U.S. patent application number 15/627223 was filed with the patent office on 2017-10-05 for compounds and methods for kinase modulation, and indications therefor.
This patent application is currently assigned to Plexxikon Inc.. The applicant listed for this patent is Plexxikon Inc.. Invention is credited to Todd Ewing, Prabha N. Ibrahim, Wayne Spevak, Jianming Tsai, Chao Zhang, Jiazhong Zhang, Ying Zhang.
Application Number | 20170283423 15/627223 |
Document ID | / |
Family ID | 44816304 |
Filed Date | 2017-10-05 |
United States Patent
Application |
20170283423 |
Kind Code |
A1 |
Zhang; Jiazhong ; et
al. |
October 5, 2017 |
COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS
THEREFOR
Abstract
Compounds and salts thereof, formulations thereof, conjugates
thereof, derivatives thereof, forms thereof and uses thereof are
described, wherein the compounds have formula Ia: ##STR00001## In
certain aspects and embodiments, the described compounds or salts
thereof, formulations thereof, conjugates thereof, derivatives
thereof, forms thereof are active on one or more of Fms, Kit, Flt3,
TrkA, TrkB and TrkC kinase protein. Also described are methods of
use thereof to treat diseases and conditions, including diseases
and conditions associated with activity of one or more of Fms, Kit,
Flt3, TrkA, TrkB and TrkC, including rheumatoid arthritis,
osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic
sclerosis, demyelinating disorders, multiple sclerosis, Charcot
Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's
disease, Parkinson's disease, global ischemia, ulcerative colitis,
Crohn's disease, immune thrombocytopenic purpura, atherosclerosis,
systemic lupus erythematosis, myelopreparation for autologous
transplantation, transplant rejection, glomerulonephritis,
interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic
nephropathy, renal hypertrophy, type I diabetes, acute pain,
inflammatory pain, neuropathic pain, acute myeloid leukemia,
melanoma, multiple myeloma, breast cancer, prostate cancer,
pancreatic cancer, lung cancer, ovarian cancer, gliomas,
glioblastoma, neurofibromatosis, osteolytic bone metastases, brain
metastases, gastrointestinal stromal tumors, and giant cell
tumors.
Inventors: |
Zhang; Jiazhong; (Foster
City, CA) ; Ibrahim; Prabha N.; (Mountain View,
CA) ; Spevak; Wayne; (Berkeley, CA) ; Tsai;
Jianming; (Vallejo, CA) ; Ewing; Todd; (Walnut
Creek, CA) ; Zhang; Ying; (Fremont, CA) ;
Zhang; Chao; (Moraga, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Plexxikon Inc. |
Berkeley |
CA |
US |
|
|
Assignee: |
Plexxikon Inc.
Berkeley
CA
|
Family ID: |
44816304 |
Appl. No.: |
15/627223 |
Filed: |
June 19, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14556709 |
Dec 1, 2014 |
9682981 |
|
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15627223 |
|
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13090969 |
Apr 20, 2011 |
8901118 |
|
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14556709 |
|
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61326626 |
Apr 21, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 19/02 20180101; C07D 487/04 20130101; A61P 37/02 20180101;
A61P 25/28 20180101; A61P 35/00 20180101; A61P 37/06 20180101; A61P
35/02 20180101; A61P 29/00 20180101; A61P 19/00 20180101; A61P
13/02 20180101; A61P 25/04 20180101; A61P 1/04 20180101; A61P 37/00
20180101; A61P 3/10 20180101; C07D 471/04 20130101; A61P 21/02
20180101; A61P 9/00 20180101; A61P 43/00 20180101; A61P 35/04
20180101; A61P 7/04 20180101; A61P 9/10 20180101; A61P 1/00
20180101; A61P 19/10 20180101; A61P 13/12 20180101; A61P 25/00
20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04 |
Claims
1. A method for treating a subject with a disease or condition
selected from the group consisting of rheumatoid arthritis,
osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic
sclerosis, demyelinating disorders, multiple sclerosis, Charcot
Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's
disease, Parkinson's disease, global ischemia, ulcerative colitis,
Crohn's disease, immune thrombocytopenic purpura, atherosclerosis,
systemic lupus erythematosis, myelopreparation for autologous
transplantation, transplant rejection, glomerulonephritis,
interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic
nephropathy, renal hypertrophy, type I diabetes, chronic pain,
acute pain, inflammatory pain, neuropathic pain, bone pain, pain
associated with cancer, surgery, or bone fracture, acute myeloid
leukemia, melanoma, multiple myeloma, breast cancer, prostate
cancer, pancreatic cancer, non-small cell lung cancer, ovarian
cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone
metastases, brain metastases, gastrointestinal stromal tumors, and
giant cell tumors, said method comprising administering to the
subject in need thereof an effective amount of a compound of
Formula Ia: ##STR00468## or a salt thereof, wherein: Y.sub.2 is
--N.dbd. and R.sup.15 is hydrogen; or Y.sub.2 is --C(H).dbd. and
R.sup.15 is fluoro or chloro; L.sub.2 is --CH.sub.2-- or --C(O)--;
Cy.sub.2 is cycloalkyl optionally substituted with one or more
R.sup.16; R.sup.14 is --N(R.sup.9a)(R.sup.9b); R.sup.9a is H and
R.sup.9b is selected from the group consisting of (i) H, lower
alkyl, lower alkyl substituted with one or more substituents
independently selected from fluoro, lower alkyl substituted with
lower alkoxy, and lower alkyl substituted with hydroxyl, and (ii)
cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which
is optionally substituted with one to three members independently
selected from lower alkyl, haloalkyl, lower alkoxy, and fluoro; or
R.sup.9a and R.sup.9b together with the nitrogen to which they are
attached form a 5- or 6-membered ring having from 0 to 1 additional
heteroatom selected from O, N, or S, each of which is optionally
substituted with one to three members independently selected from
lower alkyl, haloalkyl, lower alkoxy, and fluoro; and each R.sup.16
is independently selected from the group consisting of fluoro,
--OH, lower alkyl optionally substituted with one or more
substituents independently selected from fluoro, and lower alkoxy
optionally substituted with one or more fluoro.
2. The method of claim 1, wherein L.sub.2 is --C(O)--.
3. The method of claim 2, wherein Y.sub.2 is --C(H).dbd..
4. The method of claim 1, wherein Cy.sub.2 is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cyclopentyl, each of which
is optionally substituted with from 1 to 3 R.sup.16.
5. The method of claim 1, wherein each R.sup.16 is F.
6. The method of claim 1, wherein R.sup.9b is lower alkyl.
7. The method of claim 1, wherein R.sup.9b is lower alkyl
substituted with one or more fluoro.
8. The method of claim 1, wherein the compound is selected from the
group consisting of: ##STR00469## ##STR00470## or a salt
thereof.
9. The method of claim 1, wherein the compound is: ##STR00471## or
a salt thereof.
10. The method of claim 1, wherein the compound is: ##STR00472## or
a salt thereof.
11. The method of claim 1, wherein the compound is: ##STR00473## or
a salt thereof.
12. The method of claim 1, wherein the compound is: ##STR00474## or
a salt thereof.
13. The method of claim 1, wherein the compound is: ##STR00475## or
a salt thereof.
14. The method according to any of the preceding claims, wherein
the disease or condition is chronic pain, acute pain, inflammatory
pain, neuropathic pain, or bone pain.
15. The method according to claim 14, wherein the disease or
condition is inflammatory pain.
16. The method according to claim 1, wherein the disease or
condition is pain associated with cancer, surgery, or bone
fracture.
17. The method according to claim 1, wherein the disease or
condition is pancreatic cancer.
18. The method according to claim 1, wherein the disease or
condition is gastrointestinal stromal tumors.
19. The method according to claim 1, wherein the disease or
condition is non-small cell lung cancer.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATION
[0001] This application is a divisional application of U.S.
application Ser. No. 14/556,709 filed Dec. 1, 2014, which is a
continuation of U.S. application Ser. No. 13/090,969 filed Apr. 20,
2011, now U.S. Pat. No. 8,901,118, which claims the benefit of U.S.
Provisional Application 61/326,626, filed Apr. 21, 2010, the entire
disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] Disclosed are novel compounds and uses thereof. In certain
embodiments disclosed compounds are kinase inhibitors.
SUMMARY OF THE INVENTION
[0003] In certain aspects and embodiments disclosed herein,
compounds are provided, as well as various salts thereof,
formulations thereof, conjugates thereof, derivatives thereof,
forms thereof and uses thereof. In certain embodiments, the
compounds are active on one or more protein kinases, including Fms,
Kit, Flt3, TrkA, TrkB and/or TrkC, including any mutations thereof.
In certain embodiments, compounds are active on Fms kinase. In
certain embodiments, compounds are active on Fms and Kit kinase. In
certain embodiments, compounds are selectively active on Fms kinase
relative to Kit kinase. In certain embodiments, compounds are
active on Fms kinase and Flt3 kinase. In certain embodiments,
compounds are active on Fms kinase and one or more of TrkA, TrkB
and TrkC kinase.
[0004] Also contemplated in accordance with the present invention
are methods for the use of the compounds in treating diseases and
conditions associated with regulation of the activity of one or
more of Fms, Kit, Flt3, TrkA, TrkB and TrkC, including any
mutations thereof. Thus, the use of compounds for therapeutic
methods involving modulation of protein kinases are provided. In
certain embodiments, the compounds are used for therapeutic methods
involving the treatment of a variety of indications, including, but
not limited to, rheumatoid arthritis, osteoarthritis, osteoporosis,
peri-prosthetic osteolysis, systemic sclerosis, demyelinating
disorders, multiple sclerosis, Charcot Marie Tooth syndrome,
amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's
disease, global ischemia, ulcerative colitis, Crohn's disease,
immune thrombocytopenic purpura, atherosclerosis, systemic lupus
erythematosis, myelopreparation for autologous transplantation,
transplant rejection, glomerulonephritis, interstitial nephritis,
Lupus nephritis, tubular necrosis, diabetic nephropathy, renal
hypertrophy, type I diabetes, acute pain, inflammatory pain,
neuropathic pain, acute myeloid leukemia, melanoma, multiple
myeloma, breast cancer, prostate cancer, pancreatic cancer, lung
cancer, ovarian cancer, gliomas, glioblastoma, neurofibromatosis,
osteolytic bone metastases, brain metastases, gastrointestinal
stromal tumors, and giant cell tumors. In some embodiments,
compounds are of Formula I as described below.
[0005] In a first aspect, compounds having the structure according
to the following Formula I are provided:
##STR00002##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0006] wherein: [0007] X.sub.1 is --N.dbd., --C(H).dbd.,
or --C(R.sup.1).dbd.; [0008] Y.sub.1 is --N.dbd. and R.sup.3 is
hydrogen; or Y.sub.1 is --C(H).dbd. and R.sup.3 is fluoro or
chloro; [0009] L.sub.1 is --C(H.sub.2)-- or --C(O)--; [0010]
Cy.sub.1 is cycloalkyl optionally substituted with one or more
R.sup.4, phenyl optionally substituted with one or more R.sup.5, or
5 or 6 membered heteroaryl optionally substituted on an available
carbon atom with one or more R.sup.6 and optionally substituted on
an available nitrogen atom with R.sup.7; [0011] when X.sub.1 is
--C(R.sup.1).dbd., R.sup.2 is hydrogen; [0012] when X.sub.1 is
--N.dbd. or --C(H).dbd., R.sup.2 is selected from the group
consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.8, --N(R.sup.9a)(R.sup.9b), and
--O--R.sup.9; [0013] R.sup.1 is fluoro, chloro, or lower alkyl
optionally substituted with one or more fluoro; [0014] each R.sup.4
is independently selected from the group consisting of fluoro,
--OH, lower alkyl optionally substituted with one or more fluoro,
and lower alkoxy optionally substituted with one or more fluoro;
[0015] each R.sup.5 is independently selected from the group
consisting of fluoro, chloro, --O--R.sup.10, --S--R.sup.11,
--S(O.sub.2)--R.sup.12, and lower alkyl optionally substituted with
one or more R.sup.13; [0016] each R.sup.6 is independently selected
from the group consisting of fluoro, chloro, bromo, cycloalkyl,
lower alkyl optionally substituted with one or more fluoro, and
lower alkoxy optionally substituted with one or more fluoro; or two
R.sup.6 bound to adjacent carbon atoms of the heteroaryl ring,
taken together, form a fused cycloalkyl ring; [0017] R.sup.7 is
cycloalkyl, lower alkoxy or lower alkyl optionally substituted with
one or more fluoro; [0018] R.sup.8 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; [0019] R.sup.9a is
H and R.sup.9b is selected from the group consisting of (i) H,
lower alkyl, lower alkyl substituted with one or more fluoro, lower
alkyl substituted with lower alkoxy or lower alkyl substituted with
hydroxyl and (ii) cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, each of which is
optionally substituted with one to three members selected from
lower alkyl, haloalkyl, lower alkoxy or fluoro; or [0020] R.sup.9a
and R.sup.9b together with the nitrogen to which they are attached
form a 5- or 6-membered ring having from 0 to 1 additional
heteroatom selected from O, N or S, each of which is optionally
substituted with one to three members selected from lower alkyl,
haloalkyl, lower alkoxy or fluoro; [0021] R.sup.9 is lower alkyl,
lower alkyl substituted with one or more fluoro, or lower alkyl
substituted with lower alkoxy; [0022] each R.sup.10, R.sup.11 and
R.sup.12 are independently lower alkyl optionally substituted with
one or more fluoro; and [0023] each R.sup.13 is independently
selected from the group consisting of fluoro, --OH, and lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula I, R.sup.3 is fluoro. In
certain embodiments, the salt is a pharmaceutically acceptable
salt.
[0024] In some embodiments, the invention provides compounds of
Formula I or any of the subformulas as described herein, or a
pharmaceutically acceptable salt, a solvate, a tautomer or a
stereoisomer thereof. In other embodiments of the invention, there
are provided compounds of Formula I or any of the subformulas as
described herein, or a pharmaceutically acceptable salt or a
solvate thereof. In some embodiments, the solvate is a hydrate.
[0025] In some embodiments of compounds of Formula I, X.sub.1 is
--N.dbd. and R.sup.2 is selected from the group consisting of
cycloalkyl, lower alkyl optionally substituted with one or more
R.sup.8, for example, 1 to 3 R.sup.8, and --O--R.sup.9. In one
embodiment, X.sub.1 is --N.dbd. and R.sup.2 is selected from the
group consisting of cycloalkyl, lower alkyl, lower alkoxy, and
lower alkoxy substituted with lower alkoxy. In one embodiment,
X.sub.1 is --N.dbd. and R.sup.2 is selected from the group
consisting of C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3
alkoxy, and C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In
one embodiment, X.sub.1 is --N.dbd. and R.sup.2 is selected from
the group consisting of methyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0026] In some embodiments of compounds of Formula I, X.sub.1 is
--C(H).dbd. or --C(R.sup.1).dbd. and R.sup.1 is fluoro, chloro, or
lower alkyl optionally substituted with one or more fluoro. In one
embodiment, X.sub.1 is --C(H).dbd. or --C(R.sup.1).dbd. and R.sup.1
is chloro or lower alkyl. In one embodiment, X.sub.1 is --C(H).dbd.
or --C(R.sup.1).dbd. and R.sup.1 is chloro or C.sub.1-3 alkyl. In
one embodiment, X.sub.1 is --C(H).dbd. or --C(R.sup.1).dbd. and
R.sup.1 is chloro or methyl.
[0027] In some embodiments of compounds of Formula I, further to
any of the above embodiments of Formula I, Cy.sub.1 is cycloalkyl
optionally substituted with one or more R.sup.4, phenyl optionally
substituted with one or more R.sup.5, or 5 or 6 membered heteroaryl
optionally substituted on an available carbon atom with one or more
R.sup.6 and optionally substituted on an available nitrogen atom
with R.sup.7, wherein cycloalkyl is cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl is
pyridinyl or pyrazolyl.
[0028] In some embodiments of compounds of Formula I, further to
any of the above embodiments of Formula I, Cy.sub.1 is cycloalkyl
optionally substituted with one or more R.sup.4, phenyl optionally
substituted with one or more R.sup.5, or 5 or 6 membered heteroaryl
optionally substituted on an available carbon atom with one or more
R.sup.6 and optionally substituted on an available nitrogen atom
with R.sup.7, wherein cycloalkyl is cyclohexyl, or cycloheptyl, and
heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0029] In some embodiments of compounds of Formula I, further to
any of the above embodiments of Formula I, L.sub.1 is
--C(H.sub.2)--. In some embodiments of compounds of Formula I,
further to any of the above embodiments of Formula I, L.sub.1 is
--C(O)--.
[0030] In some embodiments of compounds of Formula I, further to
any of the above embodiments of Formula I, Y.sub.1 is --N.dbd. and
R.sup.3 is hydrogen. In some embodiments of compounds of Formula I,
further to any of the above embodiments of Formula I, Y.sub.1 is
--C(H).dbd. and R.sup.3 is fluoro.
[0031] In some embodiments (A) of compounds of Formula I, X.sub.1
is N and all the other variables are as defined herein. Within
embodiments (A), in certain instances, L.sub.1 is CH.sub.2, Y.sub.1
is CH and R.sup.3 is F. In other instances, L.sub.1 is CH.sub.2,
Y.sub.1 is N and R.sup.3 is F. In yet other instances, L.sub.1 is
--C(.dbd.O)--, Y.sub.1 is CH and R.sup.3 is F. In still other
instances, L.sub.1 is --C(.dbd.O)--, Y.sub.1 is N and R.sup.3 is
F.
[0032] In some embodiments (B) of compounds of Formula I, X.sub.1
is --C(R.sup.1).dbd., R.sup.1 and all the other variables are as
defined herein. Within embodiments (B), in certain instances,
L.sub.1 is CH.sub.2, Y.sub.1 is CH and R.sup.3 is F. In other
instances L.sub.1 is --C(.dbd.O)--, Y.sub.1 is CH and R.sup.3 is F.
In yet other instances, L.sub.1 is --CH.sub.2--, Y.sub.1 is N and
R.sup.3 is F. In still other instances, L.sub.1 is --C(.dbd.O)--,
Y.sub.1 is N and R.sup.3 is F.
[0033] In some embodiments (C) of compounds of Formula I, X.sub.1
is N, R.sup.2 is --N(R.sup.9a)(R.sup.9b), and all the other
variables are as defined herein.
[0034] In some embodiments of compounds of Formula I, Cy.sub.1 is
cycloalkyl optionally substituted with one or more R.sup.4. In
certain instances, Cy.sub.1 is cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopentyl, each of which is optionally
substituted with from 1 to 3 R.sup.4. All the other variables are
as defined herein.
[0035] In some embodiments of compounds of Formula I, Cy.sub.1 is
phenyl optionally substituted with one or more R.sup.5 and all the
other variables are as defined herein.
[0036] In some embodiments of compounds of Formula I, wherein
Cy.sub.1 is 5 or 6-membered heteroaryl optionally substituted on an
available carbon atom with one or more R.sup.6 and optionally
substituted on an available nitrogen atom with R.sup.7. In certain
instances, Cy.sub.1 is 3-pyridyl, 2-pyrrolyl, 3-pyrrolyl or
4-pyrazolyl, optionally substituted on an available carbon atom
with from 1 to 3 R.sup.6 and optionally substituted on an available
nitrogen atom with R.sup.7. In some embodiments, each R.sup.6 is
independently selected from the group consisting of fluoro, chloro,
bromo, cycloalkyl, lower alkyl optionally substituted with from one
to three fluoro, and lower alkoxy optionally substituted with one
to three fluoro; or two R.sup.6 bound to adjacent carbon atoms of
the heteroaryl ring form a fused cycloalkyl ring. All the other
variables are as defined herein.
[0037] In some embodiments of compounds of Formula I, R.sup.9a is H
and R.sup.9b is selected from H, lower alkyl, lower alkyl
substituted with hydroxy, lower alkyl substituted with lower
alkoxy, lower alkyl substituted with 1 to 3 fluoro groups,
cycloalkyl optionally substituted with lower alkyl or one to three
fluoro, cycloalkylalkyl optionally substituted with lower alkyl or
one to three fluoro substituents, heterocycloalkyl optionally
substituted with lower alkyl, heterocycloalkylalkyl, arylalkyl
optionally substituted with from 1 to 3 members selected from lower
alkyl, fluoro or haloalkyl and heteroarylalkyl optionally
substituted with from one to three members selected from alkyl,
fluoro or haloalkyl. In certain instances, R.sup.9a is H and
R.sup.9b is selected from (i) H, methyl, ethyl, t-butyl, propyl,
isopropyl, 2-butyl, n-butyl, 2-hydroxy-2-methylpropyl,
2-methoxyethyl, 3-methoxypropyl, 2,2,2-trifluoroethyl, or
4-methoxybutyl and (ii) cyclopropyl, cyclobutyl, cyclopentyl,
cylohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexymethyl, benzyl, 1-methylbenzyl, 4,4-difluorocyclohexyl,
2-tetrahydrofuranylmethyl, 4-piperadinyl, 3-pyridyl, 2-pyridyl or
4-pyridyl, each of which is optionally substituted with from 1 to 3
members selected from lower alkyl, lower alkoxy, fluoro or
CF.sub.3. All the other variables are as defined herein.
[0038] In some embodiments of compounds of Formula I,
--N(R.sup.9a)(R.sup.9b) is 1-piperadinyl, 4-morpholinyl,
1-piperazinyl or 1-pyrrolidinyl, each of which is optionally
substituted with one to three members selected from lower alkyl,
haloalkyl, lower alkoxy or fluoro. All the other variables are as
defined herein.
[0039] In a second aspect, compounds of Formula I having the
structure according to the following Formula Ia are provided:
##STR00003##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0040] wherein: [0041] Y.sub.2 is --N.dbd. and R.sup.15 is
hydrogen; or Y.sub.2 is --C(H).dbd. and R.sup.15 is fluoro or
chloro; [0042] L.sub.2 is --C(H.sub.2)-- or --C(O)--; [0043]
Cy.sub.2 is cycloalkyl optionally substituted with one or more
R.sup.16, phenyl optionally substituted with one or more R.sup.17,
or 5 or 6 membered heteroaryl optionally substituted on an
available carbon atom with one or more R.sup.18 and optionally
substituted on an available nitrogen atom with R.sup.19; [0044]
R.sup.14 is selected from the group consisting of cycloalkyl, lower
alkyl optionally substituted with one or more R.sup.20,
--N(R.sup.9a)(R.sup.9b), and --O--R.sup.21; [0045] each R.sup.16 is
independently selected from the group consisting of fluoro, --OH,
lower alkyl optionally substituted with one or more fluoro, and
lower alkoxy optionally substituted with one or more fluoro; [0046]
each R.sup.17 is independently selected from the group consisting
of fluoro, chloro, --O--R.sup.22, --S--R.sup.23,
--S(O.sub.2)--R.sup.24, and lower alkyl optionally substituted with
one or more R.sup.25; [0047] each R.sup.18 is independently
selected from the group consisting of fluoro, chloro, bromo,
cycloalkyl, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro; or two R.sup.18 bound to adjacent carbon atoms of the
heteroaryl ring, taken together, form a fused cycloalkyl ring;
[0048] R.sup.19 is cycloalkyl, lower alkoxy, or lower alkyl
optionally substituted with one or more fluoro; [0049] R.sup.20 is
fluoro or lower alkoxy optionally substituted with one or more
fluoro; [0050] R.sup.21 is lower alkyl, lower alkyl substituted
with one or more fluoro, or lower alkyl substituted with lower
alkoxy; [0051] each R.sup.22, R.sup.23 and R.sup.24 are
independently lower alkyl optionally substituted with one or more
fluoro; and [0052] each R.sup.25 is independently selected from the
group consisting of fluoro, --OH, and lower alkoxy optionally
substituted with one or more fluoro.
[0053] In some embodiments of compounds of Formula Ia, R.sup.14 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.14 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.14 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0054] In some embodiments of compounds of Formula Ia, further to
any of the above embodiments of Formula Ia, Cy.sub.2 is cycloalkyl
optionally substituted with one or more R.sup.16, phenyl optionally
substituted with one or more R.sup.17, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.18 and optionally substituted on an available
nitrogen atom with R.sup.19, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0055] In some embodiments of compounds of Formula Ia, further to
any of the above embodiments of Formula Ia, Cy.sub.2 is cycloalkyl
optionally substituted with one or more R.sup.16, phenyl optionally
substituted with one or more R.sup.17, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.18 and optionally substituted on an available
nitrogen atom with R.sup.19, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0056] In some embodiments of compounds of Formula Ia, further to
any of the above embodiments of Formula Ia, L.sub.2 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Ia,
further to any of the above embodiments of Formula Ia, L.sub.2 is
--C(O)--.
[0057] In some embodiments of compounds of Formula Ia, further to
any of the above embodiments of Formula Ia, Y.sub.2 is --N.dbd. and
R.sup.15 is hydrogen. In some embodiments of compounds of Formula
Ia, further to any of the above embodiments of Formula Ia, Y.sub.2
is --C(H).dbd. and R.sup.15 is fluoro.
[0058] In a third aspect, compounds of Formula I having the
structure according to the following Formula Ib are provided:
##STR00004##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0059] wherein: [0060] Cy.sub.3 is cycloalkyl optionally
substituted with one or more R.sup.27, phenyl optionally
substituted with one or more R.sup.28, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.29 and optionally substituted on an available
nitrogen atom with R.sup.30; [0061] R.sup.26 is selected from the
group consisting of cycloalkyl, lower alkyl optionally substituted
with one or more R.sup.31, and --O--R.sup.32; [0062] each R.sup.27
is independently selected from the group consisting of fluoro,
--OH, lower alkyl optionally substituted with one or more fluoro,
and lower alkoxy optionally substituted with one or more fluoro;
[0063] each R.sup.28 is independently selected from the group
consisting of fluoro, chloro, --O--R.sup.33, --S--R.sup.34,
--S(O.sub.2)--R.sup.35, and lower alkyl optionally substituted with
one or more R.sup.36; [0064] each R.sup.29 is independently
selected from the group consisting of fluoro, chloro, bromo,
cycloalkyl, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro; or two R.sup.29 bound to adjacent carbon atoms of the
heteroaryl ring, taken together, form a fused cycloalkyl ring;
[0065] R.sup.30 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro; [0066] R.sup.31 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; [0067] R.sup.32 is
lower alkyl, lower alkyl substituted with one or more fluoro, or
lower alkyl substituted with lower alkoxy; [0068] each R.sup.33,
R.sup.34 and R.sup.35 are independently lower alkyl optionally
substituted with one or more fluoro; and [0069] each R.sup.36 is
independently selected from the group consisting of fluoro, --OH,
and lower alkoxy optionally substituted with one or more
fluoro.
[0070] In some embodiments of compounds of Formula Ib, R.sup.26 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.26 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.26 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0071] In some embodiments of compounds of Formula Ib, further to
any of the above embodiments of Formula Ib, Cy.sub.3 is cycloalkyl
optionally substituted with one or more R.sup.27, phenyl optionally
substituted with one or more R.sup.28, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.29 and optionally substituted on an available
nitrogen atom with R.sup.30, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0072] In some embodiments of compounds of Formula Ib, further to
any of the above embodiments of Formula Ib, Cy.sub.3 is cycloalkyl
optionally substituted with one or more R.sup.27, phenyl optionally
substituted with one or more R.sup.28, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.29 and optionally substituted on an available
nitrogen atom with R.sup.30, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0073] In a fourth aspect, compounds of Formula I having the
structure according to the following Formula Ic are provided:
##STR00005##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0074] wherein: [0075] Cy.sub.4 is cycloalkyl optionally
substituted with one or more R.sup.38, phenyl optionally
substituted with one or more R.sup.39, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.40 and optionally substituted on an available
nitrogen atom with R.sup.41; [0076] R.sup.37 is selected from the
group consisting of cycloalkyl, lower alkyl optionally substituted
with one or more R.sup.42, and --O--R.sup.43; [0077] each R.sup.38
is independently selected from the group consisting of fluoro,
--OH, lower alkyl optionally substituted with one or more fluoro,
and lower alkoxy optionally substituted with one or more fluoro;
[0078] each R.sup.39 is independently selected from the group
consisting of fluoro, chloro, --O--R.sup.44, --S--R.sup.45,
--S(O.sub.2)--R.sup.46, and lower alkyl optionally substituted with
one or more R.sup.47; [0079] each R.sup.40 is independently
selected from the group consisting of fluoro, chloro, bromo,
cycloalkyl, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro; or two R.sup.40 bound to adjacent carbon atoms of the
heteroaryl ring, taken together, form a fused cycloalkyl ring;
[0080] R.sup.41 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro; [0081] R.sup.42 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; [0082] R.sup.43 is
lower alkyl, lower alkyl substituted with one or more fluoro, or
lower alkyl substituted with lower alkoxy; [0083] each R.sup.44,
R.sup.45 and R.sup.46 are independently lower alkyl optionally
substituted with one or more fluoro; and [0084] each R.sup.47 is
independently selected from the group consisting of fluoro, --OH,
and lower alkoxy optionally substituted with one or more
fluoro.
[0085] In some embodiments of compounds of Formula Ic, R.sup.37 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.37 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.37 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0086] In some embodiments of compounds of Formula Ic, further to
any of the above embodiments of Formula Ic, Cy.sub.4 is cycloalkyl
optionally substituted with one or more R.sup.38, phenyl optionally
substituted with one or more R.sup.39, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.40 and optionally substituted on an available
nitrogen atom with R.sup.41, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0087] In some embodiments of compounds of Formula Ic, further to
any of the above embodiments of Formula Ic, Cy.sub.4 is cycloalkyl
optionally substituted with one or more R.sup.38, phenyl optionally
substituted with one or more R.sup.39, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.40 and optionally substituted on an available
nitrogen atom with R.sup.41, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0088] In a fifth aspect, compounds of Formula I having the
structure according to the following Formula Id are provided:
##STR00006##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0089] wherein: [0090] Cy.sub.5 is cycloalkyl optionally
substituted with one or more R.sup.49, phenyl optionally
substituted with one or more R.sup.50, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.51 and optionally substituted on an available
nitrogen atom with R.sup.52; [0091] R.sup.48 is selected from the
group consisting of cycloalkyl, lower alkyl optionally substituted
with one or more R.sup.53, and --O--R.sup.54; [0092] each R.sup.49
is independently selected from the group consisting of fluoro,
--OH, lower alkyl optionally substituted with one or more fluoro,
and lower alkoxy optionally substituted with one or more fluoro;
[0093] each R.sup.50 is independently selected from the group
consisting of fluoro, chloro, --O--R.sup.55, --S--R.sup.56,
--S(O.sub.2)--R.sup.57, and lower alkyl optionally substituted with
one or more R.sup.58; [0094] each R.sup.51 is independently
selected from the group consisting of fluoro, chloro, bromo,
cycloalkyl, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro; or two R.sup.51 bound to adjacent carbon atoms of the
heteroaryl ring, taken together, form a fused cycloalkyl ring;
[0095] R.sup.52 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro; [0096] R.sup.53 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; [0097] R.sup.54 is
lower alkyl, lower alkyl substituted with one or more fluoro, or
lower alkyl substituted with lower alkoxy; [0098] each R.sup.55,
R.sup.56 and R.sup.57 are independently lower alkyl optionally
substituted with one or more fluoro; and [0099] each R.sup.58 is
independently selected from the group consisting of fluoro, --OH,
and lower alkoxy optionally substituted with one or more
fluoro.
[0100] In some embodiments of compounds of Formula Id, R.sup.48 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.48 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.48 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0101] In some embodiments of compounds of Formula Id, further to
any of the above embodiments of Formula Id, Cy.sub.5 is cycloalkyl
optionally substituted with one or more R.sup.49, phenyl optionally
substituted with one or more R.sup.50, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.51 and optionally substituted on an available
nitrogen atom with R.sup.52, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0102] In some embodiments of compounds of Formula Id, further to
any of the above embodiments of Formula Id, Cy.sub.5 is cycloalkyl
optionally substituted with one or more R.sup.49, phenyl optionally
substituted with one or more R.sup.50, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.51 and optionally substituted on an available
nitrogen atom with R.sup.52, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0103] In a sixth aspect, compounds of Formula I having the
structure according to the following Formula Ie are provided:
##STR00007##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0104] wherein: [0105] Cy.sub.6 is cycloalkyl optionally
substituted with one or more R.sup.60, phenyl optionally
substituted with one or more R.sup.61, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.62 and optionally substituted on an available
nitrogen atom with R.sup.63; [0106] R.sup.59 is selected from the
group consisting of cycloalkyl, lower alkyl optionally substituted
with one or more R.sup.64, and --O--R.sup.65; [0107] each R.sup.60
is independently selected from the group consisting of fluoro,
--OH, lower alkyl optionally substituted with one or more fluoro,
and lower alkoxy optionally substituted with one or more fluoro;
[0108] each R.sup.61 is independently selected from the group
consisting of fluoro, chloro, --O--R.sup.66, --S--R.sup.67,
--S(O.sub.2)--R.sup.68, and lower alkyl optionally substituted with
one or more R.sup.69; [0109] each R.sup.62 is independently
selected from the group consisting of fluoro, chloro, bromo,
cycloalkyl, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro; or two R.sup.62 bound to adjacent carbon atoms of the
heteroaryl ring, taken together, form a fused cycloalkyl ring;
[0110] R.sup.63 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro; [0111] R.sup.64 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; [0112] R.sup.65 is
lower alkyl, lower alkyl substituted with one or more fluoro, or
lower alkyl substituted with lower alkoxy; [0113] each R.sup.66,
R.sup.67 and R.sup.68 are independently lower alkyl optionally
substituted with one or more fluoro; and [0114] each R.sup.69 is
independently selected from the group consisting of fluoro, --OH,
and lower alkoxy optionally substituted with one or more
fluoro.
[0115] In some embodiments of compounds of Formula Ie, R.sup.59 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.59 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.59 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0116] In some embodiments of compounds of Formula Ie, further to
any of the above embodiments of Formula Ie, Cy.sub.6 is cycloalkyl
optionally substituted with one or more R.sup.60, phenyl optionally
substituted with one or more R.sup.61, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.62 and optionally substituted on an available
nitrogen atom with R.sup.63, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0117] In some embodiments of compounds of Formula Ie, further to
any of the above embodiments of Formula Ie, Cy.sub.6 is cycloalkyl
optionally substituted with one or more R.sup.60, phenyl optionally
substituted with one or more R.sup.61, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.62 and optionally substituted on an available
nitrogen atom with R.sup.63, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0118] In a seventh aspect, compounds of Formula I having the
structure according to the following Formula If are provided:
##STR00008##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0119] wherein: [0120] Y.sub.3 is --N.dbd. and R.sup.71 is
hydrogen; or Y.sub.3 is --C(H).dbd. and R.sup.71 is fluoro; [0121]
L.sub.3 is --C(H.sub.2)-- or --C(O)--; [0122] Cy.sub.7 is
cycloalkyl optionally substituted with one or more R.sup.72, phenyl
optionally substituted with one or more R.sup.73, or 5 or 6
membered heteroaryl optionally substituted on an available carbon
atom with one or more R.sup.74 and optionally substituted on an
available nitrogen atom with R.sup.75; [0123] R.sup.70 is hydrogen,
fluoro, chloro, or lower alkyl optionally substituted with one or
more fluoro; [0124] each R.sup.72 is independently selected from
the group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0125] each R.sup.73 is
independently selected from the group consisting of fluoro, chloro,
--O--R.sup.76, --S--R.sup.77, --S(O.sub.2)--R.sup.78, and lower
alkyl optionally substituted with one or more R.sup.79; [0126] each
R.sup.74 is independently selected from the group consisting of
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; or two R.sup.74 bound to
adjacent carbon atoms of the heteroaryl ring, taken together, form
a fused cycloalkyl ring; [0127] R.sup.75 is cycloalkyl or lower
alkyl optionally substituted with one or more fluoro; [0128] each
R.sup.76, R.sup.77 and R.sup.78 are independently lower alkyl
optionally substituted with one or more fluoro; and [0129] each
R.sup.79 is independently selected from the group consisting of
fluoro, --OH, and lower alkoxy optionally substituted with one or
more fluoro.
[0130] In some embodiments of compounds of Formula If, R.sup.70 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.70 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.70 is
hydrogen, chloro or methyl.
[0131] In some embodiments of compounds of Formula If, further to
any of the above embodiments of Formula If, Cy.sub.7 is cycloalkyl
optionally substituted with one or more R.sup.72, phenyl optionally
substituted with one or more R.sup.73, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.74 and optionally substituted on an available
nitrogen atom with R.sup.75, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0132] In some embodiments of compounds of Formula If, further to
any of the above embodiments of Formula If, Cy.sub.7 is cycloalkyl
optionally substituted with one or more R.sup.72, phenyl optionally
substituted with one or more R.sup.73, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.74 and optionally substituted on an available
nitrogen atom with R.sup.75, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0133] In some embodiments of compounds of Formula If, further to
any of the above embodiments of Formula If, L.sub.3 is
--C(H.sub.2)--. In some embodiments of compounds of Formula If,
further to any of the above embodiments of Formula If, L.sub.3 is
--C(O)--.
[0134] In some embodiments of compounds of Formula If, further to
any of the above embodiments of Formula If, Y.sub.3 is --N.dbd. and
R.sup.71 is hydrogen. In some embodiments of compounds of Formula
If, further to any of the above embodiments of Formula If, Y.sub.3
is --C(H).dbd. and R.sup.71 is fluoro.
[0135] In an eighth aspect, compounds of Formula I having the
structure according to the following Formula Ig are provided:
##STR00009##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0136] wherein: [0137] Cy.sub.8 is cycloalkyl optionally
substituted with one or more R.sup.81, phenyl optionally
substituted with one or more R.sup.82, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.83 and optionally substituted on an available
nitrogen atom with R.sup.84; [0138] R.sup.80 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0139] each R.sup.81 is independently selected from the
group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0140] each R.sup.82 is
independently selected from the group consisting of fluoro, chloro,
--O--R.sup.85, --S(O.sub.2)--R.sup.87, and lower alkyl optionally
substituted with one or more R.sup.88; [0141] each R.sup.83 is
independently selected from the group consisting of fluoro, chloro,
bromo, cycloalkyl, lower alkyl optionally substituted with one or
more fluoro, and lower alkoxy optionally substituted with one or
more fluoro; or two R.sup.83 bound to adjacent carbon atoms of the
heteroaryl ring, taken together, form a fused cycloalkyl ring;
[0142] R.sup.84 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro; [0143] each R.sup.85, R.sup.86 and
R.sup.87 are independently lower alkyl optionally substituted with
one or more fluoro; and [0144] each R.sup.88 is independently
selected from the group consisting of fluoro, --OH, and lower
alkoxy optionally substituted with one or more fluoro.
[0145] In some embodiments of compounds of Formula Ig, R.sup.80 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.80 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.80 is
hydrogen, chloro or methyl.
[0146] In some embodiments of compounds of Formula Ig, further to
any of the above embodiments of Formula Ig, Cy.sub.8 is cycloalkyl
optionally substituted with one or more R.sup.81, phenyl optionally
substituted with one or more R.sup.82, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.83 and optionally substituted on an available
nitrogen atom with R.sup.84, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0147] In some embodiments of compounds of Formula Ig, further to
any of the above embodiments of Formula Ig, Cy.sub.8 is cycloalkyl
optionally substituted with one or more R.sup.81, phenyl optionally
substituted with one or more R.sup.82, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.83 and optionally substituted on an available
nitrogen atom with R.sup.84, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0148] In a ninth aspect, compounds of Formula I having the
structure according to the following Formula Ih are provided:
##STR00010##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0149] wherein: [0150] Cy.sub.9 is cycloalkyl optionally
substituted with one or more R.sup.90, phenyl optionally
substituted with one or more R.sup.91, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.92 and optionally substituted on an available
nitrogen atom with R.sup.93; [0151] R.sup.89 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0152] each R.sup.90 is independently selected from the
group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0153] each R.sup.91 is
independently selected from the group consisting of fluoro, chloro,
--O--R.sup.94, --S--R.sup.95, --S(O.sub.2)--R.sup.96, and lower
alkyl optionally substituted with one or more R.sup.97; [0154] each
R.sup.92 is independently selected from the group consisting of
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; or two R.sup.92 bound to
adjacent carbon atoms of the heteroaryl ring, taken together, form
a fused cycloalkyl ring; [0155] R.sup.93 is cycloalkyl or lower
alkyl optionally substituted with one or more fluoro; [0156] each
R.sup.94, R.sup.95 and R.sup.96 are independently lower alkyl
optionally substituted with one or more fluoro; and [0157] each
R.sup.97 is independently selected from the group consisting of
fluoro, --OH, and lower alkoxy optionally substituted with one or
more fluoro.
[0158] In some embodiments of compounds of Formula Ih, R.sup.89 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.89 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.89 is
hydrogen, chloro or methyl.
[0159] In some embodiments of compounds of Formula Ih, further to
any of the above embodiments of Formula Ih, Cy.sub.9 is cycloalkyl
optionally substituted with one or more R.sup.90, phenyl optionally
substituted with one or more R.sup.91, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.92 and optionally substituted on an available
nitrogen atom with R.sup.93, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0160] In some embodiments of compounds of Formula Ih, further to
any of the above embodiments of Formula Ih, Cy.sub.9 is cycloalkyl
optionally substituted with one or more R.sup.90, phenyl optionally
substituted with one or more R.sup.91, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.92 and optionally substituted on an available
nitrogen atom with R.sup.93, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0161] In a tenth aspect, compounds of Formula I having the
structure according to the following Formula Ii are provided:
##STR00011##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0162] wherein: [0163] Cy.sub.10 is cycloalkyl optionally
substituted with one or more R.sup.99, phenyl optionally
substituted with one or more R.sup.100, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.101 and optionally substituted on an available
nitrogen atom with R.sup.102; [0164] R.sup.98 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0165] each R.sup.99 is independently selected from the
group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0166] each R.sup.100 is
independently selected from the group consisting of fluoro, chloro,
--O--R.sup.103, --S--R.sup.104, --S(O.sub.2)--R.sup.105, and lower
alkyl optionally substituted with one or more R.sup.106; [0167]
each R.sup.101 is independently selected from the group consisting
of fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; or two R.sup.101 bound to
adjacent carbon atoms of the heteroaryl ring, taken together, form
a fused cycloalkyl ring; [0168] R.sup.102 is cycloalkyl or lower
alkyl optionally substituted with one or more fluoro; [0169] each
R.sup.102, R.sup.104 and R.sup.105 are independently lower alkyl
optionally substituted with one or more fluoro; and [0170] each
R.sup.106 is independently selected from the group consisting of
fluoro, --OH, and lower alkoxy optionally substituted with one or
more fluoro.
[0171] In some embodiments of compounds of Formula Ii, R.sup.98 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.98 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.98 is
hydrogen, chloro or methyl.
[0172] In some embodiments of compounds of Formula Ii, further to
any of the above embodiments of Formula Ii, Cy.sub.10 is cycloalkyl
optionally substituted with one or more R.sup.99, phenyl optionally
substituted with one or more R.sup.100, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.101 and optionally substituted on an available
nitrogen atom with R.sup.102, wherein cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl
is pyridinyl or pyrazolyl.
[0173] In some embodiments of compounds of Formula Ii, further to
any of the above embodiments of Formula Ii, Cy.sub.10 is cycloalkyl
optionally substituted with one or more R.sup.99, phenyl optionally
substituted with one or more R.sup.100, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.101 and optionally substituted on an available
nitrogen atom with R.sup.102, wherein cycloalkyl is cyclohexyl, or
cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.
[0174] In an eleventh aspect, compounds of Formula I having the
structure according to the following Formula Ij are provided:
##STR00012##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0175] wherein: [0176] Cy.sub.11 is cycloalkyl optionally
substituted with one or more R.sup.108, phenyl optionally
substituted with one or more R.sup.109, or 5 or 6 membered
heteroaryl optionally substituted on an available carbon atom with
one or more R.sup.110 and optionally substituted on an available
nitrogen atom with R.sup.111; [0177] R.sup.107 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0178] each R.sup.108 is independently selected from the
group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0179] each R.sup.109 is
independently selected from the group consisting of fluoro, chloro,
--O--R.sup.112, --S--R.sup.113, --S(O.sub.2)--R.sup.114, and lower
alkyl optionally substituted with one or more R.sup.115; [0180]
each R.sup.110 is independently selected from the group consisting
of fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; or two R.sup.110 bound to
adjacent carbon atoms of the heteroaryl ring, taken together, form
a fused cycloalkyl ring; [0181] R.sup.111 is cycloalkyl or lower
alkyl optionally substituted with one or more fluoro; [0182] each
R.sup.112, R.sup.113 and R.sup.114 are independently lower alkyl
optionally substituted with one or more fluoro; and [0183] each
R.sup.115 is independently selected from the group consisting of
fluoro, --OH, and lower alkoxy optionally substituted with one or
more fluoro.
