U.S. patent application number 15/713385 was filed with the patent office on 2018-01-18 for highly active anti-neoplastic and anti-proliferative agents.
This patent application is currently assigned to G1 Therapeutics, Inc.. The applicant listed for this patent is G1 Therapeutics, Inc.. Invention is credited to John Emerson Bisi, Patrick Joseph Roberts, Jay Copeland Strum, Francis Xavier Tavares.
Application Number | 20180015096 15/713385 |
Document ID | / |
Family ID | 51527866 |
Filed Date | 2018-01-18 |
United States Patent
Application |
20180015096 |
Kind Code |
A1 |
Strum; Jay Copeland ; et
al. |
January 18, 2018 |
HIGHLY ACTIVE ANTI-NEOPLASTIC AND ANTI-PROLIFERATIVE AGENTS
Abstract
This invention is in the area of improved compounds and methods
for treating selected cancers and hyperproliferative disorders.
Inventors: |
Strum; Jay Copeland;
(Hillsborough, NC) ; Bisi; John Emerson; (Apex,
NC) ; Roberts; Patrick Joseph; (Durham, NC) ;
Tavares; Francis Xavier; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
G1 Therapeutics, Inc. |
Research Triangle Park |
NC |
US |
|
|
Assignee: |
G1 Therapeutics, Inc.
Research Triangle Park
NC
|
Family ID: |
51527866 |
Appl. No.: |
15/713385 |
Filed: |
September 22, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15201286 |
Jul 1, 2016 |
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15713385 |
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14213784 |
Mar 14, 2014 |
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15201286 |
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61949795 |
Mar 7, 2014 |
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61911354 |
Dec 3, 2013 |
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61861374 |
Aug 1, 2013 |
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61798772 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/06 20180101;
A61P 19/02 20180101; A61K 47/6803 20170801; A61P 37/02 20180101;
A61P 17/10 20180101; A61P 35/00 20180101; C07D 487/14 20130101;
A61K 51/0459 20130101; A61P 1/04 20180101; A61K 31/5377 20130101;
A61K 47/6867 20170801; A61K 51/0468 20130101; A61P 35/02 20180101;
A61K 31/529 20130101; A61P 37/06 20180101; A61P 43/00 20180101;
A61K 31/527 20130101; A61K 47/545 20170801; A61P 17/02
20180101 |
International
Class: |
A61K 31/527 20060101
A61K031/527; A61K 31/529 20060101 A61K031/529; A61K 31/5377
20060101 A61K031/5377; C07D 487/14 20060101 C07D487/14; A61K 51/04
20060101 A61K051/04 |
Goverment Interests
GOVERNMENT INTEREST
[0002] The U.S. Government has rights in this invention by virtue
of support under Grant No. 5R44AI084284 awarded by the National
Institute of Allergy and infectious Diseases.
Claims
1. A method for the treatment of psoriasis that comprises
administering to a host in need thereof an effective amount of a
compound selected from: ##STR00325## or a pharmaceutically
acceptable salt thereof.
2. The method of claim 1, wherein the host is human.
3. The method of claim 2, wherein the compound is ##STR00326## or a
pharmaceutically acceptable salt thereof.
4. The method of claim 2, wherein the compound is ##STR00327## or a
pharmaceutically acceptable salt thereof.
5. The method of claim 4 wherein the compound is ##STR00328## or a
pharmaceutically acceptable salt thereof.
6. The method of claim 2, wherein the compound is ##STR00329## or a
pharmaceutically acceptable salt thereof.
7. The method of claim 2, wherein the compound is ##STR00330## or a
pharmaceutically acceptable salt thereof.
8. The method of claim 2, wherein the compound is ##STR00331## or a
pharmaceutically acceptable salt thereof.
9. The method of claim 2, wherein the compound is administered
topically.
10. The method of claim 2, wherein the compound is administered in
combination with a second active agent.
11. A method for the treatment of atopic dermatitis that comprises
administering to a host in need thereof an effective amount of a
compound selected from: ##STR00332## or a pharmaceutically
acceptable salt thereof.
12. The method of claim 11, wherein the host is human.
13. The method of claim 12, wherein the compound is ##STR00333## or
a pharmaceutically acceptable salt thereof.
14. The method of claim 12, wherein the compound is ##STR00334## or
a pharmaceutically acceptable salt thereof.
15. The method of claim 12, wherein the compound is ##STR00335## or
a pharmaceutically acceptable salt thereof.
16. The method of claim 12, wherein the compound is ##STR00336## or
a pharmaceutically acceptable salt thereof.
17. The method of claim 12, wherein the compound is ##STR00337## or
a pharmaceutically acceptable salt thereof.
18. The method of claim 12, wherein the compound is ##STR00338## or
a pharmaceutically acceptable salt thereof.
19. The method of claim 12, wherein the compound is administered
topically.
20. The method of claim 12, wherein the compound is administered in
combination with a second active agent.
Description
RELATED APPLICATIONS
[0001] This application is continuation of U.S. application Ser.
No. 15/201,286, filed Jul. 1, 2016; which is a divisional of U.S.
application Ser. No. 14/213,784, filed on Mar. 14, 2014; which
claims priority to provisional U.S. Application No. 61/798,772,
filed Mar. 15, 2013, provisional U.S. Application No. 61/861,374,
filed on Aug. 1, 2013, provisional U.S. Application 61/911,354,
filed on Dec. 3, 2013, and provisional U.S. Application No.
61/949,795, filed on Mar. 7, 2014. The entirety of each of these
applications is hereby incorporated by reference for all
purposes.
FIELD
[0003] This invention is in the area of improved compounds and
methods for treating selected cancers and hyperproliferative
disorders.
BACKGROUND
[0004] Cancer is a group of diseases categorized by uncontrolled
growth and spread. In the United States in 2013, approximately 1.6
million new cases of cancer were expected to be diagnosed, and over
500,000 people in the U.S. were expected to die from the disease,
which is about 1,600 per day. Cancer Facts and Figures 2013,
American Cancer Society
[0005] All cancers involve a malfunction of genes that control cell
growth and division. Although all cancers share that
characteristic, cancers vary greatly according to tissue or cell
type, which specific genes are down or upregulated, which aspect of
the cell cycle is implicated, whether and which cell surface
receptors accelerate growth, types of altered metabolism, and which
drugs the cancer cells respond to with a therapeutically acceptable
effect. Therefore, one of the key goals of cancer research is to
identify drugs that show high activity against certain specific
target cancers. Non-cancerous cellular hyperproliferation presents
a similar problem.
[0006] Lymphoid neoplasms are broadly categorized into precursor
lymphoid neoplasms and mature T-cell, B-cell or natural killer cell
(NK) neoplasms. Chronic leukemias are those likely to exhibit
primary manifestations in blood and bone marrow, whereas lymphomas
are typically found in extramedullary sites, with secondary events
in the blood or bone. Some mature B-cell disorders exhibit dominant
immunosecretory manifestations.
[0007] Over 79,000 new cases of lymphoma were estimated in 2013.
Lymphoma is a cancer of lymphocytes, which are a type of white
blood cell. Lymphomas are categorized as Hodgkin or non-Hodgkin.
Over 48,000 new cases of leukemias were expected in 2013. They are
classified into four main groups according to cell type and rate of
growth: acute lymphocytic (ALL), chronic lymphocytic (CLL), acute
myeloid (AML), and chronic myeloid (CML).
[0008] WO 2012/061156 filed by Francis Tavares and assigned to G1
Therapeutics describes CDK inhibitors. Also see WO 2013/148748
filed by Francis Tavares and assigned to Gi Therapeutics, directed
to Lactam Kinase Inhibitors.
[0009] Accordingly, there is an ongoing need for highly active
compounds against specific cancers and cellular
hyperproliferation.
SUMMARY OF THE INVENTION
[0010] The present invention includes the use of an effective
amount of a compound described herein, or its pharmaceutically
acceptable salt, prodrug, or isotopic variant, optionally in a
pharmaceutical composition, to treat a host, typically a human,
with a selected cancer, tumor, hyperproliferative condition, or an
inflammatory or immune disorder as described further herein. Some
of the disclosed compounds are highly active against T-cell
proliferation and/or B-cell proliferation and/or NK-cell
proliferation.
[0011] Disorders include, but are not limited to those involving
T-cell proliferation, maintenance of peripheral tolerance, those
involving the inappropriate differentiation of Th2 cells,
maturation or survival of T and/or B cells, natural killer cell
development, or regulation of immunoglobulin class switching in B
cells.
[0012] In one embodiment, a compound/method of the present
invention is used in combination with another therapy to treat the
T, B or NK abnormal cellular proliferation, cancer or disorder. The
second therapy can be an immunotherapy. For example, the compound
can be conjugated to an antibody, radioactive agent or other
targeting agent that directs the compound to the diseased or
abnormally proliferating cell. In another embodiment, the compound
is used in combination with another pharmaceutical or a biologic
agent (for example an antibody) to increase the efficacy of
treatment with a combined or a synergistic approach. In an
embodiment, the compound can be used with T-cell vaccination, which
typically involves immunization with inactivated autoreactive T
cells to eliminate a pathogenic autoreactive T cell population. In
another embodiment, the compound is used in combination with a
bispecific T-cell Engager (BiTE), which is an antibody designed to
simultaneously bind to specific antigens on endogenous T cells and
malignant cells, linking the two types of cells.
[0013] In summary, the present invention includes the following
features: [0014] A) Selective compounds, methods, and compositions
for use as chemotherapeutics for the treatment of T-cell cancers
and other T-cell mediated disorders; [0015] B) Selective compounds,
methods, and composition for use as chemotherapeutics for the
treatment of B-cell cancers and other B-cell mediated disorders;
[0016] C) Selective compounds, methods, and compositions for use as
immunosuppressants and anti-inflammatory agents; [0017] D)
Selective compounds, methods and compositions for use against
auto-immune disorders; [0018] E) The compounds of Formulas I, II,
III, IV, and V as described herein, and pharmaceutically acceptable
compositions, salts, and prodrugs thereof, for use in medical
therapy; [0019] F) The compounds of Formulas I, III, IV, and V as
described herein, and pharmaceutically acceptable compositions,
salts, and prodrugs thereof, for use against T-cell cancers and
other T-cell mediated disorders; [0020] G) The compounds of
Formulas I, II, III, IV, and V as described herein, and
pharmaceutically acceptable compositions, salts, and prodrugs
thereof, for use against B-cell cancers and B-cell mediated
disorders; [0021] H) The compounds of Formulas I, II, III, IV, and
V as described herein, and pharmaceutically acceptable
compositions, salts, and prodrugs thereof, for use in the treatment
of immune disorders or inflammatory conditions; [0022] I) The
compounds of Formulas I, II, III, IV, and V as described herein,
and pharmaceutically acceptable compositions, salts, and prodrugs
thereof, for use in the treatment of autoimmune disorders; [0023]
J) Processes for the preparation of therapeutic products that
contain an effective amount of the compounds of Formulas I, II,
III, IV, and V as described herein; [0024] K) A method for
manufacturing a medicament of Formulas I, II, III, IV, and V
intended for therapeutic use; [0025] L) Selective compounds,
methods, and compositions for use of the compounds of Formulas I,
II, III, IV, and V in combination with one or more other
therapeutic agents; and [0026] M) The compounds of Formulas I, II,
III, IV, and V as described herein, and pharmaceutically acceptable
compositions, salts, and prodrugs thereof, for use in combination
with another one or more additional therapeutic agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIGS. 1-3 illustrate exemplary embodiments of R.sup.2 of
compounds useful in the described invention.
[0028] FIGS. 4A-4C, 5A-5D, 6A-6C, 7A-B, and 8A-8F illustrate
exemplary embodiments of the core structure of the compounds useful
in the described invention.
[0029] FIG. 9 is a graph showing the cellular proliferation of
SupT1 cells (human T-cell lymphoblastic leukemia) treated with
PD0332991 (circles) or Compound T (Table 1; squares). The SupT1
cells were seeded in Costar (Tewksbury, Mass.) 3093 96 well tissue
culture treated white walled/clear bottom plates. A nine point dose
response dilution series from 10 uM to 1 nM was performed and cell
viability was determined after four days as indicated using the
CellTiter-Glo.RTM. assay (CTG; Promega, Madison, Wis., United
States of America.) following the manufacturer's recommendations.
Plates were read on a BioTek (Winooski, Vt.) Syngergy2 multi-mode
plate reader. The Relative Light Units (RLU) were plotted as a
result of variable molar concentration and data was analyzed using
Graphpad (LaJolla, Calif.) Prism 5 statistical software to
determine the IC50 for each compound.
[0030] FIG. 10 is a graph showing the cellular proliferation of
SupT1 cells (human T-cell lymphoblastic leukemia) treated with
Compound Q (Table 1; circles) or Compound GG (Table 1; squares).
The SupT1 cells were seeded in Costar (Tewksbury, Mass.) 3093 96
well tissue culture treated white walled/clear bottom plates. A
nine point dose response dilution series from 10 uM to 1 nM was
performed and cell viability was determined after four days as
indicated using the CellTiter-Glo.RTM. assay (CTG; Promega,
Madison, Wis. , United States of America) following the
manufacturer's recommendations. Plates were read on a BioTek
(Winooski, Vt.) Syngergy2 multi-mode plate reader. The Relative
Light Units (RLU) were plotted as a result of variable molar
concentration and data was analyzed using Graphpad (Lafolla,
Calif.) Prism 5 statistical software to determine the IC50 for each
compound.
DETAILED DESCRIPTION
[0031] The present invention includes compounds and methods that
are highly active against certain cancers and hyperproliferative
conditions. In particular, compounds and methods are provided to
treat cancers and proliferative disorders of hematopoietic cells,
and in particular, T cells, B cells and NK. cells. Selected active
compounds are also useful to treat inflammatory disorders,
auto-immune conditions, and immune disorders.
[0032] I. Active Compounds
[0033] In one embodiment, the invention is directed to compounds or
the use of such compounds of Formula I, II, III, IV, or V:
##STR00001##
or a pharmaceutically acceptable salt thereof; [0034] wherein:
[0035] Z is --(CH.sub.2).sub.x-- wherein x is 1, 2, 3 or 4 or
--O--(CH.sub.2).sub.z wherein z is 2, 3 or 4; [0036] each X is
independently CH or N; [0037] each X' is independently, CH or N;
[0038] X'' is independently CH.sub.2, S or NH, arranged such that
the moiety is a stable 5-membered ring; [0039] R, R.sup.8, and
R.sup.11 are independently H, C.sub.1-C.sub.3 alkyl or haloalkyl,
cycloalkyl or cycloalkyl containing one or more heteroatoms
selected from N, O or S; -(alkylene)m-C.sub.3-C.sub.8 cycloalkyl,
-(alkylene).sub.m-aryl, -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(0)-NR.sup.3R.sup.4;
-(alkylene).sub.m-0-R.sup.5, -(alkylene).sub.m-S(0).sub.n-R.sup.5,
or -(alkylene).sub.m-S(0)n-NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R groups as
allowed by valance, and [0040] wherein two R.sup.x groups bound to
the same or adjacent atoms may optionally combine to form a ring;
[0041] each R.sup.1 is independently aryl, alkyl, cycloalkyl or
haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl
groups optionally includes O or N heteroatoms in place of a carbon
in the chain and two R.sup.1's on adjacent ring atoms or on the
same ring atom together with the ring atom(s) to which they are
attached optionally form a 3-8-membered cycle; [0042] y is 0, 1, 2,
3 or 4; [0043] R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.mC(O)NR.sup.3R.sup.4;
-(alkylene).sub.m-C(O)--O-alkyl; -(alkylene).sub.m-O--R.sup.5,
-(alkylene).sub.m-S(O).sub.n--R.sup.5, or
-(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.x groups bound
to the same or adjacent atom may optionally combine to form a ring
and wherein In is 0 or 1 and n is 0, 1 or 2; [0044] R.sup.3 and
R.sup.4 at each occurrence are independently: [0045] (i) hydrogen
or [0046] (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, aryl alkyl, or heteroarylalkyl
any of which may be optionally independently substituted with one
or more IV groups as allowed by valance, and wherein two R.sup.x
groups bound to the same or adjacent atom may optionally combine to
form a ring; or R.sup.3 and together with the nitrogen atom to
which they are attached may combine to form a heterocyclo ring
optionally' independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.x groups bound
to the same or adjacent atom may optionally combine to form a ring;
[0047] R.sup.5 and R.sup.5* at each occurrence is: [0048] (i)
hydrogen or [0049] (ii) alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl,
arylalkyl, or heteroarylalkyl any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valance; [0050] R.sup.x at each occurrence is
independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,
alkylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,
-(alkylene).sub.m-OR.sup.5, -(alkylene).sub.m-O-alkylene-OR.sup.5,
-(alkylene).sub.m-S(O).sub.nSR.sup.5,
-(alkylene).sub.m-NR.sup.3R.sup.4, -(alkylene).sub.m-CN,
-(alkylene).sub.m-C(O)--R.sup.5, -(alkylene).sub.mC(S)--R.sup.5,
-(alkylene).sub.m-C(O)--OR.sup.5,
-(alkylene).sub.m-O--C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--OR.sup.5,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--C(S)--R.sup.5,
-(alkylene).sub.m-O--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-O--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--OR.sup.5)
-(alkylene)m-N(R.sup.3) C(S)--OR.sup.5, or
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5, wherein: [0051]
said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, and heterocycloalkyl groups may be further
independently substituted with one or more -(alkylene).sub.m -CN,
-(alkylene).sub.m-OR.sup.5*;
-(alkylene).sub.m-S(O).sub.n--R.sup.5*,
-(alkylene).sub.m-NR.sup.3*R.sup.4*,
-(alkylene).sub.m-C(O)--R.sup.5*,
-(alkylene).sub.m-C(.dbd.S)R.sup.S*,
-(alkylene).sub.m-C(.dbd.O)OR.sup.5*,
-(alkylene).sub.m-OC(.dbd.O)R.sup.5*
-(alkylene).sub.m-C(S)--OR.sup.5*,
-(alkylene).sub.m-C(O)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-C(S)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)C(O)--NR.sup.3*R.sup.4*
-(alkylene).sub.m-N(R.sup.3*)--C(S)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--C(O)--R.sup.5*,
-(alkylene).sub.m-N(R.sup.3*)--C(S)--R.sup.5*,
-(alkylene).sub.m-OC(O)--NR.sup.3*R.sup.4*
-(alkylene).sub.m-O--C(S)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-SO.sub.2--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--C(O)--OR.sup.5*
-(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--NR.sup.3*R.sup.4*
-(alkylene).sub.m-N(R.sup.3*)--C(O)--OR.sup.5*,
-(alkylene).sub.m-N(R.sup.3*)--C(S)--OR.sup.5*, or
-(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--R.sup.5*, [0052] n is 0, 1
or 2, and [0053] m is 0 or 1; [0054] R.sup.3* and R.sup.4* at each
occurrence are independently: [0055] (i) hydrogen or [0056] (ii)
alkyl, alkenyl, alkynylcycloalkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl
any of which may be optionally independently substituted with one
or more R.sup.x groups as allowed by valance; or R.sup.3* and
R.sup.4* together with the nitrogen atom to which they are attached
may combine to form a heterocyclo ring optionally independently
substituted with one or more R.sup.x groups as allowed by valance;
and [0057] R.sup.6 is II or lower alkyl, -(alkylene)m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(0)-NR.sup.3R.sup.4;
-(alkylene).sub.m-0-R.sup.5, -(alkylene).sub.m-S(0).sub.n-R.sup.5,
or -(alkylene).sub.m-S(0).sub.n-NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.x groups bound
to the same or adjacent atoms may optionally combine to form a
ring; and [0058] R.sup.10 is (i) NHR.sup.A, wherein R.sup.A is
unsubstituted or substituted C.sub.1-C.sub.8 alkyl,
cycloalkylalkyl, or -TT-RR, C.sub.1-C.sub.8 cycloalkyl or
cycloalkyl containing one or more heteroatoms selected from N, O,
and S; TT is an unsubstituted or substituted C.sub.1-C.sub.8 alkyl
or C.sub.3-C.sub.8 cycloalkyl linker; and RR is a hydroxyl,
unsubstituted or substituted C.sub.1-C.sub.6 alkoxy, amino,
unsubstituted or substituted C.sub.1-C.sub.6 alkylamino,
unsubstituted or substituted di-C.sub.1-C.sub.6 alkylamino,
unsubstituted or substituted C.sub.6-C.sub.10 aryl, unsubstituted
or substituted heteroaryl comprising one or two 5- or 6-member
rings and 1-4 heteroatoms selected from N, O and S, unsubstituted
or substituted C.sub.3-C.sub.10 carbocycle, or unsubstituted or
substituted heterocycle comprising one or two 5- or 6-member rings
and 1-4 heteroatoms selected from N, O and S; or (ii)
--C(O)--R.sup.12 or --C(O)O--R.sup.13, wherein R.sup.12 is
NHR.sup.A or R.sup.A and R.sup.13 is R.sup.A; [0059] or a
pharmaceutically acceptable salt, prodrug or isotopic variant, for
example, partically or fully deuterated form thereof.
[0060] In some aspects, the compound is of Formula I or Formula II
and R.sup.6 is absent.
[0061] In some aspects, the compound is of Formula III:
##STR00002##
and the variables are as defined for compounds of Formulae I and II
and pharmaceutically acceptable salts thereof.
[0062] In some aspects, R.sup.x is not further substituted.
[0063] In some aspects, R.sup.2 is -(alkylene).sub.mheterocyclo,
-(alkylene).sub.mheteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4;
-(alkylene).sub.m-O--R.sup.5,
-(alkylene).sub.m-S(O).sub.n--R.sup.5, or
-(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.x groups bound
to the same or adjacent atom may optionally combine to form a ring
and wherein m is 0 or 1 and n is 0, 1 or 2.
[0064] In some aspects, R.sup.8 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0065] In some aspects, R is hydrogen or C.sub.1-C.sub.3 alkyl.
[0066] In some aspects, R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--O-alkyl or -(alkylene).sub.m-OR.sup.5 any
of which may be optionally independently substituted with one or
more R.sup.x groups as allowed by valance, and wherein two R.sup.x
groups bound to the same or adjacent atom may optionally combine to
form a ring.
[0067] In some aspects, R.sup.2 is -(alkylene).sub.mheterocyclo,
-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--O-alkyl or (alkylene).sub.m--OR.sup.5
without further substitution.
[0068] In some aspects, m in R.sup.2 is 1. In a further aspect, the
alkylene in R.sup.2 is methylene.
[0069] In some aspects, R.sup.2 is
##STR00003##
wherein: R.sup.2* is a bond, alkylene,
-(alkylene).sub.m-O-(alkylene).sub.m-,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-,
-(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and
-(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is
independently 0 or 1; [0070] P is a 4- to 8-membered mono- or
bicyclic saturated heterocyclyl group; [0071] each R.sup.x1 is
independently
-(alkylene).sub.m-(C(O)).sub.m-(alkylene).sub.m-(N(R.sup.N)).sub.m-(alkyl-
).sub.m wherein each m is independently 0 or 1 provided at least
one m is 1, --(C(O))--O-alkyl, -(alkylene).sub.m-cycloalkyl wherein
m is 0 or 1, --N(R.sup.N)-cycloalkyl, --C(O)-cycloalkyl,
-(alkylene).sub.m-heterocyclyl wherein in is 0 or 1, or
--N(R.sup.N)-heterocyclyl, --C(O)-heterocyclyl,
--S(O).sub.2-(alkylene).sub.m wherein m is 1 or 2, wherein: [0072]
R.sup.N is H, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.6
heteroalkyl, and [0073] wherein two R.sup.x1 can, together with the
atoms to which they attach on P, which may be the same atom, form a
ring; and [0074] t is 0, 1 or 2.
[0075] In some aspects, each R.sup.x1 is only optionally
substituted by unsubstituted alkyl, halogen or hydroxy.
[0076] In some aspects, W.sup.i is hydrogen or unsubstituted
C.sub.1-C.sub.4 alkyl.
[0077] In some aspects, at least one R.sup.x1 is
-(alkylene).sub.m-hetrocyclyl wherein m is 0 or 1.
[0078] In some aspects, R.sup.2 is
##STR00004##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0079] In some aspects, R.sup.2 is
##STR00005##
[0080] In some aspects, R.sup.2 is
##STR00006##
[0081] In some aspects, R.sup.2 is
##STR00007##
wherein: [0082] R.sup.2* is a bond, alkylene,
-(alkylene).sub.m-O-(alkylene).sub.m-,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-,
-(alkyllene).sub.m-S(O).sub.2-(alkyllene).sub.m- and
-(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is
independently 0 or 1; [0083] P is a 4- to 8-membered mono- or
bicyclic saturated heterocyclyl group; [0084] P1 is a 4- to
6-membered monocyclic saturated heterocyclyl group; [0085] each
R.sup.x2 is independently hydrogen or alkyl; and [0086] s is 0, 1
or 2,
[0087] In some aspects, R.sup.2 is
##STR00008##
[0088] In some aspects, P1 includes at least one nitrogen.
[0089] In some aspects, any alkylene in R.sup.2* in any previous
aspect is not further substituted.
[0090] In some aspects, R.sup.2 is selected from the structures
depicted in FIGS. 1-3.
[0091] In some aspects, R.sup.2 is
##STR00009##
[0092] In some aspects, the compound has general Formula I and more
specifically one of the general structures in FIGS. 4-8 wherein the
variables are as previously defined.
[0093] In some aspects, the compound has general Formula Ia:
##STR00010##
wherein R', R.sup.2, R and y are as previously defined.
[0094] In some embodiments, the compound has Formula Ia and R is
alkyl.
[0095] In some embodiments, the compound has Formula Ia and R is
H.
[0096] In some embodiments, the compound has Formula Ia and R.sup.2
is
##STR00011##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0097] In some embodiments, the compound has Formula Ia and R.sup.2
is
##STR00012##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or unsubstituted
C.sub.1-C.sub.4 alkyl and R.sup.2* is as previously defined.
[0098] In some embodiments, the compound has Formula Ib:
##STR00013##
wherein R.sup.2 and R are as previously defined.
[0099] In some embodiments, the compound has Formula Ib and R is
alkyl
[0100] In some embodiments, the compound has Formula Ib and R is
H.
[0101] In some embodiments, the compound has Formula Ib and R.sup.2
is
##STR00014##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0102] In some embodiments, the compound has Formula Ib and R.sup.2
is
##STR00015##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.xl is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2* is as previously defined.
[0103] In some embodiments, the compound has Formula Ic:
##STR00016##
wherein R.sup.2 and R are as previously defined.
[0104] In some embodiments, the compound has Formula Ic and R is
alkyl.
[0105] In some embodiments, the compound has Formula Ic and R is
H.
[0106] In some embodiments, the compound has Formula Ic and R.sup.2
is
##STR00017##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0107] In some embodiments, the compound has Formula Ic and R.sup.2
is
##STR00018##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2 is as previously defined.
[0108] In some embodiments, the compound has Formula Id:
##STR00019##
wherein R.sup.2 and R are as previously defined.
[0109] In some embodiments, the compound has Formula Id and R is
alkyl.
[0110] In some embodiments, the compound has Formula Id and R is
H.
[0111] In some embodiments, the compound has Formula Id and R.sup.2
is
##STR00020##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0112] In some embodiments, the compound has Formula Id and R.sup.2
is
##STR00021##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2* is as previously defined.
[0113] In some embodiments, the compound has Formula Ie:
##STR00022##
[0114] In some embodiments, the compound has Formula Ie and R is
alkyl.
[0115] In some embodiments, the compound has Formula Ie and R is
H.
[0116] In some embodiments, the compound has Formula Ie and R.sup.2
is
##STR00023##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyciyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0117] In some embodiments, the compound has Formula Ie and R.sup.2
is
##STR00024##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2* is as previously defined.
[0118] In some embodiments, the compound has Formula If:
##STR00025##
[0119] In some embodiments, the compound has Formula If and R is
alkyl.
[0120] In some embodiments, the compound has Formula If and R is
H.
