteric coating material with plasticizer at the
lowest possible temperature or b) in a lab scale sprayer/fluid bed
and then drying.
[0243] For aqueous active agents, it can be especially desirable to
incorporate the drug in the water phase of an emulsion. Such
"water-in-oil" emulsion provides a suitable biophysical environment
for the drug and can provide an oil-water interface that can
protect the drug from adverse effects of pH or enzymes that can
degrade the drug. Additionally, such water-in-oil formulations can
provide a lipid layer, which can interact favorably with lipids in
cells of the body, and can increase the partition of the
formulation onto the membranes of cells. Such partition can
increase the absorption of drugs in such formulations into the
circulation and therefore can increase the bioavailability of the
drug.
[0244] In some embodiments the water-in-oil emulsion contains an
oily phase composed of medium or long chain carboxylic acids or
esters or alcohols thereof, a surfactant or a surface active agent,
and an aqueous phase containing primarily water and the active
agent.
[0245] Medium and long chain carboxylic acids are those ranging
from C.sub.8 to C.sub.22 with up to three unsaturated bonds (also
branching). Examples of saturated straight chain acids are
n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid,
caproic acid, caprylic acid, capric acid, lauric acid, myristic
acid, palmitic acid, stearic acid, arachidic acid, behenic acid,
montanic acid and melissic acid. Also useful are unsaturated
monoolefinic straight chain monocarboxylic acids. Examples of these
are oleic acid, gadoleic acid and erucic acid. Also useful are
unsaturated (polyolefinic) straight chain monocarboxylic acids.
Examples of these are linoleic acid, ricinoleic acid, linolenic
acid, arachidonic acid and behenolic acid. Useful branched acids
include, for example, diacetyl tartaric acid. Unsaturated olefinic
chains may also be hydroxylated or ethoxylated to prevent oxidation
or to alter the surface properties.
[0246] Examples of long chain carboxylic acid esters include, but
are not limited to, those from the group of: glyceryl
monostearates; glyceryl monopalmitates; mixtures of glyceryl
monostearate and glyceryl monopalmitate; glyceryl monolinoleate;
glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl
monostearate, glyceryl monooleate and glyceryl monolinoleate;
glyceryl monolinolenate; glyceryl monogadoleate; mixtures of
glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate,
glyceryl monolinoleate, glyceryl monolinolenate and glyceryl
monogadoleate; acetylated glycerides such as distilled acetylated
monoglycerides; mixtures of propylene glycol monoesters, distilled
monoglycerides, sodium steroyl lactylate and silicon dioxide;
d-alpha tocopherol polyethylene glycol 1000 succinate; mixtures of
mono- and di-glyceride esters such as Atmul; calcium stearoyl
lactylate; ethoxylated mono- and di-glycerides; lactated mono- and
di-glycerides; lactylate carboxylic acid ester of glycerol and
propylene glycol; lactylic esters of long chain carboxylic acids;
polyglycerol esters of long chain carboxylic acids, propylene
glycol mono- and di-esters of long chain carboxylic acids; sodium
stearoyl lactylate; sorbitan monostearate; sorbitan monooleate;
other sorbitan esters of long chain carboxylic acids; succinylated
monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate;
cetyl esters of waxes; stearyl octanoate; C.sub.8-C.sub.30
cholesterol/lavosterol esters; and sucrose long chain carboxylic
acid esters. Examples of the self-emulsifying long chain carboxylic
acid esters include those from the groups of stearates, pamitates,
ricinoleates, oleates, behenates, ricinolenates, myristates,
laurates, caprylates, and caproates. In some embodiments the oily
phase may comprise a combination of 2 or more of the long chain
carboxylic acids or esters or alcohols thereof. In some embodiments
medium chain surfactants may be used and the oil phase may comprise
a mixture of caprylic/capric triglyceride and C.sub.8/C.sub.10
mono-/di-glycerides of caprylic acid, glyceryl caprylate or
propylene glycol monocaprylate or their mixtures.
[0247] The alcohols that can be used are exemplified by the
hydroxyl forms of the carboxylic acids exemplified above and also
strearyl alcohol.
[0248] Surface active agents or surfactants are long chain
molecules that can accumulate at hydrophilic/hydrophobic
(water/oil) interfaces and lower the surface tension at the
interface. As a result they can stabilise an emulsion. In some
embodiments of this invention, the surfactant may comprise: Tween@
(polyoxyethylene sorbate) family of surfactants, Span.RTM.
(sorbitan long chain carboxylic acid esters) family of surfactants,
Pluronic.RTM. (ethylene or propylene oxide block copolymers) family
of surfactants, Labrasol.RTM., Labrafil.RTM. and Labrafac.RTM.
(each polyglycolyzed glycerides) families of surfactants, sorbitan
esters of oleate, stearate, laurate or other long chain carboxylic
acids, poloxamers (polyethylene-polypropylene glycol block
copolymers or Pluronic.RTM.), other sorbitan or sucrose long chain
carboxylic acid esters, mono and diglycerides, PEG derivatives of
caprylic/capric triglycerides and mixtures thereof or mixture of
two or more of the above. In some embodiments the surfactant phase
may comprise a mixture of Polyoxyethylene (20) sorbitan monooleate
(Tween 80.RTM.) and sorbitan monooleate (Span 80.RTM.).
[0249] The aqueous phase may optionally comprise the active agent
suspended in water and a buffer.
[0250] In some embodiments, such emulsions are coarse emulsions,
microemulsions and liquid crystal emulsions. In other embodiments
such emulsion may optionally comprise a permeation enhancer. In
other embodiments, spray-dried dispersions or microparticles or
nanoparticles containing encapsulated microemulsion, coarse
emulsion or liquid crystal can be used.
[0251] In some embodiments, the solid dosage forms described herein
are non-enteric time-delayed release dosage forms. The term
"non-enteric time-delayed release" as used herein refers to the
delivery so that the release of the drug can be accomplished at
some generally predictable location in the intestinal tract more
distal to that which would have been accomplished if there had been
no delayed release alterations. In some embodiments the method for
delay of release is a coating that becomes permeable, dissolves,
ruptures, and/or is no longer intact after a designed duration. The
coating in the time-delayed release dosage forms can have a fixed
time to erode after which the drug is released (suitable coating
include polymeric coating such as HPMC, PEO, and the like) or has a
core comprised of a superdisinegrant(s) or osmotic agent(s) or
water attractant such as a salt, hydrophilic polymer, typically
polyethylene oxide or an alkylcellulose, salts such as sodium
chloride, magnesium chloride, sodium acetate, sodium citrate,
sugar, such as glucose, lactose, or sucrose, or the like, which
draw water through a semi-permeable membrane or a gas generating
agent such as citric acid and sodium bicarbonate with or without an
acid such as citric acid or any of the aforementioned acids
incorporated in dosage forms. The semi-permeable membrane, while
mostly not permeable to the drug nor the osmotic agent, is
permeable to water that permeates at a near constant rate to enter
the dosage form to increase the pressure and ruptures after the
swelling pressure exceeds a certain threshold over a desired delay
time. The permeability through this membrane of the drug should be
less than 1/10 than water and in one embodiment less than 1/100 the
water permeability. Alternatively, a membrane could become porous
by leaching an aqueous extractable over a desired delay time.
[0252] Osmotic dosage forms have been described in Theeuwes U.S.
Pat. No. 3,760,984, and an osmotic bursting dosage form is
described in Baker U.S. Pat. No. 3,952,741. This osmotic bursting
dosage form can provide a single pulse of release or multiple
pulses if different devices with different timings are employed.
The timing of the osmotic burst may be controlled by the choice of
polymer and the thickness or the area of the semipermeable membrane
surrounding the core that contains both the drug and the osmotic
agent or attractant. As the pressure in the dosage form increase
with additional permeated water, the membrane elongates until its
breaking point, and then the drug is released. Alternatively,
specific areas of rupture can be created in the membrane by having
a thinner, weaker area in the membrane or by adding a weaker
material to an area of the coating membrane. Some preferred
polymers with high water permeabilities that may be used as
semipermeable membranes are cellulose acetate, cellulose acetate
butyrate, cellulose nitrate, crosslinked polyvinyl, alcohol,
polyurethanes, nylon 6, nylon 6.6, and aromatic nylon. Cellulose
acetate is an especially preferred polymer.
[0253] In another embodiment, the time-delayed coating that begins
its delay to releasing drug after the enteric coating is at least
partially dissolved is comprised of hydrophilic, erodible polymers
that upon contact with water begin to gradually erode over time.
Examples of such polymers include cellulose polymers and their
derivatives including, but not limited to, hydroxyalkyl celluloses,
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose,
microcrystalline cellulose; polysaccharides and their derivatives;
polyalkylene oxides, such as polyethylene oxide or polyethylene
glycols, particularly high molecular weight polyethylene glycols;
chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride
copolymers; poly(vinyl pyrrolidone); starch and starch-based
polymers; maltodextrins; poly (2-ethyl-2-oxazoline);
poly(ethyleneimine); polyurethane; hydrogels; crosslinked
polyacrylic acids; and combinations or blends of any of the
foregoing.
[0254] Some preferred erodible hydrophilic polymers suitable for
forming the erodible coating are poly(ethylene oxide),
hydroxypropyl methyl cellulose, and combinations of poly(ethylene
oxide) and hydroxypropyl methyl cellulose. Poly(ethylene oxide) is
used herein to refer to a linear polymer of unsubstituted ethylene
oxide. The molecular weight of the poly(ethylene oxide) polymers
can range from about 10.sup.5 Daltons to about 10.sup.7. Daltons. A
preferred molecular weight range of poly(ethylene oxide) polymers
is from about 2 times 10.sup.5 to 2 times 10.sup.6 Daltons and is
commercially available from The Dow Chemical Company (Midland,
Mich.) referred to as SENTRY.RTM. POLYOX.TM. water-soluble resins,
NF (National Formulary) grade. When higher molecular weights of
polyethylene oxide are used, other hydrophilic agents, such as
salts or sugars, like glucose, sucrose, or lactose, that promote
erosion or disintegration of this coating, are also included.