[0184] In some embodiments of compounds of Formula Ij, R.sup.107 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.107 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.107
is hydrogen, chloro or methyl.
[0185] In some embodiments of compounds of Formula Ij, further to
any of the above embodiments of Formula Ij, Cy.sub.11 is cycloalkyl
optionally substituted with one or more R.sup.108, phenyl
optionally substituted with one or more R.sup.109, or 5 or 6
membered heteroaryl optionally substituted on an available carbon
atom with one or more R.sup.110 and optionally substituted on an
available nitrogen atom with R.sup.111, wherein cycloalkyl is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl,
and heteroaryl is pyridinyl or pyrazolyl.
[0186] In some embodiments of compounds of Formula Ij, further to
any of the above embodiments of Formula Ij, Cy.sub.11 is cycloalkyl
optionally substituted with one or more R.sup.108, phenyl
optionally substituted with one or more R.sup.109, or 5 or 6
membered heteroaryl optionally substituted on an available carbon
atom with one or more R.sup.110 and optionally substituted on an
available nitrogen atom with R.sup.111, wherein cycloalkyl is
cyclohexyl, or cycloheptyl, and heteroaryl is pyridin-3-yl or
pyrazol-4-yl.
[0187] In a twelfth aspect, compounds of Formula I having the
structure according to the following Formula Ik are provided:
##STR00013##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0188] wherein: [0189] X.sub.2 is --N.dbd., --C(H).dbd.,
or --C(R.sup.116).dbd.; [0190] Y.sub.4 is --N.dbd. and R.sup.118 is
hydrogen; or Y.sub.4 is --C(H).dbd. and R.sup.118 is fluoro; [0191]
L.sub.4 is --C(H.sub.2)-- or --C(O)--; [0192] Cy.sub.12 is
cycloalkyl optionally substituted with one or more R.sup.119;
[0193] when X.sub.2 is --C(R.sup.116).dbd., R.sup.117 is hydrogen;
[0194] when X.sub.2 is --N.dbd. or --C(H).dbd., R.sup.117 is
selected from the group consisting of hydrogen, cycloalkyl, lower
alkyl optionally substituted with one or more R.sup.120, and
--O--R.sup.121; [0195] R.sup.116 is fluoro, chloro, or lower alkyl
optionally substituted with one or more fluoro; [0196] each
R.sup.119 is independently selected from the group consisting of
fluoro, --OH, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro; [0197] R.sup.120 is fluoro or lower alkoxy optionally
substituted with one or more fluoro; and [0198] R.sup.121 is lower
alkyl, lower alkyl substituted with one or more fluoro, or lower
alkyl substituted with lower alkoxy.
[0199] In some embodiments of compounds of Formula Ik, X.sub.2 is
--N.dbd. and R.sup.117 is selected from the group consisting of
hydrogen, cycloalkyl, lower alkyl optionally substituted with one
or more R.sup.120, and --O--R.sup.121. In one embodiment, X.sub.2
is --N.dbd. and R.sup.117 is selected from the group consisting of
cycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted
with lower alkoxy. In one embodiment, X.sub.2 is --N.dbd. and
R.sup.117 is selected from the group consisting of C.sub.3-6
cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and C.sub.1-3 alkoxy
substituted with C.sub.1-3 alkoxy. In one embodiment, X.sub.2 is
--N.dbd. and R.sup.117 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0200] In some embodiments of compounds of Formula Ik, X.sub.2 is
--C(H).dbd. or --C(R.sup.116).dbd. and R.sup.116 is fluoro, chloro,
or lower alkyl optionally substituted with one or more fluoro. In
one embodiment, X.sub.2 is --C(H).dbd. or --C(R.sup.116).dbd. and
R.sup.116 is chloro or lower alkyl. In one embodiment, X.sub.2 is
--C(H).dbd. or --C(R.sup.116).dbd. and R.sup.116 is chloro or
C.sub.1-3 alkyl. In one embodiment, X.sub.2 is --C(H).dbd. or
--C(R.sup.116).dbd. and R.sup.116 is chloro or methyl.
[0201] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, Cy.sub.12 is
cyclopentyl optionally substituted with 1 or 2 R.sup.119,
cyclohexyl optionally substituted with 1 or 2 R.sup.119, or
cycloheptyl optionally substituted with 1 or 2 R.sup.119.
[0202] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, Cy.sub.12 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0203] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, Cy.sub.12 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0204] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, Cy.sub.12 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0205] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, Cy.sub.12 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0206] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, L.sub.4 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Ik,
further to any of the above embodiments of Formula Ik, L.sub.4 is
--C(O)--.
[0207] In some embodiments of compounds of Formula Ik, further to
any of the above embodiments of Formula Ik, Y.sub.4 is --N.dbd. and
R.sup.118 is hydrogen. In some embodiments of compounds of Formula
Ik, further to any of the above embodiments of Formula Ik, Y.sub.4
is --C(H).dbd. and R.sup.118 is fluoro.
[0208] In a thirteenth aspect, compounds of Formula I having the
structure according to the following Formula Im are provided:
##STR00014##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0209] wherein: [0210] Y.sub.5 is --N.dbd. and R.sup.123
is hydrogen; or Y.sub.5 is --C(H).dbd. and R.sup.123 is fluoro;
[0211] L.sub.5 is --C(H.sub.2)-- or --C(O)--; [0212] Cy.sub.13 is
cycloalkyl optionally substituted with one or more R.sup.124;
[0213] R.sup.122 is selected from the group consisting of
cycloalkyl, lower alkyl optionally substituted with one or more
R.sup.125, and --O--R.sup.126; [0214] each R.sup.124 is
independently selected from the group consisting of fluoro, --OH,
lower alkyl optionally substituted with one or more fluoro, and
lower alkoxy optionally substituted with one or more fluoro; [0215]
R.sup.125 is fluoro or lower alkoxy optionally substituted with one
or more fluoro; and [0216] R.sup.126 is lower alkyl, lower alkyl
substituted with one or more fluoro, or lower alkyl substituted
with lower alkoxy.
[0217] In some embodiments of compounds of Formula Im, R.sup.122 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment R.sup.122 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment R.sup.122 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0218] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, Cy.sub.13 is
cyclopentyl optionally substituted with 1 or 2 R.sup.124,
cyclohexyl optionally substituted with 1 or 2 R.sup.124, or
cycloheptyl optionally substituted with 1 or 2 R.sup.124.
[0219] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, Cy.sub.13 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0220] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, Cy.sub.13 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0221] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, Cy.sub.13 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0222] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, Cy.sub.13 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0223] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, L.sub.5 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Im,
further to any of the above embodiments of Formula Im, L.sub.5 is
--C(O)--.
[0224] In some embodiments of compounds of Formula Im, further to
any of the above embodiments of Formula Im, Y.sub.5 is --N.dbd. and
R.sup.123 is hydrogen. In some embodiments of compounds of Formula
Im, further to any of the above embodiments of Formula Im, Y.sub.5
is --C(H).dbd. and R.sup.123 is fluoro.
[0225] In a fourteenth aspect, compounds of Formula I having the
structure according to the following Formula In are provided:
##STR00015##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0226] wherein: [0227] Cy.sub.14 is cycloalkyl optionally
substituted with one or more R.sup.128; [0228] R.sup.127 is
selected from the group consisting of cycloalkyl, lower alkyl
optionally substituted with one or more R.sup.129, and
--O--R.sup.130; [0229] each R.sup.128 is independently selected
from the group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0230] R.sup.129 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0231] R.sup.130 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0232] In some embodiments of compounds of Formula In, R.sup.127 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment R.sup.127 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment R.sup.127 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0233] In some embodiments of compounds of Formula In, further to
any of the above embodiments of Formula In, Cy.sub.14 is
cyclopentyl optionally substituted with 1 or 2 R.sup.128,
cyclohexyl optionally substituted with 1 or 2 R.sup.128, or
cycloheptyl optionally substituted with 1 or 2 R.sup.128.
[0234] In some embodiments of compounds of Formula In, further to
any of the above embodiments of Formula In, Cy.sub.14 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0235] In some embodiments of compounds of Formula In, further to
any of the above embodiments of Formula In, Cy.sub.14 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0236] In some embodiments of compounds of Formula In, further to
any of the above embodiments of Formula In, Cy.sub.14 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0237] In some embodiments of compounds of Formula In, further to
any of the above embodiments of Formula In, Cy.sub.14 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0238] In a fifteenth aspect, compounds of Formula I having the
structure according to the following Formula Io are provided:
##STR00016##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0239] wherein: [0240] Cy.sub.15 is cycloalkyl optionally
substituted with one or more R.sup.132; [0241] R.sup.131 is
selected from the group consisting of cycloalkyl, lower alkyl
optionally substituted with one or more R.sup.133, and
--O--R.sup.134; [0242] each R.sup.132 is independently selected
from the group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0243] R.sup.133 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0244] R.sup.134 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0245] In some embodiments of compounds of Formula Io, R.sup.131 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment R.sup.131 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment R.sup.131 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0246] In some embodiments of compounds of Formula Io, further to
any of the above embodiments of Formula Io, Cy.sub.15 is
cyclopentyl optionally substituted with 1 or 2 R.sup.132,
cyclohexyl optionally substituted with 1 or 2 R.sup.132, or
cycloheptyl optionally substituted with 1 or 2 R.sup.132.
[0247] In some embodiments of compounds of Formula Io, further to
any of the above embodiments of Formula Io, Cy.sub.15 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0248] In some embodiments of compounds of Formula Io, further to
any of the above embodiments of Formula Io, Cy.sub.15 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0249] In some embodiments of compounds of Formula Io, further to
any of the above embodiments of Formula Io, Cy.sub.15 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0250] In some embodiments of compounds of Formula Io, further to
any of the above embodiments of Formula Io, Cy.sub.15 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0251] In a sixteenth aspect, compounds of Formula I having the
structure according to the following Formula Ip are provided:
##STR00017##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0252] wherein: [0253] Cy.sub.16 is cycloalkyl optionally
substituted with one or more R.sup.136; [0254] R.sup.135 is
selected from the group consisting of cycloalkyl, lower alkyl
optionally substituted with one or more R.sup.137, and
--O--R.sup.138; [0255] each R.sup.136 is independently selected
from the group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0256] R.sup.137 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0257] R.sup.138 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0258] In some embodiments of compounds of Formula Ip, R.sup.135 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment R.sup.135 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment R.sup.135 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0259] In some embodiments of compounds of Formula Ip, further to
any of the above embodiments of Formula Ip, Cy.sub.16 is
cyclopentyl optionally substituted with 1 or 2 R.sup.136,
cyclohexyl optionally substituted with 1 or 2 R.sup.136, or
cycloheptyl optionally substituted with 1 or 2 R.sup.136.
[0260] In some embodiments of compounds of Formula Ip, further to
any of the above embodiments of Formula Ip, Cy.sub.16 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0261] In some embodiments of compounds of Formula Ip, further to
any of the above embodiments of Formula Ip, Cy.sub.16 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0262] In some embodiments of compounds of Formula Ip, further to
any of the above embodiments of Formula Ip, Cy.sub.16 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0263] In some embodiments of compounds of Formula Ip, further to
any of the above embodiments of Formula Ip, Cy.sub.16 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0264] In a seventeenth aspect, compounds of Formula I having the
structure according to the following Formula Iq are provided:
##STR00018##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0265] wherein: [0266] Cy.sub.16 is cycloalkyl optionally
substituted with one or more R.sup.140; [0267] R.sup.139 is
selected from the group consisting of cycloalkyl, lower alkyl
optionally substituted with one or more R.sup.141, and
--O--R.sup.142; [0268] each R.sup.140 is independently selected
from the group consisting of fluoro, --OH, lower alkyl optionally
substituted with one or more fluoro, and lower alkoxy optionally
substituted with one or more fluoro; [0269] R.sup.141 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0270] R.sup.142 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0271] In some embodiments of compounds of Formula Iq, R.sup.139 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment R.sup.139 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment R.sup.139 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0272] In some embodiments of compounds of Formula Iq, further to
any of the above embodiments of Formula Iq, Cy.sub.17 is
cyclopentyl optionally substituted with 1 or 2 R.sup.140,
cyclohexyl optionally substituted with 1 or 2 R.sup.140, or
cycloheptyl optionally substituted with 1 or 2 R.sup.140.
[0273] In some embodiments of compounds of Formula Iq, further to
any of the above embodiments of Formula Iq, Cy.sub.17 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0274] In some embodiments of compounds of Formula Iq, further to
any of the above embodiments of Formula Iq, Cy.sub.17 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0275] In some embodiments of compounds of Formula Iq, further to
any of the above embodiments of Formula Iq, Cy.sub.17 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0276] In some embodiments of compounds of Formula Iq, further to
any of the above embodiments of Formula Iq, Cy.sub.17 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0277] In an eighteenth aspect, compounds of Formula I having the
structure according to the following Formula Ir are provided:
##STR00019##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0278] wherein: [0279] Y.sub.6 is --N.dbd. and R.sup.144
is hydrogen; or Y.sub.6 is --C(H).dbd. and R.sup.144 is fluoro;
[0280] L.sub.6 is --C(H.sub.2)-- or --C(O)--; [0281] Cy.sub.18 is
cycloalkyl optionally substituted with one or more R.sup.145;
[0282] R.sup.143 is hydrogen, fluoro, chloro, or lower alkyl
optionally substituted with one or more fluoro; and [0283] each
R.sup.145 is independently selected from the group consisting of
fluoro, --OH, lower alkyl optionally substituted with one or more
fluoro, and lower alkoxy optionally substituted with one or more
fluoro.
[0284] In some embodiments of compounds of Formula Ir, R.sup.143 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.143 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.143
is hydrogen, chloro or methyl.
[0285] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, Cy.sub.18 is
cyclopentyl optionally substituted with 1 or 2 R.sup.145,
cyclohexyl optionally substituted with 1 or 2 R.sup.145, or
cycloheptyl optionally substituted with 1 or 2 R.sup.145.
[0286] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, Cy.sub.18 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0287] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, Cy.sub.18 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0288] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, Cy.sub.18 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0289] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, Cy.sub.18 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0290] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, L.sub.6 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Ir,
further to any of the above embodiments of Formula Ir, L.sub.6 is
--C(O)--.
[0291] In some embodiments of compounds of Formula Ir, further to
any of the above embodiments of Formula Ir, Y.sub.6 is --N.dbd. and
R.sup.144 is hydrogen. In some embodiments of compounds of Formula
Ir, further to any of the above embodiments of Formula Ir, Y.sub.6
is --C(H).dbd. and R.sup.144 is fluoro.
[0292] In a nineteenth aspect, compounds of Formula I having the
structure according to the following Formula Is are provided:
##STR00020##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0293] wherein: [0294] Cy.sub.19 is cycloalkyl optionally
substituted with one or more R.sup.147; [0295] R.sup.146 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; and [0296] each R.sup.147 is independently
selected from the group consisting of fluoro, --OH, lower alkyl
optionally substituted with one or more fluoro, and lower alkoxy
optionally substituted with one or more fluoro.
[0297] In some embodiments of compounds of Formula Is, R.sup.146 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.146 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.146
is hydrogen, chloro or methyl.
[0298] In some embodiments of compounds of Formula Is, further to
any of the above embodiments of Formula Is, Cy.sub.19 is
cyclopentyl optionally substituted with 1 or 2 R.sup.147,
cyclohexyl optionally substituted with 1 or 2 R.sup.147, or
cycloheptyl optionally substituted with 1 or 2 R.sup.147.
[0299] In some embodiments of compounds of Formula Is, further to
any of the above embodiments of Formula Is, Cy.sub.19 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0300] In some embodiments of compounds of Formula Is, further to
any of the above embodiments of Formula Is, Cy.sub.19 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0301] In some embodiments of compounds of Formula Is, further to
any of the above embodiments of Formula Is, Cy.sub.19 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0302] In some embodiments of compounds of Formula Is, further to
any of the above embodiments of Formula Is, Cy.sub.19 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0303] In a twentieth aspect, compounds of Formula I having the
structure according to the following Formula It are provided:
##STR00021##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0304] wherein: [0305] Cy.sub.20 is cycloalkyl optionally
substituted with one or more R.sup.149; [0306] R.sup.148 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; and [0307] each R.sup.149 is independently
selected from the group consisting of fluoro, --OH, lower alkyl
optionally substituted with one or more fluoro, and lower alkoxy
optionally substituted with one or more fluoro.
[0308] In some embodiments of compounds of Formula It, R.sup.148 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.148 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.148
is hydrogen, chloro or methyl.
[0309] In some embodiments of compounds of Formula It, further to
any of the above embodiments of Formula It, Cy.sub.20 is
cyclopentyl optionally substituted with 1 or 2 R.sup.149,
cyclohexyl optionally substituted with 1 or 2 R.sup.149, or
cycloheptyl optionally substituted with 1 or 2 R.sup.149.
[0310] In some embodiments of compounds of Formula It, further to
any of the above embodiments of Formula It, Cy.sub.20 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0311] In some embodiments of compounds of Formula It, further to
any of the above embodiments of Formula It, Cy.sub.20 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0312] In some embodiments of compounds of Formula It, further to
any of the above embodiments of Formula It, Cy.sub.20 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0313] In some embodiments of compounds of Formula It, further to
any of the above embodiments of Formula It, Cy.sub.20 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0314] In a twenty-first aspect, compounds of Formula I having the
structure according to the following Formula Iu are provided:
##STR00022##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0315] wherein: [0316] Cy.sub.21 is cycloalkyl optionally
substituted with one or more R.sup.151; [0317] R.sup.150 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; and [0318] each R.sup.151 is independently
selected from the group consisting of fluoro, --OH, lower alkyl
optionally substituted with one or more fluoro, and lower alkoxy
optionally substituted with one or more fluoro.
[0319] In some embodiments of compounds of Formula Iu, R.sup.150 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.150 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.150
is hydrogen, chloro or methyl.
[0320] In some embodiments of compounds of Formula Iu, further to
any of the above embodiments of Formula Iu, Cy.sub.21 is
cyclopentyl optionally substituted with 1 or 2 R.sup.151,
cyclohexyl optionally substituted with 1 or 2 R.sup.151, or
cycloheptyl optionally substituted with 1 or 2 R.sup.151.
[0321] In some embodiments of compounds of Formula Iu, further to
any of the above embodiments of Formula Iu, Cy.sub.21 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or 1 or 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0322] In some embodiments of compounds of Formula Iu, further to
any of the above embodiments of Formula Iu, Cy.sub.21 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0323] In some embodiments of compounds of Formula Iu, further to
any of the above embodiments of Formula Iu, Cy.sub.21 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0324] In some embodiments of compounds of Formula Iu, further to
any of the above embodiments of Formula Iu, Cy.sub.21 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0325] In a twenty-second aspect, compounds of Formula I having the
structure according to the following Formula Iv are provided:
##STR00023##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0326] wherein: [0327] Cy.sub.22 is cycloalkyl optionally
substituted with one or more R.sup.153; [0328] R.sup.152 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; and [0329] each R.sup.153 is independently
selected from the group consisting of fluoro, --OH, lower alkyl
optionally substituted with one or more fluoro, and lower alkoxy
optionally substituted with one or more fluoro.
[0330] In some embodiments of compounds of Formula Iv, R.sup.152 is
hydrogen, chloro or lower alkyl. In one embodiment, R.sup.152 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.152
is hydrogen, chloro or methyl.
[0331] In some embodiments of compounds of Formula Iv, further to
any of the above embodiments of Formula Iv, Cy.sub.22 is
cyclopentyl optionally substituted with 1 or 2 R.sup.153,
cyclohexyl optionally substituted with 1 or 2 R.sup.153, or
cycloheptyl optionally substituted with 1 or 2 R.sup.153.
[0332] In some embodiments of compounds of Formula Iv, further to
any of the above embodiments of Formula Iv, Cy.sub.22 is
cyclopentyl optionally substituted with 1 or 2 fluoro, or for 2
lower alkyl, or 1 or 2 --OH, or 1 or 2 lower alkoxy; cyclohexyl
optionally substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl,
or 1 or 2 --OH, or 1 or 2 lower alkoxy; or cycloheptyl optionally
substituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2
--OH, or 1 or 2 lower alkoxy.
[0333] In some embodiments of compounds of Formula Iv, further to
any of the above embodiments of Formula Iv, Cy.sub.22 is
cyclopentyl, cyclopentyl substituted with 1 or 2 fluoro,
cyclopentyl substituted with 1 or 2 lower alkyl, cyclopentyl
substituted with 1 or 2 --OH, or cyclopentyl substituted with 1 or
2 lower alkoxy.
[0334] In some embodiments of compounds of Formula Iv, further to
any of the above embodiments of Formula Iv, Cy.sub.22 is
cyclohexyl, cyclohexyl substituted with 1 or 2 fluoro, cyclohexyl
substituted with 1 or 2 lower alkyl, cyclohexyl substituted with 1
or 2 --OH, or cyclohexyl substituted with 1 or 2 lower alkoxy.
[0335] In some embodiments of compounds of Formula Iv, further to
any of the above embodiments of Formula Iv, Cy.sub.22 is
cycloheptyl, cycloheptyl substituted with 1 or 2 fluoro,
cycloheptyl substituted with 1 or 2 lower alkyl, cycloheptyl
substituted with 1 or 2 --OH, or cycloheptyl substituted with 1 or
2 lower alkoxy.
[0336] In a twenty-third aspect, compounds of Formula I having the
structure according to the following Formula Iw are provided:
##STR00024##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0337] wherein: [0338] X.sub.3 is --N.dbd., --C(H).dbd.,
or --C(R.sup.154).dbd.; [0339] Y.sub.7 is --N.dbd. and R.sup.156 is
hydrogen; or Y.sub.7 is --C(H).dbd. and R.sup.156 is fluoro; [0340]
L.sub.7 is --C(H.sub.2)-- or --C(O)--; [0341] when X.sub.3 is
--C(R.sup.154).dbd., R.sup.155 is hydrogen; [0342] when X.sub.3 is
--N.dbd. or --C(H).dbd., R.sup.155 is selected from the group
consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.158, and --O--R.sup.159; [0343]
R.sup.154 is fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; [0344] R.sup.157 is cycloalkyl or lower
alkyl optionally substituted with one or more fluoro; [0345]
R.sup.158 is fluoro or lower alkoxy optionally substituted with one
or more fluoro; and [0346] R.sup.159 is lower alkyl, lower alkyl
substituted with one or more fluoro, or lower alkyl substituted
with lower alkoxy.
[0347] In some embodiments of compounds of Formula Iw, X.sub.3 is
--N.dbd. and R.sup.155 is selected from the group consisting of
hydrogen, cycloalkyl, lower alkyl optionally substituted with one
or more R.sup.158, and --O--R.sup.159. In one embodiment, X.sub.3
is --N.dbd. and R.sup.155 is selected from the group consisting of
cycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted
with lower alkoxy. In one embodiment, X.sub.3 is --N.dbd. and
R.sup.155 is selected from the group consisting of C.sub.3-6
cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and C.sub.1-3 alkoxy
substituted with C.sub.1-3 alkoxy. In one embodiment, X.sub.3 is
--N.dbd. and R.sup.155 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0348] In some embodiments of compounds of Formula Iw, X.sub.3 is
--C(H).dbd. or --C(R.sup.154).dbd. and R.sup.154 is fluoro, chloro,
or lower alkyl optionally substituted with one or more fluoro. In
one embodiment, X.sub.3 is --C(H).dbd. or --C(R.sup.154).dbd. and
R.sup.154 is chloro or lower alkyl. In one embodiment, X.sub.3 is
--C(H).dbd. or --C(R.sup.154).dbd. and R.sup.154 is chloro or
C.sub.1-3 alkyl. In one embodiment, X.sub.3 is --C(H).dbd. or
--C(R.sup.154)-- and R.sup.154 is chloro or methyl.
[0349] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, R.sup.157 is cycloalkyl
or lower alkyl.
[0350] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, R.sup.157 is C.sub.3-6
cycloalkyl or lower alkyl.
[0351] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, R.sup.157 is
cyclopropyl or lower alkyl.
[0352] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, R.sup.157 is lower
alkyl.
[0353] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, R.sup.157 is C.sub.1-3
alkyl.
[0354] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, R.sup.157 is ethyl.
[0355] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, L.sub.7 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Iw,
further to any of the above embodiments of Formula Iw, L.sub.7 is
--C(O)--.
[0356] In some embodiments of compounds of Formula Iw, further to
any of the above embodiments of Formula Iw, Y.sub.7 is --N.dbd. and
R.sup.156 is hydrogen. In some embodiments of compounds of Formula
Iw, further to any of the above embodiments of Formula Iw, Y.sub.7
is --C(H).dbd. and R.sup.156 is fluoro.
[0357] In a twenty-fourth aspect, compounds of Formula I having the
structure according to the following Formula Ix are provided:
##STR00025##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0358] wherein: [0359] Y.sub.8 is --N.dbd. and R.sup.161
is hydrogen; or Y.sub.8 is --C(H).dbd. and R.sup.161 is fluoro;
[0360] L.sub.8 is --C(H.sub.2)-- or --C(O)--; [0361] R.sup.160 is
selected from the group consisting of hydrogen, cycloalkyl, lower
alkyl optionally substituted with one or more R.sup.163, and
--O--R.sup.164; [0362] R.sup.162 is cycloalkyl or lower alkyl
optionally substituted with one or more fluoro; [0363] R.sup.163 is
fluoro or lower alkoxy optionally substituted with one or more
fluoro; and [0364] R.sup.164 is lower alkyl, lower alkyl
substituted with one or more fluoro, or lower alkyl substituted
with lower alkoxy.
[0365] In some embodiments of compounds of Formula Ix, R.sup.160 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.160 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.160 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0366] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, R.sup.162 is cycloalkyl
or lower alkyl.
[0367] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, R.sup.162 is C.sub.3-6
cycloalkyl or lower alkyl.
[0368] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, R.sup.162 is
cyclopropyl or lower alkyl.
[0369] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, R.sup.162 is lower
alkyl.
[0370] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, R.sup.162 is C.sub.1-3
alkyl.
[0371] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, R.sup.162 is ethyl.
[0372] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, L.sub.8 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Ix,
further to any of the above embodiments of Formula Ix, L.sub.8 is
--C(O)--.
[0373] In some embodiments of compounds of Formula Ix, further to
any of the above embodiments of Formula Ix, Y.sub.8 is --N.dbd. and
R.sup.161 is hydrogen. In some embodiments of compounds of Formula
Ix, further to any of the above embodiments of Formula Ix, Y.sub.8
is --C(H).dbd. and R.sup.161 is fluoro.
[0374] In a twenty-fifth aspect, compounds of Formula I having the
structure according to the following Formula Iy are provided:
##STR00026##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0375] wherein: [0376] R.sup.165 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.167, and --O--R.sup.168; [0377]
R.sup.166 is cycloalkyl or lower alkyl optionally substituted with
one or more fluoro; [0378] R.sup.167 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; and [0379]
R.sup.168 is lower alkyl, lower alkyl substituted with one or more
fluoro, or lower alkyl substituted with lower alkoxy.
[0380] In some embodiments of compounds of Formula Iy, R.sup.165 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.165 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.165 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0381] In some embodiments of compounds of Formula Iy, further to
any of the above embodiments of Formula Iy, R.sup.166 is cycloalkyl
or lower alkyl.
[0382] In some embodiments of compounds of Formula Iy, further to
any of the above embodiments of Formula Iy, R.sup.166 is C.sub.3-6
cycloalkyl or lower alkyl.
[0383] In some embodiments of compounds of Formula Iy, further to
any of the above embodiments of Formula Iy, R.sup.166 is
cyclopropyl or lower alkyl.
[0384] In some embodiments of compounds of Formula Iy, further to
any of the above embodiments of Formula Iy, R.sup.166 is lower
alkyl.
[0385] In some embodiments of compounds of Formula Iy, further to
any of the above embodiments of Formula Iy, R.sup.166 is C.sub.1-3
alkyl.
[0386] In some embodiments of compounds of Formula Iy, further to
any of the above embodiments of Formula Iy, R.sup.166 is ethyl.
[0387] In a twenty-sixth aspect, compounds of Formula I having the
structure according to the following Formula Iz are provided:
##STR00027##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0388] wherein: [0389] R.sup.169 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.171, and --O--R.sup.172; [0390]
R.sup.170 is cycloalkyl or lower alkyl optionally substituted with
one or more fluoro; [0391] R.sup.171 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; and [0392]
R.sup.172 is lower alkyl, lower alkyl substituted with one or more
fluoro, or lower alkyl substituted with lower alkoxy.
[0393] In some embodiments of compounds of Formula Iz, R.sup.169 is
selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.169 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.169 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0394] In some embodiments of compounds of Formula Iz, further to
any of the above embodiments of Formula Iz, R.sup.170 is cycloalkyl
or lower alkyl.
[0395] In some embodiments of compounds of Formula Iz, further to
any of the above embodiments of Formula Iz, R.sup.170 is C.sub.3-6
cycloalkyl or lower alkyl.
[0396] In some embodiments of compounds of Formula Iz, further to
any of the above embodiments of Formula Iz, R.sup.170 is
cyclopropyl or lower alkyl.
[0397] In some embodiments of compounds of Formula Iz, further to
any of the above embodiments of Formula Iz, R.sup.170 is lower
alkyl.
[0398] In some embodiments of compounds of Formula Iz, further to
any of the above embodiments of Formula Iz, R.sup.170 is C.sub.1-3
alkyl.
[0399] In some embodiments of compounds of Formula Iz, further to
any of the above embodiments of Formula Iz, R.sup.170 is ethyl.
[0400] In a twenty-seventh aspect, compounds of Formula I having
the structure according to the following Formula Iaa are
provided:
##STR00028##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0401] wherein: [0402] R.sup.173 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.175, and --O--R.sup.176; [0403]
R.sup.174 is cycloalkyl or lower alkyl optionally substituted with
one or more fluoro; [0404] R.sup.175 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; and [0405]
R.sup.176 is lower alkyl, lower alkyl substituted with one or more
fluoro, or lower alkyl substituted with lower alkoxy.
[0406] In some embodiments of compounds of Formula Iaa, R.sup.173
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.173 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.173 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0407] In some embodiments of compounds of Formula Iaa, further to
any of the above embodiments of Formula Iaa, R.sup.174 is
cycloalkyl or lower alkyl.
[0408] In some embodiments of compounds of Formula Iaa, further to
any of the above embodiments of Formula Iaa, R.sup.174 is C.sub.3-6
cycloalkyl or lower alkyl.
[0409] In some embodiments of compounds of Formula Iaa, further to
any of the above embodiments of Formula Iaa, R.sup.174 is
cyclopropyl or lower alkyl.
[0410] In some embodiments of compounds of Formula Iaa, further to
any of the above embodiments of Formula Iaa, R.sup.174 is lower
alkyl.
[0411] In some embodiments of compounds of Formula Iaa, further to
any of the above embodiments of Formula Iaa, R.sup.174 is C.sub.1-3
alkyl.
[0412] In some embodiments of compounds of Formula Iaa, further to
any of the above embodiments of Formula Iaa, R.sup.174 is
ethyl.
[0413] In a twenty-eighth aspect, compounds of Formula I having the
structure according to the following Formula Ibb are provided:
##STR00029##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0414] wherein: [0415] R.sup.177 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.179, and --O--R.sup.180; [0416]
R.sup.178 is cycloalkyl or lower alkyl optionally substituted with
one or more fluoro; [0417] R.sup.179 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; and [0418]
R.sup.180 is lower alkyl, lower alkyl substituted with one or more
fluoro, or lower alkyl substituted with lower alkoxy.
[0419] In some embodiments of compounds of Formula Ibb, R.sup.177
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.177 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.177 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0420] In some embodiments of compounds of Formula Ibb, further to
any of the above embodiments of Formula Ibb, R.sup.178 is
cycloalkyl or lower alkyl.
[0421] In some embodiments of compounds of Formula Ibb, further to
any of the above embodiments of Formula Ibb, R.sup.178 is C.sub.3-6
cycloalkyl or lower alkyl.
[0422] In some embodiments of compounds of Formula Ibb, further to
any of the above embodiments of Formula Ibb, R.sup.178 is
cyclopropyl or lower alkyl.
[0423] In some embodiments of compounds of Formula Ibb, further to
any of the above embodiments of Formula Ibb, R.sup.178 is lower
alkyl.
[0424] In some embodiments of compounds of Formula Ibb, further to
any of the above embodiments of Formula Ibb, R.sup.178 is C.sub.1-3
alkyl.
[0425] In some embodiments of compounds of Formula Ibb, further to
any of the above embodiments of Formula Ibb, R.sup.178 is
ethyl.
[0426] In a twenty-ninth aspect, compounds of Formula I having the
structure according to the following Formula Icc are provided:
##STR00030##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0427] wherein: [0428] Y.sub.9 is --N.dbd. and R.sup.182
is hydrogen; or Y.sub.9 is --C(H).dbd. and R.sup.182 is fluoro;
[0429] L.sub.9 is --C(H.sub.2)-- or --C(O)--; [0430] R.sup.181 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; and [0431] R.sup.183 is cycloalkyl or
lower alkyl optionally substituted with one or more fluoro.
[0432] In some embodiments of compounds of Formula Icc, R.sup.181
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.181 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.181
is hydrogen, chloro or methyl.
[0433] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, R.sup.183 is
cycloalkyl or lower alkyl.
[0434] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, R.sup.183 is C.sub.3-6
cycloalkyl or lower alkyl.
[0435] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, R.sup.183 is
cyclopropyl or lower alkyl.
[0436] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, R.sup.183 is lower
alkyl.
[0437] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, R.sup.183 is C.sub.1-3
alkyl.
[0438] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, R.sup.183 is
ethyl.
[0439] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, L.sub.9 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Icc,
further to any of the above embodiments of Formula Icc, L.sub.9 is
--C(O)--.
[0440] In some embodiments of compounds of Formula Icc, further to
any of the above embodiments of Formula Icc, Y.sub.9 is --N.dbd.
and R.sup.182 is hydrogen. In some embodiments of compounds of
Formula Icc, further to any of the above embodiments of Formula
Icc, Y.sub.9 is --C(H).dbd. and R.sup.182 is fluoro.
[0441] In a thirtieth aspect, compounds of Formula I having the
structure according to the following Formula Idd are provided:
##STR00031##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0442] wherein: [0443] R.sup.184 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; and [0444] R.sup.185 is cycloalkyl or lower alkyl
optionally substituted with one or more fluoro.
[0445] In some embodiments of compounds of Formula Idd, R.sup.184
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.184 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.184
is hydrogen, chloro or methyl.
[0446] In some embodiments of compounds of Formula Idd, further to
any of the above embodiments of Formula Idd, R.sup.185 is
cycloalkyl or lower alkyl.
[0447] In some embodiments of compounds of Formula Idd, further to
any of the above embodiments of Formula Idd, R.sup.185 is C.sub.3-6
cycloalkyl or lower alkyl.
[0448] In some embodiments of compounds of Formula Idd, further to
any of the above embodiments of Formula Idd, R.sup.185 is
cyclopropyl or lower alkyl.
[0449] In some embodiments of compounds of Formula Idd, further to
any of the above embodiments of Formula Idd, R.sup.185 is lower
alkyl.
[0450] In some embodiments of compounds of Formula Idd, further to
any of the above embodiments of Formula Idd, R.sup.185 is C.sub.1-3
alkyl.
[0451] In some embodiments of compounds of Formula Idd, further to
any of the above embodiments of Formula Idd, R.sup.185 is
ethyl.
[0452] In a thirty-first aspect, compounds of Formula I having the
structure according to the following Formula Tee are provided:
##STR00032##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0453] wherein: [0454] R.sup.186 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; and [0455] R.sup.187 is cycloalkyl or lower alkyl
optionally substituted with one or more fluoro.
[0456] In some embodiments of compounds of Formula Tee, R.sup.186
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.186 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.186
is hydrogen, chloro or methyl.
[0457] In some embodiments of compounds of Formula Tee, further to
any of the above embodiments of Formula Tee, R.sup.187 is
cycloalkyl or lower alkyl.
[0458] In some embodiments of compounds of Formula Tee, further to
any of the above embodiments of Formula Tee, R.sup.187 is C.sub.3-6
cycloalkyl or lower alkyl.
[0459] In some embodiments of compounds of Formula Tee, further to
any of the above embodiments of Formula Tee, R.sup.187 is
cyclopropyl or lower alkyl.
[0460] In some embodiments of compounds of Formula Tee, further to
any of the above embodiments of Formula Tee, R.sup.187 is lower
alkyl.
[0461] In some embodiments of compounds of Formula Tee, further to
any of the above embodiments of Formula Tee, R.sup.187 is C.sub.1-3
alkyl.
[0462] In some embodiments of compounds of Formula Tee, further to
any of the above embodiments of Formula Tee, R.sup.187 is
ethyl.
[0463] In a thirty-second aspect, compounds of Formula I having the
structure according to the following Formula Iff are provided:
##STR00033##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0464] wherein: [0465] R.sup.188 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; and [0466] R.sup.189 is cycloalkyl or lower alkyl
optionally substituted with one or more fluoro.
[0467] In some embodiments of compounds of Formula Iff, R.sup.188
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.188 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.188
is hydrogen, chloro or methyl.
[0468] In some embodiments of compounds of Formula Iff, further to
any of the above embodiments of Formula Iff, R.sup.189 is
cycloalkyl or lower alkyl.
[0469] In some embodiments of compounds of Formula Iff, further to
any of the above embodiments of Formula Iff, R.sup.189 is C.sub.3-6
cycloalkyl or lower alkyl.
[0470] In some embodiments of compounds of Formula Iff, further to
any of the above embodiments of Formula Iff, R.sup.189 is
cyclopropyl or lower alkyl.
[0471] In some embodiments of compounds of Formula Iff, further to
any of the above embodiments of Formula Iff, R.sup.189 is lower
alkyl.
[0472] In some embodiments of compounds of Formula Iff, further to
any of the above embodiments of Formula Iff, R.sup.189 is C.sub.1-3
alkyl.
[0473] In some embodiments of compounds of Formula Iff, further to
any of the above embodiments of Formula Iff, R.sup.189 is
ethyl.
[0474] In a thirty-third aspect, compounds of Formula I having the
structure according to the following Formula Igg are provided:
##STR00034##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0475] wherein: [0476] R.sup.190 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; and [0477] R.sup.191 is cycloalkyl or lower alkyl
optionally substituted with one or more fluoro.
[0478] In some embodiments of compounds of Formula Igg, R.sup.190
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.190 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.190
is hydrogen, chloro or methyl.
[0479] In some embodiments of compounds of Formula Igg, further to
any of the above embodiments of Formula Igg, R.sup.191 is
cycloalkyl or lower alkyl.
[0480] In some embodiments of compounds of Formula Igg, further to
any of the above embodiments of Formula Igg, R.sup.191 is C.sub.3-6
cycloalkyl or lower alkyl.
[0481] In some embodiments of compounds of Formula Igg, further to
any of the above embodiments of Formula Igg, R.sup.191 is
cyclopropyl or lower alkyl.
[0482] In some embodiments of compounds of Formula Igg, further to
any of the above embodiments of Formula Igg, R.sup.191 is lower
alkyl.
[0483] In some embodiments of compounds of Formula Igg, further to
any of the above embodiments of Formula Igg, R.sup.191 is C.sub.1-3
alkyl.
[0484] In some embodiments of compounds of Formula Igg, further to
any of the above embodiments of Formula Igg, R.sup.191 is
ethyl.
[0485] In a thirty-fourth aspect, compounds of Formula I having the
structure according to the following Formula Ihh are provided:
##STR00035##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0486] wherein: [0487] X.sub.4 is --N.dbd., --C(H).dbd.,
or --C(R.sup.192).dbd.; [0488] Y.sub.10 is --N.dbd. and R.sup.194
is hydrogen; or Y.sub.10 is --C(H).dbd. and R.sup.194 is fluoro;
[0489] L.sub.10 is --C(H.sub.2)-- or --C(O)--; [0490] when X.sub.4
is --C(R.sup.192).dbd., R.sup.193 is hydrogen; [0491] when X.sub.4
is --N.dbd. or --C(H).dbd., R.sup.193 is selected from the group
consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.197, and --O--R.sup.198; [0492]
R.sup.192 is fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; [0493] R.sup.195 is hydrogen and R.sup.196
is hydrogen, fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0494] R.sup.196
is hydrogen and R.sup.195 is fluoro, chloro, bromo, cycloalkyl,
lower alkyl optionally substituted with one or more fluoro, or
lower alkoxy optionally substituted with one or more fluoro; [0495]
R.sup.197 is fluoro or lower alkoxy optionally substituted with one
or more fluoro; and [0496] R.sup.198 is lower alkyl, lower alkyl
substituted with one or more fluoro, or lower alkyl substituted
with lower alkoxy.
[0497] In some embodiments of compounds of Formula Ihh, X.sub.4 is
--N.dbd. and R.sup.193 is selected from the group consisting of
hydrogen, cycloalkyl, lower alkyl optionally substituted with one
or more R.sup.197, and --O--R.sup.198. In one embodiment, X.sub.4
is --N.dbd. and R.sup.193 is selected from the group consisting of
cycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted
with lower alkoxy. In one embodiment, X.sub.4 is --N.dbd. and
R.sup.193 is selected from the group consisting of C.sub.3-6
cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and C.sub.1-3 alkoxy
substituted with C.sub.1-3 alkoxy. In one embodiment, X.sub.4 is
--N.dbd. and R.sup.193 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0498] In some embodiments of compounds of Formula Ihh, X.sub.4 is
--C(H).dbd. or --C(R.sup.192).dbd. and R.sup.192 is fluoro, chloro,
or lower alkyl optionally substituted with one or more fluoro. In
one embodiment, X.sub.4 is --C(H).dbd. or --C(R.sup.192).dbd. and
R.sup.192 is chloro or lower alkyl. In one embodiment, X.sub.4 is
--C(H).dbd. or --C(R.sup.192).dbd. and R.sup.192 is chloro or
C.sub.1-3 alkyl. In one embodiment, X.sub.4 is --C(H).dbd. or
--C(R.sup.192).dbd. and R.sup.192 is chloro or methyl.
[0499] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.196 is hydrogen
and R.sup.195 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ihh, further to any of the above
embodiments of Formula Ihh, R.sup.196 is hydrogen and R.sup.195 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ihh, further to any of the
above embodiments of Formula Ihh, R.sup.196 is hydrogen and
R.sup.195 is lower alkyl. In some embodiments of compounds of
Formula Ihh, further to any of the above embodiments of Formula
Ihh, R.sup.196 is hydrogen and R.sup.195 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Ihh, further to any of the
above embodiments of Formula Ihh, R.sup.196 is hydrogen and
R.sup.195 is methyl.
[0500] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ihh, further to any of the above
embodiments of Formula Ihh, R.sup.195 is hydrogen and R.sup.196 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Ihh, further to any of the above embodiments of Formula Ihh,
R.sup.195 is hydrogen and R.sup.196 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0501] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Ihh, further to any of the above embodiments of Formula
Ihh, R.sup.195 is hydrogen and R.sup.196 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Ihh, further to any of the
above embodiments of Formula Ihh, R.sup.195 is hydrogen and
R.sup.196 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ihh, further to any of the above embodiments of Formula Ihh,
R.sup.195 is hydrogen and R.sup.196 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0502] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is cycloalkyl. In some embodiments of compounds of
Formula Ihh, further to any of the above embodiments of Formula
Ihh, R.sup.195 is hydrogen and R.sup.196 is cyclopropyl.
[0503] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ihh,
further to any of the above embodiments of Formula Ihh, R.sup.195
is hydrogen and R.sup.196 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ihh, further to any of the above embodiments of Formula Ihh,
R.sup.195 is hydrogen and R.sup.196 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is trifluoromethyl. In some embodiments of compounds
of Formula Ihh, further to any of the above embodiments of Formula
Ihh, R.sup.195 is hydrogen and R.sup.196 is methyl. In some
embodiments of compounds of Formula Ihh, further to any of the
above embodiments of Formula Ihh, R.sup.195 is hydrogen and
R.sup.196 is ethyl.