[0121] In some embodiments, the compound has Formula If and R.sup.2
is
##STR00026##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0122] In some embodiments, the compound has Formula If and R.sup.2
is
##STR00027##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2 is as previously defined.
[0123] In some embodiments, the compound has Formula Ig:
##STR00028##
[0124] In some embodiments, the compound has Formula Ig and R is
alkyl.
[0125] In some embodiments, the compound has Formula Ig and R is
H.
[0126] In some embodiments, the compound has Formula Ig and R.sup.2
is
##STR00029##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated.
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0127] In some embodiments, the compound has Formula Ig and R.sup.2
is
##STR00030##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2* is as previously defined.
[0128] In some embodiments, the compound has Formula Ih:
##STR00031##
[0129] In some embodiments, the compound has Formula Ih and R is
alkyl.
[0130] In some embodiments, the compound has Formula Ih and R is
H.
[0131] In some embodiments, the compound has Formula Ih and R.sup.2
is
##STR00032##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0132] In some embodiments, the compound has Formula Ih and R.sup.2
is
##STR00033##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2 is as previously defined.
[0133] In some embodiments, the compound has Formula Ii:
##STR00034##
[0134] In some embodiments, the compound has Formula Ii and R is
alkyl.
[0135] In some embodiments, the compound has Formula Ii and R is
H.
[0136] In some embodiments, the compound has Formula Ii and R.sup.2
is
##STR00035##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated.
heterocyclyl group and R.sup.28, R.sup.x1 and t are as previously
defined.
[0137] In some embodiments, the compound has Formula Ii and R.sup.2
is
##STR00036##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4 alkyl
and R.sup.2* is as previously defined.
[0138] In some embodiments, the compound has Formula Ij:
##STR00037##
[0139] In some embodiments, the compound has Formula Ij and R is
alkyl.
[0140] In some embodiments, the compound has Formula Ij and R is
H.
[0141] In some embodiments, the compound has Formula Ij and R.sup.2
is
##STR00038##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0142] In some embodiments, the compound has Formula Ij and R.sup.2
is
##STR00039##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated.
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4
alkyl.
[0143] In some embodiments, the compound has Formula Ij and R is H,
and both X are N.
[0144] In some embodiments, the compound has the structure:
##STR00040##
[0145] In some embodiments, the compound has Formula Ik and R.sup.2
is
##STR00041##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0146] In some embodiments, the compound has Formula Ik and R.sup.2
is
##STR00042##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4
alkyl.
[0147] In some embodiments, the compound has Formula Il:
##STR00043##
[0148] In sonic embodiments, the compound has Formula Il and
R.sup.2 is
##STR00044##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0149] In some embodiments, the compound has Formula Il and R.sup.2
is
##STR00045##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4
alkyl.
[0150] In some embodiments, the compound has Formula Im:
##STR00046##
[0151] In some embodiments, the compound has Formula Im and R.sup.2
is
##STR00047##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0152] In some embodiments, the compound has Formula Im and R.sup.2
is
##STR00048##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4
alkyl.
[0153] In some embodiments, the compound has Formula IIa:
##STR00049##
[0154] In some embodiments, the compound has Formula IIa and
R.sup.2 is
##STR00050##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0155] In some embodiments, the compound has Formula IIa and
R.sup.2 is
##STR00051##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4
alkyl.
[0156] In some embodiments, the compound has Formula IIb:
##STR00052##
[0157] In some embodiments, the compound has Formula Im and R.sup.2
is
##STR00053##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0158] In some embodiments, the compound has Formula Im and R.sup.2
is
##STR00054##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or C.sub.1-C.sub.4
alkyl.
[0159] In some aspects, the active compound is:
##STR00055##
Isotopic Substitution
[0160] The present invention includes compounds and the use of
compounds with desired isotopic substitutions of atoms, at amounts
above the natural abundance of the isotope, i.e., enriched.
Isotopes are atoms having the same atomic number but different mass
numbers, i.e., the same number of protons but a different number of
neutrons. By way of general example and without limitation,
isotopes of hydrogen, for example, deuterium (.sup.2H) and tritium
(.sup.3H) may be used any-where in described structures.
Alternatively or in addition, isotopes of carbon, e.g., .sup.13C
and may be used. A preferred isotopic substitution is deuterium for
hydrogen at one or more locations on the molecule to improve the
performance of the drug. The deuterium can be bound in a location
of bond breakage during metabolism (an .alpha.-deuterium kinetic
isotope effect) or next to or near the site of bond breakage (a
.beta.-deuterium kinetic isotope effect).
[0161] Substitution with isotopes such as deuterium can afford
certain therapeutic advantages resulting from greater metabolic
stability, such as, for example, increased in vivo half-life or
reduced dosage requirements. Substitution of deuterium for hydrogen
at a site of metabolic break down can reduce the rate of or
eliminate the metabolism at that bond. At any position of the
compound that a hydrogen atom may be present, the hydrogen atom can
be any isotope of hydrogen, including protium (.sup.1H) deuterium
(.sup.2H) and tritium (.sup.3H). Thus, reference herein to a
compound encompasses all potential isotopic forms unless the
context clearly dictates otherwise.
[0162] The term "isotopically-labeled" analog refers to an analog
that is a "deuterated analog", a ".sup.13C-labeled analog," or a
"deuterated/.sup.13C-labeled analog," The term "deuterated analog"
means a compound described herein, whereby a H-isotope, i.e.,
hydrogen/protium (.sup.1H), is substituted by a H-isotope, i.e.,
deuterium (.sup.2H). Deuterium substitution can be partial or
complete. Partial deuterium substitution means that at least one
hydrogen is substituted by at least one deuterium. In certain
embodiments, the isotope is 90, 95 or 99% or more enriched in an
isotope at any location of interest. In some embodiments it is
deuterium that is 90, 95 or 99% enriched at a desired location.
[0163] Further specific compounds that fall within the present
invention and that can be used in the disclosed methods of
treatment and compositions include the structures listed in Table 1
below.
TABLE-US-00001 TABLE 1 Exemplary Non-limiting Structures of
Anti-Neoplastic and Anti-Proliferative Agents Structure Reference
Structure A ##STR00056## B ##STR00057## C ##STR00058## D
##STR00059## E ##STR00060## F ##STR00061## G ##STR00062## H
##STR00063## I ##STR00064## J ##STR00065## K ##STR00066## L
##STR00067## M ##STR00068## N ##STR00069## O ##STR00070## P
##STR00071## Q ##STR00072## R ##STR00073## S ##STR00074## T
##STR00075## U ##STR00076## V ##STR00077## W ##STR00078## X
##STR00079## Y ##STR00080## Z ##STR00081## AA ##STR00082## BB
##STR00083## CC ##STR00084## DD ##STR00085## EE ##STR00086## FF
##STR00087## GG ##STR00088## HH ##STR00089## II ##STR00090## JJ
##STR00091## KK ##STR00092## LL ##STR00093## MM ##STR00094## NN
##STR00095## OO ##STR00096## PP ##STR00097## QQ ##STR00098## RR
##STR00099## SS ##STR00100## TT ##STR00101## UU ##STR00102## VV
##STR00103## WW ##STR00104## XX ##STR00105## YY ##STR00106## ZZ
##STR00107## AAA ##STR00108## BBB ##STR00109## CCC ##STR00110## DDD
##STR00111## EEE ##STR00112## FFF ##STR00113## GGG ##STR00114## HHH
##STR00115## III ##STR00116## JJJ ##STR00117## KKK ##STR00118## LLL
##STR00119## MMM ##STR00120## NNN ##STR00121## OOO ##STR00122## PPP
##STR00123## QQQ ##STR00124## RRR ##STR00125## SSS ##STR00126## TTT
##STR00127## UUU ##STR00128## VVV ##STR00129## WWW ##STR00130## XXX
##STR00131##
Definitions
[0164] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below. As used in the specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Definition of standard chemistry terms may be found in reference
works, including Carey and Sundberg (2007) Advanced Organic
Chemistry 5.sup.th Ed. Vols. A and B, Springer Science.+-.Business
Media LLC, New York. The practice of the present invention will
employ, unless otherwise indicated, conventional methods of
synthetic organic chemistry, mass spectroscopy, preparative and
analytical methods of chromatography, protein chemistry,
biochemistry, recombinant DNA techniques and pharmacology.
Conventional methods of organic chemistry include those included in
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 6.sup.th Edition, M. B. Smith and J. March, John Wiley
& Sons, Inc., Hoboken, N.J., 2007.
[0165] The term "alkyl," either alone or within other terms such as
"haloalkyl" and "alkylamino," embraces linear or branched radicals
having one to about twelve carbon atoms. "Lower alkyl" radicals
have one to about six carbon atoms. Examples of such radicals
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The
term "alkylene" embraces bridging divalent linear and branched
alkyl radicals. Examples include methylene, ethylene, propylene,
isopropylene and the like.
[0166] The term "alkenyl" embraces linear or branched radicals
having at least one carbon-carbon double bond of two to about
twelve carbon atoms. "Lower alkenyl" radicals having two to about
six carbon atoms. Examples of alkenyl radicals include ethenyl,
propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms
"alkenyl" and "lower alkenyl," embrace radicals having "cis" and
"trans" orientations, or alternatively, "E" and "Z"
orientations.
[0167] The term "alkynyl" denotes linear or branched radicals
having at least one carbon-carbon triple bond and having two to
about twelve carbon atoms. "Lower alkynyl" radicals having two to
about six carbon atoms. Examples of such radicals include
propargyl, butynyl, and the like.
[0168] Alkyl, alkenyl, and alkynyl radicals may be optionally
substituted with one or more functional groups such as halo,
hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl,
heterocyclo and the like.
[0169] The term "alkylamino" embraces "N-alkylamino" and
"N,N-dialkylamino" where amino groups are independently substituted
with one alkyl radical and with two alkyl radicals, respectively.
"Lower alkylamino" radicals have one or two alkyl radicals of one
to six carbon atoms attached to a nitrogen atom. Suitable
alkylamino radicals may be mono or dialkylamino such as
N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino
and the like.
[0170] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[0171] The term "haloalkyl" embraces radicals wherein any one or
more of the alkyl carbon atoms is substituted with one or more halo
as defined above. Examples include monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl
radical, for one example, may have an iodo, bromo, chloro or fluoro
atom within the radical. Dihalo and polyhaloalkyl radicals may have
two or more of the same halo atoms or a combination of different
halo radicals. "Lower haloalkyl" embraces radicals having 1-6
carbon atoms. Examples of haloalkyl radicals include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl , difluoroethyl, di
fluoropropyl, di chloroethyl and dichloropropyl. "Perfluoroalkyl"
means an alkyl radical having all hydrogen atoms replaced with
fluoro atoms. Examples include trifluoromethyl and
pentafluoroethyl.
[0172] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one or two rings wherein
such rings may be attached together in a fused manner. The term
"aryl" embraces aromatic radicals such as phenyl, naphthyl,
indenyl, tetrahydronaphthyl, and indenyl. More preferred aryl is
phenyl. Said "aryl" group may have 1 or more substituents such as
lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower
alkylamino, and the like. An aryl group may be optionally
substituted with one or more functional groups such as halo,
hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl,
heterocyclo and the like.
[0173] The term "heterocyclyl" (or "heterocyclo") embraces
saturated, and partially saturated heteroatom-containing ring
radicals, where the heteroatoms may be selected from nitrogen,
sulfur and oxygen. Heterocyclic rings comprise monocyclic 6-8
membered rings, as well as 5-16 membered bicyclic ring systems
(which can include bridged fused and spiro-fused bicyclic ring
systems). It does not include rings containing --O--O--.--O--S-- or
--S--S-- portions. Said "heterocyclyl." group may have 1 to 3
substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower
alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino,
and the like.
[0174] Examples of saturated heterocyclo groups include saturated
3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen
atoms [e.g. pyrrolidinyl, imidazolidinyl, pi peridinyl, pyrrolinyl,
piperazinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of partially saturated heterocyclyl
radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl,
dihydrothiazolyl, and the like.
[0175] Particular examples of partially saturated and saturated
heterocyclo groups include pyrrolidinyl, imidazolidinyl,
piperidinyl, pyrrolinyl pyrazolidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, dihydrothienyl,
2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,
dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,
1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihydro-1H-1.lamda.'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl and dihydrothiazolyl, and the like.
[0176] Heterocyclo groups also includes radicals where heterocyclic
radicals are fused/condensed with aryl radicals: unsaturated
condensed heterocyclic group containing 1 to 5 nitrogen atoms, for
example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,
quinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl tetrazolo
[1,5-b]pyridazinyl]; unsaturated condensed. heterocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic
group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
[e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially
unsaturated and unsaturated condensed heterocyclic group containing
1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,
2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].
[0177] The term "heteroaryl" denotes aryl ring systems that contain
one or more heteroatoms selected from the group O, N and S, wherein
the ring nitrogen and sulfur atom(s) are optionally oxidized, and
nitrogen atom(s) are optionally quarternized. Examples include
unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to
4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic
group containing an oxygen atom, for example, pyranyl, 2-furyl,
3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group
containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;
unsaturated 5- to 6-membered heteromonocyclic group containing 1 to
2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,
isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl3,4-oxadiazolyl,
1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic
group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for
example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[0178] The term "heteroarylalkyl" denotes alkyl radicals
substituted with a heteroaryl group. Examples include pyridylmethyl
and thienylethyl.
[0179] The term "sulfonyl", whether used alone or linked to other
terms such as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--.
[0180] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as "carboxyalkyl", denotes --C(O)--OH.
[0181] The term "carbonyl", whether used alone or with other terms,
such as "aminocarbonyl", denotes --C(O)13 .
[0182] The term "aminocarbonyl" denotes an amide group of the
Formula --C(O)--NH.sub.2.
[0183] The terms "heterocycloalkyl" embrace
heterocyclic-substituted alkyl radicals. Examples include
piperidylmethyl and morpholinyl ethyl.
[0184] The term "arylalkyl" embraces aryl-substituted alkyl
radicals. Examples include benzyl, diphenylmethyl and phenylethyl.
The aryl in said aralkyl may be additionally substituted with halo,
alkyl alkoxy, halkoalkyl and haloalkoxy.
[0185] The term "cycloalkyl" includes saturated carbocyclic groups
of 3 to 10 carbons. Lower cycloalkyl groups include C.sub.3-C.sub.6
rings. Examples include cyclopentyl, cyclopropyl, and cyclohexyl.
Cycloalkyl groups may be optionally substituted with one or more
functional groups such as halo, hydroxy, nitro, amino, cyano,
haloalkyl, aryl, heteroaryl, heterocyclo and the like.
[0186] The term "cycloalkylalkyl" embraces cycloalkyl-substituted
alkyl radicals. "Lower cycloalkylalkyl" radicals are cycloalkyl
radicals attached to alkyl radicals having one to six carbon atoms.
Examples of include cyclohexylmethyl. The cycloalkyl in said
radicals may be additionally substituted with halo, alkyl, alkoxy
and hydroxy.
[0187] The term "cycloalkenyl" includes carbocyclic groups having
one or more carbon-carbon double bonds including "cycloalkyldienyl"
compounds. Examples include cyclopentenyl, cyclopentadienyl,
cyclohexenyl and cycloheptadienyl.
[0188] The term "comprising" is meant to be open ended, including
the indicated component but not excluding other elements.
[0189] The term "oxo" as used herein contemplates an oxygen atom
attached with a double bond.
[0190] The term "nitro" as used herein contemplates --NO.sub.2.
[0191] The term "cyano" as used herein contemplates --CN.
[0192] As used herein, the term "prodrug" means a compound which
when administered to a host in vivo is converted into the parent
drug. As used herein, the term "parent drug" means any of the
presently described chemical compounds that are useful to treat any
of the disorders described herein, or to control or improve the
underlying cause or symptoms associated with any physiological or
pathological disorder described herein in a host, typically a
human. Prodrugs can be used to achieve any desired effect,
including to enhance properties of the parent drug or to improve
the pharmaceutic or pharmacokinetic properties of the parent.
Prodrug strategies exist which provide choices in modulating the
conditions for in vivo generation of the parent drug, all of which
are deemed included herein. Nonlimiting examples of prodrug
strategies include covalent attachment of removable groups, or
removable portions of groups, for example, but not limited to
acylation, phosphorylation, phosphonylation, phosphoramidate
derivatives, amidation, reduction, oxidation, esterification,
alkylation, other carboxy derivatives, sulfoxy or sulfone
derivatives, carbonylation or anhydride, among others.
[0193] The term "host" refers to an individual, preferably a mammal
such as a human. The term "host" can include domesticated animals,
such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs,
sheep, goats, etc.), laboratory animals (e.g., mouse, monkey,
rabbit, rat, guinea pig, etc.) and birds.
Method of Treatment of Selected Cancer, Tumors, Hyperproliferative
Conditions, and Inflammatory and Immune Disorders
[0194] In certain aspects, the invention includes the use of an
effective amount of a compound described herein, or its
pharmaceutically acceptable salt, prodrug or isotopic variant
optionally in a pharmaceutical composition, to treat a host,
typically a human, with a selected cancer, tumor,
hyperproliferative condition or an inflammatory or immune disorder.
Some of the disclosed compounds are highly active against T-cell
proliferation. Given the paucity of drugs for T-cell cancers and
abnormal proliferation, the identification of such uses represents
a substantial improvement in the medical therapy for these
diseases.
[0195] Abnormal proliferation of T-cells, B-cells, and/or NK-cells
can result in a wide range of diseases such as cancer,
proliferative disorders and inflammatory/immune diseases. A host,
for example a human, afflicted with any of these disorders can be
treated with an effective amount of a compound as described herein
to achieve a decrease in symptoms (a palliative agent) or a
decrease in the underlying disease (a disease modifying agent).
[0196] Examples include T-cell or NK-cell lymphoma, for example,
but not limited to: peripheral T-cell lymphoma; anaplastic large
cell lymphoma, for example anaplastic lymphoma kinase (ALK)
positive, ALK negative anaplastic large cell lymphoma, or primary
cutaneous anaplastic large cell lymphoma; angioimmunoblastic
lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides,
Szary syndrome, primary cutaneous anaplastic large cell lymphoma,
primary cutaneous CD30+ T-cell lymphoproliferative disorder;
primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell
lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary
cutaneous small/medium CD4+ T-cell lymphoma, and lymphomatoid
papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell
Lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic
gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; Nasal
NK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for
example lymphomas that appear after solid organ or bone marrow
transplantation; T-cell prolymphocytic leukemia; T-cell large
granular lymphocytic leukemia; Chronic lymphoproliferative disorder
of NK-cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell
lymphoproliferative disease of childhood (associated with chronic
active EBV infection); Hydroa vacciniforme-like lymphoma; Adult
T-cell leukemia/lymphoma; Enteropathy-associated T-cell lymphoma;
Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like
T-cell lymphoma.
[0197] In one embodiment, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human, with a lymphoma or lymphocytic
or myelocytic proliferation disorder or abnormality. For example,
the compounds as described herein can be administered to a host
suffering from a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma. For
example, the host can be suffering from a Non-Hodgkin Lymphoma such
as, but not limited to: an AIDS-Related Lymphoma; Anaplastic
Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell
Lymphoma; Burkitt's Lymphoma; Burkitt-like Lymphoma (Small
Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large
B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular
Lymphoma; Hepatosplenic Gamma-Delta `T-Cell Lymphoma; Lymphoblastic
Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal
`I-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas;
Primary Central Nervous System Lymphoma; T-Cell Leukemias;
Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; or
Waldenstrom's Macroglobulinemia.
[0198] Alternatively, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human, with a Hodgkin Lymphoma, such
as, but not limited to: Nodular Sclerosis Classical Hodgkin's
Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL;
Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or
Nodular Lymphocyte Predominant HL.
[0199] Alternatively, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human with a specific B-cell lymphoma
or proliferative disorder such as, but not limited to: multiple
myeloma; Diffuse large B cell lymphoma; Follicular lymphoma;
Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell
lymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal
marginal zone B cell lymphoma (NMZL); Splenic marginal zone
lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary
effusion lymphoma; or Lymphomatoid granulomatosis; B-cell
prolymphocytic leukemia; Hairy cell leukemia; Splenic
lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small
B-cell lymphoma; Hairy cell leukemia-variant; Lymphoplasmacytic
lymphoma; Heavy chain diseases, for example, Alpha heavy chain
disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma
cell myeloma; Solitary plasmacytoma of bone; Extraosseous
plasmacytoma; Primary cutaneous follicle center lymphoma; T
cell/histiocyte rich large B-cell lymphoma; DLBCL associated with
chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the
elderly; Primary mediastinal (thymic) large B-cell lymphoma;
Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma;
Plasmablastic lymphoma; Large B-cell lymphoma arising in
HHV8-associated multicentric; Castleman disease; B-cell lymphoma,
unclassifiable, with features intermediate between diffuse large
B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features
intermediate between diffuse large B-cell lymphoma and classical
Hodgkin lymphoma.
[0200] In one embodiment, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human with leukemia. For example, the
host may be suffering from an acute or chronic leukemia of a
lymphocytic or myelogenous origin, such as, but not limited to:
Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia
(AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous
leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell
leukemia (HCL); acute promyelocytic leukemia (a subtype of AML);
large granular lymphocytic leukemia; or Adult T-cell chronic
leukemia. In one embodiment, the patient suffers from an acute
myelogenous leukemia, for example an undifferentiated AML (M0);
myeloblastic leukemia (M1; with/without minimal cell maturation);
myeloblastic leukemia (M2; with cell maturation); promyelocytic
leukemia (M3 or M3 variant [M3]); myelomonocytic leukemia (M4 or M4
variant with eosinophilia [M4E]); monocytic leukemia (M5);
erythroleukemia (M6); or megakaryoblastic leukemia (M7).
[0201] In another embodiment, a compound disclosed herein, or its
salt, prodrug, or isotopic variant can be used in an effective
amount to treat a host, for example a human with an autoimmune
disorder. Examples include, but are not limited to: Acute
disseminated encephalomyelitis (ADEM); Addison's disease;
Agammaglobulinemia; Alopecia areata; Amyotrophic lateral sclerosis
(Also Lou Gehrig's disease; Motor Neuron Disease); Ankylosing
Spondylitis; Antiphospholipid syndrome; Antisynthetase syndrome;
Atopic allergy; Atopic dermatitis; Autoimmune aplastic anemia;
Autoimmune arthritis; Autoimmune cardiomyopathy; Autoimmune
enteropathy; Autoimmune granulocytopenia; Autoimmune hemolytic
anemia; Autoimmune hepatitis; Autoimmune hypoparathyroidism;
Autoimmune inner ear disease; Autoimmune lymphoproliferative
syndrome; Autoimmune myocarditis; Autoimmune pancreatitis;
Autoimmune peripheral neuropathy; Autoimmune ovarian failure;
Autoimmune polyendocrine syndrome; Autoimmune progesterone
dermatitis; Autoimmune thrombocytopenic purpura; Autoimmune thyroid
disorders; Autoimmune urticarial; Autoimmune uveitis; Autoimmune
vasculitis; Balo disease/Balo concentric sclerosis; Behget's
disease; Berger's disease; Bickerstaffs encephalitis; Blau
syndrome; Bullous pemphigoid; Cancer; Castleman's disease; Celiac
disease; Chagas disease; Chronic inflammatory demyelinating
polyneuropathy; Chronic inflammatory demyelinating polyneuropathy;
Chronic obstructive pulmonary disease; Chronic recurrent multifocal
osteomyelitis; Churg-Strauss syndrome; Cicatricial pemphigoid;
Cogan syndrome; Cold agglutinin disease; Complement component 2
deficiency; Contact dermatitis; Cranial arteritis; CREST syndrome;
Crohn's disease; Cushing's Syndrome; Cutaneous leukocytoclastic
angiitis; Dego's disease; Dercum's disease; Dermatitis
herpetiformis; Dermatomyositis; Diabetes mellitus type 1; Diffuse
cutaneous systemic sclerosis; Discoid lupus erythematosus;
Dressler's syndrome; Drug-induced lupus; Eczema; Endometriosis;
Enthesitis-related arthritis; Eosinophilic fasciitis; Eosinophilic
gastroenteritis; Eosinophilic pneumonia; Epidermolysis bullosa
acquisita; Erythema nodosum; Erythroblastosis fetalis; Essential
mixed ctyoglobulinetnia; Evan's syndrome; Extrinsic and intrinsic
reactive airways disease (asthma); Fibrodysplasia ossificans
progressive; Fibrosing alveolitis (or Idiopathic pulmonary
fibrosis); Gastritis; Gastrointestinal pemphigoid;
Glomerulonephritis; Goodpasture's syndrome; Graves' disease;
Guillain-Barre syndrome (GBS); Hashimoto's encephalopathy;
Hashimoto's thyroiditis; Hemolytic anemia; Henoch-Schonlein
purpura; Herpes gestationis (Gestational Pemphigoid); Hidradenitis
suppurativa; Hughes-Stovin syndrome; Hypogammaglobulinemia;
Idiopathic inflammatory demyelinating diseases; Idiopathic
pulmonary fibrosis; Idiopathic thrombocytopenic purpura; IgA
nephropathy; Immune glomerulonephritis; Immune nephritis; Immune
pneumonitis; Inclusion body myositis; inflammatory bowel disease;
Interstitial cystitis; Juvenile idiopathic arthritis aka Juvenile
rheumatoid arthritis; Kawasaki's disease; Lambert-Eaton myasthenic
syndrome; Leukocytoclastic vasculitis; Lichen planus; Lichen
sclerosus; Linear IgA disease (LAD); Lupoid hepatitis aka
Autoimmune hepatitis; Lupus erythematosus; Majeed syndrome;
microscopic polyangiitis; Miller-Fisher syndrome; mixed connective
tissue disease; Morphea; Mucha-Habermann disease aka Pityriasis
lichenoides et varioliformis aceta; Multiple sclerosis; Myasthenia
gravis; Myositis; Meniere's disease; Narcolepsy; Neuromyelitis
optica (also Devic's disease); Neurornyotonia; Occular cicatricial
pemphigoid; Opsoclonus myoclonus syndrome; Ord's thyroiditis;
Palindromic rheumatism; PANDAS (pediatric autoimmune
neuropsychiatric disorders associated with streptococcus);
Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemogl
obi nuri a (PNH); Parry Romberg syndrome; Pars planitis;
Parsonage-Turner syndrome; Pemphigus vulgaris; Perivenous
encephalomyelitis; Pernicious anaemia; POEMS syndrome;
Polyarteritis nodosa; Polymyalgia rheumatic; Polymyositis; Primary
biliary cirrhosis; Primary sclerosing cholangitis; Progressive
inflammatory neuropathy; Psoriasis; Psoriatic arthritis; pure red
cell aplasia; Pyoderma gangrenosum; Rasmussen's encephalitis;
Raynaud phenomenon; Reiter's syndrome; relapsing polychondritis;
restless leg syndrome; retroperitoneal fibrosis; rheumatic fever;
rheumatoid arthritis; Sarcoidosis; Schizophrenia; Schmidt syndrome;
Schnitzler syndrome; Scleritis; Scleroderma; Sclerosing
cholangitis; serum sickness; Sjogren's syndrome;
Spondyloarthropathy; Stiff person syndrome; Still's disease;
Subacute bacterial endocarditis (SBE); Susac's syndrome; Sweet's
syndrome; Sydenham chorea; sympathetic ophthalmia; systemic lupus
erythematosus; Takayasu's arteritis; temporal arteritis (also known
as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome;
transverse myelitis; ulcerative colitis; undifferentiated
connective tissue disease; undifferentiated spondyloarthropathy;
urticarial vasculitis; vasculitis; vitiligo; viral diseases such as
Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,
Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV); or
Wegener's granulomatosis. In some embodiments, the autoimmune
disease is an allergic condition, including those from asthma, food
allergies, atopic dermatitis, and rhinitis.