[0255] The time-delayed dosage form can be a mechanical pill such
as an Enterion.RTM. capsule or pH sensitive capsule which can
release the drug after a pre-programmed time or when it receives a
signal which can be transmitted or once it leaves the stomach.
[0256] The amount of the compound of the disclosure in a
formulation can vary within the full range employed by those
skilled in the art. Typically, the formulation will contain, on a
weight percent (wt %) basis, from about 0.01-99.99 wt % of a
compound of Formula (I) based on the total formulation, with the
balance being one or more suitable pharmaceutical excipients. In
one embodiment, the compound is present at a level of about 1-80 wt
%.
[0257] The compounds of the present disclosure may be used in
combination with one or more other drugs in the treatment of
diseases or conditions for which compounds of the present
disclosure or the other drugs may have utility, where the
combination of the drugs together are safer or more effective than
either drug alone. Such other drug(s) may be administered, by a
route and in an amount commonly used therefore, contemporaneously
or sequentially with a compound of the present disclosure. When a
compound of the present disclosure is used contemporaneously with
one or more other drugs, a pharmaceutical composition in unit
dosage form containing such other drugs and the compound of the
present disclosure is preferred. However, the combination therapy
may also include therapies in which the compound of the present
disclosure and one or more other drugs are administered on
different overlapping schedules. It is also contemplated that when
used in combination with one or more other active ingredients, the
compounds of the present disclosure and the other active
ingredients may be used in lower doses than when each is used
singly.
[0258] Accordingly, the pharmaceutical compositions of the present
disclosure also include those that contain one or more other active
ingredients, in addition to a compound of the present
disclosure.
[0259] The above combinations include combinations of a compound of
the present disclosure not only with one other active compound, but
also with two or more other active compounds. Likewise, compounds
of the present disclosure may be used in combination with other
drugs that are used in the prevention, treatment, control,
amelioration, or reduction of risk of the diseases or conditions
for which compounds of the present disclosure are useful. Such
other drugs may be administered, by a route and in an amount
commonly used therefore, contemporaneously or sequentially with a
compound of the present disclosure. When a compound of the present
disclosure is used contemporaneously with one or more other drugs,
a pharmaceutical composition, such as a fixed-combination drug
product, containing such other drugs in addition to the compound of
the present disclosure is preferred. Accordingly, the
pharmaceutical compositions of the present disclosure also include
those that also contain one or more other active ingredients, in
addition to a compound of the present disclosure. The weight ratio
of the compound of the present disclosure to the second active
ingredient may be varied and will depend upon the effective dose of
each ingredient. Generally, an effective dose of each will be
used.
[0260] Where the subject is suffering from or at risk of suffering
from an autoimmune disease, an inflammatory disease, or an allergy
disease, a compound of Formula (I) and/or a pharmaceutically
acceptable salt thereof can be used with one or more of the
following therapeutic agents in any combination: immunosuppressants
(e.g., tacrolimus, cyclosporin, rapamicin, methotrexate,
cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or
FTY720), glucocorticoids (e.g., prednisone, cortisone acetate,
prednisolone, methylprednisolone, dexamethasone, betamethasone,
triamcinolone, beclometasone, fludrocortisone acetate,
deoxycorticosterone acetate, aldosterone), non-steroidal
anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,
2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or
sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,
celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold
thiomalate, aurofin, sulfasalazine, hydroxychloroquinine,
minocycline, TNF-.alpha. binding proteins (e.g., infliximab,
etanercept, or adalimumab), abatacept, anakinra, interferon-.beta.,
interferon-.gamma., interleukin-2, allergy vaccines,
antihistamines, antileukotrienes, beta-agonists, theophylline, or
anticholinergics.
[0261] Where the subject is suffering from or at risk of suffering
from a B-cell proliferative disorder (e.g., plasma cell myeloma),
the subject can be treated with a compound of Formula (I) and/or a
pharmaceutically acceptable salt thereof in any combination with
one or more other anti-cancer agents. In some embodiments, one or
more of the anti-cancer agents are proapoptotic agents. Examples of
anti-cancer agents include, but are not limited to, any of the
following: gossyphol, genasense, polyphenol E, Chlorofusin, all
trans-retinoic acid (ATRA), bryostatin, tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL),
5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin,
vincristine, etoposide, gemcitabine, imatinib (Gleevec.TM.),
geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG),
flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082,
PKC412, or PD184352, Taxol.TM., also referred to as "paclitaxel,"
which is a well-known anti-cancer drug which acts by enhancing and
stabilizing microtubule formation, and analogs of Taxol.TM., such
as Taxotere.TM. Compounds that have the basic taxane skeleton as a
common structure feature, have also been shown to have the ability
to arrest cells in the G2-M phases due to stabilized microtubules
and may be useful for treating cancer in combination with the
compounds described herein.
[0262] Further examples of anti-cancer agents for use in
combination with a compound of Formula (I) and/or a
pharmaceutically acceptable salt thereof include inhibitors of
mitogen-activated protein kinase signaling, e.g., U0126, PD98059,
PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,
wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and
antibodies (e.g., rituxan).
[0263] Other anti-cancer agents that can be employed in combination
with a compound of Formula (I) and/or a pharmaceutically acceptable
salt thereof include Adriamycin, Dactinomycin, Bleomycin,
Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole
hydrochloride; acronine; adozelesin; aldesleukin; altretamine;
ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;
anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
azetepa; azotomycin; batimastat; benzodepa; bicalutamide;
bisantrene hydrochloride; bisnafide dimesylate; bizelesin;
bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin;
carmustine; carubicin hydrochloride; carzelesin; cedefingol;
chlorambucil; cirolemycin; cladribine; crisnatol mesylate;
cyclophosphamide; cytarabine; dacarbazine; daunorubicin
hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine
mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;
ilmofosine; interleukin II (including recombinant interleukin II,
or rIL2), interferon alfa-2a; interferon alfa-2b; interferon
alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1
b; iproplatin; irinotecan hydrochloride; lanreotide acetate;
letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol
sodium; lomustine; losoxantrone hydrochloride; masoprocol;
maytansine; mechlorethamine hydrochloride; megestrol acetate;
melengestrol acetate; melphalan; menogaril; mercaptopurine;
methotrexate; methotrexate sodium; metoprine; meturedepa;
mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;
mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;
mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;
pegaspargase; peliomycin; pentamustine; peplomycin sulfate;
perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;
plicamycin; plomestane; porfimer sodium; porfiromycin;
prednimustine; procarbazine hydrochloride; puromycin; puromycin
hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;
safingol hydrochloride; semustine; simtrazene; sparfosate sodium;
sparsomycin; spirogermanium hydrochloride; spiromustine;
spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;
tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone
acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
zinostatin; zorubicin hydrochloride.
[0264] Other anti-cancer agents that can be employed in combination
with a compound of Formula (I) and/or a pharmaceutically acceptable
salt thereof include: 20-epi-1, 25 dihydroxyvitamin D3;
5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;
adozelesin; aldesleukin; ALL-TK antagonists; altretamine;
ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin;
amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis
inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing
morphogenetic protein-1; antiandrogen, prostatic carcinoma;
antiestrogen; antineoplaston; antisense oligonucleotides;
aphidicolin glycinate; apoptosis gene modulators; apoptosis
regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase;
asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2;
axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III
derivatives; balanol; batimastat; BCR/ABL antagonists;
benzochlorins; benzoylstaurosporine; beta lactam derivatives;
beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;
bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;
bistratene A; bizelesin; breflate; bropirimine; budotitane;
buthionine sulfoximine; calcipotriol; calphostin C; camptothecin
derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflomithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived 1; sense oligonucleotides; signal transduction inhibitors;
signal transduction modulators; single chain antigen-binding
protein; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0265] Yet other anticancer agents that can be employed in
combination with a compound of Formula (I) and/or a
pharmaceutically acceptable salt thereof include alkylating agents,
antimetabolites, natural products, or hormones, e.g., nitrogen
mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,
etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,
carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.).
[0266] Examples of antimetabolites include but are not limited to
folic acid analog (e.g., methotrexate), or pyrimidine analogs
(e.g., Cytarabine), purine analogs (e.g., mercaptopurine,
thioguanine, pentostatin).
[0267] Examples of natural products useful in combination with a
compound of Formula (I) and/or a pharmaceutically acceptable salt
thereof include but are not limited to vinca alkaloids (e.g.,
vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),
antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes
(e.g., L-asparaginase), or biological response modifiers (e.g.,
interferon alpha).
[0268] Examples of alkylating agents that can be employed in
combination a compound of Formula (I) and/or a pharmaceutically
acceptable salt thereof include, but are not limited to, nitrogen
mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,
melphalan, etc.), ethylenimine and methylmelamines (e.g.,
hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),
nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,
etc.), or triazenes (decarbazine, etc.). Examples of
antimetabolites include, but are not limited to folic acid analog
(e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,
floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine,
thioguanine, pentostatin.
[0269] Examples of hormones and antagonists useful in combination a
compound of Formula (I) and/or a pharmaceutically acceptable salt
thereof include, but are not limited to, adrenocorticosteroids
(e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate,
megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,
diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g.,
tamoxifen), androgens (e.g., testosterone propionate,
fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin
releasing hormone analog (e.g., leuprolide). Other agents that can
be used in the methods and compositions described herein for the
treatment or prevention of cancer include platinum coordination
complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,
mitoxantrone), substituted urea (e.g., hydroxyurea), methyl
hydrazine derivative (e.g., procarbazine), adrenocortical
suppressant (e.g., mitotane, aminoglutethimide).