[0504] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ihh,
further to any of the above embodiments of Formula Ihh, R.sup.195
is hydrogen and R.sup.196 is lower alkoxy. In some embodiments of
compounds of Formula Ihh, further to any of the above embodiments
of Formula Ihh, R.sup.195 is hydrogen and R.sup.196 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, R.sup.195 is hydrogen
and R.sup.196 is methoxy or ethoxy. In some embodiments of
compounds of Formula Ihh, further to any of the above embodiments
of Formula Ihh, R.sup.195 is hydrogen and R.sup.196 is methoxy. In
some embodiments of compounds of Formula Ihh, further to any of the
above embodiments of Formula Ihh, R.sup.195 is hydrogen and
R.sup.196 is ethoxy.
[0505] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, L.sub.10 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Ihh,
further to any of the above embodiments of Formula Ihh, L.sub.10 is
--C(O)--.
[0506] In some embodiments of compounds of Formula Ihh, further to
any of the above embodiments of Formula Ihh, Y.sub.10 is --N.dbd.
and R.sup.194 is hydrogen. In some embodiments of compounds of
Formula Ihh, further to any of the above embodiments of Formula
Ihh, Y.sub.10 is --C(H).dbd. and R.sup.194 is fluoro.
[0507] In a thirty-fifth aspect, compounds of Formula I having the
structure according to the following Formula Iii are provided:
##STR00036##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0508] wherein: [0509] Y.sub.11 is --N.dbd. and R.sup.200
is hydrogen; or Y.sub.11 is --C(H).dbd. and R.sup.200 is fluoro;
[0510] L.sub.11 is --C(H.sub.2)-- or --C(O)--; [0511] R.sup.199 is
selected from the group consisting of hydrogen, cycloalkyl, lower
alkyl optionally substituted with one or more R.sup.203, and
--O--R.sup.204; [0512] R.sup.201 is hydrogen and R.sup.202 is
hydrogen, fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0513] R.sup.202 is
hydrogen and R.sup.201 is fluoro, chloro, bromo, cycloalkyl, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro; [0514]
R.sup.203 is fluoro or lower alkoxy optionally substituted with one
or more fluoro; and [0515] R.sup.204 is lower alkyl, lower alkyl
substituted with one or more fluoro, or lower alkyl substituted
with lower alkoxy.
[0516] In some embodiments of compounds of Formula Iii, R.sup.199
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.199 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.199 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0517] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.202 is hydrogen
and R.sup.201 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iii, further to any of the above
embodiments of Formula Iii, R.sup.202 is hydrogen and R.sup.201 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iii, further to any of the
above embodiments of Formula Iii, R.sup.202 is hydrogen and
R.sup.201 is lower alkyl. In some embodiments of compounds of
Formula Iii, further to any of the above embodiments of Formula
Iii, R.sup.202 is hydrogen and R.sup.201 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Iii, further to any of the
above embodiments of Formula Iii, R.sup.202 is hydrogen and
R.sup.201 is methyl.
[0518] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iii, further to any of the above
embodiments of Formula Iii, R.sup.201 is hydrogen and R.sup.202 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Iii, further to any of the above embodiments of Formula Iii,
R.sup.201 is hydrogen and R.sup.202 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0519] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Iii, further to any of the above embodiments of Formula
Iii, R.sup.201 is hydrogen and R.sup.202 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Iii, further to any of the
above embodiments of Formula Iii, R.sup.201 is hydrogen and
R.sup.202 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Iii, further to any of the above embodiments of Formula Iii,
R.sup.201 is hydrogen and R.sup.202 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0520] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is cycloalkyl. In some embodiments of compounds of
Formula Iii, further to any of the above embodiments of Formula
Iii, R.sup.201 is hydrogen and R.sup.202 is cyclopropyl.
[0521] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Iii,
further to any of the above embodiments of Formula Iii, R.sup.201
is hydrogen and R.sup.202 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Iii, further to any of the above embodiments of Formula Iii,
R.sup.201 is hydrogen and R.sup.202 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is trifluoromethyl. In some embodiments of compounds
of Formula Iii, further to any of the above embodiments of Formula
Iii, R.sup.201 is hydrogen and R.sup.202 is methyl. In some
embodiments of compounds of Formula Iii, further to any of the
above embodiments of Formula Iii, R.sup.201 is hydrogen and
R.sup.202 is ethyl.
[0522] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Iii,
further to any of the above embodiments of Formula Iii, R.sup.201
is hydrogen and R.sup.202 is lower alkoxy. In some embodiments of
compounds of Formula Iii, further to any of the above embodiments
of Formula Iii R.sup.201 is hydrogen and R.sup.202 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, R.sup.201 is hydrogen
and R.sup.202 is methoxy or ethoxy. In some embodiments of
compounds of Formula Iii, further to any of the above embodiments
of Formula Iii, R.sup.201 is hydrogen and R.sup.202 is methoxy. In
some embodiments of compounds of Formula Iii, further to any of the
above embodiments of Formula Iii, R.sup.201 is hydrogen and
R.sup.202 is ethoxy.
[0523] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, L.sub.11 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Iii,
further to any of the above embodiments of Formula Iii, L.sub.11 is
--C(O)--.
[0524] In some embodiments of compounds of Formula Iii, further to
any of the above embodiments of Formula Iii, Y.sub.11 is --N.dbd.
and R.sup.200 is hydrogen. In some embodiments of compounds of
Formula Iii, further to any of the above embodiments of Formula
Iii, Y.sub.11 is --C(H).dbd. and R.sup.200 is fluoro.
[0525] In a thirty-sixth aspect, compounds of Formula I having the
structure according to the following Formula Ijj are provided:
##STR00037##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0526] wherein: [0527] R.sup.205 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.208, and --O--R.sup.209; [0528]
R.sup.206 is hydrogen and R.sup.207 is hydrogen, fluoro, chloro,
bromo, cycloalkyl, lower alkyl optionally substituted with one or
more fluoro, or lower alkoxy optionally substituted with one or
more fluoro; or [0529] R.sup.207 is hydrogen and R.sup.206 is
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; [0530] R.sup.208 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0531] R.sup.209 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0532] In some embodiments of compounds of Formula Ijj, R.sup.205
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.205 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.205 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0533] In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.207 is hydrogen
and R.sup.206 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ijj, further to any of the above
embodiments of Formula Ijj, R.sup.207 is hydrogen and R.sup.206 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ijj, further to any of the
above embodiments of Formula Ijj, R.sup.207 is hydrogen and
R.sup.206 is lower alkyl. In some embodiments of compounds of
Formula Ijj, further to any of the above embodiments of Formula
Ijj, R.sup.207 is hydrogen and R.sup.206 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Ijj, further to any of the
above embodiments of Formula Ijj, R.sup.207 is hydrogen and
R.sup.206 is methyl.
[0534] In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ijj, further to any of the above
embodiments of Formula Ijj, R.sup.206 is hydrogen and R.sup.207 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Ijj, further to any of the above embodiments of Formula Ijj,
R.sup.206 is hydrogen and R.sup.207 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0535] In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Ijj, further to any of the above embodiments of Formula
Ijj, R.sup.206 is hydrogen and R.sup.207 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Ijj, further to any of the
above embodiments of Formula Ijj, R.sup.206 is hydrogen and
R.sup.207 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ijj, further to any of the above embodiments of Formula Ijj,
R.sup.206 is hydrogen and R.sup.207 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0536] In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is cycloalkyl. In some embodiments of compounds of
Formula Ijj, further to any of the above embodiments of Formula
Ijj, R.sup.206 is hydrogen and R.sup.207 is cyclopropyl.
[0537] In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ijj,
further to any of the above embodiments of Formula Ijj, R.sup.206
is hydrogen and R.sup.207 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ijj, further to any of the above embodiments of Formula Ijj,
R.sup.206 is hydrogen and R.sup.207 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is trifluoromethyl. In some embodiments of compounds
of Formula Ijj, further to any of the above embodiments of Formula
Ijj, R.sup.206 is hydrogen and R.sup.207 is methyl. In some
embodiments of compounds of Formula Ijj, further to any of the
above embodiments of Formula Ijj, R.sup.206 is hydrogen and
R.sup.207 is ethyl.
[0538] In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ijj,
further to any of the above embodiments of Formula Ijj, R.sup.206
is hydrogen and R.sup.207 is lower alkoxy. In some embodiments of
compounds of Formula Ijj, further to any of the above embodiments
of Formula Ijj, R.sup.206 is hydrogen and R.sup.207 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Ijj, further to
any of the above embodiments of Formula Ijj, R.sup.206 is hydrogen
and R.sup.207 is methoxy or ethoxy. In some embodiments of
compounds of Formula Ijj, further to any of the above embodiments
of Formula Ijj, R.sup.206 is hydrogen and R.sup.207 is methoxy. In
some embodiments of compounds of Formula Ijj, further to any of the
above embodiments of Formula Ijj, R.sup.206 is hydrogen and
R.sup.207 is ethoxy.
[0539] In a thirty-seventh aspect, compounds of Formula I having
the structure according to the following Formula Ikk are
provided:
##STR00038##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0540] wherein: [0541] R.sup.210 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.213, and --O--R.sup.214; [0542]
R.sup.211 is hydrogen and R.sup.212 is hydrogen, fluoro, chloro,
bromo, cycloalkyl, lower alkyl optionally substituted with one or
more fluoro, or lower alkoxy optionally substituted with one or
more fluoro; or [0543] R.sup.212 is hydrogen and R.sup.211 is
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; [0544] R.sup.213 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0545] R.sup.214 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0546] In some embodiments of compounds of Formula Ikk, R.sup.210
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.210 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.210 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0547] In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.212 is hydrogen
and R.sup.211 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ikk, further to any of the above
embodiments of Formula Ikk, R.sup.212 is hydrogen and R.sup.211 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ikk, further to any of the
above embodiments of Formula Ikk, R.sup.212 is hydrogen and
R.sup.211 is lower alkyl. In some embodiments of compounds of
Formula Ikk, further to any of the above embodiments of Formula
Ikk, R.sup.212 is hydrogen and R.sup.211 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Ikk, further to any of the
above embodiments of Formula Ikk, R.sup.212 is hydrogen and
R.sup.211 is methyl.
[0548] In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ikk, further to any of the above
embodiments of Formula Ikk, R.sup.211 is hydrogen and R.sup.212 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Ikk, further to any of the above embodiments of Formula Ikk,
R.sup.211 is hydrogen and R.sup.212 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0549] In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Ikk, further to any of the above embodiments of Formula
Ikk, R.sup.211 is hydrogen and R.sup.212 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Ikk, further to any of the
above embodiments of Formula Ikk, R.sup.211 is hydrogen and
R.sup.212 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ikk, further to any of the above embodiments of Formula Ikk,
R.sup.211 is hydrogen and R.sup.212 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0550] In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is cycloalkyl. In some embodiments of compounds of
Formula Ikk, further to any of the above embodiments of Formula
Ikk, R.sup.211 is hydrogen and R.sup.212 is cyclopropyl.
[0551] In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ikk,
further to any of the above embodiments of Formula Ikk, R.sup.211
is hydrogen and R.sup.212 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ikk, further to any of the above embodiments of Formula Ikk,
R.sup.211 is hydrogen and R.sup.212 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is trifluoromethyl. In some embodiments of compounds
of Formula Ikk, further to any of the above embodiments of Formula
Ikk, R.sup.211 is hydrogen and R.sup.212 is methyl. In some
embodiments of compounds of Formula Ikk, further to any of the
above embodiments of Formula Ikk, R.sup.211 is hydrogen and
R.sup.212 is ethyl.
[0552] In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ikk,
further to any of the above embodiments of Formula Ikk, R.sup.211
is hydrogen and R.sup.212 is lower alkoxy. In some embodiments of
compounds of Formula Ikk, further to any of the above embodiments
of Formula Ikk, R.sup.211 is hydrogen and R.sup.212 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Ikk, further to
any of the above embodiments of Formula Ikk, R.sup.211 is hydrogen
and R.sup.212 is methoxy or ethoxy. In some embodiments of
compounds of Formula Ikk, further to any of the above embodiments
of Formula Ikk, R.sup.211 is hydrogen and R.sup.212 is methoxy. In
some embodiments of compounds of Formula Ikk, further to any of the
above embodiments of Formula Ikk, R.sup.211 is hydrogen and
R.sup.212 is ethoxy.
[0553] In a thirty-eighth aspect, compounds of Formula I having the
structure according to the following Formula Imm are provided:
##STR00039##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0554] wherein: [0555] R.sup.215 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.218, and --O--R.sup.219; [0556]
R.sup.216 is hydrogen and R.sup.217 is hydrogen, fluoro, chloro,
bromo, cycloalkyl, lower alkyl optionally substituted with one or
more fluoro, or lower alkoxy optionally substituted with one or
more fluoro; or [0557] R.sup.217 is hydrogen and R.sup.216 is
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; [0558] R.sup.218 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0559] R.sup.219 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0560] In some embodiments of compounds of Formula Imm, R.sup.215
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.215 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.215 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0561] In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.217 is hydrogen
and R.sup.216 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Imm, further to any of the above
embodiments of Formula Imm, R.sup.217 is hydrogen and R.sup.216 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Imm, further to any of the
above embodiments of Formula Imm, R.sup.217 is hydrogen and
R.sup.216 is lower alkyl. In some embodiments of compounds of
Formula Imm, further to any of the above embodiments of Formula
Imm, R.sup.217 is hydrogen and R.sup.216 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Imm, further to any of the
above embodiments of Formula Imm, R.sup.217 is hydrogen and
R.sup.216 is methyl.
[0562] In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Imm, further to any of the above
embodiments of Formula Imm, R.sup.216 is hydrogen and R.sup.217 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Imm, further to any of the above embodiments of Formula Imm,
R.sup.216 is hydrogen and R.sup.217 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0563] In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Imm, further to any of the above embodiments of Formula
Imm, R.sup.216 is hydrogen and R.sup.217 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Imm, further to any of the
above embodiments of Formula Imm, R.sup.216 is hydrogen and
R.sup.217 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Imm, further to any of the above embodiments of Formula Imm,
R.sup.216 is hydrogen and R.sup.217 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0564] In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is cycloalkyl. In some embodiments of compounds of
Formula Imm, further to any of the above embodiments of Formula
Imm, R.sup.216 is hydrogen and R.sup.217 is cyclopropyl.
[0565] In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Imm,
further to any of the above embodiments of Formula Imm, R.sup.216
is hydrogen and R.sup.217 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Imm, further to any of the above embodiments of Formula Imm,
R.sup.216 is hydrogen and R.sup.217 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is trifluoromethyl. In some embodiments of compounds
of Formula Imm, further to any of the above embodiments of Formula
Imm, R.sup.216 is hydrogen and R.sup.217 is methyl. In some
embodiments of compounds of Formula Imm, further to any of the
above embodiments of Formula Imm, R.sup.216 is hydrogen and
R.sup.217 is ethyl.
[0566] In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Imm,
further to any of the above embodiments of Formula Imm, R.sup.216
is hydrogen and R.sup.217 is lower alkoxy. In some embodiments of
compounds of Formula Imm, further to any of the above embodiments
of Formula Imm, R.sup.216 is hydrogen and R.sup.217 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Imm, further to
any of the above embodiments of Formula Imm, R.sup.216 is hydrogen
and R.sup.217 is methoxy or ethoxy. In some embodiments of
compounds of Formula Imm, further to any of the above embodiments
of Formula Imm, R.sup.216 is hydrogen and R.sup.217 is methoxy. In
some embodiments of compounds of Formula Imm, further to any of the
above embodiments of Formula Imm, R.sup.216 is hydrogen and
R.sup.217 is ethoxy.
[0567] In a thirty-ninth aspect, compounds of Formula I having the
structure according to the following Formula Inn are provided:
##STR00040##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0568] wherein: [0569] R.sup.220 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.223, and --O--R.sup.224; [0570]
R.sup.221 is hydrogen and R.sup.222 is hydrogen, fluoro, chloro,
bromo, cycloalkyl, lower alkyl optionally substituted with one or
more fluoro, or lower alkoxy optionally substituted with one or
more fluoro; or [0571] R.sup.222 is hydrogen and R.sup.221 is
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; [0572] R.sup.223 is fluoro or
lower alkoxy optionally substituted with one or more fluoro; and
[0573] R.sup.224 is lower alkyl, lower alkyl substituted with one
or more fluoro, or lower alkyl substituted with lower alkoxy.
[0574] In some embodiments of compounds of Formula Inn, R.sup.220
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.220 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.220 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0575] In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.222 is hydrogen
and R.sup.221 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Inn, further to any of the above
embodiments of Formula Inn, R.sup.222 is hydrogen and R.sup.221 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Inn, further to any of the
above embodiments of Formula Inn, R.sup.222 is hydrogen and
R.sup.221 is lower alkyl. In some embodiments of compounds of
Formula Inn, further to any of the above embodiments of Formula
Inn, R.sup.222 is hydrogen and R.sup.221 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Inn, further to any of the
above embodiments of Formula Inn, R.sup.222 is hydrogen and
R.sup.221 is methyl.
[0576] In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Inn, further to any of the above
embodiments of Formula Inn, R.sup.221 is hydrogen and R.sup.222 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Inn, further to any of the above embodiments of Formula Inn,
R.sup.221 is hydrogen and R.sup.222 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0577] In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Inn, further to any of the above embodiments of Formula
Inn, R.sup.221 is hydrogen and R.sup.222 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Inn, further to any of the
above embodiments of Formula Inn, R.sup.221 is hydrogen and
R.sup.222 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Inn, further to any of the above embodiments of Formula Inn,
R.sup.221 is hydrogen and R.sup.222 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0578] In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is cycloalkyl. In some embodiments of compounds of
Formula Inn, further to any of the above embodiments of Formula
Inn, R.sup.221 is hydrogen and R.sup.222 is cyclopropyl.
[0579] In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Inn,
further to any of the above embodiments of Formula Inn, R.sup.221
is hydrogen and R.sup.222 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Inn, further to any of the above embodiments of Formula Inn,
R.sup.211 is hydrogen and R.sup.222 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is trifluoromethyl. In some embodiments of compounds
of Formula Inn, further to any of the above embodiments of Formula
Inn, R.sup.221 is hydrogen and R.sup.222 is methyl. In some
embodiments of compounds of Formula Inn, further to any of the
above embodiments of Formula Inn, R.sup.221 is hydrogen and
R.sup.222 is ethyl.
[0580] In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Inn,
further to any of the above embodiments of Formula Inn, R.sup.221
is hydrogen and R.sup.222 is lower alkoxy. In some embodiments of
compounds of Formula Inn, further to any of the above embodiments
of Formula Inn, R.sup.221 is hydrogen and R.sup.222 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Inn, further to
any of the above embodiments of Formula Inn, R.sup.221 is hydrogen
and R.sup.222 is methoxy or ethoxy. In some embodiments of
compounds of Formula Inn, further to any of the above embodiments
of Formula Inn, R.sup.221 is hydrogen and R.sup.222 is methoxy. In
some embodiments of compounds of Formula Inn, further to any of the
above embodiments of Formula Inn, R.sup.221 is hydrogen and
R.sup.222 is ethoxy.
[0581] In a fortieth aspect, compounds of Formula I having the
structure according to the following Formula Ioo are provided:
##STR00041##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0582] wherein: [0583] Y.sub.12 is --N.dbd. and R.sup.226
is hydrogen; or Y.sub.12 is --C(H).dbd. and R.sup.226 is fluoro;
[0584] L.sub.12 is --C(H.sub.2)-- or --C(O)--; [0585] R.sup.225 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; [0586] R.sup.227 is hydrogen and R.sup.228
is hydrogen, fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0587] R.sup.228
is hydrogen and R.sup.227 is fluoro, chloro, bromo, cycloalkyl,
lower alkyl optionally substituted with one or more fluoro, or
lower alkoxy optionally substituted with one or more fluoro.
[0588] In some embodiments of compounds of Formula Ioo, R.sup.225
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.225 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.225
is hydrogen, chloro or methyl.
[0589] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.228 is hydrogen
and R.sup.227 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ioo, further to any of the above
embodiments of Formula Ioo, R.sup.228 is hydrogen and R.sup.227 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ioo, further to any of the
above embodiments of Formula Ioo, R.sup.228 is hydrogen and
R.sup.227 is lower alkyl. In some embodiments of compounds of
Formula Ioo, further to any of the above embodiments of Formula
Ioo, R.sup.228 is hydrogen and R.sup.227 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Ioo, further to any of the
above embodiments of Formula Ioo, R.sup.228 is hydrogen and
R.sup.227 is methyl.
[0590] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ioo, further to any of the above
embodiments of Formula Ioo, R.sup.227 is hydrogen and R.sup.228 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Ioo, further to any of the above embodiments of Formula Ioo,
R.sup.227 is hydrogen and R.sup.228 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0591] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Ioo, further to any of the above embodiments of Formula
Ioo, R.sup.227 is hydrogen and R.sup.228 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Ioo, further to any of the
above embodiments of Formula Ioo, R.sup.227 is hydrogen and
R.sup.228 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ioo, further to any of the above embodiments of Formula Ioo,
R.sup.227 is hydrogen and R.sup.228 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0592] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is cycloalkyl. In some embodiments of compounds of
Formula Ioo, further to any of the above embodiments of Formula
Ioo, R.sup.227 is hydrogen and R.sup.228 is cyclopropyl.
[0593] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ioo,
further to any of the above embodiments of Formula Ioo, R.sup.227
is hydrogen and R.sup.228 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ioo, further to any of the above embodiments of Formula Ioo,
R.sup.227 is hydrogen and R.sup.228 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is trifluoromethyl. In some embodiments of compounds
of Formula Ioo, further to any of the above embodiments of Formula
Ioo, R.sup.227 is hydrogen and R.sup.228 is methyl. In some
embodiments of compounds of Formula Ioo, further to any of the
above embodiments of Formula Ioo, R.sup.227 is hydrogen and
R.sup.228 is ethyl.
[0594] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ioo,
further to any of the above embodiments of Formula Ioo, R.sup.227
is hydrogen and R.sup.228 is lower alkoxy. In some embodiments of
compounds of Formula Ioo, further to any of the above embodiments
of Formula Ioo, R.sup.227 is hydrogen and R.sup.228 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, R.sup.227 is hydrogen
and R.sup.228 is methoxy or ethoxy. In some embodiments of
compounds of Formula Ioo, further to any of the above embodiments
of Formula Ioo, R.sup.227 is hydrogen and R.sup.228 is methoxy. In
some embodiments of compounds of Formula Ioo, further to any of the
above embodiments of Formula Ioo, R.sup.227 is hydrogen and
R.sup.228 is ethoxy.
[0595] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, L.sub.12 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Ioo,
further to any of the above embodiments of Formula Ioo, L.sub.12 is
--C(O)--.
[0596] In some embodiments of compounds of Formula Ioo, further to
any of the above embodiments of Formula Ioo, Y.sub.12 is --N.dbd.
and R.sup.226 is hydrogen. In some embodiments of compounds of
Formula Ioo, further to any of the above embodiments of Formula
Ioo, Y.sub.12 is --C(H).dbd. and R.sup.226 is fluoro.
[0597] In a forty-first aspect, compounds of Formula I having the
structure according to the following Formula Ipp are provided:
##STR00042##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0598] wherein: [0599] R.sup.229 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0600] R.sup.230 is hydrogen and R.sup.231 is hydrogen,
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0601] R.sup.231 is
hydrogen and R.sup.230 is fluoro, chloro, bromo, cycloalkyl, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro.
[0602] In some embodiments of compounds of Formula Ipp, R.sup.229
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.229 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.229
is hydrogen, chloro or methyl.
[0603] In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.231 is hydrogen
and R.sup.230 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ipp, further to any of the above
embodiments of Formula Ipp, R.sup.231 is hydrogen and R.sup.230 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ipp, further to any of the
above embodiments of Formula Ipp, R.sup.231 is hydrogen and
R.sup.230 is lower alkyl. In some embodiments of compounds of
Formula Ipp, further to any of the above embodiments of Formula
Ipp, R.sup.231 is hydrogen and R.sup.230 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Ipp, further to any of the
above embodiments of Formula Ipp, R.sup.231 is hydrogen and
R.sup.230 is methyl.
[0604] In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ipp, further to any of the above
embodiments of Formula Ipp, R.sup.230 is hydrogen and R.sup.231 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Ipp, further to any of the above embodiments of Formula Ipp,
R.sup.230 is hydrogen and R.sup.231 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0605] In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Ipp, further to any of the above embodiments of Formula
Ipp, R.sup.230 is hydrogen and R.sup.231 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Ipp, further to any of the
above embodiments of Formula Ipp, R.sup.230 is hydrogen and
R.sup.231 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ipp, further to any of the above embodiments of Formula Ipp,
R.sup.230 is hydrogen and R.sup.231 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0606] In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is cycloalkyl. In some embodiments of compounds of
Formula Ipp, further to any of the above embodiments of Formula
Ipp, R.sup.230 is hydrogen and R.sup.231 is cyclopropyl.
[0607] In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ipp,
further to any of the above embodiments of Formula Ipp, R.sup.230
is hydrogen and R.sup.231 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Ipp, further to any of the above embodiments of Formula Ipp,
R.sup.230 is hydrogen and R.sup.231 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is trifluoromethyl. In some embodiments of compounds
of Formula Ipp, further to any of the above embodiments of Formula
Ipp, R.sup.230 is hydrogen and R.sup.231 is methyl. In some
embodiments of compounds of Formula Ipp, further to any of the
above embodiments of Formula Ipp, R.sup.230 is hydrogen and
R.sup.231 is ethyl.
[0608] In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Ipp,
further to any of the above embodiments of Formula Ipp, R.sup.230
is hydrogen and R.sup.231 is lower alkoxy. In some embodiments of
compounds of Formula Ipp, further to any of the above embodiments
of Formula Ipp, R.sup.230 is hydrogen and R.sup.231 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Ipp, further to
any of the above embodiments of Formula Ipp, R.sup.230 is hydrogen
and R.sup.231 is methoxy or ethoxy. In some embodiments of
compounds of Formula Ipp, further to any of the above embodiments
of Formula Ipp, R.sup.230 is hydrogen and R.sup.231 is methoxy. In
some embodiments of compounds of Formula Ipp, further to any of the
above embodiments of Formula Ipp, R.sup.230 is hydrogen and
R.sup.231 is ethoxy.
[0609] In a forty-second aspect, compounds of Formula I having the
structure according to the following Formula Iqq are provided:
##STR00043##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0610] wherein: [0611] R.sup.232 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0612] R.sup.233 is hydrogen and R.sup.234 is hydrogen,
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0613] R.sup.234 is
hydrogen and R.sup.233 is fluoro, chloro, bromo, cycloalkyl, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro.
[0614] In some embodiments of compounds of Formula Iqq, R.sup.232
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.232 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.232
is hydrogen, chloro or methyl.
[0615] In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.234 is hydrogen
and R.sup.233 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iqq, further to any of the above
embodiments of Formula Iqq, R.sup.234 is hydrogen and R.sup.233 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iqq, further to any of the
above embodiments of Formula Iqq, R.sup.234 is hydrogen and
R.sup.233 is lower alkyl. In some embodiments of compounds of
Formula Iqq, further to any of the above embodiments of Formula
Iqq, R.sup.234 is hydrogen and R.sup.233 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Iqq, further to any of the
above embodiments of Formula Iqq, R.sup.234 is hydrogen and
R.sup.233 is methyl.
[0616] In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iqq, further to any of the above
embodiments of Formula Iqq, R.sup.233 is hydrogen and R.sup.234 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Iqq, further to any of the above embodiments of Formula Iqq,
R.sup.233 is hydrogen and R.sup.234 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0617] In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Iqq, further to any of the above embodiments of Formula
Iqq, R.sup.233 is hydrogen and R.sup.234 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Iqq, further to any of the
above embodiments of Formula Iqq, R.sup.233 is hydrogen and
R.sup.234 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Iqq, further to any of the above embodiments of Formula Iqq,
R.sup.233 is hydrogen and R.sup.234 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0618] In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is cycloalkyl. In some embodiments of compounds of
Formula Iqq, further to any of the above embodiments of Formula
Iqq, R.sup.233 is hydrogen and R.sup.234 is cyclopropyl.
[0619] In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Iqq,
further to any of the above embodiments of Formula Iqq, R.sup.233
is hydrogen and R.sup.234 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Iqq, further to any of the above embodiments of Formula Iqq,
R.sup.233 is hydrogen and R.sup.234 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is trifluoromethyl. In some embodiments of compounds
of Formula Iqq, further to any of the above embodiments of Formula
Iqq, R.sup.233 is hydrogen and R.sup.234 is methyl. In some
embodiments of compounds of Formula Iqq, further to any of the
above embodiments of Formula Iqq, R.sup.233 is hydrogen and
R.sup.234 is ethyl.
[0620] In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Iqq,
further to any of the above embodiments of Formula Iqq, R.sup.233
is hydrogen and R.sup.234 is lower alkoxy. In some embodiments of
compounds of Formula Iqq, further to any of the above embodiments
of Formula Iqq, R.sup.233 is hydrogen and R.sup.234 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Iqq, further to
any of the above embodiments of Formula Iqq, R.sup.233 is hydrogen
and R.sup.234 is methoxy or ethoxy. In some embodiments of
compounds of Formula Iqq, further to any of the above embodiments
of Formula Iqq, R.sup.233 is hydrogen and R.sup.234 is methoxy. In
some embodiments of compounds of Formula Iqq, further to any of the
above embodiments of Formula Iqq, R.sup.233 is hydrogen and
R.sup.234 is ethoxy.
[0621] In a forty-third aspect, compounds of Formula I having the
structure according to the following Formula Irr are provided:
##STR00044##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0622] wherein: [0623] R.sup.235 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0624] R.sup.236 is hydrogen and R.sup.237 is hydrogen,
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0625] R.sup.237 is
hydrogen and R.sup.236 is fluoro, chloro, bromo, cycloalkyl, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro.
[0626] In some embodiments of compounds of Formula Irr, R.sup.235
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.235 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.235
is hydrogen, chloro or methyl.
[0627] In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.237 is hydrogen
and R.sup.236 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Irr, further to any of the above
embodiments of Formula Irr, R.sup.237 is hydrogen and R.sup.236 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Irr, further to any of the
above embodiments of Formula Irr, R.sup.237 is hydrogen and
R.sup.236 is lower alkyl. In some embodiments of compounds of
Formula Irr, further to any of the above embodiments of Formula
Irr, R.sup.237 is hydrogen and R.sup.236 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Irr, further to any of the
above embodiments of Formula Irr, R.sup.237 is hydrogen and
R.sup.236 is methyl.
[0628] In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Irr, further to any of the above
embodiments of Formula Irr, R.sup.236 is hydrogen and R.sup.237 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Irr, further to any of the above embodiments of Formula Irr,
R.sup.236 is hydrogen and R.sup.237 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0629] In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Irr, further to any of the above embodiments of Formula
Irr, R.sup.236 is hydrogen and R.sup.237 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Irr, further to any of the
above embodiments of Formula Irr, R.sup.236 is hydrogen and
R.sup.237 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Irr, further to any of the above embodiments of Formula Irr,
R.sup.236 is hydrogen and R.sup.237 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0630] In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is cycloalkyl. In some embodiments of compounds of
Formula Irr, further to any of the above embodiments of Formula
Irr, R.sup.236 is hydrogen and R.sup.237 is cyclopropyl.
[0631] In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Irr,
further to any of the above embodiments of Formula Irr, R.sup.236
is hydrogen and R.sup.237 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Irr, further to any of the above embodiments of Formula Irr,
R.sup.236 is hydrogen and R.sup.237 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is trifluoromethyl. In some embodiments of compounds
of Formula Irr, further to any of the above embodiments of Formula
Irr, R.sup.236 is hydrogen and R.sup.237 is methyl. In some
embodiments of compounds of Formula Irr, further to any of the
above embodiments of Formula Irr, R.sup.236 is hydrogen and
R.sup.237 is ethyl.
[0632] In some embodiments of compounds of Formula Irr, further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Irr,
further to any of the above embodiments of Formula Irr, R.sup.236
is hydrogen and R.sup.237 is lower alkoxy. In some embodiments of
compounds of Formula Irr, further to any of the above embodiments
of Formula Irr R.sup.236 is hydrogen and R.sup.237 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Irr further to
any of the above embodiments of Formula Irr, R.sup.236 is hydrogen
and R.sup.237 is methoxy or ethoxy. In some embodiments of
compounds of Formula Irr, further to any of the above embodiments
of Formula Irr, R.sup.236 is hydrogen and R.sup.237 is methoxy. In
some embodiments of compounds of Formula Irr, further to any of the
above embodiments of Formula Irr, R.sup.236 is hydrogen and
R.sup.237 is ethoxy.
[0633] In a forty-fourth aspect, compounds of Formula I having the
structure according to the following Formula Iss are provided:
##STR00045##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0634] wherein: [0635] R.sup.238 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0636] R.sup.239 is hydrogen and R.sup.240 is hydrogen,
fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0637] R.sup.240 is
hydrogen and R.sup.239 is fluoro, chloro, bromo, cycloalkyl, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro.
[0638] In some embodiments of compounds of Formula Iss, R.sup.238
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.238 is
hydrogen, chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.238
is hydrogen, chloro or methyl.
[0639] In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.240 is hydrogen
and R.sup.239 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iss, further to any of the above
embodiments of Formula Iss, R.sup.240 is hydrogen and R.sup.239 is
lower alkyl optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iss, further to any of the
above embodiments of Formula Iss, R.sup.240 is hydrogen and
R.sup.239 is lower alkyl. In some embodiments of compounds of
Formula Iss, further to any of the above embodiments of Formula
Iss, R.sup.240 is hydrogen and R.sup.239 is C.sub.1-3 alkyl. In
some embodiments of compounds of Formula Iss, further to any of the
above embodiments of Formula Iss, R.sup.240 is hydrogen and
R.sup.239 is methyl.
[0640] In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is fluoro, chloro, bromo, cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iss, further to any of the above
embodiments of Formula Iss, R.sup.239 is hydrogen and R.sup.240 is
fluoro, chloro, bromo. In some embodiments of compounds of Formula
Iss, further to any of the above embodiments of Formula Iss,
R.sup.239 is hydrogen and R.sup.240 is cycloalkyl, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro.
[0641] In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is cycloalkyl or lower alkyl optionally substituted
with one or more fluoro. In some embodiments of compounds of
Formula Iss, further to any of the above embodiments of Formula
Iss, R.sup.239 is hydrogen and R.sup.240 is cycloalkyl or C.sub.1-3
alkyl optionally substituted with 1, 2, or 3 fluoro. In some
embodiments of compounds of Formula Iss, further to any of the
above embodiments of Formula Iss, R.sup.239 is hydrogen and
R.sup.240 is cyclopropyl or C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Iss, further to any of the above embodiments of Formula Iss,
R.sup.239 is hydrogen and R.sup.240 is cyclopropyl,
trifluoromethyl, methyl or ethyl.
[0642] In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is cycloalkyl. In some embodiments of compounds of
Formula Iss, further to any of the above embodiments of Formula
Iss, R.sup.239 is hydrogen and R.sup.240 is cyclopropyl.
[0643] In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is lower alkyl optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Iss,
further to any of the above embodiments of Formula Iss, R.sup.239
is hydrogen and R.sup.240 is C.sub.1-3 alkyl optionally substituted
with 1, 2, or 3 fluoro. In some embodiments of compounds of Formula
Iss, further to any of the above embodiments of Formula Iss,
R.sup.239 is hydrogen and R.sup.240 is trifluoromethyl, methyl or
ethyl. In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is trifluoromethyl. In some embodiments of compounds
of Formula Iss, further to any of the above embodiments of Formula
Iss, R.sup.239 is hydrogen and R.sup.240 is methyl. In some
embodiments of compounds of Formula Iss, further to any of the
above embodiments of Formula Iss, R.sup.239 is hydrogen and
R.sup.240 is ethyl.
[0644] In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is lower alkoxy optionally substituted with one or
more fluoro. In some embodiments of compounds of Formula Iss,
further to any of the above embodiments of Formula Iss, R.sup.239
is hydrogen and R.sup.240 is lower alkoxy. In some embodiments of
compounds of Formula Iss, further to any of the above embodiments
of Formula Iss, R.sup.239 is hydrogen and R.sup.240 is C.sub.1-3
alkoxy. In some embodiments of compounds of Formula Iss, further to
any of the above embodiments of Formula Iss, R.sup.239 is hydrogen
and R.sup.240 is methoxy or ethoxy. In some embodiments of
compounds of Formula Iss, further to any of the above embodiments
of Formula Iss, R.sup.239 is hydrogen and R.sup.240 is methoxy. In
some embodiments of compounds of Formula Iss, further to any of the
above embodiments of Formula Iss, R.sup.239 is hydrogen and
R.sup.240 is ethoxy.
[0645] In a forty-fifth aspect, compounds of Formula I having the
structure according to the following Formula Itt are provided:
##STR00046##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0646] wherein: [0647] X.sub.5 is --N.dbd., --C(H).dbd.,
or --C(R.sup.241).dbd.; [0648] Y.sub.13 is --N.dbd. and R.sup.243
is hydrogen; or Y.sub.13 is --C(H).dbd. and R.sup.243 is fluoro;
[0649] L.sub.13 is --C(H.sub.2)-- or --C(O)--; [0650] when X.sub.5
is --C(R.sup.241).dbd., R.sup.242 is hydrogen; [0651] when X.sub.5
is --N.dbd. or --C(H).dbd., R.sup.242 is selected from the group
consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.247, and --O--R.sup.248; [0652]
R.sup.241 is fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; [0653] R.sup.244 and R.sup.245 are
hydrogen and R.sup.246 is selected from the group consisting of
fluoro, chloro, --O--R.sup.249, --S--R.sup.250,
--S(O.sub.2)--R.sup.251, and lower alkyl optionally substituted
with one or more R.sup.252; or [0654] R.sup.244 and R.sup.246 are
hydrogen and R.sup.245 is fluoro, chloro, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0655] R.sup.245 and
R.sup.246 are hydrogen and R.sup.244 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0656] R.sup.244
is hydrogen, R.sup.245 is fluoro, chloro, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro and R.sup.246 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro;
[0657] R.sup.247 is fluoro or lower alkoxy optionally substituted
with one or more fluoro; [0658] R.sup.248 is lower alkyl, lower
alkyl substituted with one or more fluoro, or lower alkyl
substituted with lower alkoxy; [0659] R.sup.249, R.sup.250 and
R.sup.251 are lower alkyl optionally substituted with one or more
fluoro; and [0660] R.sup.252 is fluoro, --OH, or lower alkoxy
optionally substituted with one or more fluoro.
[0661] In some embodiments of compounds of Formula Itt, X.sub.5 is
--N.dbd. and R.sup.242 is selected from the group consisting of
hydrogen, cycloalkyl, lower alkyl optionally substituted with one
or more R.sup.247, and --O--R.sup.248. In one embodiment, X.sub.5
is --N.dbd. and R.sup.242 is selected from the group consisting of
cycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted
with lower alkoxy. In one embodiment, X.sub.5 is --N.dbd. and
R.sup.242 is selected from the group consisting of C.sub.3-6
cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and C.sub.1-3 alkoxy
substituted with C.sub.1-3 alkoxy. In one embodiment, X.sub.5 is
--N.dbd. and R.sup.242 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0662] In some embodiments of compounds of Formula Itt, X.sub.5 is
--C(H).dbd. or --C(R.sup.241).dbd. and R.sup.241 is fluoro, chloro,
or lower alkyl optionally substituted with one or more fluoro. In
one embodiment, X.sub.5 is --C(H).dbd. or --C(R.sup.241).dbd. and
R.sup.241 is chloro or lower alkyl. In one embodiment, X.sub.5 is
--C(H).dbd. or --C(R.sup.241).dbd. and R.sup.241 is chloro or
C.sub.1-3 alkyl. In one embodiment, X.sub.5 is --C(H).dbd. or
--C(R.sup.241).dbd. and R.sup.241 is chloro or methyl.
[0663] In some embodiments of compounds of Formula Itt, further to
any of the above embodiments of Formula Itt, R.sup.244 and
R.sup.245 are hydrogen and R.sup.246 is selected from the group
consisting of fluoro, chloro, --O--R.sup.249, --S--R.sup.250,
--S(O.sub.2)--R.sup.251, and lower alkyl optionally substituted
with one or more R.sup.252. In some embodiments of compounds of
Formula Itt, further to any of the above embodiments of Formula
Itt, R.sup.244 and R.sup.245 are hydrogen and R.sup.246 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Itt, further to any of the above embodiments
of Formula Itt, R.sup.244 and R.sup.245 are hydrogen and R.sup.246
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0664] In some embodiments of compounds of Formula Itt, further to
any of the above embodiments of Formula Itt, R.sup.244 and
R.sup.246 are hydrogen and R.sup.245 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Itt, further to any of the above
embodiments of Formula Itt, R.sup.244 and R.sup.246 are hydrogen
and R.sup.245 is fluoro, chloro, lower alkyl or lower alkoxy.
[0665] In some embodiments of compounds of Formula Itt, further to
any of the above embodiments of Formula Itt, R.sup.245 and
R.sup.246 are hydrogen and R.sup.244 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Itt, further to any of the above
embodiments of Formula Itt, R.sup.245 and R.sup.246 are hydrogen
and R.sup.244 is fluoro, chloro, lower alkyl or lower alkoxy.
[0666] In some embodiments of compounds of Formula Itt, further to
any of the above embodiments of Formula Itt, R.sup.244 is hydrogen,
R.sup.245 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.246 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Itt, further to any of the
above embodiments of Formula Itt, R.sup.244 is hydrogen, R.sup.245
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.246 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Itt, further to any of the above embodiments
of Formula Itt, R.sup.244 is hydrogen, R.sup.245 is fluoro, chloro,
or lower alkoxy and R.sup.246 is fluoro, chloro, or lower
alkoxy.
[0667] In some embodiments of compounds of Formula Itt, further to
any of the above embodiments of Formula Itt, L.sub.13 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Itt,
further to any of the above embodiments of Formula Itt, L.sub.13 is
--C(O)--.
[0668] In some embodiments of compounds of Formula Itt, further to
any of the above embodiments of Formula Itt, Y.sub.13 is --N.dbd.
and R.sup.243 is hydrogen. In some embodiments of compounds of
Formula Itt, further to any of the above embodiments of Formula
Itt, Y.sub.13 is --C(H).dbd. and R.sup.243 is fluoro.
[0669] In a forty-sixth aspect, compounds of Formula I having the
structure according to the following Formula Iuu are provided:
##STR00047##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0670] wherein: [0671] Y.sub.14 is --N.dbd. and R.sup.254
is hydrogen; or Y.sub.14 is --C(H).dbd. and R.sup.254 is fluoro;
[0672] L.sub.14 is --C(H.sub.2)-- or --C(O)--; [0673] R.sup.253 is
selected from the group consisting of hydrogen, cycloalkyl, lower
alkyl optionally substituted with one or more R.sup.258, and
--O--R.sup.259; [0674] R.sup.255 and R.sup.256 are hydrogen and
R.sup.257 is selected from the group consisting of fluoro, chloro,
--O--R.sup.260, --S--R.sup.261, --S(O.sub.2)--R.sup.262, and lower
alkyl optionally substituted with one or more R.sup.263; or [0675]
R.sup.255 and R.sup.257 are hydrogen and R.sup.256 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro; or
[0676] R.sup.256 and R.sup.257 are hydrogen and R.sup.255 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; or [0677] R.sup.255 is hydrogen, R.sup.256 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro and
R.sup.257 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro; [0678] R.sup.258 is fluoro or lower alkoxy
optionally substituted with one or more fluoro; [0679] R.sup.259 is
lower alkyl, lower alkyl substituted with one or more fluoro, or
lower alkyl substituted with lower alkoxy; [0680] R.sup.260,
R.sup.261 and R.sup.262 are lower alkyl optionally substituted with
one or more fluoro; and [0681] R.sup.263 is fluoro, --OH, or lower
alkoxy optionally substituted with one or more fluoro.
[0682] In some embodiments of compounds of Formula Iuu, R.sup.253
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.253 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.253 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0683] In some embodiments of compounds of Formula Iuu, further to
any of the above embodiments of Formula Iuu, R.sup.255 and
R.sup.256 are hydrogen and R.sup.257 is selected from the group
consisting of fluoro, chloro, --O--R.sup.260, --S--R.sup.261,
--S(O.sub.2)--R.sup.262, and lower alkyl optionally substituted
with one or more R.sup.263. In some embodiments of compounds of
Formula Iuu, further to any of the above embodiments of Formula
Iuu, R.sup.255 and R.sup.256 are hydrogen and R.sup.257 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iuu, further to any of the above embodiments
of Formula Iuu, R.sup.255 and R.sup.256 are hydrogen and R.sup.257
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0684] In some embodiments of compounds of Formula Iuu, further to
any of the above embodiments of Formula Iuu, R.sup.255 and
R.sup.257 are hydrogen and R.sup.256 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iuu, further to any of the above
embodiments of Formula Iuu, R.sup.255 and R.sup.257 are hydrogen
and R.sup.256 is fluoro, chloro, lower alkyl or lower alkoxy.