[0202] In yet another embodiment, a compound disclosed herein, or
its salt, prodrug, or isotopic variant can be used in an effective
amount to treat a host, for example a human with a disease
involving the immune system. In one example, a compound disclosed
herein can be used to prevent organ transplant rejection (e.g. ,
allograft rejection and graft versus host disease).
[0203] A compound disclosed herein, or its salt, prodrug, or
isotopic variant can be used in an effective amount to treat a
host, for example a human with a skin disorders such as psoriasis
(for example, psoriasis vulgaris), atopic dermatitis, skin rash,
skin irritation, skin sensitization (e.g., contact dermatitis or
allergic contact dermatitis). For example, certain substances
including some pharmaceuticals when topically applied can cause
skin sensitization. In some embodiments, the skin disorder is
treated by topical administration of compounds known in the art in
combination with the compounds disclosed herein.
[0204] A compound disclosed herein, or its salt, prodrug, or
isotopic variant can be used in an effective amount to treat a
host, for example a human with a proliferative condition such as a
myeloproliferative disorder (MPD), polycythemi a vera (PV),
essential thrombocythemia (ET), myeloid metaplasia with
myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML),
hypereosinophilic syndrome (HES), systemic mast cell disease
(SMCD), and the like.
[0205] A compound disclosed herein, or its salt, prodrug, or
isotopic variant can be used in an effective amount to treat a
host, for example a human with an inflammatory disorder. Example
inflammatory diseases include inflammatory diseases of the eye
(e.g., iritis, uveitis, conjunctivitis, or related disease),
inflammatory diseases of the respiratory tract (e.g., the upper
respiratory tract including the nose and sinuses such as rhinitis
or sinusitis or the lower respiratory tract including bronchitis,
chronic obstructive pulmonary disease, and the like), inflammatory
myopathy such as myocarditis, and other inflammatory diseases.
[0206] A compound disclosed herein, or its salt, prodrug, or
isotopic variant can be used in an effective amount to treat a
host, for example a human with an inflammatory ischemic event such
as stroke or cardiac arrest.
[0207] In another embodiment, the compounds provided herein is
useful for the treatment of primary myelofibrosis,
post-polycythemia vera myelofibrosis, post-essential
thrombocythemia myelofibrosis, and secondary acute myelogenous
leukemia. In another embodiment, the compounds provided herein can
be used to treat patients with intermediate or high-risk
myelofibrosis, including primary myelofibrosis, post-polycythemia
vera myelofibrosis and post-essential thrombocythemia
myellofibrosis. In some embodiments, the host to be treated (e.g.,
a human) is determined to be non-responsive or resistant to one or
more therapies for myeloproliferative disorders, In a particular
embodiment, provided herein is a method of treating a
myeloproliferative neoplasm in a host in need thereof, comprising
administering to the host an effective amount of a composition
comprising a compound described herein, or a pharmaceutically
acceptable salt thereof.
Combination Therapy
[0208] In one aspect of the invention, the compounds disclosed
herein can be beneficially administered in combination with another
therapeutic regimen for beneficial, additive or synergy stic
effects.
[0209] In one embodiment, a compoundlmethod of the present
invention is used in combination with another therapy to treat the
T, B or NK abnormal cellular proliferation including cancer or
disorder. The second therapy can be an immunotherapy. As discussed
in more detail below, the compound can be conjugated to an
antibody, radioactive agent or other targeting agent that directs
the compound to the diseased or abnormally proliferating cell. In
another embodiment, the compound is used in combination with
another pharmaceutical or a biologic agent (for example an
antibody) to increase the efficacy of treatment with a combined or
a synergistic approach. In an embodiment, the compound can be used
with T-cell vaccination, which typically involves immunization with
inactivated autoreactive T cells to eliminate a pathogenic
autoreactive T cell population. In another embodiment, the compound
is used in combination with a bispecific T-cell Engager (BiTE),
which is an antibody designed to simultaneously bind to specific
antigens on endogenous T cells and malignant cells, linking the two
types of cells.
[0210] In one embodiment, the additional therapy is a monoclonal
antibody (MAb). Some MAbs stimulate an immune response that
destroys cancer cells. Similar to the antibodies produced naturally
by B cells, these MAbs "coat" the cancer cell surface, triggering
its destruction by the immune system. FDA-approved MAbs of this
type include rituximab, which targets the CD20 antigen found on
non-Hodgkin lymphoma cells, and alemtuzumab, which targets the CD52
antigen found on B-cell chronic lymphocyticleukemia (CLL) cells.
Rituximab may also trigger cell death (apoptosis) directly. Another
group of MAbs stimulates an anticancer immune response by binding
to receptors on the surface of immune cells and inhibiting signals
that prevent immune cells from attacking the body's own tissues,
including cancer cells. Other MAbs interfere with the action of
proteins that are necessary' for tumor growth. For example,
bevacizumab targets vascular endothelial growth factor(VEGF), a
protein secreted by tumor cells and other cells in the tumor's
microenvironment that promotes the development of tumor blood
vessels. When bound to bevacizmnab, VEGF cannot interact with its
cellular receptor, preventing the signaling that leads to the
growth of new blood vessels. Similarly, cetuximab and panitumumab
target the epidermal growth factor receptor (EGFR), and trastuzumab
targets the human epidermal growth factor receptor 2 (HER-2). MAbs
that bind to cell surface growth factor receptors prevent the
targeted receptors from sending their normal growth-promoting
signals, They may also trigger apoptosis and activate the immune
system to destroy tumor cells. Another group of cancer therapeutic
MAbs are the immunoconjugates, These MAbs, which are sometimes
called immunotoxins or antibody-drug conjugates, consist of an
antibody attached to a cell-killing substance, such as a plant or
bacterial toxin, a chemotherapy drug, or a radioactive molecule,
The antibody latches onto its specific antigen on the surface of a
cancer cell, and the cell-killing substance is taken up by the
cell. FDA-approved conjugated MAbs that work this way include
.sup.90Y-ibritumomab tiuxetan, which targets the CD20 antigen to
deliver radioactive yttrium-90 to B-cell non-Hodgkin lymphoma
cells; .sup.131I-tositumomab, which targets the CD20 antigen to
deliver radioactive iodine-131 to non-Hodgkin lymphoma cells; and
ado-trastuzutnab emtansine, which targets the HER-2 molecule to
deliver the drug DM1, which inhibits cell proliferation, to HER-2
expressing metastatic breast cancer cells.
[0211] Immunotherapies with' cells engineered to recognize cancer
cells via bispecific antibodies (bsAbs) or chimeric antigen
receptors (CARS) are particularly promising approaches with
potential to ablate both dividing and non/slow-dividing
subpopulations of cancer cells,
[0212] Bispecific antibodies, by simultaneously recognizing target
antigen and an activating receptor on the surface of an immune
effector cell, offer an opportunity to redirect immune effector
cells to kill cancer cells. The other approach is the generation of
chimeric antigen receptors by fusing extracellular antibodies to
intracellular signaling domains. Chimeric antigen
receptor-engineered T cells are able to specifically kill tumor
cells in a MHC-independent way.
[0213] General anticancer pharinaccuti cal agents include:
Vincristine (Oncovin.RTM.) or liposomal. vincristine
(Marqibo.RTM.), Daunorubicin {daunomycin or Cerubidine.RTM.) or
doxotubiein (Adriamycin.RTM.), Cytarabine (cytosine arabinoside,
ara-C, or Cytosar.RTM.), L-asparaginase (Elspar.RTM.) or
PEG-L-asparaginase (peaspargase or Oncaspar.RTM.), Etoposi de
(VP-16), Teniposide (Vumon.RTM.), 6-mercaptopurine (6-MP or
Purinethol.RTM.), Methotrexate, Cyclophosphamide (Cytoxan.RTM.),
Prednisone, Dexamethasone (Decadron), imatinib (Gleevec.RTM.),
dasatinib (Sprycel.RTM.), nilotinib (Tasigna.RTM.), bosutinib
(Bosulif.RTM.), and ponatinib (Iclusig.TM.) Trastuzumab
(Herceptin.RTM.), Pertuzutnab (Pedeta.TM.), Lapatinib
(Tykerb.RTM.), Gefitinib (Iressa.RTM.), Erlotinib (Tarceva.RTM.),
Cetuximab (Erbitux.RTM.), Panitumumab (Vectibix.RTM.), Vandetanib
(Caprelsa.RTM.), Vemurafenib (Zelboraf.RTM.), Vorinostat
(Zolinza.RTM.), Romidepsi n (Istodax.RTM.), Bexarotene
(Tagretin.RTM.) Alitretinoin (Panretin.RTM.), Tretinoin
(Vesanoid.RTM.), Carfilizomib (Kyprolis.RTM.), Pralatrexate
(Folotyn.RTM.), Bevacizumab (Avastin.RTM.), Ziv-aflibercept
(Zaltrap.RTM.), Sorafenib (Nexavar.RTM.), Sunitinib (Sutent.RTM.),
Pazopanib (Votrient.RTM.), Regorafenib (Stivarga.RTM.), and
Cabozantinib (Cometriq.TM.).
[0214] Current chemotherapeutic drugs used to treat AML are
cytarabine (cytosine arabinoside or ara-C) and the anthracycline
drugs (such as daunorubicin/daunomycin, idarubicin, and
mitoxantrone). Some of the other chemo drugs that may he used to
treat AML include: Cladribine (Leustatin.RTM., 2-CdA), Fludarabine
(Fludara.RTM.), Topotecan, Etoposide (VP-16), 6-thioguanine (6-TG),
Hydroxyurea (Hydrea.RTM.), Corticosteroid drugs, such as prednisone
or dexamethasone (Decadron.RTM.), Methotrexate (MTX),
6-mercaptopurine (6-MP), Azacitidine (Vidaza.RTM.), Decitabine
(Dacogen.RTM.)
[0215] Current chemotherapeutic drugs for CLL and other lymphomas
include: purine analogs such as fludarabine (Fludara.RTM.),
pentostatin (Nipent.RTM.), and dadribine (2-CdA, Leustatin.RTM.),
and alkylating agents, which include chlorambucil (Leukeran.RTM.)
and cyclophosphamide (Cytoxan.RTM.) and bendamustine
(Treanda.RTM.). Other drugs sometimes used for CLL include
doxombicin (Adriamycin.RTM.), methotrexate, oxaliplatin,
vincristine (Oncovin.RTM.), etoposi de (VP-16), and cytarabine
(ara-C). Other drugs include Rituximab (Rituxan), Obinutuzuinab
(Gazyva.TM.), Ofatumumab (Arzerrat), Alemtuzumab (Campath.RTM.) and
Ibrutinib (Imbruvica.TM.).
[0216] Current chemotherapies for CML include: Interferon, imatinib
(Gleevec), the chemo drug hydroxyurea (Hydrea.RTM.), cytarabine
(Ara-C), busul fan, cyclophosphamide (Cytoxan.RTM.), and
vincristine (Oncovin.RTM.). Omacetaxine (Synribo.RTM.) is a chemo
drug that was approved to treat CML that is resistant to some of
the TKIs now in use.
[0217] CMML is now treated with Deferasirox (Exjade.RTM.),
cytarabine with idarubicin, cytarabine with topotecan, and
cytarabine with fludarabine, Hydroxyurea (hydroxycarbamate,
Hydrea.RTM.), azacytidine (Vidaza.RTM.) and decitabine
(Dacogen.RTM.).
[0218] Erythropoietin (Epo.RTM. or Procrit.RTM.), a growth factor
that promotes red blood cell production, can help avoid
transfusions of red blood cells in some patients. R.ecently it has
been found that combining erythropoietin with a growth factor for
white blood cells (G-CSF, Neupogen.RTM., or filgrastim) improves
the patient's response to the ery.sup.-thropoietin. Darbepoetin
(Aranesp.RTM.) is a long-acting form of erythropoietin. It works in
the same way but can be given less often. Oprelvekin (Neumega.RTM.,
interleukin-11, or IL-11) can be used to stimulate platelet
production after chemotherapy and in some other diseases.
[0219] Therapies for multiple myeloma include Pomalidomide
(Pomalyst.RTM.), Carfilzomib (Kyprolis.TM.), Everolimus
(Afinitor.RTM.), dexamethasone (Decadron), prednisone and
methylprednisolone (Solu-medro.RTM.) and hydrocortisone.
[0220] Therapies for Hodgkins disease include Brentuximab vedotin
(Adcetris.TM.): anti-CD-30, Rituximab, Adriamycin.RTM.
(doxorubicin), Bleornycin, Vinblastine, Dacarbazine (DTIC).
[0221] Monoclonal antibodies for Non-Hodgkins disease include
Rituximab {Rituxan.RTM.), Ibritumomab (Zevalin.RTM.), tositumomab
(Bexxar.RTM.), Alemtuzumab (Campath.RTM.) (CD52 antigen),
Ofatumumab (Arzerra.RTM.), Brentuximab vedotin (Adcetris.RTM. and
Lenalidomide (Revlimid.RTM.).
[0222] B-cell Lymphoma approved therapies include: [0223] Diffuse
large B-cell lymphoma: CHOP (cyclophosphamide, doxorubicin,
vincristine, and prednisone), plus the monoclonal antibody
rituximab (Rituxan). [0224] This regimen, known as R-CHOP, is
usually given for about 6 months. [0225] Primary mediastinal B-cell
lymphoma: R-CHOP [0226] Follicular lymphoma: rituximab (Rituxan)
combined with chemo, using either a single chemo drug (such as
bendamustine or fludarabine) or a combination of drugs, such as the
CHOP or CVP (cyclophosphamide, vincristine, prednisone regimens.
The radioactive monoclonal antibodies, ibritumomah (Zevalin) and
tositumomab (Bexxar) are also possible treatment options. For
patients who may not be able to tolerate more intensive chemo
regimens, rituximab alone, milder chemo drugs (such as chlorambucil
or cyclophosphamide). [0227] Chronic lymphocytic leukemia/small
lymphocytic lymphoma: R-CHOP Mantle cell lymphoma: fludarabine,
cladribine, or pentostatin; bortezomib (Velcade) and lenalidomide
(Revlimid) and ibrutinib (Imbruvica) Extranodal marginal zone
B-cell lymphoma--mucosa-associated lymphoid tissue (MALT) lymphoma:
rituximab; chlorambucil or fludarabine or combinations such as CVP,
often along with rituximab. [0228] Nodal marginal zone B-cell
lymphoma: rituximab (Rituxan) combined with chemo, using either a
single chemo drug (such as bendamustine or fludarabine) or a
combination of drugs, such as the CHOP or CVP (cyclophosphamide,
vincristine, prednisone regimens. The radioactive monoclonal
antibodies, ibritumomab (Zevalin) and tositumomab (Bexxar) are also
possible treatment options. For patients who may not be able to
tolerate more intensive chemo regimens, rituximab alone, milder
chemo drugs (such as chlorambucil or cyclophosphamide). Splenic
marginal zone B-cell lymphoma: rituximab; patients with Hep
C--anti-virals [0229] Burkitt lymphoma: methotrexate;
hyper-CVAD--cyclophosphamide, vincristine, doxorubicin (also known
as Adriamycin), and dexamethasone. Course B consists of
methotrexate and cytarabine; CODOX-M--cyclophosphamide,
doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and
high-dose cytarabine; etoposide, vincristine, doxorubicin,
cyclophosphamide, and prednisone (EPOCH) Lymphoplasmacytic
lymphoma-rituximab [0230] Hairy cell leukemia--cladribine (2-CdA)
or pentostatin; rituximab, interferon-alfa
[0231] Current therapies for T-cell lymphomas include: [0232]
Precursor T-lymphoblastic lymphoma/leukemia cyclophosphamide,
doxorubicin (Adriamycin), vincristine, L-asparaginase,
methotrexate, prednisone, and, sometimes, cytarabine (ara-C).
Because of the risk of spread to the brain and spinal cord, a chemo
drug such as methotrexate is also given into the spinal fluid. Skin
lymphomas: Gemcitabine Liposomal doxorubicin (Doxil), Methotrexate;
Chlorambucil; Cyclophosphamide; Pentostatin; Etoposide;
Temozolomide; Pralatrexate; R-CHOP [0233] Angioimmunoblastic T-cell
lymphoma: prednisone or dexamethasone [0234] Extranodal natural
killer/T-cell lymphoma, nasal type: CHOP [0235] Anaplastic large
well lymphoma: CHOP; pralatrexate (Folotyn), targeted drugs such as
bortezomib (Velcade) or romidepsin (Istodax), or immunotherapy
drugs such as alemtuzumab (Campath) and denileukin diftitox (Ontak)
[0236] Primary central nervous system (CNS) lymphoma--methotrexate;
rituximab
[0237] A more general list of suitable chemotherapeutic agents
include, but are not limited to, radioactive molecules, toxins,
also referred to as cytotoxins or cytotoxic agents, which includes
any agent that is detrimental to the viability of cells, agents,
and liposomes or other vesicles containing chemotherapeutic
compounds. Examples of suitable chemotherapeutic agents include but
are not limited to 1-dehydrotestosterone, 5-fluorouracil
decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D,
adriamycin, aldesleukin, alkylating agents, allopurinol sodium,
altretamine, amifostine, anastrozole, anthramycin (AMC)),
anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP)
cisplatin), diamino dichloro platinum, anthracyclines, antibiotics,
antis, asparaginase, BCG live (intravesical), betamethasone sodium
phosphate and betamethasone acetate, .sup.-bicaluta.mide, bleomycin
sulfate, busulfan, calcium leucovorin, calicheamicin, capecitabine,
carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil,
Cisplatin, Cladribine, Collchicin, conjugated estrogens,
Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine,
cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin
(formerly actinomycin), daunirubicin HCL, daunorucbicin citrate,
denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy
anthracin dione, Docetaxel, dolasetron mesyl ate, doxorubicin HCL,
dronabinol, E. coli L-asparaginase, emetine, epoetin-.alpha.,
Erwirtia L-asparaginase, esterified estrogens, estradiol,
estramustine phosphate sodium, ethidium bromide, ethinyl estradiol,
etidronate, etoposide citrororum factor, etoposide phosphate,
filgrastim, floxuridine, fluconazole, fludarabine phosphate,
fluorouracil, flutamide, folinic acid, gemcitabine HCL,
glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL,
hydroxyurea, idarubicin HCL, ifosfamide, interferon .alpha.-2b,
irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate,
levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine
HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL,
mercaptipurine, Inesna, methotrexate, methyltestosterone,
mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide,
octreotide acetate, ondansetron HCL, paclitaxel, pamidronate
disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20
with carmustine implant, porfimer sodium, procaine, procarbazine
HCL, propranolol, rituximab, sargramostim, streptozotocin,
tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine,
thioepa. chlorambucil, thioguanine, thiotepa, topotecan HCL,
toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine
sulfate, vincristine sulfate, and vinorelbine tartrate.
[0238] Additional therapeutic agents that can be administered in
combination with the compounds disclosed herein can include
bevacizumab, sutinib, sorafenib, 2-methoxyestradiol, finasunate,
vatalanib, vandetanib, aflibercept, volociximab, etaracizumab,
cilengitide, erlotinib, cetuximab, panitumumab, gefitinib,
trastuzumab, atacicept, rituximab, alemtuzumab, aldesleukine,
atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab,
dacetuzumab, atiprimod, natalizumab, bortezomib, carfilzomib,
marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir
mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab,
lexatumumab, oblimersen, plitidepsin, talmapimod, enzastaurin,
tipifarnib, perifosine, imatinib, dasatinib, lenalidotnide,
thalidomide, simvastatin, and celecoxib.
[0239] In one aspect of the present invention, the compounds
disclosed herein are combined with at least one immunosuppressive
agent. The immunosuppressive agent may be selected from the group
consisting of a calcineurin inhibitor, e.g. a cyclosporin or an
ascomycin, e.g. Cyclosporin A (NEORAL.RTM.), tacrolimus, a mTOR
inhibitor, e.g, rapamycin or a derivative thereof, e.g. Sirolimus
(RAPAMUNE.RTM.), Everolimus (Certican.RTM.), temsirolimus,
biolimus-7, biolimus-9, a rapalog, e.g. azathioprine, campath 1H,
receptor modulator, e.g. fingolimod or an analogue thereof, an anti
IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium
salt, or a prodrug thereof, e.g. Mycophenolate Mofetil
(CELLCEPT.RTM.), OKT3 (ORTHOCLONE OKT3.RTM.), Prednisone,
ATGAM.RTM., THYMOGLOBULIN.RTM., Brequinar Sodium,
15-deoxyspergualin, tresperimus, Leflunomide ARAVA.RTM., anti-CD25,
anti-IL2R, Basiliximab (SIMULECT.RTM.), Daclizumab (ZENAPAX.RTM.),
mizorbine, methotrexate, dexamethasone, pimecrolimus (Elidel.RTM.),
abatacept, belatacept, etanercept (Enbrel.RTM.), adalimumab
(Humira.RTM.), infliximab (Remicade.RTM.), an anti-LFA-1 antibody,
natalizumab (Antegren.RTM.), Enlimomab, ABX-CBL, antithymocyte
immunoglobulin, siplizumab, and efalizumab.
[0240] Drugs sometimes used to treat autoimmune disorders include:
methylprednisolone oral, Kenalog inj, Medrol oral, Medrol (Pak)
oral, Depo-Medrol inj, prednisolone oral, Solu-Medrol inj,
Solu-Medrol IV, Cortef oral, hydrocortisone oral, cortisone oral,
Celestone Soluspan inj, Orapred oral, Orapred ODT oral,
methylprednisolone acetate inj, betamethasone acet & sod phos
inj, Veripred 20 oral, Solu-Medrol (PF) inj, methylprednisolone
sodium succ IV, Solu-Medrol (PF) IV methytprednisolone sodium succ
inj, Solu-Cortef inj, Pediapred oral, Millipred oral, Aristospan
Intra-Articular inj, hydrocortisone sod succinate inj, prednisolone
sodium phosphate oral, methylprednisolone sod suc(PF) IV, Flo-Pred
oral, triamcinolone hexacetonide inj, A-Hydrocort inj, A-Methapred
inj, Millipred DP oral, prednisolone acetate oral, Aristospan
Intralesional inj, methylprednisolone sod suc(PF) inj,
hydrocortisone sod succ (PF) inj, Solu-Cortef (PF) injection and
dexamethasone in 0.9 % NaCl IV.
Drug Conjugates
[0241] In one embodiment, the activity of an active compound for a
purpose described herein can be augmented through conjugation to an
agent that targets the diseased or abnormally proliferating cell or
otherwise enhances activity, delivery, pharmacokinetics or other
beneficial property.
[0242] For example, the compound can be administered as an
antibody-drug conjugates (ADC). In certain embodiments, a selected
compound described herein can be administered in conjugation or
combination with an antibody or antibody fragment. Fragments of an
antibody can be produced through chemical or genetic mechanisms. In
one embodiment, the antibody fragment is an antigen binding
fragment. For example, the antigen binding fragment can be selected
from an Fab, Fab', (Fab')2, or Fv. In one embodiment, the antibody
fragment is a Fab. Monovalent F(ab) fragments have one antigen
binding site, in one embodiment, the antibody is a divalent (Fab')2
fragment, which has two antigen binding regions that are linked by
disulfide bonds. In one embodiment, the antigen fragment is a
(Fab'). Reduction of F(ab')2 fragments produces two monovalent Fab'
fragments, which have a free sulfhydryl group that is useful for
conjugation to other molecules.
[0243] In one embodiment, a selected compound described herein can
be administered in conjugation or combination with a Fv fragment.
Fv fragments are the smallest fragment made from enzymatic cleavage
of IgG and IgM class antibodies. Fv fragments have the
antigen-binding site made of the VH and VC regions, but they lack
the CH1 and CL regions. The VH and VL chains are held together in
Fv fragments by non-covalent interactions.
[0244] In one embodiment, a selected compound as described herein
can be administered in combination with an antibody fragment
selected from the group consisting of an ScFv, diabody, triabody,
tetrabody, Bis-scFv, minibody, Fab2, or Fab3 antibody fragment. In
one embodiment, the antibody fragment is a ScFv. Genetic
engineering methods allow the production of single chain variable
fragments (ScFv) , which are Fv type fragments that include the VH
and VL domains linked with a flexible peptide When the linker is at
least 12 residues long, the ScFv fragments are primarily monomeric.
Manipulation of the orientation of the V-domains and the linker
length creates different forms of Fv molecules Linkers that are
3-11 residues long yield scFv molecules that are unable to fold
into a functional Fv domain. These molecules can associate with a
second scFv molecule, to create a bivalent diabody. In one
embodiment, the antibody fragment administered in combination with
a selected compound described herein is a bivalent diabody, if the
linker length is less than three residues, say molecules associate
into triabodies or tetrabodies. In one embodiment, the antibody
fragment is a triabody. In one embodiment, the antibody fragment is
a tetrabody. Multivalent scFvs possess greater functional binding
affinity to their target antigens than their monovalent
counterparts by having binding to two more target antigens, which
reduces the off-rate of the antibody fragment. In one embodiment,
the antibody fragment is a minibody. Minibodies are scFv-CH3 fusion
proteins that assemble into bivalent dimers. In one embodiment, the
antibody fragment is a Bis-scFv fragment. Bis-scFv fragments are
bispecific. Miniaturized ScFv fragments can be generated that have
two different variable domains, allowing these Bis-scFv molecules
to concurrently bind to two different epitopes.
[0245] In one embodiment, a selected compound described herein is
administered in conjugation or combination with a bispecific dimer
(Fab2) or trispecific dimer (Fab3). Genetic methods are also used
to create bispecific Fab dimers (Fab2) and trispecific Fab trimers
(Fab3). These antibody fragments are able to bind 2 (Fab2) or 3
(Fab3) different antigens at once.
[0246] In one embodiment, a selected compound described herein is
administered in conjugation or combination with an rIgG antibody
fragment. rIgG antibody fragments refers to reduced IgG (75,000
daltons) or half-IgG. It is the product of selectively reducing
just the hinge-region disulfide bonds. Although several disulfide
bonds occur in IgG, those in the hinge-region are most accessible
and easiest to reduce, especially with mild reducing agents like
2-mercaptoethylamine (2-MEA). Half-IgG are frequently prepared for
the purpose of targeting the exposing hinge-region sulfhydryl
groups that can be targeted for conjugation, either antibody
immobilization or enzyme labeling.
[0247] In other embodiments, a selected active compound described
herein can be linked to a radioisotope to increase efficacy, using
methods well known in the art. Any radioisotope that is useful
against the T, B or NK abnormal cells can be incorporated into the
conjugate, for example, but not limited to .sup.131I, .sup.123I,
.sup.192Ir, .sup.32P, .sup.90Sr, .sup.198Au, .sup.226Ra, .sup.90Y,
.sup.241Am, .sup.252Cf, .sup.60Co, or .sup.137Cs.
[0248] Of note, the linker chemistry can be important to efficacy
and tolerability of the drug conjugates. The thio-ether linked
T-DM1 increases the serum stability relative to a disulfide linker
version and appears to undergo endosomal degradation, resulting in
intra-cellular release of the cytotoxic agent, thereby improving
efficacy and tolerability, See, Barginear, M. F. and Budman, D. R.,
Tra.stuzumab-DM1: A review of the novel immune-conjugate for
HER2-overexpressing breast cancer, The Open Breast Cancer Journal,
1:25-30, 2009.
[0249] Examples of early and recent antibody-drug conjugates,
discussing drugs, linker chemistries and classes of targets for
product development that may be used in the present invention can
be found in the reviews by Casi, G. and Neri D., Antibody-drug
conjugates: basic concepts, examples and future perspectives, J.
Control Release 161(2):422-428, 2012, Chari, R. V., Targeted cancer
therapy: conferring specificity to cytotoxic drugs, Acc. Chem.
Rev., 41(1):98-107, 2008, Sapra, P. and Shor, B., Monoclonal
antibody-based therapies in cancer: advances and challenges,
Pharmacol. Ther., 138(3):452-69, 2013, Schliema.nn, C. and Neri,
D., Antibody-based targeting of the tumor vasculature, Biochim.