[0270] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which can be
used in combination with an BTK inhibitor compound of the
disclosure include without limitation the following marketed drugs
and drugs in development: Erbulozole (also known as R-55104),
Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin
isethionate (also known as CI-980), Vincristine, NSC-639829,
Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also
known as E-7010), Altorhyrtins (such as Altorhyrtin A and
Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin
2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6,
Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin
hydrochloride (also known as LU-103793 and NSC-D-669356),
Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also
known as desoxyepothilone A or dEpoA), Epothilone D (also referred
to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E,
Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,
16-aza-epothilone B, 21-aminoepothilone B (also known as
BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone
F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H16 (Kansas State
University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also
known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi).
[0271] Where the subject is suffering from or at risk of suffering
from a thromboembolic disorder (e.g., stroke), the subject can be
treated with a compound of Formula (I) in any combination with one
or more other anti-thromboembolic agents. Examples of
anti-thromboembolic agents include, but are not limited any of the
following: thrombolytic agents (e.g., alteplase anistreplase,
streptokinase, urokinase, or tissue plasminogen activator),
heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran
etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux,
rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),
ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315),
ximelagatran, or BIBR 1048.
EXAMPLES
[0272] The following preparations of compounds of Formula (I) and
intermediates (References) are given to enable those skilled in the
art to more clearly understand and to practice the present
disclosure. They should not be considered as limiting the scope of
the disclosure, but merely as being illustrative and representative
thereof. The line at the alkene carbon, in the compounds below
denotes that the compounds are isolated as an undefined mixture of
(E) and (Z) isomers.
Reference 1
Synthesis of tert-butyl
(R,E)-3-(4-(((dimethylamino)methylene)amino)-2-oxo-2,3-dihydro-1H-imidazo-
[4,5-c]pyridin-1-yl)piperidine-1-carboxylate
##STR00026##
[0273] Step 1
##STR00027##
[0275] Into a 100-mL round-bottom flask, was placed
2,4-dichloro-3-nitropyridine (8 g, 41.45 mmol, 1.00 equiv),
N,N-dimethylformamide (50 mL), tert-butyl
(R)-3-aminopiperidine-1-carboxylate (8.3 g, 41.44 mmol, 1.00
equiv), and TEA (6.29 g, 62.16 mmol, 1.50 equiv). The resulting
solution was stirred overnight at 25.degree. C. The resulting
solution was diluted with H.sub.2O, extracted with ethyl acetate
and the organic layers were combined. The resulting mixture was
washed with saturated sodium chloride and dried over anhydrous
sodium sulfate and concentrated. The residue was applied onto a
silica gel column and eluted with ethyl acetate/petroleum ether
(1:1) to give 8 g (51%) of tert-butyl
(R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate
as a yellow oil.
Step 2
##STR00028##
[0277] Into a 250-mL round-bottom flask was placed tert-butyl
(R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate
(8 g, 22.42 mmol, 1.00 equiv), i-propanol (100 mL),
bis[(4-methoxyphenyl)methyl]amine (5.78 g, 22.46 mmol, 1.00 equiv),
and TEA (2.955 g, 29.20 mmol, 1.30 equiv). The resulting solution
was stirred overnight at 95.degree. C. The reaction mixture was
cooled and concentrated under vacuum. This resulted in 12 g (92%)
of tert-butyl
(R)-3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)piperidin-
e-1-carboxylate as a yellow oil.
Step 3
##STR00029##
[0279] Into a 250-mL round-bottom flask was placed tert-butyl
(R)-3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)piperidin-
e-1-carboxylate (10 g, 17.31 mmol, 1.00 equiv), AcOH/MeOH (1:1,100
mL), and Fe (9.69 g, 173.04 mmol, 10.00 equiv). The resulting
solution was stirred overnight at 25.degree. C. and then
concentrated under vacuum. The pH value of the solution was
adjusted to 8.0-9.0 with sodium bicarbonate. The resulting solution
was extracted with dichloromethane and the organic layers were
washed with sodium bicarbonate, filtered and dried over anhydrous
sodium sulfate, then concentrated under vacuum to give 8.8 g
(92.8%) of tert-butyl
(R)-3-((3-amino-2-(bis(4-methoxybenzyl)-amino)pyridin-4-yl)amino)piperidi-
ne-1-carboxylate as a yellow oil.
Step 4
##STR00030##
[0281] Into a 250-mL round-bottom flask was placed tert-butyl
(R)-3-((3-amino-2-(bis(4-methoxy-benzyl)amino)pyridin-4-yl)amino)piperidi-
ne-1-carboxylate (12 g, 19.72 mmol, 1.00 equiv, 90%), CH.sub.3CN
(100 mL), and CDI (5.336 g, 32.91 mmol, 1.50 equiv). The resulting
solution was stirred overnight at 80.degree. C. The reaction
mixture was cooled and concentrated. The residue was applied onto a
silica gel column and eluted with ethyl acetate/petroleum ether
(1:5) to give 11 g (89%) of tert-butyl
(R)-3-(4-[bis[(4-methoxy-phenyl)methyl]-amino]-2-oxo-1H,2H,3H-imidazo[4,5-
-c]pyridin-1-yl)piperidine-1-carboxylate as a yellow solid oil.
Step 5
##STR00031##
[0283] Into a 50-mL round-bottom flask was placed tert-butyl
(R)-3-(4-[bis[(4-methoxyphenyl)-methyl]amino]-2-oxo-1H,2H,3H-imidazo[4,5--
c]pyridin-1-yl)piperidine-1-carboxylate (1.5 g, 2.61 mmol, 1.00
equiv), dichloromethane (30 mL), and trifluoroacetic acid (30 mL).
The resulting solution was stirred for 4 h at 50.degree. C. The pH
value of the solution was adjusted to 9 with sodium bicarbonate.
The resulting solution was extracted with dichloromethane and the
organic layers combined and dried over anhydrous sodium sulfate.
The resulting mixture was concentrated under vacuum to give 0.45 g
(73.7%) of
(R)-4-amino-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one
as a light yellow solid.
Step 6
##STR00032##
[0285] Into a 100-mL round-bottom flask was placed
(R)-4-amino-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one
(1 g, 4.29 mmol, 1.00 equiv), 1,4-dioxane/H.sub.2O (1:1, 50 mL),
Boc.sub.2O (1.03 g, 4.72 mmol, 1.03 equiv), and sodium carbonate
(1.5 g, 14.15 mmol, 1.50 equiv). The resulting solution was stirred
for 1 h at 25.degree. C., then extracted with dichloromethane and
the organic layers were combined. The resulting organic layer was
washed with water and saturated sodium chloride and then
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with dichloromethane/methanol (30:1) to give
1.2 g (84%) of tert-butyl
(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-
-1-carboxylateas a light yellow solid.
Step 7
##STR00033##
[0287] Into a 100-mL round-bottom flask was placed tert-butyl
(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-
-1-carboxylate (6.5 g, 19.50 mmol, 1.00 equiv) and DMF-DMA (50 mL).
The resulting solution was stirred for 1 h at 40.degree. C. and
then concentrated under vacuum. The resulting mixture was then
dissolved with CH.sub.2Cl.sub.2 and washed with brine. The organic
layers combined and concentrated under vacuum, and washed with
hexane. The solids were collected by filtration to give 5.0289 g
(66%) of tert-butyl
(R,E)-3-(4-(((dimethylamino)methylene)amino)-2-oxo-2,3-dihydro-1H-imidazo-
[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a solid.
[0288] LC-MS m/z: 389.2 (M+1)
Reference 2
Synthesis of
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo[4,5--
c]pyridin-2-one
##STR00034##
[0289] Step 1
##STR00035##
[0291] Into a 250-mL round-bottom flask, was placed tert-butyl
(R)-3-(4-[bis[(4-methoxyphenyl)-methyl]amino]-2-oxo-1H,2H,3H-imidazo[4,5--
c]pyridin-1-yl)piperidine-1-carboxylate (10 g, 17.43 mmol, 1.00
equiv), dichloromethane (100 mL), (4-phenoxyphenyl)boronic acid
(7.5 g, 35.04 mmol, 2.00 equiv), TEMPO (3 g, 19.20 mmol, 1.10
equiv), and TEA (7 g, 69.18 mmol, 4.00 equiv), Cu(OAc).sub.2 (1.6
g, 8.81 mmol, 0.50 equiv). The resulting solution was stirred
overnight at 25.degree. C. under ambient-pressure oxygen
atmosphere. (4-Phenoxyphenyl)boronic acid (7.5 g, 35.04 mmol, 2.00
equiv) was added and the resulting solution was allowed to react
overnight at 25.degree. C. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:3) to
give 1.5 g (12%) of tert-butyl
(R)-3-(4-[bis[(4-methoxyphenyl)methyl]amino]-2-oxo-3-(4-phenoxyphenyl)-1H-
,2H,3H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a
yellow solid.
Step 6
##STR00036##
[0293] Into a 250-mL round-bottom flask, was placed tert-butyl
(R)-3-(4-[bis[(4-methoxyphenyl)-methyl]amino]-2-oxo-3-(4-phenoxyphenyl)-1-
H,2H,3H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (5 g,
6.07 mmol, 1.00 equiv, 90%), dichloromethane (80 mL), and
trifluoroacetic acid (80 mL). The resulting solution was stirred
for 5 h at 50.degree. C. The resulting mixture was concentrated
under vacuum. The pH value of the solution was adjusted to 9 with
sodium bicarbonate. The resulting solution was extracted with of
dichloromethane and the organic layers combined and dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column and eluted with dichloromethane/methanol (30:1) to give 1 g
(41%) of
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo[4,5--
c]pyridin-2-one as a light yellow solid.