[0685] In some embodiments of compounds of Formula Iuu, further to
any of the above embodiments of Formula Iuu, R.sup.256 and
R.sup.257 are hydrogen and R.sup.255 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iuu, further to any of the above
embodiments of Formula Iuu, R.sup.256 and R.sup.257 are hydrogen
and R.sup.255 is fluoro, chloro, lower alkyl or lower alkoxy.
[0686] In some embodiments of compounds of Formula Iuu, further to
any of the above embodiments of Formula Iuu, R.sup.255 is hydrogen,
R.sup.256 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.257 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iuu, further to any of the
above embodiments of Formula Iuu, R.sup.255 is hydrogen, R.sup.256
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.257 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iuu, further to any of the above embodiments
of Formula Iuu, R.sup.255 is hydrogen, R.sup.256 is fluoro, chloro,
or lower alkoxy and R.sup.257 is fluoro, chloro, or lower
alkoxy.
[0687] In some embodiments of compounds of Formula Iuu, further to
any of the above embodiments of Formula Iuu, L.sub.14 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Iuu,
further to any of the above embodiments of Formula Iuu, L.sub.14 is
--C(O)--.
[0688] In some embodiments of compounds of Formula Iuu, further to
any of the above embodiments of Formula Iuu, Y.sub.14 is --N.dbd.
and R.sup.254 is hydrogen. In some embodiments of compounds of
Formula Iuu, further to any of the above embodiments of Formula
Iuu, Y.sub.14 is --C(H).dbd. and R.sup.254 is fluoro.
[0689] In a forty-seventh aspect, compounds of Formula I having the
structure according to the following Formula Ivv are provided:
##STR00048##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0690] wherein: [0691] R.sup.264 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.268, and --O--R.sup.269; [0692]
R.sup.265 and R.sup.266 are hydrogen and R.sup.267 is selected from
the group consisting of fluoro, chloro, --O--R.sup.270,
--S--R.sup.271, --S(O.sub.2)--R.sup.272, and lower alkyl optionally
substituted with one or more [0693] R.sup.273; or [0694] R.sup.265
and R.sup.267 are hydrogen and R.sup.266 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro; or [0695]
R.sup.266 and R.sup.267 are hydrogen and R.sup.265 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro; or
[0696] R.sup.265 is hydrogen, R.sup.266 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro and R.sup.267
is fluoro, chloro, lower alkyl optionally substituted with one or
more fluoro, or lower alkoxy optionally substituted with one or
more fluoro; [0697] R.sup.268 is fluoro or lower alkoxy optionally
substituted with one or more fluoro; [0698] R.sup.269 is lower
alkyl, lower alkyl substituted with one or more fluoro, or lower
alkyl substituted with lower alkoxy; [0699] R.sup.270, R.sup.271
and R.sup.272 are lower alkyl optionally substituted with one or
more fluoro; and [0700] R.sup.273 is fluoro, --OH, or lower alkoxy
optionally substituted with one or more fluoro.
[0701] In some embodiments of compounds of Formula Ivv, R.sup.264
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.264 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.264 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0702] In some embodiments of compounds of Formula Ivv, further to
any of the above embodiments of Formula Ivv, R.sup.265 and
R.sup.266 are hydrogen and R.sup.267 is selected from the group
consisting of fluoro, chloro, --O--R.sup.270, --S--R.sup.271,
--S(O.sub.2)--R.sup.272, and lower alkyl optionally substituted
with one or more R.sup.273. In some embodiments of compounds of
Formula Ivv, further to any of the above embodiments of Formula
Ivv, R.sup.265 and R.sup.266 are hydrogen and R.sup.267 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Ivv, further to any of the above embodiments
of Formula Ivv, R.sup.265 and R.sup.266 are hydrogen and R.sup.267
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0703] In some embodiments of compounds of Formula Ivv, further to
any of the above embodiments of Formula Ivv, R.sup.265 and
R.sup.267 are hydrogen and R.sup.266 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ivv, further to any of the above
embodiments of Formula Ivv, R.sup.265 and R.sup.267 are hydrogen
and R.sup.266 is fluoro, chloro, lower alkyl or lower alkoxy.
[0704] In some embodiments of compounds of Formula Ivv, further to
any of the above embodiments of Formula Ivv, R.sup.266 and
R.sup.267 are hydrogen and R.sup.265 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ivv, further to any of the above
embodiments of Formula Ivv, R.sup.266 and R.sup.267 are hydrogen
and R.sup.265 is fluoro, chloro, lower alkyl or lower alkoxy.
[0705] In some embodiments of compounds of Formula Ivv, further to
any of the above embodiments of Formula Ivv, R.sup.265 is hydrogen,
R.sup.266 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.267 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ivv, further to any of the
above embodiments of Formula Ivv, R.sup.265 is hydrogen, R.sup.266
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.267 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Ivv, further to any of the above embodiments
of Formula Ivv, R.sup.265 is hydrogen, R.sup.266 is fluoro, chloro,
or lower alkoxy and R.sup.267 is fluoro, chloro, or lower
alkoxy.
[0706] In a forty-eighth aspect, compounds of Formula I having the
structure according to the following Formula Iww are provided:
##STR00049##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0707] wherein: [0708] R.sup.274 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.278, and --O--R.sup.279; [0709]
R.sup.275 and R.sup.276 are hydrogen and R.sup.277 is selected from
the group consisting of fluoro, chloro, --O--R.sup.280,
--S--R.sup.281, --S(O.sub.2)--R.sup.282, and lower alkyl optionally
substituted with one or more R.sup.283; or [0710] R.sup.275 and
R.sup.277 are hydrogen and R.sup.276 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0711] R.sup.276
and R.sup.277 are hydrogen and R.sup.275 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro; or [0712]
R.sup.275 is hydrogen, R.sup.276 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro and R.sup.277 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; [0713] R.sup.278 is fluoro or lower alkoxy optionally
substituted with one or more fluoro; [0714] R.sup.279 is lower
alkyl, lower alkyl substituted with one or more fluoro, or lower
alkyl substituted with lower alkoxy; [0715] R.sup.280, R.sup.281
and R.sup.282 are lower alkyl optionally substituted with one or
more fluoro; and [0716] R.sup.283 is fluoro, --OH, or lower alkoxy
optionally substituted with one or more fluoro.
[0717] In some embodiments of compounds of Formula Iww, R.sup.274
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.274 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.274 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0718] In some embodiments of compounds of Formula Iww, further to
any of the above embodiments of Formula Iww, R.sup.275 and
R.sup.276 are hydrogen and R.sup.277 is selected from the group
consisting of fluoro, chloro, --O--R.sup.280, --S--R.sup.281,
--S(O.sub.2)--R.sup.282, and lower alkyl optionally substituted
with one or more R.sup.283. In some embodiments of compounds of
Formula Iww, further to any of the above embodiments of Formula
Iww, R.sup.275 and R.sup.276 are hydrogen and R.sup.277 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iww, further to any of the above embodiments
of Formula Iww, R.sup.275 and R.sup.276 are hydrogen and R.sup.277
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0719] In some embodiments of compounds of Formula Iww, further to
any of the above embodiments of Formula Iww, R.sup.275 and
R.sup.277 are hydrogen and R.sup.276 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iww, further to any of the above
embodiments of Formula Iww, R.sup.275 and R.sup.277 are hydrogen
and R.sup.276 is fluoro, chloro, lower alkyl or lower alkoxy.
[0720] In some embodiments of compounds of Formula Iww, further to
any of the above embodiments of Formula Iww, R.sup.276 and
R.sup.277 are hydrogen and R.sup.275 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iww, further to any of the above
embodiments of Formula Iww, R.sup.276 and R.sup.277 are hydrogen
and R.sup.275 is fluoro, chloro, lower alkyl or lower alkoxy.
[0721] In some embodiments of compounds of Formula Iww, further to
any of the above embodiments of Formula Iww, R.sup.275 is hydrogen,
R.sup.276 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.277 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iww, further to any of the
above embodiments of Formula Iww, R.sup.275 is hydrogen, R.sup.276
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.277 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iww, further to any of the above embodiments
of Formula Iww, R.sup.275 is hydrogen, R.sup.276 is fluoro, chloro,
or lower alkoxy and R.sup.277 is fluoro, chloro, or lower
alkoxy.
[0722] In a forty-ninth aspect, compounds of Formula I having the
structure according to the following Formula Ixx are provided:
##STR00050##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0723] wherein: [0724] R.sup.284 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.288, and --O--R.sup.289; [0725]
R.sup.285 and R.sup.286 are hydrogen and R.sup.287 is selected from
the group consisting of fluoro, chloro, --O--R.sup.290,
--S--R.sup.291, --S(O.sub.2)--R.sup.292, and lower alkyl optionally
substituted with one or more R.sup.293; or [0726] R.sup.285 and
R.sup.287 are hydrogen and R.sup.286 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0727] R.sup.286
and R.sup.287 are hydrogen and R.sup.285 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro; or [0728]
R.sup.285 is hydrogen, R.sup.286 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro and R.sup.287 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; [0729] R.sup.288 is fluoro or lower alkoxy optionally
substituted with one or more fluoro; [0730] R.sup.289 is lower
alkyl, lower alkyl substituted with one or more fluoro, or lower
alkyl substituted with lower alkoxy; [0731] R.sup.290, R.sup.291
and R.sup.292 are lower alkyl optionally substituted with one or
more fluoro; and [0732] R.sup.293 is fluoro, --OH, or lower alkoxy
optionally substituted with one or more fluoro.
[0733] In some embodiments of compounds of Formula Ixx, R.sup.284
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.284 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.284 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0734] In some embodiments of compounds of Formula Ixx, further to
any of the above embodiments of Formula Ixx, R.sup.285 and
R.sup.286 are hydrogen and R.sup.287 is selected from the group
consisting of fluoro, chloro, --O--R.sup.290, --S--R.sup.291,
--S(O.sub.2)--R.sup.292, and lower alkyl optionally substituted
with one or more R.sup.293. In some embodiments of compounds of
Formula Ixx, further to any of the above embodiments of Formula
Ixx, R.sup.285 and R.sup.286 are hydrogen and R.sup.287 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Ixx, further to any of the above embodiments
of Formula Ixx, R.sup.285 and R.sup.286 are hydrogen and R.sup.287
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0735] In some embodiments of compounds of Formula Ixx, further to
any of the above embodiments of Formula Ixx, R.sup.285 and
R.sup.287 are hydrogen and R.sup.286 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ixx, further to any of the above
embodiments of Formula Ixx, R.sup.285 and R.sup.287 are hydrogen
and R.sup.286 is fluoro, chloro, lower alkyl or lower alkoxy.
[0736] In some embodiments of compounds of Formula Ixx, further to
any of the above embodiments of Formula Ixx, R.sup.286 and
R.sup.287 are hydrogen and R.sup.285 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Ixx, further to any of the above
embodiments of Formula Ixx, R.sup.286 and R.sup.287 are hydrogen
and R.sup.285 is fluoro, chloro, lower alkyl or lower alkoxy.
[0737] In some embodiments of compounds of Formula Ixx, further to
any of the above embodiments of Formula Ixx, R.sup.285 is hydrogen,
R.sup.286 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.287 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Ixx, further to any of the
above embodiments of Formula Ixx, R.sup.285 is hydrogen, R.sup.286
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.287 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Ixx, further to any of the above embodiments
of Formula Ixx, R.sup.285 is hydrogen, R.sup.286 is fluoro, chloro,
or lower alkoxy and R.sup.287 is fluoro, chloro, or lower
alkoxy.
[0738] In a fiftieth aspect, compounds of Formula I having the
structure according to the following Formula Iyy are provided:
##STR00051##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0739] wherein: [0740] R.sup.294 is selected from the
group consisting of hydrogen, cycloalkyl, lower alkyl optionally
substituted with one or more R.sup.298, and --O--R.sup.299; [0741]
R.sup.295 and R.sup.296 are hydrogen and R.sup.297 is selected from
the group consisting of fluoro, chloro, --O--R.sup.300,
--S--R.sup.301, --S(O.sub.2)--R.sup.302, and lower alkyl optionally
substituted with one or more R.sup.303; or [0742] R.sup.295 and
R.sup.297 are hydrogen and R.sup.296 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0743] R.sup.296
and R.sup.297 are hydrogen and R.sup.295 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro; or [0744]
R.sup.295 is hydrogen, R.sup.296 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro and R.sup.297 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; [0745] R.sup.298 is fluoro or lower alkoxy optionally
substituted with one or more fluoro; [0746] R.sup.299 is lower
alkyl, lower alkyl substituted with one or more fluoro, or lower
alkyl substituted with lower alkoxy; [0747] R.sup.300, R.sup.301
and R.sup.302 are lower alkyl optionally substituted with one or
more fluoro; and [0748] R.sup.303 is fluoro, --OH, or lower alkoxy
optionally substituted with one or more fluoro.
[0749] In some embodiments of compounds of Formula Iyy, R.sup.294
is selected from the group consisting of cycloalkyl, lower alkyl,
lower alkoxy, and lower alkoxy substituted with lower alkoxy. In
one embodiment, R.sup.294 is selected from the group consisting of
C.sub.3-6 cycloalkyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, and
C.sub.1-3 alkoxy substituted with C.sub.1-3 alkoxy. In one
embodiment, R.sup.294 is selected from the group consisting of
methyl, cyclopropyl, methoxy, ethoxy, and 2-methoxy-ethoxy.
[0750] In some embodiments of compounds of Formula Iyy, further to
any of the above embodiments of Formula Iyy, R.sup.295 and
R.sup.296 are hydrogen and R.sup.297 is selected from the group
consisting of fluoro, chloro, --O--R.sup.300, --S--R.sup.301,
--S(O.sub.2)--R.sup.302, and lower alkyl optionally substituted
with one or more R.sup.303. In some embodiments of compounds of
Formula Iyy, further to any of the above embodiments of Formula
Iyy, R.sup.295 and R.sup.296 are hydrogen and R.sup.297 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iyy, further to any of the above embodiments
of Formula Iyy, R.sup.295 and R.sup.296 are hydrogen and R.sup.297
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0751] In some embodiments of compounds of Formula Iyy, further to
any of the above embodiments of Formula Iyy, R.sup.295 and
R.sup.297 are hydrogen and R.sup.296 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iyy, further to any of the above
embodiments of Formula Iyy, R.sup.295 and R.sup.297 are hydrogen
and R.sup.296 is fluoro, chloro, lower alkyl or lower alkoxy.
[0752] In some embodiments of compounds of Formula Iyy, further to
any of the above embodiments of Formula Iyy, R.sup.296 and
R.sup.297 are hydrogen and R.sup.295 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iyy, further to any of the above
embodiments of Formula Iyy, R.sup.296 and R.sup.297 are hydrogen
and R.sup.295 is fluoro, chloro, lower alkyl or lower alkoxy.
[0753] In some embodiments of compounds of Formula Iyy, further to
any of the above embodiments of Formula Iyy, R.sup.295 is hydrogen,
R.sup.296 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.297 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iyy, further to any of the
above embodiments of Formula Iyy, R.sup.295 is hydrogen, R.sup.296
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.297 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iyy, further to any of the above embodiments
of Formula Iyy, R.sup.295 is hydrogen, R.sup.296 is fluoro, chloro,
or lower alkoxy and R.sup.297 is fluoro, chloro, or lower
alkoxy.
[0754] In a fifty-first aspect, compounds of Formula I having the
structure according to the following Formula Izz are provided:
##STR00052##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0755] wherein: [0756] Y.sub.15 is --N.dbd. and R.sup.305
is hydrogen; or Y.sub.15 is --C(H).dbd. and R.sup.305 is fluoro;
[0757] L.sub.15 is --C(H.sub.2)-- or --C(O)--; [0758] R.sup.304 is
hydrogen, fluoro, chloro, or lower alkyl optionally substituted
with one or more fluoro; [0759] R.sup.306 and R.sup.307 are
hydrogen and R.sup.308 is selected from the group consisting of
fluoro, chloro, --O--R.sup.309, --S--R.sup.310,
--S(O.sub.2)--R.sup.311 and lower alkyl optionally substituted with
one or more R.sup.312; or [0760] R.sup.306 and R.sup.308 are
hydrogen and R.sup.307 is fluoro, chloro, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro; or [0761] R.sup.307 and
R.sup.308 are hydrogen and R.sup.306 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro; or [0762] R.sup.306
is hydrogen, R.sup.307 is fluoro, chloro, lower alkyl optionally
substituted with one or more fluoro, or lower alkoxy optionally
substituted with one or more fluoro and R.sup.308 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro;
[0763] R.sup.309, R.sup.310 and R.sup.311 are lower alkyl
optionally substituted with one or more fluoro; and [0764]
R.sup.312 is fluoro, --OH, or lower alkoxy optionally substituted
with one or more fluoro.
[0765] In some embodiments of compounds of Formula Izz, R.sup.304
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.304 is
chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.304 is chloro
or methyl.
[0766] In some embodiments of compounds of Formula Izz, further to
any of the above embodiments of Formula Izz, R.sup.306 and
R.sup.307 are hydrogen and R.sup.308 is selected from the group
consisting of fluoro, chloro, --O--R.sup.309, --S--R.sup.310,
--S(O.sub.2)--R.sup.311, and lower alkyl optionally substituted
with one or more R.sup.312. In some embodiments of compounds of
Formula Izz, further to any of the above embodiments of Formula
Izz, R.sup.306 and R.sup.307 are hydrogen and R.sup.308 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Izz, further to any of the above embodiments
of Formula Izz, R.sup.306 and R.sup.307 are hydrogen and R.sup.308
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0767] In some embodiments of compounds of Formula Izz, further to
any of the above embodiments of Formula Izz, R.sup.306 and
R.sup.308 are hydrogen and R.sup.307 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Izz, further to any of the above
embodiments of Formula Izz, R.sup.306 and R.sup.308 are hydrogen
and R.sup.307 is fluoro, chloro, lower alkyl or lower alkoxy.
[0768] In some embodiments of compounds of Formula Izz, further to
any of the above embodiments of Formula Izz, R.sup.307 and
R.sup.308 are hydrogen and R.sup.306 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Izz, further to any of the above
embodiments of Formula Izz, R.sup.307 and R.sup.308 are hydrogen
and R.sup.306 is fluoro, chloro, lower alkyl or lower alkoxy.
[0769] In some embodiments of compounds of Formula Izz, further to
any of the above embodiments of Formula Izz, R.sup.306 is hydrogen,
R.sup.307 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.308 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Izz, further to any of the
above embodiments of Formula Izz, R.sup.306 is hydrogen, R.sup.307
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.308 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Izz, further to any of the above embodiments
of Formula Izz, R.sup.306 is hydrogen, R.sup.307 is fluoro, chloro,
or lower alkoxy and R.sup.308 is fluoro, chloro, or lower
alkoxy.
[0770] In some embodiments of compounds of Formula Izz, further to
any of the above embodiments of Formula Izz, L.sub.15 is
--C(H.sub.2)--. In some embodiments of compounds of Formula Izz,
further to any of the above embodiments of Formula Izz, L.sub.15 is
--C(O)--.
[0771] In some embodiments of compounds of Formula Izz, further to
any of the above embodiments of Formula Izz, Y.sub.15 is --N.dbd.
and R.sup.305 is hydrogen. In some embodiments of compounds of
Formula Izz, further to any of the above embodiments of Formula
Izz, Y.sub.15 is --C(H).dbd. and R.sup.305 is fluoro.
[0772] In a fifty-second aspect, compounds of Formula I having the
structure according to the following Formula Iab are provided:
##STR00053##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0773] wherein: [0774] R.sup.313 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0775] R.sup.314 and R.sup.315 are hydrogen and R.sup.316
is selected from the group consisting of fluoro, chloro,
--O--R.sup.317, --S--R.sup.318, --S(O.sub.2)--R.sup.319, and lower
alkyl optionally substituted with one or more R.sup.320; or [0776]
R.sup.314 and R.sup.316 are hydrogen and R.sup.315 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro; or
[0777] R.sup.315 and R.sup.316 are hydrogen and R.sup.314 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; or [0778] R.sup.314 is hydrogen, R.sup.315 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro and
R.sup.316 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro; [0779] R.sup.317, R.sup.318 and R.sup.319
are lower alkyl optionally substituted with one or more fluoro; and
[0780] R.sup.320 is fluoro, --OH, or lower alkoxy optionally
substituted with one or more fluoro.
[0781] In some embodiments of compounds of Formula Iab, R.sup.313
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.313 is
chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.313 is chloro
or methyl.
[0782] In some embodiments of compounds of Formula Iab, further to
any of the above embodiments of Formula Iab, R.sup.314 and
R.sup.315 are hydrogen and R.sup.316 is selected from the group
consisting of fluoro, chloro, --O--R.sup.317, --S--R.sup.318,
--S(O.sub.2)--R.sup.319, and lower alkyl optionally substituted
with one or more R.sup.320. In some embodiments of compounds of
Formula Iab, further to any of the above embodiments of Formula
Iab, R.sup.314 and R.sup.315 are hydrogen and R.sup.316 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iab, further to any of the above embodiments
of Formula Iab, R.sup.314 and R.sup.315 are hydrogen and R.sup.316
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0783] In some embodiments of compounds of Formula Iab, further to
any of the above embodiments of Formula Iab, R.sup.314 and
R.sup.316 are hydrogen and R.sup.315 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iab, further to any of the above
embodiments of Formula Iab, R.sup.314 and R.sup.316 are hydrogen
and R.sup.315 is fluoro, chloro, lower alkyl or lower alkoxy.
[0784] In some embodiments of compounds of Formula Iab, further to
any of the above embodiments of Formula Iab, R.sup.315 and
R.sup.316 are hydrogen and R.sup.314 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iab, further to any of the above
embodiments of Formula Iab, R.sup.315 and R.sup.316 are hydrogen
and R.sup.314 is fluoro, chloro, lower alkyl or lower alkoxy.
[0785] In some embodiments of compounds of Formula Iab, further to
any of the above embodiments of Formula Iab, R.sup.314 is hydrogen,
R.sup.315 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.316 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iab, further to any of the
above embodiments of Formula Iab, R.sup.314 is hydrogen, R.sup.315
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.316 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iab, further to any of the above embodiments
of Formula Iab, R.sup.314 is hydrogen, R.sup.315 is fluoro, chloro,
or lower alkoxy and R.sup.316 is fluoro, chloro, or lower
alkoxy.
[0786] In a fifty-third aspect, compounds of Formula I having the
structure according to the following Formula Iac are provided:
##STR00054##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0787] wherein: [0788] R.sup.321 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0789] R.sup.322 and R.sup.323 are hydrogen and R.sup.324
is selected from the group consisting of fluoro, chloro,
--O--R.sup.325, --S--R.sup.326, --S(O.sub.2)--R.sup.327, and lower
alkyl optionally substituted with one or more R.sup.328; or [0790]
R.sup.322 and R.sup.324 are hydrogen and R.sup.323 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro; or
[0791] R.sup.323 and R.sup.324 are hydrogen and R.sup.322 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; or [0792] R.sup.322 is hydrogen, R.sup.323 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro and
R.sup.324 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro; [0793] R.sup.325, R.sup.326 and R.sup.327
are lower alkyl optionally substituted with one or more fluoro; and
[0794] R.sup.328 is fluoro, --OH, or lower alkoxy optionally
substituted with one or more fluoro.
[0795] In some embodiments of compounds of Formula Iac, R.sup.321
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.321 is
chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.321 is chloro
or methyl.
[0796] In some embodiments of compounds of Formula Iac, further to
any of the above embodiments of Formula Iac, R.sup.322 and
R.sup.323 are hydrogen and R.sup.324 is selected from the group
consisting of fluoro, chloro, --O--R.sup.325, --S--R.sup.326,
--S(O.sub.2)--R.sup.327, and lower alkyl optionally substituted
with one or more R.sup.328. In some embodiments of compounds of
Formula Iac, further to any of the above embodiments of Formula
Iac, R.sup.322 and R.sup.323 are hydrogen and R.sup.324 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iac, further to any of the above embodiments
of Formula Iac, R.sup.322 and R.sup.323 are hydrogen and R.sup.324
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0797] In some embodiments of compounds of Formula Iac, further to
any of the above embodiments of Formula Iac, R.sup.322 and
R.sup.324 are hydrogen and R.sup.323 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iac, further to any of the above
embodiments of Formula Iac, R.sup.322 and R.sup.324 are hydrogen
and R.sup.323 is fluoro, chloro, lower alkyl or lower alkoxy.
[0798] In some embodiments of compounds of Formula Iac, further to
any of the above embodiments of Formula Iac, R.sup.323 and
R.sup.324 are hydrogen and R.sup.322 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iac, further to any of the above
embodiments of Formula Iac, R.sup.323 and R.sup.324 are hydrogen
and R.sup.322 is fluoro, chloro, lower alkyl or lower alkoxy.
[0799] In some embodiments of compounds of Formula Iac, further to
any of the above embodiments of Formula Iac, R.sup.322 is hydrogen,
R.sup.323 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.324 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iac, further to any of the
above embodiments of Formula Iac, R.sup.322 is hydrogen, R.sup.323
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.324 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iac, further to any of the above embodiments
of Formula Iac, R.sup.322 is hydrogen, R.sup.323 is fluoro, chloro,
or lower alkoxy and R.sup.324 is fluoro, chloro, or lower
alkoxy.
[0800] In a fifty-fourth aspect, compounds of Formula I having the
structure according to the following Formula Iad are provided:
##STR00055##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0801] wherein: [0802] R.sup.329 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0803] R.sup.330 and R.sup.331 are hydrogen and R.sup.332
is selected from the group consisting of fluoro, chloro,
--O--R.sup.333, --S--R.sup.334, --S(O.sub.2)--R.sup.335, and lower
alkyl optionally substituted with one or more R.sup.336; or [0804]
R.sup.330 and R.sup.332 are hydrogen and R.sup.331 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro; or
[0805] R.sup.331 and R.sup.332 are hydrogen and R.sup.330 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; or [0806] R.sup.330 is hydrogen, R.sup.331 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro and
R.sup.332 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro; [0807] R.sup.333, R.sup.334 and R.sup.335
are lower alkyl optionally substituted with one or more fluoro; and
[0808] R.sup.336 is fluoro, --OH, or lower alkoxy optionally
substituted with one or more fluoro.
[0809] In some embodiments of compounds of Formula Iad, R.sup.329
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.329 is
chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.329 is chloro
or methyl.
[0810] In some embodiments of compounds of Formula Iad, further to
any of the above embodiments of Formula Iad, R.sup.330 and
R.sup.331 are hydrogen and R.sup.332 is selected from the group
consisting of fluoro, chloro, --O--R.sup.333, --S--R.sup.334,
--S(O.sub.2)--R.sup.335, and lower alkyl optionally substituted
with one or more R.sup.336. In some embodiments of compounds of
Formula Iad, further to any of the above embodiments of Formula
Iad, R.sup.330 and R.sup.331 are hydrogen and R.sup.332 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iad, further to any of the above embodiments
of Formula Iad, R.sup.330 and R.sup.331 are hydrogen and R.sup.332
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0811] In some embodiments of compounds of Formula Iad, further to
any of the above embodiments of Formula Iad, R.sup.330 and
R.sup.332 are hydrogen and R.sup.331 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iad, further to any of the above
embodiments of Formula Iad, R.sup.330 and R.sup.332 are hydrogen
and R.sup.331 is fluoro, chloro, lower alkyl or lower alkoxy.
[0812] In some embodiments of compounds of Formula Iad, further to
any of the above embodiments of Formula Iad, R.sup.331 and
R.sup.332 are hydrogen and R.sup.330 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iad, further to any of the above
embodiments of Formula Iad, R.sup.331 and R.sup.332 are hydrogen
and R.sup.330 is fluoro, chloro, lower alkyl or lower alkoxy.
[0813] In some embodiments of compounds of Formula Iad, further to
any of the above embodiments of Formula Iad, R.sup.330 is hydrogen,
R.sup.331 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.332 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iad, further to any of the
above embodiments of Formula Iad, R.sup.330 is hydrogen, R.sup.331
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.332 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iad, further to any of the above embodiments
of Formula Iad, R.sup.330 is hydrogen, R.sup.331 is fluoro, chloro,
or lower alkoxy and R.sup.332 is fluoro, chloro, or lower
alkoxy.
[0814] In a fifty-fifth aspect, compounds of Formula I having the
structure according to the following Formula Iae are provided:
##STR00056##
or a salt, a prodrug, a solvate, a tautomer or a stereoisomer
thereof, [0815] wherein: [0816] R.sup.337 is hydrogen, fluoro,
chloro, or lower alkyl optionally substituted with one or more
fluoro; [0817] R.sup.338 and R.sup.339 are hydrogen and R.sup.340
is selected from the group consisting of fluoro, chloro,
--O--R.sup.341, --S--R.sup.342, --S(O.sub.2)--R.sup.343, and lower
alkyl optionally substituted with one or more R.sup.344; or [0818]
R.sup.338 and R.sup.340 are hydrogen and R.sup.339 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro; or
[0819] R.sup.339 and R.sup.340 are hydrogen and R.sup.338 is
fluoro, chloro, lower alkyl optionally substituted with one or more
fluoro, or lower alkoxy optionally substituted with one or more
fluoro; or [0820] R.sup.338 is hydrogen, R.sup.339 is fluoro,
chloro, lower alkyl optionally substituted with one or more fluoro,
or lower alkoxy optionally substituted with one or more fluoro and
R.sup.340 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro; [0821] R.sup.341, R.sup.342 and R.sup.343
are lower alkyl optionally substituted with one or more fluoro; and
[0822] R.sup.344 is fluoro, --OH, or lower alkoxy optionally
substituted with one or more fluoro.
[0823] In some embodiments of compounds of Formula Iae, R.sup.337
is hydrogen, chloro or lower alkyl. In one embodiment, R.sup.337 is
chloro or C.sub.1-3 alkyl. In one embodiment, R.sup.337 is chloro
or methyl.
[0824] In some embodiments of compounds of Formula Iae, further to
any of the above embodiments of Formula Iae, R.sup.338 and
R.sup.339 are hydrogen and R.sup.340 is selected from the group
consisting of fluoro, chloro, --O--R.sup.341, --S--R.sup.342,
--S(O.sub.2)--R.sup.343, and lower alkyl optionally substituted
with one or more R.sup.344. In some embodiments of compounds of
Formula Iae, further to any of the above embodiments of Formula
Iae, R.sup.338 and R.sup.339 are hydrogen and R.sup.340 is selected
from the group consisting of fluoro, chloro, lower alkoxy, lower
alkylthio, lower alkylsulfonyl, and lower alkyl optionally
substituted with one or more fluoro or --OH. In some embodiments of
compounds of Formula Iae, further to any of the above embodiments
of Formula Iae, R.sup.338 and R.sup.339 are hydrogen and R.sup.340
is selected from the group consisting of fluoro, chloro, lower
alkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl.
[0825] In some embodiments of compounds of Formula Iae, further to
any of the above embodiments of Formula Iae, R.sup.338 and
R.sup.340 are hydrogen and R.sup.339 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iae, further to any of the above
embodiments of Formula Iae, R.sup.338 and R.sup.340 are hydrogen
and R.sup.339 is fluoro, chloro, lower alkyl or lower alkoxy.
[0826] In some embodiments of compounds of Formula Iae, further to
any of the above embodiments of Formula Iae, R.sup.339 and
R.sup.340 are hydrogen and R.sup.338 is fluoro, chloro, lower alkyl
optionally substituted with one or more fluoro, or lower alkoxy
optionally substituted with one or more fluoro. In some embodiments
of compounds of Formula Iae, further to any of the above
embodiments of Formula Iae, R.sup.339 and R.sup.340 are hydrogen
and R.sup.338 is fluoro, chloro, lower alkyl or lower alkoxy.
[0827] In some embodiments of compounds of Formula Iae, further to
any of the above embodiments of Formula Iae, R.sup.338 is hydrogen,
R.sup.339 is fluoro, chloro, lower alkyl optionally substituted
with one or more fluoro, or lower alkoxy optionally substituted
with one or more fluoro and R.sup.340 is fluoro, chloro, lower
alkyl optionally substituted with one or more fluoro, or lower
alkoxy optionally substituted with one or more fluoro. In some
embodiments of compounds of Formula Iae, further to any of the
above embodiments of Formula Iae, R.sup.338 is hydrogen, R.sup.339
is fluoro, chloro, lower alkyl or lower alkoxy and R.sup.340 is
fluoro, chloro, lower alkyl or lower alkoxy. In some embodiments of
compounds of Formula Iae, further to any of the above embodiments
of Formula Iae, R.sup.338 is hydrogen, R.sup.339 is fluoro, chloro,
or lower alkoxy and R.sup.340 is fluoro, chloro, or lower
alkoxy.
[0828] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of those set forth in Table
1.
TABLE-US-00001 TABLE 1
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohex-
yl-amine (P-3001),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopen-
tyl-amine (P-3003),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-dif-
luoro-cyclohexyl)-amine (P-3004),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopro-
pyl-amine (P-3005),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohep-
tyl-amine (P-3006),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclobut-
yl-amine (P-3007),
Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyri-
din-2-yl]-amine (P-3008),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methy-
l-cyclohexyl)-amine (P-3009),
(4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimi-
din-2-yl]-amine (P-3010),
(4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimi-
din-2-yl]-amine (P-3011),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluor-
o-phenyl)-amine (P-3012),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(-
4,4-difluoro-cyclohexyl)- amine (P-3013),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluor-
o-phenyl)-amine (P-3014),
(2-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimi-
din-2-yl]-amine (P-3015),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-metho-
xy-phenyl)-amine (P-3016),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluor-
o-phenyl)-amine (P-3017),
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifl-
uoromethyl-pyridin-3-yl)- amine (P-3018),
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(-
6-methoxy-pyridin-3-yl)- amine (P-3019),
(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
-pyrimidin-2-yl]-amine (P-3020),
(4-Methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3021),
(4-Fluoro-3-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmeth-
yl)-pyrimidin-2-yl]-amine (P-3022),
(3-Fluoro-4-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmeth-
yl)-pyrimidin-2-yl]-amine (P-3023),
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-propo-
xy-phenyl)-amine (P-3024),
(4-Ethyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimid-
in-2-yl]-amine (P-3025),
(4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimi-
din-2-yl]-amine (P-3026),
(6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)--
pyrimidin-2-yl]-amine (P-3027),
[5-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridi-
n-3-ylmethyl)-pyrimidin-2- yl]-amine (P-3028),
(5-tert-Butyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylm-
ethyl)-pyrimidin-2-yl]-amine (P-3029),
(4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-py-
rimidin-2-yl]-amine (P-3030),
1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmeth-
yl)-pyrimidin-2-ylamino]- phenyl}-propan-2-ol (P-3031),
(5-Cyclopropyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
methyl)-pyrimidin-2-yl]- amine (P-3032),
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methy-
lsulfanyl-phenyl)-amine (P-3033),
(4-Methanesulfonyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyrimidin-2-yl]-amine (P-3034),
(1-Ethyl-1H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3035),
(1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3036),
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-trifl-
uoromethyl-2H-pyrazol-3-yl)- amine (P-3037),
(5-Isopropoxy-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylm-
ethyl)-pyrimidin-2-yl]- amine (P-3038),
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyridin-2-yl]-amine (P-3039),
[2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)- methanone (P-3040),
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(-
6-methyl-pyridin-3-yl)-amine (P-3041),
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(-
6-methyl-pyridin-3-yl)-amine (P-3042),
[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)- methanone (P-3043),
(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-y-
lamino)-pyridin-3-yl]- methanone (P-3044),
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)- methanone (P-3045),
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
methyl)-pyridin-2-yl]-amine (P-3048),
[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo-
[2,3-b]pyridin-3-yl)- methanone (P-3049),
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridi-
n-3-ylmethyl)-pyridin-2-yl]- amine (P-3050),
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-p-
yrrolo[2,3-b]pyridin-3-yl)- methanone (P-3051),
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2,-
3-b]pyridin-3-yl)-methanone (P-3052),
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyridin-2-yl]-amine (P-3053),
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl-
]-(6-methoxy-pyridin-3- yl)-amine (P-4001),
[6-Fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-
-(6-methoxy-pyridin-3-yl)- amine (P-4002),
(6-Chloro-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]- amine (P-4003),
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrim-
idin-5-ylmethyl)-pyridin-2- yl]-amine (P-4004),
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]- amine (P-4005),
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]- amine (P-4006),
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]- amine (P-4007),
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl]- pyridin-2-yl}-amine (P-4008),
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5--
ylmethyl)-pyridin-2-yl]- amine (P-4009),
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl-
]-(6-methyl-pyridin-3-yl)- amine (P-4010),
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidi-
n-5-ylmethyl)-pyridin-2- yl]-amine (P-4011),
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-
-(1-ethyl-1H-pyrazol-4-yl)- amine (P-4012),
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-pyridin-2-yl]- amine (P-4013),
(1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-
-d]pyrimidin-5-ylmethyl]- pyridin-2-yl}-amine (P-4014),
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-p-
yridin-2-yl}-(6-methyl- pyridin-3-yl)-amine (P-4015),
(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]-
pyrimidin-5-ylmethyl]- pyridin-2-yl}-amine (P-4016),
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-
-(6-methyl-pyridin-3-yl)- amine (P-4017),
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-
-(6-methoxy-pyridin-3-yl)- amine (P-4018),
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-p-
yridin-2-yl}-(6-methoxy- pyridin-3-yl)-amine (P-4019),
(6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-
-6-fluoro-pyridin-2-yl]- amine (P-4020),
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-
-pyridin-3-yl-amine (P-4021),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyr-
idin-3-ylamino)-pyridin-3- yl]-methanone (P-4022),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(6-methoxy-pyridin-3- yl)-amine (P-4023),
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)- methanone (P-4024),
(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin--
3-ylamino)-pyridin-3-yl]- methanone (P-4025),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(6-ethoxy-pyridin-3- yl)-amine (P-4026),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-yla-
mino)-2-fluoro-pyridin-3- yl]-methanone (P-4027),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(6-ethyl-pyridin-3-yl)- amine (P-4028),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylam-
ino)-2-fluoro-pyridin-3-yl]- methanone (P-4029),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(6-methyl-pyridin-3- yl)-amine (P-4030),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyri-
din-3-ylamino)-pyridin-3- yl]-methanone (P-4031),
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrol-
o[2,3-d]pyrimidin-5-yl)- methanone (P-4032),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(1-ethyl-1H-pyrazol- 4-yl)-amine (P-4036),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(1-ethyl-1H-pyrazol-4-y-
lamino)-2-fluoro-pyridin-3- yl]-methanone (P-4037),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(5-methyl-pyridin-3- yl)-amine (P-4038),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(5-methyl-pyri-
din-3-ylamino)-pyridin-3- yl]-methanone (P-4039),
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-
-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-methanone (P-4040),
(6-Cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-6-fluoro- pyridin-2-yl]-amine (P-4041),
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin--
2-yl]-(6,7-dihydro-5H- [1]pyrindin-3-yl)-amine (P-4042),
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6,7-dihydro-5H-[1]pyri-
ndin-3-ylamino)-2-fluoro- pyridin-3-yl]-methanone (P-4043),
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimi-
din-5-ylmethyl)-pyridin-2- yl]-amine (P-4044),
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-p-
yrrolo[2,3-d]pyrimidin-5- yl)-methanone (P-4045),
(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-chloro-6-[(4,4-difluorocycloh-
exyl)amino]-3- pyridyl]methanone (P-4046),
[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(2-methylprop-1--
enylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4047),
(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-[(6-cyclopropyl-3-pyridyl)ami-
no]-2-fluoro-3- pyridyl]methanone (P-4048),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(2-hydroxy-2-m-
ethyl-propyl)amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4049),
[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(ethylamino)-7H--
pyrrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4050),
[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(ethylamino)-7H--
pyrrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4051),
[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(2,2,2-trifluoro-
ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4052),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocy-
clohexyl)amino]-5- fluoro-3-pyridyl]methanone (P-4053),
[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(methylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4054),
[4-(tert-butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-meth-
oxy-3-pyridyl)amino]-3- pyridyl]methanone (P-4055),
[4-[(4,4-difluorocyclohexyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-flu-
oro-6-[(6-methoxy-3- pyridyl)amino]-3-pyridyl]methanone (P-4056),
[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoro-
ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4057),
[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(methylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4058),
[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(cyclopropylamin-
o)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4059),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4060),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoro-
ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4061),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocy-
clohexyl)amino]-2- fluoro-3-pyridyl]methanone (P-4062),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4063),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(2-hydroxy-2-methyl--
propyl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4064),
(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-[(6-ethyl-3-pyridyl)amino]-2--
fluoro-3- pyridyl]methanone (P-4065),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4066),
[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[-
(6-methoxy-3- pyridyl)amino]-3-pyridyl]methanone (P-4067),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(propylamino)-7H-py-
rrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4068),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(1-piperidyl)-7H-py-
rrolo[2,3-d]pyrimidin-5- yl]methanone (P-4069),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-(4-morpholino-7H-pyrro-
lo[2,3-d]pyrimidin-5- yl)methanone (P-4070),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-[[6-(trifluoromethy-
l)-3-
pyridyl]methylamino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4071),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-[[(1S)-1-(4-fluorop-
henyl)ethyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4072),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(tetrahydrofuran-2--
ylmethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4073),
[4-[(1-ethyl-4-piperidyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-
-6-[(6-methoxy-3- pyridyl)amino]-3-pyridyl]methanone (P-4074),
[4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-met-
hoxy-3-pyridyl)amino]- 3-pyridyl]methanone (P-4075),
[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-meth-
oxy-3-pyridyl)amino]- 3-pyridyl]methanone (P-4076),
[4-(1-ethylpropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-m-
ethoxy-3- pyridyl)amino]-3-pyridyl]methanone (P-4077),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(sec-butylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4078),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(3-methoxypropylami-
no)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4079),
[4-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-
-pyridyl)amino]-3- pyridyl]methanone (P-4080),
[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-
-pyridyl)amino]-3- pyridyl]methanone (P-4081),
[4-(cyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-meth-
oxy-3-pyridyl)amino]- 3-pyridyl]methanone (P-4082),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-py-
rrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4083),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroeth-
ylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4084),
[2-methoxy-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-p-
yrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4085),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(6-methyl-3-pyridyl)-
amino]-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4086),
[6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamin-
o)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4087),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocy-
clohexyl)amino]-3- pyridyl]methanone (P-4088),
[6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[-
2,3-d]pyrimidin-5- yl]methanone (P-4089),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluor-
oethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4090),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[[6-(tr-
ifluoromethyl)-3- pyridyl]amino]-3-pyridyl]methanone (P-4091),
[2-fluoro-6-[[6-(trifluoromethyl)-3-pyridyl]amino]-3-pyridyl]-[4-(methylam-
ino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4092),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-cyclopropyl--
3-pyridyl)amino]-2- fluoro-3-pyridyl]methanone (P-4093),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7-
H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4094),
[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyrid-
yl)amino]-2-fluoro-3- pyridyl]methanone (P-4095),
[4-[(4,4-difluorocyclohexyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-
-ethyl-3-pyridyl)amino]- 2-fluoro-3-pyridyl]methanone (P-4096),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-(4-fluorophe-
nyl)ethyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4097),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(3-methoxypropylamino-
)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4098),
[4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyri-
dyl)amino]-2-fluoro-3- pyridyl]methanone (P-4099),
[4-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)am-
ino]-2-fluoro-3- pyridyl]methanone (P-4100),
[6-(cyclohexylamino)-2-fluoro-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,-
3-d]pyrimidin-5- yl]methanone (P-4101),
[6-(cyclohexylamino)-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d-
]pyrimidin-5- yl]methanone (P-4102),
[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroeth-
ylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4103),
[4-(cyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(5-meth-
oxy-3-pyridyl)amino]- 3-pyridyl]methanone (P-4104),
[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(propylamino)-7H-py-
rrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4105),
[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4106),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(5-met-
hoxy-3-pyridyl)amino]- 3-pyridyl]methanone (P-4107),
[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-py-
rrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4108),
[2-chloro-6-(cyclohexylamino)-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,-
3-d]pyrimidin-5- yl]methanone (P-4109),
[2-chloro-6-(cyclohexylamino)-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d-
]pyrimidin-5- yl]methanone (P-4110),
[4-(cyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-meth-
yl-3-pyridyl)amino]-3- pyridyl]methanone (P-4111),
[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethy-
lamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4112),
[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[-
(6-methyl-3- pyridyl)amino]-3-pyridyl]methanone (P-4113),
[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(propylamino)-7H-pyr-
rolo[2,3-d]pyrimidin-5- yl]methanone (P-4114),
[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyr-
rolo[2,3-d]pyrimidin-5- yl]methanone (P-4115),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-yl-
amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4116),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(isopropylamino)-7H-p-
yrrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4117),
[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl--
3-pyridyl)amino]-2- fluoro-3-pyridyl]methanone (P-4118),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(2-methoxyethylamino)-
-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4119),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoroethyl-
amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4120),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(isobutylamino)-7H-py-
rrolo[2,3-d]pyrimidin-5- yl]methanone (P-4121),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(propylamino)-7H-pyrr-
olo[2,3-d]pyrimidin-5- yl]methanone (P-4122),
[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)am-
ino]-2-fluoro-3- pyridyl]methanone (P-4123),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrr-
olo[2,3-d]pyrimidin-5- yl]methanone (P-4124),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyri-
dyl)amino]-2-fluoro-3-
pyridyl]methanone (P-4125),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-met-
hoxy-3-pyridyl)amino]- 3-pyridyl]methanone (P-4126),
N-cyclopropyl-5-[[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]met-
hyl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine (P-4127),
5-[[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methyl]-N-(2,2,2--
trifluoroethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (P-4128),
N-cyclopropyl-5-[[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]met-
hyl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine (P-4129),
5-[[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methyl]-N-(2,2,2-
-trifluoroethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (P-4130),
5-[[6-(cyclohexylamino)-2-fluoro-3-pyridyl]methyl]-N-cyclopropyl-7H-pyrrol-
o[2,3-d]pyrimidin-4- amine (P-4131),
[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-[[(1R)-1-(4-fluorop-
henyl)ethyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4132),
[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1-(4-fluorophe-
nyl)ethyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4133),
[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyr-
rolo[2,3-d]pyrimidin-5- yl]methanone (P-4134),
[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluorocyc-
lohexyl)amino]-3- pyridyl]methanone (P-4135),
[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H--
pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4136),
[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-flu-
orocyclohexyl)amino]-3- pyridyl]methanone (P-4137),
[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethy-
lamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4138),
[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fl-
uoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4139),
[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fl-
uoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4140),
[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(methoxymethylamino)-
-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4141),
[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(3-methoxypropylamin-
o)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4142),
[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(tetrahydropyran-4-y-
lamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4143),
[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluo-
rocyclohexyl)amino]-3- pyridyl]methanone (P-4144),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4145),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)-7H--
pyrrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4146),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(propylamino)-7H-
-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4147),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(isopropylamino)-
-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4148),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoro-
ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4149),
[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(-
3,3- difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone
(P-4150),
[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(-
3,3- difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone
(P-4151),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(methoxymethylam-
ino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4152),
[6-[(3,3-15difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(tetrahydropyr-
an-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4153),
[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(3,3-difluorocyc-
lobutyl)amino]-2-fluoro- 3-pyridyl]methanone (P-4154),
[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(3-methoxypropyl-
amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4155),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(3-methoxypropyl-
amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4156),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(2-methoxyethyla-
mino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4157),
[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyc-
lohexyl)amino]-2-fluoro- 3-pyridyl]methanone (P-4158),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(tetrahydropyran-
-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4159),
[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(-
4,4- difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone
(P-4160),
[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(-
4,4- difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone
(P-4161),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)-7H--
pyrrolo[2,3-d]pyrimidin- 5-yl]methanone (P-4162),
[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyc-
lohexyl)amino]-5-fluoro- 3-pyridyl]methanone (P-4163),
[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(methoxymethylam-
ino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4164),
[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(3-methoxypropyl-
amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone (P-4165),
[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(tetrahydropyran-
-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4166),
[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(-
4,4- difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone
(P-4167),
[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(-
4,4- difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone
(P-4168),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-methyl-
propyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4169),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(3-hydroxy-1-m-
ethyl-propyl)amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4170),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1-(hydro-
xymethyl)propyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4171),
4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-
-pyrrolo[2,3- d]pyrimidin-4-yl]amino]pyrrolidin-2-one (P-4172),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-hydrox-
y-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4173),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3-hyd-
roxycyclohexyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4174),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hyd-
roxycyclopentyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4175),
1-[3-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-
-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]pyrrolidin-1-yl]ethanone
(P-4176),
(2R)-2-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbony-
l]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]cyclohexanone (P-4177),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothio-
lan-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4178),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hyd-
roxycyclohexyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4179),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-methox-
y-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4180),
4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-
-pyrrolo[2,3- d]pyrimidin-4-yl]amino]piperidin-2-one (P-4181),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2-tr-
ifluoro-1-methyl-
ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4182),
4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-
-pyrrolo[2,3- d]pyrimidin-4-yl]amino]-1-methyl-piperidin-2-one
(P-4183),
[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothia-
n-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4184),
1-cyclopropyl-4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine--
3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one
(P-4185),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-methylp-
ropyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4186),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(3-hydroxy-1-me-
thyl-propyl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4187),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1-(hydrox-
ymethyl)propyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4188),
4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin- 4-yl]amino]pyrrolidin-2-one (P-4189),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-hydroxy-
-1-methyl-ethyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4190),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3-hydr-
oxycyclohexyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4191),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hydr-
oxycyclopentyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4192),
1-[3-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]--
7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]pyrrolidin-1-yl]ethanone
(P-4193),
(2R)-2-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl-
]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]cyclohexanone (P-4194),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothiol-
an-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4195),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hydr-
oxycyclohexyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4196),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-methoxy-
-1-methyl-ethyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone
(P-4197),
4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin- 4-yl]amino]piperidin-2-one (P-4198),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2-tri-
fluoro-1-methyl-
ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4199),
4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin- 4-yl]amino]-1-methyl-piperidin-2-one
(P-4200),
[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothian-
-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4201),
1-cyclopropyl-4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-
-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one
(P-4202); and any salt, prodrug, solvate, tautomer, or stereoisomer
thereof. In some embodiments, the salt is a pharmaceutically
acceptable salt.