Biophys. Acta., 1776(2):175-92, 2007, Sun, Y., Yu, F., and Sun, B.
W., Antibody-drug conjugates as targeted cancer therapeutics, Yao
Xue Xue Bao, 44(9):943-52, 2009, `reicher, B. A., and Chari, R. V.,
Antibody conjugate therapeutics: challenges and potential, Clin.
Cancer Res., 17(20):6389-97, 2011, Firer, M. A., and Gellerman, G.
J., Targeted drug delivery for cancer therapy: the other side of
antibodies, J. Hematol. Oncol., 5:70, 2012, Vlachakis, D. and
Kossida, S., Antibody Drug Conjugate bioinformatics: drug delivery
through the letterbox, Comput. Math. Methods Med., 2013;
2013:282398, Epub 2013 June 19, Lambert, J. M., Drug-conjugated
antibodies for the treatment of cancer, Br. J. Clin. Pharmacol.,
76(2):248-62, 2013, Concalves, A., Tredan, O., Villanueva, C. and
Dumontet, C., Antibody-drug conjugates in oncology: from the
concept to trastuzumab emtansine (T-DM1), Bull. Cancer,
99(12):1183-1191, 2012, Newland, A. M., Brentuximab vedotin: a
CD-30-directed antibody-cytotoxic drug conjugate, Pharmacotherapy,
33(1):93-104, 2013, Lopus, M., Antibody-DM1 conjugates as cancer
therapeutics, Cancer Lett., 307(2):113-118, 2011, Chu, Y. W. and
Poison, A., Antibody-drug conjugates for the treatment of B-cell
non-Hodgkin's lymphoma and leukemia, Future Oncol., 9(3):355-368,
2013, Bertholjotti, I., Antibody-drug conjugate--a new age for
personalized cancer treatment, Chimia, 65(9): 746-748, 2011,
Vincent, K. J., and Zurini, M., Current strategies in antibody
engineering: Fc engineering and pH dependent antigen binding,
bispecific antibodies and antibody drug conjugates, Biotechnol. J.,
7(12):1444-1450, 2012, Haeuw, J. F., Caussanel, V., and Beck, A.,
Immunoconjugates, drug-armed antibodies to fight against cancer,
Med. Sci., 25(12):1046-1052, 2009 and Govindan, S. V., and
Goldenberg, D. M., Designing immunoconjugates for cancer therapy,
Expert Opin. Biol. Ther., 12(7):873-890, 2012.
Pharmaceutical Compositions and Dosage Forms
[0250] The active compounds described herein, or their salt or
prodrug can be administered to the host using any suitable approach
which achieves the desired therapeutic result. The amount and
timing of active compound administered will, of course, be
dependent on the host being treated, the instructions of the
supervising medical specialist, on the time course of the exposure,
on the manner of administration, on the pharmacokinetic properties
of the particular active compound, and on the judgment of the
prescribing physician. Thus, because of host to host variability,
the dosages given below are a guideline and the physician can
titrate doses of the compound to achieve the treatment that the
physician considers appropriate for the host. In considering the
degree of treatment desired, the physician can balance a variety of
factors such as age and weight of the host, presence of preexisting
disease, as well as presence of other diseases. Pharmaceutical
formulations can be prepared for any desired route of
administration including, but not limited to, systemic, topical,
oral, intravenous, subcutaneous, transdermal, buccal, sublingual,
intraaortal, intranasal, parenteral, or aerosol administration, as
discussed in greater detail below.
[0251] The therapeutically effective dosage of any active compound
described herein will be determined by the health care practitioner
depending on the condition, size and age of the patient as well as
the route of delivery. In one non-limited embodiment, a dosage from
about 0.1 to about 200 mg/kg has therapeutic efficacy, with all
weights being calculated based upon the weight of the active
compound, including the cases where a salt is employed. In some
embodiments, the dosage can be the amount of compound needed to
provide a serum concentration of the active compound of up to
between about 1 and 5, 10, 20, 30, or 40 .mu.M. In some
embodiments, a dosage from about 10 mg/kg to about 50 mg/kg can be
employed for oral administration. Typically, a dosage from about
0.5 mg/kg to 5 mg/kg can be employed for intramuscular injection.
In some embodiments, dosages can be from about 1 .mu.mol/kg, to
about 50 .mu.mol/kg or, optionally, between about 22 .mu.mol/kg and
about 33 .mu.mol/kg of the compound for intravenous or oral
administration. An oral dosage form can include any appropriate
amount of active material, including for example from 5 mg to, 50,
100, 200, or 500 mg per tablet or other solid dosage form.
[0252] In accordance with certain embodiments of the invention, in
the presently disclosed methods, pharmaceutically active compounds
as described herein can be administered orally as a solid or as a
liquid, or can be administered intramuscularly, intravenously, or
by inhalation as a solution, suspension, or emulsion. In some
embodiments, the compounds or salts also can be administered by
inhalation, intravenously, or intramuscularly as a liposomal
suspension. When administered through inhalation the active
compound or salt can be in the form of a plurality of solid
particles or droplets having any desired particle size, and for
example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more
microns, and optionally from about 1 to about 2 microns.
[0253] Compounds as disclosed in the present invention have
demonstrated good pharmacokinetic and pharmacodynamics properties,
for instance when administered by the oral or intravenous
routes.
[0254] The pharmaceutical formulations can comprise an active
compound described herein or a pharmaceutically acceptable salt
thereof, in any pharmaceutically acceptable carrier. If a solution
is desired, water may be the carrier of choice for water-soluble
compounds or salts. With respect to the water-soluble compounds or
salts, an organic vehicle, such as glycerol, propylene glycol,
polyethylene glycol, or mixtures thereof, can be suitable. In the
latter instance, the organic vehicle can contain a substantial
amount of water. The solution in either instance can then be
sterilized in a suitable manner known to those in the art, and for
illustration by filtration through a 0.22-micron filter. Subsequent
to sterilization, the solution can be dispensed into appropriate
receptacles, such as depyrogenated glass vials. The dispensing is
optionally done by an aseptic method. Sterilized closures can then
be placed on the vials and, if desired, the vial contents can be
lyophilized.
[0255] In addition to the active compounds or their salts, the
pharmaceutical formulations can contain other additives, such as
pH-adjusting additives. In particular, useful pH-adjusting agents
include acids, such as hydrochloric acid, bases or buffers, such as
sodium lactate, sodium acetate, sodium phosphate, sodium citrate,
sodium borate, or sodium gluconate. Further, the formulations can
contain antimicrobial preservatives. Useful antimicrobial
preservatives include methylparaben, propylparaben, and benzyl
alcohol. An antimicrobial preservative is typically employed when
the formulations is placed in a vial designed for multi-dose use.
The pharmaceutical formulations described herein can be lyophilized
using techniques well known in the art.
[0256] For oral administration a pharmaceutical composition can
take the form of solutions, suspensions, tablets, pills, capsules,
powders, and the like. Tablets containing various excipients such
as sodium citrate, calcium carbonate and calcium phosphate may be
employed along with various disintegrants such as starch (e.g.,
potato or tapioca starch) and certain complex silicates, together
with binding agents such as polyvinylpyrrolidone, sucrose, gelatin
and acacia. Additionally, lubricating agents such as magnesium
stearate, sodium lauryl sulfate, and talc are often very useful for
tableting purposes. Solid compositions of a similar type may be
employed as fillers in soft and hard-filled gelatin capsules.
Materials in this connection also include lactose or milk sugar as
well as high molecular weight polyethylene glycols. When aqueous
suspensions and/or elixirs are desired for oral administration, the
compounds of the presently disclosed host matter can be combined
with various sweetening agents, flavoring agents, coloring agents,
emulsifying agents and/or suspending agents, as well as such
diluents as water, ethanol, propylene glycol glycerin and various
like combinations thereof.
[0257] In yet another embodiment of the host matter described
herein, there are provided injectable, stable, sterile formulations
comprising an active compound as described herein, or a salt
thereof, in a unit dosage form in a sealed container. The compound
or salt is provided in the form of a lyophilizate, which is capable
of being reconstituted with a suitable pharmaceutically acceptable
carrier to form liquid formulation suitable for injection thereof
into a host. When the compound or salt is substantially
water-insoluble, a sufficient amount of emulsifying agent, which is
physiologically acceptable, can be employed in sufficient quantity
to emulsify the compound or salt in an aqueous carrier.
Particularly useful emulsifying agents include phosphatidyl
cholines and lecithin.
[0258] Additional embodiments provided herein include liposomal
formulations of the active compounds disclosed herein. The
technology for forming liposomal suspensions is well known in the
art. When the compound is an aqueous-soluble salt, using
conventional liposome technology, the same can be incorporated into
lipid vesicles. In such an instance, due to the water solubility of
the active compound, the active compound can be substantially
entrained within the hydrophilic center or core of the liposomes.
The lipid layer employed can be of any conventional composition and
can either contain cholesterol or can be cholesterol-free. When the
active compound of interest is water-insoluble, again employing
conventional liposome formation technology, the salt can be
substantially entrained within the hydrophobic lipid bilayer that
forms the structure of the liposome. In either instance, the
liposomes that are produced can be reduced in size, as through the
use of standard sonication and homogenization techniques. The
liposomal formulations comprising the active compounds disclosed
herein can be lyophilized to produce a lyophilizate, which can be
reconstituted with a pharmaceutically acceptable carrier, such as
water, to regenerate a liposomal suspension.
[0259] Pharmaceutical formulations also are provided which are
suitable for administration as an aerosol by inhalation. These
formulations comprise a solution or suspension of a desired
compound described herein or a salt thereof, or a plurality of
solid particles of the compound or salt. The desired formulations
can be placed in a small chamber and nebulized. Nebulization can be
accomplished by compressed air or by ultrasonic energy to form a
plurality of liquid droplets or solid particles comprising the
compounds or salts. The liquid droplets or solid particles may for
example have a particle size in the range of about 0.5 to about 10
microns, and optionally from about 0.5 to about 5 microns. The
solid particles can be obtained by processing the solid compound or
a salt thereof, in any appropriate manner known in the art, such as
by micronization. Optionally, the size of the solid particles or
droplets can be from about 1 to about 2 microns. In this respect,
commercial nebulizers are available to achieve this purpose. The
compounds can be administered via an aerosol suspension of
respirable particles in a manner set forth in U.S. Pat. No.
5,628,984, the disclosure of which is incorporated herein by
reference in its entirety.
[0260] When the pharmaceutical formulations suitable for
administration as an aerosol is in the form of a liquid, the
formulations can comprise a water-soluble active compound in a
carrier that comprises water. A surfactant can be present, which
lowers the surface tension of the formulations sufficiently to
result in the formation of droplets within the desired size range
when hosted to nebulization.
[0261] The term "pharmaceutically acceptable salts" as used herein
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with hosts (e.g., human
hosts) without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the presently disclosed
host matter.
[0262] Thus, the term "salts" refers to inorganic and organic acid
addition salts of compounds of the presently disclosed compounds.
These salts can be prepared by any means known in the art,
including, without limitation, in situ during the final isolation
and purification of the compounds or by separately reacting the
purified compound in its free base form with a suitable organic or
inorganic acid and isolating the salt thus formed. As the compounds
of the presently disclosed host matter are basic compounds, they
are all capable of forming a wide variety of different salts with
various inorganic and organic acids. Acid addition salts of the
basic compounds are prepared by contacting the free base form with
a sufficient amount of the desired acid to produce the salt in the
conventional manner. The free base form can be regenerated by
contacting the salt form with a base and isolating the free base in
the conventional manner. The free base forms may differ from their
respective salt forms in certain physical properties such as
solubility in polar solvents. Pharmaceutically acceptable base
addition salts may be formed with metals or amines, such as alkali
and alkaline earth metal hydroxides, or of organic amines. Examples
of metals used as cations, include, but are not limited to, sodium,
potassium, magnesium, calcium, and the like. Examples of suitable
amines include, but are not limited to,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
The base addition salts of acidic compounds are prepared by
contacting the free acid form with a sufficient amount of the
desired base to produce the salt in the conventional manner. The
free acid form can be regenerated by contacting the salt form with
an acid and isolating the free acid in a conventional manner. The
free acid forms may differ from their respective salt forms
somewhat in certain physical properties such as solubility in polar
solvents.
[0263] Salts can be prepared from inorganic acids sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide such as hydrochloric,
nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus,
and the like. .Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate mesylate, glucoheptonate,
lactobionate, laurylsulphonate and isethionate salts, and the like.
Salts can also be prepared from organic acids, such as aliphatic
mono- and dicarboxylic acids, phenyl-substituted alkanoic acids,
hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, etc. and the like.
Representative salts include acetate, propionate, caprylate,
isobutyrate, oxalate, malonate, succinate, suberate, sebacate,
fumarate, maleate, mandelate, benzoate, chlorobenzoate,
methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,
toluenesulfonate, pheny [acetate, citrate, lactate, maleate,
tartrate, methanesulfonate, and the like. Pharmaceutically
acceptable salts can include cations based on the alkali and
alkaline earth metals, such as sodium, lithium, potassium, calcium,
magnesium and the like, as well as non-toxic ammonium, quaternary
ammonium, and amine cations including, but not limited to,
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the
like. Also contemplated are the salts of amino acids such as
arginate, gluconate, galacturonate, and the like. See, for example,
Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated
herein by reference.
Syntheses
[0264] The disclosed compounds can be made by the following general
schemes:
##STR00132## ##STR00133##
[0265] In Scheme 1, Ref-1 is WO 2010/020675 A1; Ref-2 is White, J.
D.; et at. J. Org, Chem. 1995, 60, 3600; and Ref-3 Presser, A. and
Huffier, A. Monatshefte fur Chemie 2004, 135, 1015.
##STR00134## ##STR00135##
[0266] In Scheme 2, Ref-1 is WO 2010/020675 A1; Ref-4 is WO
2005/040166 and Ref-5 is Schoenauer, K and Zbiral, E. Tetrahedron
Letters 1983, 24 573.
##STR00136##
[0267] In Scheme 3, Ref 1 is WO 2010/020675 A1,
##STR00137##
##STR00138##
##STR00139##
##STR00140##
##STR00141## ##STR00142##
[0268] In Scheme 8, Ref-1 is WO 2010/020675 A1; Ref-2 is WO
2005/040166 A1; and Ref-3 is Schoenauer, K and Zbiral, E.
Tetrahedron Letters 1983, 24, 573.
[0269] Alternatively, the lactam can be generated by reacting the
carboxylic acid with a protected amine in the presence of a strong
acid and a dehydrating agent, which can be together in one moiety
as a strong acid anhydride. Examples of strong acid anhydrides
include, but are not limited to, trifluoroacetic acid anhydride,
tribromoacetic acid anhydride, trichloroacetic acid anhydride, or
mixed anhydrides. The dehydrating agent can be a carbodiimide based
compound such as but not limited to DCC
(N,N-dicyclohexylcarbodiimide), EDC
(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DIC
(N,N-diisopropylcarbodiimide). An additional step may be necessary
to take off the N-protecting group and the methodologies are known
to those skilled in the art.
[0270] Other amine intermediates and final amine compounds can be
synthesized by those skilled in the art. It will be appreciated
that the chemistry can employ reagents that comprise reactive
functionalities that can be protected and de-protected and will be
known to those skilled in the art at the time of the invention. See
for example, Greene, T M, and Wuts, P. G. M., Greene's Protective
Groups in Organic Synthesis, 4.sup.th edition, John Wiley and
Sons.
EXAMPLES
[0271] Intermediates B, E, K, L, 1A, 1E and 1CA were prepared
according to the methods of Tavares, F. X. and Strum, J. C., See,
U.S. Pat. No. 8598,186 entitled CDK inhibitors. Patents U.S. Pat.
No. 8,598,186 entitled CDK Inhibitors to Tavares, F. X.and Strum,
J. C., WO 2013/163239 entitled Synthesis of Lactams to Tavares, F.
X., and WO 2013/148748 entitled Lactam Kinase Inhibitors to
Tavares, F. X. are herein incorporated by reference in their
entirety.
Example 1
Synthesis of tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4yl)amino]ethyl]carbamate,
Compound 1
##STR00143##
[0273] To a solution of 5-bromo-2,4-dichloropyrimidine (3.2 g,
0.0135 mol) in ethanol (80 mL) was added Hunig's base (3.0 mL)
followed by the addition of a solution of
N-(tert-butoxycarbonyl)-1,2-diaminoethane (2.5 g, 0.0156 mole) in
ethanol (20 mL). The contents were stirred overnight for 20 hrs.
The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and
water (100 mL) were added and the layers separated. The organic
layer was dried with magnesium sulfate and then concentrated under
vacuum. Column chromatography on silica gel using hexane/ethyl
acetate (0-60%) afforded tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yk)amino]ethyl]carbamate.
.sup.1HNMR (d6-DMSO) .delta. ppm 8.21 (s, 1H), 7.62 (brs, 1H), 7.27
(brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351
(M+H).
Example 2
Synthesis of tert-butyl
N-[2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-y]amino]ethyl]carba-
mate, Compound 2
##STR00144##
[0275] To tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (1.265
g, 3.6 mmol) in THF (10 mL) was added the acetal (0.778 mL, 5.43
mmol), Pd(dppOCH.sub.2Cl.sub.2 (148 mg), and triethylamine (0.757
mL, 5.43 mmol). The contents were degassed and then purged with
nitrogen. To this was then added CuI (29 mg). The reaction mixture
was heated at reflux for 48 hrs. After cooling, the contents were
filtered over CELITE.TM. and concentrated. Column chromatography of
the resulting residue using hexanelethyl acetate (0-30%) afforded
tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]car-
bamate. .sup.1HNMR (d6-DMSO) .delta. ppm 8.18 (s, 1H), 7.63 (brs,
1H), 7.40 (brs, 1H), 5.55 (s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.42
(m, 2H), 3.15 (m, 2H), 1.19-1.16 (m, 15H). LCMS (ESI) 399
(M+H).
Example 3
Synthesis of tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carba-
mate, Compound 3
##STR00145##
[0277] To a solution of the coupled product (2.1 g, 0.00526 mole)
in THF (30 mL) was added TBAF solid (7.0 g). The contents were
heated to and maintained at 65 degrees for 2 hrs, Concentration
followed by column chromatography using ethyl acetate/hexane
(0-50%) afforded tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carba-
mate as a pale brown liquid (1.1 g). .sup.1HNMR (d6-DMSO) .delta.
ppm 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29
(m, 2H), 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H),
1.17 (m, 6H).
[0278] LCMS (ESI) 399 (M+H).
Example 4
Synthesis of tert-butyl
N-[2-(2-chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate,
Compound 4
##STR00146##
[0280] To the acetal (900 mg) from the preceeding step was added
AcOH (8.0 mL) and water (1.0 mL). The reaction was stirred at room
temperature for 16 hrs. Cone, and column chromatography over silica
gel using ethyl acetate/hexanes (0-60%) afforded tort-butyl
N-[2-(2-chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate
as a foam (0.510 g). (d6-DMSO) .delta. ppm 9.98 (s, 1H), 9.18 (s,
1H), 7.66 (s, 1H), 6.80 (brs, 1H) 4.52 (m, 2H) 4.36 (m, 2H), 1.14
(s, 9H).
[0281] LCMS (ESI) 325 (M+H).
Example 5
Synthesis of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-
-carboxylic acid, Compound 5
##STR00147##
[0283] To the aldehyde (0.940 g) from the preceeding step in DMF (4
mL) was added ozone (1.95 g, 1.1 eq). The contents were stirred at
room temp for 7 hrs. Silica gel column chromatography using
hexane/ethyl acetate (0-100%) afforded
7-[2-(tert-butoxycarbonylamino)ethyl]-Z-chloro-pyrrolo[2,3-d]pyrimidine-6-
-carboxylic acid (0.545 g). .sup.1HNMR (d6-DMSO) .delta. ppm 9.11
(s, 1H), 7.39 (s, 1H), 4.38 (m, 2H), 4.15 (m, 2H), 1.48 (m, 9H).
LCMS (ESI) 341(M+H).
Example 6
Synthesis of methyl
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-
-carboxylate, Compound 6
##STR00148##
[0285] To a solution of
2-chloro-7-propyl-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.545
g, 0.00156 mole) from the preceeding step in toluene (3.5 mL) and
MeOH (1 mL) was added TMS-diazomethane (1.2 mL). After stirring
overnight at room temperature, the excess of TMS-diazomethane was
quenched with acetic acid (3 mL) and the reaction was concentrated
under vacuum. The residue was purified by silica gel column
chromatography with hexane/ethyl acetate (0-70%) to afford methyl
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-
-carboxy late as an off white solid (0.52 g). .sup.1HNMR (d6-DMSO)
8 ppm 9.10 (s, 1H), 7.45 (s, 1H), 6.81 (brs, 1H) 4.60 (iii, 2H),
3.91 (s, 3H), 3.29 (m, 2H), 1.18 (m, 9H) LCMS (ESI) 355 (M+H).
Example 7
Synthesis of Chloro tricyclic amide, Compound 7
##STR00149##
[0287] To methyl
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-
-carboxylate (0.50 g, 0.0014 mole) from the preceeding step in
dichloromethane (2.0 mL) was added TFA (0.830 mL). The contents
were stirred at room temperature for 1 hr. Concentration under
vacuum afforded the crude amino ester which was suspended in
toluene (5 mL) and Hunig's base (0.5 mL). The contents were heated
at reflux for 2 hrs. Concentration followed by silica gel column
chromatography using hexanelethyl acetate (0-50%) afforded the
desired chloro tricyclic amide (0.260 g). (d6-DMSO) 6 ppm 9.08 (s,
1H), 8.48 (brs, 1H), 7.21 (s, 1H) 4.33 (m, 2H), 3.64 (m, 2H), LCMS
(ESI) 223 (M+H).
Example 8
Synthesis of chloro-N-methyltricyclic amide, Compound 8
##STR00150##
[0289] To a solution of the chloro tricycliclactam, Compound 7,
(185 mg, 0.00083 mole) in DMF (2.0 mL) was added sodium hydride
(55% dispersion in oil, 52 mg). After stirring for 15 mins, methyl
iodide (62 .mu.L, 1.2 eq). The contents were stirred at room
temperature for 30 mins. After the addition of methanol (5 mL), sat
NaCO.sub.3 was added followed by the addition of ethyl acetate.
Separation of the organic layer followed by drying with magnesium
sulfate and concentration under vacuum afforded the N-methylated
amide in quantitative yield. .sup.1HNMR (d6-DMSO) .delta. ppm 9.05
(s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H).
LCMS (ESI) 237 (M+H).
Example 9
Synthesis of 1-methyl-4-(6-nitro-3-pyridyl)piperazine, Compound
9
##STR00151##
[0291] To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmole) in DMF (20
mL) was added N-methylpiperazine (2.96 g, 1.1 eq) followed by the
addition of DIPEA (4.65 mL, 26.7 mmole). The contents were heated
at 90 degrees for 24 hrs. After addition of ethyl acetate (200 mL),
water (100 mL) was added and the layers separated. Drying followed
by concentration afforded the crude product which was purified by
silica gel column chromatography using (0-10%) DCM/Methanol.
[0292] .sup.1HNMR (d6-DMSO) .delta. ppm 8.26 (s, 1H), 8.15 (1H, d,
J=9.3 Hz), 7.49 (1H, d, J=9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22
(s, 3H).
Example 10
Synthesis of 5(4-methylpiperazin-1-yl)pyridin-2-amine, Compound
10
##STR00152##
[0294] To 1-methyl-4-(6-nitro-3-pyridyl)piperazine (3.4 g) in ethyl
acetate (100 mL) and ethanol (100 mL) was added 10% Pd/C (400 mg)
and then the reaction was stirred under hydrogen (10 psi)
overnight. After filtration through CELITE.TM., the solvents were
evaporated and the crude product was purified by silica gel column
chromatography using DCM/7N ammonia in MeOH (0-5%) to afford
5-(4-methylpiperazin-1-yppyridin-2-amine (2.2 g). (d6-DMSO) .delta.
ppm 7.56 (1H, d, J=3 Hz), 7.13 (1H, m), 6.36 (1H, d, J=8.8 Hz),
5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).
Example 11
Synthesis of tert-butyl
4-(6-amino-3-pyridyl)piperazine-1-carboxylate, Compound 11
##STR00153##
[0296] This compound was prepared as described in WO 2010/020675
A1.
Example 12
Synthesis of tert-butyl
N-benzyloxycarbonylamino)-3-methyl-butyl]carbamate, Compound 12
##STR00154##
[0298] To benzyl N[1-(hydroxymethyl)-2-methyl-propyl]carbamate
(11.0 g, 0.0464 mole) in dioxane (100 mL) cooled to 0.degree. C.
was added diphenylphosphoryl azide (10.99 mL, 1 eq) followed by the
addition of DBU (8.32 mL, 1.2 eq). The contents were allowed to
warm to room temperature and stirred for 16 hrs. After the addition
of ethyl acetate (300 mL) and water (100 mL), the organic layer was
separated and washed with satd. NaHCO.sub.3 (100 mL). The organic
layer was then dried (magnesium sulfate) and concentrated under
vacuum. To this intermediate in DMSO (100 mL) was added sodium
azide (7.54 g) and the contents then heated to 90 degrees for 2
hrs. After addition of ethyl acetate and water the layers were
separated. The organic layer was dried with magnesium sulfate
followed by concentration under vacuum to afford an oil that was
purified by silica gel column chromatography using hexanelethyl
acetate (0-70%) to afford benzyl
N-[-1-(azidomethyl)-2-methyl-propyl] carbamate 6.9 g as a colorless
oil.
[0299] To benzyl N-[1-(azidomethyl)-2-methyl-propyl] carbamate (6.9
g, 0.0263 mole) in THF (100 mL) was added triphenyl phosphine (7.59
g, 1.1 eq). The contents were stirred for 20 hrs. After addition of
water (10 mL), and stirring for an additional 6 hrs, ethyl acetate
was added and the layers separated. After drying with magnesium
sulfate and concentration under vacuum, the crude product was
purified by silica gel column chromatography using DCM/MeOH (0-10%)
to afford benzyl N-[1-(aminomethyl)-2-methyl-propyl] carbamate as a
yellow oil.
[0300] To benzyl N-[1-(aminomethyl)-2-methyl-propyl] carbamate
(4.65 g, 0.019 mole) in THF (70 mL) was added 2N NaOH (20 mL)
followed by the addition of di-tert-butyl dicarbonate (5.15 g, 1.2
eq). After stirring for 16 hrs, ethyl acetate was added and the
layers separated. After drying with magnesium sulfate and
concentration under vacuum, the crude product was purified using
hexane; ethyl acetate (0-40%) over a silica gel column to afford
intermediate A, tert-butyl N-[2-(benzyloxycarbonyl
amino)-3-methyl-butyl] carbamate, (6.1 g). .sup.1HNMR (600 MHz,
CHLOROFORM-d) .delta. ppm 0.89 (d,1=6.73 Hz, 3H) 0.92 (d, J=6.73
Hz, 3H) 1.38 (s, 9H) 1.70-1.81 (m, 1H) 3.18 (d, J=5.56 Hz, 2H)
3.47-3.60 (m, 1H) 4.76 (s, 1H) 4.89 (d, J=7.90 Hz. 1H) 5.07 (s, 2H)
7.25-7.36 (m, 5H). LCMS (ESI) 337 (M+H).
Example 13
Synthesis of tert-butyl
N-[2-(benzyloxycarbonylamino)-4-methyl-pentyl] carbamate, Compound
13
##STR00155##
[0302] To a solution of benzyl
N-[1-(hydroxymethyl)-3-methyl-butyl]carbamate (6.3 g, 0.025 mole)
in DCM (100 mL) was added diisopropylethyl amine (5.25 mL, 1.2 eq)
followed by the addition of methane sulfonylchloride (2.13 mL, 1.1
eq) at 0 degrees. After stirring for 3 hrs, water (100 mL) was
added and the organic layer separated. After drying with magnesium
sulfate and concentration under vacuum, the crude
[2-(benzyloxycarbonylamino)-4-methyl-pentyl] methanesulfonate which
was taken directly to the next step.