Example 1
Synthesis of
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazo[4,5-c]pyri-
din-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile
##STR00037##
[0294] Step 1
##STR00038##
[0296] Into a 10-mL round-bottom flask was placed
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo[4,5--
c]pyridin-2-one (79 mg, 0.20 mmol, 1.00 equiv),
N,N-dimethylformamide (2 mL), TEA (0.082 mL, 1.50 equiv), HATU (113
mg, 0.30 mmol, 1.50 equiv), and 2-cyano-4,4-dimethylpent-2-enoic
acid (46 mg, 0.30 mmol, 3.00 equiv). The resulting solution was
stirred for 2.5 h at room temperature and then quenched by the
addition of water. The resulting solution was extracted with
dichloromethane and the organic layers combined and concentrated
under vacuum. The crude product was purified by Prep-HPLC with the
following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column,
Gemini-NX C18 AXAI Packed, 21.2.times.150 mm 5 um 11 nm; mobile
phase, WATER WITH 0.05% TFA and ACN (20.0% ACN up to 50.0% in 8
min); Detector, 254 nm to give 50 mg (47%) of the title compound as
a white solid. LC-MS m/z: 537.2 (M+1)
Example 2
Synthesis of
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazo[4,5-c]pyri-
din-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)-
pent-2-enenitrile
##STR00039##
[0297] Step 1
##STR00040##
[0299] Into a 50-mL round-bottom flask, was placed tert-butyl
(R,E)-3-(4-(((dimethylamino)-methylene)amino)-2-oxo-2,3-dihydro-1H-imidaz-
o[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (200 mg, 0.51 mmol,
1.00 equiv), dichloromethane (20 mL), TEA (208 mg, 2.06 mmol, 4.00
equiv), TEMPO (88.5 mg, 0.57 mmol, 1.10 equiv), and Cu(OAc).sub.2
(46.7 mg, 0.26 mmol, 0.50 equiv). The resulting solution was
stirred for 0.5 h at 25.degree. C. (4-Phenoxyphenyl)boronic acid
(220 mg, 1.03 mmol, 2.00 equiv) was added and the resulting
solution was allowed to react overnight at 25.degree. C. The
residue was applied onto a silica gel column and eluted with
dichloromethane/ethyl acetate (5:1) to give 150 mg (52%) of
tert-butyl
(R)-3-[4-[(E)-[(dimethylamino)methylidene]amino]-2-oxo-3-(4-phenoxyphenyl-
)-1H,2H,3H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylate as a
light yellow solid.
Step 2
##STR00041##
[0301] Into a 25-mL round-bottom flask was placed tert-butyl
(3R)-3-[4-[(E)-[(dimethylamino)-methylidene]-amino]-2-oxo-3-(4-phenoxyphe-
nyl)-1H,2H,3H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylate
(150 mg, 0.27 mmol, 1.00 equiv), 1,4-dioxane (6 mL), and hydrogen
chloride (3 mL). The resulting solution was stirred overnight at
50.degree. C. The reaction mixture was quenched with water. The pH
of the solution was adjusted to 9 with sodium bicarbonate. The
resulting solution was extracted with
dichloromethane:CH.sub.3OH=10:1 and the organic layers were
combined. The resulting mixture was washed with sodium chloride and
the organic layers were combined, dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column and eluted with dichloromethane/methanol (30:1)
to give 80 mg (74%) of
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imi-
dazo[4,5-c]pyridin-2-one as a light yellow solid.
Step 3
##STR00042##
[0303] Into a 50-mL round-bottom flask was placed
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo[4,5--
c]pyridin-2-one (2 g, 4.98 mmol, 1.00 equiv), N,N-dimethylformamide
(20 mL), 2-cyanoacetic acid (402.5 mg, 4.73 mmol, 0.95 equiv), HATU
(2.84 g, 7.47 mmol, 1.50 equiv), and TEA (1.51 g, 14.92 mmol, 3.00
equiv). The resulting solution was stirred for 1 h at room
temperature and then quenched with water. The resulting solution
was extracted with ethyl acetate and the organic layers combined.
The organic layer was washed with saturated sodium chloride, dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with
dichloromethane/methanol (30:1) to give 1.3 g (56%) of
3-[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,
2H,3H-imidazo[4,5-c]pyridin-1-yl]piperidin-1-yl]-3-oxopropanenitrile
as a light yellow solid.
Step 4
##STR00043##
[0305] Into a 50-mL round-bottom flask was placed
3-[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyrid-
in-1-yl]piperidin-1-yl]-3-oxopropanenitrile (800 mg, 1.71 mmol,
1.00 equiv), dichloromethane (20 mL),
2-methyl-2-[4-(oxetan-3-yl)piperazin-1-yl]propanal (1.0875 g, 5.12
mmol, 3.00 equiv), TMSCl (922 mg, 8.49 mmol, 4.97 equiv), and
pyrrolidine (0.607 g). The resulting solution was stirred for 1 h
at room temperature. The resulting mixture was concentrated under
vacuum. The crude product was purified by Prep-TLC, then purified
by Prep-HPLC under the following conditions
(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, Gemini-NX C18 AXAI
Packed, 21.2.times.150 mm 5 um 11 nm; mobile phase, water with
0.05% TFA and ACN (20.0% ACN up to 40.0% in 10 min); Detector, uv
254 nm) to give 0.478 g (42%) of the title compound as a light
yellow solid. LC-MS m/z: 663.3 (M+1).
Example 3
Synthesis of
(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4-
,5-c]pyridin-2(3H)-one
##STR00044##
[0307] Into a 100-mL round-bottom flask, was placed
(R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyrid-
in-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), DCM-CH3OH (6 mL), TEA
(113 mg, 1.12 mmol, 3.00 equiv). This was followed by the addition
of prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv) dropwise
with stirring at 0.degree. C. in 5 min. The resulting solution was
stirred for 2 h at 0.degree. C. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with dichloromethane/methanol (30:1). The crude product
(100 mg) was purified by Prep-HPLC with the following conditions
(Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile
phase, water with 0.05% TFA and ACN (25.0% ACN up to 45.0% in 8
min). 54.5 mg product of
(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4-
,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m/z:
465.2 (M+1)
Example 4
Synthesis of
(R)-4-amino-1-(1-(but-2-ynoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imid-
azo[4,5-c]pyridin-2(3H)-one
##STR00045##
[0309] Into a 100-mL round-bottom flask, was placed
(R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyrid-
in-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), N,N-dimethylformamide
(15 mL), but-2-ynoic acid (31.42 mg, 0.37 mmol, 1.00 equiv), HATU
(213.2 mg, 0.56 mmol, 1.50 equiv), TEA (113.4 mg, 1.12 mmol, 3.00
equiv). The resulting solution was stirred for 2 h at room
temperature. The reaction was then quenched by the addition of 50
mL of water. The resulting solution was extracted with 3.times.50
mL of dichloromethane and the organic layers combined. The
resulting mixture was washed with 50 mL of brine. The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was applied onto a silica gel column with
dichloromethane/methanol (30:1). The crude product (100 mg) was
purified by Prep-HPLC as described in ex 3 to obtain 86.5 mg (50%)
of
(R)-4-amino-1-(1-(but-2-ynoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imid-
azo[4,5-c]pyridin-2(3H)-one as a white solid. LC-MS m/z: 468.2
(M+1).
Example 5
Synthesis of
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1-methylpiperidin-4-yl)pen-
t-2-enenitrile
##STR00046##
[0310] Step 1
[0311] Into a 250-mL 3-necked round-bottom flask, was placed methyl
2-(piperidin-4-yl)acetate hydrochloride (10 g, 51.63 mmol, 1.00
equiv), dichloromethane (100 mL), The resulting solution was
stirred for 30 min at 0.degree. C. Next was added triethylamine
(15.65 g, 154.66 mmol, 3 equiv), Boc.sub.2O (12.4 g, 56.82 mmol,
1.1 equiv). The resulting solution was allowed to react, with
stirring, for an additional 14 h at 25.degree. C. The pH value of
the solution was adjusted to 7.0 with citric acid (3%). The
resulting mixture was washed with 2.times.100 mL of water and
2.times.100 mL of saturated salt water. The residue was applied
onto a silica gel column with ethyl acetate/petroleum ether (1:10).
This resulted in 10 g (75.2%) of tert-butyl
4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate as colorless
oil.
Step 2
[0312] Into a 250-mL 3-necked round-bottom flask, was placed LDA
(46.7 mL, 3.00 equiv), tetrahydrofuran (80 mL), tert-butyl
4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (8 g, 31.1 mmol,
1.00 equiv), The resulting solution was stirred for 30 min at
-78.degree. C. Then CH.sub.3I (22 g, 155 mmol, 5.00 equiv) was
added. The resulting solution was allowed to react, with stirring,
for an additional 1 h at -78.degree. C. Additional LDA (46.7 mL,
3.00 equiv) was added at -78.degree. C. and after 0.5 h, CH.sub.3I
(22 g, 155 mmol, 5.00 equiv) was added. The reaction was stirred 16
h at r.t. The reaction was then quenched by the addition of 200 mL
of NH.sub.4Cl. The resulting solution was extracted with
2.times.200 mL of ethyl acetate and the organic layers combined.
The resulting mixture was washed with 2.times.200 mL of water and
2.times.200 mL of saturated sodium chloride. The residue was
purified by silica gel chromatography using ethyl acetate/petroleum
ether (1:35). This resulted in 6 g (68%) of tert-butyl
4-(1-methoxy-2-methyl-1-oxopropan-2-yl)piperidine-1-carboxylate as
light yellow oil.
Step 3
[0313] Into a 100-mL 3-necked round-bottom flask, was placed LiAlH4
(1.6 g, 42.2 mmol, 4.00 equiv), tetrahydrofuran (50 mL), tert-butyl
4-(1-methoxy-2-methyl-1-oxopropan-2-yl)piperidine-1-carboxylate (3
g, 10.5 mmol, 1.00 equiv). The resulting solution was stirred for 3
h at -78.degree. C. The reaction mixture was warmed to 0.degree. C.
The reaction was then quenched by the addition of 1.6 mL of water,
then 1.6 mL of 15% NaOH was added followed by 4.8 mL H2O. The
solids were filtered to afford in 1.5 g (83%) of
2-methyl-2-(1-methylpiperidin-4-yl)propan-1-ol as a pink oil.