[0829] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0830]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
xyl-amine (P-3001), [0831]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclope-
ntyl-amine (P-3003), [0832]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-di-
fluoro-cyclohexyl)-amine (P-3004), [0833]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopr-
opyl-amine (P-3005), [0834]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
ptyl-amine (P-3006), [0835]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclobu-
tyl-amine (P-3007), [0836]
Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyr-
idin-2-yl]-amine (P-3008), [0837]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-meth-
yl-cyclohexyl)-amine (P-3009), [0838]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(4,4-difluoro-cyclohexyl)-amine (P-3013), and any salt, prodrug,
solvate, tautomer, or stereoisomer thereof. In some embodiments,
the salt is a pharmaceutically acceptable salt.
[0839] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0840]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-di-
fluoro-cyclohexyl)-amine (P-3004), [0841]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
ptyl-amine (P-3006), [0842]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(4,4-difluoro-cyclohexyl)-amine (P-3013), and any salt, prodrug,
solvate, tautomer, or stereoisomer thereof. In some embodiments,
the salt is a pharmaceutically acceptable salt.
[0843] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0844]
(1-Ethyl-1H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyrimidin-2-yl]-amine (P-3035), [0845]
(1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyrimidin-2-yl]-amine (P-3036), [0846]
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimid-
in-5-ylmethyl)-pyridin-2-yl]-amine (P-4011), [0847]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4012), [0848]
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidi-
n-5-ylmethyl)-pyridin-2-yl]-amine (P-4013), [0849]
(1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,-
3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4014), [0850]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4036), [0851]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(1-ethyl-1H-pyrazol-4--
ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4037), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[0852] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0853]
(4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3010), [0854]
(4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3011), [0855]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluo-
ro-phenyl)-amine (P-3012), [0856]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluo-
ro-phenyl)-amine (P-3014), [0857]
(2-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3015), [0858]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-meth-
oxy-phenyl)-amine (P-3016), [0859]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluo-
ro-phenyl)-amine (P-3017), [0860]
(4-Methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyri-
midin-2-yl]-amine (P-3021), [0861]
(4-Fluoro-3-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-yl]-amine (P-3022), [0862]
(3-Fluoro-4-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-yl]-amine (P-3023), [0863]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-prop-
oxy-phenyl)-amine (P-3024), [0864]
(4-Ethyl-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimid-
in-2-yl]-amine (P-3025), [0865]
(4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3026), [0866]
(4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p-
yrimidin-2-yl]-amine (P-3030), [0867]
1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol (P-3031), [0868]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-meth-
ylsulfanyl-phenyl)-amine (P-3033), [0869]
(4-Methanesulfonyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmeth-
yl)-pyrimidin-2-yl]-amine (P-3034), and any salt, prodrug, solvate,
tautomer, or stereoisomer thereof. In some embodiments, the salt is
a pharmaceutically acceptable salt.
[0870] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0871]
(4-Fluoro-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimi-
din-2-yl]-amine (P-3010), [0872]
(4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3011), [0873]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluo-
ro-phenyl)-amine (P-3012), [0874]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluo-
ro-phenyl)-amine (P-3014), [0875]
(4-Methoxy-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3021), [0876]
(4-Ethyl-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimid-
in-2-yl]-amine (P-3025), [0877]
(4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3026), [0878]
(4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p-
yrimidin-2-yl]-amine (P-3030), [0879]
1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol (P-3031), [0880]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-meth-
ylsulfanyl-phenyl)-amine (P-3033), and any salt, prodrug, solvate,
tautomer, or stereoisomer thereof. In some embodiments, the salt is
a pharmaceutically acceptable salt.
[0881] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0882]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trif-
luoromethyl-pyridin-3-yl)-amine (P-3018), [0883]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine (P-3019), [0884]
(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3020), [0885]
(6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
-pyrimidin-2-yl]-amine (P-3027), [0886]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
ylmethyl)-pyridin-2-yl]-amine (P-3039), [0887]
[2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrr-
olo[2,3-b]pyridin-3-yl)-methanone (P-3040), [0888]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3045), [0889]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-y-
l]-(6-methoxy-pyridin-3-yl)-amine (P-4001), [0890]
[6-Fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine (P-4002), [0891]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-pyridin-2-yl]-amine (P-4005), [0892]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]-amine (P-4006), [0893]
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3--
d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4008), [0894]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine (P-4018), [0895]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine (P-4019), [0896]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-py-
ridin-3-ylamino)-pyridin-3-yl]-methanone (P-4022), [0897]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4023), [0898]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7H-pyrr-
olo[2,3-d]pyrimidin-5-yl)-methanone (P-4024), [0899]
(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-
-3-ylamino)-pyridin-3-yl]-methanone (P-4025), [0900]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethoxy-pyridin-3-yl)-amine (P-4026), [0901]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-yl-
amino)-2-fluoro-pyridin-3-yl]-methanone (P-4027), [0902]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)-methanone (P-4032), and any salt, prodrug,
solvate, tautomer, or stereoisomer thereof. In some embodiments,
the salt is a pharmaceutically acceptable salt.
[0903] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0904]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trif-
luoromethyl-pyridin-3-yl)-amine (P-3018), [0905]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine (P-3019), [0906]
(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3020), [0907]
(6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
-pyrimidin-2-yl]-amine (P-3027), [0908]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
ylmethyl)-pyridin-2-yl]-amine (P-3039), [0909]
[2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrr-
olo[2,3-b]pyridin-3-yl)-methanone (P-3040), [0910]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3045), [0911]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-y-
l]-(6-methoxy-pyridin-3-yl)-amine (P-4001), [0912]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-pyridin-2-yl]-amine (P-4005), [0913]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]-amine (P-4006), [0914]
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3--
d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4008), [0915]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine (P-4018), [0916]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine (P-4019), [0917]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-py-
ridin-3-ylamino)-pyridin-3-yl]-methanone (P-4022), [0918]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4023), [0919]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethoxy-pyridin-3-yl)-amine (P-4026), [0920]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-yl-
amino)-2-fluoro-pyridin-3-yl]-methanone (P-4027), [0921]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)-methanone (P-4032), and any salt, prodrug,
solvate, tautomer, or stereoisomer thereof. In some embodiments,
the salt is a pharmaceutically acceptable salt.
[0922] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0923]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3041), [0924]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3042), [0925]
[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3043), [0926]
(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3--
ylamino)-pyridin-3-yl]-methanone (P-3044), [0927]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyridin-2-yl]-amine (P-3048), [0928]
[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)-methanone (P-3049), [0929]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyrid-
in-3-ylmethyl)-pyridin-2-yl]-amine (P-3050), [0930]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H--
pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3051), [0931]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2-
,3-b]pyridin-3-yl)-methanone (P-3052), [0932]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylme-
thyl)-pyridin-2-yl]-amine (P-3053), [0933]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyri-
midin-5-ylmethyl)-pyridin-2-yl]-amine (P-4004), [0934]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]-amine (P-4007), [0935]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]-amine (P-4009), [0936]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-y-
l]-(6-methyl-pyridin-3-yl)-amine (P-4010), [0937]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methyl-pyridin-3-yl)-amine (P-4015), [0938]
(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4016), [0939]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methyl-pyridin-3-yl)-amine (P-4017), [0940]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethyl-pyridin-3-yl)-amine (P-4028), [0941]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-yla-
mino)-2-fluoro-pyridin-3-yl]-methanone (P-4029), [0942]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4030), [0943]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyr-
idin-3-ylamino)-pyridin-3-yl]-methanone (P-4031), [0944]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropy-
l-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4040), [0945]
(6-Cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4041), [0946]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6,7-dihydro-5H-[1]pyrindin-3-yl)-amine (P-4042), [0947]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6,7-dihydro-5H-[1]pyr-
indin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4043), [0948]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrim-
idin-5-ylmethyl)-pyridin-2-yl]-amine (P-4044), [0949]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4045), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[0950] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0951]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3041), [0952]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3042), [0953]
[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3043), [0954]
(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3--
ylamino)-pyridin-3-yl]-methanone (P-3044), [0955]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyridin-2-yl]-amine (P-3048), [0956]
[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)-methanone (P-3049), [0957]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyrid-
in-3-ylmethyl)-pyridin-2-yl]-amine (P-3050), [0958]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H--
pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3051), [0959]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2-
,3-b]pyridin-3-yl)-methanone (P-3052), [0960]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylme-
thyl)-pyridin-2-yl]-amine (P-3053), [0961]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyri-
midin-5-ylmethyl)-pyridin-2-yl]-amine (P-4004), [0962]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]-amine (P-4007), [0963]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]-amine (P-4009), [0964]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-y-
l]-(6-methyl-pyridin-3-yl)-amine (P-4010), [0965]
(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4016), [0966]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methyl-pyridin-3-yl)-amine (P-4017), [0967]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethyl-pyridin-3-yl)-amine (P-4028), [0968]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-yla-
mino)-2-fluoro-pyridin-3-yl]-methanone (P-4029), [0969]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4030), [0970]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyr-
idin-3-ylamino)-pyridin-3-yl]-methanone (P-4031), [0971]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropy-
l-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4040), [0972]
(6-Cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4041), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[0973] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0974]
(6-Chloro-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-pyridin-2-yl]-amine (P-4003), [0975]
(6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl-
)-6-fluoro-pyridin-2-yl]-amine (P-4020), [0976]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-pyridin-3-yl-amine (P-4021), [0977]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(5-methyl-pyridin-3-yl)-amine (P-4038), [0978]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(5-methyl-pyr-
idin-3-ylamino)-pyridin-3-yl]-methanone (P-4039), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[0979] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0980]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine (P-3019), [0981]
(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3020), [0982]
(4-Methoxy-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3021), [0983]
[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3043), [0984]
(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3--
ylamino)-pyridin-3-yl]-methanone (P-3044), [0985]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3045), [0986]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyridin-2-yl]-amine (P-3048), [0987]
[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)-methanone (P-3049), [0988]
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3--
d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4008), [0989]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]-amine (P-4009), [0990]
(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4016), [0991]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine (P-4018), [0992]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine (P-4019), [0993]
(6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl-
)-6-fluoro-pyridin-2-yl]-amine (P-4020), [0994]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4023), [0995]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethoxy-pyridin-3-yl)-amine (P-4026), [0996]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethyl-pyridin-3-yl)-amine (P-4028), [0997]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-yla-
mino)-2-fluoro-pyridin-3-yl]-methanone (P-4029), [0998]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4030), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[0999] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [1000]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine (P-3019), [1001]
(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3020), [1002]
(4-Methoxy-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3021), [1003]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyridin-2-yl]-amine (P-3048), [1004]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]-amine (P-4009), [1005]
(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4016), [1006]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine (P-4018), [1007]
(6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl-
)-6-fluoro-pyridin-2-yl]-amine (P-4020), [1008]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethoxy-pyridin-3-yl)-amine (P-4026), [1009]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethyl-pyridin-3-yl)-amine (P-4028), [1010]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-yla-
mino)-2-fluoro-pyridin-3-yl]-methanone (P-4029), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[1011] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [1012]
[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3043), [1013]
(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3--
ylamino)-pyridin-3-yl]-methanone (P-3044), [1014]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3045), [1015]
[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)-methanone (P-3049), [1016]
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3--
d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4008), [1017]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine (P-4019), [1018]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4023), [1019]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4030), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[1020] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [1021]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-di-
fluoro-cyclohexyl)-amine (P-3004), [1022]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(4,4-difluoro-cyclohexyl)-amine (P-3013), [1023]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3041), [1024]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3042), [1025]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-y-
l]-(6-methyl-pyridin-3-yl)-amine (P-4010), [1026]
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimid-
in-5-ylmethyl)-pyridin-2-yl]-amine (P-4011), [1027]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4012), [1028]
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidi-
n-5-ylmethyl)-pyridin-2-yl]-amine (P-4013), [1029]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4036), and any salt,
prodrug, solvate, tautomer, or stereoisomer thereof. In some
embodiments, the salt is a pharmaceutically acceptable salt.
[1030] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [1031]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
ptyl-amine (P-3006), [1032]
(4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3010), [1033]
(4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3011), [1034]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluo-
ro-phenyl)-amine (P-3012), [1035]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluo-
ro-phenyl)-amine (P-3014), [1036]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trif-
luoromethyl-pyridin-3-yl)-amine (P-3018), [1037]
(4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3026), [1038]
(6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
-pyrimidin-2-yl]-amine (P-3027), [1039]
(1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyrimidin-2-yl]-amine (P-3036), [1040]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
ylmethyl)-pyridin-2-yl]-amine (P-3039), [1041]
(1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,-
3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4014), [1042]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methyl-pyridin-3-yl)-amine (P-4017), and any salt, prodrug,
solvate, tautomer, or stereoisomer thereof. In some embodiments,
the salt is a pharmaceutically acceptable salt. In some
embodiments, the invention provides a compound as set forth in
Table 7 and any salt, solvate, prodrug, stereoisomer, or tautomer
thereof. In some embodiments, the salt is a pharmaceutically
acceptable salt.
[1043] In reference to compounds herein, unless clearly indicated
to the contrary, specification of a compound or group of compounds
includes salts of such compound(s) (including pharmaceutically
acceptable salts), formulations of such compound(s) (including
pharmaceutically acceptable formulations), conjugates thereof,
derivatives thereof, forms thereof, prodrugs thereof, and all
stereoisomers thereof. In reference to compositions, kits, methods
of use, etc. of compounds of Formula I described herein, it is
understood (unless indicated otherwise) that a compound of Formula
I includes all sub-embodiments thereof (Including any sub-generic
Formulae Ia through Iae).
[1044] In a fifty-sixth aspect, a compound of Formula I is an
inhibitor of Fms kinase and has an IC.sub.50 of less than 500 nm,
less than 100 nM, less than 50 nM, less than 20 nM, less than 10
nM, less than 5 nM, or less than 1 nM as determined in a generally
accepted Fms kinase activity assay. In some embodiments, the
compound is selective relative to other protein kinases, such that
the ratio of IC.sub.50 for another kinase assessed comparably,
divided by the IC.sub.50 for Fms kinase is >20, also >30,
also >40, also >50, also >60, also >70, also >80,
also >90, also >100, wherein the other protein kinase
includes, but is not limited to CSK, Insulin receptor kinase, AMPK,
PDGFR or VEGFR. In some embodiments, the compound is selective
relative to Kit protein kinase, such that the ratio of IC.sub.50
for Kit kinase assessed comparably, divided by the IC.sub.50 for
Fms kinase is >20, also >30, also >40, also >50, also
>60, also >70, also >80, also >90, also >100.
[1045] In fifty-seventh aspect, a compound of Formula I is a Fms
selective inhibitor, i.e. will selectively inhibit Fms kinase
relative to Kit kinase. In some embodiments the compound will have
an IC.sub.50 of less than 500 nm, less than 100 nM, less than 50
nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than
1 nM as determined in a generally accepted Fms kinase activity
assay and when determined in a comparable generally accepted Kit
kinase activity assay will have a ratio of IC.sub.50 for Kit kinase
divided by the IC.sub.50 for Fms kinase of >20, also >30,
also >40, also >50, also >60, also >70, also >80,
also >90, also >100. In some embodiments, the compound is
also selective relative to protein kinases other than Kit, such
that the ratio of IC.sub.50 for another kinase assessed comparably,
divided by the IC.sub.50 for Fms kinase is >20, also >30,
also >40, also >50, also >60, also >70, also >80,
also >90, also >100, wherein the other protein kinase
includes, but is not limited to Flt-3, CSK, Insulin receptor
kinase, AMPK, PDGFR or VEGFR. In one embodiment, the Fms selective
inhibitor does not effectively cross the blood brain barrier. In
one embodiment, the Fms selective inhibitor does effectively cross
the blood brain barrier.
[1046] In a fifty-eighth aspect, a compound of Formula I is a dual
Fms/Kit inhibitor, i.e. will be approximately equipotent with
respect to inhibition of Fms kinase and Kit kinase. In some
embodiments the compound will have an IC.sub.50 of less than 500
nm, less than 100 nM, less than 50 nM, less than 20 nM, less than
10 nM, less than 5 nM, or less than 1 nM as determined in a
generally accepted Fms kinase activity assay and will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
as determined in a comparable generally accepted Kit kinase
activity assay, wherein the ratio of IC.sub.50 for Kit kinase
divided by the IC.sub.50 for Fms kinase is in the range of 20 to
0.05, also 10 to 0.1, also 5 to 0.2. In some embodiments, the
compound is selective relative to other protein kinases, such that
the ratio of IC.sub.50 for another kinase assessed comparably,
divided by the IC.sub.50 for Fms kinase (and/or Kit kinase) is
>20, also >30, also >40, also >50, also >60, also
>70, also >80, also >90, also >100, wherein the other
protein kinase includes, but is not limited to CSK, Insulin
receptor kinase, AMPK, PDGFR or VEGFR.
[1047] In a fifty-ninth aspect, a compound of Formula I is a dual
Fms/Flt-3 inhibitor, i.e. will be approximately equipotent with
respect to inhibition of Fms kinase and Flt-3 kinase. In some
embodiments the compound will have an IC.sub.50 of less than 500
nm, less than 100 nM, less than 50 nM, less than 20 nM, less than
10 nM, less than 5 nM, or less than 1 nM as determined in a
generally accepted Fms kinase activity assay and will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
as determined in a comparable generally accepted Flt-3 kinase
activity assay, wherein the ratio of IC.sub.50 for Flt-3 kinase
divided by the IC.sub.50 for Fms kinase is in the range of 20 to
0.05, also 10 to 0.1, also 5 to 0.2. In some embodiments, the
compound is selective relative to other protein kinases, such that
the ratio of IC.sub.50 for another kinase assessed comparably,
divided by the IC.sub.50 for Fms kinase (and/or Flt3 kinase) is
>20, also >30, also >40, also >50, also >60, also
>70, also >80, also >90, also >100, wherein the other
protein kinase includes, but is not limited to CSK, Insulin
receptor kinase, AMPK, PDGFR or VEGFR. In some embodiments, the
dual Fms/Flt-3 inhibitor is selective with respect to Kit. In some
embodiments, the dual Fms/Flt-3 inhibitor also inhibits Kit.
[1048] In a sixtieth aspect, a compound of Formula I is a dual
Fms/Trk inhibitor, i.e. will be approximately equipotent with
respect to inhibition of Fms kinase and Trk kinase. In some
embodiments the compound will have an IC.sub.50 of less than 500
nm, less than 100 nM, less than 50 nM, less than 20 nM, less than
10 nM, less than 5 nM, or less than 1 nM as determined in a
generally accepted Fms kinase activity assay and will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
as determined in a comparable generally accepted Trk kinase
activity assay (including any one or more of TrkA, TrkB, and TrkC),
wherein the ratio of IC.sub.50 for Trk kinase (at least one of
TrkA, TrkB, and TrkC) divided by the IC.sub.50 for Fms kinase is in
the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. In some
embodiments, the compound is selective relative to other protein
kinases, such that the ratio of IC.sub.50 for another kinase
assessed comparably, divided by the IC.sub.50 for Fms kinase
(and/or Trk kinase) is >20, also >30, also >40, also
>50, also >60, also >70, also >80, also >90, also
>100, wherein the other protein kinase includes, but is not
limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR. In
some embodiments, the dual Fms/Trk inhibitor is selective with
respect to Kit. In some embodiments, the dual Fms/Trk inhibitor
also inhibits Kit.
[1049] Further to any of the above mentioned aspects and
embodiments, a compound of Formula I will also inhibit the effects
of a mutation of the kinase, including, but not limited to, a
mutation that is related to a disease state, such as a cancer.
[1050] In a sixty-first aspect, compositions are provided that
include a therapeutically effective amount of any one or more
compound(s) of Formula I and at least one pharmaceutically
acceptable carrier, excipient, and/or diluent, including
combinations of any two or more compounds of Formula I. The
composition can further include a plurality of different
pharmacologically active compounds, which can include a plurality
of compounds of Formula I. In certain embodiments, the composition
can include any one or more compound(s) of Formula I along with one
or more compounds that are therapeutically effective for the same
disease indication. In one aspect, the composition includes any one
or more compound(s) of Formula I along with one or more compounds
that are therapeutically effective for the same disease indication,
wherein the compounds have a synergistic effect on the disease
indication. In one embodiment, the composition includes any one or
more compound(s) of Formula I effective in treating a cancer and
one or more other compounds that are effective in treating the same
cancer, further wherein the compounds are synergistically effective
in treating the cancer.
[1051] In a sixty-second aspect, methods are provided for treating
a disease or condition related to any one or more of Fms protein
kinase, Kit protein kinase, Flt3 protein kinase, and Trk protein
kinase in an animal subject in need thereof, wherein the method
involves administering to the subject an effective amount of any
one or more compound(s) of Formula I or a composition comprising
any one or more compound(s) of Formula I. In certain embodiments,
the method involves administering to the subject an effective
amount of a compound of Formula I or a composition comprising a
compound of Formula I in combination with one or more other
therapies for the disease or condition.
[1052] In a sixty-third aspect, methods are provided for treating a
disease or condition related to Fms protein kinase in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
of Formula I or a composition comprising any one or more
compound(s) of Formula I. In certain embodiments, the method
involves administering to the subject an effective amount of a
compound of Formula I or a composition comprising a compound of
Formula I in combination with one or more other therapies for the
disease or condition.
[1053] In a sixty-fourth aspect, methods are provided for treating
a disease or condition related to Trk protein kinase in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
of Formula I or a composition comprising any one or more
compound(s) of Formula I. In certain embodiments, the method
involves administering to the subject an effective amount of a
compound of Formula I or a composition comprising a compound of
Formula I in combination with one or more other therapies for the
disease or condition.
[1054] In a sixty-fifth aspect, methods are provided for treating a
disease or condition related to Kit protein kinase in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
of Formula I or a composition comprising any one or more
compound(s) of Formula I. In certain embodiments, the method
involves administering to the subject an effective amount of a
compound of Formula I or a composition comprising a compound of
Formula I in combination with one or more other therapies for the
disease or condition.
[1055] In a sixty-sixth aspect, methods are provided for treating a
disease or condition related to Flt3 protein kinase in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
of Formula I or a composition comprising any one or more
compound(s) of Formula I. In certain embodiments, the method
involves administering to the subject an effective amount of a
compound of Formula I or a composition comprising a compound of
Formula I in combination with one or more other therapies for the
disease or condition.
[1056] In a sixty-seventh aspect, methods are provided for treating
a disease or condition related to Fms protein kinase and Kit
protein kinase in an animal subject in need thereof, wherein the
method involves administering to the subject an effective amount of
any one or more dual Fms/Kit inhibitor(s) of Formula I or a
composition comprising any one or more dual Fms/Kit inhibitor(s) of
Formula I. In certain embodiments, the method involves
administering to the subject an effective amount of a dual Fms/Kit
inhibitor of Formula I or a composition comprising a dual Fms/Kit
inhibitor of Formula I in combination with one or more other
therapies for the disease or condition.
[1057] In a sixty-eighth aspect, methods are provided for treating
a disease or condition related to Fms protein kinase and Flt-3
protein kinase in an animal subject in need thereof, wherein the
method involves administering to the subject an effective amount of
any one or more dual Fms/Flt-3 inhibitor(s) of Formula I or a
composition comprising any one or more dual Fms/Flt-3 inhibitor(s)
of Formula I. In certain embodiments, the method involves
administering to the subject an effective amount of a dual
Fms/Flt-3 inhibitor of Formula I or a composition comprising a dual
Fms/Flt-3 inhibitor of Formula I in combination with one or more
other therapies for the disease or condition.
[1058] In a sixty-ninth aspect, methods are provided for treating a
disease or condition related to Fms protein kinase and Trk protein
kinase in an animal subject in need thereof, wherein the method
involves administering to the subject an effective amount of any
one or more dual Fms/Trk inhibitor(s) of Formula I or a composition
comprising any one or more dual Fms/Trk inhibitor(s) of Formula I.
In certain embodiments, the method involves administering to the
subject an effective amount of a dual Fms/Trk inhibitor of Formula
I or a composition comprising a dual Fms/Trk inhibitor of Formula I
in combination with one or more other therapies for the disease or
condition.
[1059] In a seventieth aspect, the invention provides a method of
treating a cancer in a subject in need thereof by administering to
the subject an effective amount of any one or more compound(s) of
Formula I or a composition comprising any one or more compound(s)
of Formula I, in combination with one or more other therapies or
medical procedures effective in treating the cancer. Other
therapies or medical procedures include suitable anticancer therapy
(e.g. drug therapy, vaccine therapy, gene therapy, photodynamic
therapy) or medical procedure (e.g. surgery, radiation treatment,
hyperthermia heating, bone marrow or stem cell transplant). In one
embodiment, the one or more suitable anticancer therapies or
medical procedures is selected from treatment with a
chemotherapeutic agent (e.g. chemotherapeutic drug), radiation
treatment (e.g. x-ray, .quadrature.-ray, or electron, proton,
neutron, or .quadrature. particle beam), hyperthermia heating (e.g.
microwave, ultrasound, radiofrequency ablation), Vaccine therapy
(e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral
vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer
vaccine, dendritic cell peptide vaccines), gene therapy (e.g.
Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor
necrosis factor alpha), photodynamic therapy (e.g. aminolevulinic
acid, motexafin lutetium), surgery, or bone marrow and stem cell
transplantation.
[1060] In a seventy-first aspect, the invention provides a method
of treating a cancer in a subject in need thereof by administering
to the subject an effective amount of any one or more compound(s)
of Formula I or a composition comprising any one or more
compound(s) of Formula I, in combination with one or more suitable
chemotherapeutic agents. In one embodiment, the one or more
suitable chemotherapeutic agents is selected from an alkylating
agent, including, but not limited to, adozelesin, altretamine,
bendamustine, bizelesin, busulfan, carboplatin, carboquone,
carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide,
dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam,
ifosfamide, improsulfan, irofulven, lomustine, mannosulfan,
mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine,
oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine,
satraplatin, semustine, streptozocin, temozolomide, thiotepa,
treosulfan, triaziquone, triethylenemelamine, triplatin
tetranitrate, trofosphamide, and uramustine; an antibiotic,
including, but not limited to, aclarubicin, amrubicin, bleomycin,
dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin,
idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin,
pirarubicin, plicamycin, valrubicin, and zorubicin; an
antimetabolite, including, but not limited to, aminopterin,
azacitidine, azathioprine, capecitabine, cladribine, clofarabine,
cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil,
2'-F-ara-deoxyuridine, gemcitabine, hydroxyurea, mercaptopurine,
methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,
raltitrexed, tegafur-uracil, thioguanine, trimethoprim,
trimetrexate, and vidarabine; an immunotherapy, including, but not
limited to, alemtuzumab, bevacizumab, cetuximab, denileukin
diftitox, galiximab, gemtuzumab, ofatumumab, panitumumab,
pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y
ibritumomab tiuxetan, ipilimumab, and tremelimumab; a hormone or
hormone antagonist, including, but not limited to, anastrozole,
androgens, bicalutamide, buserelin, Degarelix, diethylstilbestrol,
exemestane, flutamide, fulvestrant, goserelin, idoxifene,
letrozole, leuprolide, megestrol, nilutamide, raloxifene,
tamoxifen, 4-hydroxytamoxifen, toremifene, and triptorelin; a
taxane, including, but not limited to, DJ-927, docetaxel, TPI 287,
larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; a
retinoid, including, but not limited to, alitretinoin, bexarotene,
fenretinide, isotretinoin, and tretinoin; an alkaloid, including,
but not limited to, demecolcine, homoharringtonine, vinblastine,
vincristine, vindesine, vinflunine, and vinorelbine; an
antiangiogenic agent, including, but not limited to, AE-941
(GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide,
and thalidomide; a topoisomerase inhibitor, including, but not
limited to, amsacrine, belotecan, edotecarin, etoposide, etoposide
phosphate, exatecan, irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not limited
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), pazopanib, seliciclib,
sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), PLX4032, vatalanib, mTOR inhibitors (e.g.
temsirolimus, everolimus, deforolimus, rapamycin), PI3K inhibitors
(e.g. BEZ235, GDC-0941, XL147, XL765, CAL-101, PX-866, BGT226,
GSK1059615), Cdk4 inhibitors (e.g. PD-332991, AG-024322), Akt
inhibitors (e.g. GSK2110183, SR13668), MEK inhibitors (e.g.
PD0325901, AZD8330, GSK1120212, RO4987655, RDEA119, XL518); a
targeted signal transduction inhibitor including, but not limited
to bortezomib, and geldanamycin; a biological response modifier,
including, but not limited to, imiquimod, interferon-.quadrature.,
and interleukin-2; and other chemotherapeutics, including, but not
limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
altrasentan, aminoglutethimide, anagrelide, asparaginase,
bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389),
ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen,
sulindac, testolactone, tiazofurin, COX-2 inhibitors (e.g.
celecoxib, rofecoxib, valdecoxib, lumiracoxib, etoricoxib), Hsp90
inhibitors (e.g. tanespimycin) and farnesyltransferase inhibitors
(e.g. tipifarnib).
[1061] In a seventy-second aspect, the invention provides kits that
include any one or more compound(s) of Formula I or a composition
comprising any one or more compound(s) of Formula I. In some
embodiments, the compound or composition is packaged, e.g., in a
vial, bottle, flask, which may be further packaged, e.g., within a
box, envelope, or bag; the compound or composition is approved by
the U.S. Food and Drug Administration or similar regulatory agency
for administration to a mammal, e.g., a human; the compound or
composition is approved for administration to a mammal, e.g., a
human, for a protein kinase mediated disease or condition; the
invention kit includes written instructions for use and/or other
indication that the compound or composition is suitable or approved
for administration to a mammal, e.g., a human, for a protein
kinase-mediated disease or condition; and the compound or
composition is packaged in unit dose or single dose form, e.g.,
single dose pills, capsules, or the like.
[1062] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition with any one or more
compound(s) of Formula I or a composition comprising any one or
more compound(s) of Formula I, the invention provides methods for
treating a disease or condition related to Kit in an animal subject
in need thereof (e.g. a mammal such as a human, other primates,
sports animals, animals of commercial interest such as cattle, farm
animals such as horses, or pets such as dogs and cats), e.g., a
disease or condition characterized by abnormal Kit activity (e.g.
kinase activity). In some embodiments invention methods may involve
administering to the subject suffering from or at risk of a disease
or condition related to Kit an effective amount of any one or more
compound(s) of Formula I or a composition comprising any one or
more compound(s) of Formula I. In one embodiment, the disease
related to Kit is selected from the group consisting of
malignancies, including, but not limited to, mast cell tumors,
small cell lung cancer, non-small cell lung cancer (NSCLC),
testicular cancer, pancreatic cancer, breast cancer, prostate
cancer, merkel cell carcinoma, carcinomas of the female genital
tract, sarcomas of neuroectodermal origin, colorectal carcinoma,
carcinoma in situ, gastrointestinal stromal tumors (GISTs),
multiple myeloma, tumor angiogenesis, brain metastases,
glioblastoma, astrocytoma, neuroblastoma, neurofibromatosis
(including Schwann cell neoplasia associated with
neurofibromatosis), acute myeloid leukemia, acute lymphocytic
leukemia, chronic myeloid leukemia, mastocytosis, melanoma, and
canine mast cell tumors; cardiovascular disease, including but not
limited to atherosclerosis, cardiomyopathy, heart failure,
pulmonary arterial hypertension and pulmonary fibrosis;
inflammatory and autoimmune indications, including, but not limited
to, allergy, anaphylaxis, asthma, rheumatoid arthritis, allergic
rhinitis, multiple sclerosis, inflammatory bowel disease,
transplant rejection, hypereosinophilia, urticaria and dermatitis;
gastrointestinal indications, including but not limited to
gastroesophageal reflux disease (GERD), esophagitis, and
gastrointestinal tract ulcers; ophthalmic indications, including
but not limited to uveitis and retinitis; and neurologic
indications, including but not limited to migraine.
[1063] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition with any one or more
compound(s) of Formula I or a composition comprising any one or
more compound(s) of Formula I, the invention provides methods for
treating a disease or condition related to Fms in an animal subject
in need thereof (e.g. a mammal such as a human, other primates,
sports animals, animals of commercial interest such as cattle, farm
animals such as horses, or pets such as dogs and cats), e.g., a
disease or condition characterized by abnormal Fms activity (e.g.
kinase activity). In some embodiments, invention methods may
involve administering to the subject suffering from or at risk of a
disease or condition related to Fms an effective amount of any one
or more compound(s) of Formula I or a composition comprising any
one or more compound(s) of Formula I. In one embodiment, the
disease related to Fms is selected from the group consisting of
inflammatory and autoimmune indications, including, but not limited
to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis,
psoriasis, dermatitis, ankylosing spondylitis, polymyositis,
dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis,
polymyalgia rheumatica, Sjogren's disease, Langerhan's cell
histiocytosis (LCH), Still's disease, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, systemic lupus erythematosis
(SLE), immune thrombocytopenic purpura (ITP), myelopreparation for
autologous transplantation, transplant rejection, chronic
obstructive pulmonary disease (COPD), emphysema, Kawasaki's
Disease, hemophagocytic syndrome (macrophage activation syndrome),
multicentric reticulohistiocytosis, and atherosclerosis; metabolic
disorders, including, but not limited to, Type I diabetes, Type II
diabetes, insulin resistance, hyperglycemia, obesity, and
lipolysis; disorders of bone structure, mineralization and bone
formation and resorption, including, but not limited to,
osteoporosis, osteodystrophy, increased risk of fracture, Paget's
disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), and peri-prosthetic or wear-debris-mediated
osteolysis; kidney and genitourinary diseases, including, but not
limited to, endometriosis, nephritis (e.g. glomerulonephritis,
interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic
nephropathy), and renal hypertrophy; disorders of the nervous
system, including, but not limited to, demyelinating disorders
(e.g. multiple sclerosis, Charcot Marie Tooth syndrome),
amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic
demyelinating polyneuropathy, other demyelinating disorders,
stroke, Alzheimer's disease and Parkinson's disease; pain,
including, but not limited to, chronic pain, acute pain,
inflammatory pain, neuropathic pain, bone pain; malignancies,
including, but not limited to, multiple myeloma, acute myeloid
leukemia (AML), chronic myeloid leukemia (CIVIL), lung cancer,
pancreatic cancer, prostate cancer, breast cancer, ovarian cancer,
neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g.
giant cell tumor of bone, giant cell tumor of tendon sheath
(TGCT)), pigmented villonodular synovitis (PVNS), tumor
angiogenesis, melanoma, glioblastoma multiforme, glioma, other
tumors of the central nervous system, brain metastases, osteolytic
bone metastases, metastasis of tumors to other tissues, and other
chronic myeloproliferative diseases such as myelofibrosis;
vasculitis, including but not limited to collagen vascular disease,
polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar
Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis,
giant cell arteritis, Takayasu's arteritis; ophthalmic indications,
including but not limited to uveitis, scleritis, retinitis, age
related macular degeneration, choroidal neovascularization,
diabetic retinopathy; inherited disorders, including but not
limited to cherubism, neurofibromatosis; infectious disease
indications, including but not limited to infections associated
with human immunodeficiency virus, hepatitis B virus, hepatitis C
virus, human granulocytic anaplasmosis; lysosomal storage
disorders, including but not limited to Gaucher's disease, Fabry's
disease, Niemann-Pick disease; gastrointestinal indications,
including but not limited to liver cirrhosis; pulmonary
indications, including but not limited to pulmonary fibrosis, acute
lung injury (e.g. ventilator-induced, smoke- or toxin-induced);
global ischemia, and surgical indications, including but not
limited to (cardiopulmonary) bypass surgery, vascular surgery, and
vascular grafts.
[1064] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition with the any one or more
compound(s) of Formula I or a composition comprising any one or
more compound(s) of Formula I, the invention provides methods for
treating a disease or condition related to Flt-3 in an animal
subject in need thereof (e.g. a mammal such as a human, other
primates, sports animals, animals of commercial interest such as
cattle, farm animals such as horses, or pets such as dogs and
cats), e.g., a disease or condition characterized by abnormal Flt-3
activity (e.g. kinase activity). In some embodiments, invention
methods may involve administering to the subject suffering from or
at risk of a disease or condition related to Flt-3 an effective
amount of any one or more compound(s) of Formula I or a composition
comprising any one or more compound(s) of Formula I. In one
embodiment, the disease related to Flt-3 is selected from the group
consisting of malignancies, including, but not limited to, glioma,
glioblastoma, brain metastases, lung cancer, breast cancer,
colorectal cancer, prostate cancer, gastric cancer, esophageal
cancer, pancreatic cancer, ovarian cancer, non-Hodgkin's lymphoma,
Hodgkin's lymphoma, multiple myeloma, acute lymphocytic leukemia,
acute myeloid leukemia, acute myeloid leukemia with trilineage
myelodysplasia, acute promyelocytic leukemia, chronic lymphocytic
leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia,
acute undifferentiated leukemia, anaplastic large-cell lymphoma,
prolymphocyte leukemia, juvenile myelomonocyctic leukemia, adult
T-cell acute lymphocytic leukemia, T-cell type acute lymphocytic
leukemia, B-cell type acute lymphocytic leukemia, mixed lineage
leukemia, multiple myeloma, chronic myelocytic leukemia, acute
lymphoblastic leukemia, acute myeloblastic leukemia, chronic
myelomonocytic leukemia; other diseases including psoriasis, atopic
dermatitis, axonal degeneration, acute transverse myelitis,
amyotrophic lateral sclerosis, infantile spinal muscular atrophy,
juvenile spinal muscular atrophy, Creutzfeldt-Jakob disease,
subacute sclerosing panencephalitis, organ rejection, bone marrow
transplant rejection, non-myeloablative bone marrow transplant
rejection, ankylosing spondylitis, aplastic anemia, Behcet's
disease, graft-versus-host disease, Graves' disease, autoimmune
hemolytic anemia, Wegener's granulomatosis, hyper IgE syndrome,
idiopathic thrombocytopenia purpura, Myasthenia gravis, type 1
diabetes mellitus, rheumatoid arthritis, Crohn's disease, multiple
sclerosis, systemic lupus erythematosus, myelodysplastic syndrome,
thrombocythemia, essential thrombocytosis, angiogenic myeloid
metaplasia, myelofibrosis, myelofibrosis with myeloid metaplasia,
chronic idiopathic myelofibrosis, polycythemia vera, anemia,
leukopenia, neutropenia, thrombocytopenia, granulocytopenia, and
pancytopenia.