[0303] To the crude [2-(benzyloxycarbonylamino)-4-methyl-pentyl]
methanesulfonate from the above reaction in I)MF (50 mL), was added
sodium azide 2.43 g. The reaction mixture was then heated to 85
degrees for 3 hrs. After cooling, ethyl acetate (300 mL) and water
was added. The organic layer was separated, dried with magnesium
sulfate and then concentrated under vacuum to afford the crude
benzyl N-[1-(azidomethyl)-3-methyl-butyl] carbamate. To this crude
intermediate was added THF (100 mL) followed by triphenylphosphine
7.21 g and stirred under nitrogen for 16 hrs. After addition of
water (10 mL), and stirring for an additional 6 hrs, ethyl acetate
was added and the layers separated. After drying with magnesium
sulfate and concentration under vacuum, the crude product was
columned using DCM/MeOH (0-10%) to afford benzyl
N-[1-(aminomethyl)-3-methyl-butyl] carbamate (4.5 g).
[0304] To benzyl N-[1-(aminomethyl)-3-methyl.-butyl] carbamate (4.5
g, 0.018 mole) in THF (60 mL) was added 2N NaOH (18 mL) followed by
the addition of di-tert-butyl dicarbonate (4.19 g, 1.07 eq). After
stirring for 16 hrs, ethyl acetate was added and the layers
separated. After drying with magnesium sulfate and concentration
under vacuum, the crude product was taken to the next step.
.sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm 0.89 (d, J=6.73 Hz,
6H) 1.25-1.34 (m, 1H) 1.39 (s, 9H) 1.57-1.71 (m, 2H) 3.04-3.26 (m,
2H) 3.68-3.80 (m, 1H) 4.72-4.89 (m, 2H) 5.06 (s, 2H) 7.25-7.38 (m,
5H). LCMS (ESI) 351 (M+H).
Example 14
Synthesis of tert-butyl
N-[(2R)-2-(benzyloxycarbonylamino)-3-methyl-butyl] carbamate,
Compound 14
##STR00156##
[0306] Compound 14 was synthesized from benzyl
N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using similar
synthetic steps as that described for Compound 13. The analytical
data (NMR and mass spec) was consistent with that for Compound
12.
Example 15
Synthesis of tert-butyl
N-[(2S)-2-(benzyloxycarbonylamino)-3-methyl-butyl]carbamate,
Compound 15
##STR00157##
[0308] Compound 15 was synthesized from benzyl
N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using similar
synthetic steps as that described for Compound 13. The analytical
data (NMR and mass spec) was consistent with that for Compound
12.
Example 16
Synthesis of tert-butyl N-](1S)-1-(aminomethyl)-2-methyl-propyl
carbamate, Compound 16
##STR00158##
[0310] To a solution of tert-butyl
N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]carbamate (6.3 g, 0.025
mole) in THF (100 mL) was added diisopropylethyl amine (5.25 mL,
1.2 eq) followed by the addition of methane sulfonylchloride (2.13
mL, 1.1 eq) at 0 degrees. After stirring for 3 hrs, water (100 mL)
was added and the organic layer separated. After drying with
magnesium sulfate and concentration under vacuum, the crude
[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyl] methanesulfonate
was taken directly to the next step.
[0311] To the crude
[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyl] methanesulfonate
from the above reaction in DMSO (50 mL), was added sodium azide
(2.43 g). The reaction mixture was then heated to 85 degrees for 3
hrs. After cooling, ethyl acetate (300 mL) and water were added.
The organic layer was separated, dried with magnesium sulfate and
then concentrated under vacuum to afford the crude benzyl
N-[1-(azidomethyl)-3-methyl-butyl] carbamate. To this crude
intermediate was added THF (100 mL) followed by triphenylphosphine
(7.21 g) and the reaction was stirred under nitrogen for 16 hrs.
After addition of water (10 mL), and stirring for an additional 6
hrs, ethyl acetate was added and the layers separated. After drying
with magnesium sulfate and concentration under vacuum, the crude
product was purified by silica gel column chromatography using
DCM/MeOH (0-10%) to afford benzyl
N-]1-(aminomethyl)-3-methyl-butyl] carbamate (4.5 g). LCMS (ESI)
203 (M+H).
Example 17
Synthesis of tert-butyl
N-[(1R)-1-(aminomethyl)-2-methyl-propyl]carbamate. Compound 17
##STR00159##
[0313] Compound 17 was synthesized from tert-butyl
N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using a
similar synthetic sequence as described for Compound 16. The
analytical data (NMR and mass spec) was consistent with Compound
16.
Example 18
Synthesis of tert-butyl
N-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentyl] carbamate,
Compound 18
##STR00160##
[0315] Compound 18 was synthesized from benzyl
N-](1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamate using a similar
synthetic sequence as described for Compound 13. The analytical
data (NMR and mass spec) was consistent with Compound 13.
Example 19
Synthesis of tert-butyl
N-[(2S)-2-(benzloxycarbonylamino)-2-phenyl-ethyl] carbamate,
Compound 19
##STR00161##
[0317] Compound 19 was synthesized from benzyl
N-[(1S)-2-hydroxy-1-phenyl-ethyl] carbamate using a similar
synthetic sequence as described for Compound 13. .sup.1HNMR (600
MHz, DMSO d.sub.6) .delta. ppm 1.20-1.33 (m, 9H) 3.11 (t, J=6.29
Hz, 2H) 4.59-4,68 (m, 1H) 4.88-5.01 (m, 2H) 6.81 (t, J=5.42 Hz, 1H)
7.14-7.35 (m, 10H) 7.69 (d, J=8.49 Hz, 1H). LCMS (ESI) 371
(M+H).
Example 20
Synthesis of tert-butyl
N-[(2S)-2-(benzyloxycarbonylamino)-3-methyl-pentyl] carbamate,
Compound 20
##STR00162##
[0319] Compound 20 was synthesized from benzyl
N-[(1S)-1-(hydroxymethyl)-2-methyl-butyl] carbamate using a similar
synthetic sequence as described for Compound 13. .sup.1HNMR (600
MHz, CHLOROFORM-d) .delta. ppm 0.85-0.92 (m, 6H) 1.05-1.15(m,
1H)1.35-1.41(m,9H) 1.45-1.56 (m, 2H) 3.14-3.24 (m, 2H) 3.54-3.64
(m, 1H) 4.78 (s, 1H) 4.96 (d, =7.91 Hz, 1H) 5.06 (s, 2H) 7.27-7.37
(m, 5H), LCMS (ESI) 351 (M+H).
Example 21
Synthesis of tert-butyl
N-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butyl] carbamate,
Compound 21
##STR00163##
[0321] Compound 21 was synthesized from benzyl
N-[(1S)-1-(hydroxymethyl)-2,2-dimethyl-propyl]carbamate using a
similar synthetic sequence as described for Compound 13. LCMS (ESI)
351.
Example 22
Synthesis of tert-butyl
N-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl] carbamate,
Compound 22
##STR00164##
[0323] To a solution of benzyl
N-[1-(aminomethyl)cyclohexyl]carbamate (10.0 g, 0.0381 mole) in THF
(150 mL) was added di-tert-butyl dicarbonate (9.15 g, 1.1 eq) and
the contents were stirred at room temperature for 16 hrs. Ethyl
acetate and water were then added. The organic layer was separated,
dried over magnesium sulfate and then concentrated under vacuum to
afford text-butyl N-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl]
carbamate (13.1 g). .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
0.92-1.54 (m, 17H) 1.76-2.06 (m, 2H) 3.09 (d, J=6.15 Hz, 2H) 4.92
(s, 2H) 6.63 (d, J=17.27 Hz, 1H) 7.16-7.49 (m, 6H). LCMS (ESI) 363
(M+H).
Example 23
Synthesis of tert-butyl
N-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl] carbamate,
Compound 23
##STR00165##
[0325] Tert-butyl
N-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl]carbamate was
synthesized in an analogous manner to tert-butyl
N-[[1-(benzyloxycarbonylamino) cyclohexyl]methyl]carbamate. LCMS
(ESI) 349 (M+H).
Example 24
Synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine,
Compound 24
##STR00166##
[0327] To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL)
was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and
triethylamine (0.99 mL, 7.1 mmole). The contents were heated to
120.degree. C. in a GEM Discovery microwave system for 3 hours. The
crude reaction was then purified by silica gel column
chromatography with DCM/methanol (0-20%) to afford
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg).
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.26-1.36 (m, 2H)
1,43 (m, 6H) 1.76 (m, 2H) 2.37 (m, 5H) 2.94 (d, J=12.74 Hz, 2H)
4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1H) 8.08 (d,
J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz, 1H).
Example 25
Synthesis of 5-[(4-(1-piperidyl)-1-piperidyl]pyridin-2-amine,
Compound 25
##STR00167##
[0329] 5-[4-(1-piperidyl)-1-piperidylipyridin-2-amine was prepared
in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.13-1.37 (m, 6H) 1.40-1.63 (m, 6H) 1.71
(m, 2H), 2.24 (m, 1H) 2.43 (m, 2H) 3.33 (d, J=12.30 Hz, 2H) 5.31
(s, 2H) 6.33 (d, J=8.78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55
(d, J=2.64 Hz, 1H). LCMS (ESI) 261 (M+H).
Example 26
Synthesis of 4-[1-(6-nitro-3-pyridyl)-4-piperidyl]morpholine,
Compound 26
##STR00168##
[0331] 4-[1-(6-nitro-3-pyridyl)-4-piperidyl]morpholine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl pyridine. .sup.1HNMR (600
MHz, DMSO-d.sub.6) .delta. ppm 1.41 (m, 2H) 1.82 (m, 2H) 2.42 (m,
5H) 2.98 (t, J=12.44 Hz, 2H) 3.52 (s, 4H) 4.04 (d, J=12.88 Hz, 2H)
7.42 (d, J=9.37 Hz, 1H) 8.08 (d, J=9.08 Hz, 1H) 8.21 (s, 1H).
Example 27
Synthesis of 5-(4-morpholino-1-piperidyl) pyridin-2-amine, Compound
27
##STR00169##
[0333] 5-(4-morpholino-1-piperidyl)pyridin-2-amine was prepared in
a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR. (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.34-1.52 (m, 2H) 1.78 (m, 2H) 2.14 (m,
1H) 2.43 (m, 4H) 3.32 (d, J=12.30 Hz, 4H) 3.47-3.59 (m, 4H) 5.32
(s, 2H) 6.34 (d, J=8.78 Hz, 1H) 7.11 (dd, J=8.93, 2.78 Hz, 1H)
7.47-7.62 (m, 1H), LCMS (ESI) 263 (M+H),
Example 28
Synthesis of 4-[1-(6-nitro-3-pyridyl)-4-piperidyl] thiomorpholine.
Compound 28
##STR00170##
[0335] 4-[1-(6-nitro-3-pyridyl)-4-piperidyl] thiomorpholine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. .sup.1HNMR (600
MHz, DMSO-d.sub.6) .delta. ppm 1.40-1.52 (m, 2H) 1,71 (m, 2H)
2.49-2.55 (m, 4H) 2.56-2.63 (m, 1H) 2.68-2.75 (m, 4H) 2.88-2.98 (m,
2H) 4.09 (d, J=13.18 Hz, 2H) 7.42 (dd, J=9.22, 3.07 Hz, 1H) 8.08
(d, J=9.37 Hz, 1H) 8.20 (d, J=3.22 Hz, 1H).
Example 29
Synthesis of 5-(4-thiomorpholino-1-piperidyl) pyridin-2-amine,
Compound 29
##STR00171##
[0337] 5-(4-thiomorpholino-1-piperidyl) pyridin-2-amine was
prepared in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.47-1.59 (m, 2H) 1.65 (m, 2H) 2.22-2,38
(m, 1H) 2.50-2.59 (m, 6H) 2.68-2.82 (m, 4H) 3.33 (d, J=12.00 Hz,
2H) 5.31 (s, 2H) 6.33 (d, J=9.08 Hz, 1H) 7.10 (dd,J=8.78, 2.93 Hz,
1H) 7.55 (d, J=2.64 Hz, 1H). LCMS (ESI) 279 (M+H).
Example 30
Synthesis of 2-nitro-5-(1-piperidyl)pyridine, Compound 30
##STR00172##
[0339] 2-nitro-5-(1-piperidyl) pyridine was synthesized in a manner
similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. .sup.1HNMR (600
MHz, DMSO-d.sub.6) .delta. ppm 1.56 (m, 6H) 3.49 (d, J=4.39 Hz, 4H)
730-7.47 (m, 1H) 8.02-8,12 (m, 1H) 8.15-8.26 (m, 1H).
Example 31
Synthesis of 5-(1-piperidyl)pyridin-2-amine, Compound 31
##STR00173##
[0341] 5-(1-piperidyl) pyridin-2-amine was prepared in a manner
similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.39-1.46 (m, 2H) 1.51-1.62 (m, 4H)
2.75-2.92 (m, 4H) 5.30 (s, 2H) 6.34 (d. J=8,78 Hz, 1H) 7.09 (dd,
J=8.78, 2.93 Hz, 1H) 7.54 (d, J=2.93 Hz, 1H). LCMS (ESI) 178
(M+H).
Example 32
Synthesis of 4-(6-nitro-3-pyridyl) thiomorpholine, Compound 32
##STR00174##
[0343] 4-(6-nitro-3-pyridyl) thiomorpholine was synthesized in a
manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. .sup.1HNMR (600
MHz, DMSO-d.sub.6) .delta. ppm 2.56-2.69 (m, 4H) 3.79-3 92 (m, 4H)
7.43 (dd, J=9.22, 3.07 Hz, 1H) 8.10 (d, J=9.37 Hz, 1H) 8.20 (d,
J=2.93 Hz, 1H).
Example 33
Synthesis of 5-thiomorpholinopyridin-2-amine, Compound 33
##STR00175##
[0345] 5-thiomorpholinopyridin-2-amine was prepared in a manner
similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)
pyridin-2-amine. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
2.59-2.73 (m, 4H) 3.04-3.20 (m, 4H) 5.41 (s, 2H) 6.35 (d, J=8.78
Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.57 (d, J=2.64 Hz, 1H).
LCMS (ESI) 196 (M+H).
Example 34
Synthesis of tert-butyl
(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,
Compound 34
##STR00176##
[0347] tert-butyl
(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
was synthesized in a manner similar to that used in the synthesis
of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. .sup.1HNMR (600
MHz, DMSO-d.sub.6) .delta. ppm 1.33 (d, J=32,21 Hz, 11H) 1.91 (m,
2H) 3.15 (d, J=10.25 Hz, 1H) 3.58 (m, 1H) 4.46 (m, 1H) 4.83 (s, 1H)
7.16 (s, 1H) 7.94 (s, 1H) 8.05-8.16 (m, 1H).
Example 35
Synthesis of tert-butyl (4R
)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1.]heptane-2-carboxylate,
Compound 35
##STR00177##
[0349] tert-butyl
(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
was prepared in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0350] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.31 (d,
J=31.91 Hz, 11H) 1.83 (m, 2H) 2.71-2.82 (m, 1H) 3.44 (m,1H) 4.30
(d, 2H) 5.08 (s, 2H) 6.35 (d, J=8.78 Hz, 1H) 6.77-6.91 (m, 1H) 7.33
(s, 1H). LCMS (ESI) 291 (M+H).
Example 36
Synthesis of N,N-dimethyl-1-(6-nitro-3-pyridyl)piperidin-4-amine,
Compound 36
##STR00178##
[0352] N,N-dimethyl-1-(6-nitro-3-pyridyl) piperidin-4-amine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. .sup.1HNMR (600
MHz, DMSO-d.sub.6) .delta. ppm 1.30-1.45 (m, 2H) 1.79 (m, 2H) 2.14
(s, 6H) 2.33 (m, 1H) 2.92-3.04 (m, 2H) 4.03 (d, J=13.76 Hz, 2H)
7.42 (dd, J=9.22, 3.07 Hz, 1H) 8.04-8.11 (m, 1H) 8.21 (d, J=2.93
Hz, 1H).
Example 37
Synthesis of 5-[4-(dimethylamino)-1-piperidyl] pyridin-2-amine,
Compound 37
##STR00179##
[0354] 5-[4-(dimethylamino)-1-piperidyl)pyridin-2-amine was
prepared in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.35-1.50 (m, 2H) 1.69-1,81 (m, 2H)
2,00-2.10 (in, 1 14) 2.11-2.22 (s, 6H) 3.17-3.36 (m, 4H) 5.19-5.38
(s, 2H) 6.34 (d, J=8.78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55
(d, J=2.63 Hz, 1H). LCMS (ESI) 221 (M+H).
Example 38
Synthesis of 4-(6-nitro-3-pyridyl) morpholine, Compound 38
##STR00180##
[0356] 4-(6-nitro-3-pyridyl) morpholine was synthesized in a manner
similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl] pyridine.
Example 39
Synthesis of 5-morpholinopyridin-2-amine, Compound 39
##STR00181##
[0358] 5-morpholinopyridin-2-amine was prepared in a manner similar
to that used in the synthesis of 5-(4-methylpiperazin-1-yl)
pyridin-2-amine. .sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm
2.91-3.00 (m, 4H) 3.76-3.84 (m, 4H) 4.19 (br. s., 2H) 6.45 (d,
J=8.78 Hz, 1H) 7.12 (dd, J=8.78, 2.93 Hz, 1H) 7.72 (d, J=2.93 Hz,
1H).
Example 40
Synthesis of 5-(4-isobutylpiperazin-1-yl) pyridin-2-amine, Compound
40
##STR00182##
[0360] 1-isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized
in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl pyridine which was then
converted 5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner
similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
CHLOROFORM-d) .delta. ppm 0.88 (d, J=6.73 Hz, 6H) 1.71-1.84 (m, 1H)
2.10 (d, J=7.32 Hz, 2H) 2.46-2.58 (m, 4H) 2.97-3.07 (m, 4H) 4.12
(s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.75
(d, J=2.93 Hz, 1H). LCMS (ESI) 235 (M+H).
Example 41
Synthesis of 5-(4-isopropylpiperazin-1-yl) pyridin-2-amine,
Compound 41
##STR00183##
[0362] 1-isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized
in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted to 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a
manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
CHLOROFORM-d) .delta. ppm 1.06 (d, J=6.41 Hz, 6H) 2.59-2.75 (m, 5H)
2.97-3.10 (m, 4H) 4.13 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.15 (dd,
J=9.08, 2.93 Hz, 1H) 7.76 (d, J=2.93 Hz, 1H), LCMS (ESI) 221
(M+H).
Example 42
Synthesis of 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine,
Compound 42
##STR00184##
[0364] (2S,6R)-2,6-dimethyl-4-(6-nitro-3-pyridyl)morpholine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted to 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine
in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
CHLOROFORM-d) .delta. ppm 1.20 (d, J=6.44 Hz, 6H) 2.27-2.39 (m, 2H)
3.11-3.21 (m, 2H) 3.70-3.84 (m, 2H) 4.15 (s, 2H) 6.45 (d, J=8.78
Hz, 1H) 7.12 (dd, J=8.78, 2.93 Hz, 1H) 7.72 (d, J=2.63 Hz, 1H).
LCMS (ESI) 208 (M+H).
Example 43
Synthesis of 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine,
Compound 43
##STR00185##
[0366] (3S,5R)-3,5-dimethyl-1-(6-nitro-3-pyridyl)piperazine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted to 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine
in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1HNMR (600 MHz,
CHLOROFORM-d) .delta. ppm 1.09 (d, J=6.44 Hz, 6H) 2.20 (t, J=10.83
Hz, 2H) 2.95-3.08 (m, 2H) 3.23 (dd, J=11.71, 2.05 Hz, 2H) 4.13 (s,
2H) 6.45 (d, J=8.78 Hz, 1H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.73 (d,
J=2.63 Hz, 1H). LCMS (ESI) 207 (M+H).
Example 44
Synthesis of Compound 44
##STR00186##
[0368] tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]
carbamate
##STR00187##
[0369] A solution of intermediate A in ethanol (100 mL) was
hydrogenated under 30 psi of hydrogen using 10% Pd/C (0.7 g) in a
pressure bomb for 7 hrs. After filtration of the reaction mixture
through CELITE.TM., the organic layer was concentrated under vacuum
to afford text-butyl N-(2-amino-3-methyl-butyl) carbamate (3.8
g).
[0370] To a solution of 5-bromo-2,4-dichloro-pyrimidine (7.11 g,
0.0312 mole) in ethanol (100 mL) was added diisopropylethyl amine
(5.45 mL, 1.0 eq) and tert-butyl N-(2-amino-3-methyl-butyl)
carbamate (6.31 g, 0.0312 mole). The reaction mixture was stirred
at room temperature for 20 hrs. After concentration under vacuum,
ethyl acetate and water were added. The organic layer was
separated, dried with magnesium sulfate and then concentrated under
vacuum. The crude product was purified by silica gel column
chromatography using hexane/ethyl acetate (0-30%) to afford
tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]
carbamate.
[0371] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.77-0.85 (d,
J=6.5 Hz, 3H) 0.87 (d, J=6.73 Hz. 3H) 1.31-1.39 (m, 9H) 1.82-1.93
(m, 1H) 2.94 (d, J=5.56 Hz, 1H) 3.08-3.22 (m, 2H) 3.98 (d, J=8.20
Hz, 1H) 6.96 (d, J=8.78 Hz, 1H) 8.21 (s, 1H) LCMS (ESI) 393
(M+H).
tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]--
3-methyl-butyl]carbamate
##STR00188##
[0373] tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methyl-b-
utyl]carbamate was synthesized by hosting tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate
to Sonogoshira conditions as described for tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]car-
bamate followed by subsequent treatment with TBAF as described in
the synthesis of tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carba-
mate. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.11 (d,
J=6.44 Hz, 3H) 1.18 (t, J=7.03 Hz, 6H) 1.21-1.26 (m, 12H) 2.88 (br.
s., 1H) 3.43-3.78 (m, 6H) 3.97-4.08 (m, 1H) 5.61 (s, 1H) 6.65 (s,
1H) 6.71-6.78 (m, 1H) 8.87 (s, 1H). LCMS (ESI) 441 (M+H).
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-7-chloro-pyrrolo[-
2,3-d]pyrimidine-6-carboxylic acid
##STR00189##
[0375] To a solution tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]car-
bamate in THF was added TBAF and the contents were heated at reflux
for 3 hrs. Ethyl acetate and water were then added and the organic
layer separated, dried with magnesium sulfate and then concentrated
under vacuum. To this crude reaction was added acetic acid/water
(9:1) and the contents were stirred for 12 hrs at room temperature.
After concentration under vacuum, sat NaHCO.sub.3 and ethyl acetate
were added. The organic layer was separated, dried and then
concentrated under vacuum. The crude reaction product thus obtained
was dissolved in axone was then added and the contents stirred for
3 hrs. After addition of ethyl acetate, the reaction mixture was
filtered through CELITE.TM. and concentrated under vacuum. Column
chromatography of the crude product over silica gel using
hexane/ethyl acetate (0-100%) afforded
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 0.85 (d, J=7.03 Hz, 3H) 0.97 (d, J=6.73
Hz 3H) 1.52 (s, 9H) 1.99-2,23 (m, 1H) 3.98 (dd, J=14.05, 3.51 Hz,
1H) 4.47-4.71 (m, 2H) 7.47 (s, 1H) 9.17 (s, 1H). LCMS (ESI) 383
(M+H).
Compound 44
[0376] To
7-[1-[(tert-butoxycarbonylamino)methyl-propyl]-2-chloro-pyrrolo[-
2,3-d]pyrimidine-6-carboxylic acid (0.050 g, 0.00013 mole) in DCM
(1.5 mL) was added DIC (32.7 mg) and DMAP (10 mg). The contents
were stirred for 2 hrs. Trifluoroacetic acid (0.4 mL) was then
added and stirring continued for an additional 30 minutes. After
addition of said NaHCO.sub.3 to neutralize the excess acid, ethyl
acetate was added and the organic layer separated, dried using
magnesium sulfate and then concentrated under vacuum. The crude
product was purified by silica gel column chromatography using
hexane/ethyl acetate (0-100%) to afford the product.
[0377] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.72 (d,
J=6.73 Hz, 3H) 0.97 (d, J=6.73 Hz. 3H) 2.09-2.22 (m, 1H) 3.57 (dd,
J=13.18, 4.98 Hz, 1H) 3.72 (dd, J=13.61, 4.25 Hz, 1H) 4.53 (dd,
J=8.05, 3.95 Hz, 1H) 7.20 (s, 1H) 8.34 (d, J=4.98 Hz, 1H) 9.08 (s,
1H). LCtS (ESI) 265 (M+H).
Example 45
Synthesis of Compound 45
##STR00190##
[0379] Compound 14 was hydrogenated with 10% Pd/C to afford the
intermediate tert-butyl N-[(2R)-2-amino-3-methyl-butyl] carbamate,
which was then treated with 5-bromo-2,4-dichloro-pyrimidine using
analogous reaction conditions as described for Compound 44 to
afford Compound 45 The analytical data is consistent with that
reported for the racemate (Intermediate 1A).
Example 46
Synthesis of Compound 46
##STR00191##
[0381] Compound 15 was hydrogenated with 10% Pd/C to afford the
intermediate tert-butyl N-[(2S)-2-amino-3-methyl-butyl]carbamate,
which was then treated with 5-bromo-2,4-dichloro-pyrimidine using
analogous reaction conditions as described for Compound 44 to
afford Compound 46. The analytical data (NMR and LCMS) was
consistent with that reported for the racemate Compound 44.
Example 47
Synthesis of Compound 47
##STR00192##
[0383] To a solution of Compound 44 (80 mg, 0.00030 mole) in DMF (3
mL) was added a 60% dispersion of sodium hydride in oil (40 mg).
After stirring for 15 minutes, methyl iodide (37 .mu.L, 2 eq) was
added. The contents were stirred at room temperature for 30
minutes. Saturated NaHCO.sub.3 was then added followed by ethyl
acetate. The organic layer was dried with magnesium sulfate and
then concentrated under vacuum to afford the product. .sup.1HNMR
(600 MHz, DMSO-d.sub.6) .delta. ppm 0.74 (d, J=6.73 Hz, 3H) 0.91
(d, J=6.73 Hz, 3H) 2.04-2.20 (m, 1H) 3.04 (s, 3H) 3.69 (dd,
J=13.76, 1.17 Hz, 1H) 3.96 (dd, J=13.76, 4.68 Hz, 1H) 4.58 (dd,
J=7.32, 3.51 Hz, 1H) 7.16 (s, 1H) 9.05 (s, 1H). LCMS (ESI) 279
(M+H).
Example 48
Synthesis of Compound 48
##STR00193##
[0384] tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbam-
ate
##STR00194##
[0386] Compound 18 was hydrogenated with 10% Pd/C in ethanol under
a blanket of hydrogen at 50 psi in a pressure bomb to afford
tert-butyl N-[(2S)-2-amino-4-methyl-pentyl]carbamate which was then
reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous
reaction conditions as described for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate
to afford tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbam-
ate. .sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm 0.91 (d, J=6.44
Hz, 3H) 0.94 (d, J=6.44 Hz, 3H) 1.32-1.51 (m, 11H) 1.55-1.67 (m,
1H) 3.28 (t1=5.86 Hz, 2H) 4.21-4.42 (m, 1H) 4.84 (s, 1H) 5.84 (d,
J=7.32 Hz, 1H) 8,07 (s, 1H). LCMS (ESI) 407 (M+H).
##STR00195##
[0387] To a solution of tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbam-
ate (5.0 g, 12.3 mmole) in tolune (36 mL) and triethylamine (7.2
was added under nitrogen, 3,3-diethoxyprop-1-yne (2.8 mL, 19.7
mmole), Pd.sub.2(dba).sub.3 (1.1g., 1.23 mmole), and
triphenylarsine (3.8 g, 12.3 mmole). The contents were heated to 70
degrees for 24 hrs. After cooling to room temperature, the reaction
mixture was filtered through CELITE.TM. and then concentrated under
vacuum. The crude product was purified by silica gel column
chromatography using hexane/ethyl acetate (0-30%) to afford
(2S)--N2-[2chloro-5-(3,3,-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-me-
thyl-pentane-1,2-diamine. LCMS (ESI) 455 (M+H).