Step 4
[0314] Into a 100-mL round-bottom flask, was placed oxalic
dichloride (440 mg, 3.47 mmol, 1.20 equiv), dichloromethane (50
mL), At -78.degree. C. put in DMSO (684 mg, 8.75 mmol, 3.00 equiv),
2-methyl-2-(1-methylpiperidin-4-yl)propan-1-ol (500 mg, 2.92 mmol,
1.00 equiv), TEA (1.48 g, 14.6 mmol, 5.00 equiv). The resulting
solution was stirred for 30 min at -78.degree. C. The resulting
solution was allowed to react, with stirring, for an additional 2 h
at 25.degree. C. The reaction was then quenched by the addition of
water. The resulting solution was extracted with of dichloromethane
and the organic layers combined and dried over anhydrous sodium
sulfate and concentrated under vacuum. This resulted in 385 mg
(88%) of 2-methyl-2-(1-methylpiperidin-4-yl)propanal as yellow
oil.
Step 5
[0315] Into a 100-mL round-bottom flask, was placed
(R)-3-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (100 mg, 0.19
mmol, 1.00 equiv, 90%), dichloromethane (50 mL),
2-methyl-2-(1-methylpiperidin-4-yl)propanal (108 mg, 0.57 mmol,
3.00 equiv), TMSCl (115 mg, 1.01 mmol, 5.00 equiv, 95%),
pyrrolidine (75.8 mg, 1.01 mmol, 5.00 equiv, 95%). The resulting
solution was stirred for 16 h at rt. The crude product was purified
by Prep-HPLC with the following conditions (Column, Gemini-NX C18
AXAI Packed, 21.2.times.150 mm Sum 11 nm; mobile phase, WATER WITH
0.05% TFA and ACN (20.0% ACN up to 50.0% in 8 min); Detector, 254
nm. This resulted in 15.5 mg (12%) of
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1-methylpiperidin-4-yl)pen-
t-2-enenitrile as a light yellow solid.
[0316] LC-MS m/z: 620.3 (M+1).
Example 6
Synthesis of
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-6-hydroxy-4-(2-hydroxyethyl)hex-2-enen-
itrile
##STR00047##
[0317] Step 1
[0318] Into a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, HMPA (6.0 mL) and
LDA (16.8 mmol) in dry THF (20 mL) at -78.degree. C. was treated
with acetonitrile (690 mg, 16.8 mmol). The solution was stirred for
30 min, and (2-bromoethoxy)(tert-butyl)dimethylsilane (3.4 g, 14.3
mmol) in THF (15 mL) was added dropwise. Stirring was continued for
2 h, after which a second portion of LDA (16.8 mmol in 20 mL THF)
was added. The solution was stirred for 30 min, and
(2-bromoethoxy)(tert-butyl)dimethylsilane (3.4, 14.3 mmol) in THF
(15 mL) was added dropwise. The reaction was allowed to proceed for
2 h. Saturated aqueous NH.sub.4Cl was added, and the mixture was
allowed to reach room temperature. Diethyl ether was added, the
phases were separated, and the aqueous layer was extracted with
diethyl ether. The combined organic phases were washed with brine,
dried over Na2SO4, and concentrated. Column chromatography [silica,
petroleum ether] afforded a colorless oil (3.2 g, 53%).
Step 2
[0319] Into a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed
4-[(tert-butyldimethylsilyl)oxy]-2-[2-[(tert-butyldimethylsilyl)oxy]ethyl-
]butanenitrile (1 g, 2.80 mmol, 1.00 equiv) in toluene (15 mL).
DIBAL-H (1M) (3.36 mL, 1.20 equiv) was added at -78.degree. C. and
the resulting solution was stirred for 1 h at -78.degree. C. in a
liquid nitrogen bath. Water (0.7 mL) was added and the mixture was
allowed to reach RT. Aqueous NaOH (0.7 mL, 4M) was added and
stirring was continued for 15 min. Water (2.1 mL) was added and the
suspension was stirred for a further 15 min. The mixture was dried
over with Na2SO4 and concentrated under vacuum. The residue was
purified by silica gel column with PE/EA (20:1). This resulted in
900 mg (89%) of
4-[(tert-butyldimethylsilyl)oxy]-2-[2-[(tert-butyldimethylsilyl)oxy]ethyl-
]butanal as colorless oil.
Step 3
[0320] Into a 8-mL vial, was placed
3-[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyrid-
in-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.32 mmol,
1.00 equiv),
4-[(tert-butyldimethylsilyl)oxy]-2-2-[(tert-butyldimethylsilyl)ox-
y]ethylbutanal (346 mg, 0.96 mmol, 3.00 equiv), TMSCl (173 mg, 1.59
mmol, 5.00 equiv), pyrrolidine (114 mg, 1.61 mmol, 5.00 equiv),
dichloromethane (2 mL). The resulting solution was stirred for 3 h
at rt. The resulting mixture was concentrated under vacuum. The
residue was applied onto a silica gel column with
dichloromethane/methanol (30:1). This resulted in 120 mg (46%) of
2-[[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyri-
din-1-yl]piperidin-1-yl]carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-4-[2-[(-
tert-butyldimethylsilyl)oxy]ethyl]hex-2-enenitrile as a yellow
solid.
Step 4
[0321] Into a 25-mL round-bottom flask, was placed
2-[[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyri-
din-1-yl]piperidin-1-yl]carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-4-[2-[(-
tert-butyldimethylsilyl)oxy]ethyl]hex-2-enenitrile (120 mg, 0.15
mmol, 1.00 equiv), trifluoroacetic acid (1 mL), dichloromethane (5
mL). The resulting solution was stirred for 2 h at rt. The reaction
was then quenched by the addition of saturated sodium bicarbonate.
The resulting solution was extracted with 3.times.20 mL of DCM/MeOH
(10:1) and the organic layers combined. The resulting mixture was
washed with saturated sodium chloride. The mixture was dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by Prep-TLC with DCM/MeOH (15:1). The crude product
was purified by Prep-HPLC with the following conditions (Atlantis
Prep T3 OBD Column, 19*150 mm 5 um 10 nm; mobile phase, Water with
0.1% FA and MeCN (20.0% MeCN up to 50.0% in 10 min); Detector, 254
nm. This resulted in 7.9 mg (9%) of
(R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]-
pyridin-1-yl)piperidine-1-carbonyl)-6-hydroxy-4-(2-hydroxyethyl)hex-2-enen-
itrile as a white solid. LC-MS m/z: 583.2 (M+1).
Example 7
Synthesis of
(R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H--
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3--
yl)piperazin-1-yl)pent-2-enenitrile
##STR00048##
[0322] Step 1
[0323] Into a 250-mL round-bottom flask purged and maintained with
an atmosphere of 02, was placed Cu(OAc).sub.2 (6.96 g, 38.3 mmol,
1.00 equiv), pyridine (15.2 g, 192 mmol, 5.00 equiv) and 4 A mol.
sieves (5 g) in dichloromethane (100 mL). The resulting solution
was stirred for 30 min and then 2,6-difluorophenol (5 g, 38.4 mmol,
1.00 equiv) and (4-bromophenyl)boronic acid (15.4 g, 76.6 mmol,
2.00 equiv) were added. The resulting solution was stirred
overnight at rt. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column and eluted
with petroleum ether. This resulted in 5.5 g (50%) of
2-(4-bromophenoxy)-1,3-difluorobenzene as yellow oil.
Step 2
[0324] Into a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed
2-(4-bromophenoxy)-1,3-difluorobenzene (5.5 g, 19.3 mmol, 1.00
equiv) in tetrahydrofuran (100 mL). A 2.5 M solution of nBuLi in
hexane (11.6 mL, 1.50 equiv) was added at -78.degree. C. and the
resulting solution was stirred for 30 min and then trimethyl borate
(4.03 g, 38.8 mmol, 2.00 equiv) was added. The reaction was allowed
to be warmed to RT and the resulting solution was stirred for 3 h
at rt. The reaction was then quenched by the addition of hydrogen
chloride (2M). The resulting solution was extracted with
3.times.150 mL of ether and the organic layers combined. The
resulting mixture was washed with 1.times.200 mL of sodium chloride
(saturated). The mixture was dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was applied onto a
silica gel column with dichloromethane/methanol (50:1). This
resulted in 2.15 g (45%) of [4-(2,6-difluorophenoxy)phenyl]boronic
acid as a brown solid.
Step 3
[0325] Into a 100-mL round-bottom flask purged and maintained with
an atmosphere of O.sub.2, was placed (R,E)-tert-butyl
3-(4-(((dimethylamino)methylene)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)piperidine-1-carboxylate (500 mg, 1.29 mmol, 1.00
equiv), TEA (521 mg, 5.15 mmol, 4.00 equiv), Cu(OAc).sub.2 (117 mg,
0.64 mmol, 0.50 equiv), TEMPO (221 mg, 1.41 mmol, 1.10 equiv) and
Ms (4 A) (500 mg) in dichloromethane (50 mL). The resulting
solution was stirred for 30 min and then
[4-(2,6-difluorophenoxy)phenyl]boronic acid (644 mg, 2.58 mmol,
2.00 equiv) was added. The resulting solution was stirred overnight
at room temperature. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with
dichloromethane/methanol (30:1). This resulted in 490 mg of
(R,E)-tert-butyl
3-(4-(((dimethylamino)methylene)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihy-
dro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a
brown solid.
Step 4
[0326] To a solution of (R,E)-tert-butyl
3-(4-(((dimethylamino)methylene)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihy-
dro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (490 mg,
0.83 mmol, 1.00 equiv) in 30 mL dioxane was added 15 mL of hydrogen
chloride (12M). The resulting solution was stirred for 3 h at
85.degree. C. in an oil bath. The reaction was then quenched by the
addition of sodium bicarbonate (sat.). The resulting solution was
extracted with 3.times.100 mL of DCM/MeOH (10:1) and the organic
layers combined. The resulting mixture was washed with 1.times.100
mL of sodium chloride (sat.). The mixture was dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in 360
mg (100%) of
4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H,2H,3-
H-imidazo[4,5-c]pyridin-2-one as a brown solid.
