U.S. patent application number 16/479299 was filed with the patent office on 2020-12-03 for (hetero)arylamide compound for inhibiting protein kinase activity.
This patent application is currently assigned to Shenzhen TargetRx, Inc.. The applicant listed for this patent is Shenzhen TargetRx, Inc.. Invention is credited to Yixin AI, Yihan WANG, Jiuyang ZHAO.
Application Number | 20200377473 16/479299 |
Document ID | / |
Family ID | 1000005218616 |
Filed Date | 2020-12-03 |
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United States Patent
Application |
20200377473 |
Kind Code |
A9 |
WANG; Yihan ; et
al. |
December 3, 2020 |
(HETERO)ARYLAMIDE COMPOUND FOR INHIBITING PROTEIN KINASE
ACTIVITY
Abstract
Provided are a (hetero)arylamide compound as shown in formula
(I) having an inhibitory effect on protein kinase activity, a
pharmaceutically acceptable salt, a stereoisomer, a solvate or
hydrate thereof, a pharmaceutical composition comprising the
compound or a derivative thereof, and a method for preparing the
compound. The compound can be used as an irreversible inhibitor for
protein kinase for preparing a plurality of drugs comprising an
anti-tumour drug. ##STR00001##
Inventors: |
WANG; Yihan; (Shenzhen,
CN) ; ZHAO; Jiuyang; (Shenzhen, CN) ; AI;
Yixin; (Shenzhen, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shenzhen TargetRx, Inc. |
Shenzhen, Guangdong |
|
CN |
|
|
Assignee: |
Shenzhen TargetRx, Inc.
Shenzhen, Guangdong
CN
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20190382374 A1 |
December 19, 2019 |
|
|
Family ID: |
1000005218616 |
Appl. No.: |
16/479299 |
Filed: |
January 19, 2018 |
PCT Filed: |
January 19, 2018 |
PCT NO: |
PCT/CN2018/073339 PCKC 00 |
371 Date: |
July 19, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 403/10 20130101;
A61P 35/00 20180101; C07D 401/04 20130101; C07D 403/14 20130101;
C07D 401/14 20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 401/04 20060101 C07D401/04; C07D 403/10 20060101
C07D403/10; C07D 403/14 20060101 C07D403/14; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 20, 2017 |
CN |
201710051737.X |
Claims
1-13. (canceled)
14. A compound of formula (I), or a pharmaceutically acceptable
salt, a stereoisomer, a solvate or a hydrate thereof: ##STR00094##
wherein: Y.sub.1 is selected from CR.sub.a or N; Y is independently
selected from CR.sub.a or N; R.sub.1 is selected from hydrogen,
halo, nitrile, nitro, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl,
wherein the said C.sub.1-6 alkyl or C.sub.1-6 haloalkyl is
optionally substituted by R.sub.1a group; R.sub.2 is selected from
hydrogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl, wherein the said
C.sub.1-6 alkyl or C.sub.1-6 haloalkyl is optionally substituted by
R.sub.2a group; Z is a chemical bond, O, S(O).sub.0-2 or NR.sub.b;
or --Z--R.sub.2 together form --SF.sub.5; Ar is ##STR00095##
wherein X.sub.1 is CR, X.sub.2 to X.sub.4 are independently
selected from CR or N, and at least one of X.sub.2, X.sub.3 and
X.sub.4 is N; Het is ##STR00096## wherein X.sub.9 is selected from
O, S, NR.sub.b or C(R).sub.2; m is 0, 1 or 2; n is 0, 1, 2, 3, 4, 5
or 6; R.sub.a is independently selected from hydrogen, halo,
nitrile, nitro, hydroxy, --NH.sub.2, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or
C.sub.1-6 alkoxyl; R.sub.b is independently selected from hydrogen,
C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.1a, R.sub.2a and R
are independently selected from hydrogen, halo, hydroxy,
--NH.sub.2, --NHC.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxyl, C.sub.3-7
cycloalkyl, C.sub.3-7 heterocyclyl, C.sub.6-10 aryl or C.sub.5-10
heteroaryl; or two R groups on the same or adjacent atoms may
together form C.sub.3-7 cycloalkyl, C.sub.3-7 heterocyclyl,
C.sub.6-10 aryl or C.sub.5-10 heteroaryl.
15. The compound according to claim 14, which is formula (Ia), or a
pharmaceutically acceptable salt, a stereoisomer, a solvate or a
hydrate thereof: ##STR00097## wherein, Ar and Het are as defined in
claim 14.
16. The compound according to claim 14, or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein: Ar is selected from the following groups that are
optionally substituted by one, two or three R: ##STR00098##
wherein, R are as defined in claim 14.
17. The compound according to claim 14, or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein: Het is ##STR00099## wherein, X.sub.9 is C(R).sub.2, and m,
n and R are as defined in claim 14.
18. The compound according to claim 14, or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein: Het is selected from the following groups that are
optionally substituted by one, two, three or more R: ##STR00100##
wherein R are as defined in claim 14.
19. The compound according to claim 14, or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein: Het is selected from the following groups:
##STR00101##
20. The compound according to claim 14, which is formula (Ib), or a
pharmaceutically acceptable salt, a stereoisomer, a solvate or a
hydrate thereof: ##STR00102## wherein: Ar is selected from the
following groups that are optionally substituted by one, two or
three R: ##STR00103## R is selected from hydrogen, halo, hydroxy,
--NH.sub.2, --NHC.sub.1-6 alkyl or --N(C.sub.1-6 alkyl).sub.2.
21. The compound according to claim 14, which is formula (Ib), or a
pharmaceutically acceptable salt, a stereoisomer, a solvate or a
hydrate thereof: ##STR00104## wherein: Ar is selected from the
following groups that are optionally substituted by one, two or
three R: ##STR00105## R is selected from hydrogen, halo, hydroxy,
--NH.sub.2, --NHC.sub.1-6 alkyl or --N(C.sub.1-6 alkyl).sub.2.
22. The compound according to claim 14, which is formula (Ib), or a
pharmaceutically acceptable salt, a stereoisomer, a solvate or a
hydrate thereof: ##STR00106## wherein: Ar is selected from the
following groups: ##STR00107## R is selected from hydrogen, halo or
hydroxy.
23. The compound according to claim 14, or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein the compound is selected from: ##STR00108##
##STR00109##
24. The compound according to claim 23, which is ##STR00110## or a
pharmaceutically acceptable salt thereof.
25. The compound according to claim 23, which is ##STR00111## or a
pharmaceutically acceptable salt thereof.
26. The compound according to claim 23, which is ##STR00112## or a
pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition, comprising: the compound
according to claim 14 or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, and pharmaceutically
acceptable excipients.
28. A pharmaceutical composition, comprising: the compound
according to claim 24 or a pharmaceutically acceptable salt
thereof, and pharmaceutically acceptable excipients.
29. A pharmaceutical composition, comprising: the compound
according to claim 25 or a pharmaceutically acceptable salt
thereof, and pharmaceutically acceptable excipients.
30. A pharmaceutical composition, comprising: the compound
according to claim 26 or a pharmaceutically acceptable salt
thereof, and pharmaceutically acceptable excipients.
31. A method of treating and/or preventing Bcr-Abl mediated
diseases in a subject, comprising administering to the subject a
compound according to claim 14 or a pharmaceutically acceptable
salt, a stereoisomer, a solvate or a hydrate thereof.
32. The method according to claim 31, wherein the said Bcr-Abl
mediated diseases is a proliferative disease selected from: solid
tumor, sarcoma, acute lymphocytic leukemia, acute myeloid leukemia,
chronic lymphocytic leukemia, chronic myeloid leukemia,
gastrointestinal stromal tumor, thyroid cancer, gastric cancer,
rectal cancer, multiple myeloma, neoplasia, and other proliferative
disease or proliferative diseases; or the Bcr-Abl mediated diseases
is metastatic invasive cancer, virus infection, or CNS diseases.
Description
FIELD OF THE PRESENT DISCLOSURE
[0001] The present disclosure belongs to the pharmaceutical field.
In particular, the present disclosure relates to (hetero)arylamide
compounds which inhibit the tyrosine kinase activity of Abelson
protein (Abl1), Abelson-related protein (Abl2) and related chimeric
proteins, particularly Bcr-Abl1, relates to pharmaceutical
compositions containing the same, and methods for their preparation
and use thereof.
BACKGROUND OF THE PRESENT DISCLOSURE
[0002] Protein tyrosine kinases (PTKs) are a class of kinases that
are involved in proteinases, which catalyze the transfer of
.gamma.-phosphate on ATP to protein tyrosine residues, and catalyze
the phosphorylation of the phenolic hydroxyl groups on various
protein tyrosine residues, thereby in turn activate functional
proteins. Protein tyrosine kinases play an important role in the
cellular signal transduction pathway, regulating a series of
physiological and biochemical processes such as cell growth,
differentiation and death. Abnormal expression of protein tyrosine
kinase can lead to disturbances in cell proliferation regulation,
which in turn leads to tumorigenesis. In addition, the abnormal
expression of protein tyrosine kinase is also closely related to
tumor invasion and metastasis, tumor angiogenesis, and chemotherapy
resistance of tumors.
[0003] The tyrosine kinase expressed by the Bcr-Abl fusion gene can
cause changes in cell proliferation, adhesion and survival
properties, leading to the occurrence of various tumors. Inhibition
of Bcr-Abl tyrosine kinase can effectively inhibit tumor
growth.
[0004] ABL-001 (also known as Asciminib, chemical name
(R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(-
1H-pyrazol-5-yl)nicotinamide, which has the following structural
formula) is an allosteric inhibitor of ABL1 kinase developed by
Novartis Pharmaceuticals Co., Ltd., which inactivates ABL1 by
targeting its myristoyl pocket, and is effective in preventing the
emergence of drug resistance in the application of ATP inhibitors
and/or allosteric inhibitors when used in combination with
inhibitors of BCR-ABL tyrosine kinase that compete with ATP.
ABL-001 has been shown to be effective in eradicating CML in a
mouse model when combined with the second-generation BCR-ABL
inhibitor nilotinib (Andrew A. Wylie et al. (2017) Nature 543,
733-737). Novartis is developing a clinical treatment regimen of
ABL-001 in combination with various ATP-competitive BCR-ABL
inhibitors, including imatinib, nilotinib, and dasatinib.
##STR00002##
[0005] Therefore, it is necessary to further develop novel Bcr-Abl
inhibitors.
SUMMARY OF THE PRESENT DISCLOSURE
[0006] The present disclosure provides a novel (hetero)arylamide
compound and a composition comprising the same and use thereof,
which have better Bcr-Abl kinase inhibitory activity (especially
for T315I mutation), lower side effects and/or better
pharmacodynamics/pharmacokinetic properties, and thus can be used
to treat diseases mediated by Bcr-Abl kinase.
[0007] In this regard, the technical solution adopted by the
present disclosure is as follows:
[0008] In the first aspect, the present disclosure provides a
(hetero)arylamide compound represented by formula (I), or a
pharmaceutically acceptable salt, a stereoisomer, a solvate or a
hydrate thereof:
##STR00003##
wherein:
[0009] Y.sub.1 is selected from CR.sub.a or N;
[0010] Y is independently selected from CR.sub.a or N;
[0011] R.sub.1 is selected from hydrogen, halo, nitrile, nitro,
C.sub.1-6 alkyl or C.sub.1-6 haloalkyl, wherein the said C.sub.1-6
alkyl or C.sub.1-6 haloalkyl is optionally substituted by R.sub.1a
group;
[0012] R.sub.2 is selected from hydrogen, C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, wherein the said C.sub.1-6 alkyl or C.sub.1-6
haloalkyl is optionally substituted by R.sub.2a group;
[0013] Z is a chemical bond, O, S(O).sub.0-2 or NR.sub.b;
[0014] or --Z--R.sub.2 together form --SF.sub.5;
[0015] Ar is
##STR00004##
[0016] wherein X.sub.1 to X.sub.8 are independently selected from
CR or N, and at least one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4
is N, or at least one of X.sub.5, X.sub.6, X.sub.7 and X.sub.8 is
N;
[0017] wherein each P.sub.1 and Q.sub.1 is independently selected
from O, S, NR.sub.b or C(R).sub.2, each P.sub.2 and Q.sub.2 is
independently selected from CR or N;
[0018] Het is
##STR00005##
[0019] wherein X.sub.9 is selected from O, S, NR.sub.b or
C(R).sub.2;
[0020] m is 0, 1 or 2;
[0021] n is 0, 1, 2, 3, 4, 5 or 6;
[0022] R.sub.a is independently selected from hydrogen, halo,
nitrile, nitro, hydroxy, --NH.sub.2, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or
C.sub.1-6 alkoxyl;
[0023] R.sub.b is independently selected from hydrogen, C.sub.1-6
alkyl or C.sub.1-6 haloalkyl;
[0024] R.sub.1a, R.sub.2a and R are independently selected from
hydrogen, halo, hydroxy, --NH.sub.2, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxyl, C.sub.3-7 cycloalkyl, C.sub.3-7 heterocyclyl,
C.sub.6-10 aryl or C.sub.5-10 heteroaryl;
[0025] or two R groups on the same or adjacent atoms may together
form C.sub.3-7 cycloalkyl, C.sub.3-7 heterocyclyl, C.sub.6-10 aryl
or C.sub.5-10 heteroaryl.