[1065] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition with the any one or more
compound(s) of Formula I or a composition comprising any one or
more compound(s) of Formula I, the invention provides methods for
treating a disease or condition related to Trk in an animal subject
in need thereof (e.g. a mammal such as a human, other primates,
sports animals, animals of commercial interest such as cattle, farm
animals such as horses, or pets such as dogs and cats), e.g., a
disease or condition characterized by abnormal Trk activity (e.g.
kinase activity). In some embodiments, invention methods may
involve administering to the subject suffering from or at risk of a
disease or condition related to Trk an effective amount of any one
or more compound(s) of Formula I or a composition comprising any
one or more compound(s) of Formula I. In one embodiment, the
disease related to Trk is selected from the group consisting of
malignancies, including, but not limited to, prostate cancer, small
cell lung cancer, non-small cell lung cancer, Wilms tumors,
mesoblastic nephroma, infantile fibrosarcoma, neuroblastoma, brain
cancer, squamous cell cancer, bladder cancer, gastric cancer,
pancreatic cancer, breast cancer, head and neck cancer, esophageal
cancer, colorectal cancer, renal cancer, hepatocellular cancer,
ovarian cancer, gynecological cancer, thyroid cancer, cervical
cancer, ewings tumor, tumors of the central and peripheral nervous
system, melanoma, multiple myeloma, acute myelogenous leukemia, and
myeloid leukemia; neuropathies, including, but not limited to,
stroke, multiple sclerosis, Parkinson's disease, Alzheimer's
disease, transverse myelitis, and encephalitis; pain, including,
but not limited to, chronic pain, acute pain, inflammatory pain,
neuropathic pain, and pain associated with cancer, surgery, or bone
fracture; bone-related diseases, including, but not limited to,
metastatic bone disease, treatment-induced bone loss, osteoporosis,
rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and
periodontal disease; other diseases, including, but not limited to,
asthma, arthritis, diabetic retinopathy, macular degeneration,
psoriasis, acute and chronic inflammation, Kaposi's sarcoma,
haemangioma, acute and chronic nephropathies, atheroma,
atherosclerosis, arterial restenosis, fibrosarcoma, osteosarcoma,
panic disorder, and infectious disease (e.g. Typanosoma cruzi
infection (Chagas disease)).
[1066] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more compound(s) of
Formula I or a composition comprising any one or more compound(s)
of Formula I to a subject in need thereof suffering from or at risk
of a disease or condition selected from the group consisting of
rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic
osteolysis, systemic sclerosis, demyelinating disorders, multiple
sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral
sclerosis, Alzheimer's disease, Parkinson's disease, global
ischemia, ulcerative colitis, Crohn's disease, immune
thrombocytopenic purpura, atherosclerosis, systemic lupus
erythematosis, myelopreparation for autologous transplantation,
transplant rejection, glomerulonephritis, interstitial nephritis,
Lupus nephritis, tubular necrosis, diabetic nephropathy, renal
hypertrophy, type I diabetes, acute pain, inflammatory pain,
neuropathic pain, acute myeloid leukemia, melanoma, multiple
myeloma, breast cancer, prostate cancer, pancreatic cancer, lung
cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis,
osteolytic bone metastases, brain metastases, gastrointestinal
stromal tumors, and giant cell tumors.
[1067] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more compound(s) of
Formula I or a composition comprising any one or more compound(s)
of Formula I to a subject in need thereof suffering from or at risk
of a disease or condition selected from the group consisting of
rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic
osteolysis, multiple sclerosis, Alzheimer's disease, Parkinson's
disease, global ischemia, renal hypertrophy, acute myeloid
leukemia, melanoma, multiple myeloma, breast cancer, prostate
cancer, pancreatic cancer, glioblastoma, neurofibromatosis, brain
metastases, and gastrointestinal stromal tumors.
[1068] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more Kit
inhibitor(s) of Formula I or a composition comprising any one or
more Kit inhibitor(s) of Formula I to a subject in need thereof
suffering from or at risk of a disease or condition selected from
the group consisting of rheumatoid arthritis, gastrointestinal
stromal tumors, melanoma and neurofibromatosis.
[1069] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more Fms selective
inhibitor(s) of Formula I or a composition comprising any one or
more Fms selective inhibitor(s) of Formula I to a subject in need
thereof suffering from or at risk of a disease or condition
selected from the group consisting of multiple sclerosis,
Alzheimer's disease, Parkinson's disease, global ischemia,
rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic
osteolysis, glomerulonephritis, interstitial nephritis, Lupus
nephritis, diabetic nephropathy, and renal hypertrophy.
[1070] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more Fms selective
inhibitor(s) of Formula I or a composition comprising any one or
more Fms selective inhibitor(s) of Formula I to a subject in need
thereof suffering from or at risk of a disease or condition
selected from the group consisting of multiple sclerosis,
Alzheimer's disease, Parkinson's disease, and global ischemia,
wherein the one or more Fms selective inhibitor(s) does effectively
cross the blood brain barrier.
[1071] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more Fms selective
inhibitor(s) of Formula I or a composition comprising any one or
more Fms selective inhibitor(s) of Formula I to a subject in need
thereof suffering from or at risk of a disease or condition
selected from the group consisting of rheumatoid arthritis,
osteoarthritis, osteoporosis, peri-prosthetic osteolysis,
glomerulonephritis, interstitial nephritis, Lupus nephritis,
diabetic nephropathy, and renal hypertrophy, wherein the one or
more Fms selective inhibitor(s) does not effectively cross the
blood brain barrier.
[1072] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more dual Fms/Kit
inhibitor(s) of Formula I or a composition comprising any one or
more dual Fms/Kit inhibitor(s) of Formula I to a subject in need
thereof suffering from or at risk of a disease or condition
selected from the group consisting of breast cancer, prostate
cancer, multiple myeloma, melanoma, acute myeloid leukemia,
glioblastoma, brain metastases, neurofibromatosis, gastrointestinal
stromal tumors, rheumatoid arthritis, and multiple sclerosis.
[1073] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more dual Fms/Flt-3
inhibitor(s) of Formula I or a composition comprising any one or
more dual Fms/Flt-3 inhibitor(s) of Formula I to a subject in need
thereof suffering from or at risk of a disease or condition
selected from the group consisting of breast cancer, prostate
cancer, multiple myeloma, melanoma, acute myeloid leukemia,
glioblastoma, brain metastases, neurofibromatosis, gastrointestinal
stromal tumors, rheumatoid arthritis, and multiple sclerosis,
preferably wherein the disease is acute myeloid leukemia.
[1074] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition, methods may involve
administering an effective amount of any one or more dual Fms/Trk
inhibitor(s) of Formula I or a composition comprising any one or
more dual Fms/Trk inhibitor(s) of Formula I to a subject in need
thereof suffering from or at risk of a disease or condition
selected from the group consisting of pancreatic cancer, prostate
cancer, and multiple myeloma.
[1075] In a seventy-third aspect, any one or more compound(s) of
Formula I can be used in the preparation of a medicament for the
treatment of a disease or condition related to Kit selected from
the group consisting of malignancies, including, but not limited
to, mast cell tumors, small cell lung cancer, non-small cell lung
cancer (NSCLC), testicular cancer, pancreatic cancer, breast
cancer, prostate cancer, merkel cell carcinoma, carcinomas of the
female genital tract, sarcomas of neuroectodermal origin,
colorectal carcinoma, carcinoma in situ, gastrointestinal stromal
tumors (GISTs), multiple myeloma, tumor angiogenesis, brain
metastases, glioblastoma, astrocytoma, neuroblastoma,
neurofibromatosis (including Schwann cell neoplasia associated with
neurofibromatosis), acute myeloid leukemia, acute lymphocytic
leukemia, chronic myeloid leukemia, mastocytosis, melanoma, and
canine mast cell tumors; cardiovascular disease, including but not
limited to atherosclerosis, cardiomyopathy, heart failure,
pulmonary arterial hypertension and pulmonary fibrosis;
inflammatory and autoimmune indications, including, but not limited
to, allergy, anaphylaxis, asthma, rheumatoid arthritis, allergic
rhinitis, multiple sclerosis, inflammatory bowel disease,
transplant rejection, hypereosinophilia, urticaria and dermatitis;
gastrointestinal indications, including but not limited to
gastroesophageal reflux disease (GERD), esophagitis, and
gastrointestinal tract ulcers; ophthalmic indications, including
but not limited to uveitis and retinitis; and neurologic
indications, including but not limited to migraine.
[1076] In a seventy-fourth aspect, any one or more compound(s) of
Formula I can be used in the preparation of a medicament for the
treatment of a disease or condition related to Fms selected from
the group consisting of inflammatory and autoimmune indications,
including, but not limited to, rheumatoid arthritis,
osteoarthritis, psoriatic arthritis, psoriasis, dermatitis,
ankylosing spondylitis, polymyositis, dermatomyositis, systemic
sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica,
Sjogren's disease, Langerhan's cell histiocytosis (LCH), Still's
disease, inflammatory bowel disease, ulcerative colitis, Crohn's
disease, systemic lupus erythematosis (SLE), immune
thrombocytopenic purpura (ITP), myelopreparation for autologous
transplantation, transplant rejection, chronic obstructive
pulmonary disease (COPD), emphysema, Kawasaki's Disease,
hemophagocytic syndrome (macrophage activation syndrome),
multicentric reticulohistiocytosis, and atherosclerosis; metabolic
disorders, including, but not limited to, Type I diabetes, Type II
diabetes, insulin resistance, hyperglycemia, obesity, and
lipolysis; disorders of bone structure, mineralization and bone
formation and resorption, including, but not limited to,
osteoporosis, osteodystrophy, increased risk of fracture, Paget's
disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), and peri-prosthetic or wear-debris-mediated
osteolysis; kidney and genitourinary diseases, including, but not
limited to, endometriosis, nephritis (e.g. glomerulonephritis,
interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic
nephropathy), and renal hypertrophy; disorders of the nervous
system, including, but not limited to, demyelinating disorders
(e.g. multiple sclerosis, Charcot Marie Tooth syndrome),
amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic
demyelinating polyneuropathy, other demyelinating disorders,
stroke, Alzheimer's disease and Parkinson's disease; pain,
including, but not limited to, chronic pain, acute pain,
inflammatory pain, neuropathic pain, bone pain; malignancies,
including, but not limited to, multiple myeloma, acute myeloid
leukemia (AML), chronic myeloid leukemia (CIVIL), lung cancer,
pancreatic cancer, prostate cancer, breast cancer, ovarian cancer,
neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g.
giant cell tumor of bone, giant cell tumor of tendon sheath
(TGCT)), pigmented villonodular synovitis (PVNS), tumor
angiogenesis, melanoma, glioblastoma multiforme, glioma, other
tumors of the central nervous system, brain metastases, osteolytic
bone metastases, metastasis of tumors to other tissues, and other
chronic myeloproliferative diseases such as myelofibrosis;
vasculitis, including but not limited to collagen vascular disease,
polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar
Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis,
giant cell arteritis, Takayasu's arteritis; ophthalmic indications,
including but not limited to uveitis, scleritis, retinitis, age
related macular degeneration, choroidal neovascularization,
diabetic retinopathy; inherited disorders, including but not
limited to cherubism, neurofibromatosis; infectious disease
indications, including but not limited to infections associated
with human immunodeficiency virus, hepatitis B virus, hepatitis C
virus, human granulocytic anaplasmosis; lysosomal storage
disorders, including but not limited to Gaucher's disease, Fabry's
disease, Niemann-Pick disease; gastrointestinal indications,
including but not limited to liver cirrhosis; pulmonary
indications, including but not limited to pulmonary fibrosis, acute
lung injury (e.g. ventilator-induced, smoke- or toxin-induced);
global ischemia, and surgical indications, including but not
limited to (cardiopulmonary) bypass surgery, vascular surgery, and
vascular grafts.
[1077] In a seventy-fifth aspect, any one or more compound(s) of
Formula I can be used in the preparation of a medicament for the
treatment of a disease or condition related to Flt-3 selected from
the group consisting of malignancies, including, but not limited
to, glioma, glioblastoma, brain metastases, lung cancer, breast
cancer, colorectal cancer, prostate cancer, gastric cancer,
esophageal cancer, pancreatic cancer, ovarian cancer, non-Hodgkin's
lymphoma, Hodgkin's lymphoma, multiple myeloma, acute lymphocytic
leukemia, acute myeloid leukemia, acute myeloid leukemia with
trilineage myelodysplasia, acute promyelocytic leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, chronic
neutrophilic leukemia, acute undifferentiated leukemia, anaplastic
large-cell lymphoma, prolymphocyte leukemia, juvenile
myelomonocyctic leukemia, adult T-cell acute lymphocytic leukemia,
T-cell type acute lymphocytic leukemia, B-cell type acute
lymphocytic leukemia, mixed lineage leukemia, multiple myeloma,
chronic myelocytic leukemia, acute lymphoblastic leukemia, acute
myeloblastic leukemia, chronic myelomonocytic leukemia; other
diseases including psoriasis, atopic dermatitis, axonal
degeneration, acute transverse myelitis, amyotrophic lateral
sclerosis, infantile spinal muscular atrophy, juvenile spinal
muscular atrophy, Creutzfeldt-Jakob disease, subacute sclerosing
panencephalitis, organ rejection, bone marrow transplant rejection,
non-myeloablative bone marrow transplant rejection, ankylosing
spondylitis, aplastic anemia, Behcet's disease, graft-versus-host
disease, Graves' disease, autoimmune hemolytic anemia, Wegener's
granulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia
purpura, Myasthenia gravis, type 1 diabetes mellitus, rheumatoid
arthritis, Crohn's disease, multiple sclerosis, systemic lupus
erythematosus, myelodysplastic syndrome, thrombocythemia, essential
thrombocytosis, angiogenic myeloid metaplasia, myelofibrosis,
myelofibrosis with myeloid metaplasia, chronic idiopathic
myelofibrosis, polycythemia vera, anemia, leukopenia, neutropenia,
thrombocytopenia, granulocytopenia, and pancytopenia.
[1078] In a seventy-sixth aspect, any one or more compound(s) of
Formula I can be used in the preparation of a medicament for the
treatment of a disease or condition related to Trk selected from
the group consisting of malignancies, including, but not limited
to, prostate cancer, small cell lung cancer, non-small cell lung
cancer, Wilms tumors, mesoblastic nephroma, infantile fibrosarcoma,
neuroblastoma, brain cancer, squamous cell cancer, bladder cancer,
gastric cancer, pancreatic cancer, breast cancer, head and neck
cancer, esophageal cancer, colorectal cancer, renal cancer,
hepatocellular cancer, ovarian cancer, gynecological cancer,
thyroid cancer, cervical cancer, ewings tumor, tumors of the
central and peripheral nervous system, melanoma, multiple myeloma,
acute myelogenous leukemia, and myeloid leukemia; neuropathies,
including, but not limited to, stroke, multiple sclerosis,
Parkinson's disease, Alzheimer's disease, transverse myelitis, and
encephalitis; pain, including, but not limited to, chronic pain,
acute pain, inflammatory pain, neuropathic pain, and pain
associated with cancer, surgery, or bone fracture; bone-related
diseases, including, but not limited to, metastatic bone disease,
treatment-induced bone loss, osteoporosis, rheumatoid arthritis,
ankylosing spondylitis, Paget's disease, and periodontal disease;
other diseases, including, but not limited to, asthma, arthritis,
diabetic retinopathy, macular degeneration, psoriasis, acute and
chronic inflammation, Kaposi's sarcoma, haemangioma, acute and
chronic nephropathies, atheroma, atherosclerosis, arterial
restenosis, fibrosarcoma, osteosarcoma, panic disorder, and
infectious disease (e.g. Typanosoma cruzi infection (Chagas
disease)).
[1079] In a seventy-seventh aspect, any one or more compound(s) of
Formula I can be used in the preparation of a medicament for the
treatment of a disease or condition selected from the group
consisting of rheumatoid arthritis, osteoarthritis, osteoporosis,
peri-prosthetic osteolysis, systemic sclerosis, demyelinating
disorders, multiple sclerosis, Charcot Marie Tooth syndrome,
amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's
disease, global ischemia, ulcerative colitis, Crohn's disease,
immune thrombocytopenic purpura, atherosclerosis, systemic lupus
erythematosis, myelopreparation for autologous transplantation,
transplant rejection, glomerulonephritis, interstitial nephritis,
Lupus nephritis, tubular necrosis, diabetic nephropathy, renal
hypertrophy, type I diabetes, acute pain, inflammatory pain,
neuropathic pain, acute myeloid leukemia, melanoma, multiple
myeloma, breast cancer, prostate cancer, pancreatic cancer, lung
cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis,
osteolytic bone metastases, brain metastases, gastrointestinal
stromal tumors, and giant cell tumors.
[1080] In a seventy-eighth aspect, any one or more compound(s) of
Formula I can be used in the preparation of a medicament for the
treatment of a disease or condition selected from the group
consisting of rheumatoid arthritis, osteoarthritis, osteoporosis,
peri-prosthetic osteolysis, multiple sclerosis, Alzheimer's
disease, Parkinson's disease, global ischemia, renal hypertrophy,
acute myeloid leukemia, melanoma, multiple myeloma, breast cancer,
prostate cancer, pancreatic cancer, glioblastoma,
neurofibromatosis, brain metastases, and gastrointestinal stromal
tumors.
[1081] In a seventy-ninth aspect, one or more compounds as
described herein that are Kit inhibitors can be used in the
preparation of a medicament for the treatment of rheumatoid
arthritis, gastrointestinal stromal tumors, melanoma or
neurofibromatosis.
[1082] In an eightieth aspect, one or more compounds as described
herein that are Fms selective inhibitors can be used in the
preparation of a medicament for the treatment of multiple
sclerosis, Alzheimer's disease, Parkinson's disease, global
ischemia, rheumatoid arthritis, osteoarthritis, osteoporosis,
peri-prosthetic osteolysis, glomerulonephritis, interstitial
nephritis, Lupus nephritis, diabetic nephropathy, or renal
hypertrophy.
[1083] In an eighty-first aspect, one or more compounds as
described herein that are Fms selective inhibitors that effectively
cross the blood brain barrier can be used in the preparation of a
medicament for the treatment of multiple sclerosis, glioblastoma,
Alzheimer's disease, Parkinson's disease, or global ischemia.
[1084] In an eighty-second aspect, one or more compounds as
described herein that are Fms selective inhibitors that do not
effectively cross the blood brain barrier can be used in the
preparation of a medicament for the treatment of rheumatoid
arthritis, osteoarthritis, osteoporosis, peri-prosthetic
osteolysis, glomerulonephritis, interstitial nephritis, Lupus
nephritis, diabetic nephropathy, or renal hypertrophy.
[1085] In an eighty-third aspect, one or more compounds as
described herein that are dual Fms/Kit inhibitors can be used in
the preparation of a medicament for the treatment of breast cancer,
prostate cancer, multiple myeloma, melanoma, acute myeloid
leukemia, glioblastoma, brain metastases, neurofibromatosis,
gastrointestinal stromal tumors, rheumatoid arthritis, or multiple
sclerosis.
[1086] In an eighty-fourth aspect, one or more compounds as
described herein that are dual Fms/Flt-3 inhibitors can be used in
the preparation of a medicament for the treatment of breast cancer,
prostate cancer, multiple myeloma, melanoma, acute myeloid
leukemia, glioblastoma, brain metastases, neurofibromatosis,
gastrointestinal stromal tumors, rheumatoid arthritis, or multiple
sclerosis, preferably wherein the disease is acute myeloid
leukemia.
[1087] In an eighty-fifth aspect, one or more compounds as
described herein that are dual Fms/Trk inhibitors can be used in
the preparation of a medicament for the treatment of pancreatic
cancer, prostate cancer, and multiple myeloma.
[1088] In an eighty-sixth aspect, there are provided compounds of
Formula I for the treatment of a disease or condition related to
Kit selected from the group consisting of malignancies, including,
but not limited to, mast cell tumors, small cell lung cancer,
non-small cell lung cancer (NSCLC), testicular cancer, pancreatic
cancer, breast cancer, prostate cancer, merkel cell carcinoma,
carcinomas of the female genital tract, sarcomas of neuroectodermal
origin, colorectal carcinoma, carcinoma in situ, gastrointestinal
stromal tumors (GISTs), multiple myeloma, tumor angiogenesis, brain
metastases, glioblastoma, astrocytoma, neuroblastoma,
neurofibromatosis (including Schwann cell neoplasia associated with
neurofibromatosis), acute myeloid leukemia, acute lymphocytic
leukemia, chronic myeloid leukemia, mastocytosis, melanoma, and
canine mast cell tumors; cardiovascular disease, including but not
limited to atherosclerosis, cardiomyopathy, heart failure,
pulmonary arterial hypertension and pulmonary fibrosis;
inflammatory and autoimmune indications, including, but not limited
to, allergy, anaphylaxis, asthma, rheumatoid arthritis, allergic
rhinitis, multiple sclerosis, inflammatory bowel disease,
transplant rejection, hypereosinophilia, urticaria and dermatitis;
gastrointestinal indications, including but not limited to
gastroesophageal reflux disease (GERD), esophagitis, and
gastrointestinal tract ulcers; ophthalmic indications, including
but not limited to uveitis and retinitis; and neurologic
indications, including but not limited to migraine.
[1089] In an eighty-seventh aspect there are provided compounds of
Formula I for the treatment of a disease or condition related to
Fms selected from the group consisting of inflammatory and
autoimmune indications, including, but not limited to, rheumatoid
arthritis, osteoarthritis, psoriatic arthritis, psoriasis,
dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis,
systemic sclerosis, juvenile idiopathic arthritis, polymyalgia
rheumatica, Sjogren's disease, Langerhan's cell histiocytosis
(LCH), Still's disease, inflammatory bowel disease, ulcerative
colitis, Crohn's disease, systemic lupus erythematosis (SLE),
immune thrombocytopenic purpura (ITP), myelopreparation for
autologous transplantation, transplant rejection, chronic
obstructive pulmonary disease (COPD), emphysema, Kawasaki's
Disease, hemophagocytic syndrome (macrophage activation syndrome),
multicentric reticulohistiocytosis, and atherosclerosis; metabolic
disorders, including, but not limited to, Type I diabetes, Type II
diabetes, insulin resistance, hyperglycemia, obesity, and
lipolysis; disorders of bone structure, mineralization and bone
formation and resorption, including, but not limited to,
osteoporosis, osteodystrophy, increased risk of fracture, Paget's
disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), and peri-prosthetic or wear-debris-mediated
osteolysis; kidney and genitourinary diseases, including, but not
limited to, endometriosis, nephritis (e.g. glomerulonephritis,
interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic
nephropathy), and renal hypertrophy; disorders of the nervous
system, including, but not limited to, demyelinating disorders
(e.g. multiple sclerosis, Charcot Marie Tooth syndrome),
amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic
demyelinating polyneuropathy, other demyelinating disorders,
stroke, Alzheimer's disease and Parkinson's disease; pain,
including, but not limited to, chronic pain, acute pain,
inflammatory pain, neuropathic pain, bone pain; malignancies,
including, but not limited to, multiple myeloma, acute myeloid
leukemia (AML), chronic myeloid leukemia (CML), lung cancer,
pancreatic cancer, prostate cancer, breast cancer, ovarian cancer,
neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g.
giant cell tumor of bone, giant cell tumor of tendon sheath
(TGCT)), pigmented villonodular synovitis (PVNS), tumor
angiogenesis, melanoma, glioblastoma multiforme, glioma, other
tumors of the central nervous system, brain metastases, osteolytic
bone metastases, metastasis of tumors to other tissues, and other
chronic myeloproliferative diseases such as myelofibrosis;
vasculitis, including but not limited to collagen vascular disease,
polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar
Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis,
giant cell arteritis, Takayasu's arteritis; ophthalmic indications,
including but not limited to uveitis, scleritis, retinitis, age
related macular degeneration, choroidal neovascularization,
diabetic retinopathy; inherited disorders, including but not
limited to cherubism, neurofibromatosis; infectious disease
indications, including but not limited to infections associated
with human immunodeficiency virus, hepatitis B virus, hepatitis C
virus, human granulocytic anaplasmosis; lysosomal storage
disorders, including but not limited to Gaucher's disease, Fabry's
disease, Niemann-Pick disease; gastrointestinal indications,
including but not limited to liver cirrhosis; pulmonary
indications, including but not limited to pulmonary fibrosis, acute
lung injury (e.g. ventilator-induced, smoke- or toxin-induced);
global ischemia, and surgical indications, including but not
limited to (cardiopulmonary) bypass surgery, vascular surgery, and
vascular grafts.
[1090] In an eighty-eighth aspect, there are provided compounds of
Formula I for the treatment of a disease or condition related to
Flt-3 selected from the group consisting of malignancies,
including, but not limited to, glioma, glioblastoma, brain
metastases, lung cancer, breast cancer, colorectal cancer, prostate
cancer, gastric cancer, esophageal cancer, pancreatic cancer,
ovarian cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma,
multiple myeloma, acute lymphocytic leukemia, acute myeloid
leukemia, acute myeloid leukemia with trilineage myelodysplasia,
acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic
myeloid leukemia, chronic neutrophilic leukemia, acute
undifferentiated leukemia, anaplastic large-cell lymphoma,
prolymphocyte leukemia, juvenile myelomonocyctic leukemia, adult
T-cell acute lymphocytic leukemia, T-cell type acute lymphocytic
leukemia, B-cell type acute lymphocytic leukemia, mixed lineage
leukemia, multiple myeloma, chronic myelocytic leukemia, acute
lymphoblastic leukemia, acute myeloblastic leukemia, chronic
myelomonocytic leukemia; other diseases including psoriasis, atopic
dermatitis, axonal degeneration, acute transverse myelitis,
amyotrophic lateral sclerosis, infantile spinal muscular atrophy,
juvenile spinal muscular atrophy, Creutzfeldt-Jakob disease,
subacute sclerosing panencephalitis, organ rejection, bone marrow
transplant rejection, non-myeloablative bone marrow transplant
rejection, ankylosing spondylitis, aplastic anemia, Behcet's
disease, graft-versus-host disease, Graves' disease, autoimmune
hemolytic anemia, Wegener's granulomatosis, hyper IgE syndrome,
idiopathic thrombocytopenia purpura, Myasthenia gravis, type 1
diabetes mellitus, rheumatoid arthritis, Crohn's disease, multiple
sclerosis, systemic lupus erythematosus, myelodysplastic syndrome,
thrombocythemia, essential thrombocytosis, angiogenic myeloid
metaplasia, myelofibrosis, myelofibrosis with myeloid metaplasia,
chronic idiopathic myelofibrosis, polycythemia vera, anemia,
leukopenia, neutropenia, thrombocytopenia, granulocytopenia, and
pancytopenia.
[1091] In an eighty-ninth aspect, there are provided compounds of
Formula I for the treatment of a disease or condition related to
Trk selected from the group consisting of malignancies, including,
but not limited to, prostate cancer, small cell lung cancer,
non-small cell lung cancer, Wilms tumors, mesoblastic nephroma,
infantile fibrosarcoma, neuroblastoma, brain cancer, squamous cell
cancer, bladder cancer, gastric cancer, pancreatic cancer, breast
cancer, head and neck cancer, esophageal cancer, colorectal cancer,
renal cancer, hepatocellular cancer, ovarian cancer, gynecological
cancer, thyroid cancer, cervical cancer, ewings tumor, tumors of
the central and peripheral nervous system, melanoma, multiple
myeloma, acute myelogenous leukemia, and myeloid leukemia;
neuropathies, including, but not limited to, stroke, multiple
sclerosis, Parkinson's disease, Alzheimer's disease, transverse
myelitis, and encephalitis; pain, including, but not limited to,
chronic pain, acute pain, inflammatory pain, neuropathic pain, and
pain associated with cancer, surgery, or bone fracture;
bone-related diseases, including, but not limited to, metastatic
bone disease, treatment-induced bone loss, osteoporosis, rheumatoid
arthritis, ankylosing spondylitis, Paget's disease, and periodontal
disease; other diseases, including, but not limited to, asthma,
arthritis, diabetic retinopathy, macular degeneration, psoriasis,
acute and chronic inflammation, Kaposi's sarcoma, haemangioma,
acute and chronic nephropathies, atheroma, atherosclerosis,
arterial restenosis, fibrosarcoma, osteosarcoma, panic disorder,
and infectious disease (e.g. Typanosoma cruzi infection (Chagas
disease)).
[1092] In a ninetieth aspect, there are provided compounds of
Formula I for the treatment of a disease or condition selected from
the group consisting of rheumatoid arthritis, osteoarthritis,
osteoporosis, peri-prosthetic osteolysis, systemic sclerosis,
demyelinating disorders, multiple sclerosis, Charcot Marie Tooth
syndrome, amyotrophic lateral sclerosis, Alzheimer's disease,
Parkinson's disease, global ischemia, ulcerative colitis, Crohn's
disease, immune thrombocytopenic purpura, atherosclerosis, systemic
lupus erythematosis, myelopreparation for autologous
transplantation, transplant rejection, glomerulonephritis,
interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic
nephropathy, renal hypertrophy, type I diabetes, acute pain,
inflammatory pain, neuropathic pain, acute myeloid leukemia,
melanoma, multiple myeloma, breast cancer, prostate cancer,
pancreatic cancer, lung cancer, ovarian cancer, gliomas,
glioblastomas, neurofibromatosis, osteolytic bone metastases, brain
metastases, gastrointestinal stromal tumors, and giant cell
tumors.
[1093] In a ninety-first aspect, there are provided compounds of
Formula I for the treatment of a disease or condition selected from
the group consisting of rheumatoid arthritis, osteoarthritis,
osteoporosis, peri-prosthetic osteolysis, multiple sclerosis,
Alzheimer's disease, Parkinson's disease, global ischemia, renal
hypertrophy, acute myeloid leukemia, melanoma, multiple myeloma,
breast cancer, prostate cancer, pancreatic cancer, glioblastoma,
neurofibromatosis, brain metastases, and gastrointestinal stromal
tumors.
[1094] In a ninety-second aspect, there are provided compounds as
described herein that are Kit inhibitors for the treatment of a
disease or condition selected from the group consisting of
rheumatoid arthritis, gastrointestinal stromal tumors, melanoma and
neurofibromatosis.
[1095] In a ninety-third aspect, there are provided compounds as
described herein that are Fms selective inhibitors for the
treatment of a disease or condition selected from the group
consisting of multiple sclerosis, Alzheimer's disease, Parkinson's
disease, global ischemia, rheumatoid arthritis, osteoarthritis,
osteoporosis, peri-prosthetic osteolysis, glomerulonephritis,
interstitial nephritis, Lupus nephritis, diabetic nephropathy, and
renal hypertrophy.
[1096] In a ninety-fourth aspect, there are provided compounds as
described herein that are Fms selective inhibitors that effectively
cross the blood brain barrier for the treatment of a disease or
condition selected from the group consisting of multiple sclerosis,
glioblastoma, Alzheimer's disease, Parkinson's disease, and global
ischemia.
[1097] In a ninety-fifth aspect, there are provided compounds as
described herein that are Fms selective inhibitors that do not
effectively cross the blood brain barrier for the treatment of a
disease or condition selected from the group consisting of
rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic
osteolysis, glomerulonephritis, interstitial nephritis, Lupus
nephritis, diabetic nephropathy, and renal hypertrophy.
[1098] In a ninety-sixth aspect, there are provided compounds as
described herein that are dual Fms/Kit inhibitors for the treatment
of a disease or condition selected from the group consisting of
breast cancer, prostate cancer, multiple myeloma, melanoma, acute
myeloid leukemia, glioblastoma, brain metastases,
neurofibromatosis, gastrointestinal stromal tumors, rheumatoid
arthritis, and multiple sclerosis.
[1099] In a ninety-seventh aspect, there are provided compounds as
described herein that are dual Fms/Flt-3 inhibitors for the
treatment of a disease or condition selected from the group
consisting of breast cancer, prostate cancer, multiple myeloma,
melanoma, acute myeloid leukemia, glioblastoma, brain metastases,
neurofibromatosis, gastrointestinal stromal tumors, rheumatoid
arthritis, and multiple sclerosis, preferably wherein the disease
is acute myeloid leukemia.
[1100] In a ninety-eighth aspect, there are provided compounds as
described herein that are dual Fms/Trk inhibitors for the treatment
of a disease or condition selected from the group consisting of
pancreatic cancer, prostate cancer, and multiple myeloma.
[1101] In a ninety-ninth aspect, the invention provide a compound
of Formula II:
##STR00057##
wherein P.sup.1 and P.sup.2 are each independently H or an amino
protecting group. P.sup.3 is H or a hydroxyl protecting group or a
labile group. In one embodiment, P.sup.1 and P.sup.2 are each
independently amino protecting group. In one embodiment, P.sup.3 is
H. All the other variables X.sub.1, R.sup.2, R.sup.3, Y.sub.1 and
Cy.sub.1 are as defined in any of the embodiments of Formula I
described herein.
[1102] In a 100.sup.th aspect, the invention provides a compound of
Formula IIa:
##STR00058##
wherein P.sup.1 and P.sup.2 are each independently H or an amino
protecting group. P.sup.3 is H or a hydroxyl protecting group or a
labile group. Z.sup.1 is Br, Cl or R.sup.2, wherein R.sup.2 is as
defined in any of the embodiments of formula I descried herein. In
one embodiment, Z.sup.1 is Cl or Br. In one embodiment, P.sup.1 and
P.sup.2 are each independently amino protecting group. In one
embodiment, P.sup.3 is H. All the other variables X.sub.1, R.sup.3,
Y.sub.1 and Cy.sub.1 are as defined in any of the embodiments of
Formula I described herein.
[1103] In a 101.sup.st aspect, the invention provides a method of
preparing a compound of Formula I. The method includes contacting a
compound of Formula II with an agent under conditions sufficient to
form a compound of Formula I. The agent can be an oxidizing or a
reducing agent. Examples of the oxidizing agent include, but are
not limited to, Dess-Martin periodinane (DMP). Examples of the
reducing agents include, but are not limited to, trialkylsilane. In
some embodiments, the method is provided to prepare any of the
compounds set forth in Tables 1 or 2, or any of compounds of
Formula I or any compounds as described herein.
[1104] In a 102.sup.nd aspect, the invention provides a method of
preparing a compound of Formulas II or IIa. The method includes
contacting a compound of Formula III:
##STR00059##
with a compound of Formula IV:
##STR00060##
under conditions sufficient to form a compound of Formula II or
IIa, wherein Z.sup.2 is Br, Cl or R.sup.2 as defined in any of the
embodiments described herein; Z.sup.3 is iodo, a leaving group or a
labile group; P.sup.1 and P.sup.2 are each independently an amino
protecting group. In one embodiment, Z.sup.2 is Cl or Br and
Z.sup.3 is I. In another embodiment, Z.sup.2 is R.sup.2. In some
embodiments, Z.sup.3 is iodo, methanesulfonyloxy,
p-toluenesulfonyloxy, trifluoromethanesulfonyloxy. All the other
variables X.sub.1, R.sup.3, Y.sub.1 and Cy.sub.1 are as defined in
any of the embodiments of Formula I described herein. In some
embodiments, the method is provided to prepare any of the compounds
set forth in Tables 1 or 2, or any of compounds of Formula I or any
of the compounds as described herein. In some embodiments, a
compound of Formula IV is an aldehyde selected from those set forth
in Tables 3, 4, 5 and/or 6. In some embodiments, compounds of
Formula III is a pyrrolo[2,3-b]pyridine compound selected from
those set forth in Tables 4, 5 and/or 6. In some embodiments,
compounds of formula IV is a pyrrolo[2,3-b]pyrimidine selected from
those set forth in Table 5.
[1105] Any one or more of compounds of Formula I demonstrate
desirable inhibitory activity on one or more of Fms, Kit, Flt3 and
Trk kinases, including desirable activity profiles as described
herein with selectivity relative to other kinases. Compounds of
Formula I further demonstrate one or more desirable properties,
including enhanced pharmacokinetic properties, favorable
solubility, favorable lack of Cyp inhibition, and the like.
[1106] Additional aspects and embodiments will be apparent from the
following Detailed Description of the Invention and from the
claims.
DETAILED DESCRIPTION OF THE INVENTION
[1107] As used herein the following definitions apply unless
clearly indicated otherwise:
[1108] It is noted here that as used in this specification and the
appended claims, the singular forms "a," "an," and "the" include
plural reference unless the context clearly dictates otherwise.
[1109] All atoms designated within a Formula described herein,
either within a structure provided, or within the definitions of
variables related to the structure, is intended to include any
isotope thereof, unless clearly indicated to the contrary. It is
understood that for any given atom, the isotopes may be present
essentially in ratios according to their natural occurrence, or one
or more particular atoms may be enhanced with respect to one or
more isotopes using synthetic methods known to one skilled in the
art. Thus, hydrogen includes for example .sup.1H, .sup.2H, .sup.3H;
carbon includes for example .sup.11C, .sup.12C, .sup.13C, .sup.14C;
oxygen includes for example .sup.16O, .sup.17O, .sup.18O; nitrogen
includes for example .sup.13N, .sup.14N, .sup.15N; sulfur includes
for example .sup.32S, .sup.33S, .sup.34S, .sup.35S, .sup.36S,
.sup.37S, .sup.38S; fluoro includes for example .sup.17F, .sup.18F,
.sup.19F; chloro includes for example .sup.35Cl, .sup.36Cl,
.sup.37Cl, .sup.38Cl, .sup.39Cl; and the like.
[1110] "Halogen" refer to all halogens, that is, chloro (Cl),
fluoro (F), bromo (Br), or iodo (I).
[1111] "Haloalkyl," is meant to include alkyl substituted by one to
seven halogen atoms. Haloalkyl includes monohaloalkyl and
polyhaloalkyl. For example, the term "C.sub.1-6 haloalkyl" is meant
to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,
4-chlorobutyl, 3-bromopropyl, and the like.
[1112] "Hydroxyl" or "hydroxy" refer to the group --OH.
[1113] "Thiol" refers to the group --SH.
[1114] "Lower alkyl" alone or in combination means an
alkane-derived radical containing from 1 to 6 carbon atoms (unless
otherwise specified) that includes a straight chain alkyl or
branched alkyl. The straight chain or branched lower alkyl group is
chemically feasible and attached at any available point to provide
a stable compound. In many embodiments, a lower alkyl is a straight
or branched alkyl group containing from 1-6, 1-4, 1-3, or 1-2,
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, and the like. In some instances, the option of the number
of carbon atoms in a lower alkyl is specified, for example,
C.sub.1-3 alkyl refers to lower alkyl having 1, 2 or 3 carbon
atoms. A "substituted lower alkyl" denotes lower alkyl that is
independently substituted, unless indicated otherwise, with one or
more, preferably 1, 2, 3, 4, 5 or 6, also 1, 2, or 3 substituents,
as described herein, attached at any available atom to provide a
stable compound. For example "fluoro substituted lower alkyl"
denotes a lower alkyl group substituted with one or more fluoro
atoms, such as perfluoroalkyl, where preferably the lower alkyl is
substituted with 1, 2, 3, 4, 5 or 6 fluoro atoms, also 1, 2, or 3
fluoro atoms. It is understood that substitutions are chemically
feasible and attached at any available atom to provide a stable
compound.
[1115] "Lower alkoxy" denotes the group --OR.sup.a, where R.sup.a
is lower alkyl. In some instances, the option of the number of
carbon atoms in the lower alkyl is specified, for example,
C.sub.1-3 alkoxy refers to lower alkoxy having 1, 2 or 3 carbon
atoms. "Substituted lower alkoxy" denotes lower alkoxy in which
R.sup.z is lower alkyl substituted with one or more substituents as
indicated herein, for example, in the description of compounds of
Formula I, including descriptions of substituted cycloalkyl, phenyl
and heteroaryl, attached at any available atom to provide a stable
compound. Preferably, substitution of lower alkoxy is with 1, 2, 3,
4, 5 or 6 substituents, also 1, 2, or 3 substituents. For example
"fluoro substituted lower alkoxy" denotes lower alkoxy in which the
lower alkyl is substituted with one or more fluoro atoms, where
preferably the lower alkoxy is substituted with 1, 2, 3, 4, 5 or 6
fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that
substitutions on alkoxy are chemically feasible and attached at any
available atom to provide a stable compound.
[1116] "Lower alkylthio" denotes the group --SR.sup.b, where
R.sup.b is lower alkyl. In some instances, the option of the number
of carbon atoms in the lower alkyl is specified, for example,
C.sub.1-3 alkylthio refers to lower alkylthio having 1, 2 or 3
carbon atoms. "Substituted lower alkylthio" denotes lower alkylthio
in which R.sup.z is lower alkyl substituted with one or more
substituents as indicated herein, for example, in the description
of compounds of Formula I, including descriptions of substituted
cycloalkyl, phenyl and heteroaryl, attached at any available atom
to provide a stable compound. Preferably, substitution of lower
alkylthio is with 1, 2, 3, 4, 5 or 6 substituents, also 1, 2, or 3
substituents. For example "fluoro substituted lower alkylthio"
denotes lower alkylthio in which the lower alkyl is substituted
with one or more fluoro atoms, where preferably the lower alkylthio
is substituted with 1, 2, 3, 4, 5 or 6 fluoro atoms, also 1, 2, or
3 fluoro atoms. It is understood that substitutions on alkylthio
are chemically feasible and attached at any available atom to
provide a stable compound.
[1117] "Lower alkylsulfonyl" denotes the group --S(O).sub.2R.sup.c,
where R.sup.c is lower alkyl. In some instances, the option of the
number of carbon atoms in the lower alkyl is specified, for
example, C.sub.1-3 alkylsulfonyl refers to lower alkylsulfonyl
having 1, 2 or 3 carbon atoms. "Substituted lower alkylsulfonyl"
denotes lower alkysulfonyl in which R.sup.z is lower alkyl
substituted with one or more substituents as indicated herein, for
example, in the description of compounds of Formula I, including
descriptions of substituted cycloalkyl, phenyl and heteroaryl,
attached at any available atom to provide a stable compound.
Preferably, substitution of lower alkylsulfonyl is with 1, 2, 3, 4,
5 or 6 substituents, also 1, 2, or 3 substituents. For example
"fluoro substituted lower alkylsulfonyl" denotes lower
alkylsulfonyl in which the lower alkyl is substituted with one or
more fluoro atoms, where preferably the lower alkylsulfonyl is
substituted with 1, 2, 3, 4, 5 or 6 fluoro atoms, also 1, 2, or 3
fluoro atoms. It is understood that substitutions on alkylsulfonyl
are chemically feasible and attached at any available atom to
provide a stable compound.
[1118] "Cycloalkyl" refers to saturated or unsaturated,
non-aromatic monocyclic carbon ring systems of 3-8, more preferably
3-6, ring members per ring, such as cyclopropyl, cyclopentyl,
cyclohexyl, and the like. In some instances, the option of the
number of carbon atoms in the cycloalkyl is specified, for example,
C.sub.1-3 cycloalkyl refers to cycloalkyl having 1, 2 or 3 carbon
atoms. A "substituted cycloalkyl" is a cycloalkyl that is
independently substituted, unless indicated otherwise, with one or
more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, as
described herein, attached at any available atom to provide a
stable compound. It is understood that substitutions are chemically
feasible and attached at any available atom to provide a stable
compound.
[1119] "Cycloalkylalkyl" refers to an -(alkylene)-cycloalkyl group
where alkylene as defined herein has the indicated number of carbon
atoms or if unspecified having six or fewer, preferably four or
fewer main chain carbon atoms; and cycloalkyl is as defined herein
has the indicated number of carbon atoms. C.sub.3-8cycloalkylalkyl
is meant to have 3 to 8 ring carbon atoms. Exemplary
cycloalkylalkyl include, e.g., cyclopropylmethylene,
cyclobutylethylene, cyclobutylmethylene, and the like.
[1120] The term "alkylene" by itself or as part of another
substituent means a linear or branched saturated divalent
hydrocarbon moiety derived from an alkane having the number of
carbon atoms indicated in the prefix. For example, (i.e., C.sub.1-6
means one to six carbons; C.sub.1-6 alkylene is meant to include
methylene, ethylene, propylene, 2-methylpropylene, pentylene,
hexylene and the like). C.sub.1-4 alkylene includes methylene
--CH.sub.2--, ethylene --CH.sub.2CH.sub.2--, propylene
--CH.sub.2CH.sub.2CH.sub.2--, and isopropylene
--CH(CH.sub.3)CH.sub.2--, --CH.sub.2CH(CH.sub.3)--,
--CH.sub.2--(CH.sub.2).sub.2CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)CH.sub.2--,
--CH.sub.2--C(CH.sub.3).sub.2--,
--CH.sub.2--CH.sub.2CH(CH.sub.3)--. Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms
being preferred in the present invention. When a prefix is not
included to indicate the number of carbon atoms in an alkylene
portion, the alkylene moiety or portion thereof will have 12 or
fewer main chain carbon atoms or 8 or fewer main chain carbon
atoms, 6 or fewer main chain carbon atoms or 4 or fewer main chain
carbon atoms.