Step 5
[0327] Into a 50-mL round-bottom flask, was placed
4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H,2H,3-
H-imidazo[4,5-c]pyridin-2-one (360 mg, 0.82 mmol, 1.00 equiv),
2-cyanoacetic acid (70 mg, 0.82 mmol, 1.00 equiv), HATU (470 mg,
1.24 mmol, 1.50 equiv), TEA (250 mg, 2.47 mmol, 3.00 equiv),
N,N-dimethylformamide (10 mL). The resulting solution was stirred
for 2 h at rt. The resulting solution was extracted with
dichloromethane and the organic layers combined. The resulting
mixture was washed with 6.times.100 mL of water. The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was applied onto a silica gel column with
dichloromethane/methanol (30:1). This resulted in 260 mg (63%) of
(R)-3-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H--
imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a
brown solid.
[0328] Following the protocol in step 4 of example 2 afforded
(R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H--
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3--
yl)piperazin-1-yl)pent-2-enenitrile.
[0329] LC-MS m/z: 699.2 (M+1)
Example 8
Synthesis of
(R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H--
imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3--
yl)piperazin-1-yl)pent-2-enenitrile
##STR00049##
[0330] Step 1
[0331] Into a 250-mL round-bottom flask purged and maintained with
an atmosphere of 02, was placed Cu(OAc).sub.2 (6.96 g, 38.3 mmol,
1.00 equiv), pyridine (15.2 g, 192 mmol, 5.00 equiv) and 4 A mol.
sieves (5 g) in dichloromethane (100 mL). The resulting solution
was stirred for 30 min and then 2,3-difluorophenol (5 g, 38.43
mmol, 1.00 equiv) and (4-bromophenyl)boronic acid (15.4 g, 76.6
mmol, 2.00 equiv) were added. The resulting solution was stirred
overnight at rt. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether. This resulted in 3.17 g (29%) of
1-(4-bromophenoxy)-2,3-difluorobenzene as colorless oil.
Step 2
[0332] Into a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed
1-(4-bromophenoxy)-2,3-difluorobenzene (3.17 g, 11.12 mmol, 1.00
equiv) in tetrahydrofuran (100 mL). A 2.5 M solution of nBuLi (6.7
mL, 1.50 equiv) was added at -78.degree. C. and the resulting
solution was stirred for 30 min and then trimethyl borate (2.32 g,
22.3 mmol, 2.00 equiv) was added. The resulting solution was
stirred for 3 h at rt. The reaction was then quenched by the
addition of HCl (2M). The resulting solution was extracted with
3.times.150 mL of ether and the organic layers combined. The
resulting mixture was washed with 1.times.200 mL of sodium chloride
(sat'd.). The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column with dichloromethane/methanol (50:1). This resulted in 1
g (36%) of [4-(2,3-difluorophenoxy)phenyl]boronic acid as a white
solid.
[0333] Following the protocols described in Example 2 but using
[4-(2,3-difluorophenoxy)phenyl]boronic acid afforded title
compound. LC-MS m/z: 699.2 (M+1).
Example 9
Synthesis of
(R)-2-(3-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imida-
zo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile
##STR00050##
[0335] Following the protocols described in example 7 but using
(3-fluoro-4-phenoxyphenyl)boronic acid afforded (the title compound
using the methods described in Example 2. LC-MS m/z:
681.4(M+1).
Example 10
Synthesis of
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imida-
zo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile
##STR00051##
[0337] Following the protocols described in Example 7 but using
(2-fluoro-4-phenoxyphenyl)boronic acid (prepared as described in
PCT Int. Appl., 2012158764, 22 Nov. 201 afforded the title
compound. LC-MS m/z: 681.2 (M+1).
Example 11
Synthesis of
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile
##STR00052##
[0338] Step 1
[0339] To a solution of 2,4-dichloro-3-nitropyridine (5 g, 25.9
mmol) in DMF (50 mL) were added Et.sub.3N (5.2 g, 51.8 mmol) and
(S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (5.4 g,
27.2 mmol). The resulted mixture was stirred at rt overnight, then
filtered and the filtrate was concentrated to dryness. The residue
was treated with water (150 mL) and extracted with DCM (30
mL.times.3). The combined organic phase was washed with brine (40
mL), dried over Na.sub.2SO.sub.4, and concentrated to dryness. The
resulting 6.9 g of (S)-tert-butyl
2-(((2-chloro-3-nitropyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate
was used in next step without further purification.
Step 2
[0340] To a solution of (S)-tert-butyl
2-(((2-chloro-3-nitropyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate
(6.9 g, 19.4 mmol) in i-PrOH (100 mL) was added
bis(4-methoxybenzyl)amine (7.5 g, 29.1 mmol) and TEA (5.9 g, 58.2
mmol). The mixture was refluxed overnight. After cooling to rt, the
mixture was concentrated to dryness. The residue was purified by
silica gel chromatography (eluent: petroleum ether/ethyl acetate
from 5:1 to 2:1) to give 4.4 g of (S)-tert-butyl
2-(((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)methyl)pyrro-
lidine-1-carboxylate as a light yellow solid.
Step 3
[0341] To a solution of (S)-tert-butyl
2-(((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)methyl)pyrro-
lidine-1-carboxylate (4.4 g, 7.6 mmol) in EtOH (100 mL) were added
NH.sub.4Cl (2.0 g, 38.1 mmol) and H.sub.2O (10 mL), followed by
batch-wise addition of Zn dust (2.5 g, 38.1 mmol) while stirring.
The resulted mixture was refluxed for 3 h before filtering through
celite. The filtrate was concentrated to afford a residue which was
re-dissolved in water (50 mL) and extracted with ethyl acetate (100
mL.times.3). The combined organic phase was washed with brine (400
mL), dried over Na.sub.2SO.sub.4, concentrated to give 2.9 g of
(S)-tert-butyl
2-(((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)methyl)pyrro-
lidine-1-carboxylate as a light yellow solid which was used
directly in the next step.
Step 4
[0342] To a solution of (S)-tert-butyl
2-(((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)methyl)pyrro-
lidine-1-carboxylate (2.9 g, 5.3 mmol) in anhydrous acetonitrile
(30 mL) was added CDI (2.6 g, 15.9 mmol) portion wise. The resulted
mixture was refluxed for 2 h before concentration to give a residue
which was purified by silica gel chromatography with PE:EtOAc=2:1
to afford 2.6 g of (S)-tert-butyl
2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyri-
din-1-yl)methyl)pyrrolidine-1-carboxylate as a light yellow solid
which was used directly in the next step.
Step 5
[0343] To a solution of (S)-tert-butyl
2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyri-
din-1-yl)methyl)pyrrolidine-1-carboxylate (7 g, 12.2 mmol) in
anhydrous DCM (100 mL) were added Cu(OAc).sub.2 (2.2 g, 12.4 mmol),
TEMPO (2.1 g, 13.4 mmol), 4 A molecular sieves (20 g) and Et.sub.3N
(20 g, 196 mmol), followed by portionwise addition of
4-phenoxyphenylboronic acid (10.5 g, 48.9 mmol) while stirring. The
mixture was stirred at rt for 78 h under O.sub.2 atmosphere. The
solvent was concentrated and the residue was purified by silica gel
column with PE:EtOAc=2:1 to yield (S)-tert-butyl
2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1-
H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carboxylate (3.2
g, 36%) as a light yellow solid.
Step 5
[0344] The (S)-tert-butyl
2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1-
H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carboxylate (2 g,
2.7 mmol) was dissolved in TFA (10 mL) and stirred at rt overnight.
The reaction was concentrated and the residue was diluted with H2O
(50 mL) and extracted with EtOAc. The aqueous phase was adjusted to
pH=13 with aqueous NaOH and extracted with EtOAc (2.times.100 mL),
and the organic phase was concentrated to give 870 mg of
(S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5--
c]pyridin-2(3H)-one which was used in next step without further
purification.
Step 6
[0345] To a solution of
(S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5--
c]pyridin-2(3H)-one (200 mg, 0.5 mmol) in DMF (10 mL) at 0.degree.
C. were added Et.sub.3N (150 mg, 1.5 mmol), 2-cyanoacetic acid (47
mg, 0.55 mmol) and HATU (284 mg, 0.75 mmol). After stirring for 30
min at 0.degree. C., the reaction was poured into water (20 mL) and
extracted by EtOAc (30 mL for twice), the organic phase was
concentrated and the residue was purified by silica gel
chromatography eluting with PE:EtOAc=1:1 to afford 70 mg of
(S)-3-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imid-
azo[4,5-c]pyridin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile
as a white solid.
Step 7
[0346] To a solution of
(S)-3-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (80 mg,
0.17 mmol), 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanal (72
mg, 0.34 mmol) and pyrrolidine (120 mg, 1.7 mmol) in DCM (2 mL) at
room temperature was slowly added chloro(trimethyl)silane (69 mg,
0.68 mmol) dropwise. After 30 min, the reaction was diluted with
DCM (20 mL) and washed with aq. NaHCO3 (20 mL). The organic layer
was dried over anhydrous Na2SO4, filtered and concentrated to give
a crude residue, which was purified by Prep-TLC to afford
(S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c-
]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)pi-
perazin-1-yl)pent-2-enenitrile as white solid (10 mg, 9%). LC-MS
m/z: 662.8 (M+1).