[0026] In another aspect, the disclosure provides a pharmaceutical
composition comprising a compound disclosed herein and a
pharmaceutically acceptable excipient. In a particular embodiment,
the compound disclosed herein is provided in the pharmaceutical
composition in an effective amount. In a particular embodiment, the
compound disclosed herein is provided in a therapeutically
effective amount. In a particular embodiment, the compound
disclosed herein is provided in a prophylactically effective
amount.
[0027] In another aspect, the disclosure provides a pharmaceutical
composition comprising a compound disclosed herein and a
pharmaceutically acceptable excipient.
[0028] In another aspect, the disclosure provides a kit containing
a compound disclosed herein and other therapeutic agents, and
pharmaceutically acceptable carriers, adjuvants or vehicles.
[0029] In another aspect, the disclosure provides the use of a
compound disclosed herein in the manufacture of a medicament for
the treatment and/or prevention of diseases caused by Bcr-Abl.
[0030] In another aspect, the disclosure provides a method of
treating and/or preventing diseases caused by Bcr-Abl in a subject,
comprising administering to the subject a compound disclosed herein
or a composition disclosed herein.
[0031] In another aspect, the disclosure provides a compound
disclosed herein or a composition disclosed herein, for use in the
treatment and/or prevention of diseases caused by Bcr-Abl.
[0032] In a specific embodiment, the disease may be selected from
the group consisting of: solid tumor, sarcoma, acute lymphocytic
leukemia, acute myeloid leukemia, chronic lymphocytic leukemia,
chronic myeloid leukemia, gastrointestinal stromal tumor, thyroid
cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia,
and other proliferative disease or proliferative diseases.
[0033] In a specific embodiment, the Bcr-Abl caused disease is
chronic myeloid leukemia, gastrointestinal stromal tumor, acute
myeloid leukemia, thyroid cancer, metastatic invasive cancer, or a
combination thereof.
[0034] In another aspect, the compounds disclosed herein also have
the potential to treat or prevent diseases or disorders associated
with abnormally activated kinase activity of wild-type Abl,
including non-malignant diseases or disorders, such as CNS diseases
in particular neurodegenerative diseases (for example Alzheimer's,
Parkinson's diseases), motoneuroneuron diseases (amyotophic lateral
sclerosis), muscular dystrophies, autoimmune and inflammatory
diseases (diabetes and pulmonary fibrosis), viral infections, and
prion diseases.
[0035] In a specific embodiment, the compound is administered
orally, subcutaneously, intravenously or intramuscularly. In a
specific embodiment, the compound is administered chronically.
[0036] Other objects and advantages of the present disclosure will
be apparent to those skilled in the art from the following specific
embodiments, examples and claims.
Definitions
Chemical Definitions
[0037] Definitions of specific functional groups and chemical terms
are described in more detail below.
[0038] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5
and C.sub.5-6 alkyl.
[0039] It should be understood that when described herein any of
the moieties defined forth below may be substituted with a variety
of substituents, and that the respective definitions are intended
to include such substituted moieties within their scope as set out
below. Unless otherwise stated, the term "substituted" is to be
defined as set out below.
[0040] "C.sub.1-6 alkyl" refers to a radical of a straight-chain or
branched saturated hydrocarbon group having from 1 to 6 carbon
atoms, and it is also referred to herein as "lower alkyl". In some
embodiments, C.sub.1-4 alkyl is particularly preferred. Examples of
alkyl groups include methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl
(C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
and n-hexyl (C.sub.6). Unless otherwise specified, each instance of
an alkyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents; e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkyl group is
unsubstituted C.sub.1-6 alkyl (e.g., --CH.sub.3). In certain
embodiments, the alkyl group is substituted C.sub.1-6 alkyl.
[0041] "C.sub.1-6 alkoxy" refers to the group --OR wherein R is a
substituted or unsubstituted C.sub.1-6 alkyl group. In some
embodiments, C.sub.1-4 alkoxy group is particularly preferred.
Specific alkoxy groups include, but are not limited to, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.
[0042] "Halo" or "halogen" means fluorine (F), chlorine (Cl),
bromine (Br) and iodine (I). In some embodiments, the halo group is
F, --Cl or Br. In some embodiments, the halogen group is Cl. In
some embodiments, the halogen group is F. In some embodiments, the
halogen group is Br.
[0043] Thus, "C.sub.1-6 haloalkyl" refers to the above "C.sub.1-6
alkyl", which is substituted by one or more halo groups. In some
embodiments, C.sub.1-4 haloalkyl group is particularly preferred,
and more preferably C.sub.1-2 haloalkyl group. Exemplary haloalkyl
groups include, but are not limited to, --CF.sub.3, --CH.sub.2F,
--CHF.sub.2, --CClF.sub.2, --CHFCH.sub.2F, --CH.sub.2CHF.sub.2,
--CF.sub.2CF.sub.3, --CF.sub.2CClF.sub.2, --CF.sub.2CH.sub.3,
--CCl.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
[0044] "C.sub.3-7 cycloalkyl" refers to a radical of a non-aromatic
cyclic hydrocarbon group having from 3 to 7 ring carbon atoms and
zero heteroatoms. In some embodiments, C.sub.3-6 cycloalkyl is
especially preferred, and C.sub.5-6 cycloalkyl is more preferred.
Cycloalkyl also includes ring systems wherein the cycloalkyl ring,
as defined above, is fused with one or more aryl or heteroaryl
groups wherein the point of attachment is on the cycloalkyl ring,
and in such instances, the number of carbons continue to designate
the number of carbons in the cycloalkyl ring system. Exemplary
cycloalkyl groups include, but is not limited to, cyclopropyl
(C.sub.3), cyclopropenyl (C.sub.3), cyclobutyl (C.sub.4),
cyclobutenyl (C.sub.4), cyclopentyl (C.sub.5), cyclopentenyl
(C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl (C.sub.6),
cyclohexadienyl (C.sub.6), cycloheptyl (C.sub.7), cycloheptenyl
(C.sub.7), cycloheptadienyl (C.sub.7), cycloheptatrienyl (C.sub.7),
and the like. Unless otherwise specified, each instance of a
cycloalkyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted cycloalkyl") or substituted (a
"substituted cycloalkyl") with one or more substituents. In certain
embodiments, the cycloalkyl group is unsubstituted C.sub.3-7
cycloalkyl. In certain embodiments, the cycloalkyl group is a
substituted C.sub.3-7 cycloalkyl.
[0045] "C.sub.3-7 heterocyclyl" refers to a radical of a 3- to
7-membered non-aromatic ring system having ring carbon atoms and 1
to 4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, sulfur, boron, phosphorus, and
silicon. In heterocyclyl groups that contain one or more nitrogen
atoms, the point of attachment can be a carbon or nitrogen atom, as
valency permits. In some embodiments, C.sub.3-6 heterocyclyl is
especially preferred, which is a radical of a 3- to 6-membered
non-aromatic ring system having ring carbon atoms and 1 to 3 ring
heteroatoms. In some embodiments, C.sub.5-6 heterocyclyl is more
preferred, which is a radical of a 5- to 6-membered non-aromatic
ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
Unless otherwise specified, each instance of heterocyclyl is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted heterocyclyl") or substituted (a "substituted
heterocyclyl") with one or more substituents. In certain
embodiments, the heterocyclyl group is unsubstituted C.sub.3-7
heterocyclyl. In certain embodiments, the heterocyclyl group is
substituted C.sub.3-7 heterocyclyl. Heterocyclyl also includes ring
systems wherein the heterocyclyl ring, as defined above, is fused
with one or more cycloalkyl groups, wherein the point of attachment
is on the cycloalkyl ring; or wherein the heterocyclyl ring, as
defined above, is fused with one or more aryl or heteroaryl groups,
wherein the point of attachment is on the heterocyclyl ring; and in
such instances, the number of ring members continue to designate
the number of ring members in the heterocyclyl ring system.
Exemplary 3-membered heterocyclyl groups containing one heteroatom
include, without limitation, azirdinyl, oxiranyl, thiorenyl.
Exemplary 4-membered heterocyclyl groups containing one heteroatom
include, without limitation, azetidinyl, oxetanyl and thietanyl.
Exemplary 5-membered heterocyclyl groups containing one heteroatom
include, without limitation, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,
dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered
heterocyclyl groups containing two heteroatoms include, without
limitation, dioxolanyl, oxasulfuranyl disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclyl groups containing three heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups
containing one heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 5-membered heterocyclyl groups
fused to a aryl ring (also referred to herein as a 5,6-bicyclic
heterocyclic ring) include, without limitation, indolinyl,
isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl
groups fused to an C.sub.6 aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0046] "C.sub.6-10 aryl" refers to a radical of a monocyclic or
polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having
6, 10 .pi. electrons shared in a cyclic array) having 6-10 ring
carbon atoms and zero heteroatoms. In some embodiments, an aryl
group has six ring carbon atoms ("C.sub.6 aryl"; e.g., phenyl). In
some embodiments, an aryl group has ten ring carbon atoms
("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). Aryl also includes ring systems wherein the aryl ring,
as defined above, is fused with one or more cycloalkyl, or
heterocyclyl groups wherein the radical or point of attachment is
on the aryl ring, and in such instances, the number of carbon atoms
continue to designate the number of carbon atoms in the aryl ring
system. Unless otherwise specified, each instance of an aryl group
is independently optionally substituted, i.e., unsubstituted (an
"unsubstituted aryl") or substituted (a "substituted aryl") with
one or more substituents. In certain embodiments, the aryl group is
unsubstituted C.sub.6-10 aryl. In certain embodiments, the aryl
group is substituted C.sub.6-10 aryl.
[0047] "C.sub.5-10 heteroaryl" refers to a radical of a 5-10
membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g.,
having 6 or 10 .pi. electrons shared in a cyclic array) having ring
carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen and sulfur. In
heteroaryl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. Heteroaryl further includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more cycloalkyl, or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. In some
embodiments, C.sub.5-6 heteroaryl is especially preferred, which is
a radical of a 5-6 membered monocyclic or bicyclic 4n+2 aromatic
ring system having ring carbon atoms and 1-4 ring heteroatoms.
Unless otherwise specified, each instance of a heteroaryl group is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted heteroaryl") or substituted (a "substituted
heteroaryl") with one or more substituents. In certain embodiments,
the heteroaryl group is unsubstituted 5- to 10-membered heteroaryl.
In certain embodiments, the heteroaryl group is substituted 5- to
10-membered heteroaryl. Exemplary 5-membered heteroaryl groups
containing one heteroatom include, without limitation, pyrrolyl,
furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups
containing two heteroatoms include, without limitation, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
Exemplary 5-membered heteroaryl groups containing three heteroatoms
include, without limitation, triazolyl, oxadiazolyl, and
thiadiazolyl. Exemplary 5-membered heteroaryl groups containing
four heteroatoms include, without limitation, tetrazolyl. Exemplary
6-membered heteroaryl groups containing one heteroatom include,
without limitation, pyridinyl. Exemplary 6-membered heteroaryl
groups containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0048] "Nitrile group" represents the group --CN.
[0049] "Nitro group" represents the group --NO.sub.2.
Other Definitions
[0050] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al., describes pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
Pharmaceutically acceptable salts of the compounds of the present
disclosure include those derived from suitable inorganic and
organic acids and bases.
[0051] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g, infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or a non-human animal, e.g., a mammal such as
primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs,
horses, sheep, goats, rodents, cats, and/or dogs. In certain
embodiments, the subject is a human. In certain embodiments, the
subject is a non-human animal. The terms "human," "patient," and
"subject" are used interchangeably herein.
[0052] Disease, disorder, and condition are used interchangeably
herein.
[0053] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" contemplate an action that
occurs while a subject is suffering from the specified disease,
disorder or condition, which reduces the severity of the disease,
disorder or condition, or retards or slows the progression of the
disease, disorder or condition ("therapeutic treatment"), and also
contemplates an action that occurs before a subject begins to
suffer from the specified disease, disorder or condition
("prophylactic treatment").