[1121] "Aryl" by itself or as part of another substituent refers to
a monocyclic, bicyclic or polycyclic polyunsaturated aromatic
hydrocarbon moiety containing 6 to 14 ring carbon atoms.
Non-limiting examples of unsubstituted aryl groups include phenyl,
1-naphthyl, 2-naphthyl and 4-biphenyl. Exemplary aryl group, such
as phenyl or naphthyl, which may be optionally fused with a
cycloalkyl of preferably 5-7, more preferably 5-6, ring
members.
[1122] "Arylalkyl" refers to -(alkylene)-aryl, where the alkylene
group is as defined herein and has the indicated number of carbon
atoms, or if unspecified having six or fewer main chain carbon
atoms or four or fewer main chain carbon atoms; and aryl is as
defined herein. Examples of arylalkyl include benzyl, phenethyl,
and the like.
[1123] A "substituted phenyl" is a phenyl ring that is
independently substituted, unless indicated otherwise, with one or
more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, as
described herein, attached at any available atom to provide a
stable compound. It is understood that substitutions are chemically
feasible and attached at any available atom to provide a stable
compound.
[1124] "Heteroaryl" by itself or as part of another substituent
refers to a monocyclic aromatic ring structure containing 5 or 6
ring atoms, or a bicyclic aromatic group having 8 to 10 atoms,
containing one or more, preferably 1-4, more preferably 1-3, even
more preferably 1-2, heteroatoms independently selected from the
group consisting of O, S, and N. "5 or 6 membered heteroaryl" alone
or in combination refers to a monocyclic aromatic ring structure
containing 5 or 6 ring atoms, containing one or more, preferably
1-4, more preferably 1-3, even more preferably 1-2, heteroatoms
independently selected from the group consisting of O, S, and N.
Heteroaryl is also intended to include oxidized S or N, such as
sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A
carbon or nitrogen atom is the point of attachment of the
heteroaryl ring structure such that a stable compound is provided.
Examples of heteroaryl groups include, but are not limited to,
pyridinyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl,
quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl,
pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl,
oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl,
furanyl, benzofuryl, indolyl, triazinyl, quinoxalinyl, cinnolinyl,
phthalaziniyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl,
benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl,
indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl,
pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl,
benzothienyl, quinolyl, isoquinolyl, indazolyl, pteridinyl and
thiadiazolyl, and the like. A "substituted heteroaryl" is a
heteroaryl that is independently substituted, unless indicated
otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2,
or 3 substituents, as described herein, attached at any available
atom to provide a stable compound. It is understood that
substitutions are chemically feasible and attached at any available
atom to provide a stable compound.
[1125] "Heteroarylalkyl" refers to -(alkylene)-heteroaryl, where
the alkylene group is as defined herein and has the indicated
number of carbon atoms, or if unspecified having six or fewer main
chain carbon atoms or four or fewer main chain carbon atoms; and
heteroaryl is as defined herein. Examples of heteroarylalkyl
include 2-pyridylmethyl, 2-thiazolylethyl, and the like.
[1126] "Heterocycloalkyl" refers to a saturated or unsaturated
non-aromatic cycloalkyl group that contains from one to five
heteroatoms selected from N, O, and S, wherein the nitrogen and
sulfur atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized, the remaining ring atoms being C, where one
or two C atoms may optionally be replaced by a carbonyl. The
heterocycloalkyl may be a monocyclic, a bicyclic or a polycyclic
ring system of 3 to 12, preferably 4 to 10 ring atoms, more
preferably 5 to 8 ring atoms in which one to five ring atoms are
heteroatoms selected from --N.dbd., --N--, --O--, --S--, --S(O)--,
or --S(O).sub.2-- and further wherein one or two ring atoms are
optionally replaced by a --C(O)-- group. The heterocycloalkyl can
also be a heterocyclic alkyl ring fused with a cycloalkyl, an aryl
or a heteroaryl ring. Non limiting examples of heterocycloalkyl
groups include pyrrolidinyl, piperidinyl, imidazolidinyl,
pyrazolidinyl, butyrolactam moiety, valerolactam moiety,
imidazolidinone moiety, hydantoin, dioxolane moiety, phthalimide
moiety, piperidine, 1,4-dioxane moiety, morpholinyl,
thiomorpholinyl, thiomorpholinyl-S-oxide,
thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridine moiety,
3-pyrrolinyl, thiopyranyl, pyrone moiety, tetrahydrofuranyl,
tetrahydrothiophenyl, quinuclidinyl, and the like. A
heterocycloalkyl group can be attached to the remainder of the
molecule through a ring carbon or a heteroatom.
[1127] "Heterocycloalkylalkyl" refers to
-(alkylene)-heterocycloalkyl, where the alkylene group is as
defined herein and has the indicated number of carbon atoms, or if
unspecified having six or fewer main chain carbon atoms or four or
fewer main chain carbon atoms; and heterocycloalkyl is as defined
herein. Examples of heterocycloalkylalkyl include 2-pyridylmethyl,
2-thiazolylethyl, and the like.
[1128] "Protecting group" refers to a grouping of atoms that when
attached to a reactive group in a molecule masks, reduces or
prevents that reactivity. Examples of protecting groups can be
found in T. W. Greene and P. G. Wuts, PROTECTIVE GROUPS IN ORGANIC
CHEMISTRY, (Wiley, 4th ed. 2006), Beaucage and Iyer, Tetrahedron
48:2223-2311 (1992), and Harrison and Harrison et al., COMPENDIUM
OF SYNTHETIC ORGANIC METHODS, Vols. 1-8 (John Wiley and Sons.
1971-1996). Representative amino protecting groups include formyl,
acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),
tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),
2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted
trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl
(TIPS), phenylsulphonyl and the like (see also, Boyle, A. L.
(Editor), carbamates, amides, N-sulfonyl derivatives, groups of
formula --C(O)OR, wherein R is, for example, methyl, ethyl,
t-butyl, benzyl, phenylethyl, CH.sub.2.dbd.CHCH.sub.2--, and the
like, groups of the formula --C(O)R', wherein R' is, for example,
methyl, phenyl, trifluoromethyl, and the like, groups of the
formula --SO.sub.2R'', wherein R'' is, for example, tolyl, phenyl,
trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,
2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl
containing groups, such as 2-trimethyl silylethoxymethyl,
t-butyldimethylsilyl, triisopropylsilyl, and the like, CURRENT
PROTOCOLS IN NUCLEIC ACID CHEMISTRY, John Wiley and Sons, New York,
Volume 1, 2000). Representative hydroxyl protecting groups include,
but are not limited to, acetyl, benzoyl, dimethoxytrityl,
methoxyethyoxymethyl, methoxymethyl, p-methoxybenzyl,
tetrahydropyranyl, methylthiomethyl, trityl,
t-butyldimethylsilyloxymethyl and trialkylsilyl, such as TMS, TIPS
and the like.
[1129] As used herein, "Leaving group" or "Labile group" has the
meaning conventionally associated with it in synthetic organic
chemistry, i.e., an atom or a group capable of being displaced by a
nucleophile and includes halo (such as chloro, bromo, and iodo),
alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.,
acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,
trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),
methoxy, N,O-dimethylhydroxylamino, and the like.
[1130] "Tautomer" means compounds produced by the phenomenon
wherein a proton of one atom of a molecule shifts to another atom.
See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms
and Structures, Fourth Edition, John Wiley & Sons, pages 69-74
(1992). The tautomers also refer to one of two or more structural
isomers that exist in equilibrium and are readily converted from
one isomeric form to another. Examples of include keto-enol
tautomers, such as acetone/propen-2-ol, imine-enamine tautomers and
the like, ring-chain tautomers, such as
glucose/2,3,4,5,6-pentahydroxy-hexanal and the like, the tautomeric
forms of heteroaryl groups containing a --N.dbd.C(H)--NH-- ring
atom arrangement, such as pyrazoles, imidazoles, benzimidazoles,
triazoles, and tetrazoles. Where the compound contains, for
example, a keto or oxime group or an aromatic moiety, tautomeric
isomerism (tautomerism') can occur. The compounds described herein
may have one or more tautomers and therefore include various
isomers. A person of ordinary skill in the art would recognize that
other tautomeric ring atom arrangements are possible. All such
isomeric forms of these compounds are expressly included in the
present invention.
[1131] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. "Hydrate" refers to a complex formed by combination of water
molecules with molecules or ions of the solute. "Solvate" refers to
a complex formed by combination of solvent molecules with molecules
or ions of the solute. The solvent can be an organic compound, an
inorganic compound, or a mixture of both. Solvate is meant to
include hydrate. Some examples of solvents include, but are not
limited to, methanol, N,N-dimethylformamide, tetrahydrofuran,
dimethylsulfoxide, and water. In general, the solvated forms are
equivalent to unsolvated forms and are encompassed within the scope
of the present invention. Certain compounds of the present
invention may exist in multiple crystalline or amorphous forms. In
general, all physical forms are equivalent for the uses
contemplated by the present invention and are intended to be within
the scope of the present invention
[1132] As used herein, the term "Fms and Kit related disease or
condition" refers to a disease or condition in which the biological
function of a Fms protein kinase, including any mutation thereof, a
Kit protein kinase, including any mutation thereof, or both a Fms
and Kit protein kinase, including any mutations thereof, affects
the development, course, and/or symptoms of the disease or
condition, and/or in which modulation of the Fms and/or Kit protein
kinase alters the development, course, and/or symptoms of the
disease or condition. A Fms and/or Kit related disease or condition
includes a disease or condition for which modulation provides a
therapeutic benefit, e.g. wherein treatment with a Fms and/or Kit
protein kinase inhibitor, preferably a dual Fms/Kit inhibitor,
including one or more compound(s) described herein, provides a
therapeutic benefit to the subject suffering from or at risk of the
disease or condition.
[1133] As used herein, the term "Fms related disease or condition"
and the like refers to a disease or condition in which the
biological function of a Fms protein kinase, including any
mutations thereof, affects the development, course, and/or symptoms
of the disease or condition, and/or in which modulation of the Fms
protein kinase alters the development, course, and/or symptoms of
the disease or condition. The Fms related disease or condition
includes a disease or condition for which Fms inhibition provides a
therapeutic benefit, e.g. wherein treatment with a Fms inhibitor,
preferably a Fms selective inhibitor including one or more
compound(s) described herein, provides a therapeutic benefit to the
subject suffering from or at risk of the disease or condition.
[1134] As used herein, the terms "Kit related disease or condition"
and the like refers to a disease or condition in which the
biological function of a Kit protein kinase, including any
mutations thereof, affects the development, course, and/or symptoms
of the disease or condition, and/or in which modulation of the Kit
protein kinase alters the development, course, and/or symptoms of
the disease or condition. The Kit related disease or condition
includes a disease or condition for which Kit inhibition provides a
therapeutic benefit, e.g. wherein treatment with a Kit inhibitor,
including one or more compound(s) described herein, provides a
therapeutic benefit to the subject suffering from or at risk of the
disease or condition.
[1135] As used herein, the term "dual Fms/Kit inhibitor" refers to
a compound that inhibits both Fms and Kit protein kinases, i.e. a
compound having an IC.sub.50 of less than 500 nm, less than 100 nM,
less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM,
or less than 1 nM as determined in a generally accepted Fms kinase
activity assay and having an IC.sub.50 of less than 500 nm, less
than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM,
less than 5 nM, or less than 1 nM as determined in a comparable
generally accepted Kit kinase activity assay, wherein the activity
is approximately equipotent on each. Compounds are considered
approximately equipotent if the ratio of IC.sub.50 for Kit kinase
activity divided by the IC.sub.50 for Fms kinase activity is in the
range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. Such compounds
are effective in treating a disease or condition that is either or
both of a Fms related and Kit related disease or condition. Such
compounds are preferably, but not necessarily, selective with
respect to other protein kinases, i.e. when compared to another
protein kinase, the IC.sub.50 for the other kinase divided by the
IC.sub.50 for Fms kinase (and/or Kit kinase) is >20, also
>30, also >40, also >50, also >60, also >70, also
>80, also >90, also >100. Preferably, the compounds are
selective relative to other protein kinases including, but not
limited to, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
While it is understood that a dual Fms/Kit inhibitor may be used to
treat any Fms related disease or condition, the dual inhibition of
Fms and Kit provides beneficial effects in treating certain
diseases or conditions, including, but not limited to, breast
cancer, prostate cancer, multiple myeloma, melanoma, acute myeloid
leukemia, glioblastoma, brain metastases, neurofibromatosis,
gastrointestinal stromal tumors, rheumatoid arthritis, or multiple
sclerosis.
[1136] As used herein, the term "dual Fms/Flt-3 inhibitor" refers
to a compound that inhibits both Fms and Flt-3 protein kinases,
i.e. a compound having an IC.sub.50 of less than 500 nm, less than
100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less
than 5 nM, or less than 1 nM as determined in a generally accepted
Fms kinase activity assay and having an IC.sub.50 of less than 500
nm, less than 100 nM, less than 50 nM, less than 20 nM, less than
10 nM, less than 5 nM, or less than 1 nM as determined in a
comparable generally accepted Flt-3 kinase activity assay, wherein
the activity is approximately equipotent on each. Compounds are
considered approximately equipotent if the ratio of IC.sub.50 for
Flt-3 kinase activity divided by the IC.sub.50 for Fms kinase
activity is in the range of 20 to 0.05, also 10 to 0.1, also 5 to
0.2. Such compounds are effective in treating a disease or
condition that is either or both of a Fms related and Flt-3 related
disease or condition. Such compounds are preferably, but not
necessarily, selective with respect to other protein kinases, i.e.
when compared to another protein kinase, the IC.sub.50 for the
other kinase divided by the IC.sub.50 for Fms kinase (and/or Flt3
kinase) is >20, also >30, also >40, also >50, also
>60, also >70, also >80, also >90, also >100.
Preferably, the compounds are selective relative to other protein
kinases including, but not limited to, CSK, Insulin receptor
kinase, AMPK, PDGFR or VEGFR. While it is understood that a dual
Fms/Flt-3 inhibitor may be used to treat any Fms related mediated
disease or condition, the dual inhibition of Fms and Flt-3 provides
beneficial effects in treating certain diseases or conditions,
including, but not limited to, breast cancer, prostate cancer,
multiple myeloma, melanoma, acute myeloid leukemia, glioblastoma,
brain metastases, neurofibromatosis, gastrointestinal stromal
tumors, rheumatoid arthritis, or multiple sclerosis.
[1137] As used herein, the term "dual Fms/Trk inhibitor" refers to
a compound that inhibits both Fms and Trk protein kinases, i.e. a
compound having an IC.sub.50 of less than 500 nm, less than 100 nM,
less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM,
or less than 1 nM as determined in a generally accepted Fms kinase
activity assay and having an IC.sub.50 of less than 500 nm, less
than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM,
less than 5 nM, or less than 1 nM as determined in a comparable
generally accepted Trk kinase activity assay (i.e. any one or more
of TrkA, TrkB and TrkC), wherein the activity is approximately
equipotent on each. Compounds are considered approximately
equipotent if the ratio of IC.sub.50 for Trk kinase activity (i.e.
at least one of TrkA, TrkB and TrkC) divided by the IC.sub.50 for
Fms kinase activity is in the range of 20 to 0.05, also 10 to 0.1,
also 5 to 0.2. Such compounds are effective in treating a disease
or condition that is either or both of a Fms related and Trk
related disease or condition. Such compounds are preferably, but
not necessarily, selective with respect to other protein kinases,
i.e. when compared to another protein kinase, the IC.sub.50 for the
other kinase divided by the IC.sub.50 for Fms kinase (and/or Trk
kinase) is >20, also >30, also >40, also >50, also
>60, also >70, also >80, also >90, also >100.
Preferably, the compounds are selective relative to other protein
kinases including, but not limited to, CSK, Insulin receptor
kinase, AMPK, PDGFR or VEGFR. While it is understood that a dual
Fms/Trk inhibitor may be used to treat any Fms related mediated
disease or condition, the dual inhibition of Fms and Trk provides
beneficial effects in treating certain diseases or conditions,
including, but not limited to, pancreatic cancer, prostate cancer,
and multiple myeloma.
[1138] As used herein, the term "Fms selective inhibitor" refers to
a compound that selectively inhibits Fms kinase relative to Kit
kinase, i.e. a compound having an IC.sub.50 of less than 500 nm,
less than 100 nM, less than 50 nM, less than 20 nM, less than 10
nM, less than 5 nM, or less than 1 nM as determined in a generally
accepted Fms kinase activity assay and when determined in a
comparable generally accepted Kit kinase activity assay will have a
ratio of IC.sub.50 for Kit kinase divided by the IC.sub.50 for Fms
kinase of >20, also >30, also >40, also >50, also
>60, also >70, also >80, also >90, also >100. Such
compounds are effective in treating a disease or condition that is
Fms protein kinase mediated, without effecting Kit protein kinase.
Such compounds are preferably, but not necessarily, selective with
respect to other protein kinases, i.e. when compared to another
protein kinase, the IC.sub.50 for the other kinase divided by the
IC.sub.50 for Fms kinase is >20, also >30, also >40, also
>50, also >60, also >70, also >80, also >90, also
>100. Preferably, the compounds are selective relative to other
protein kinases including, but not limited to, CSK, Insulin
receptor kinase, AMPK, PDGFR or VEGFR. While it is understood that
a Fms selective inhibitor may be used to treat any Fms related
disease or condition, the Fms selectivity provides beneficial
effects in treating certain diseases or conditions, including, but
not limited to, multiple sclerosis, Alzheimer's disease,
Parkinson's disease, global ischemia, rheumatoid arthritis,
osteoarthritis, osteoporosis, peri-prosthetic osteolysis,
glomerulonephritis, interstitial nephritis, Lupus nephritis,
diabetic nephropathy, or renal hypertrophy.
[1139] As used herein, the term "blood brain barrier" refers to the
physical barrier in the circulation system that prevents many
substances, including certain small molecule drugs, from entering
into the central nervous system (CNS). Drugs which are intended to
interact with molecular targets in the CNS must cross the blood
brain barrier to reach their intended targets. Conversely,
peripherally acting agents should not cross the blood brain barrier
so as to avoid any CNS related side effects. The ability of a
compound to penetrate the blood brain barrier is expressed as the
blood brain barrier permeability or the ratio of the steady-state
concentrations of the compound in the brain and in the blood. The
experimental blood brain barrier permeability can be measured by in
vivo methods. Various methods can be employed for measuring the
fraction of compound transported from the blood to brain tissue,
including brain blood partitioning, brain perfusion, brain uptake
index, and intracerebral microdialysis. However, these in vivo
methods are laborious and low-throughput in nature. In practice, in
silico computational methods are often used to predict the blood
brain barrier permeability prior to in vivo confirmation. Most of
the blood brain barrier models that have been built so far are
based on the assumption that the majority of the compounds are
transported across the blood brain barrier by passive diffusion. Of
all the physicochemical properties, polar surface area (PSA) shows
the best correlation with the blood brain barrier permeability for
passively diffused compounds. Empirical evidence suggests that
compounds having a polar surface area of 100 or greater typically
have a low probability of crossing the blood brain barrier. Polar
surface area is readily calculated from the compound structure
using a published algorithm (Ertl et al., J. Med. Chem. 2000,
43:3714-3717). While it is understood that a Fms selective
inhibitor may be used to treat any Fms related disease or
condition, compounds that effectively cross the blood brain barrier
provide beneficial effects in treating certain diseases or
conditions, including, but not limited to, multiple sclerosis,
Alzheimer's disease, Parkinson's disease, and global ischemia,
while compounds that do not effectively cross the blood brain
barrier provide beneficial effects in treating certain diseases or
conditions, including, but not limited to, rheumatoid arthritis,
osteoarthritis, osteoporosis, peri-prosthetic osteolysis,
glomerulonephritis, interstitial nephritis, Lupus nephritis,
diabetic nephropathy, or renal hypertrophy.
[1140] As used herein, the terms "treat", "treating", "therapy",
"therapies", and like terms refer to the administration of
material, e.g., any one or more compound(s) as described herein in
an amount effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or condition, i.e., indication, and/or
to prolong the survival of the subject being treated.
[1141] As used herein, the term "solid form" refers to a solid
preparation (i.e. a preparation that is neither gas nor liquid) of
a pharmaceutically active compound that is suitable for
administration to an intended animal subject for therapeutic
purposes. The solid form includes any complex, such as a salt,
co-crystal or an amorphous complex, as well as any polymorph of the
compound. The solid form may be substantially crystalline,
semi-crystalline or substantially amorphous. The solid form may be
administered directly or used in the preparation of a suitable
composition having improved pharmaceutical properties. For example,
the solid form may be used in a formulation comprising at least one
pharmaceutically acceptable carrier or excipient.
[1142] As used herein, the term "substantially crystalline"
material embraces material which has greater than about 90%
crystallinity; and "crystalline" material embraces material which
has greater than about 98% crystallinity.
[1143] As used herein, the term "substantially amorphous" material
embraces material which has no more than about 10% crystallinity;
and "amorphous" material embraces material which has no more than
about 2% crystallinity.
[1144] As used herein, the term "semi-crystalline" material
embraces material which is greater than 10% crystallinity, but no
greater than 90% crystallinity; preferably "semi-crystalline"
material embraces material which is greater than 20% crystallinity,
but no greater than 80% crystallinity. In one aspect of the present
invention, a mixture of solid forms of a compound may be prepared,
for example, a mixture of amorphous and crystalline solid forms,
e.g. to provide a "semi-crystalline" solid form. Such a
"semi-crystalline" solid form may be prepared by methods known in
the art, for example by mixing an amorphous solid form with a
crystalline solid form in the desired ratio. In some instances, a
compound mixed with acid or base forms an amorphous complex; a
semi-crystalline solid can be prepared employing an amount of
compound component in excess of the stoichiometry of the compound
and acid or base in the amorphous complex, thereby resulting in an
amount of the amorphous complex that is based on the stoichiometry
thereof, with excess compound in a crystalline form. The amount of
excess compound used in the preparation of the complex can be
adjusted to provide the desired ratio of amorphous complex to
crystalline compound in the resulting mixture of solid forms. For
example, where the amorphous complex of acid or base and compound
has a 1:1 stoichiometry, preparing said complex with a 2:1 mole
ratio of compound to acid or base will result in a solid form of
50% amorphous complex and 50% crystalline compound. Such a mixture
of solid forms may be beneficial as a drug product, for example, by
providing an amorphous component having improved biopharmaceutical
properties along with the crystalline component. The amorphous
component would be more readily bioavailable while the crystalline
component would have a delayed bioavailability. Such a mixture may
provide both rapid and extended exposure to the active
compound.
[1145] As used herein, the term "complex" refers to a combination
of a pharmaceutically active compound and an additional molecular
species that forms or produces a new chemical species in a solid
form. In some instances, the complex may be a salt, i.e. where the
additional molecular species provides an acid/base counter ion to
an acid/base group of the compound resulting in an acid:base
interaction that forms a typical salt. While such salt forms are
typically substantially crystalline, they can also be partially
crystalline, substantially amorphous, or amorphous forms. In some
instances, the additional molecular species, in combination with
the pharmaceutically active compound, forms a non-salt co-crystal,
i.e. the compound and molecular species do not interact by way of a
typical acid:base interaction, but still form a substantially
crystalline structure. Co-crystals may also be formed from a salt
of the compound and an additional molecular species. In some
instances, the complex is a substantially amorphous complex, which
may contain salt-like acid:base interactions that do not form
typical salt crystals, but instead form a substantially amorphous
solid, i.e. a solid whose X-ray powder diffraction pattern exhibits
no sharp peaks (e.g. exhibits an amorphous halo).
[1146] As used herein, the term "stoichiometry" refers to the molar
ratio of two or more reactants that combine to form a complex, for
example, the molar ratio of acid or base to compound that form an
amorphous complex. For example, a 1:1 mixture of acid or base with
compound (i.e. 1 mole acid or base per mole of compound) resulting
in an amorphous solid form has a 1:1 stoichiometry.
[1147] As used herein, the term "composition" refers to a
pharmaceutical preparation suitable for administration to an
intended animal subject for therapeutic purposes that contains at
least one pharmaceutically active compound, including any solid
form thereof. The composition may include at least one
pharmaceutically acceptable component to provide an improved
formulation of the compound, such as a suitable carrier or
excipient.
[1148] The term "pharmaceutically acceptable" indicates that the
indicated material does not have properties that would cause a
reasonably prudent medical practitioner to avoid administration of
the material to a patient, taking into consideration the disease or
conditions to be treated and the respective route of
administration. For example, it is commonly required that such a
material be essentially sterile, e.g., for injectables.
[1149] In the present context, the term "therapeutically effective"
or "effective amount" indicates that the materials or amount of
material is effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or medical condition, and/or to prolong
the survival of the subject being treated.
[1150] "Unit dosage form" refers to a composition intended for a
single administration to treat a subject suffering from a disease
or medical condition. Each unit dosage form typically comprises
each of the active ingredients of this invention plus
pharmaceutically acceptable excipients. Examples of unit dosage
forms are individual tablets, individual capsules, bulk powders,
liquid solutions, ointments, creams, eye drops, suppositories,
emulsions or suspensions. Treatment of the disease or condition may
require periodic administration of unit dosage forms, for example:
one unit dosage form two or more times a day, one with each meal,
one every four hours or other interval, or only one per day. The
expression "oral unit dosage form" indicates a unit dosage form
designed to be taken orally.
[1151] In the present context, the terms "synergistically
effective" or "synergistic effect" indicate that two or more
compounds that are therapeutically effective, when used in
combination, provide improved therapeutic effects greater than the
additive effect that would be expected based on the effect of each
compound used by itself.
[1152] In the context of compounds binding to a target, the terms
"greater affinity" and "selective" indicates that the compound
binds more tightly than a reference compound, or than the same
compound in a reference condition, i.e., with a lower dissociation
constant. In some embodiments, the greater affinity is at least 2,
3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold
greater affinity.
[1153] As used herein in connection with compounds of the
invention, the term "synthesizing" and like terms means chemical
synthesis from one or more precursor materials.
[1154] By "assaying" is meant the creation of experimental
conditions and the gathering of data regarding a particular result
of the experimental conditions. For example, enzymes can be assayed
based on their ability to act upon a detectable substrate. A
compound or ligand can be assayed based on its ability to bind to a
particular target molecule or molecules.
[1155] As used herein, the term "modulating" or "modulate" refers
to an effect of altering a biological activity, especially a
biological activity associated with a particular biomolecule such
as a protein kinase. For example, an agonist or antagonist of a
particular biomolecule modulates the activity of that biomolecule,
e.g., an enzyme, by either increasing (e.g. agonist, activator), or
decreasing (e.g. antagonist, inhibitor) the activity of the
biomolecule, such as an enzyme. Such activity is typically
indicated in terms of an inhibitory concentration (IC.sub.50) or
excitation concentration (EC.sub.50) of the compound for an
inhibitor or activator, respectively, with respect to, for example,
an enzyme.
[1156] In the context of the use, testing, or screening of
compounds that are or may be modulators, the term "contacting"
means that the compound(s) are caused to be in sufficient proximity
to a particular molecule, complex, cell, tissue, organism, or other
specified material that potential binding interactions and/or
chemical reaction between the compound and other specified material
can occur.
[1157] "Pain" or a "pain condition" can be acute and/or chronic
pain, including, without limitation, arachnoiditis; arthritis (e.g.
osteoarthritis, rheumatoid arthritis, ankylosing spondylitis,
gout); back pain (e.g. sciatica, ruptured disc, spondylolisthesis,
radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches
(e.g. migraine, cluster headaches, tension headaches); head and
facial pain (e.g. cranial neuralgia, trigeminal neuralgia);
hyperalgesia; hyperpathia; inflammatory pain (e.g. pain associated
with irritable bowel syndrome, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, cystitis, pain from bacterial,
fungal or viral infection); keloid or scar tissue formation; labor
or delivery pain; muscle pain (e.g. as a result of polymyositis,
dermatomyositis, inclusion body myositis, repetitive stress injury
(e.g. writer's cramp, carpal tunnel syndrome, tendonitis,
tenosynovitis)); myofascial pain syndromes (e.g. fibromyalgia);
neuropathic pain (e.g. diabetic neuropathy, causalgia, entrapment
neuropathy, brachial plexus avulsion, occipital neuralgia, gout,
reflex sympathetic dystrophy syndrome, phantom limb or
post-amputation pain, postherpetic neuralgia, central pain
syndrome, or nerve pain resulting from trauma (e.g. nerve injury),
disease (e.g. diabetes, multiple sclerosis, Guillan-Barre Syndrome,
myasthenia gravis, neurodegenerative diseases such as Parkinson's
disease, Alzheimer's disease, amyotrophic lateral sclerosis, or
cancer treatment); pain associated with skin disorders (e.g.
shingles, herpes simplex, skin tumors, cysts, neurofibromatosis);
sports injuries (e.g. cuts, sprains, strains, bruises,
dislocations, fractures, spinal chord, head); spinal stenosis;
surgical pain; tactile allodynia; temporomandibular disorders;
vascular disease or injury (e.g. vasculitis, coronary artery
disease, reperfusion injury (e.g. following ischemia, stroke, or
myocardial infarcts)); other specific organ or tissue pain (e.g.
ocular pain, corneal pain, bone pain, heart pain, visceral pain
(e.g. kidney, gall bladder, gastrointestinal), joint pain, dental
pain, pelvic hypersensitivity, pelvic pain, renal colic, urinary
incontinence); other disease associated pain (e.g. sickle cell
anemia, AIDS, herpes zoster, psoriasis, endometriosis, asthma,
chronic obstructive pulmonary disease (COPD), silicosis, pulmonary
sarcoidosis, esophagitis, heart burn, gastroesophageal reflux
disorder, stomach and duodenal ulcers, functional dyspepsia, bone
resorption disease, osteoporosis, cerebral malaria, bacterial
meningitis); or pain due to graft v. host rejection or allograft
rejections.
Kinase Targets and Indications of the Invention
[1158] Protein kinases play key roles in propagating biochemical
signals in diverse biological pathways. More than 500 kinases have
been described, and specific kinases have been implicated in a wide
range of diseases or conditions (i.e., indications), including for
example without limitation, cancer, cardiovascular disease,
inflammatory disease, neurological disease, and other diseases. As
such, kinases represent important control points for small molecule
therapeutic intervention. Specific target protein kinases
contemplated by the present invention are described in the art,
including, without limitation, protein kinases as described in U.S.
patent application Ser. No. 11/473,347 (see also, PCT publication
WO2007002433), the disclosure of which is hereby incorporated by
reference with respect to such kinase targets, as well as the
following:
[1159] Fms:
[1160] Target kinase Fms (i.e., feline McDonough sarcoma) is a
member of the family of genes originally isolated from the Susan
McDonough strain of feline sarcoma viruses. Fms is a transmembrane
tyrosine kinase of 108.0 kDa coded by chromosome 5q33.2-q33.3
(symbol: CSF1R). The structure of the transmembrane receptor Fms
comprises two Ig-like domains, a IgC2-like domain, two additional
Ig-like domains, a TM domain, and the TK domain.
[1161] Fms is the receptor for the macrophage colony-stimulating
factor (M-CSF), and is crucial for the growth and differentiation
of the monocyte-macrophage lineage. Upon binding of M-CSF to the
extracellular domain of Fms, the receptor dimerizes and
trans-autophosphorylates cytoplasmic tyrosine residues.
[1162] M-CSF, first described by Robinson and co-workers (Blood.
1969, 33:396-9), is a cytokine that controls the production,
differentiation, and function of macrophages. M-CSF stimulates
differentiation of progenitor cells to mature monocytes, and
prolongs the survival of monocytes. Furthermore, M-CSF enhances
cytotoxicity, superoxide production, phagocytosis, chemotaxis, and
secondary cytokine production of additional factors in monocytes
and macrophages. Examples of such additional factors include
granulocyte colony stimulating factor (G-CSF), interleukin-6
(IL-6), and interleukin-8 (IL-8). M-CSF stimulates hematopoiesis,
promotes differentiation and proliferation of osteoclast progenitor
cells, and has profound effects on lipid metabolism. Furthermore,
M-CSF is important in pregnancy. Physiologically, large amounts of
M-CSF are produced in the placenta, and M-CSF is believed to play
an essential role in trophoblast differentiation (Motoyoshi, Int J
Hematol. 1998, 67:109-22). The elevated serum M-CSF levels of early
pregnancy may participate in the immunologic mechanisms responsible
for the maintenance of the pregnancy (Flanagan & Lader, Curr
Opin Hematol. 1998, 5:181-5).
[1163] Aberrant expression and/or activation of Fms has been
implicated in acute myeloid leukemia, AML (Ridge et al, Proc. Nat.
Acad. Sci., 1990, 87:1377-1380). Mutations at codon 301 are
believed to lead to neoplastic transformation by ligand
independence and constitutive tyrosine kinase activity of the
receptor. The tyrosine residue at codon 969 has been shown to be
involved in a negative regulatory activity, which is disrupted by
amino acid substitutions. Accordingly, Fms mutations are most
prevalent (20%) in chronic myelomonocytic leukemia and AML type M4
(23%), both of which are characterized by monocytic
differentiation.
[1164] A condition related to AML is chronic myeloid leukemia
(CIVIL). During the myeloid blast crisis (BC) of CIVIL, non-random
additional chromosome abnormalities occur in over 80% of patients.
However, these cytogenetic changes have been reported to precede
the clinical signs of CML-BC by several months to years suggesting
that other biological events may participate in the multistep
process of acute transformation of CIVIL. The autocrine production
of growth factors has been shown to occur in several hematological
malignancies and particularly in AML. Specchia et al [Br J
Haematol. 1992 March; 80(3):310-6] have demonstrated that IL-1 beta
gene is expressed in almost all cases of CIVIL in myeloid blast
crisis, and that a high proportion of cases showed constitutive
expression of the M-CSF gene. Many of the same patients in the
Specchia et al study demonstrated simultaneous co-expression of
Fms. After exposure of leukemic cells to phorbol myristate acetate
(PMA), release of M-CSF protein was documented in three of five
patients studied; however, no significant interleukin-3 (IL-3),
granulocyte-macrophage colony-stimulating factor (GM-CSF) or
granulocyte colony-stimulating factor (G-CSF), was detected in
these patients. This demonstrates that different patterns of growth
factors secretion exist in AML and CML, and that distinct molecular
events are likely involved in the control of leukemic
proliferation.
[1165] The observation that production of M-CSF, the major
macrophage growth factor, is increased in tissues during
inflammation (Le Meur et al, J. Leukocyte Biology. 2002;
72:530-537) provides a role for Fms in certain diseases. For
example, COPD is characterized by airflow limitation that is not
fully reversible. The airflow limitation is usually progressive and
associated with an abnormal inflammatory response of the lungs to
noxious particles or gases. The chronic inflammation of COPD is
observed through the airways, parenchyma, and pulmonary
vasculature. The inflammatory cell population consists of
neutrophils, macrophages, and T lymphocytes, along with eosinophils
in some patients. Macrophages are postulated to play an
orchestrating role in COPD inflammation by releasing mediators such
as TNF-a, IL-8 and LTB4, which are capable of damaging lung
structures and/or sustaining neutrophilic inflammation.
[1166] Further, M-CSF/fms signaling is critical to osteoclast
formation and survival of osteoclast precursors. For example,
estrogen loss in menopause results in increased M-CSF and thus
increased osteoclast number and bone resorption which leads to
increased risk of fracture and osteoporosis. Accordingly, blockage
of this signal is a target for the inhibition of bone resorption
(Teitelbaum, Science. 2000; 289:1504; Rohan, Science. 2000;
289:1508).
[1167] Atherosclerosis, an inflammatory disease of the vessel
walls, is associated with significant morbidity and mortality. A
beneficial effect for Fms inhibition in the treatment and
prevention of atherosclerosis depends on several observations
(Libby, Nature. 2002; 420:868-874). First, monocytes resident in
the arterial intima increase expression of scavenger receptors and
internalize modified lipoproteins. The resulting lipid-laden
macrophages develop into foam cells characteristic of the
atherosclerotic lesion. Macrophages in atheroma secrete cytokines
and growth factors involved in lesion progression. Additionally,
macrophages replicate within the intima. Through Fms, M-CSF
activates the transition from monocyte to lipid-laden macrophage
and augments expression of scavenger receptor A. Indeed,
atherosclerotic plaques over-express M-CSF which is critical for
atherosclerotic progression. Mice deficient in M-CSF have been
found to experience less severe atherosclerosis than mice with
normal M-CSF (Rajavashisth, et. al., J. Clin. Invest. 1998;
101:2702-2710; Qiao, et. al., Am. J. Path. 1997; 150:1687-1699).
Accordingly, inhibitors of Fms disrupt M-CSF signaling,
compromising monocyte to macrophage foam cell progression,
macrophage survival and replication, and cytokine signaling that
participates in lesion progression.
[1168] The role of M-CSF and Fms in emphysema appears to involve
the regulation of elastin metabolism through control of matrix
metalloproteins. M-CSF has a role in the modulation of the
accumulation and function of alveolar macrophages (AMs) in vivo
(Shibata et al, Blood 2001, 98: pp. 2845-2852). Osteopetrotic
(Op/Op) mice have no detectable M-CSF and show variable
tissue-specific reductions in macrophage numbers. Accordingly, it
was hypothesized that AMs would be decreased in number and have
altered function in Op/Op mice because of the absence of M-CSF.
Shibata et al found that lung macrophages identified in lung
sections were decreased in number in 20-day-old Op/Op mice but not
Op/Op mice older than 4 months compared with findings in
age-matched littermate controls. The numbers of AMs recovered by
bronchioalveolar lavage (BAL) were also reduced in young but not
adult Op/Op mice compared with controls. Importantly, AMs of Op/Op
mice spontaneously release higher levels of matrix
metalloproteinases (MMPs) than AMs of controls. Consistent with an
increased release of MMP, Op/Op mice have abnormal elastin
deposition and spontaneously develop emphysema in the absence of
molecular or cellular evidence of lung inflammation. Accordingly,
the modulation of metalloelastase activity in macrophages by M-CSF
may control the degradation of elastin fibers in lungs or blood
vessels.
[1169] Metastatic cancer cells cause bone destruction, with
associated fracture, pain, deformation, and hypercalcaemia, due to
production of osteoclasticogenic factors including M-CSF by tumor
cells (Clohisy et al, Clin. Orthop. 2000, 373: 104-14). Binding of
M-CSF to the Fms product stimulates formation of osteoclasts and
osteolytic activity (Kodama et al, J. Exp. Med. 1991, 173: 269-72;
Feng et al, Endocrinology 2002, 143: 4868-74). Accordingly,
inhibition of osteoclast activity at the level of Fms offers a
compelling target for amelioration of bone metastasis.
[1170] Nephritis is inflammation of the kidneys. It may be caused
for example by a bacterial infection of the kidneys or exposure to
a toxin. However, nephritis more commonly develops from an abnormal
immune reaction, which can occur, for example, when an antibody
attacks either the kidney itself or an antigen attached to kidney
cells, or when an antigen-antibody complex formed elsewhere in the
body attaches to cells in the kidney. Some types of nephritis
involve infiltration of kidney tissues by white blood cells and
deposits of antibodies. In other types of nephritis, inflammation
may consist of tissue swelling or scarring without white blood
cells or antibodies. Furthermore, nephritis can occur anywhere in
the kidneys. With respect to the glomeruli, progressive damage to
glomeruli causes urine production to fall and metabolic waste
products to build up in the blood. When damage to glomeruli is
severe, inflammatory cells and injured glomerular cells accumulate,
compressing the capillaries within the glomerulus and interfering
with filtration. Scarring may develop, impairing kidney function
and reducing urine production. In some cases, microthrombi may form
in the small blood vessels, further decreasing kidney function.
Less commonly, nephritis involves the tubulointerstitial tissues;
such inflammation is called tubulointerstitial nephritis. When
inflammation damages the tubules and the tubulointerstitial
tissues, the kidneys may become unable to concentrate urine,
eliminate (excrete) metabolic waste products from the body, or
balance the excretion of sodium and other electrolytes, such as
potassium. When the tubules and tubulointerstitial tissues are
damaged, kidney failure often develops. Accordingly, inhibition of
Fms offers a target for therapeutic intervention in nephritis due
to the modulation of the inflammatory response comprising the
etiology of the disease.
[1171] Lupus nephritis, i.e., renal involvement in systemic lupus
erythematosus (SLE), is a common disease manifestation with a poor
prognosis. At least three potentially overlapping,
immuno-pathogenic mechanisms for lupus nephritis are supported by
experimental data. First, circulating immune complexes consisting
chiefly of DNA and anti-DNA are deposited in the kidney. Resulting
complement activation and chemotaxis of neutrophils leads to a
local inflammatory process. Second, in situ formation of antigen
and antibody complexes may similarly lead to complement activation
and leucocyte mediated injury. Third, antibodies against specific
cellular targets may produce renal injury. An additional mechanism
is observed in SLE patients with the antiphospholipid antibody
syndrome. Glomerular thrombosis can result from the
hypercoagulability that accompanies antibodies directed against
negatively charged phospholipid-protein complexes (e.g. biologic
false positive VDRL, anticardiolipin antibodies, and lupus
anticoagulant). Mesangial lupus nephritis is accompanied by normal
diagnostic findings or with a mild degree of proteinuria but
typically absence of hypertension or abnormal urinary sediment.
Focal and diffuse proliferative lupus glomerulonephritis are often
associated with the worst prognosis for renal survival and can be
accompanied by nephrotic syndrome, significant hypertension and
abnormal urine sediment. Membranous lupus nephritis often presents
with proteinuria, moderate to high grade, but usually normal
urinary sediment in the absence of hypertension. Mesangial lupus
nephropathy is generally associated with an excellent prognosis,
whereas proliferative lupus nephropathy, especially diffuse
variant, is often characterized by hypertension, red cell casts and
significant deterioration of renal function. Nephrotic syndrome in
the absence of hypertension, active urinary sediment or significant
hypocomplementemia suggest the membranous variant of lupus
nephropathy. Membranous nephropathy generally is associated with a
good prognosis and relative preservation of renal function.
However, in the presence of persistent nephrotic range proteinuria,
membranous lupus nephropathy can, in fact, lead to loss of renal
function and end stage renal disease (ESRD). Accordingly,
inhibition of Fms offers a target for therapeutic intervention in
lupus due to the modulation of the inflammatory response comprising
the etiology of the disease.
[1172] Macrophage accumulation is a prominent feature in many forms
of glomerulonephritis. Local proliferation of macrophages within
the kidney has been described in human and experimental
glomerulonephritis and may have an important role in augmenting the
inflammatory response. Isbel et al (Nephrol Dial Transplant 2001,
16: 1638-1647) examined the relationship between local macrophage
proliferation and renal expression of M-CSF. Glomerular and
tubulointerstitial M-CSF expression was found to be up-regulated in
human glomerulonephritis, being most prominent in proliferative
forms of disease. Because this correlates with local macrophage
proliferation, it suggests that increased renal M-CSF production
plays an important role in regulating local macrophage
proliferation in human glomerulonephritis. In a model of renal
inflammation (UUO-- unilateral ureteric obstruction) anti-Fms
antibody treatment reduced macrophage accumulation (Le Meur et.
al., J Leukocyte Biology, 2002, 72: 530-537). Accordingly,
inhibition of Fms offers a target for therapeutic intervention in
glomerulonephritis.
[1173] Insulin resistance and obesity are hallmarks of type II
diabetes and a strong correlation exists between insulin resistance
and abdominal visceral fat accumulation (Bjorntrop, Diabetes Metab.
Res. Rev., 1999, 15: 427-441). Current evidence indicates that
macrophages accumulating in adipose tissue release TNF-a and other
factors that cause adipocyte changes (hypertrophy, lipolysis,
reduced insulin sensitivity) and also promote insulin resistance in
surrounding tissues. Therefore, macrophage accumulation in type 2
diabetes is important for disease progression. Accordingly,
inhibition of Fms has potential in preventing the development of
insulin resistance and hyperglycemia.
[1174] Similarly, the observation that production of M-CSF, the
major macrophage growth factor, is increased in tissues during
inflammation points out a role for Fms in diseases, such as for
example inflammatory diseases. More particularly, because elevated
levels of M-CSF are found in the disease state, modulation of the
activity of Fms can ameliorate disease associated with increased
levels of M-CSF.