Example 12
Synthesis of
(S)-1-((1-acryloylpyrrolidin-2-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1H--
imidazo[4,5-c]pyridin-2(3H)-one
##STR00053##
[0348] To a solution of
(S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5--
c]pyridin-2(3H)-one (200 mg, 0.17 mmol) and DIPEA (129 mg, 1.0
mmol) in DCM (2 mL) was slowly added acryloyl chloride (45 mg, 0.50
mmol) dropwise at 0.degree. C. After 30 min, the reaction was
diluted with DCM (20 mL) and washed with aq. NaHCO.sub.3 (20 mL).
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give a crude residue, which was
purified by Prep-TLC to afford 70 mg of
(S)-1-((1-acryloylpyrrolidin-2-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1H--
imidazo[4,5-c]pyridin-2(3H)-one as white solid. LC-MS m/z: 455.9
(M+1).
Example 13
Synthesis of
(S)-4-amino-1-((1-(but-2-ynoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl-
)-1H-imidazo[4,5-c]pyridin-2(3H)-one
##STR00054##
[0350] To a solution of
(S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5--
c]pyridin-2(3H)-one (200 mg, 0.17 mmol) and DIPEA (129 mg, 1.0
mmol) in DCM (10 mL) was slowly added but-2-ynoyl chloride (50 mg,
0.50 mmol) dropwise at 0.degree. C. 0.5 h later, the reaction was
diluted with DCM (20 mL) and washed with aq. NaHCO.sub.3 (20 mL).
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give a crude residue, which was
purified by Prep-TLC to afford 50 mg of
(S)-4-amino-1-((1-(but-2-ynoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl-
)-1H-imidazo[4,5-c]pyridin-2(3H)-one as white solid. LC-MS m/z:
467.9 (M+1).
Example 14
Synthesis of
(R)-4-amino-1-(1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-
-imidazo[4,5-c]pyridin-2(3H)-one
##STR00055##
[0352] To a solution of
(R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyrid-
in-2(3H)-one (154 mg, 0.38 mmol, 1.0 equiv) in 2 mL of DMF was
added diisopropylethylamine (0.2 mL, 1.1 mmol).
2-fluoroprop-2-enoic acid (51.8 mg, 0.580 mmol) was added followed
by HATU (97 mg, 1.1 mmol). After stirring 1 h, the material was
purified directly by Prep HPLC (Shimadzu, C18 column; mobile phase
water with 0.05% TFA and ACN (10% to 90% over 20 min). The purified
fractions were diluted with saturated sodium bicarbonate and DCM
and the layers separated. The organic layer was dried with
MgSO.sub.4, filtered and concentrated. It was dissolved in a
minimum of water and acetonitrile and lyophilized to obtain 65 mg
of
(R)-4-amino-1-(1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-
-imidazo[4,5-c]pyridin-2(3H)-one as a white solid. LC-MS m/z: 474.1
(M+1).
BIOLOGICAL EXAMPLES
Example 1
BTK Enzymatic Activity Assay
[0353] A Caliper-based kinase assay (Caliper Life Sciences,
Hopkinton, Mass.) was used to measure inhibition of BTK kinase
activity of a compound of the present disclosure. Serial dilutions
of test compounds were incubated with human recombinant BTK (0.5
nM), ATP (16 M) and a phosphoacceptor peptide substrate
FAM-GEEPLYWSFPAKKK-NH.sub.2 (1 .mu.M) at room temperature for 3 h.
The reaction was then terminated with EDTA, final concentration 20
mM and the phosphorylated reaction product was quantified on a
Caliper Desktop Profiler (Caliper LabChip 3000). Percent inhibition
was calculated for each compound dilution and the concentration
that produced 50% inhibition was calculated. This value is
presented as the IC.sub.50. The ICso for certain compounds of the
disclosure are provided below.
TABLE-US-00002 Compound No. in Compound Table I IC.sub.50 (uM) 1
0.0082 2 0.0091 3 0.0216 4 0.0078 5 0.0025 6 0.0059 7 0.0018 8
0.0239 9 0.0078 10 0.007 11 0.0786 12 0.0066 13 0.0211 14 0.0172 15
0.0723 16 0.0012 17 0.0133 18 0.0037 19 0.0078 20 0.0145 21 0.0046
22 0.0048 23 0.0259 24 0.0047 25 0.0054 26 0.0035 27 0.0049 28
0.0048 29 0.0018 30 0.0015 31 0.0037 32 0.0029 34 0.0231 35 0.0262
36 0.0157 37 0.0043 38 0.0057 39 0.0053 40 0.0057 41 0.0031 42
0.0041 43 0.0225 44 0.0033 45 0.0251 46 0.0131 47 0.0031 48 0.009
49 0.0128 50 0.0083 51 0.0241 52 0.012 53 0.0042 54 0.0178 55
0.0031 56 0.0078 57 0.0614 58 0.0042 59 0.0026 60 0.0024 61 0.0025
62 0.0059 63 0.0014 65 0.0024 66 0.002 67 0.0012
Example 2
Measurement of BTK Occupancy in Human Peripheral Blood Mononuclear
Cells
[0354] The potency of compounds for inhibition of BTK activity can
be assessed by binding of compounds to the target in human
peripheral blood mononuclear cells (PBMC) that contain BTK. The
extent of BTK occupancy is measured after treating the cells with
compounds and detecting unoccupied BTK through binding of occupancy
of
(R,E)-N-(2-(4-(4-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-
-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)-
-3-(5,5-difluoro-7,9-dimethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]di-
azaborinin-2-yl)propanamide as the probe.
[0355] Briefly, human blood was obtained from healthy volunteers
and distributed 5 ml each in 9 separate 15 ml tubes. Serial
dilution of the compound to be tested for potency was added such
the final concentrations started at 10 uM and were serially diluted
3-fold for a total of 9 serial dilutions. The compounds were
allowed to interact with the blood for 1 h. PBMC were then isolated
from each tube using Ficoll. Isolated PBMCs were then resuspended
in 1 ml of RPMI1640 media and the occupancy probe was added to a
concentration of 1 uM for each sample for 1 h. PBMCs were washed,
lysed, and evaluated by SDS-PAGE. In-gel fluorescence was used to
measure the extent of inhibition of BTK occupancy probe binding to
BTK. Subsequently, total BTK in each sample was determined by
Western blotting with a BTK antibody (BD Bioscience
Cat#611117).
[0356] This assay was also modified to measure the durability of
BTK binding in PBMCs. Here, a concentration of 2 uM compound was
added to human whole blood for 1 h. PBMCs were isolated using
Ficoll, washed, and resuspended in media for either 4 h or 18 h at
37.degree. C. The occupancy probe was added to a concentration of 1
uM for each sample for 1 h, and BTK occupancy was then determined
in the same manner as described above.
Example 3
Blockade of CD69 Expression in Human Whole Blood Samples
[0357] Activation of the B cell receptor leads to increased BTK
activity, calcium mobilization and B cell activation (see Honigberg
L. A., et. al., Proc Natl Acad Sci USA. 107:13075-80. 2010). BTK
inhibitors have been shown to block B cell activation as measured
by CD69 expression (see Karp, R., et. al., Inhibition of BTK with
AVL-292 Translates to Protective Activity in Animal Models of
Rheumatoid Arthritis. Inflammation Research Association Meeting,
September, 2010). CD69 was expressed following B cell activation as
a measure of BTK activity in whole blood. Aliquots of whole blood
were pre-incubated with serial dilutions of test compound for 30
min followed by activation with anti-IgM (goat Fab'2, 50 .mu.g/ml).
Samples were incubated overnight at 37.degree. C. and then stained
with PE labeled anti-CD20 and APC labeled anti-CD69 (BD Pharmingen)
for 30 min according to the manufacturer's directions. Whole blood
was then lysed and cells gated on CD20 expression were quantified
for CD 69 expression by FACS. The percent inhibition was calculated
based on a DMSO control for no inhibition and plotted as a function
of test compound concentration from which an IC.sub.50 value was
calculated.
Example 4
Inhibition of Mouse Collagen-Induced Arthritis
[0358] Inhibition of murine collagen-induced arthritis (mCIA) is a
standard animal disease model for rheumatoid arthritis. Previous
studies have demonstrated that inhibition of BTK is efficacious in
blocking mCIA (see Honigberg L. A., et. al., Proc Natl Acad Sci
USA. 107:13075-80. 2010). Starting on day 0 DBA/1 mice are injected
with an emulsion of Type II collagen in Complete Freund's Adjuvant.
Mice are boosted 21 days later to synchronize development of
disease. After development of mild disease, animals are enrolled in
the study and randomized. Dosing is oral, Q.D. typically for 11
days with test compound or dexamethasone (0.2 mg/kg) as control.
One group receives vehicle alone. Clinical scoring (0-4) is based
on the extent of swelling and severity of arthritis. Scores for all
four paws are added for maximum score of 16. Anti-collagen
antibodies and total Ig are measured for each animal by Elisa at
the end of the study (Bolder BioPath, Boulder, Colo.).
Example 5
Recovery of Kinase Activity Upon Dialysis to Evaluate Irreversible
Vs. Reversible Covalent Binding
[0359] A compound and/or pharmaceutically acceptable salt of the
present disclosure at a concentration 10 times greater than its
IC.sub.50 value is added to a solution of protein kinase (5 nM) in
a buffer containing 20 mM Hepes [pH 7.5], 5 mM MgCl.sub.2, 0.01%
Triton X-100, and 1 mM dithiothreitol. After 60 min at 22.degree.
C., the reactions are transferred to a dialysis cassette (0.1-0.5
mL Slide-A-Lyzer, MWCO 10 kDa, Pierce) and dialyzed against 1 L of
buffer (20 mM Hepes [pH 7.5], 5 mM MgCl.sub.2, 0.01% Triton X-100,
and 1 mM dithiothreitol.) at 22.degree. C. The dialysis buffer is
exchanged twice per day until the end of the experiment. Aliquots
are removed from the dialysis cassettes every 24 h and analyzed for
protein kinase activity. Kinase activity for each sample is
normalized to the DMSO control for that time point and expressed as
the mean.+-.SD. It will be observed that the kinase activity will
return on dialysis for a compound of the present disclosure where
R.sup.a is cyano and will not return for for a compound of the
present disclosure where R.sup.a is hydrogen or fluoro.