[0054] In general, the "effective amount" of a compound refers to
an amount sufficient to elicit the desired biological response. As
will be appreciated by those of ordinary skill in this art, the
effective amount of a compound disclosed herein may vary depending
on such factors as the desired biological endpoint, the
pharmacokinetics of the compound, the disease being treated, the
mode of administration, and the age, health, and condition of the
subject. An effective amount encompasses therapeutically effective
amount and prophylactically effective amount.
[0055] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment of a
disease, disorder or condition, or to delay or minimize one or more
symptoms associated with the disease, disorder or condition. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment of the
disease, disorder or condition. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or condition, or
enhances the therapeutic efficacy of another therapeutic agent.
[0056] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease, disorder or condition, or one or
more symptoms associated with the disease, disorder or condition,
or prevent its recurrence. A prophylactically effective amount of a
compound means an amount of a therapeutic agent, alone or in
combination with other agents, which provides a prophylactic
benefit in the prevention of the disease, disorder or condition.
The term "prophylactically effective amount" can encompass an
amount that improves overall prophylaxis or enhances the
prophylactic efficacy of another prophylactic agent.
[0057] "Bcr-Abl1" refers to a fusion protein created from the
N-terminal exons of the breakpoint cluster region (BCR) gene and
the major C-terminal part (exons 2-11) of the Abelson (ABL1) gene.
The most common fusion transcripts encode for a 210-kDa protein
(p210 Bcr-Abl1), while rarer transcripts encode a 190-kDa protein
(p190 Bcr-Abl1) and a 230-kDa protein (p230 Bcr-Abl1). The Abl1
sequences of these proteins contains an Abl1 tyrosine kinase domain
which is tightly regulated in the wild-type protein, but
constitutively activated in the Bcr-Abl1 fusion proteins. This
deregulated tyrosine kinase interacts with multiple cellular
signalling pathways leading to transformation and deregulated
proliferation of the cells.
[0058] "Bcr-Abl1 mutants" refers to the numerous single site
mutations in Bcr-Abl1 including: Glu255.fwdarw.Lys,
Glu255.fwdarw.Val, Thr315.fwdarw.Ile, Met244.fwdarw.Val,
Phe317.fwdarw.Leu, Leu248.fwdarw.Val, Met343.fwdarw.Thr,
Gly250.fwdarw.Ala, Met351.fwdarw.Thr, Gly250.fwdarw.Glu,
Glu355.fwdarw.Gly, Gln252.fwdarw.His, Phe358.fwdarw.Ala,
Gln252.fwdarw.Arg, Phe359.fwdarw.Val, Tyr253.fwdarw.His,
Val379.fwdarw.Ile, Tyr253.fwdarw.Phe, Phe382.fwdarw.Leu,
Glu255.fwdarw.Lys, Leu387.fwdarw.Met, Glu255.fwdarw.Val,
His396.fwdarw.Pro, Phe311.fwdarw.Ile, His396.fwdarw.Arg,
Phe311.fwdarw.Leu, Ser417.fwdarw.Tyr, Thr315.fwdarw.Ile,
Glu459.fwdarw.Lys and Phe486.fwdarw.Ser.
[0059] "C-Abl" refers to the full length gene product of a
non-mutated wild-type Abl1.
DESCRIPTION OF FIGURES
[0060] FIG. 1 shows the growth of tumor volume of mice for the
treated and control group in the BA/F.sub.3 (BCR-ABL.sup.T315I)
subcutaneous tumor model.
[0061] FIG. 2 shows the changes in body weight of the experimental
mice versus the treatment time in the BA/F.sub.3
(BCR-ABL.sup.T315I) subcutaneous tumor model.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Compound
[0062] In the present disclosure, "compound disclosed herein"
refers to the following compound of formula (I), (Ia) and (Ib), or
a pharmaceutically acceptable salt, a stereoisomer, a solvate, or a
hydrate thereof.
[0063] In one embodiment, the present disclosure relates to a
compound of formula (I), or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof:
##STR00006##
wherein:
[0064] Y.sub.1 is selected from CR.sub.a or N;
[0065] Y is independently selected from CR.sub.a or N;
[0066] R.sub.1 is selected from hydrogen, halo, nitrile, nitro,
C.sub.1-6 alkyl or C.sub.1-6 haloalkyl, wherein the said C.sub.1-6
alkyl or C.sub.1-6 haloalkyl is optionally substituted by R.sub.1a
group;
[0067] R.sub.2 is selected from hydrogen, C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, wherein the said C.sub.1-6 alkyl or C.sub.1-6
haloalkyl is optionally substituted by R.sub.2a group;
[0068] Z is a chemical bond, O, S(O).sub.0-2 or NR.sub.b;
[0069] or --Z--R.sub.2 together form --SF.sub.5;
[0070] Ar is
##STR00007##
[0071] wherein X.sub.1 to X.sub.8 are independently selected from
CR or N, and at least one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4
is N, or at least one of X.sub.5, X.sub.6, X.sub.7 and X.sub.8 is
N;
[0072] wherein each P.sub.1 and Q.sub.1 is independently selected
from O, S, NR.sub.b or C(R).sub.2, each P.sub.2 and Q.sub.2 is
independently selected from CR or N;
[0073] Het is
##STR00008##
[0074] wherein X.sub.9 is selected from O, S, NR.sub.b or
C(R).sub.2;
[0075] m is 0, 1 or 2;
[0076] n is 0, 1, 2, 3, 4, 5 or 6;
[0077] R.sub.a is independently selected from hydrogen, halo,
nitrile, nitro, hydroxy, --NH.sub.2, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or
C.sub.1-6 alkoxyl;
[0078] R.sub.b is independently selected from hydrogen, C.sub.1-6
alkyl or C.sub.1-6 haloalkyl;
[0079] R.sub.1a, R.sub.2a and R are independently selected from
hydrogen, halo, hydroxy, --NH.sub.2, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxyl, C.sub.3-7 cycloalkyl, C.sub.3-7 heterocyclyl,
C.sub.6-10 aryl or C.sub.5-10 heteroaryl;
[0080] or two R groups on the same or adjacent atoms may together
form C.sub.3-7 cycloalkyl, C.sub.3-7 heterocyclyl, C.sub.6-10 aryl
or C.sub.5-10 heteroaryl.
[0081] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof:
wherein,
[0082] Ar is
##STR00009##
[0083] wherein X.sub.1 is CR, X.sub.2 to X.sub.4 are independently
selected from CR or N, and at least one of X.sub.2, X.sub.3 and
X.sub.4 is N.
[0084] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ia), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate
thereof:
##STR00010##
[0085] wherein, Ar and Het are as defined herein.
[0086] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, wherein:
[0087] Ar is
##STR00011##
[0088] wherein, X.sub.1 to X.sub.4 are as defined herein;
[0089] or, Ar is selected from the following groups that are
optionally substituted by one, two or three R:
##STR00012##
[0090] wherein, R are as defined herein.
[0091] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, wherein:
[0092] Ar is selected from the following groups that are optionally
substituted by one, two or three R:
##STR00013##
[0093] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, wherein:
[0094] Ar is
##STR00014##
wherein, X.sub.5 to X.sub.8 are as defined herein;
[0095] or, Ar is selected from the following groups that are
optionally substituted by one, two or three R:
##STR00015##
wherein, R are as defined herein.
[0096] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, wherein:
[0097] Ar is
##STR00016##
wherein, P.sub.1, P.sub.2, Q.sub.1 and Q.sub.2 are as defined
herein.
[0098] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, wherein:
[0099] Het is
##STR00017##
wherein, X.sub.9 is C(R).sub.2, and m, n and R are as defined
herein;
[0100] or, Het the following groups that are optionally substituted
by one, two, three or more R:
##STR00018##
wherein R is as defined herein;
[0101] or, Het is selected from the following groups:
##STR00019##
[0102] In one embodiment, the present disclosure relates to the
above compound, or a pharmaceutically acceptable salt, a
stereoisomer, a solvate or a hydrate thereof, wherein:
[0103] Het is
##STR00020##
wherein, wherein one X.sub.9 is selected from O, S or NR.sub.b, and
the optionally present other X.sub.9 is C(R).sub.2, and m, n, R and
R.sub.b are as defined herein;
[0104] or, Het is selected from the following groups:
##STR00021##
[0105] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ib), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate
thereof:
##STR00022##
wherein:
[0106] Ar is
##STR00023##
X.sub.1 to X.sub.4 are as defined herein;
[0107] or, Ar is selected from the following groups that are
optionally substituted by one, two or three R:
##STR00024##
[0108] R is selected from hydrogen, halo, hydroxy, --NH.sub.2,
--NHC.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2.
[0109] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ib), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate
thereof:
##STR00025##
wherein:
[0110] Ar is selected from the following groups that are optionally
substituted by one, two or three R:
##STR00026##
[0111] R is selected from hydrogen, halo, hydroxy, --NH.sub.2,
--NHC.sub.1-6 alkyl or --N(C.sub.1-6 alkyl).sub.2.
[0112] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ib), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate
thereof:
##STR00027##
wherein:
[0113] Ar is selected from the following groups:
##STR00028##
[0114] R is selected from hydrogen, halo, hydroxy, --NH.sub.2,
--NHC.sub.1-6 alkyl or --N(C.sub.1-6 alkyl).sub.2.
[0115] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ib), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate
thereof:
##STR00029##
wherein:
[0116] Ar is selected from the following groups:
##STR00030##
[0117] R is selected from hydrogen, halo or hydroxy.
[0118] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ib), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein:
##STR00031##
wherein:
[0119] Ar is
##STR00032##
wherein, X.sub.5 to X.sub.8 are as defined herein;
[0120] or, Ar is selected from the following groups that are
optionally substituted by one, two or three R:
##STR00033##
[0121] R is selected from hydrogen, halo, hydroxy, --NH.sub.2,
--NHC.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2.
[0122] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ic), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein:
##STR00034##
wherein:
[0123] Ar is selected from the following groups:
##STR00035##
[0124] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ic), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein:
##STR00036##
wherein
[0125] Ar is selected from the following groups:
##STR00037##
[0126] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ic), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein:
##STR00038##
wherein:
[0127] Ar is selected from the following groups:
##STR00039##
[0128] In one embodiment, the present disclosure relates to the
above compound, which is formula (Ic), or a pharmaceutically
acceptable salt, a stereoisomer, a solvate or a hydrate thereof,
wherein:
##STR00040##
wherein:
[0129] Ar is selected from the following groups:
##STR00041##
Y.sub.1 and Y
[0130] In one specific embodiment, Y.sub.1 is N; in another
specific embodiment, Y.sub.1 is CR.sub.a; in another specific
embodiment, Y.sub.1 is CH.
[0131] In one specific embodiment, Y is CR.sub.a; in another
specific embodiment, Y is N; in another specific embodiment, Y is
CH.
R.sub.1
[0132] In one specific embodiment, R.sub.1 is selected from
hydrogen, halo, nitrile, nitro, C.sub.1-6 alkyl or C.sub.1-6
haloalkyl; in another specific embodiment, R.sub.1 is selected from
hydrogen, halo, nitrile, nitro or C.sub.1-6 alkyl; in another
specific embodiment, R.sub.1 is selected from hydrogen or halo; in
another specific embodiment, R.sub.1 is hydrogen; in another
specific embodiment, R.sub.1 is halo (F, Cl, Br or I); in another
specific embodiment, R.sub.1 is nitrile; in another specific
embodiment, R.sub.1 is nitro; in another specific embodiment,
R.sub.1 is C.sub.1-6 alkyl (methyl, ethyl, propyl, isopropyl,
butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, and the
like); in another specific embodiment, R.sub.1 is C.sub.1-6
haloalkyl (--CF.sub.3, --CH.sub.2F, --CHF.sub.2, --CClF.sub.2,
--CHFCH.sub.2F, --CH.sub.2CHF.sub.2, --CF.sub.2CF.sub.3,
--CF.sub.2CClF.sub.2, --CF.sub.2CH.sub.3, --CCl.sub.3,
--CH.sub.2Cl, --CHCl.sub.2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and
the like).
R.sub.2 and Z
[0133] In one specific embodiment, R.sub.2 is selected from
hydrogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; in another
specific embodiment, R.sub.2 is selected from C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.2 is
hydrogen; in another specific embodiment, R.sub.2 is C.sub.1-6
alkyl (methyl, ethyl, propyl, isopropyl, butyl, iso-butyl,
tert-butyl, pentyl, iso-pentyl, hexyl, and the like); in another
specific embodiment, R.sub.2 is C.sub.1-6 haloalkyl (--CF.sub.3,
--CH.sub.2F, --CHF.sub.2, --CClF.sub.2, --CHFCH.sub.2F,
--CH.sub.2CHF.sub.2, --CF.sub.2CF.sub.3, --CF.sub.2CClF.sub.2,
--CF.sub.2CH.sub.3, --CCl.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like).