##STR00196##
[0388]
7-[(1S)-1-[tert-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chlor-
o-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using
the analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 0.88 (d, J=6.44 Hz, 3H) 0.97 (d, J=6.44
Hz, 3H) 1.47 (s, 9H) 1.49-1.54 (m, 1H) 1.56 (t. J=7.17 Hz, 2H) 3.98
(dd, J=13.91, 3.07 Hz, 1H) 3.76 (dd, J=13.31, 4.13 Hz, 1H) 4.38 (d,
J=14.05 Hz, 1H) 4.90 (t, J=7.17 Hz, 1H) 7.41 (s, 1H) 9.11 (s, 1H).
LCMS (M+H) 397.
[0389] Compound 48 was synthesized using an analogous synthetic
sequence as that described for Compound 44. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 0.82 (d, J=6.73 Hz, 3H) 0.97 (d, J=6.44
Hz, 3H) 1.34-1.46 (m, 1H) 1.48-1.65 (m, 2H) 3.40 (dd, J=13.32, 5.42
Hz, 1H) 3.76 (dd, J=13.47, 4.10 Hz, 1H) 4.76-4.92 (m, 1H) 7.17 (s,
1H) 8.34 (d, J=5.27 Hz, 1H) 9.04 (s, 1H).
[0390] LCMS (ESI) 279 (M+H).
Example 49
Synthesis of Compound 49
##STR00197##
[0392] Compound 49 was synthesized in a manner similar to that
described for Compound 47.
[0393] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.82 (d,
J=6.44 Hz, 3H) 0.97 (d, J=6.44 Hz, 3H) 137-1.68 (m, 3H) 3.04 (s,
3H) 3.56 (d, J=13.47 Hz, 1H) 4.00 (dd, J=13.32, 4.25 Hz, 1H)
4.82-4.94 (m, 1H) 7.16 (s, 1H) 9.03 1H). LCMS (ESI) 293 (M+H).
Example 50
Synthesis of Compound 50
##STR00198##
[0394] tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino-3-methyl-pentyl]carbama-
te
##STR00199##
[0396] Compound 20 was hydrogenated using 10% Pd/C under hydrogen
at 50 psi in a pressure vessel to afford tert-butyl
N-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with
5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions
as described for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate
to afford tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbam-
ate. .sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm 0.88-0.95 (m,
6H) 1.11-1.20 (m, 1H) 1.34 (s, 9H) 1.44-1.54 (m, 1H) 1.64-1.72 (m,
1H) 3.17-3.27 (m, 1H) 3.33-3.43 (m, 1H) 4.11-4.21 (m, 1H) 4.81 (s,
1H) 5.92. (d, J=8.20 Hz, 1H) 8.05 (s, 1H). LCMS (ESI) 407.
tert-butyl
N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-
amino]-3-methyl-pentyl]carbamate
##STR00200##
[0398] tert-butyl
N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3-m-
ethyl-pentyl]carbamate was synthesized using similar experimental
conditions to that used in the synthesis of
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine, .sup.1HNMR, (600 MHz, DMSO-d.sub.6) .delta. ppm
0.76-0.89 (m, 6H) 1.03 (q, J=7.22 Hz, 3H) 1.10-1.17 (m, 3H)
1.25-1.42 (m, 11H) 1.59-1.73 (m, 1H) 3.35-3.47 (m, 4H) 3.51-3.73
(m, 2H) 3.99-4.11 (m, 1H) 5.52-5.56 (m, 1H) 6.76-7.03 (m, 2H)
8.12-8.23 (m, 1H). LCMS (ESI) 455 (M+H).
7-[(1S)-1-[(tert-butoxycarbonylamino)methyl]-2-methyl-butyl]-2-chloro-pyrr-
olo[2,3-d]pyrimidine-6-carboxylic acid
##STR00201##
[0400]
7-[(1S)-1-[(tert-butoxycarbonylamino)methyl]-2-methyl-butyl]-2-chlo-
ro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using
the analogous synthetic sequence as that described for
7-[1-(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[-
2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) 5 ppm 0.80 (t, J=7.47 Hz, 3H) 0.86 (d, J=7.03 Hz, 3H)
1.06-1.30 (m, 2H) 1.48 (s, 9H) 1.79-1.96 (m, 1H) 3.95 (dd, J=14.05,
3.22 Hz, 1H) 4.52 (d, J=14.35 Hz, 1H) 4.61-4.73 (m, 1H) 7.43 (s,
1H) 9.13 (s, 1H). LCMS (ESI) 397 (M+H).
[0401] Compound 50 was synthesized using an analogous synthetic
sequence as that described for Compound 44. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 0.74 (t, J=7.32 Hz, 3H) 0.89 (d, J=6.73
Hz, 3H) 1.00-1.12 (m, 2H) 1.82-1.94 (m, 1H) 3.55 (dd, J=13.91, 4.83
Hz, 1H) 3.70 (dd, J=13.61, 4.25 Hz, 1H) 4.57 (dd, J=7.91, 4.10 Hz,
1H) 7.17 (s, 1H) 8.31 (d, J=5.27 Hz, 1H) 9.05 (s, 1H). LCMS (ESI)
279 (M+H).
Example 51
Synthesis of Compound 51
##STR00202##
[0403] Compound 51 was synthesized in a manner similar to Compound
47 . .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.77 (t, J=7.47
Hz, 3H) 0.84 (d, J=6.73 Hz, 3H) 1.07-1.16 (m, 2H) 1.82-1.95 (m, 1H)
3.03 (s, 3H) 3.68 (d, J=13.76 Hz, 1H) 3.96 (dd, J=13.76, 4.39 Hz,
1H) 4.59-4.70 (m, 1H) 7.16 (s, 1H) 9.04 (s, 1H). LCMS (ESI) 293
(M+H).
Example 52
Synthesis of Compound 52
##STR00203##
[0404] tert-butyl N-[(2S
-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]
carbamate
##STR00204##
[0406] Compound 21 was hydrogenated using 10% Pd/C under hydrogen
at 50 psi in a pressure vessel to afford tert-butyl
N-[(2S)-2-amino-3,3-dimethyl-butyl]carbamate which was then reacted
with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction
conditions as described using analogous reaction conditions as
described for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate
to afford tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]car-
bamate. LCMS (ESI) 407 (M+H).
tert-butyl
N-[(2S)-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]am-
ino]-3,3-dimethyl-butyl]carbamate
##STR00205##
[0408] tert-butyl
N-[(2S)-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3,3-d-
imethyl-butyl]carbamate was synthesized using similar experimental
conditions to that used in the synthesis of
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine. LCMS (ESI) 455 (M+H).
7-[(1S)-1-[(tert-butoxycarbonylamino)methyl]-2,2-dimethyl-propyl]-2-chloro-
-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid
##STR00206##
[0410]
7-[(1S)-1-[(tert-butoxycarbonylamino)methyl]-2,2-dimethyl-propyl]-2-
-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized
using the analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. LCMS (ESI) 397 (M+H).
[0411] Intermediate 1F was synthesized using an analogous synthetic
sequence as that described for intermediate 1A. LCMS (ESI) 279
(M+H).
Example 53
Synthesis of Compound 53
##STR00207##
[0413] Compound 53 was synthesized in a manner similar to that
described for Intermediate 1CA.
[0414] LCMS (ESI) 293 (M+H).
Example 54
Synthesis of Compound 54
##STR00208##
[0415] tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]
carbamate
##STR00209##
[0417] Compound 21 was hydrogenated using 10% Pd/C under hydrogen
at 50 psi in a pressure vessel to afford tert-butyl
N-[(2S)-2-amino-2-phenyl-ethyl]carbamate which was then reacted
with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction
conditions as described for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate
to afford tert-butyl
N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbama-
te, .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.32 (s, 9H)
3.29-3.50 (m, 2H) 5.12-5.24 (m, 1H) 7.10 (t, J=5.27 Hz, 1H) 7.21
(t, J=6.88 Hz, 1H) 7.26-7.34 (m, 4H) 7.89 (d, J=7.32 Hz, 1H) 8.24
(s, 1H). LCMS (ESI) 42.7 (M+H).
tert-butyl
N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-
amino]-2-phenyl-ethyl]carbamate
##STR00210##
[0419] tert-butyl
N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-p-
henyl-ethyl]carbamate was synthesized using similar experimental
conditions to those used in the synthesis of
(2S)--N2-2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pen-
tane-1,2-diamine. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
1.14 (t, J=7.03 Hz, 6H) 1.32 (s, 9H) 3.39 (s, 2H) 3.52-3.61 (m, 2H)
3.64-3.73 (m, 2H) 5.17-5.26 (m, 1H) 5.57 (s, 1H) 7.07-7.14 (m, 1H)
7.20-7.25 (m, 1H) 7.26-7.33 (m, 4H) 7.90 (d, J=7.61 Hz, 1H) 8.19
(s, 1H).
[0420] LCMS (ESI) 475 (M+H).
7-[(1S)-2-(tert-butoxycarbonylamino)-1-phenyl-ethyl]-2-chloro-pyrrolo[2,3--
d]pyrimidine-6-carboxylic acid
##STR00211##
[0422]
7-[(1S)-2-(tert-butoxycarbonylamino)-1-phenyl-ethyl]-2-chloro-pyrro-
lo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using the
analogous synthetic sequence as that described for 7-[1
-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-
-d]pyrimidine-6-carboxyic acid. LCMS (ESI) 417 (M+H).
Compound 54
[0423] Compound 54 was synthesized using an analogous synthetic
sequence as that described for Compound 44. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 3.58-3.69 (m, 1H) 4.13 (dd, J=13.47, 4.39
Hz, 1H) 6.07 (d, J=3.81 Hz, 1H) 6.85 (d, J=7.32 Hz, 2H) 7.19-7.31
(m, 3H) 7.34 (s, 1H) 8.27 (d, J=5.27 Hz. 1H) 9.13 (s, 1H). LCMS
(ESI) 299 (M+H).
Example 55
[0424] Synthesis of Compound 55
##STR00212##
[0425] tert-butyl
N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propy-
l] carbamate
##STR00213##
[0426] tert-butyl
N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propy-
l]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine
and Intermediate E using analogous reaction conditions as described
for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
.sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm 0.95-1.02 (m, 6H)
1.35-1.45 (m, 9H) 1.75-1.90 (m, 1H) 3.35-3.48 (m, 1H) 3.52-3.61 (m,
1H) 3.64-3.76 (m, 1H) 4.56 (d, J=8.49 Hz, 1H) 6.47 (s, 1H) 8.07 (s,
1H). LCMS (ESI) 393 (M+H).
tert-butyl
N-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl-
]amino]methyl]-2-methyl-propyl] carbamate
##STR00214##
[0428] tert-butyl
N-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]met-
hyl]-2-methyl-propyl]carbamate was synthesized using similar
experimental conditions to those used in the synthesis
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine. .sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm
0.90-1.00 (m, 6H) 1.18-1.25 (m, 6H) 1.34-1.36 (m, 9H) 1.69-1.90 (m,
1H) 3.34-3.82 (m, 6H) 4.53-4.77 (m, 1H) 5.45-5.55 (m, 1H) 6.37 (dd,
J=15.37, 6.59 Hz, 1H) 6.56 (s, 1H) 8.05 (s, 1H). LCMS (ESI) 441
(M+H).
7-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyl]-2-chloro-pyrrolo[2,3--
d]pyrimidine-6-carboxylic acid
##STR00215##
[0430]
7-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyl]-2-chloro-pyrro-
lo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using the
analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
CHLOROFORM-d) .delta. ppm 0.90 (d, J=6.73 Hz, 3H) 0.96 (d, J=7.03
Hz, 3H) 1.55-1.66 (m, 10H) 4.14 (did J=13.61, 3.95 Hz, 1H)
4.52-4.63 (m, 1H) 4.84 (dd, J=13.61, 1.32 Hz, 1H) 7.37 (s, 1H) 8.95
(s, 1H). LCMS (ESI) 383 (M+H).
Compound 55
[0431] Compound 55 was synthesized using an analogous synthetic
sequence as that described for Compound 44. LCMS (ESI) 265
(M+H).
Example 56
Synthesis of Compound 56
##STR00216##
[0433] Compound 56 was synthesized using
5-bromo-2,4-dichloro-pyrimidine and Compound 17 as starting
materials, and following a similar sequence of synthetic steps as
for Compound 55. The analytical data was consistent with that
described for its antipode (Compound 55). .sup.1HNMR. (600 MHz,
DMSO-d.sub.6) .delta. ppm 0.88 (d, J=6.44 Hz, 6H) 1.73-1.86 (m, 1H)
3.67-3.76 (m, 2H) 4.11-4.21 (m, 1H) 7.13-7,19 (m, 1H) 8.56 (s, 1H)
9.05 (s, 1H). LCMS (ESI) 265 (M+H).
Example 57
Synthesis of Compound 57
##STR00217##
[0434] tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate
##STR00218##
[0436] tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate
was synthesized using 5-bromo-2,4-dichloro-pyrimidine and
tert-butyl N-(2-amino-2-methyl-propyl)carbamate using analogous
reaction conditions as described for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
LCMS (ESI) 379 (M+H).
tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino-
]-2-methyl-propyl]carbamate
##STR00219##
[0438] tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-
-propyl]carbamate was synthesized using similar experimental
conditions to those used in the synthesis of
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine, .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
1.11-1.22 (m, 6H) 1.31-1.45 (m, 15H) 3,10-3.24 (m, 2H) 3.51-3.76
(m, 4H) 5.60 (s, 1H) 694 (s, 1H) 7.33 (t, J=6.44 Hz, 1H) 8.18 (s,
1H). LCMS (ESI) 427 (M+H).
7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d-
]pyrimidine-6-carboxylic acid
##STR00220##
[0440]
7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrol-
o[2,3-d]pyrimidine-6-carboxylic acid was synthesized using the
analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.43 (s, 9H) 1.73 (s, 6H) 4.06 (s, 2H)
7.46 (s, 1H) 9.23 (s, 1H). LCMS (ESI) 369 (M+H).
Compound 57
[0441] Compound 57 was synthesized using an analogous synthetic
sequence as that described for Compound 44. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.73 (s, 6H) 3.50 (d, J=2.93 Hz, 2H) 7.25
(s, 1H) 8.46-8.55 (m, 1H) 9.07 (s, 1H). LCMS (ESI) 251 (M+H).
Example 58
Synthesis of Compound 58
##STR00221##
[0442] tert-butyl
N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate
##STR00222##
[0444] tert-butyl
N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]
carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and
Intermediate K using the analogous reaction conditions as described
for tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]
carbamate. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.18-1.54
(m, 17H) 2.23 (d, J=14.35 Hz, 2H) 3.36 (d, J=6.44 Hz, 2H) 5.82 (s,
1H) 6.93 (s, 1H) 8.22 (s, 1H). LCMS (ESI) 419 (M+H).
tert-butyl
N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amin- o
cyclohexyl] methyl] carbamate
##STR00223##
[0446] tert-butyl
N-[[1-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclohexy-
l]methyl] carbamate was synthesized using similar experimental
conditions to those used in the synthesis of
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
1.08-1.16 (m, 6H) 1.17-1.54 (m, 17H) 2.13 (br. s., 2H) 3.36 (d,
J=6.73 Hz, 2H) 3.50-3.69 (m, 4H) 5.72 (s, 1H) 6.94 (s, 1H) 5.72
(br. s., 1H) 8.17 (s, 1H). LCMS (ESI) 467 (M+H).
7-[1-[(tert-butoxycarbonylamino)methyl]cyclohexyl]-2-chloro-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid
##STR00224##
[0448]
7-[1-[(tert-butoxycarbonylamino)methyl]cyclohexyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous
synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.37-1.54 (m, 13H) 1.75 (br. s., 4H) 2.74
(br. s., 2H) 3.78-3.84 (m, 2H) 7.44-7.51 (m, 1H) 8.23 (s, 1H) 9.11
(s, 1H). LCMS (ESI) 409 (M+H).
Compound 58
[0449] Compound 58 was synthesized using an analogous synthetic
sequence as that described for Compound 44, .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.28 (br. s., 2H) 1.42 (br. s., 2H) 1,70
(br. s., 4H) 1.85-1.95 (m, 2H) 2.69 (m, 2H) 7.16-7.25 (m, 1H) 8.41
(br. s., 1H) 9.04 (s, 1H). LCMS 291 (M+H).
Example 59
Synthesis of Compound 59
##STR00225##
[0450] tert-butyl
N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]
carbamate
##STR00226##
[0452] tert-butyl
N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl] methyl]
carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and
Intermediate L using analogous reaction conditions as described for
tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.34 (s, 9H)
1.50-1.58 (m, 2H) 1.63-1.78 (m, 4H) 1.96-2.06 (m, 2H) 3.25 (d,
J=6.15 Hz, 2H) 6.71 (s, 1H) 7.18 (t, J=6.29 Hz, 1H) 8.20 (s, 1H).
LCMS (ESI) 405 (M+H).
tert-butyl
N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amin-
o]cyclopentyl] methyl] carbamate
##STR00227##
[0454] tert-butyl N-[[1-[[2-chloro-5-(3,3-diethoxy
prop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamate was
synthesized using similar experimental conditions to that used in
the synthesis of
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine. LCMS (ESI) 453 (M+H).
7-[1-[(tert-butoxycarbonylamino)methyl]cyclopentyl]-2-chloro-pyrrolo[2,3-d-
]pyrimidine-6-carboxylic acid
##STR00228##
[0456]
7-[1-[(tert-butoxycarbonylamino)methyl]cyclopentyl]-2-chloro-pyrrol-
o[2,3-d]pyrimidine-6-carboxylic acid was synthesized using the
analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.47 (s, 9H) 1.74 (br. s., 2H) 1.88 (br.
s., 2H) 2.04 (br. s., 2H) 2.41-2.45 (m, 2H) 4.06 (s, 2H) 7.45 (s,
1H) 9.11 (s, 1H). LCMS (ESI) 395 (M+H).
Compound 59
[0457] Compound 59 was synthesized using an analogous synthetic
sequence as that described for Compound 44. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.72 (br. s., 2H) 1.86-1.93 (m, 2H) 1.99
(d, J=3.81 Hz, 2H) 2.40 (br. s., 2H) 3.48 (d, J=2.34 Hz, 2H) 7.22
(s, 1H) 8.53 (br. s., 1H) 9.05 (s, 1H). LCMS (ESI) 277 (M+H).
Example 60
Synthesis of Compound 60
##STR00229##
[0458] tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]
carbamate
##STR00230##
[0460] tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate
was synthesized using 5-bronco-2,4-dichloro-pyrimidine and
Intermediate B using analogous reaction conditions as described for
tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino
3-methyl-butyl]carbamate. The analytical data is consistent with
that described for the L-enantiomer,
tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino-
]-4-methyl-pentyl] carbamate
##STR00231##
[0462] tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-4-methyl-
-pentyl]carbamate was synthesized using similar experimental
conditions to that used in the synthesis of tort-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]car-
bamate .sup.1HNMR (600 MHz, CHLOROFORM-d) .delta. ppm 1.21-1.31 (m,
12H) 1.38-1.46 (m, 11H) 1.70 (m, 1H) 3.24 (m, 2H) 3.65-3.82 (m, 4H)
4.86 (br s., 1H), 5.65 (s, 1H) 5.85 (br s., III) 6.94 (s, 1H) 8.21
(s, 1H). LCMS (ESI) 455 (M+H).
7-[1-[(tert-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloro-pyrrolo[2-
,3-d]pyrimidine-6-carboxylic acid
##STR00232##
[0464]
7-[1-[(tert-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloro-py-
rrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using
analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acid. The analytical data was
consistent with that described for the L-isomer.
Compound 60
[0465] Compound 60 was synthesized using an analogous synthetic
sequence as that described for Compound 44. The analytical data was
consistent with that described for the L-isomer.
Example 61
Synthesis of Compound 61
##STR00233##
[0467] To a solution of Compound 60 (100 mg, 0.00024 mole) in DMF
(3.0 mL) was added sodium hydride (60% dispersion in oil), (27.6
mg, 3 eq). After stirring for 15 mins, methyl iodide (30, 2 eq) was
added. The contents were stirred at room temperature for 30 mins.
After the addition of sat NaHCO.sub.3, ethyl acetate was added.
Separation of the organic layer followed by drying with magnesium
sulfate and concentration under vacuum afforded the product.
Analytical data was similar to the Compound 49.
Example 62
Synthesis of Compound 62
##STR00234##
[0468] tert-butyl
N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamat-
e
##STR00235##
[0470] tert-butyl
N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamat-
e was synthesized by treating tert-butyl
N-[(1S,2S)-2-aminocyclopentyl]carbamate with
5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions
as described for teat-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) 5 ppm 1.27 (s, 9H) 1.42-1.54 (m,
2H) 1,56-1.65 (m, 2H) 1.80-1.88 (m, 1H) 1.96-2.01 (m, 1H) 3.88-3.96
(m, 1H) 4.03-4.09 (m, 1H) 6.91 (d, J=8.20 Hz, 1H) 7.41 (d, J=7.32
Hz, 1H) 8.18 (s, 1H). LCMS (ESI) 391 (M+H).
tert-butyl
N-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4--
yl]amino]cyclopentyl]carbamate
##STR00236##
[0472] tert-butyl
N-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]c-
yclopentyl]carbamate was synthesized using similar experimental
conditions to that used in the synthesis of
(2S)--N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pe-
ntane-1,2-diamine. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
1.13 (t, 6H) 1.28 (s, 9H) 1.42-1.52 (m, 2H) 1.58-1.65 (m, 2H)
1.81-1.90 (m, 1H) 1.99-2.08 (m, 1H) 3.49-3.60 (m, 2H) 3.63-3.71 (m,
2H) 3.84-3.93 (m, 1H) 3.96-4.04 (m, 1H) 5.53 (s, 1H) 6.96 (d,
J=7.90 Hz, 1H) 7.34 (d, J=7.03 Hz, 1H) 8.14 (s, 1H). LCMS (ESI) 439
(M+H).
7-[(1S,2S)-2-(tert-butoxycarbonylamino)cyclopentyl]-2-chloro-pyrrolo[2,3-d-
]pyrimidine-6-carboxylic acid
##STR00237##
[0474]
7-[(1S,2S)-2-(tert-butoxycarbonylamino)cyclopentyl]-2-chloro-pyrrol-
o[2,3-d]pyrimidine-6-carboxylic acid was synthesized using the
analogous synthetic sequence as that described for
7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo-
[2,3-d] pyrimidine-6-carboxylic acid. .sup.1HNMR (600 MHz, DMSO-6)
.delta. ppm 1.41-1.52 (m, 9H) 1.55-1.68 (m, 1H) 1.88-2.00 (m, 2H)
2.05-2.15 (m, 1H) 2.26-2.35 (m, 1H) 2.71-2.89 (m, 1H) 4.01 -4.16
(m, 1H) 4.28-4.45 (m, 1H) 7.41 (s, 1H) 9.11 (s, 1H). LCMS (ESI) 381
(M+H).
Compound 62
[0475] Compound 62 was synthesized using an analogous synthetic
sequence as that described for Compound 44. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.48-1.60 (m, 1H) 1.88-1.98 (m, 3H)
1.99-2.08 (m, 1H) 2.66-2.75 (m, 1H) 3.63-3.74 (m, 1H) 3.99-4.12 (m,
1H) 7.21 (s, 1H) 8.89 (s, 1H) 9.04 (s, 1H). LCMS (ESI) 263
(M+H).
Example 63
Synthesis of Compound 63
##STR00238##
[0477] To chloro tricycliclactam (0.050 g, 0.225 mmole) in dioxane
(2.0 mL) under nitrogen was added
5-(4-methylpiperazin-1-yl)pyridin-2-amine (0.052 g, 1.2 eq, 0.270
mmole) followed by the addition of Pd.sub.2(dba).sub.3 (18.5 mg),
BINAP (25 mg) and sodium-tert-butoxide (31 mg , 0.324 mmole). The
contents of the flask are degassed for 10 minutes and then heated
to 100 degrees for 12 hours. The crude reaction was loaded on a
silica gel column and eluted with DCM/MeOH (0-15%) to afford the
desired product (26 mg). To this compound dissolved in DCM/MeOH
(10%) was added 3N HCl in iso-propanol (2 eq) and the reaction was
stirred overnight. Concentration under vacuum afforded the
hydrochloride salt. .sup.1HNMR (d6-DMSO) .delta. ppm 11.13 (brs,
1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.03 (br m 1H), 7.99 (s, 1H), 7.67
(brm, 1H), 7.18 (s, 1H), 4.33 (m, 2H), 3.79 (m, 2H), 3.64 (m, 2H),
3.50 (m, 2H), 3.16 (m, 4H), 2.79 (s, 3H). LCMS (ESI) 379 (M+H).
Example 64
Synthesis of Compound 64
##STR00239##
[0479] To chloro tricycliclactam (0.075 g, 0.338 mmole) dioxane
(3.5 mL) under nitrogen was added text-butyl
4-(6-amino-3-pyridyl)piperazine-1-carboxylate (0.098 g, 1.05 eq)
followed by the addition of Pd.sub.2(dba).sub.3 (27 mg), BINAP (36
mg) and sodium-tert-butoxide (45 mg). The contents were heated at
reflux for 11 hrs. The crude reaction was loaded onto a silica gel
column and eluted with DCM/MeOH (0-10%) to afford the desired
product (32 mg). .sup.1HNMR (d6-DMSO) .delta. ppm 9.48 (s, 1H),
8.84 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.42 (m,
1H), 6.98 (s, 1H), 4.23 (m, 2H), 3.59 (m, 2H), 3.45 (m, 4H), 3.50
(m, 2H), 3.05 (m, 4H). LCMS (ESI) 465 (M+H).
Example 65
Synthesis of Compound 65
##STR00240##
[0481] To a solution of Compound 64 (23 mg) in 10% DCM/MeOH was
added 10 mL of a 3M solution of HCl in iso-propanol. The contents
were stirred for 16 hrs. Concentration of the reaction mixture
afforded the hydrochloride salt. .sup.1HNMR (d6-DMSO) .delta. ppm
9.01 (s, 1H), 7.94 (m, 1H), 7.86 (m, 1H), 7.23 (s, 1H), 4.30 (m,
2H), 3.64 (m, 2H), 3.36 (m, 4H), 3.25 (m, 4H). LCMS (ESI) 465
(M+H).
Example 66
Synthesis of Compound 66
##STR00241##
[0483] To chloro-N-methyltricyclic amide (0.080 g, 0.338 mmole) in
dioxane (3.5 mL) under nitrogen was added tert-butyl
4-(6-amino-3-pyridyl)piperazine-1-carboxylate 0.102 g (1.1 eq)
followed by the addition of Pd.sub.2(dba).sub.3 (27 mg), BINAP (36
mg) and sodium-tert-butoxide (45 mg). The contents were heated at
reflux for 11 hrs. The crude product was purified using silica gel
column chromatography with an eluent of dichloromethane/methanol
(0-5%) to afford the desired product (44 mg). .sup.1HNMR (d6-DMSO)
.delta. ppm 9.49 (s, 1H), 8.85 (s, 1H), 8.32 (m, 1H), 8.02 (s, 1H),
7,44 (m, 1H), 7.00 (s, 1H), 4.33 (m, 2H), 3.80 (m, 2H), 3.48 (m,
4H), 3.07 (m, 4H), 3.05 (s, 3H), 1.42 (s, 9H). LCMS (ESI) 479
(M+H).