Example 6
Mass Spectral Analysis
[0360] A protein kinase that is inhibited by compound and/or a
pharmaceutically acceptable salt of the present disclosure may be
subjected to mass spectral analysis to assess the formation of
permanent, irreversible covalent adducts. Suitable analytical
methods to examine intact full protein or peptide fragments
generated upon tryptic cleavage of the protein kinase are generally
known in the art (see Lipton, Mary S., Ljiljana, Pasa-Tolic, Eds.
Mass Spectrometry of Proteins and Peptides, Methods and Protocols,
Second Edition. Humana Press. 2009). Such methods identify
permanent, irreversible covalent protein adducts by observing a
mass peak that corresponds to the mass of a control sample plus the
mass of an irreversible adduct. Two such methods are described
below.
Mass Spectral Analysis of Intact Full Kinase
Method:
[0361] A protein kinase (5 .mu.M) (such as BTK) is incubated with a
compound of the present disclosure (25 .mu.M, 5 equiv) for 1 h at
room temperature in buffer (20 mM Hepes [pH 8.0], 100 mM NaCl, 10
mM MgCl.sub.2). A control sample is also prepared which does not
have a compound of the present disclosure. The reaction is stopped
by adding an equal volume of 0.4% formic acid, and the samples are
analyzed by liquid chromatography (Microtrap C18 Protein column
[Michrom Bioresources], 5% MeCN, 0.2% formic acid, 0.25 mL/min;
eluted with 95% MeCN, 0.2% formic acid) and in-line ESI mass
spectrometry (LCT Premier, Waters). Molecular masses of the protein
kinase and any adducts may be determined with MassLynx
deconvolution software (see patent application WO2014 011900, and
PCT/US2010/048916).
[0362] Results: High-resolution intact mass spectrometry analysis
of protein kinase, such as BTK, that is inhibited by a compound of
the present disclosure where R.sup.a is cyano will reveal a
spectrum similar to the kinase in the absence of inhibitor (e.g.
control sample). There will be no formation of a new peak in the
mass spectrum corresponding to the molecular mass of the kinase
plus the molecular mass of the compound. Conversely,
high-resolution intact mass spectrometry analysis of a protein
kinase that is inhibited by a a compound of the present disclosure
where R.sup.a is hydrogen or fluoro will reveal formation of a new
peak (e.g. a peak not present in the control sample without
inhibitor) in the mass spectrum corresponding to the molecular mass
of the kinase plus the molecular mass of the irreversible kinase
inhibitor. On the basis of this experiment, an irreversible protein
adduct will be apparent to one skilled in the art.
Mass Spectral Analysis of Kinase Tryptic Digest
Method:
[0363] A protein (10-100 pmols) is incubated with a compound and/or
a pharmaceutically acceptable salt of the present disclosure
(100-1000 pmols, 10 equiv) for 3 h prior to tryptic digestion.
Iodoacetamide may be used as the alkylating agent after compound
incubation. A control sample is also prepared which does not
utilize the compound and/or a pharmaceutically acceptable salt of
the present disclosure. For tryptic digests a 1 .mu.l aliquot (3.3
pmols) ise diluted with 10 .mu.l of 0.1% TFA prior to micro C18 Zip
Tipping directly onto the MALDI target using alpha cyano-4-hydroxy
cinnamic acid as the desorption matrix (5 mg/mol in 0.1%
TFA:Acetonitrile 50:50) or Sinapinic acid as the desorption matrix
(10 mg/mol in 0.1% TFA:Acetonitrile 50:50) (see
PCT/US2010/048916).
[0364] Results: High-resolution mass spectrometry analysis of the
tryptic fragments of a kinase that is inhibited by a compound
and/or pharmaceutically acceptable salt of the present disclosure
where R.sup.a is cyano, will reveal a spectrum similar to the
kinase in the absence of inhibitor (e.g. control sample). There
will be no evidence of any modified peptides that are not present
in the control sample. On the basis of this experiment, no
permanent, irreversible protein adducts will be apparent to one
skilled in the art.
[0365] On the contrary, High-resolution mass spectrometry analysis
of the tryptic fragments of a kinase that is inhibited by compounds
of the disclosure where R.sup.a is hydrogen or fluoro, will reveal
a spectrum that contains modified peptides that are not present in
the control sample. On the basis of this experiment, irreversible
protein adducts will be apparent to one skilled in the art.
Furthermore, on the basis of the exact mass and MS-MS fragmentation
pattern, the sequence of the modified peptide may be ascertained,
there by defining the cysteine residue that is the site of covalent
modification.
Example 7
Determination of Drug-Kinase Residence Time
[0366] The following is a protocol that can be used to distinguish
whether a compound displays a slow or non-existent dissociation
rate from BTK, such as typically would occur if a covalent bond is
formed between the compound and the target. The read-out for slow
dissociation is the ability of the compound of interest to block
binding of a high affinity fluorescent tracer molecule to the
kinase active site, as detected using time-resolved fluorescence
resonance energy transfer (TR-FRET). The experiment was conducted
in a buffer consisting of 50 mM Hepes pH 7.5, 10 mM MgCl.sub.2,
0.01% Triton X-100, and 1 mM EGTA.
[0367] The first step of the procedure was incubation of 500 nM BTK
(Invitrogen Cat. #PV3587) with 1.5 .mu.M of a compound of the
present disclosure for 30 min in a volume of 10 .mu.L. The mixture
was then diluted 5-fold by addition of 40 .mu.L of buffer. A 10
.mu.L volume of the diluted kinase/compound solution was then added
to a well of a small volume 384 well plate (such as Greiner Cat.
#784076). In order to probe for reversibility of the
kinase-compound binding interaction, a competition solution
containing both a high affinity fluorescent tracer and an antibody
coupled to Europium was prepared. For BTK, the competition solution
contained 1.5 .mu.M Tracer 178 (Invitrogen Cat. #PV5593), which is
a proprietary high affinity ligand for BTK coupled to the
fluorophore AlexaFluor 647. The competition solution also contained
80 nM of an Anti-polyhistidine antibody coupled to Europium
(Invitrogen Cat. #PV5596) which is designed to bind the
polyhistidine purification tag in BTK.
[0368] After addition of 10 .mu.L of the competition solution to
the Greiner plate, the mixture was incubated for one hour or
greater to allow time for dissociation of non-covalent inhibitors
and binding of the high affinity tracer. It is to be expected that
covalent and slow dissociating inhibitors will block binding of the
tracer while rapidly dissociating non-covalent inhibitors will not.
Binding of the tracer to BTK is detected using TR-FRET between the
Europium moiety of the Anti-histidine antibody and the AlexaFluor
647 group of Tracer 178. Binding was evaluated using a Perkin Elmer
Envision instrument (Model 2101) equipped with filters and mirrors
compatible with LANCE-type TR-FRET experiments. Data were plotted
at percentage of signal obtained in the absence of competitor
compound. The background signal was obtained by omission of BTK
from the reaction. If the compound is an irreversible covalent
inhibitor, tracer will be completely blocked from binding to the
target throughout the entire course of the experiment. If the
compound is a reversible covalent inhibitor, the tracer will bind
the target as the compound dissociates from the target. For the
durability measurements, the range of occupancy for the compounds
disclosed herein at 1, 6, and 24 h of washout is shown below.
TABLE-US-00003 Compound in compound Table I % occupany at above 1,
6, & 24 h 1 97.036 82.199 70.975 2 93.602 85.49 65.826 3 65.626
58.519 46.073 4 90.005 66.344 18.2 5 93.773 83.103 57.488 6 94.404
86.64 67.505 7 61.932 -1.3946 -12.344 8 93.335 89.195 80.873 9
93.363 70.733 31.4 10 94.392 77.985 49.145 12 95.906 96.44 90.847
13 91.54 83.963 49.152 14 91.481 76.396 22.922 15 91.927 85.356
50.188 16 96.326 97.673 102.07 17 81.247 78.623 74.744 18 93.065
73.513 31.704
Example 8
Reversibility of Binding
[0369] The following approach was developed to determine if a
compound forms irreversible covalent or reversible covalent bond
with its targets. Reactions are prepared with the protein target at
a higher concentration than the compounds of interest. Both
irreversible and reversible covalent compounds bind the target and
became depleted from solution. The reactions are then treated with
perturbations including both denaturation with 5 M guanidine
hydrochloride and digestion with trypsin, disrupting proper folding
of the target. It will be found that the perturbation returns
reversible covalent compounds to solution due to dissociation from
the target while irreversible covalent compounds remain bound to
the target. The concentration of compound in solution is assessed
both preceding and following perturbation using high performance
liquid chromatography (HPLC) coupled to tandem mass spectrometry.
Using this technique, it can be demonstrated that irreversible
covalent compound of the disclosure where R.sup.a is hydrogen or
fluoro is depleted from solution in both the native and perturbed
state, while compounds disclosed herein where R.sup.a is cyano are
depleted in the folded state but returned to solution following
perturbation of the target evidencing that such compounds form
reversible covalent bond.
FORMULATION EXAMPLES
[0370] The following are representative pharmaceutical formulations
containing a compound of Formula (I).
Tablet Formulation
[0371] The following ingredients are mixed intimately and pressed
into single scored tablets.
TABLE-US-00004 Quantity per tablet Ingredient mg compound of this
disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120
magnesium stearate 5
Capsule Formulation
[0372] The following ingredients are mixed intimately and loaded
into a hard-shell gelatin capsule.
TABLE-US-00005 Quantity per capsule Ingredient mg compound of this
disclosure 200 lactose spray dried 148 magnesium stearate 2
Injectable Formulation
[0373] Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1%
Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20
mg/mL
[0374] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the disclosure should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *
References