[0134] In one specific embodiment, Z is a chemical bond; in another
specific embodiment, Z is O; in another specific embodiment, Z is
S(O).sub.0-2; in another specific embodiment, Z is NR.sub.b; in
another specific embodiment, Z is NH.
[0135] In one specific embodiment, --Z--R.sub.2 together form
--SF.sub.5.
Ar, X.sub.1 to X.sub.8, P.sub.1, P.sub.2, Q.sub.1 and Q.sub.2
[0136] In one specific embodiment, Ar is
##STR00042##
wherein X.sub.1 to X.sub.4 are independently selected from CR or N,
and at least one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4 is N; in
another specific embodiment, Ar is
##STR00043##
wherein X.sub.5 to X.sub.8 are independently selected from CR or N,
and at least one of X.sub.5, X.sub.6, X.sub.7 and X.sub.8 is N.
[0137] In the above specific embodiment regarding Ar, X.sub.1 is
CR; in another specific embodiment, X.sub.1 is CH; in another
specific embodiment, X.sub.1 is N. In the above specific embodiment
regarding Ar, X.sub.2 is CR; in another specific embodiment,
X.sub.2 is CH; in another specific embodiment, X.sub.2 is N. In the
above specific embodiment regarding Ar, X.sub.3 is CR; in another
specific embodiment, X.sub.3 is CH; in another specific embodiment,
X.sub.3 is N. In the above specific embodiment regarding Ar,
X.sub.4 is CR; in another specific embodiment, X.sub.4 is CH; in
another specific embodiment, X.sub.4 is N. In the above specific
embodiment regarding Ar, X.sub.5 is CR; in another specific
embodiment, X.sub.5 is CH; in another specific embodiment, X.sub.5
is N. In the above specific embodiment regarding Ar, X.sub.6 is CR;
in another specific embodiment, X.sub.6 is CH; in another specific
embodiment, X.sub.6 is N. In the above specific embodiment
regarding Ar, X.sub.7 is CR; in another specific embodiment,
X.sub.7 is CH; in another specific embodiment, X.sub.7 is N. In the
above specific embodiment regarding Ar, X.sub.8 is CR; in another
specific embodiment, X.sub.8 is CH; in another specific embodiment,
X.sub.8 is N.
[0138] In more specific embodiment, Ar is selected from the
following groups that are optionally substituted by one, two or
three R:
##STR00044##
wherein, R are as defined in claim 1.
[0139] In more specific embodiment, Ar is selected from the
following groups that are optionally substituted by one, two or
three R:
##STR00045##
wherein, R are as defined in claim 1.
[0140] In one specific embodiment, Ar is
##STR00046##
in another specific embodiment, Ar is
##STR00047##
in another specific embodiment, Ar is
##STR00048##
in another specific embodiment, Ar is
##STR00049##
in another specific embodiment, Ar is
##STR00050##
[0141] In the above specific embodiment regarding Ar, P.sub.1 is O;
in another specific embodiment, P.sub.1 is S; in another specific
embodiment, P.sub.1 is NR.sub.b; in another specific embodiment,
P.sub.1 is NH; in another specific embodiment, P.sub.1 is
C(R).sub.2; in another specific embodiment, P.sub.1 is CH.sub.2. In
the above specific embodiment regarding Ar, Q.sub.1 is O; in
another specific embodiment, Q.sub.1 is S; in another specific
embodiment, Q.sub.1 is NR.sub.b; in another specific embodiment,
Q.sub.1 is NH; in another specific embodiment, Q.sub.1 is
C(R).sub.2; in another specific embodiment, Q.sub.1 is CH.sub.2. In
the above specific embodiment regarding Ar, P.sub.2 is CR; in
another specific embodiment, P.sub.2 is CH; in another specific
embodiment, P.sub.2 is N. In the above specific embodiment
regarding Ar, Q.sub.2 is CR; in another specific embodiment,
Q.sub.2 is CH; in another specific embodiment, Q.sub.2 is N.
[0142] In more specific embodiment, the said
##STR00051##
moiety is selected from the following groups:
##STR00052##
[0143] in more specific embodiment, the said
##STR00053##
moiety is selected from the following groups:
##STR00054##
in more specific embodiment, the said
##STR00055##
moiety is selected from the following groups:
##STR00056##
[0144] in more specific embodiment, the said
##STR00057##
moiety is selected from the following groups:
##STR00058##
[0145] in more specific embodiment, the said
##STR00059##
moiety is selected from the following groups:
##STR00060##
[0146] in more specific embodiment, Ar is selected from the
following groups that are optionally substituted by R.sub.b or
R:
##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065##
##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070##
##STR00071## ##STR00072## ##STR00073##
[0147] wherein, R.sub.b and R are as defined herein.
Het, X.sub.9, m and n
[0148] In one specific embodiment, Het is
##STR00074##
[0149] In the above specific embodiment regarding Het, X.sub.9 is
O; in another specific embodiment, X.sub.9 is S; in another
specific embodiment, X.sub.9 is NR.sub.b; in another specific
embodiment, X.sub.9 is C(R).sub.2. In the above specific embodiment
regarding Het, m is 0; in another specific embodiment, m is 1; in
another specific embodiment, m is 2. In the above specific
embodiment regarding Het, n is 0; in another specific embodiment, n
is 1; in another specific embodiment, n is 2; in another specific
embodiment, n is 3; in another specific embodiment, n is 4; in
another specific embodiment, n is 5; in another specific
embodiment, n is 6.
[0150] In more specific embodiment, Het is
##STR00075##
wherein, X.sub.9 is C(R).sub.2. In more specific embodiment, Het
the following groups that are optionally substituted by one, two,
three or more R:
##STR00076##
[0151] in more specific embodiment, Het is selected from the
following groups:
##STR00077##
[0152] in more specific embodiment, Het is
##STR00078##
wherein, one X.sub.9 is selected from O, S or NR.sub.b, and the
optionally present other X.sub.9 is C(R).sub.2; in more specific
embodiment, Het is selected from the following groups:
##STR00079##
R.sub.a, R.sub.b, R.sub.1a, R.sub.2a and R
[0153] In one specific embodiment, R.sub.a is independently
selected from hydrogen, halo, nitrile, nitro, hydroxy, --NH.sub.2,
--NHC.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl or C.sub.1-6 alkoxyl; in another specific
embodiment, R.sub.a is hydrogen; in another specific embodiment,
R.sub.a is halo; in another specific embodiment, R.sub.a is
nitrile; in another specific embodiment, R.sub.a is nitro; in
another specific embodiment, R.sub.a is hydroxy; in another
specific embodiment, R.sub.a is --NH.sub.2; in another specific
embodiment, R.sub.a is --NHC.sub.1-6 alkyl; in another specific
embodiment, R.sub.a is --N(C.sub.1-6 alkyl).sub.2; in another
specific embodiment, R.sub.a is C.sub.1-6 alkyl; in another
specific embodiment, R.sub.a is C.sub.1-6 haloalkyl; in another
specific embodiment, R.sub.a is C.sub.1-6 alkoxyl.
[0154] In one specific embodiment, R.sub.b is independently
selected from hydrogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; in
another specific embodiment, R.sub.b is hydrogen; in another
specific embodiment, R.sub.b is C.sub.1-6 alkyl; in another
specific embodiment, R.sub.b is C.sub.1-6 haloalkyl.
[0155] In one specific embodiment, R.sub.1a, R.sub.2a and R are
independently selected from hydrogen, halo, hydroxy, --NH.sub.2,
--NHC.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 heterocyclyl, C.sub.6-10 aryl or C.sub.5-10 heteroaryl;
in another specific embodiment, R.sub.1a, R.sub.2a and R are
hydrogen; in another specific embodiment, R.sub.1a, R.sub.2a and R
are halo; in another specific embodiment, R.sub.1a, R.sub.2a and R
are hydroxy; in another specific embodiment, R.sub.1a, R.sub.2a and
R are --NH.sub.2; in another specific embodiment, R.sub.1a,
R.sub.2a and R are --NHC.sub.1-6 alkyl; in another specific
embodiment, R.sub.1a, R.sub.2a and R are --N(C.sub.1-6
alkyl).sub.2; in another specific embodiment, R.sub.1a, R.sub.2a
and R are C.sub.1-6 alkyl; in another specific embodiment,
R.sub.1a, R.sub.2a and R are C.sub.1-6 haloalkyl; in another
specific embodiment, R.sub.1a, R.sub.2a and R are C.sub.1-6
alkoxyl; in another specific embodiment, R.sub.1a, R.sub.2a and R
are C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.1a,
R.sub.2a and R are C.sub.3-7 heterocyclyl; in another specific
embodiment, R.sub.1a, R.sub.2a and R are C.sub.6-10 aryl; in
another specific embodiment, R.sub.1a, R.sub.2a and R are
C.sub.5-10 heteroaryl.
[0156] In one specific embodiment, two R groups on the same or
adjacent atoms may together form C.sub.3-7 cycloalkyl, or C.sub.3-7
heterocyclyl; in another specific embodiment, two R groups on the
same or adjacent atoms may together form C.sub.3-7 cycloalkyl; in
another specific embodiment, two R groups on the same or adjacent
atoms may together form C.sub.3-7 heterocyclyl.
[0157] Any technical solution in any one of the above specific
embodiments, or any combination thereof, may be combined with any
technical solution in other specific embodiments or any combination
thereof. For example, any technical solution of Y.sub.1 or any
combination thereof may be combined with any technical solution of
Y, R.sub.1, R.sub.2, Z, Ar, X.sub.1 to X.sub.8, P.sub.1, P.sub.2,
Q.sub.1, Q.sub.2, Het, m, n, R.sub.a, R.sub.b, R.sub.1a, R.sub.2a
and R or any combination thereof. The present disclosure is
intended to include all combination of such technical solutions,
which are not exhaustively listed here to save space.
[0158] In some embodiments, the compounds disclosed herein are
selected from the following compounds:
##STR00080## ##STR00081##
[0159] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various stereoisomeric
forms, e.g., enantiomers and/or diastereomers. For example, the
compounds described herein can be in the form of an individual
enantiomer, diastereomer or geometric isomer (such as cis- and
trans-isomer), or can be in the form of a mixture of stereoisomers,
including racemic mixtures and mixtures enriched in one or more
stereoisomer. Isomers can be isolated from mixtures by methods
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts; or preferred isomers can be prepared by asymmetric
syntheses.
[0160] Those skilled in the art will appreciate that many organic
compounds can form complexes with solvents that react in or
precipitate or crystallize from the solvent. These complexes are
referred to as "solvates." When the solvent is water, the complex
is referred to as a "hydrate." The disclosure encompasses all
solvates of the compounds disclosed herein.
Pharmacology and Efficacy
[0161] The compounds disclosed herein show therapeutic efficacy
especially on diseases or disorders that are dependent on the
activity of Bcr-Abl1. In particular, the compounds disclosed herein
inhibit the ATP binding site of Bcr-Abl1 (including wild-type
Bcr-Abl1 and/or its mutations (including T315I mutations)).
[0162] Carcinoma cells utilize invapodia to degrade the extra
cellular matrix during tumor invasion and metastasis. Abl kinase
activity is required for Src-induced invapodia formation,
regulating distinct stages of invapodia assembly and function. The
compounds disclosed herein, therefore, as inhibitors of Abl, have
the potential to be used as therapies for the treatment of
metastatic invasive carcinomas.
[0163] An inhibitor of c-Abl kinase can be used to treat brain
cancers: including Glioblastoma which is the most common and most
aggressive malignant primary brain tumor in which the expression of
c-Abl is immunohistochemically detectable in a subset of patients.
Therefore a new c-Abl inhibitor with high brain exposure represents
a solid therapeutic approach for glioblastoma and other brain
cancers.
[0164] Compounds disclosed herein can be useful in the treatment of
viruses. For example, viral infections can be mediated by Abl1
kinase activity, as in the case of pox viruses and the Ebola virus.
Imatinib and nilotinib have been shown to stop the release of Ebola
viral particles from infected cells, in vitro. Compounds disclosed
herein that inhibit c-Abl kinase, therefore, can be expected to
reduce the pathogen's ability to replicate.