Example 67
Synthesis of Compound 67
##STR00242##
[0485] To Compound 66 (32 mg) was added 3N HCL (10 mL) in
isopropanol and the contents were stirred at room temperature
overnight for 16 hrs. Concentration afforded the hydrochloride
salt. .sup.1HNMR (d6-DMSO) .delta. ppm 9.13 (m, 2H), 8.11 (m, 1H),
8.10 (s, 1H), 7.62 (m, 1H), 7.21 (s, 1H), 4.43 (m, 2H), 3.85 (m,
2H), 3.41 (m, 4H), 3.28 (m, 4H), 3.08 (s, 3H). LCMS (ESI) 379
(M+H).
Example 68
Synthesis of Compound 68
##STR00243##
[0487] Compound 68 was synthesized using similar experimental
conditions to that described for compound 64. .sup.1HNMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 0.79 (d, J=7.03 Hz, 3H) 101 (d, J=6.73
Hz, 3H) 1.35-1.48 (m, 9H) 2.16 (dd, J=14.64, 6.73 Hz, 1H) 3.00-3.14
(m, 4H) 3.40-3.51 (m, 4H) 3.51-3.60 (m, 1H) 3.63-3.74 (m, 1H) 4.44
(dd, J=7.90, 3.81 Hz, 1H) 6.99 (s, 1H) 7.46 (dd, J=8.93, 2.78 Hz,
1H) 7.94-8.09 (m, 2H) 8.31 (dd, J=9.08, 1.46 Hz, 1H) 8.85 (s, 1H)
9.46 (s, 1H). LCMS (ESI) 507 (M+H).
Example 69
Synthesis of Compound 69
##STR00244##
[0489] Compound 69 was synthesized using similar experimental
conditions to those described for compound 63 and was recovered as
an HCl salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm
0.77-0.86 (m, 3H) 0.96 (d, J=7.03 Hz, 3H) 2.10-2.24 (m, 1H) 3.07
(s, 3H) 3.37-3.79 (m, 8H) 4.00 (dd, J=13.61, 4.54 Hz, 2H) 4.63-4.73
(m, 1H) 7.20 (s, 1H) 7.58-7.71 (m, 1H) 7.99 (d, J=2.34 Hz, 1H) 8.12
(d, J=9.37 Hz, 1H) 9.11 (s, 1H) 9.41 (br. s., 2H) 11.76 (br. s.,
1H). LCMS (ESI) 421 (M+H).
Example 70
Synthesis of Compound 70
##STR00245##
[0491] Compound 70 was synthesized using similar experimental
conditions to those described for compounds 64 and 65 and was
recovered as an HCl salt. The characterization data (NMR and LCMS)
was consistent with that reported for compound 71.
Example 71
Synthesis of Compound 71
##STR00246##
[0493] Compound 71 was synthesized using similar experimental
conditions to those described for compounds 64 and 65 and was
recovered as an HCl salt, .sup.1HNMR (600 MHz, DMSO-d.sub.6)
.delta. ppm 0.79 (d, J=6.73 Hz, 3H) 1.01 (d, J=6.73 Hz, 3H) 2.18
(dd, J=14.49, 7.17 Hz, 1H) 3.18-3.84 (m, 10H) 4.53-4.71 (m, 1H)
7.24 (s, 1H) 7.65 (d, J=9.37 Hz, 1H) 8.01 (d, J=2.64 Hz, 1H) 8.14
(d, J=1.46 Hz, 1H) 8.35 (d, J=5.27 Hz, 1H) 9.14 (s, 1H) 9.46 (s,
2H) 11.80 (s, 1H) LCMS (ESI) 407 (M+H).
Example 72
Synthesis of Compound 72 (Compound UUU)
##STR00247##
[0495] Compound 72 was synthesized using similar experimental
conditions to that described for compounds 64 and 65 and was
recovered as an HCl salt, .sup.1HNMR (600 MHz, DMSO-d.sub.6)
.delta. ppm 0.77 (d, J=7.03 Hz, 3H) 0.99 (d, J=6.73 Hz, 3H)
2.10-2.24 (m, 1H) 3.18-3.81 (m, 10H) 4.54-4.69 (m, 1H) 7.22 (s, 1H)
7.63 (d, J=9.08 Hz, 1H) 7.99 (d, J=2.63 Hz, 1H) 8.11 (s, 1H) 8.33
(d, J=5.27 Hz, 1H) 9.12 (s, 1H) 9.43 (s, 2H) 11.77 (s, 1H). LCMS
(ESI) 407 (M+H).
Example 73
Synthesis of Compound 73
##STR00248##
[0497] Compound 73 was synthesized using similar experimental
conditions to those described for compounds 64 and 65 and was
recovered as an HCl salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6)
.delta. ppm 0.84 (d, J=6.73 Hz, 3H) 0.98 (d, J=6.73 Hz, 3H)
2.12-2.26 (m, 1H) 3.09 (s, 3H) 3.22-3.81 (m, 8H) 4.01 (dd, J=13.61,
4.25 Hz, 2H) 4.59-4.72 (m, 1H) 7.19 (s, 1H) 7.74 (s, I H) 7.96-8.10
(m, 2H) 9.08 (s, 1H) 9.22 (s, 2H). LCMS (ESI) 421 (M+H).
Example 74
Synthesis of Compound 74
##STR00249##
[0499] Compound 74 was synthesized using similar experimental
conditions to those described for compound 63 and was recovered as
an HCl salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.85
(d, J=4.98 Hz, 3H) 0.95 (d, J=4.98 Hz, 3H) 1.42-1.70 (m, 3H) 2.77
(d, J=2.93 Hz, 3H) 3.07-4.14 (m, 10H) 4.95 (s, 1H) 7.20 (s, 1H)
7.66 (d, J=9.66 Hz, 1H) 7.94 (s, 1H) 8.08-8.16 (m, 1H) 8.33 (d,
J=1.68 Hz, 1H) 9.09 (s, 1H) 11.38 (s, 1H) 11.71 (s, 1H). LCMS (ESI)
435 (M+H).
Example 75
Synthesis of Compound 75
##STR00250##
[0501] Compound 75 was synthesized using similar experimental
conditions to those described for compounds 64 and 65 and was
recovered as an HCl salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6)
.delta. ppm 0.87 (d, J=6.15 Hz, 3H) 0.94 (d, J=6.15 Hz, 3H) 1.57
(d, J=84.61 Hz, 3H) 3.05 (s, 3H) 3.13-3.55 (m, 8H) 3.69 (d, J=78.17
Hz, 2H) 4.90 (s, 1H) 7.15 (s, 1H) 7.63-7.85 (m, 1H) 7.93 (s, 1H)
8.26 (s, 1H) 9.03 (s, 1H) 9.20 (s, 2H). LCMS (ESI) 421 (M+H).
Example 76
Synthesis of Compound 76
##STR00251##
[0503] Compound 76 was synthesized using similar experimental
conditions to those described for compound 63 and was recovered as
an HCl salt. .sup.1HNMR, (600 MHz, DMSO-d.sub.6) .delta. ppm 0.85
(d, J=6.44 Hz, 3H) 0.95 (d, J=6.44 Hz, 3H) 1.43-1.70 (m, 3H) 2.78
(d, J=2.93 Hz, 3H) 3.05 (s, 3H) 3.24-3.84 (m, 8H) 4.01 (d, J=9.66
Hz, 2H) 4.89-5.01 (m, 1H) 7.15 (s, 1H) 7.77 (s, 1H) 7.91-8.05 (m,
2H) 9.03 (s, 1H) 10.96-11.55 (m, 2H). LCMS (ESI) 449 (M+H).
Example 77
Synthesis of Compound 77
##STR00252##
[0505] Compound 77 was synthesized using similar experimental
conditions to those described for compounds 64 and 65 and was
recovered as an HCl salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6)
.delta. ppm 0.83-0.88 (d, J=6.15 Hz, 3H) 0.95 (d, J=6.15 Hz, 3H)
1.40-1.71 (m, 3H) 3.28-3.83 (m, 8H) 4.00 (d, J=3.22 Hz, 2H)
4.91-5.08 (m, 1H) 7.17 (s, 1H) 7.68 (d, J=9.66 Hz, 1H) 7.93 (s, 1H)
8.07 (s, 1H) 9.06 (s, 1H) 9.40 (s, 2H) 11.59 (s, 1H). LCMS (ESI)
435 (M+H).
Example 78
Synthesis of Compound 78
##STR00253##
[0507] To Compound 50 0.060 g (0.205 mmole) was added
5-(4-methylpiperazin-1-yl)pyridin-2-amine (35.42 mg, 0.9 eq)
followed by the addition of 1,4-dioxane (3 mL). After degassing
with nitrogen, Pd.sub.2dba.sub.3 (12 mg), BINAP (16 mg) and sodium
tert-butoxide (24 mg) were added. The contents were then heated at
90 degrees in a CEM Discovery microwave for 3 hrs. The reaction was
then loaded onto a silica gel column and purified by eluting with
DCM/MeOH (0-15%),
[0508] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.75 (t,
J=7.47 Hz, 3H) 0.91 (d, J=6.73 Hz, 3H) 1.04-1.20 (m, 2H) 1.80-1.98
(m, 1H) 2.77 (d, J=3.81 Hz, 3H) 2.94-3.90 (m, 10H) 4.54-4.68 (m,
1H) 7.06-7,23 (m, 2H) 7.56-7.75 (m, 1H) 7.90-8.12 (m, 2H) 8.29 (s,
1H) 9.07 (s, 1H) 10.98-11.74 (m, 2H). LCMS (ESI) 435 (M+H).
Example 79
Synthesis of Compound 79
##STR00254##
[0510] Compound 79 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an salt.
[0511] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.75 (t,
J=7.32 Hz, 3H) 0.90 (d, J=6.73 Hz, 3H) 1.07-1.15 (m, 2H) 1.85-1.94
(m, 1H) 3.17-3.75 (m, 10H) 4.58-4.67 (m, 1H) 7.17 (s. 1H) 7.71 (s,
1H) 7.96 (s, 1H) 7.98-8.05 (m, 1H) 8.28 (d, J=4.10 Hz, 1H) 9.06 (s,
1H) 9.39 (s, 2H). LCMS (ESI) 421 (M+H).
Example 80
Synthesis of Compound 80
##STR00255##
[0513] Compound 80 was synthesized in a similar manner to that
described for compound 78.
[0514] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.78 (t,
J=7.32 Hz, 3H) 0.86 (d, J=6.73 Hz, 3H) 1.13-1.21 (m, 2H) 1.84-1.96
(m, 1H) 2.77 (d, J=4.39 Hz, 3H) 3.04 (s, 3H) 3.11-3.84 (m, 8H) 3.98
(dd, J=13.61, 4.25 Hz, 2H) 4.66-4.74 (m, 1H) 7.17 (s, 1H) 7.64 (s,
1H) 7.96 (d, J=2.34 Hz, 1H) 8.03-8.13 (m, 1H) 9.08 (s, 1H) 11.26
(s, 1H) 11.66 (s, 1H). LCMS (ESI) 449 (M+H).
Example 81
Synthesis of Compound 81
##STR00256##
[0516] The compound was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0517] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.78 (t,
J=7.32 Hz, 3H) 0.85 (d, J=6.73 Hz, 3H) 1.10-1.27 (m, 2H) 1.82-1.99
(m, 1H) 3.04 (s, 3H) 3.28-3.77 (m, 8H) 3.97 (dd, J=13.91, 4.54 Hz,
2H) 4.62-4.75 (m, 1H) 7.07-7.24 (m, 1H) 7.62-7.75 (m, 1H) 7.94 (d,
J=2.34 Hz, 1H) 7.97-8.08 (m, 1H) 9.05 (s, 1H) 9.29 (s, 2H). LCMS
(ESI) 435 (M+H).
Example 82
Synthesis of Compound 82
##STR00257##
[0519] The compound was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt,
[0520] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.96 (s, 9H)
3.15-3.87 (m, 10H) 4.42-4.53 (m, 1H) 6.99 (s, 1H) 7.24 (s. 1H) 8.06
(s, 1H) 8.11-8.21 (m, 1H) 8.79-8.98 (m, 2H) 9.25 (s, 2H) 9.88 (s,
1H). LCMS (ESI) 421 (M+H).
Example 83
Synthesis of Compound 83
##STR00258##
[0522] Compound 83 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0523] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.95 (s, 9H)
2.79 (d, J=4.10 Hz, 3H) 3.06-3.86 (m, 10H) 4.56-4.67 (m, 1H) 7.17
(s, 1H) 7.70 (s, 1H) 7.96 (d, J-2.63 Hz, 1H) 7,99-8.08 (m, 1H) 8.26
(s, 1H) 9.06 (s, 1H) 10.80 (s, 1H). LCMS (ESI) 435 (M+H).
Example 84
Synthesis of Compound 84
##STR00259##
[0525] Compound 84 was synthesized in a similar manner to that
described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 2.75-2.81 (m, 3H)
3.12-3.16 (m, 2H) 3.46-3.54 (m, 4H) 3.60-3.69 (m, 2H) 3.72-3.79 (m,
1H) 4.07-4.18 (m, 2H) 6.06-6.09 (m, 1H) 6.90 (d, J=7.61 Hz, 2H)
7.20-7.31 (m, 3H) 7.33 (s, 1H) 7.49-7.55 m, 1H) 7.62-7.70 (m, 1H)
7.92 (d, J=2.93 Hz, 1H) 8.22 (s, 1H) 9.14 (s, LCMS (ESI) 455
(M+H).
Example 85
Synthesis of Compound 85
##STR00260##
[0527] Compound 85 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0528] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 3.21 (s, 4H)
3.35-3.67 (m, 5H) 4.07-4.20 (m, 2H) 6.13 (s, 1H) 6.90 (d, J=7.32
Hz, 2H) 7.22-7.31 (m, 3H) 7.36 (s, 1H) 7.48 (d, J=9.37 Hz, 1H) 7.93
(d, J=2.34 Hz, 1H) 8.04-8.11 (m, 1H) 8.25 (d, J=4.98 Hz, 1H) 9.17
(s, 1H) 11.77 (br, s., 1H).
[0529] LCMS (ESI) 441 (M+H).
Example 86
Synthesis of Compound 86
##STR00261##
[0531] Compound 86 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0532] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.90 (d,
J=6.15 Hz, 6H) 1.72-1.89 (m, 1H) 3.15-3.92 (m, 9H) 4.10-4.46 (m,
2H) 7.18 (s, 1H) 7.59 (d, J=8.78 Hz, 1H) 8.00 (s, 1H) 8.13 (d,
J=9.37 Hz, 1H) 8.55 (s. 1H) 9.09 (s, 1H) 9.67 (s, 2H) 11.91 (s,
1H). LCMS (ESI) 407 (ESI).
Example 87
Synthesis of Compound 87
##STR00262##
[0534] Compound 87 was synthesized in a manner similar to compound
86 and was converted to an HCl salt. The characterization data (NMR
and LCMS) was similar to that obtained for the antipode compound
86.
Example 88
Synthesis of Compound 88
##STR00263##
[0536] Compound 88 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0537] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.78 (s, 6H)
3.40-3.53 (m, 6H) 3.64-3.73 (m, 4H) 7.27 (s, 1H) 7.66 (d, J=9.37
Hz, 1H) 7.98 (d, J=2.34 Hz, 1H) 8.12 (br. s., 1H) 8.47 (br. s., 1H)
9.11 (s, 1H) 9.45 (br. s., 2H) 11.62 (br. s., 1H). LCMS (ESI) 393
(M+H).
Example 89
Synthesis of Compound 89 (also referred to as Compound T)
##STR00264##
[0539] Compound 89 was synthesized in a similar manner to that
described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.47 (br. s., 6H)
1.72 (br. s., 2H) 1.92 (br. s., 2H) 2.77 (br. s., 3H) 3.18 (br, s.,
2 H) 3.46 (br. s., 2H) 3.63 (br. s., 2H) 3.66 (d, J=6.15 Hz, 2H)
3.80 (br. s., 2H) 7.25 (s, 1H) 7.63 (br. s., 2H) 7.94 (br. s., 1H)
8.10 (br. s., 1H) 8.39 (br. s., 1H) 9.08 (br. s., 1H) 11.59 (br.
s., 1H). LCMS (ESI) 447 (M+H).
Example 90
Synthesis of Compound 90 (also referred to as Compound Q)
##STR00265##
[0541] Compound 90 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0542] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.27-1.64 (m,
6H) 1.71 (br. s., 2H) 1.91 (br. s., 2H) 2.80 (br. s., 1H) 3.17-3.24
(m, 2H) 3.41 (br. s., 4H) 3.65 (br. s., 4H) 7.26 (br. s., 1H) 7.63
(br. s., 1H) 7.94 (br. s., 1H) 8.13 (br. s., 1H) 8.40 (br. s., 1H)
9.09 (br. s., 1H) 9.62 (br. s., 1H) 11.71 (br. s., 1H). LCMS (ESI)
433 (M+H).
Example 91
Synthesis of Compound 91 (Also Referred to as Compound ZZ)
##STR00266##
[0544] Compound 91 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.64-1.75 (m, 2H)
1.83-1.92 (m, 2H) 1.96-2.06 (m, 2H) 2.49-2.58 (m, 2H) 2.79 (d,
J=3.81 Hz, 3H) 3.06-3,18 (m, 4H) 3.59-3.69 (m, 2H) 3.73-3.83 (m,
2H) 4.04-4.12 (m, 2H) 7.17 (br. s., 1H) 7.60-7.70 (m, 2H) 7.70-7.92
(m, 2H) 7.96 (br. s., 1H) 8.41 (br. s., 1H) 8.98 (br. s., 1 11
10.77 (br. s., 1H). LCMS (ESI) 433 (M+H).
Example 92
Synthesis of Compound 92
##STR00267##
[0546] Compound 92 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt.
[0547] .sup.1HNMR. (600 MHz, DMSO-d.sub.6) .delta. ppm 1.64-1.75
(m, 2H) 1.84-1.92 (m, 2H) 1.96-2.05 (m, 2H) 2.48-2.56 (m, 2H) 3.22
(br. s., 4H) 3.42-3.48 (m, 4H) 3.60-3.69 (m, 21-I) 4.05-4.13 (m,
1H) 7.18 (s, 1H) 7.65 (d, J=13.47 Hz, 1H) 7.70-7.77 (m, 1H) 7.94
(d,1=1.76 Hz, 1H) 8.42 (br. s., 1H) 9.00 (s, 1H) 9.15 (br. s., 2H).
LCMS (ESI) 419 (M+H).
Example 93
Synthesis of Compound 93
##STR00268##
[0549] Compound 93 was synthesized in a similar manner to that
described for compound 78 followed by the deblocking step described
for compound 65 and was converted to an HCl salt,
[0550] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.76 (br. s.,
2H) 1.89 (br. s., 2H) 2.03 (br. s., 2H) 2.47-2.58 (m, 2H) 3.04 (s,
3H) 3.22 (br, s., 4H) 3.39 (br. s., 4H) 3.66 (s, 2H) 7.21 (s, 1H)
7.67 (d, J=9.37 Hz, 1H) 7.93 (br. s., 1H) 7.98-8.09 (m, 1H) 9.04
(s, 1H) 9.34 (br. s., 2H) 11.31 (br. s., 1H). LCMS (ESI) 433
(M+H).
Example 94
Synthesis of Compound 94
##STR00269##
[0552] Compound 94 was synthesized using similar conditions to that
described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.66-1.77 (m, 2H)
1.84-1.94 (m, 2H) 1.96-2.08 (m, 2H) 2.48-2.57 (m, 2H) 3.36-3.52 (m,
4H) 3.60-3.80 (m, 6H) 7.21 (s, 1H) 7.53-7.74 (m, 2H) 7.86 (s, 1H)
8.02 (s, 1H) 8.45 (s, 1H) 9.03 1H) 11.19 (br. s., 1H). LCMS (ESI)
420 (M+H).
Example 95
Synthesis of Compound 95
##STR00270##
[0554] Compound 95 was synthesized using similar conditions to that
described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6).delta. ppm 1.65-1.79 (m, 2H)
1.85-1.95 (m, 2H) 1.97-2.08 (m, 2H) 2.47-2.54 (m, 2H) 3.40-3.58 (m,
5H) 3.65 (dd, J=21.67, 5.56 Hz, 1H) 3.69-3.78 (m, 4H) 7.24 (s, 1H)
7.97-8.17 (m, 2H) 8.48 (s, 1H) 9.08 (s, 1H) 11.81 (s, 1H). LCMS
(ESI) 421 (M+H).
Example 96
Synthesis of Compound 96
##STR00271##
[0556] Compound 96 was synthesized using similar conditions to that
described for compound 78 and was converted to an HCl salt,
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.55-1.74 (m, 2H)
1.80-1.98 (m, 4H) 2.48-2.60 (m, 2H) 3.40-3.50 (m, 4H) 3.57-3.72 (m,
2H) 3.90-4.20 (m, 4H) 7.08 (s, 1H) 7.37-7.57 (m, 2H) 7.70 (m, 2H)
8.32 (s, 1H) 8.88 (s, 1H) 9.98 (s, 1H). LCMS (ESI) 419 (M+H).
Example 97
Synthesis of Compound 97 (Also Referred to as Compound III)
##STR00272##
[0558] Compound 97 was synthesized using similar conditions to that
described for compound 78 and was converted to an HCl salt.
.sup.1`HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.30 (d, J=5.27 Hz,
6H) 1.65-1.78 (m, 2H) 1.83-1.95 (m, 2H) 1.97-2.10 (m, 2H) 2.45-2.55
(m, 2H) 3.25-3.36 (m, 1H) 3.39-3.48 (m, 4H) 3.60-3.70 (m, 4H)
3.75-4.15 (m, 2H) 7.24 (s, 1H) 7.54-7.75 (m, 2H) 7.95 (s, 1H) 8.10
(s, 1H) 8.49 (s, 1H) 9.07 (s, 1H) 11.25 (s, 1H) 11.48 (s, 1H). LCMS
(ESI) 461 (M+H).
Example 98
Synthesis of Compound 98
##STR00273##
[0560] Compound 98 was synthesized using similar conditions to that
described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.99 (d, J=6.15 Hz,
6H) 1.65-1.78 (m, 2H) 1.90 (m, 2H) 1.97-2.08 (m, 2H) 2.08-2.17 (m,
1H) 2.45-2.55 (m, 2H) 2.88-3.02 (m, 2H) 3.33-3.48 (m, 4H) 3.50-3.90
(m, 6H) 7.24 (s, 1H) 7.67 (s, 2H) 7.94 (s, 1H) 8.12 (s, 1H) 8.49
(s, 1H) 9.07 (s, 1H) 10.77 (s, 1H) 11.51 (s, 1H). LCMS (ESI) 475
(M+H).
Example 99
Synthesis of Compound 99
##STR00274##
[0562] Compound 99 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=5.86 Hz,
6H) 1.66-1.77 (m, 2H) 1.84-1.94 (m, 2H) 1.97-2.09 (m, 2H) 2.40-2.53
(m, 2H) 3.37-3.49 (m, 2H) 3.50-3.59 (m, 2H) 3.59-3.73 (m, 4H) 7.23
(s, 1H) 7.64 (m, 3H) 7.85 (s, 1H) 8.11 (s, 1H) 8.47 (s, 1H) 9.05
(s, 1H). 11.35 (br s., 1H). LCMS (ESI) 448 (M+H).
Example 100
Synthesis of Compound 100
##STR00275##
[0564] Compound 100 was synthesized using similar conditions to
that described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.50-1.57 (m, 2H)
1.62-1.68 (m, 3H) 1.68-1.75 (m, 2H) 1.84-1.92 (m, 2H) 1.97-2.08 (m,
2H) 2.48-2.53 (m, 2H) 3.14-3.23 (m, 4H) 3.43-3.47 (m, 2H) 3.58-3.70
(m, 2H) 7.22 (s, 1H) 7.58-7.70 (m, 2H) 7.85-8.00 (m, 1H) 8.16 (d,
1H) 8.46 (s, 1H) 9.04 (s, 1H) 11.37 (br s., 1H). LCMS (ESI) 418
(M+H).
Example 101
Synthesis of Compound 101 (Also Referred to as Compound WW)
##STR00276##
[0566] Compound 101 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1`HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.72 (s, 2H) 1.90
(s, 4H) 2.03 (s, 2H) 2.21 (s, 2H) 2.48-2.54 (m, 2H) 2.73 (s, 2H)
3.03 (s, 2H) 3.25-3.35 (m, 1H) 3.38-3.48 (m, 4H) 3.65-3,99 (m, 5H)
7.23 (s, 1H) 7.63 (d, J=9.66 Hz, 1H) 7.90 (s, 1H) 8.13 (s, 1H) 8.47
(s, 1H) 9.06 (s, 1H) 10.50 (br s., 1H). LCMS (ESI) 503 (M+H).
Example 102
Synthesis of Compound 102 (Also Referred to as Compound HHH)
##STR00277##
[0568] Compound 102 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.63-1.85 (m, 6H)
1.87-1.92 (m, 2H) 1.99-2.06 (m, 2H) 2.15-2.23 (m, 2H) 2.47-2.53 (m,
1H) 2.69-2.79 (m, 2H) 2.81-2.91 (m, 2H) 2.98-3.08 (m, 2H) 3.32-3.48
(m, 4H) 3.57-3.72 (m, 4H) 3.77-3.85 (m, 2H) 7.22 (s, 1H) 7.60-7,68
(m, 2H) 7.90 (s, 1H) 8.07 (s, 1H) 8.46 (s, 1H) 9.04 (s, 1H). 11.41
(br s., 1H). LCMS (ESI) 501 (M+H).
Example 103
Synthesis of Compound 103
##STR00278##
[0570] Compound 103 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.64-1.76 (m, 2H)
1.87-1.93 (m, 2H) 2.00-2.07 (m, 2H) 2.48-2.53 (m, 2H) 2.67-2.72 (m,
4H) 3.44-3.47 (m, 2H) 3.50-3.55 (m, 4H) 7.24 (s, 1H) 7.61 (d,
J=9.37 Hz, 2H) 7.86 (d, J=2.63 Hz, 1H) 8.09 (d, J=12.88 Hz, 1H)
8.48 (s, 1H) 9.06 (s, 1H) 11.41 (br s., 1H). LCMS (ESI) 436
(M+H).
Example 104
Synthesis of Compound 104
##STR00279##
[0572] Compound 104 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.29 (d, J=6.73 Hz,
6H) 1.66-1.79 (m, 2H) 1.84-1.95 (m, 2H) 1.98-2.09 (m, 2H) 2.46-2.55
(m, 2H) 3.29-3.39 (m, 21) 3.58-3.70 (m, 4H) 3.77-3.86 (m, 4H) 7.24
(s, 1H) 7.66 (d, J=9.37 Hz, 1H) 7.96 (d, J=2.93 Hz, 1H) 8.08 (s,
1H) 8.48 (s, 1H) 9.06 (s, 1H) 9.28 (s, 1H) 9.67 (s, 1H) 11.36 (s,
1H). LCMS (ESI) 447 (M+H).
Example 105
Synthesis of Compound 105
##STR00280##
[0574] Compound 105 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt,
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.73 (s, 2H)
1.76-1.85 (m, 2H) 1.85-1.94 (m, 2H) 1.98-2.07 (m, 2H) 2.19-2.26 (m,
2H) 2.48-2.52 (m, 1H) 4.70-2.81 (m, 4H) 3.13-3.20 (m, 1H) 3.30-3.48
(m, 3H) 3.58-3.71 (m, 4H) 3.78-3.84 (m, 4H) 7.24 (s, 1H) 7.62 (d,
J=9.37 Hz, 2H) 7.89 (d, J=1.17 Hz, 1H) 8.09-8.18 (m, 1H) 8.48 (s,
1H) 9.06 (s, 1H) 11.46 (br s., 1H). LCMS (ESI) 519 (M+H).
Example 106
Synthesis of Compound 106
##STR00281##
[0576] Compound 106 was synthesized using similar conditions to
those described for compound 78 followed by the deblocking step
described for compound 65 and was converted to an HCl salt.