[0165] Parkinson's disease is the second most prevalent chronic
neurodegenerative disease with the most common familial
autosomal-recessive form being caused by mutations in the E3
ubiquitin ligase, parkin. Recent studies showed that activated
c-ABL was found in the striatum of patients with sporadic
Parkinson's disease. Concomitantly, parkin was
tyrosine-phosphorylated, causing loss of its ubiquitin ligase and
cytoprotective activities as indicated by the accumulation of
parkin substrates
[0166] The compounds or compositions disclosed herein are also
useful in the treatment of diseases, disorders or conditions
mediated by Bcr-Abl kinase: respiratory diseases, allergies,
rheumatoid arthritis, osteoarthritis, rheumatic disorders,
psoriasis, ulcerative colitis, Crohn's disease, septic shock,
proliferative disorders, atherosclerosis, allograft rejection after
transplantation, diabetes, stroke, obesity or restenosis, leukemia,
stromal tumor, thyroid cancer, systemic mastocytosis, eosinophilia
syndrome, fibrosis, polyarthritis, scleroderma, lupus
erythematosus, graft versus host disease, neurofibromatosis,
pulmonary hypertension, Alzheimer's disease, seminoma,
dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma,
dysgerminoma, testicular intraepithelial neoplasia, melanoma,
breast cancer, neuroblastoma, papillary/follicular parathyroid
hyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian
cancer, prostate cancer, glioblastoma, brain tumor, malignant
glioma, pancreatic cancer, malignant pleura tumor,
hemangioblastoma, hemangioma, kidney cancer, liver cancer, adrenal
cancer, bladder cancer, stomach cancer, rectal cancer, vaginal
cancer, cervical cancer, endometrial cancer, multiple myeloma, neck
and head tumors, neoplasia and other proliferative disease or
proliferative diseases, or the combination thereof.
Pharmaceutical Compositions, Formulations and Kits
[0167] In another aspect, the disclosure provides a pharmaceutical
composition comprising a compound of the present disclosure (also
referred to as the "active ingredient") and a pharmaceutically
acceptable excipient. In certain embodiments, the pharmaceutical
composition comprises an effective amount of the compound of the
present disclosure. In certain embodiments, the pharmaceutical
composition comprises a therapeutically effective amount of the
compound of the present disclosure. In certain embodiments, the
pharmaceutical composition comprises a prophylactically effective
amount of the compound of the present disclosure.
[0168] A pharmaceutically acceptable excipient for use in the
present disclosure refers to a non-toxic carrier, adjuvant or
vehicle which does not destroy the pharmacological activity of the
compound formulated together. Pharmaceutically acceptable carriers,
adjuvants, or vehicles that can be used in the compositions of the
present disclosure include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins (e.g., human
serum albumin), buffer substances (such as phosphate), glycine,
sorbic acid, potassium sorbate, a mixture of partial glycerides of
saturated plant fatty acids, water, salt or electrolyte (such as
protamine sulfate), disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salt, silica gel, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based materials,
polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate,
wax, polyethylene-polyoxypropylene block polymers, polyethylene
glycol and lanolin.
[0169] The present disclosure also includes kits (e.g.,
pharmaceutical packs). Kits provided may include a compound
disclosed herein, other therapeutic agents, and a first and a
second containers (eg, vials, ampoules, bottles, syringes, and/or
dispersible packages or other suitable container) containing the
compound disclosed herein or other therapeutic agents. In some
embodiments, kits provided can also optionally include a third
container containing a pharmaceutically acceptable excipient for
diluting or suspending the compound disclosed herein and/or other
therapeutic agent. In some embodiments, the compound disclosed
herein provided in the first container and the other therapeutic
agents provided in the second container is combined to form a unit
dosage form.
[0170] The following formulation examples illustrate representative
pharmaceutical compositions that may be prepared in accordance with
this disclosure. The present disclosure, however, is not limited to
the following pharmaceutical compositions.
Exemplary Formulation 1--Tablets
[0171] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg
of active compound per tablet) in a tablet press.
Exemplary Formulation 2--Tablets
[0172] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of
active compound per tablet) in a tablet press.
Exemplary Formulation 3--Tablets
[0173] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg
of active compound per tablet) in a tablet press.
Exemplary Formulation 4--Tablets
[0174] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg
of active compound per tablet) in a tablet press.
Exemplary Formulation 5--Tablets
[0175] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg
of active compound per tablet) in a tablet press.
Exemplary Formulation 6--Tablets
[0176] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg
of active compound per tablet) in a tablet press.
Exemplary Formulation 7--Tablets
[0177] A compound of the present disclosure may be admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 450-900 mg tablets (150-300
mg of active compound) in a tablet press.
Exemplary Formulation 8--Capsules
[0178] A compound of the present disclosure may be admixed as a dry
powder with a starch diluent in an approximate 1:1 weight ratio.
The mixture is filled into 250 mg capsules (125 mg of active
compound per capsule).
Exemplary Formulation 9--Liquid
[0179] A compound of the present disclosure (125 mg) may be admixed
with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant
mixture may be blended, passed through a No. 10 mesh U.S. sieve,
and then mixed with a previously made solution of microcrystalline
cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in
water. Sodium benzoate (10 mg), flavor, and color are diluted with
water and added with stirring. Sufficient water may then be added
to produce a total volume of 5 mL.
Exemplary Formulation 10--Injection
[0180] A compound of the present disclosure may be dissolved or
suspended in a buffered sterile saline injectable aqueous medium to
a concentration of approximately 5 mg/mL.
Administration
[0181] The pharmaceutical composition provided by the present
disclosure can be administered by a variety of routes including,
but not limited to, oral administration, parenteral administration,
inhalation administration, topical administration, rectal
administration, nasal administration, oral administration, vaginal
administration, administration by implant or other means of
administration. For example, parenteral administration as used
herein includes subcutaneous administration, intradermal
administration, intravenous administration, intramuscular
administration, intra-articular administration, intraarterial
administration, intrasynovial administration, intrasternal
administration, intracerebroventricular administration,
intralesional administration, and intracranial injection or
infusion techniques.
[0182] Generally, the compounds provided herein are administered in
an effective amount. The amount of the compound actually
administered will typically be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound
administered, the age, weight, and response of the individual
patient, the severity of the patient's symptoms, and the like.
[0183] When used to prevent the disorder disclosed herein, the
compounds provided herein will be administered to a subject at risk
for developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Subjects at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
[0184] The pharmaceutical compositions provided herein can also be
administered chronically ("chronic administration"). Chronic
administration refers to administration of a compound or
pharmaceutical composition thereof over an extended period of time,
e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3
years, 5 years, etc, or may be continued indefinitely, for example,
for the rest of the subject's life. In certain embodiments, the
chronic administration is intended to provide a constant level of
the compound in the blood, e.g., within the therapeutic window over
the extended period of time.
[0185] The pharmaceutical compostions of the present disclosure may
be further delivered using a variety of dosing methods. For
example, in certain embodiments, the pharmaceutical composition may
be given as a bolus, e.g., in order to raise the concentration of
the compound in the blood to an effective level. The placement of
the bolus dose depends on the systemic levels of the active
ingredient desired through the body, e.g., an intramuscular or
subcutaneous bolus dose allows a slow release of the active
ingredient, while a bolus delivered directly to the veins (e.g.,
through an IV drip) allows a much faster delivery which quickly
raises the concentration of the active ingredient in the blood to
an effective level. In other embodiments, the pharmaceutical
composition may be administered as a continuous infusion, e.g., by
IV drip, to provide maintenance of a steady-state concentration of
the active ingredient in the subject's body. Furthermore, in still
yet other embodiments, the pharmaceutical composition may be
administered as first as a bolus dose, followed by continuous
infusion.
[0186] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the compound is usually a
minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder
being various vehicles or excipients and processing aids helpful
for forming the desired dosing form.
[0187] With oral dosing, one to five and especially two to four and
typically three oral doses per day are representative regimens.
Using these dosing patterns, each dose provides from about 0.01 to
about 20 mg/kg of the compound provided herein, with preferred
doses each providing from about 0.1 to about 10 mg/kg, and
especially about 1 to about 5 mg/kg.
[0188] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses,
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight.
[0189] Injection dose levels range from about 0.1 mg/kg/hour to at
least 10 mg/kg/hour, all for from about 1 to about 120 hours and
especially 24 to 96 hours. A preloading bolus of from about 0.1
mg/kg to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human
patient.
[0190] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0191] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
excipients known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
excipient and the like.
[0192] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s). When
formulated as a ointment, the active ingredients will typically be
combined with either a paraffinic or a water-miscible ointment
base. Alternatively, the active ingredients may be formulated in a
cream with, for example an oil-in-water cream base. Such
transdermal formulations are well-known in the art and generally
include additional ingredients to enhance the dermal penetration of
stability of the active ingredients or Formulation. All such known
transdermal formulations and ingredients are included within the
scope provided herein.
[0193] The compounds provided herein can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0194] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0195] The compounds of the present disclosure can also be
administered in sustained release forms or from sustained release
drug delivery systems. A description of representative sustained
release materials can be found in Remington's Pharmaceutical
Sciences.
[0196] The present disclosure also relates to the pharmaceutically
acceptable formulations of a compound of the present disclosure. In
one embodiment, the formulation comprises water. In another
embodiment, the formulation comprises a cyclodextrin derivative.
The most common cyclodextrins are .alpha.-, .beta.- and
.gamma.-cyclodextrins consisting of 6, 7 and 8 .alpha.-1,4-linked
glucose units, respectively, optionally comprising one or more
substituents on the linked sugar moieties, which include, but are
not limited to, methylated, hydroxyalkylated, acylated, and
sulfoalkylether substitution. In certain embodiments, the
cyclodextrin is a sulfoalkyl ether .beta.-cyclodextrin, e.g., for
example, sulfobutyl ether .beta.-cyclodextrin, also known as
Captisol. See, e.g., U.S. Pat. No. 5,376,645. In certain
embodiments, the formulation comprises
hexapropyl-.beta.-cyclodextrin (e.g., 10-50% in water).
Treatment
[0197] The compounds disclosed herein are also useful in the
treatment of diseases, disorders or conditions mediated by Bcr-Abl
kinase: respiratory diseases, allergies, rheumatoid arthritis,
osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis,
Crohn's disease, septic shock, proliferative disorders,
atherosclerosis, allograft rejection after transplantation,
diabetes, stroke, obesity or restenosis, leukemia, stromal tumor,
thyroid cancer, systemic mastocytosis, eosinophilia syndrome,
fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft
versus host disease, neurofibromatosis, pulmonary hypertension,
Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung
cancer, bronchial carcinoma, dysgerminoma, testicular
intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma,
papillary/follicular parathyroid hyperplasia/adenoma, colon cancer,
colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma,
brain tumor, malignant glioma, pancreatic cancer, malignant pleura
tumor, hemangioblastoma, hemangioma, kidney cancer, liver cancer,
adrenal cancer, bladder cancer, stomach cancer, rectal cancer,
vaginal cancer, cervical cancer, endometrial cancer, multiple
myeloma, neck and head tumors, neoplasia and other proliferative
disease or proliferative diseases, or the combination thereof.
[0198] The present disclosure thus provides the use of the compound
disclosed herein, especially in the treatment of diseases and
disorders mediated by inappropriate Bcr-Abl activity.
[0199] The inappropriate Bcr-Abl activity referred to herein is any
Bcr-Abl activity that deviates from the normal Bcr-Abl activity
expected in a particular mammalian subject. Inappropriate Bcr-Abl
activity may take the form of, for instance, an abnormal increase
in activity, or an aberration in the timing and or control of
Bcr-Abl activity. Such inappropriate activity may result then, for
example, from overexpression or mutation of the protein kinase
leading to inappropriate or uncontrolled activation.
[0200] In a further embodiment, the present disclosure is directed
to methods of regulating, modulating, or inhibiting Bcr-Abl for the
prevention and/or treatment of disorders related to unregulated or
inappropriate Bcr-Abl activity.
[0201] In another embodiment, the said disorder mediated by Bcr-Abl
activity is respiratory diseases. In another embodiment, the said
disorder is proliferative diseases. In yet another embodiment, the
said disorder is cancer. In another embodiment, the said disorder
is leukemia.
[0202] In another embodiment, compounds disclosed herein can also
be useful in the treatment of neural degeneration. While native
c-ABL tyrosine kinase remains relatively quiescent in healthy adult
brain, it can be activated in the brain of patients with CNS
diseases, including neurodegenerative diseases such as, Alzheimer's
disease (AD), Parkinson's disease (AD), frontotemporal dementia
(FTD), Picks disease, Niemann-Pick type C disease (NPC) and other
degenerative, inflammatory and autoimmune diseases and ageing.
[0203] An effective amount of a compound disclosed herein will
generally be administered in a single or multiple doses at an
average daily dose of from 0.01 mg to 50 mg of compound per
kilogram of patient body weight, preferably from 0.1 mg to 25 mg of
compound per kilogram of patient body weight. In general, the
compounds disclosed herein may be administered to a patient in need
of such treatment in a daily dosage range of from about 1 mg to
about 3500 mg per patient, preferably from 10 mg to 1000 mg. For
example, the daily dose per patient can be 10, 20, 30, 40, 50, 60,
70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800,
900 or 1000 mg. It can be administered one or more times daily,
weekly (or several days apart) or on an intermittent schedule. For
example, the compound can be administered one or more times per day
on a weekly basis (e.g., every Monday), continually or for several
weeks, such as 4-10 weeks. Alternatively, the administration may be
continued for several days (e.g., 2-10 days), followed by a few
days (e.g., 1-30 days) without administration of the compound, and
the cycle may be repeated indefinitely or repeated for a given
number of times, such as 4-10. Cycles. For example, the compounds
disclosed herein may be administered daily for 5 days, then
intermittently for 9 days, then administered daily for 5 days, then
intermittent for 9 days, and so on, and the cycle is repeated
indefinitely or repeated 4-10 times.
EXAMPLES
[0204] The following examples are provided to provide those skilled
in the art with a complete disclosure and description of how to
carry out, prepare and evaluate the methods and compounds claimed
herein, which are only for illustrative purpose and not constitute
any limitation of the scope of the invention.
Synthetic Method
[0205] The compounds of the present disclosure can be prepared
according to conventional methods in the art and using suitable
reagents, starting materials, and purification methods known to
those skilled in the art.
[0206] The preparation of the compounds of formula (I) of the
present disclosure is more specifically described below, but these
specific methods do not constitute any limitation to the present
disclosure. The compounds of the present disclosure may also be
conveniently prepared by combining various synthetic methods
described in the specification or known in the art, and such
combinations are readily available to those skilled in the art to
which the present disclosure pertains.
[0207] Usually, in the preparation, each reaction is usually
carried out in an inert solvent at room temperature to reflux
temperature (e.g., 0.degree. C. to 100.degree. C., preferably
0.degree. C. to 80.degree. C.). The reaction time is usually from
0.1 to 60 hours, preferably from 0.5 to 24 hours.
Example 1 Preparation of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodifluoromet-
hoxy)phenyl)ni cotinamide (Compound 6)
##STR00082##
[0208] Step 1: Synthesis of
6-chloro-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide
(Compound 3)
[0209] To a reaction flask were added 6-chloro-5-bromonicotinic
acid (1.17 g, 4.97 mmol), 4-(chlorodifluoromethoxy)aniline (0.8 g,
4.15 mmol), dissolved with 20 mL anhydrous DMF,
2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU, 2.1 g, 5.39 mmol) and
N,N-diisopropylethylamine (DIPEA, 534 mg, 4.15 mmol) were added,
and the reaction was stirred under nitrogen protection at room
temperature for 18 hours. The reaction was diluted with large
amount of water, extracted with ethyl acetate for 3-4 times, the
organic layers were combined, washed with brine, concentrated,
purified by column chromatography, dried in vacuum to afford 1.18 g
of a product, yield: 69.5%.
Step 2: Synthesis of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phen-
yl)nicotinamide (Compound 4)
[0210] To a reaction flask were added compound 3 (0.92 g, 2.0 mmol)
and (R)-3-hydroxypyrrolidine (209.1 mg, 2.4 mmol), 2 mL isopropyl
alcohol was added, DIPEA (568.7 mg, 4.4 mmol) was added, and the
reaction was heated to 140.degree. C. and stirred for 2 hours. The
temperature was cooled to room temperature, concentrated to remove
solvent, purified by silica gel column chromatography to afford 813
mg of a product, yield: 88.2%.
Step 3: Synthesis of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)-N-(4-(chloro difluoromethoxy)phenyl)nicotinamide (Compound
5)
[0211] In a reaction flask were added compound 4 (322.7 mg, 0.7
mmol), bis(pinacolato)diboron (711.03 mg, 2.8 mmol), palladium
acetate (4.71 mg, 0.021 mmol), Xphos (25.0 mg, 0.053 mmol) and
potassium phosphate (445.8 mg, 2.1 mmol), dissolved in 10 mL
anhydrous dioxane, and the reaction was heated to 60.degree. C. in
microwave and reacted for 4 hours. TLC detected the starting
material was not completely consumed, bis(pinacolato)diboron (356
mg, 1.4 mmol) was additionally added and reacted at 60.degree. C.
overnight. TLC detected the reaction was complete, the reaction was
concentrated, purified by silica gel column chromatography to
afford 262 mg of a product, yield: 73.5%.
Step 4: Synthesis of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodifluoromet-
hoxy)phenyl)nicotinamide (Compound 6)
[0212] To a reaction flask were added compound 5 (200 mg, 0.392
mmol), 2-bromopyrazine (92.9 mg, 0.588 mmol), Pd(dppf)Cl.sub.2 (32
mg, 0.02 mmol) and sodium carbonate (126 mg, 1.18 mmol), 2 mL
glycol dimethyl ether and 0.4 mL water were added, bubbled with
nitrogen gas for 10 minutes, heated to 120.degree. C. in microwave
and reacted for 0.5 hour. After TLC detected the reaction was
complete, the reaction was concentrated, purified by silica gel
column chromatography to afford 83 mg of a product, yield: 46%.
LC-MS(APCI): m/z=462.1 (M+1).sup.+; .sup.1H NMR (400 MHz, DMSO)
.delta. 10.23 (s, 1H), 8.87-8.79 (m, 2H), 8.76-8.70 (m, 1H), 8.63
(d, J=2.5 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.87 (d, J=9.1 Hz, 2H),
7.34 (d, J=8.9 Hz, 2H), 4.87 (d, J=3.3 Hz, 1H), 4.21 (s, 1H), 3.41
(dd, J=17.1, 10.5 Hz, 1H), 3.21 (dd, J=11.3, 4.5 Hz, 2H), 2.85 (d,
J=11.6 Hz, 1H), 1.86 (dd, J=8.7, 4.1 Hz, 1H), 1.75 (s, 1H).
Example 2 Preparation of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyridazine-3-yl)-N-(4-(chlorodifluoro-
methoxy)phenyl)nicotinamide (Compound 7)
##STR00083##
[0214] To a reaction flask were added compound 5 (200 mg, 0.392
mmol), 3-bromopyridazine (92.9 mg, 0.588 mmol), Pd(dppf)Cl.sub.2
(32 mg, 0.02 mmol) and sodium carbonate (126 mg, 1.18 mmol), 2 mL
glycol dimethyl ether and 0.4 mL water were added, bubbled with
nitrogen gas for 10 minutes, and the reaction was heated to
120.degree. C. in microwave and reacted for half an hour. After TLC
detected the reaction was complete, the reaction was concentrated,
purified by silica gel column chromatography to afford 57 mg of a
product, yield: 31.7%. LC-MS(APCI): m/z=462.1 (M+1).sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 10.26 (s, 1H), 9.24 (d, J=3.4 Hz, 1H),
8.84 (d, J=2.2 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 7.87 (t, J=7.7 Hz,
3H), 7.80 (dd, J=8.4, 4.9 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 4.87 (d,
J=3.3 Hz, 1H), 4.20 (s, 1H), 3.44-3.36 (m, 1H), 3.17 (d, J=5.3 Hz,
2H), 2.82 (d, J=11.2 Hz, 1H), 1.85 (dd, J=8.6, 4.3 Hz, 1H), 1.74
(s, 1H).
Example 3 Preparation of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyridazine-4-yl)-N-(4-(chlorodifluoro-
methoxy)phenyl)nicotinamide (Compound 8)
##STR00084##
[0216] To a reaction flask were added compound 5 (200 mg, 0.392
mmol), 4-bromopyridazine (92.9 mg, 0.588 mmol), Pd(dppf)Cl.sub.2
(32 mg, 0.02 mmol) and sodium carbonate (126 mg, 1.18 mmol), 2 mL
glycol dimethyl ether and 0.4 mL water were added, bubbled with
nitrogen gas for 10 minutes, and the reaction was heated to
120.degree. C. in microwave and reacted for half an hour. After TLC
detected the reaction was complete, the reaction was concentrated,
purified by silica gel column chromatography to afford 96 mg of a
product, yield: 53.1%. LC-MS(APCI): m/z=462.1 (M+1).sup.+; .sup.1H
NMR (400 MHz, DMSO) .delta. 10.24 (s, 1H), 9.35 (s, 1H), 9.29 (d,
J=5.2 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H),
7.96-7.79 (m, 2H), 7.71 (dd, J=5.3, 2.3 Hz, 1H), 7.35 (d, J=9.1 Hz,
2H), 4.91 (d, J=3.5 Hz, 1H), 4.22 (s, 1H), 3.43 (dd, J=17.2, 9.9
Hz, 1H), 3.23 (dd, J=11.1, 3.9 Hz, 2H), 2.83 (d, J=11.5 Hz, 1H),
1.92-1.83 (m, 1H), 1.78 (d, J=3.9 Hz, 1H).
Example 4 Preparation of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-amino-1,2,4-triazin-6-yl)-N-(4-(chl-
orodifluoromethoxy)phenyl)nicotinamide (Compound 11)
##STR00085##
[0217] Step 1: Synthesis of 3-amino-6-bromo-1,2,4-triazine
(compound 10)
[0218] To a reaction flask was added 3-amino-1,2,4-triazine (500
mg, 5.2 mmol), 5 mL acetonitrile and 7.8 mL water were added to
dissolve the substance, which was cooled to 0.degree. C. in an ice
bath. N-bromosuccinimide (NBS, 971 mg, 5.46 mmol) was added, and
the reaction was stirred for 40 minutes. After TLC detected the
reaction was complete, ethyl acetate was added to extract for 3-4
times, and the organic layers were combined, washed with saturated
solution of sodium carbonate and brine sequentially, concentrated
and purified by silica gel column chromatography to afford 312 mg
of a product, yield was 34.4%.
Step 2: Synthesis of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-amino-1,2,4-triazin-6-yl)-N-(4-(chl-
orodifluoromethoxy) phenyl)nicotinamide (11)
[0219] To a reaction flask were added compound 5 (200 mg, 0.392
mmol), compound 10 (102.3 mg, 0.588 mmol), Pd(dppf)Cl.sub.2 (32 mg,
0.02 mmol) and sodium carbonate (126 mg, 1.18 mmol), 2 mL glycol
dimethyl ether and 0.4 mL water were added, bubbled with nitrogen
gas for 10 minutes, and the reaction was heated to 120.degree. C.
in microwave and reacted for half an hour. After TLC detected the
reaction was complete, the reaction was concentrated, purified by
silica gel column chromatography to afford 105 mg of a product,
yield: 56.1%. LC-MS(APCI): m/z=478.2 (M+1).sup.+; .sup.1H NMR (400
MHz, DMSO) .delta. 10.25 (s, 1H), 8.80 (d, J=2.2 Hz, 1H), 8.42 (s,
1H), 8.14 (d, J=2.1 Hz, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.33 (d, J=9.0
Hz, 3H), 4.90 (d, J=3.2 Hz, 1H), 4.23 (s, 1H), 3.45-3.38 (m, 1H),
3.26 (d, J=10.8 Hz, 2H), 2.94 (d, J=11.1 Hz, 1H), 1.86 (dd, J=8.2,
5.3 Hz, 1H), 1.80-1.70 (m, 1H).
Example 5 Preparation of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1,2,4-triazin-6-yl)-N-(4-(chlorodiflu-
oromethoxy)phen yl)nicotinamide (Compound 12)
##STR00086##
[0221] To a reaction flask were added compound 11 (100 mg, 0.214
mmol) and isoamyl nitrite (75 mg, 0.64 mmol), 10 mL anhydrous
tetrahydrofuran was added to dissolve the substances, and the
reaction was heated under nitrogen protection to 65.degree. C. and
reacted for 3 hours. TLC detected the starting material was not
completely consumed, and isoamyl nitrite (75 mg, 0.64 mmol) was
additionally added, and the reaction was heated to 75.degree. C.
and reacted for 18 hours. After TLC detected the reaction was
complete, the reaction was concentrated to remove solvent, purified
by silica gel column chromatography to afford 22 mg of a product,
yield: 22.2%. LC-MS(APCI): m/z=463.3 (M+1).sup.+; .sup.1H NMR (400
MHz, DMSO) .delta. 10.32 (s, 1H), 9.78 (s, 1H), 9.11 (s, 1H), 8.89
(d, J=2.3 Hz, 1H), 8.35 (d, J=2.2 Hz, 1H), 7.90 (s, 2H), 7.34 (d,
J=8.8 Hz, 2H), 4.92 (d, J=3.1 Hz, 1H), 4.23 (s, 1H), 3.51 (s, 1H),
3.22 (dd, J=11.5, 4.3 Hz, 2H), 2.86 (d, J=11.4 Hz, 1H), 1.87 (s,
1H), 1.78 (s, 1H).
Example 6 Preparation of
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1,2,4-triazin-3-yl)-N-(4-(chlorodiflu-
oromethoxy)phen yl)nicotinamide (Compound 13)
##STR00087##
[0223] To a reaction flask were added compound 5 (200 mg, 0.392
mmol), 3-methylthio-1,2,4-triazine (149.3 mg, 1.176 mmol),
Pd(PPh.sub.3).sub.4 (23.1 mg, 0.02 mmol) and Copper iodide (7.6 mg,
0.04 mmol), 3 mL tetrahydrofuran was added, bubbled with nitrogen
gas for 10 minutes, and the reaction was heated to 120.degree. C.
and reacted for 1 hour. After TLC detected the reaction was
complete, the reaction was concentrated, purified by silica gel
column chromatography to afford 32 mg of a product, yield: 17.6%.