[0577] .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.65-1.75 (m,
2H) 1.85-1.93 (m, 2H) 1.93-1.99 (m, 1H) 2.00-2.06 (m, 2H) 2.08-2.14
(m, 1H) 2.47-2.55 (m, 2H) 3.07-3.25 (m, 2H) 3.25-3.69 (m, 5H) 4.46
(s, 1H) 4.67 (s, 1H) 7.22 (s, 1H) 7.58-7.69 2H) 8.46 (s, 1H) 9.02
(s, 1H) 9.34 (s, 1H) 9.65 (s, 1H). LCMS (ESI) 431 (M+H).
Example 107
Synthesis of Compound 107 (Also Referred to as Compound YY)
##STR00282##
[0579] Compound 107 was synthesized using similar conditions to
those described for compound 78 and was converted to an HCl salt.
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.65-1.82 (m, 3H)
1.89 (br. s., 2H) 1.98-2.08 (m, 2H) 2.13 (br. s., 2H) 2.47-2.55 (m,
2H) 2.68 (d, J=4.98 Hz, 6H) 2.71-2.80 (m, 2H) 3.29-3.71 (m, 10H)
7.16-7.26 (m, 1H) 7.67 (d, J=9.66 Hz, 2H) 7.91 (d, J=2.05 Hz, 1H)
8.14 (br. s., 1H) 8.48 (br. s., 1H) 9.05 (s, 1H) 11.14 (br. s., 1H)
11.43 (br. s., 1H). LCMS (ESI) 461 (M+H).
Example 108
Synthesis of Compound 108
##STR00283##
[0581] Compound 108 was synthesized in a manner similar to that
described for compounds 64 and 65 and was recovered as an HCl salt.
The analytical data was consistent with that described for the
antipode compound 75.
Example 109
Synthesis of Compound 109
##STR00284##
[0583] Compound 109 was synthesized in a manner similar to that
described for compounds 64 and 65 and was recovered as an HCl salt.
The analytical data was consistent with that described for the
antipode compound 75.
Example 110
Synthesis of Compound 110
##STR00285##
[0585] Compound 110 was synthesized in a similar manner to that
described for compound 78 and then converted to its hydrochloride
salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.50-1.65 (m,
1H) 1.92-2.02 (m, 3H) 2.06-2.15 (m, 1H) 2.78 (d, J=3.81 Hz, 4H)
3.10-3.20 (m, 4H) 3.47-3.51 (m, 2H) 3.64-3.71 (m, 1H) 3.76-3.83 (m,
2H) 3.98-4.14 (m, 1H) 7.20 (s, 2H) 7.77 (s, 1H) 7.97 (s, 2H) 8.81
(s, 1H) 9.03 1H) 10.97 (br s., 1H). LCMS (ESI) 419 (M+H).
Example 111
Synthesis of Compound 111
##STR00286##
[0587] Compound 111 was synthesized in a similar manner to that
described for compound 78 and then converted to its hydrochloride
salt. .sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.54-1.59 (m,
1H) 1.92-2.01 (m, 3H) 2.06-2.15 (m, 1H) 2.76-2.84 (m, 1H) 3.17-3.24
(m, 6H) 3.64-3.71 (m, 2H) 4.02-4.11 (m, 2H) 7.22 (s, 2H) 7.64 (s,
1H) 7.97 (s, 2H) 8.75 (s, 1H) 8.97 (s, 1H) 9.21 (s, 1H). LCMS (ESI)
405 (M+H).
Example 112
Synthesis of Compound 112
##STR00287##
[0589] Compound 112 was synthesized using similar experimental
conditions to that described for compound 64.
Example 113
Synthesis of tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate,
Compound 113
##STR00288##
[0591] To a solution of 5-bromo-2,4-dichloropyrimidine (12.80 g,
0.054 mole) in ethanol (250 mL) was added Hunig's base (12.0 mL)
followed by the addition of a solution of
N-(tert-butoxycarbonyl)-1,2-diaminoethane (10 g, 0.0624 mole) in
ethanol (80 mL). The contents were stirred overnight for 20 hrs.
The solvent was evaporated under vacuum. Ethyl acetate (800 mL) and
water (300 mL) were added and the layers separated. The organic
layer was dried with magnesium sulfate and then concentrated under
vacuum. Column chromatography on silica gel using hexane/ethyl
acetate (0-60%) afforded tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS
(ESI) 351 (M+H).
Example 114
Synthesis of tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4
y]amino]ethyl]carbamate, Compound 114
##STR00289##
[0593] To tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (5 g,
14.23 mmole) in toluene (42 mL) and triethylamine (8.33 mL) under
nitrogen was added triphenyl arsine (4.39 g),
3,3-diethoxyprop-1-yne (3.24 mL) and Pddba (1.27 g). The contents
were heated at 70 degrees for 24 hrs. After filtration through
CELITE.RTM., the crude reaction was columned using hexane/ethyl
acetate (0-20%) to afford the desired product 3.9 g). Column
chromatography of the resulting residue using hexane/ethyl acetate
(0-30%) afforded tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]car-
bamate. LCMS (ESI) 399 (M+H).
Example 115
Synthesis of tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carba-
mate, Compound 115
##STR00290##
[0595] To a solution of Compound 114 (3.9 g, 0.00976 mole) in THF
(60 mL) was added TBAF (68.3 mL, 7 eq). The contents were heated to
45 degrees for 2 hrs. Concentration followed by column
chromatography using ethyl acetate/hexane (0-50%) afforded
tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carba-
mate as a pale brown liquid (1.1 g).
[0596] .sup.1HNMR (d6-DMSO) .delta. ppm 8.88 (s, 1H), 6.95 (brs,
1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 44), 3.34
(m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399
(M+H).
Example 116
Synthesis of tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]eth-
yl]carbamate, Compound 116
##STR00291##
[0598] To tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carba-
mate (0.1 g, 0.00025 mol) in acetonitrile (2 mL) was added
1,3-diiodo-5,5-dimethylhydantoin (95 mg, 1 eq), and solid
NaHCO.sub.3 (63 mg, 3 eq). The reaction was stirred at room
temperature for 16 hrs. The reaction was filtered and concentrated
in vacuo. The product was purified by silica gel column
chromatography using hexane/ethylacetate (0-50%) to afford
tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]eth-
yl]carbamate as a pale yellow solid (0.03 g). LCMS (ESI) 525
(M+H).
Example 117
Synthesis of tert-Butyl
N-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl-
]ethyl]carbamate, Compound 117
##STR00292##
[0600] To tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]eth-
yl]carbamate (0.1g, 0.19 mmole) in dioxane (3 mL) was added
2-methylphenylboronic acid (28 mg),
tetrakis(triphenylphosphine)palladium (25 mg) and potassium
phosphate (250 mg) in water (0.3 mL). The reaction was heated in a
GEM Discovery microwave at 90.degree. C. for 3 hrs. The crude
reaction was loaded onto silica gel and columned using hexane/ethyl
acetate (0-30%) to afford tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyppyrrolo[2,3-d]pyrimidin-7-yl]-
ethyl]carbamate (0.06 g). LCMS (ESI) 489 (M+H).
Example 118
Synthesis of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]p-
yrimidine-6-carboxylic acid, Compound 118
##STR00293##
[0602] To tert-butyl
N-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]et-
hyl]carbamate (0.85 g, 1.74 mmole) in AcOH (10 mL) was added water
(1.5 mL). The reaction was stirred at room temperature for 16 hrs.
The crude reaction was then concentrated under vacuum. After the
addition of ethyl acetate (50 mL), the organic layer was washed
with satd. NaHCO.sub.3. The organic layer was dried with magnesium
sulfate and then concentrated under vacuum to afford the crude
intermediate, tert-butyl
N-[2-[2-chloro-6-formyl-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]car-
bamate. To this crude intermediate in DMF (5 mL) was added oxone
(1.3 g). After stirring for 2.5 hrs, water (20 mL) and ethyl
acetate (100 mL) were added. The organic layer was separated, dried
and then concentrated under vacuum to afford the crude product
which was columned over silica gel using hexanelethyl acetate
(0-50%) to afford
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]p-
yrimidine-6-carboxylic acid (0.112 g). LCMS (ESI) 431 (M+H).
Example 119
Synthesis of Compound 119
##STR00294##
[0604] To
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrol-
o[2,3-d]pyrimidine-6-carboxylic acid (0.1 g, 0.261 mmol) in DCM
(4.1 mL) was added DMAP (20 mg) followed by the addition of
N,N'-diisopropylcarbodiimide (0.081 mL, 2 eq). After stirring for 3
hrs, TFA (0.723 mL) was added. Stirring was then continued for
another 30 minutes. The reaction mixture was neutralized with satd.
NaHCO.sub.3. DCM (20 mL) was then added and the organic layer
separated, dried with magnesium sulfate and then concentrated under
vacuum to afford the crude product which was columned using
hexane/ethylacetate (0-100%) to afford chloro tricyclic amide
Compound 119 (0.65 g). LCMS (ESI) 313 (M+H).
Example 120
Synthesis of Compound 120
##STR00295##
[0606] To the chloro tricyclic amide (0.040 g, 0.128 mmole)
(Compound 119) in dioxane (2.5 mL) under nitrogen was added
Pd.sub.2(dba).sub.3 (12 mg), sodium tert-butoxide (16 mg), BINAP
(16 mg) and 4-morpholinoaniline (22.7 mg, 1 eq). The reaction
mixture was heated at 90.degree. C. in a CEM Discovery microwave
for 3.0 hrs. The crude reaction was loaded onto a silica gel column
and the contents eluted with DCM/MeOH (0-6%) to afford the product
(10 mg). LCMS (ESI) 455 (M+H). .sup.1HNMR (600 MHz, DMSO-d.sub.6)
.delta. ppm 2.14 (s, 3H) 3.23-3.50 (m, 2H) 3.57-3.73 (m, 2H),
3.81-3.92 (m, 8H), 7.11-7.31 (m, 4H) 7.31-7.48 (m, 1H) 7.58-7.73
(m, 1H) 7.77-7.95 (m, 2H) 8.05-8.21 (m, 1H) 8.44 (s, 1 IT)
9.85-10.01 (m, 1H).
Example 121
Synthesis of Compound 121
##STR00296##
[0608] To the chloro tricyclic amide (0.024 g) (Compound 119) in
N-methyl-2-pyrrolidone (NMP) (1.5 mL) was added
trans-4-aminocyclohexanol (0.0768 mmol, 26.54 mg, 3 eq) and Hunig's
base (0.4 mL). The reaction was heated in a CEM Discovery microwave
vessel at 150.degree. C. for 1.2 hrs. The crude reaction was loaded
onto a silica gel column and the contents eluted. with DCM/MeOH
(0-10%) to afford the product (21 mg). LCMS (ESI) 392 (M+H).
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.23 (d, J=8.78 Hz,
4H) 1.84 (br. s., 4H) 2.11 (s, 3H) 3.34-3.43 (m, 1H) 3.55 (br. s.,
2H) 3.72 (br. s., 1H) 4.13 (br. s., 2H) 4.50 (br. s., 1H) 7.03 (br.
s., 1H) 7.12-7.28 (m, 4H) 7.96 (br. s., 1H) 8.18 (br. s., 1H).
Example 122
Synthesis of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-
-carboxylic acid, Compound 122
##STR00297##
[0610]
7-[2-(tert-butoxycarbonylamino)ethyl[-2-chloro-pyrrolo[2,3-d]pyrimi-
dine-6-carboxylic acid was synthesized using a similar experimental
procedure as that described for the synthesis of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]p-
yrimidine-6-carboxylic acid. LCMS (ESI) 341 (M+H).
Example 123
Synthesis of Compound 123
##STR00298##
[0612] Chloro tricyclic amide, Compound 123, was synthesized using
a similar experimental procedure as that described for the
synthesis of chloro tricyclic amide (Compound 119), LCMS (ESI) 223
(M+H).
Example 124
Synthesis of Compound 124
##STR00299##
[0614] To the chloro tricyclic amide, Compound 123 (0.035 g,
0.00157 mole) in NMP (1.5 mL) was added Hunig's base (0.3 mL)
followed by the addition of the trans-4-aminocyclohexanol (54.2
mg). The reaction mixture was heated at 150.degree. C. for 1.5 hrs.
The crude reaction was loaded onto a silica gel column and the
column was eluted with DCM/MeOH (0-10%) to afford the product (5
mg). LCMS (ESI) 302 (M+H)
Example 125
Synthesis of tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate,
Compound 125
##STR00300##
[0616] tert-butyl N-8
2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate
was synthesized by treating 5-bromo-2,4-dichloropyrimidine with
tert-butyl N-(2-amino-2-methyl-propyl)carbamate using similar
experimental conditions as described for the synthesis of
tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS
(ESI) (M+H) 379.
Example 126
Synthesis of tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-
-propyl]carbamate, Compound 126
##STR00301##
[0618] tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-methyl-p-
ropyl]carbamate was synthesized by treating tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate
with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as
Pddba using similar experimental conditions as described for the
synthesis of tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4amino]ethyl]carbama-
te.
[0619] LCMS (ESI) (M+H) 427.
Example 127
Synthesis of tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methyl-p-
ropyl]carbamate, Compound 127
##STR00302##
[0621] tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methyl-p-
ropyl]carbamate was synthesized by treating tert-butyl
N-[2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl--
propyl]carbamate with TBAF using similar experimental conditions as
described for the synthesis tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carba-
mate. LCMS (ESI) (M+H) 427.
Example 128
Synthesis of
7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3--
d]pyrimidine-6-carboxylic acid, Compound 128
##STR00303##
[0623]
7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrol-
o[2,3-d]pyrimidine-6-carboxylic acid was synthesized using a
similar experimental procedure as that described for the synthesis
of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]p-
yrimidine-6-carboxylic acid. LCMS (ESI) 369 (M+H).
Example 129
Synthesis of Compound 129
##STR00304##
[0625] Chloro tricyclic amide, Compound 129, was synthesized using
a similar procedure as that described for the synthesis of chloro
tricyclic amide, Compound 119. LCMS (ESI) 251 (M+H).
Example 130
Synthesis of Compound 130
##STR00305##
[0627] Compound 130 was synthesized by treating chlorotricyclic
amine Compound 129 with trans-4-aminocyclohexanol using similar
experimental conditions as for compound 124. LCMS (ESI) 330 (M+H)
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.07-1.34 (m, 4H)
1.47-2.05 (m, 10H) 3.09 (m, 1H) 3.51 (d, J=2.91 Hz, 2H) 3.57 (m,
1H) 4.50 (br. s., 1H) 6.89 (s, 1H) 6.94-7.05 (m, 1H) 8.04 (br. s.,
1H) 8.60 (s, 1H) 9.00 (br. s., 1H).
Example 131
Synthesis of benzyl
N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamate,
Compound 131
##STR00306##
[0629] Benzyl
N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamate
was synthesized by treating 5-bromo-2,4-dichloropyrimidine with
benzyl N-[1-(aminomethyl)propyl]carbamate using similar
experimental conditions as described for the synthesis of
tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS
(ESI) (M+H) 413.
Example 132
Synthesis of benzyl
N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]p-
ropyl]carbamate, Compound 132
##STR00307##
[0631] Benzyl
N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]p-
ropyl]carbamate was prepared by treating benzyl
N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]-carbamate
with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as
Pddba using similar experimental conditions as described for the
synthesis of tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]car-
bamate
[0632] LCMS (ESI) (M+H) 461.
Example 133
Synthesis of benzyl
N-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-yl]
methyl]propyl]carbamate, Compound 133
##STR00308##
[0634] Benzyl
N-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]pro-
pyl]carbamate was synthesized by treating benzyl
N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]p-
ropyl]carbamate with TBAF using similar experimental conditions as
described for the synthesis tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3
d]pyrimidin-7-yl]ethyl]carbamate, LCMS (ESI) (M+H) 461.
Example 134
Synthesis of
7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]carboxylic
acid, Compound 134
##STR00309##
[0636]
7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidi-
ne-6-carboxyic acid was synthesized using a similar experimental
procedure as that described for the synthesis of
7-[2-(tert-butoxycarbonyl
amino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylic
acid. LCMS (ESI) 403 (M+H).
Example 135
Synthesis of Compound 135
##STR00310##
[0638] To a solution of
7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-c-
arboxylic acid in dichloromethane was added HBr, the reaction was
stirred at 45 degrees for 3 hrs. After concentration, 2N NaOH was
added to basify (pH=8.0) the reaction followed by the addition of
THF (20 mL), Boc.sub.2O was then added (1.2 eq) and the reaction
was stirred for 16 hrs. To the crude reaction mixture was then
added ethyl acetate (100 mL) and water (50 mL) and the organic
phase was separated, dried (magnesium sulfate) and then
concentrated under vacuum. To the crude product was added
dichloromethane (30 mL) followed by DIC and DMAP. After stirring
for 2 hrs, TFA was added and the contents stirred for an hour. The
solvents were evaporated under vacuum and the residue basified with
satd, NHCO.sub.3. Ethyl acetate was then added and the organic
layer separated, dried (magnesium sulfate) and then concentrated
under vacuum. Colum chromatography with hexane/ethyl acetate
(0-100%) afforded the desired chlorotricyclic core, Compound 135.
LCMS (ESI) 251 (M+H).
Example 136
Synthesis of Compound 136
##STR00311##
[0640] Compound 136 was synthesized by treating chlorotricyclic
amine, Compound 135, with trans-4-aminocyclohexanol using similar
experimental conditions as for compound 124. LCMS (ESI) 330 (M+H).
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 0.80-0995 (m, 3H)
1.35-1.92 (m, 10H) 3.66 (br. m., 3H) 4.17 (br. s., 2H) 4.47 (br.
s., 1H) 6.85 (s, 1H) 6.96 (br. s., 1H) 8.15 (br. s., 1H) 8.62 (br.
s., 1H).
Example 137
Synthesis of tert-butyl
N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamat-
e, Compound 137
##STR00312##
[0642] tert-butyl
N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamat-
e was synthesized by treating 5-bromo-2,4-dichloropyrimidine with
tert-butyl N-[1-(aminomethyl)cyclopentyl]carbamate using similar
experimental conditions as described for the synthesis of
tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS
(ESI) 405 (M+H).
Example 138
Synthesis of tert-butyl
N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]c-
yclopentyl]carbamate, Compound 138
##STR00313##
[0644] tert-butyl
N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]c-
yclopentyl]carbamate was synthesized by treating tert-butyl
N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamat-
e with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as
Pddba using similar experimental conditions as described for the
synthesis of tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4
yl]amino]ethyl]carbamate LCMS (ESI) 453 (M+H).
Example 139
Synthesis of tert-butyl
N-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]cyc-
lopentyl]carbamate, Compound 139
##STR00314##
[0646] tert-butyl
N-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]cyc-
lopentyl]carbamate was synthesized by treating tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-
-propyl]carbamate with TBAF using similar experimental conditions
as described for the synthesis tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3
d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 453 (M+H).
Example 140
Synthesis of
7-[[1-(tert-butoxycarbonylamino)cyclopentyl]methyl]-2-chloro-pyrrolo[2,3--
d]pyrimidine-6-carboxylic acid, Compound 140
##STR00315##
[0648]
7-[[1-(tert-butoxycarbonylamino)cyclopentyl]methyl]-2-chloro-pyrrol-
o[2,3-d]pyrimidine-6-carboxylic acid was synthesized using a
similar experimental procedure as that described for the synthesis
of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]p-
yrimidine-6-carboxylic acid. LCMS (ESI) 395 (M+H).
Example 141
Synthesis of Compound 141
##STR00316##
[0650] Chlorotricyclic core Compound 141 was synthesized using a
similar experimental procedure as that described for the synthesis
of chloro tricyclic amide Compound 119. LCMS (ESI) 277 (M+H).
Example 142
Synthesis of Compound 142
##STR00317##
[0652] Compound 142 was synthesized by treating chlorotricyclic
amine, Compound 141, with trans-4-aminocyclohexanol using similar
experimental conditions as for Compound 124. LCMS (ESI) 356 (M+H).
.sup.1HNMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.08-1.32 (m, 8H)
1.60-2.09 (m, 8 H) 3.03-3.17 (m, 1H) 3.35 (s, 2H) 3.54-3.62 (m, 1H)
4.51 (d, J=4.39 Hz, 1H) 6.88 (s, 1H) 6.96 (br. s., 1H) 8.07 (br.
s., 1H) 8.58 (s, 1H).
Example 143
Synthesis of tert-butyl
N-[[1-1(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamat-
e, Compound 143
##STR00318##
[0654] tert-butyl
N-[[1-(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate
was synthesized by treating 5-bromo-2,4-dichloropyrimidine with
tert-butyl N-[(1-aminocyclopentyl)methyl]carbamate using similar
experimental conditions as described for the synthesis of
tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS
(ESI) 405 (M+H).
Example 144
Synthesis of tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-
-propyl]c arbamate, Compound 144
##STR00319##
[0656] tert-butyl
N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopen-
tyl]methyl]carbamate was synthesized by treating tert-butyl
N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate
with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as
Pddba using similar experimental conditions as described for the
synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxy
prop-1-ynyl)pyrimidin-4 yl]amino]ethyl]carbamate.
[0657] LCMS (ESI) 453 (M+H).
Example 145
Synthesis of tert-butyl
N-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopenty-
l]methyl]carbamate. Compound 145
##STR00320##
[0659] tert-Butyl
N-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopenty-
l]methyl]carbamate was synthesized by treating tert-butyl
N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-
-propyl]carbamate with TBAF using similar experimental conditions
as described for the synthesis tert-butyl
N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbam-
ate. LCMS (ESI) 4534 (M+H).
Example 146
Synthesis of
7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3--
d]pyrimidine-6carboxylic acid, Compound 146
##STR00321##
[0661]
7-[2-(tert-Butoxycarbonylamino)-1,1-dimethyl-ethyl]-chloro-pyrrolo[-
2,3-d]pyrimidine-6-carboxylic acid was synthesized using a similar
experimental procedure as that described for the synthesis of
7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]p-
yrimidine-6-carboxylic acid, LCMS (ESI) 395 (M+H).
Example 147
Synthesis of Compound 147
##STR00322##
[0663] Chloro tricyclic amide, Compound 147 was synthesized using a
similar experimental procedure as that described for the chloro
bicyclic amide, Compound 119. LCMS (ESI) 277 (M+H).
Example 148
Synthesis of Compound 148
##STR00323##
[0665] Compound 148 was synthesized by treating chlorotricyclic
amine, Compound 147, with trans-4-aminocyclohexanol using similar
experimental conditions as for Compound 124. LCMS (ESI) 356 (M+H).
(600 MHz, DMSO-d.sub.6) .delta. ppm 1.06-1.35 (m, 8H) 1.45-1.95 (m,
8H) 3.10 (m, 1H) 3.58 (br. s., 2H) 3.95 (br. s., 1H) 4.49 (br. s.,
1H) 6.84 (s, 1H) 6.85-6.93 (m, 1H) 8,29 (s, 1H) 8.61 (br. s.,
1H),
Example 149
Synthesis of Compound 149
[0666] ##STR00324## [0667] Step 1: Compound 59 is Hoc protected
according to the method of A. Sarkar et al. (JOC, 2011, 76,
7132-7140). [0668] Step 2: Boc-protected Compound 59 is treated
with 5 mol % NiCl.sub.2(Ph.sub.3).sub.2, 0.1 eq triphenylphosphine,
3 eq Mn, 0.1 eq tetraethylammonium iodide, in DMI under CO.sub.2 (1
atm) at 25.degree. C. for 20 hours to convert the aryl halide
derivative into the carboxylic acid. [0669] Step 3: The carboxylic
acid from Step 2 is converted to the corresponding acid chloride
using standard conditions. [0670] Step 4: The acid chloride from
Step 3 is reacted with N-methyl piperazine to generate the
corresponding amide. [0671] Step 5: The amide from Step 4 is
deprotected using trifluoroacetic acid in methylene chloride to
generate the target compound. Compound 149 was purified by silica
gel column chromatography eluting with a dichloromethane-methanol
gradient to provide Compound 149.
[0672] Each of Compounds 119 through 147 and corresponding
compounds with various R.sup.8, R.sup.1 and Z definitions may be
reacted with sodium hydride and an alkyl halide or other halide to
insert the desired R substitution prior to reaction with an amine,
such as described above for the synthesis of Compound 120, to
produce the desired product of Formulae I, II, III, IV, or V.
Example 150
Inhibition of Cellular Proliferation
[0673] FIG. 9 is a graph showing the cellular proliferation of
SupT1 cells (human T-cell lymphoblastic leukemia) treated with
PD0332991 (circles) or Compound T (Table 1; squares). FIG. 10 is a
graph showing the cellular proliferation of SupT1 cells (human
T-cell lymphoblastic leukemia) treated with Compound Q (Table 1;
circles) or Compound GG (Table 1; squares). The SupT1 cells were
seeded in Costar (Tewksbury, Mass.) 3093 96 well tissue culture
treated white walled/clear bottom plates. A nine point dose
response dilution series from 10 uM to 1 nM was performed and cell
viability was determined after four days as indicated using the
CellTiter-Glo.RTM. assay (CTG; Promega, Madison, Wis., United
States of America) following the manufacturer's recommendations.
Plates were read on a BioTek (Winooski, Vt.) Syngergy2 multi-mode
plate reader. The Relative Light Units (RLU) were plotted as a
result of variable molar concentration and data was analyzed using
Graphpad (Lajolla, Calif.) Prism 5 statistical software to
determine the IC50 for each compound.
Example 151
Inhibition of Cellular Proliferation in T-cell and B-cell Specific
Cancer Cells
[0674] The compounds listed in Table 1 were tested for the
inhibition of cellular proliferation using SupT1 (human T-cell
lymphoblastic leukemia) and Daudi (human B-lymphoblastoid cell from
Burkitt's Lymphoma patient). FIGS. 9 and 10 and Example 150
illustrate how the EC.sub.50S were measured.
[0675] Most of the compounds tested showed significant inhibition
of the SupT1 T-cell lymphoblastic leukemia cell line. The range for
the EC.sub.50 of the compounds tested that were necessary for
inhibition of SupT1 I lymphoblastic leukemia cell proliferation was
9.3 nM to 3037 nM. Many of the compounds also had significant
effects on the inhibition of the B-cell lymphoblastoid cell line
(Daudi). The range for the EC.sub.50 of the compounds tested that
were necessary for inhibition of Daudi B-cell lymphoblastoid cell
proliferation was 111 nM to 3345 nM.
TABLE-US-00002 TABLE 2 Inhibition of Cellular Proliferation in
Cancer Cells SupT1 Cellular EC.sub.50 Daudi Cellular EC.sub.50
Structure [nM] [nM] A 57 281 B 96 385 C 74 373 D 55 297 E 9.3 140 F
107 692 G 156 1530 H 118 719 I 39 249 J 47 362 K 134 167 L 153 1262
M 184 1455 N 34 122 O 44 123 P 33 140 Q 40 561 R 43 299 S 110 634 T
113 392 U 48 363 V 35 194 W 57 731 X 36 318 Y 85 548 Z 87 359 AA 58
233 BB 70 472 CC 17 111 DD 105 546 EE 89 259 FF 90 380 GG 57 784 HH
79 681 II 42 347 JJ 49 389 KK 112 147 LL 84 501 MM 84 681 NN 84
1042 OO 114 880 PP 81 260 QQ 68 851 RR 102 158 SS 11 967 TT 92 589
UU 228 3163 VV 115 683 WW 77 1692 XX 94 499 YY 97 356 ZZ 272 584
AAA 15 3345 BBB 41 758 CCC 133 1865 DDD 161 839 EEE 65 475 FFF ND
ND GGG 161 586 HHH 85 984 III 230 775 JJJ 143 448 KKK ND ND LLL 241
1548 MMM 37 294 NNN 160 519 OOO 104 668 PPP 3037 ND QQQ 258 485 RRR
278 2011 SSS 305 >3000 TTT 587 3299 UUU 311 1425 VVV 224 1072
WWW 264 1266 XXX 270 1170
* * * * *