LC-MS(APCI): m/z=463.3 (M+1).sup.+; .sup.1H NMR (400 MHz, DMSO)
.delta. 10.34 (s, 1H), 9.41 (d, J=2.3 Hz, 1H), 8.97 (d, J=2.3 Hz,
1H), 8.89 (d, J=2.2 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 7.89 (d, J=9.1
Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 4.92 (d, J=3.1 Hz, 1H), 4.23 (s,
1H), 3.51 (s, 1H), 3.22 (dd, J=11.5, 4.3 Hz, 2H), 2.86 (d, J=11.4
Hz, 1H), 1.87 (s, 1H), 1.78 (s, 1H).
Example 7 Preparation of
(R)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodifluorometh-
oxy)phenyl)nicotinamide (Compound 17)
##STR00088##
[0224] Step 1: Synthesis of
(R)-6-(3-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)pheny-
l)nicotinamide (Compound 15)
[0225] To a reaction flask were added compound 14 (0.90 g, 2.19
mmol) and (R)-3-fluoropyrrolidine hydrochloride (330 mg, 2.63
mmol), 15 mL isopropyl alcohol, and DIPEA (621 mg, 4.82 mmol) were
added, and the reaction was heated to 140.degree. C. and stirred
for 2 hours. After cooling to room temperature, the reaction was
concentrated to remove solvent, purified by silica gel column
chromatography to afford 841 mg of a product, yield: 83%.
Step 2: Synthesis of
(R)-6-(3-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-N-(4-(chlorodi fluoromethoxy)phenyl)nicotinamide (Compound
16)
[0226] In a reaction flask were added compound 15 (628 mg, 1.35
mmol), bis(pinacolato)diboron (1.03 g, 4.06 mmol), palladium
acetate (10 mg, 0.041 mmol), Xphos (50 mg, 0.101 mmol) and
potassium phosphate (861 mg, 4.06 mmol), 20 mL anhydrous dioxane
was added to dissolve the substances, and the reaction was heated
to 60.degree. C. in microwave and reacted for 4 hours. TLC detected
the starting material was not completely consumed,
bis(pinacolato)diboron (1.03 g, 4.06 mmol) was additionally added
and then reacted at 60.degree. C. overnight. After TLC detected the
reaction was complete, the reaction was concentrated, purified by
silica gel column chromatography to afford 514.3 mg of a product,
yield: 75%.
Step 3: Synthesis of
(R)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodifluorometh-
oxy)phenyl)nicotinamide (Compound 17)
[0227] To a reaction flask were added compound 16 (200 mg, 0.372
mmol), 2-bromopyrazine (50 mg, 0.27 mmol), Pd(dppf)Cl.sub.2 (10 mg,
0.01 mmol) and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol
dimethyl ether and 0.9 mL water were added, bubbled with nitrogen
gas for 10 minutes, and the reaction was heated to 100.degree. C.
in microwave and reacted for half an hour. After TLC detected the
reaction was complete, the reaction was concentrated, purified by
silica gel column chromatography to afford 35 mg of a product,
yield: 20.3%. LC-MS(APCI): m/z=464.5 (M+1).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.78 (d, J=2.0 Hz, 1H), 8.73 (s, 1H), 8.64
(s, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.95 (s,
1H), 7.67 (d, J=8.9 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 5.28 (s, 1H),
5.14 (s, 1H), 3.70-3.57 (m, 1H), 3.52 (d, J=10.8 Hz, 1H), 3.42 (t,
J=11.6 Hz, 1H), 3.30 (t, J=9.5 Hz, 1H), 2.26-2.17 (m, 1H), 2.02
(dd, J=9.5, 3.8 Hz, 1H).
Example 8 Preparation of
(R)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridazine-3-yl)-N-(4-(chlorodifluorom-
ethoxy)phenyl)nicotinamide (Compound 18)
##STR00089##
[0229] Please refer to Example 7 step 3 for the specific synthetic
step, and the title product compound 18 was finally obtained,
LC-MS(APCI): m/z=464.8 (M+1).sup.+.
Example 9 Preparation of
(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodiflu-
oromethoxy)phenyl)nicotinamide (Compound 22)
##STR00090##
[0230] Step 1: Synthesis of
(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethox-
y)phenyl)nicotinamide (Compound 20)
[0231] To a reaction flask were added compound 19 (0.90 g, 2.19
mmol) and (R)-3-dimethylaminopyrrolidine hydrochloride (300 mg,
2.63 mmol), 15 mL isopropyl alcohol, and DIPEA (621 mg, 4.82 mmol)
were added, and the reaction was heated to 140.degree. C. and
stirred for 2 hours. After cooling to room temperature, the
reaction was concentrated to remove solvent, purified by silica gel
column chromatography to afford 1.06 g of a product, yield:
99%.
Step 2: Synthesis of
(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide
(Compound 21)
[0232] In a reaction flask were added compound 20 (633 mg, 1.3
mmol), bis(pinacolato)diboron (0.98 g, 3.89 mmol), palladium
acetate (25 mg, 0.039 mmol), Xphos (50 mg, 0.1 mmol) and potassium
phosphate (826 mg, 3.9 mmol), 20 mL anhydrous dioxane was added to
dissolve the substances, and the reaction was heated to 60.degree.
C. in microwave and reacted for 4 hours. TLC detected the starting
material was not completely consumed, bis(pinacolato)diboron (0.98
g, 3.89 mmol) was additionally added and reacted at 60.degree. C.
overnight. After TLC detected the reaction was complete, the
reaction was concentrated, purified by silica gel column
chromatography to afford 564 mg of a product, yield: 81%.
Step 3: Synthesis of
(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodiflu-
oromethoxy)phenyl)nicotinamide (Compound 22)
[0233] To a reaction flask were added compound 21 (100 mg, 0.186
mmol), 2-bromopyrazine (50 mg, 0.279 mmol), Pd(dppf)Cl.sub.2 (5 mg,
0.006 mmol) and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol
dimethyl ether and 0.9 mL water were added, bubbled with nitrogen
gas for 10 minutes, and the reaction was heated to 100.degree. C.
in microwave and reacted for half an hour. After TLC detected the
reaction was complete, the reaction was concentrated, purified by
silica gel column chromatography to afford 72 mg of a product,
yield: 79.1%. LC-MS(APCI): m/z=489.7 (M+1).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.77 (d, J=2.2 Hz, 1H), 8.71 (s, 1H), 8.63
(s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (s,
1H), 7.69 (d, J=9.0 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 3.45-3.36 (m,
1H), 3.27 (dt, J=20.1, 8.5 Hz, 3H), 2.75-2.66 (m, 1H), 2.23 (s,
6H), 2.06 (dd, J=11.1, 5.1 Hz, 1H), 1.85-1.74 (m, 1H).
Example 10 Preparation of
(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(pyridazine-3-yl)-N-(4-(chlorodi-
fluoromethoxy) phenyl)nicotinamide (Compound 23)
##STR00091##
[0235] Please refer to Example 9 step 3 for the specific synthetic
step, and the title product compound 23 was finally obtained,
LC-MS(APCI): m/z=489.9 (M+1).sup.+.
Example 11 Preparation of
6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodifluo-
romethoxy)phen yl)nicotinamide (Compound 29)
##STR00092##
[0236] Step 1: Synthesis of
3-hydroxy-4-fluoro-N-tert-butoxycarbonylpyrrolidine (Compound
25)
[0237] To a reaction flask were added
3-tert-butoxycarbonyl-6-oxa-3-azabicyclo[3.1.0]hexane (1.11 g, 6.0
mmol) and triethylamine trihydrofluoride (967.3 mg, 7.2 mmol), and
the reaction was heated to 100.degree. C. and stirred overnight.
After cooling to room temperature, the reaction was purified by
silica gel column chromatography to afford 881 mg of a product,
yield: 71.6%.
Step 2: Synthesis of 3-hydroxy-4-fluoropyrrolidine (Compound
26)
[0238] To a reaction flask were added compound 25 (881 mg, 4.29
mmol) and 4 M HCl in dioxane (27 ml, 107.4 mmol), and the reaction
was stirred at room temperature for 3-4 hours. After TLC detected
the reaction was complete, the reaction was concentrated to remove
solvent, which was used in the next step without purification.
Step 3: Synthesis of
6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy-
)phenyl)nicotinamide (Compound 27)
[0239] To a reaction flask were added compound 3 (883 mg, 2.15
mmol) and compound 26 (276.1 mg, 2.63 mmol), 15 mL isopropyl
alcohol was added, DIPEA (610 mg, 4.73 mmol) was added, and the
reaction was heated to 140.degree. C. and stirred for 2 hours.
After cooling to room temperature, the reaction was concentrated to
remove solvent, purified by silica gel column chromatography to
afford 896 mg of a product, yield: 87%.
Step 4: Synthesis of
6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide
(Compound 28)
[0240] In a reaction flask were added compound 27 (650 mg, 1.35
mmol), bis(pinacolato)diboron (1.03 g, 4.06 mmol), palladium
acetate (10 mg, 0.045 mmol), Xphos (50 mg, 0.1 mmol) and potassium
phosphate (861 mg, 4.06 mmol), 20 mL anhydrous dioxane was added to
dissolved the substances, and the reaction was heated to 60.degree.
C. in microwave and reacted for 4 hours. TLC detected the starting
material was not completely consumed, bis(pinacolato)diboron (1.03
g, 4.06 mmol) was additionally added and reacted at 60.degree. C.
overnight. After TLC detected the reaction was complete, it was
concentrated, purified by silica gel column chromatography to
afford 664 mg of a product, yield: 93.4%.
Step 5: Synthesis of
6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)-N-(4-(chlorodifluo-
romethoxy)phenyl)nicotinamide (Compound 29)
[0241] To a reaction flask were added compound 28 (100 mg, 0.189
mmol), 2-bromopyrazine (50 mg, 0.27 mmol), Pd(dppf)Cl.sub.2 (5 mg,
0.006 mmol) and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol
dimethyl ether and 0.9 mL water were added, bubbled with nitrogen
gas for 10 minutes, and the reaction was heated to 100.degree. C.
in microwave and reacted for half an hour. After TLC detected the
reaction was complete, the reaction was concentrated, purified by
silica gel column chromatography to afford 41 mg of a product,
yield: 45.3%. LC-MS(APCI): m/z=480.3 (M+1).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.68 (s, 2H), 8.58 (s, 1H), 8.52 (s, 1H),
8.30 (s, 1H), 8.03 (s, 1H), 7.68 (d, J=8.9 Hz, 2H), 7.22 (d, J=8.5
Hz, 2H), 4.91 (d, J=50.6 Hz, 1H), 4.35 (s, 1H), 3.68 (dd, J=36.4,
23.2 Hz, 2H), 3.37-3.28 (m, 1H), 3.15 (d, J=12.4 Hz, 1H).
Example 12 Preparation of
6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(pyridazine-3-yl)-N-(4-(chlorodif-
luoromethoxy)phenyl)nicotinamide (Compound 30)
##STR00093##
[0243] Please refer to Example 11 step 5 for the specific synthetic
step, and the title product compound 30 was finally obtained,
LC-MS(APCI): m/z=480.4 (M+1).sup.+.
Biological Activity Test
Example 13: Cytotoxicity Experiment
[0244] The inhibitory effect of the Example compounds on the
activity of Ba/F.sub.3 parent cell, Ba/F.sub.3 Bcr-Abl.sup.T315I
cell was examined.
[0245] Materials and reagents: RPMI-1640 medium (GIBCO, Cat. No.
A10491-01), fetal bovine serum (GIBCO, Cat. No. 10099141),
antibiotics (penicillin-streptomycin), IL-3 (PeproTech), puromycin;
Cell lines: Ba/F.sub.3 parental cell, Ba/F.sub.3 Bcr-Abl.sup.T315I
(purchased from American Standard Biological Collection Center,
ATCC), live cell assay kit CellTiter-Glo4 (Promega, Cat. No.
G7572), 96-well cell culture plate with black wall and transparent
flat bottom (Corning, Cat. No. 3340).
Experimental Procedures:
[0246] 1. Preparation of cell plate: Ba/F.sub.3 parental cells,
Ba/F.sub.3 Bcr-Abl.sup.T315I cells were seeded in 96-well plates,
and 8 ng/ml IL-3 was added to Ba/F.sub.3 parental cells. The cell
plates were placed in carbon dioxide culture and incubated
overnight.
[0247] 2. Preparation of test compounds: The test compounds were
dissolved in DMSO and subjected to a 3.16-fold gradient dilution in
triplicate, 9 concentrations were obtained, starting from the
concentration of 10 .mu.M.
[0248] 3. Treatment of Cells with compounds: Compounds at various
concentrations were transferred to cell plates. The cell plates
were incubated in a carbon dioxide incubator for 3 days.
[0249] 4. Detection: CellTiter-Glo4 reagent was added to the cell
plates, which were incubated for 30 minutes at room temperature to
stabilize the luminescence signal. Readings were performed using a
PerkinElmer Envision multi-label analyzer.
[0250] The results of in vitro inhibition of cell proliferation in
the examples are summarized in Table 1 below, wherein A represents
IC.sub.50.ltoreq.100 nM, B represents 100
nM<IC.sub.50.ltoreq.500 nM, C represents 500
nM<IC.sub.50.ltoreq.1000 nM, and D represents IC.sub.50>1000
nM.
TABLE-US-00001 TABLE 1 cytotoxic effects of the Example compounds
Ba/F.sub.3 parent cells Ba/F.sub.3 Bcr-Abl1.sup.T315I Example No.
IC.sub.50 IC.sub.50 Example 1 D A Example 2 D B Example 3 D C
Example 4 D B Example 5 D B Example 6 D D Example 7 D A
[0251] The experimental results show that, the compounds disclosed
herein exhibit relatively low inhibitory activity against
Ba/F.sub.3 cells that are related to drug side effects (IC.sub.50
greater than 1000 nM), and exhibit excellent inhibitory activity
against Ba/F.sub.3 Bcr-Abl.sup.T315I mutant cells (the optimal
IC.sub.50.ltoreq.100 nM). Therefore, the compounds disclosed herein
can be used as Bcr-Abl inhibitors for use in the treatment of
patients with tumor that is resistant to existing tyrosine kinase
inhibitor (TKI) treatment, with have good prospects, such as
chronic, blast, and accelerated phases of chronic myeloid leukemia
(CML) patients and chronic myeloid leukemia and acute lymphoblastic
leukemia patients with Philadelphia chromosome-positive
(Ph.sup.+).
[0252] Furthermore, the compounds disclosed herein also have an
excellent therapeutic index (obtained by dividing the IC.sub.50 of
the Ba/F.sub.3 parent cells by the IC.sub.50 of Ba/F.sub.3
Bcr-Abl.sup.T315I), for example, the compounds of Example 1 and 7
have a therapeutic index greater than 200.
Example 14: Pharmacokinetic Experiment in Rats
[0253] 9 Male Sprague-Dawley rats, 7-8 weeks old, weighted 210 g,
divided into 3 groups with 3 rats in each group, were intravenously
(2 mg/kg) or orally (20 mg/kg) given a single dose of compound, and
differences in pharmacokinetics of the rats were compared.
[0254] Rats were fed with a standard diet and water. Fasting began
16 hours before the test. The drugs were dissolved in PEG400 and
dimethyl sulfoxide. Blood was collected from the eyelids at a time
point of 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours,
6 hours, 8 hours, 12 hours, and 24 hours after administration.
[0255] Rats were briefly anesthetized after inhalation of ether,
and 300 .mu.L of blood samples were collected from the eyelids to
test tubes. There was 30 .mu.L of 1% heparin salt solution in the
test tube. The tubes were dried overnight at 60.degree. C. before
use. After the blood sample was collected at the last time point,
rats were anesthetized with ether and sacrificed.
[0256] Immediately after the collection, blood samples were
sufficiently mixed by gently inverting the tube at least 5 times,
and were placed on ice. Blood samples were centrifuged at 5000 rpm
for 5 minutes at 4.degree. C. to separate plasma from red blood
cells. 100 .mu.L of the plasma was pipetted into a clean plastic
centrifuge tube, marking the name of the compound and collecting
time. Plasma was stored at -80.degree. C. prior to analysis. The
concentration of the compounds disclosed herein in plasma was
determined by LC-MS/MS. Pharmacokinetic parameters were calculated
based on drug concentrations in plasma of each animal at different
time points.
[0257] In this experiment, ABL-001 was used as a positive control,
and the experimental results are shown in Table 2 below.
TABLE-US-00002 TABLE 2 PK parameters of Example compounds in rats
PK ABL-001 Example 1 Example 7 parameters IV PO IV PO IV PO
C.sub.max 10081.3 1766.2 4822.6 4329.4 4513.3 2369.0 (ng/mL)
AUC.sub.last 6900.6 13706.4 5702.8 38023.6 3736.3 23146.8 (h*ng/mL)
MRT.sub.INF.sub.--.sub.pred 1.12 5.52 1.37 5.43 1.14 5.43 (h)
Vz.sub.--.sub.pred 0.54 5.14 0.70 1.68 0.79 2.52 (L/kg)
Cl.sub.--.sub.pred 0.30 1.66 0.35 0.54 0.54 0.90 (L/kg) F(%) 19.86
66.68 61.95
[0258] The experimental results indicate that the compounds
disclosed herein have better pharmacokinetic properties. For
example, after orally administering the compounds of Example 1 and
7 and ABL-001 to rats, the compounds of Example 1 and 7 were found
to have better metabolic parameters--maximum plasma exposure
(C.sub.max), plasma exposure (AUC.sub.last), and oral availability
(F %).
Example 15: Pharmacodynamic Evaluation of BA/F3 (BCR-ABL.sup.T315I)
in Subcutaneous Tumor Model
[0259] Experimental Animals:
[0260] 32 NOD/SCID mice, female, 7-8 weeks old (age at tumor cell
inoculation), average body weight 21.8 g, were purchased from
Beijing Huafukang Bioscience Co., Inc, animal certificate number:
11401300068166. Feeding environment: SPF level.
[0261] Environmental Conditions of the Breeding Room for
Experimental Animals:
[0262] The experimental animals were kept in separate ventilated
boxes with constant temperature and humidity, wherein the
temperature of the breeding room was 22.3-24.5.degree. C., the
humidity was 51-58%, the ventilation is 10-20 times/hour, and 12
h/12 h day and night; rat full-price pellet feed, that was
sterilized with cobalt 60 radiation, was continuous supplied and
freely accessible without limitation, and drinking tap water (used
after high-pressure steam sterilization), was continuous supplied
in water bottle and freely accessible. The rat boxes are
polysulfone mouse boxes, which were used after autoclaving. The
specification of the boxes is 325 mm.times.210 mm.times.180 mm, the
bedding is autoclaved corn cob, 4 animals per box. The IACUC
approval number, experiment number, experiment starting time,
project leader, experimenter, animal source, group, animal number,
etc. were indicated on the cage; and experimental animals were
marked with ear tags.
[0263] Methods:
[0264] Each NOD/SCID mouse was subcutaneously inoculated with
5.times.10.sup.6 BA/F3 (BCR-ABL.sup.T315I) cells in the right
dorsal area, wherein the cells were resuspended in PBS (0.1
ml/mouse), to establish a subcutaneous tumor model. The tests were
divided into vehicle control group, positive control ABL-001 15
mg/kg group, the compound of Example 7 15 mg/kg group; 6 mice in
each group. The mice were dosed twice a day, vehicle control group
was administered for 15 days, positive control ABL-001 15 mg/kg was
administered for 19 days, and the compound of Example 7 15 mg/kg
group was administered for 21 days. The efficacy was evaluated
according to the relative tumor growth inhibition rate (TGI), and
the safety evaluation was performed according to the body weight
changes and deaths of the animals.
[0265] The experimental protocols for animal experiment disclosed
herein were reviewed and approved by the CrownBio IACUC committee.
During the experiment, the procedures of the animal experiment were
carried out according to the requirements of AAALAC. After tumor
inoculation, the effects of tumor growth and treatment on normal
animal behavior were routinely monitored, including experimental
animal activity, feeding and drinking, weight gain or loss, eye,
hair and other abnormalities. Abnormal clinical symptoms observed
during the experiment were recorded in the raw data. Mice body
weight and tumor size were measured and recorded three times per
week during the experiment. The mice were weighed before each
administration and administered according to the weight
thereof.
[0266] Relative tumor growth inhibition rate TGI (%):
[0267] TGI %=(1-T/C).times.100%. T/C % is the relative tumor
proliferation rate, that is, the percentage of tumor volume or
tumor weight of the treatment group and the control group at a
certain time point. T and C are the relative tumor volume (RTV) or
tumor weight (TW) of the treatment group and the control group at a
specific time point, respectively.
[0268] Statistical Analysis:
[0269] All experimental results were expressed as mean.+-.standard
error (x.+-.s), and the significant difference of the tumor volume
at 12 days after grouping between the control group and each
treatment group was evaluated with one-way ANOVA, and significant
difference of the tumor volume between the control group and each
treatment group or between each treatment group was evaluated using
Games-Howell (heterogeneity of variance), p<0.05 was considered
to be significant.
Experimental Results:
[0270] 1. Results of Anti-Tumor Effects in BA/F.sub.3
(BCR-ABL.sup.T315I) Subcutaneous Tumor Model
[0271] At day 15 after grouping, the average tumor volume of the
mice in the vehicle control group was 2492 mm.sup.3. The positive
drug ABL-001 at a dose of 15 mg/kg had a significant anti-tumor
effect (p value of 0.007) as compared with the vehicle control
group, with the average tumor volume of 1545 mm.sup.3, and the
relative tumor growth inhibition rate TGI of 36.5%. The test drug
of Example 7 produced a very significant anti-tumor effect at a
dose of 15 mg/kg (p value<0.001), with the average tumor volume
of 1145 mm.sup.3, and the relative tumor growth inhibition rate TGI
of 53.1%. Compared with the positive drug ABL-001 15 mg/kg group,
the test drug of Example 7 15 mg/kg group was significantly more
potent.
[0272] The tumor growth of each treatment group and control group
is shown in Table 3, Table 4 and FIG. 1.
TABLE-US-00003 TABLE 3 Changes in the tumor volume of mice in each
group versus the treatment time in the BA/F3(BCR-ABL.sup.T315I)
model Tumor volume (mm.sup.3) (x .+-. S) Group 1 Group 2 Group 3
vehicle control ABL-001 Example 7 Time (day) group 15 mg/kg 15
mg/kg At the day of grouping 160 .+-. 10 160 .+-. 12 160 .+-. 11 At
day 2 after grouping 235 .+-. 15 187 .+-. 22 175 .+-. 17 At day 5
after grouping 563 .+-. 40 368 .+-. 56 237 .+-. 27 At day 8 after
grouping 860 .+-. 59 553 .+-. 61 432 .+-. 24 At day 10 after 1186
.+-. 111 685 .+-. 68 590 .+-. 51 grouping At day 12 after 1610 .+-.
155 1011 .+-. 129 790 .+-. 64 grouping At day 15 after 2492 .+-.
178 1545 .+-. 241 1145 .+-. 116 grouping At day 17 after -- 1823
.+-. 292 1532 .+-. 129 grouping At day 19 after -- 2124 .+-. 274
1761 .+-. 212 grouping At day 22 after -- -- 2216 .+-. 126
grouping
TABLE-US-00004 TABLE 4 TGI values of each group in the
BA/F3(BCR-ABL.sup.T315I) model at day 15 after grouping Group 1
Group 2 Group 3 The experimental vehicle control ABL-001 Example 7
group group 15 mg/kg 15 mg/kg TGI -- 36.5 53.1
2. Results in the Safety Study in the BA/F3 (BCR-ABLT315I)
Subcutaneous Tumor Model
[0273] During the experiment, some mice in the ABL-001 15 mg/kg
group had a decrease in the body weight, and no mouse in the
Example 7 15 mg/kg group had a decrease in the body weight; at day
15 after grouping, the average body weight of the mice in the
ABL-001 15 mg/kg group decreased by 0.5%, and at day 22 after
grouping, the average body weight of the mice of in the Example 7
15 mg/kg group increased by 1.3%. Specifically, the changes in the
body weight after administration in each treatment group and the
control group are shown in FIG. 2. From the changes in the body
weight of the mice during the experiment, it can be concluded that
the safety of Example 7 is higher than that of ABL-001.
[0274] It is to be understood that the examples are merely
illustrative of the invention and are not intended to limit the
scope of the invention, and the experimental methods in which the
specific conditions are not indicated, are carried out generally in
accordance with conventional conditions, or in accordance with the
conditions suggested by the manufacturer. Parts and percentages are
parts by weight and percentage by weight unless otherwise
stated.
[0275] The above is a further detailed description of the present
disclosure in connection with the specific preferred embodiments,
and the specific embodiments of the present disclosure are not
limited to the description. It will be apparent to those skilled in
the art that the present disclosure may be practiced by making
various simple deduction and replacement, without departing from
the spirit and scope of the invention.
* * * * *