[1175] Fms inhibitors may be useful in treating inflammatory and
autoimmune indications, including, but not limited to, rheumatoid
arthritis, osteoarthritis, psoriatic arthritis, psoriasis,
dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis,
systemic sclerosis, juvenile idiopathic arthritis, polymyalgia
rheumatica, Sjogren's disease, Langerhan's cell histiocytosis
(LCH), Still's disease, inflammatory bowel syndrome, ulcerative
colitis, Crohn's disease, systemic lupus erythematosis (SLE),
transplant rejection, chronic obstructive pulmonary disease (COPD),
emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage
activation syndrome), multicentric reticulohistiocytosis, and
atherosclerosis; metabolic disorders, including, but not limited
to, Type I diabetes, Type II diabetes, insulin resistance,
hyperglycemia, obesity, and lipolysis; disorders of bone structure,
mineralization and bone formation and resorption, including, but
not limited to, osteoporosis, osteodystrophy, increased risk of
fracture, Paget's disease, hypercalcemia, infection-mediated
osteolysis (e.g. osteomyelitis), and peri-prosthetic or
wear-debris-mediated osteolysis; kidney and genitourinary diseases,
including, but not limited to, endometriosis, nephritis (e.g.
glomerulonephritis, interstitial nephritis, Lupus nephritis),
tubular necrosis, diabetes-associated renal complications (e.g.
diabetic nephropathy), and renal hypertrophy; disorders of the
central nervous system, including, but not limited to, multiple
sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis,
chronic demyelinating polyneuropathy, other demyelinating
disorders, stroke, Alzheimer's disease and Parkinson's disease;
inflammatory and chronic pain, including, but not limited to, bone
pain; malignancies, including, but not limited to, multiple
myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia
(CML), lung cancer, pancreatic cancer, prostate cancer, breast
cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant
cell tumor of bone, giant cell tumor of tendon sheath (TGCT),
pigmented villonodular synovitis (PVNS), tumor angiogenesis,
melanoma, glioblastoma multiforme, glioma, other tumors of the
central nervous system, metastasis of tumors to other tissues, and
other chronic myeloproliferative diseases such as myelofibrosis;
vasculitis, including but not limited to collagen vascular disease,
polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar
Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis,
giant cell arteritis, Takayasu's arteritis; ophthalmic indications,
including but not limited to uveitis, scleritis, retinitis, age
related macular degeneration, choroidal neovascularization,
diabetic retinopathy; inherited disorders, including but not
limited to cherubism, neurofibromatosis; infectious disease
indications, including but not limited to infections associated
with human immunodeficiency virus, hepatitis B virus, hepatitis C
virus, human granulocytic anaplasmosis; lysosomal storage
disorders, including but not limited to Gaucher's disease, Fabry's
disease, Niemann-Pick disease; gastrointestinal indications,
including but not limited to liver cirrhosis; pulmonary
indications, including but not limited to pulmonary fibrosis, acute
lung injury (e.g. ventilator-induced, smoke- or toxin-induced); and
surgical indications, including but not limited to
(cardiopulmonary) bypass surgery, vascular surgery, and vascular
grafts.
[1176] Kit:
[1177] Target kinase Kit (i.e., feline Hardy-Zuckerman 4 sarcoma
viral oncogene) is a 109.9 kDa transmembrane tyrosine kinase
encoded by chromosome 4q12 (symbol: KIT). Receptor protein tyrosine
kinases (RPTKs) regulate key signal transduction cascades that
control cellular growth and proliferation. The Stem Cell Factor
(SCF) receptor Kit is a type III transmembrane RPTK that includes
five extracellular immunoglobulin (IG) domains, a single
transmembrane domain, and a split cytoplasmic kinase domain
separated by a kinase insert segment. Kit plays an important role
in the development of melanocytes, mast, germ, and hematopoietic
cells.
[1178] Stem Cell Factor (SCF) is a protein encoded by the 51 locus,
and has also been called kit ligand (KL) and mast cell growth
factor (MGF), based on the biological properties used to identify
it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland,
et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al., Clin
Immunol 1997, 100:435-440; Broudy, Blood 1997, 90:1345-1364;
Pignon, Hermatol Cell Ther 1997, 39:114-116; and Lyman, et al.,
Blood 1998, 91:1101-1134.). Herein the abbreviation SCF refers to
the ligand for Kit.
[1179] SCF is synthesized as a transmembrane protein with a
molecular weight of 220 or 248 Dalton, depending on alternative
splicing of the mRNA to encode exon 6. The larger protein can be
proteolytically cleaved to form a soluble, glycosylated protein
which noncovalently dimerizes. Both the soluble and membrane-bound
forms of SCF can bind to and activate Kit. For example, in the
skin, SCF is predominantly expressed by fibroblasts, keratinocytes,
and endothelial cells, which modulate the activity of melanocytes
and mast cells expressing Kit. In bone, marrow stromal cells
express SCF and regulate hematopoiesis of Kit expressing stem
cells. In the gastrointestinal tract, intestinal epithelial cells
express SCF and affect the interstitial cells of Cajal and
intraepithelial lymphocytes. In the testis, sertoli cells and
granulosa cells express SCF which regulates spermatogenesis by
interaction with Kit on germ cells.
[1180] According to OMIM, signaling from Kit is essential for
primordial germ cell growth both in vivo and in vitro. Many
downstream effectors of the KIT signaling pathway have been
identified in other cell types, but how these molecules control
primordial germ cell survival and proliferation are unknown.
Determination of the KIT effectors acting in primordial germ cells
has been hampered by the lack of effective methods to manipulate
easily gene expression in these cells. De Miguel et al. (2002)
overcame this problem by testing the efficacy of
retroviral-mediated gene transfer for manipulating gene expression
in mammalian germ cells. They found that primordial germ cells can
successfully be infected with a variety of types of retroviruses.
They used this method to demonstrate an important role of the AKT1
in regulating primordial germ cell growth (OMIM MIM Number: 164920:
Apr. 17, 2006).
[1181] Aberrant expression and/or activation of Kit has been
implicated in a variety of pathologic states. For example, evidence
for a contribution of Kit to neoplastic pathology includes its
association with leukemias and mast cell tumors, small cell lung
cancer, testicular cancer, and some cancers of the gastrointestinal
tract and central nervous system. In addition, Kit has been
implicated in playing a role in carcinogenesis of the female
genital tract sarcomas of neuroectodermal origin, and Schwann cell
neoplasia associated with neurofibromatosis. It was found that mast
cells are involved in modifying the tumor microenvironment and
enhancing tumor growth (Yang et al., J Clin Invest. 2003,
112:1851-1861; Viskochil, J Clin Invest. 2003, 112:1791-1793).
[1182] Kit inhibitors may be useful in treating malignancies,
including, but not limited to, mast cell tumors, small cell lung
cancer, non-small cell lung cancer (NSCLC), testicular cancer,
pancreatic cancer, breast cancer, merkel cell carcinoma, carcinomas
of the female genital tract, sarcomas of neuroectodermal origin,
colorectal carcinoma, carcinoma in situ, gastrointestinal stromal
tumors (GISTs), tumor angiogenesis, glioblastoma, astrocytoma,
neuroblastoma, Schwann cell neoplasia associated with
neurofibromatosis, neurofibromatosis not associated with Schwann
cell neoplasia, acute myelocytic leukemia, acute lymphocytic
leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and
canine mast cell tumors; cardiovascular disease, including but not
limited to atherosclerosis, cardiomyopathy, heart failure,
pulmonary hypertension; inflammatory and autoimmune indications,
including, but not limited to, allergy, anaphylaxis, asthma,
rheumatoid arthritis, allergic rhinitis, multiple sclerosis,
inflammatory bowel syndrome, transplant rejection,
hypereosinophilia, urticaria and dermatitis; gastrointestinal
indications, including but not limited to gastroesophageal reflux
disease (GERD), esophagitis, and gastrointestinal tract ulcers;
ophthalmic indications, including but not limited to uveitis and
retinitis; and neurologic indications, including but not limited to
migraine.
[1183] Flt3:
[1184] Target kinase Flt3 (i.e., Fms-like tyrosine kinase 3) is a
transmembrane tyrosine kinase of 112.8 kDa encoded by chromosome
13q12 (symbol: FLT3). According to OMIM, Rosnet et al. (Genomics
1991, 9: 380-385) isolated a novel member of the class 3 receptors
discussed above. They demonstrated that this gene of the tyrosine
kinase family, called FLT3, has strong sequence similarities with
other members of the group. Lymphohematopoietic stem cells serve as
a reservoir for virtually all blood cells but make up only
approximately 0.01% of human or murine marrow cells. The ability to
isolate and expand this population has clinical applications in
bone marrow transplantations for cancer and genetic diseases. Small
et al. (Proc. Nat. Acad. Sci. 1994, 91: 459-463) cloned the cDNA
for stem cell tyrosine kinase 1, the human homolog of murine
Flk2/Flt3, from a CD34+ hematopoietic stem cell-enriched library.
The cDNA encoded a protein of 993 amino acids with 85% identity and
92% similarity to the murine homolog. STK1, which is identical to
FLT3, is a member of the type III receptor tyrosine kinase family
that includes KIT, FMS, and platelet-derived growth factor
receptor. STK1 expression in human blood and marrow is restricted
to CD34+ cells, a population greatly enriched by stem/progenitor
cells. Antisense oligonucleotides directed against STK1 sequences
inhibited hematopoietic colony formation, most strongly in
long-term bone marrow cultures. The data suggested that STK1 may
function as a growth factor receptor on hematopoietic stem and/or
progenitor cells (OMIM MIM Number: 136351: Mar. 3, 2005).
[1185] Levis et al., state that Internal tandem duplication (ITD)
mutations of the receptor tyrosine kinase FLT3 have been found in
20% to 30% of patients with acute myeloid leukemia (AML). These
mutations constitutively activate the receptor and appear to be
associated with a poor prognosis. In their study, dose-response
cytotoxic assays were performed with AG1295, a tyrosine kinase
inhibitor active against FLT3, on primary blasts from patients with
AML, and they found that AG1295 was specifically cytotoxic to AML
blasts harboring FLT3/ITD mutations. They suggest that these
mutations contribute to the leukemic process and that the FLT3
receptor represents a therapeutic target in AML (Levis et al.,
Blood 2001, 98:885-887). An Flt3 inhibitor may be useful in
treating acute myeloid leukemia, myelodysplastic syndrome, acute
lymphoblastic leukemia.
[1186] TrkA:
[1187] Target kinase TrkA (i.e., neurotrophic tyrosine kinase,
receptor, type 1) is a 140 kDa tyrosine kinase encoded by
chromosome 1q21-q22 (symbol: NTRK1). TrkA inhibitors may be useful
in treating pain (e.g. chronic pain, neuropathic pain), cancer
(e.g. prostate cancer, lung cancer, myeloid leukemia, pancreatic
cancer), allergic disorders (e.g. asthma), arthritis, diabetic
retinopathy, macular degeneration and psoriasis.
[1188] TrkA is a plasma member receptor composed of an
extracellular domain (responsible for high affinity binding to
nerve growth factor, NGF), a transmembrane segment and an
intracellular protein tyrosine kinase domain (responsible to
transmit the NGF signal to initiate and coordinate neuronal
responses). NGF binding induces TrkA clustering on the membrane and
activates the kinase. The kinase initiates a cascade of protein
phosphorylation events through multiple pathways including
SHC/Ras/MAPK, PI3K and PLCg1. A TrkA kinase inhibitor would not be
expected to prevent NGF/TrkA binding, but could prevent down-stream
signal transduction.
[1189] Nerve Growth Factor (NGF) is produced by a number of tissues
and inflammatory cells during tissue injury and host immune
response. It initiates and maintains hypersensitivity to incoming
stimulus (hyperalgesia) and the perception of non-noxious stimuli
(allodynia). Through its high-affinity receptor TrkA, NGF increases
the excitation state of sensory neurons leading to the central
nervous system (peripheral sensitization), and increases
transmitter release from the dorsal spinal cord (central
sensitization). In clinical trials, a single NGF subcutaneous
injection generated local hyperalgesia persisting up to 7 weeks. At
doses above 0.1 microgram/kg, NGF caused muscle pain that varied
from mild to moderate, primarily in the bulbar and truncal
musculature. Intravenous NGF produced earlier and more pronounced
systemic effects (Petty et al, 1994, Ann Neurol. 36: 244-6).
Conversely, TrkA kinase inhibitors could be used to treat diseases
of enhanced states of nociception.
[1190] In Complete Freund's Adjuvant (CFA)-induced hind-paw
inflammation, spinal nerve ligation and streptozoticin-induced
neuropathic pain models, a single intraperitoneal injection of
anti-NGF reversed established tactile allodynia from day 3 to day 7
following treatment. In the mouse CCI model, anti-NGF reversed
tactile allodynia when administered 2 weeks after surgery. Repeated
administration of this antibody to CCI mice for 3 weeks produced a
sustained reversal of tactile allodynia (Wild et al, 2007, J.
Pharmacol. Exp. Ther. 322:282-287).
[1191] Prostate tumors that have metastasized to bone frequently
induce bone pain which can be difficult to fully control as it
seems to be driven simultaneously by inflammatory, neuropathic, and
tumorigenic mechanisms. Anti-NGF produced a significant reduction
in both early and late stage bone cancer pain-related behaviors.
This therapy did not influence tumor-induced bone remodeling,
osteoblast proliferation, osteoclastogenesis, tumor growth, or
markers of sensory or sympathetic innervation in the skin or bone.
All nerve fibers that innervate the bone express TrkA and p75, and
these are the receptors through which NGF sensitizes and/or
activates nociceptors (Halvorson et al, 2005, Cancer Res.
65:9426-35).
[1192] In patients with mild asthma due to exposure to cat
allergen, NGF expression was strongly induced in epithelial cells,
fibroblasts, blood vessels, and a few infiltrating cells. TrkA mRNA
and protein levels in bronchial biopsies were increased
significantly after allergen exposure in infiltrating mast cells
before the onset of symptoms (Kassel et al, 2001, Clin Exp Allergy
31:1432-40).
[1193] The late phase reaction in asthma following allergen
provocation is dominated by an influx of activated eosinophils into
the bronchial lumen, which correlates with the release of
eosinophilic products into the airways to increase disease
severity. The viability and activation of eosinophils from patients
with mild asthma were significantly enhanced after NGF stimulation.
Addition of neutralizing anti-NGF antibodies ex vivo abrogated the
effects (Nassentein et al, 2003, J Exp Med 198:455-467). TrkA
kinase inhibitors could decrease this paracrine loop between the
respiratory tract and infiltrating mast cells as well as
endobronchial eosinophils, and thus be useful for the treatment of
asthma and other allergic disorders.
[1194] TrkB:
[1195] Target kinase TrkB (i.e., neurotrophic tyrosine kinase,
receptor, type 2) is a 145 kDa tyrosine kinase encoded by
chromosome 9q22.1 (symbol: NTRK2). TrkB inhibitors may be useful in
treating various cancers and their metastases (e.g. prostate
cancer, lung cancer, Wilms tumors, neuroblastoma, and pancreatic
cancer), and various neuropathies (e.g. stroke, multiple sclerosis,
transverse myelitis, and encephalitis).
[1196] In clinical trials with recombinant BDNF, paresthesia was
developed at the site of subcutaneous injection (Coulie et al,
2000, Gastroenterology 119:41-50). Intrathecal infusion of BDNF in
humans also induced paresthesia and warmth as side effects (Ochs et
al, 2000, Amyotroph Lateral Scler Other Motor Neuron Disord.
1:201-6). Chronic paresthesia is often a symptom of an underlying
neurological disease or traumatic nerve damage. Paresthesia can be
caused by disorders affecting the central nervous system, such as
stroke and transient ischemic attacks (mini-strokes), multiple
sclerosis, transverse myelitis, and encephalitis. Since BDNF binds
to TrkB specifically with high affinity these neuropath effects are
mediated through TrkB signaling. Thus Trkb kinase inhibitors could
be used to treat certain patients with neuropathy.
[1197] BDNF is known to act at the synapses between primary sensory
and spinal dorsal horn neurons to affect pain transmission during
inflammation. The primary afferent is the only source of BDNF in
the spinal cord, and it is up-regulated in the dorsal root ganglion
(DRG) by peripheral NGF a few days after inflammation, and is
transported and released into the superficial dorsal horn in an
activity-dependent manner. TrkB expression in the dorsal horn also
increases for a few days after inflammation. These findings suggest
that BDNF may act during the restricted period in the early phase
of inflammation. Through TrkB, BDNF activates two distinct
channels: (1) transient receptor potential canonicals (TRPC3),
which produces a slow response by opening of a non-selective cation
channel; and (2) Na+ channel, which mediates a rapid depolarization
in the hippocampus. These channels have been strongly associated
with inflammatory pain. Anti-BDNF significantly increased the
withdrawal threshold in CFA-treated rats, a model of inflammatory
pain. Since the swelling at the site of CFA injection was not
affected by antiserum, the residual component might be due to
peripheral sensitization (Matayoshi et al, 2005, J Physiol.
569:685-95).
[1198] In patients with neuroblastomas, co-expression of TrkB and
BDNF, co-expression of TrkB with N-Myc amplification, and
expression of truncated TrkB are found to be associated with poorer
clinical outcome (Nakagawara et al, 1994, Mol Cell Biol.
14:759-767). Co-expression of TrkB with its ligand BDNF could
generate a positive feedback loop through autocrine and paracrine
loops. Also TrkB truncations found in these tumors generate
activated forms of the intracellular protein tyrosine kinase. The
constitutively active TrkB signals through multiple pathways to
promote cancer initiation, progression and metastasis. These
truncated TrkB kinases were also found in hepatocellular carcinoma
(Yang et al, 2005, Cancer. Res 65:219-225). Thus TrkB inhibitors
could be used to treat a sub-population of cancer patients with an
activated TrkB pathway.
[1199] In patients with pancreatic cancer, TrkB expression is
correlated with perineural invasion, positive retroperitoneal
margin, and shorter latency to development of liver metastasis
(Sclabas et al, 2005, Clin. Cancer. Res V11:440-449).
Mechanistically, TrkB activates the PI3K pathway to suppress
anoikis (apoptosis resulting from loss of cell-matrix interactions)
which is one of the physiological barriers to metastasis. TrkB
kinase inhibition could break down resistance to anoikis of
metastasizing tumors (Douma et al, 2004, Nature 430:1034-9).
Therefore, TrkB inhibitors could have utility in a broad range of
tumor types.
[1200] TrkC:
[1201] Target kinase TrkC (i.e., neurotrophic tyrosine kinase,
receptor, type 3) is a 145 kDa tyrosine kinase encoded by
chromosome 15q25 (symbol: NTRK3). TrkC inhibitors may be useful in
treating pain (e.g. chronic pain, neuropathic pain), cancer (e.g.
lung cancer, breast cancer, pancreatic cancer, mesoblastic
nephroma, infantile fibrosarcoma, neuroblastoma, gastric cancer),
and panic disorder.
[1202] Involvement of TrkC in the molecular and cellular changes
underlying panic attacks and opiate dependence has been indicated
(Gallego et al., Front Behav. Neurosci., 2010, 3:60). TrkC
expression in mechanosensory neurons suggests a role for TrkC
inhibition in treatment of pain (J Comp. Neurol., 2008,
511(4):543-56.
[1203] TrkC is also involved in a variety of cancers, for example
neuroblastoma (J. Clin. Invest., 2010, 120(3):850-8), mesoblastic
nephroma, infantile fibrosarcoma, and secretory breast cancer,
where ETV6-NTRK3 gene fusion is present (Pediatr. Radiol. 2009,
39(10):1066-74; J. Clin. Pathol. 2009, 62(7):604-12) and cancers
involving mutations in TrkC, such as lung cancer, gastric cancer,
and pancreatic cancer (Marchetti et al., Hum. Mutat. 2008,
29(5):609-16; Kubo et al., Carcinogenesis, 2009, 30(11):1857-64);
and Kubo et al., Pancreas, 2009, 38(7):e200-6).
Kinase Activity Assays
[1204] A number of different assays for kinase activity can be
utilized for assaying for active modulators and/or determining
specificity of a modulator for a particular kinase or group or
kinases. In addition to the assay mentioned in the Examples below,
one of ordinary skill in the art will know of other assays that can
be utilized and can modify an assay for a particular application.
For example, numerous papers concerning kinases describe assays
that can be used.
[1205] Additional alternative assays can employ binding
determinations. For example, this sort of assay can be formatted
either in a fluorescence resonance energy transfer (FRET) format,
or using an AlphaScreen (amplified luminescent proximity
homogeneous assay) format by varying the donor and acceptor
reagents that are attached to streptavidin or the phosphor-specific
antibody.
Organic Synthetic Techniques
[1206] A wide array of organic synthetic techniques exist in the
art to facilitate the construction of potential modulators. Many of
these organic synthetic methods are described in detail in standard
reference sources utilized by those skilled in the art. One example
of such a reference is March, 1994, Advanced Organic Chemistry;
Reactions, Mechanisms and Structure, New York, McGraw Hill. Thus,
the techniques useful to synthesize a potential modulator of kinase
function are readily available to those skilled in the art of
organic chemical synthesis.
Alternative Compound Forms or Derivatives
[1207] Compounds contemplated herein are described with reference
to both generic formulae and specific compounds. In addition,
invention compounds may exist in a number of different forms or
derivatives, all within the scope of the present invention.
Alternative forms or derivatives, include, for example, (a)
prodrugs, and active metabolites (b) tautomers, isomers (including
stereoisomers and regioisomers), and racemic mixtures (c)
pharmaceutically acceptable salts and (d) solid forms, including
different crystal forms, polymorphic or amorphous solids, including
hydrates and solvates thereof, and other forms.
[1208] (a) Prodrugs and Metabolites
[1209] In addition to the present formulae and compounds described
herein, the invention also includes prodrugs (generally
pharmaceutically acceptable prodrugs), active metabolic derivatives
(active metabolites), and their pharmaceutically acceptable
salts.
[1210] Prodrugs are compounds or pharmaceutically acceptable salts
thereof which, when metabolized under physiological conditions or
when converted by solvolysis, yield the desired active compound.
Prodrugs include, without limitation, esters, amides, carbamates,
carbonates, ureides, solvates, or hydrates of the active compound.
Typically, the prodrug is inactive, or less active than the active
compound, but may provide one or more advantageous handling,
administration, and/or metabolic properties. For example, some
prodrugs are esters of the active compound; during metabolysis, the
ester group is cleaved to yield the active drug. Esters include,
for example, esters of a carboxylic acid group, or S-acyl or O-acyl
derivatives of thiol, alcohol, or phenol groups. In this context, a
common example is an alkyl ester of a carboxylic acid. Prodrugs may
also include variants wherein an --NH group of the compound has
undergone acylation, such as the 1-position of the
1H-pyrrolo[2,3-b]pyridine ring or the 7-position of the
7H-pyrrolo[2,3-d]pyrimidine of compounds of Formula I, where
cleavage of the acyl group provides the free --NH group of the
active drug. Some prodrugs are activated enzymatically to yield the
active compound, or a compound may undergo further chemical
reaction to yield the active compound. Prodrugs may proceed from
prodrug form to active form in a single step or may have one or
more intermediate forms which may themselves have activity or may
be inactive.
[1211] As described in The Practice of Medicinal Chemistry, Ch.
31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001),
prodrugs can be conceptually divided into two non-exclusive
categories, bioprecursor prodrugs and carrier prodrugs. Generally,
bioprecursor prodrugs are compounds that are inactive or have low
activity compared to the corresponding active drug compound, that
contain one or more protective groups and are converted to an
active form by metabolism or solvolysis. Both the active drug form
and any released metabolic products should have acceptably low
toxicity. Typically, the formation of active drug compound involves
a metabolic process or reaction that is one of the following
types:
[1212] Oxidative Reactions:
[1213] Oxidative reactions are exemplified without limitation by
reactions such as oxidation of alcohol, carbonyl, and acid
functionalities, hydroxylation of aliphatic carbons, hydroxylation
of alicyclic carbon atoms, oxidation of aromatic carbon atoms,
oxidation of carbon-carbon double bonds, oxidation of
nitrogen-containing functional groups, oxidation of silicon,
phosphorus, arsenic, and sulfur, oxidative N-dealkylation,
oxidative 0- and S-dealkylation, oxidative deamination, as well as
other oxidative reactions.
[1214] Reductive Reactions:
[1215] Reductive reactions are exemplified without limitation by
reactions such as reduction of carbonyl functionalities, reduction
of alcohol functionalities and carbon-carbon double bonds,
reduction of nitrogen-containing functional groups, and other
reduction reactions.
[1216] Reactions without Change in the Oxidation State:
[1217] Reactions without change in the state of oxidation are
exemplified without limitation by reactions such as hydrolysis of
esters and ethers, hydrolytic cleavage of carbon-nitrogen single
bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration
and dehydration at multiple bonds, new atomic linkages resulting
from dehydration reactions, hydrolytic dehalogenation, removal of
hydrogen halide molecule, and other such reactions.
[1218] Carrier prodrugs are drug compounds that contain a transport
moiety, e.g., that improves uptake and/or localized delivery to a
site(s) of action. Desirably for such a carrier prodrug, the
linkage between the drug moiety and the transport moiety is a
covalent bond, the prodrug is inactive or less active than the drug
compound, the prodrug and any release transport moiety are
acceptably non-toxic. For prodrugs where the transport moiety is
intended to enhance uptake, typically the release of the transport
moiety should be rapid. In other cases, it is desirable to utilize
a moiety that provides slow release, e.g., certain polymers or
other moieties, such as cyclodextrins. (See, e.g., Cheng et al.,
U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,
incorporated herein by reference.) Such carrier prodrugs are often
advantageous for orally administered drugs. In some instances, the
transport moiety provides targeted delivery of the drug, for
example the drug may be conjugated to an antibody or antibody
fragment. Carrier prodrugs can, for example, be used to improve one
or more of the following properties: increased lipophilicity,
increased duration of pharmacological effects, increased
site-specificity, decreased toxicity and adverse reactions, and/or
improvement in drug formulation (e.g., stability, water solubility,
suppression of an undesirable organoleptic or physiochemical
property). For example, lipophilicity can be increased by
esterification of hydroxyl groups with lipophilic carboxylic acids,
or of carboxylic acid groups with alcohols, e.g., aliphatic
alcohols. Wermuth, supra.
[1219] Metabolites, e.g., active metabolites, overlap with prodrugs
as described above, e.g., bioprecursor prodrugs. Thus, such
metabolites are pharmacologically active compounds or compounds
that further metabolize to pharmacologically active compounds that
are derivatives resulting from metabolic processes in the body of a
subject. Of these, active metabolites are such pharmacologically
active derivative compounds. For prodrugs, the prodrug compound is
generally inactive or of lower activity than the metabolic product.
For active metabolites, the parent compound may be either an active
compound or may be an inactive prodrug. For example, in some
compounds, one or more alkoxy groups can be metabolized to hydroxyl
groups while retaining pharmacologic activity and/or carboxyl
groups can be esterified, e.g., glucuronidation. In some cases,
there can be more than one metabolite, where an intermediate
metabolite(s) is further metabolized to provide an active
metabolite. For example, in some cases a derivative compound
resulting from metabolic glucuronidation may be inactive or of low
activity, and can be further metabolized to provide an active
metabolite.
[1220] Metabolites of a compound may be identified using routine
techniques known in the art, and their activities determined using
tests such as those described herein. See, e.g., Bertolini et al.,
1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci
86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth,
supra.
[1221] (b) Tautomers, Stereoisomers, and Regioisomers
[1222] It is understood that some compounds may exhibit
tautomerism. In such cases, the formulae provided herein expressly
depict only one of the possible tautomeric forms. It is therefore
to be understood that the formulae provided herein are intended to
represent any tautomeric form of the depicted compounds and are not
to be limited merely to the specific tautomeric form depicted by
the drawings of the formulae.
[1223] Likewise, some of the compounds according to the present
invention may exist as stereoisomers, i.e. having the same atomic
connectivity of covalently bonded atoms yet differing in the
spatial orientation of the atoms. For example, compounds may be
optical stereoisomers, which contain one or more chiral centers,
and therefore, may exist in two or more stereoisomeric forms (e.g.
enantiomers or diastereomers). Thus, such compounds may be present
as single stereoisomers (i.e., essentially free of other
stereoisomers), racemates, and/or mixtures of enantiomers and/or
diastereomers. As another example, stereoisomers include geometric
isomers, such as cis- or trans-orientation of substituents on
adjacent carbons of a double bond, or on carbon atoms of a
cycloalkyl. All such single stereoisomers, racemates and mixtures
thereof are intended to be within the scope of the present
invention. Unless specified to the contrary, all such
stereoisomeric forms are included within the formulae provided
herein.
[1224] In some embodiments, a chiral compound of the present
invention is in a form that contains at least 80% of a single
isomer (60% enantiomeric excess ("e.e.") or diastereomeric excess
("d.e.")), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or
d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99%
(98% e.e. or d.e.). As generally understood by those skilled in the
art, an optically pure compound having one chiral center is one
that consists essentially of one of the two possible enantiomers
(i.e., is enantiomerically pure), and an optically pure compound
having more than one chiral center is one that is both
diastereomerically pure and enantiomerically pure. In some
embodiments, the compound is present in optically pure form, such
optically pure form being prepared and/or isolated by methods known
in the art (e.g. by recrystallization techniques, chiral synthetic
techniques (including synthesis from optically pure starting
materials), and chromatographic separation using a chiral
column.
[1225] (c) Pharmaceutically Acceptable Salts
[1226] Unless specified to the contrary, specification of a
compound herein includes pharmaceutically acceptable salts of such
compound. Thus, compounds of Formula I can be in the form of
pharmaceutically acceptable salts, or can be formulated as
pharmaceutically acceptable salts. Contemplated pharmaceutically
acceptable salt forms include, without limitation, mono, bis, tris,
tetrakis, and so on. Pharmaceutically acceptable salts are
non-toxic in the amounts and concentrations at which they are
administered. The preparation of such salts can facilitate the
pharmacological use by altering the physical characteristics of a
compound without preventing it from exerting its physiological
effect. Useful alterations in physical properties include lowering
the melting point to facilitate transmucosal administration and
increasing the solubility to facilitate administering higher
concentrations of the drug. A compound of the invention may possess
a sufficiently acidic, a sufficiently basic, or both functional
groups, and accordingly can react with any of a number of inorganic
or organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt.
[1227] Pharmaceutically acceptable salts include acid addition
salts such as those containing chloride, bromide, iodide,
hydrochloride, acetate, phenylacetate, acrylate, ascorbate,
aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,
bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate,
caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate,
fumarate, glycolate, gluconate, glucarate, glucuronate,
glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate,
isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate,
malate, maleate, hydroxymaleate, methylmaleate, malonate,
mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,
oxalate, pamoate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, orthophosphate, metaphosphate, pyrophosphate,
2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate,
phenylpropionate, propiolate, pyruvate, quinate, salicylate,
4-aminosalicylate, sebacate, stearate, suberate, succinate,
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate,
sulfonate, benzenesulfonate (i.e. besylate), ethanesulfonate (i.e.
esylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (i.e.
isethionate), methanesulfonate (i.e. mesylate),
naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e. napsylate),
propanesulfonate, p-toluenesulfonate (i.e. tosylate),
xylenesulfonates, cyclohexylsulfamate, tartrate, and
trifluoroacetate. These pharmaceutically acceptable acid addition
salts can be prepared using the appropriate corresponding acid.
[1228] When acidic functional groups, such as carboxylic acid or
phenol are present, pharmaceutically acceptable salts also include
basic addition salts such as those containing benzathine,
chloroprocaine, choline, ethanolamine, diethanolamine,
triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine,
N,N'-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine,
piperidine, morpholine, piperazine, procaine, aluminum, calcium,
copper, iron, lithium, magnesium, manganese, potassium, sodium,
zinc, ammonium, and mono-, di-, or tri-alkylamines (e.g.
diethylamine), or salts derived from amino acids such as
L-histidine, L-glycine, L-lysine, and L-arginine. For example, see
Remington's Pharmaceutical Sciences, 19.sup.th ed., Mack Publishing
Co., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceutically
acceptable base addition salts can be prepared using the
appropriate corresponding base.
[1229] Pharmaceutically acceptable salts can be prepared by
standard techniques. For example, the free-base form of a compound
can be dissolved in a suitable solvent, such as an aqueous or
aqueous-alcohol solution containing the appropriate acid and then
isolated by evaporating the solution. In another example, a salt
can be prepared by reacting the free base and acid in an organic
solvent. If the particular compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an appropriate
inorganic or organic base.
[1230] (d) Other Compound Forms
[1231] In the case of agents that are solids, it is understood by
those skilled in the art that the compounds and salts may exist in
different crystal or polymorphic forms, or may be formulated as
co-crystals, or may be in an amorphous form, or may be any
combination thereof (e.g. partially crystalline, partially
amorphous, or mixtures of polymorphs) all of which are intended to
be within the scope of the present invention and specified
formulae. Whereas salts are formed by acid/base addition, i.e. a
free base or free acid of the compound of interest forms an
acid/base reaction with a corresponding addition base or addition
acid, respectively, resulting in an ionic charge interaction,
co-crystals are a new chemical species that is formed between
neutral compounds, resulting in the compound and an additional
molecular species in the same crystal structure.
[1232] In some instances, compounds of the invention are complexed
with an acid or a base, including base addition salts such as
ammonium, diethylamine, ethanolamine, ethylenediamine,
diethanolamine, t-butylamine, piperazine, meglumine; acid addition
salts, such as acetate, acetylsalicylate, besylate, camsylate,
citrate, formate, fumarate, glutarate, hydrochlorate, maleate,
mesylate, nitrate, oxalate, phosphate, succinate, sulfate,
tartrate, thiocyanate and tosylate; and amino acids such as
alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,
glutamic acid, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine or valine. In combining the compound of the invention with
the acid or base, an amorphous complex is preferably formed rather
than a crystalline material such as a typical salt or co-crystal.
In some instances, the amorphous form of the complex is facilitated
by additional processing, such as by spray-drying, mechanochemical
methods such as roller compaction, or microwave irradiation of the
parent compound mixed with the acid or base. Such methods may also
include addition of ionic and/or non-ionic polymer systems,
including, but not limited to, hydroxypropyl methyl cellulose
acetate succinate (HPMCAS) and methacrylic acid copolymer (e.g.
Eudragit.RTM. L100-55), that further stabilize the amorphous nature
of the complex. Such amorphous complexes provide several
advantages. For example, lowering of the melting temperature
relative to the free base facilitates additional processing, such
as hot melt extrusion, to further improve the biopharmaceutical
properties of the compound. Also, the amorphous complex is readily
friable, which provides improved compression for loading of the
solid into capsule or tablet form.
[1233] Additionally, the formulae are intended to cover hydrated or
solvated as well as unhydrated or unsolvated forms of the
identified structures. For example, the indicated compounds include
both hydrated and non-hydrated forms. Other examples of solvates
include the structures in combination with a suitable solvent, such
as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl
acetate, acetic acid, or ethanolamine.
Formulations and Administration
[1234] The methods and compounds will typically be used in therapy
for human subjects. However, they may also be used to treat similar
or identical indications in other animal subjects. Compounds of
Formula I or any of the subformulas as described herein, or any of
the compounds disclosed in any of the embodiments and examples, and
pharmaceutically acceptable salts or solvates thereof can be
administered by different routes, including injection (i.e.
parenteral, including intravenous, intraperitoneal, subcutaneous,
and intramuscular), oral, transdermal, transmucosal, rectal, or
inhalant. Such dosage forms should allow the compound to reach
target cells. Other factors are well known in the art, and include
considerations such as toxicity and dosage forms that retard the
compound or composition from exerting its effects. Techniques and
formulations generally may be found in Remington: The Science and
Practice of Pharmacy, 21.sup.st edition, Lippincott, Williams and
Wilkins, Philadelphia, Pa., 2005 (hereby incorporated by reference
herein).
[1235] In some embodiments, compositions will comprise
pharmaceutically acceptable carriers or excipients, such as
fillers, binders, disintegrants, glidants, lubricants, complexing
agents, solubilizers, and surfactants, which may be chosen to
facilitate administration of the compound by a particular route.
Examples of carriers include calcium carbonate, calcium phosphate,
various sugars such as lactose, glucose, or sucrose, types of
starch, cellulose derivatives, gelatin, lipids, liposomes,
nanoparticles, and the like. Carriers also include physiologically
compatible liquids as solvents or for suspensions, including, for
example, sterile solutions of water for injection (WFI), saline
solution, dextrose solution, Hank's solution, Ringer's solution,
vegetable oils, mineral oils, animal oils, polyethylene glycols,
liquid paraffin, and the like. Excipients may also include, for
example, colloidal silicon dioxide, silica gel, talc, magnesium
silicate, calcium silicate, sodium aluminosilicate, magnesium tri
silicate, powdered cellulose, macrocrystalline cellulose,
carboxymethyl cellulose, cross-linked sodium
carboxymethylcellulose, sodium benzoate, calcium carbonate,
magnesium carbonate, stearic acid, aluminum stearate, calcium
stearate, magnesium stearate, zinc stearate, sodium stearyl
fumarate, syloid, stearowet C, magnesium oxide, starch, sodium
starch glycolate, glyceryl monostearate, glyceryl dibehenate,
glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated
cotton seed oil, castor seed oil mineral oil, polyethylene glycol
(e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone,
crospovidone, croscarmellose sodium, alginic acid, casein,
methacrylic acid divinylbenzene copolymer, sodium docusate,
cyclodextrins (e.g. 2-hydroxypropyl-.delta.-cyclodextrin),
polysorbates (e.g. polysorbate 80), cetrimide, TPGS
(d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium
lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers,
di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene
sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester
Tween.RTM.), polyoxyethylene sorbitan fatty acid esters, sorbitan
fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty
acid such as oleic, stearic or palmitic acid, mannitol, xylitol,
sorbitol, maltose, lactose, lactose monohydrate or lactose spray
dried, sucrose, fructose, calcium phosphate, dibasic calcium
phosphate, tribasic calcium phosphate, calcium sulfate, dextrates,
dextran, dextrin, dextrose, cellulose acetate, maltodextrin,
simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl
methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl
cellulose, hypromellose, and the like.
[1236] In some embodiments, oral administration may be used.
Pharmaceutical preparations for oral use can be formulated into
conventional oral dosage forms such as capsules, tablets, and
liquid preparations such as syrups, elixirs, and concentrated
drops. Compounds of Formula I may be combined with solid
excipients, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain, for example, tablets, coated tablets, hard
capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or
oily solutions) and the like. Suitable excipients are, in
particular, fillers such as sugars, including lactose, glucose,
sucrose, mannitol, or sorbitol; cellulose preparations, for
example, corn starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),
and/or polyvinylpyrrolidone (PVP: povidone); oily excipients,
including vegetable and animal oils, such as sunflower oil, olive
oil, or codliver oil. The oral dosage formulations may also contain
disintegrating agents, such as the cross-linked
polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such
as sodium alginate; a lubricant, such as talc or magnesium
stearate; a plasticizer, such as glycerol or sorbitol; a sweetening
such as sucrose, fructose, lactose, or aspartame; a natural or
artificial flavoring agent, such as peppermint, oil of wintergreen,
or cherry flavoring; or dye-stuffs or pigments, which may be used
for identification or characterization of different doses or
combinations. Also provided are dragee cores with suitable
coatings. For this purpose, concentrated sugar solutions may be
used, which may optionally contain, for example, gum arabic, talc,
poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures.
[1237] Pharmaceutical formulations may be presented in unit dose
forms containing a predetermined amount of active ingredient per
unit dose. Such a unit may contain, for example, 0.5 mg to 1 g,
preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a
compound of the invention (as a free-base, solvate (including
hydrate) or salt, in any form), depending on the condition being
treated, the route of administration, and the age, weight and
condition of the patient. Preferred unit dosage formulations are
those containing a daily dose, weekly dose, monthly dose, a
sub-dose or an appropriate fraction thereof, of an active
ingredient. Furthermore, such pharmaceutical formulations may be
prepared by any of the methods well known in the pharmacy art.
[1238] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin ("gelcaps"), as well as soft,
sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols.
[1239] In some embodiments, injection (parenteral administration)
may be used, e.g., intramuscular, intravenous, intraperitoneal,
and/or subcutaneous. Compounds of Formula I for injection may be
formulated in sterile liquid solutions, preferably in
physiologically compatible buffers or solutions, such as saline
solution, Hank's solution, or Ringer's solution. Dispersions may
also be prepared in non-aqueous solutions, such as glycerol,
propylene glycol, ethanol, liquid polyethylene glycols, triacetin,
and vegetable oils. Solutions may also contain a preservative, such
as methylparaben, propylparaben, chlorobutanol, phenol, sorbic
acid, thimerosal, and the like. In addition, the compounds may be
formulated in solid form, including, for example, lyophilized
forms, and redissolved or suspended prior to use.
[1240] In some embodiments, transmucosal, topical or transdermal
administration may be used. In such formulations of compounds of
Formula I, penetrants appropriate to the barrier to be permeated
are used. Such penetrants are generally known in the art, and
include, for example, for transmucosal administration, bile salts
and fusidic acid derivatives. In addition, detergents may be used
to facilitate permeation. Transmucosal administration, for example,
may be through nasal sprays or suppositories (rectal or vaginal).
Compositions of compounds of Formula I for topical administration
may be formulated as oils, creams, lotions, ointments, and the like
by choice of appropriate carriers known in the art. Suitable
carriers include vegetable or mineral oils, white petrolatum (white
soft paraffin), branched chain fats or oils, animal fats and high
molecular weight alcohol (greater than C.sub.12). In some
embodiments, carriers are selected such that the active ingredient
is soluble. Emulsifiers, stabilizers, humectants and antioxidants
may also be included as well as agents imparting color or
fragrance, if desired. Creams for topical application are
preferably formulated from a mixture of mineral oil,
self-emulsifying beeswax and water in which mixture the active
ingredient, dissolved in a small amount of solvent (e.g., an oil),
is admixed. Additionally, administration by transdermal means may
comprise a transdermal patch or dressing such as a bandage
impregnated with an active ingredient and optionally one or more
carriers or diluents known in the art. To be administered in the
form of a transdermal delivery system, the dosage administration
will be continuous rather than intermittent throughout the dosage
regimen.
[1241] In some embodiments, compounds are administered as
inhalants. Compounds of Formula I may be formulated as dry powder
or a suitable solution, suspension, or aerosol. Powders and
solutions may be formulated with suitable additives known in the
art. For example, powders may include a suitable powder base such
as lactose or starch, and solutions may comprise propylene glycol,
sterile water, ethanol, sodium chloride and other additives, such
as acid, alkali and buffer salts. Such solutions or suspensions may
be administered by inhaling via spray, pump, atomizer, or
nebulizer, and the like. The compounds of Formula I may also be
used in combination with other inhaled therapies, for example
corticosteroids such as fluticasone proprionate, beclomethasone
dipropionate, triamcinolone acetonide, budesonide, and mometasone
furoate; beta agonists such as albuterol, salmeterol, and
formoterol; anticholinergic agents such as ipratroprium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes
such as DNAase; therapeutic proteins; immunoglobulin antibodies; an
oligonucleotide, such as single or double stranded DNA or RNA,
siRNA; antibiotics such as tobramycin; muscarinic receptor
antagonists; leukotriene antagonists; cytokine antagonists;
protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
cromoglycate.
[1242] The amounts of various compounds to be administered can be
determined by standard procedures taking into account factors such
as the compound activity (in vitro, e.g. the compound IC.sub.50 vs.
target, or in vivo activity in animal efficacy models),
pharmacokinetic results in animal models (e.g. biological half-life
or bioavailability), the age, size, and weight of the subject, and
the disorder associated with the subject. The importance of these
and other factors are well known to those of ordinary skill in the
art. Generally, a dose will be in the range of about 0.01 to 50
mg/kg, also about 0.1 to 20 mg/kg of the subject being treated.
Multiple doses may be used.
[1243] The compounds of Formula I may also be used in combination
with other therapies for treating the same disease. Such
combination use includes administration of the compounds and one or
more other therapeutics at different times, or co-administration of
the compound and one or more other therapies. In some embodiments,
dosage may be modified for one or more of the compounds of the
invention or other therapeutics used in combination, e.g.,
reduction in the amount dosed relative to a compound or therapy
used alone, by methods well known to those of ordinary skill in the
art.
[1244] It is understood that use in combination includes use with
other therapies, drugs, medical procedures etc., where the other
therapy or procedure may be administered at different times (e.g.
within a short time, such as within hours (e.g. 1, 2, 3, 4-24
hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days,
1-4 weeks)) than a compound of Formula I, or at the same time as a
compound of Formula I. Use in combination also includes use with a
therapy or medical procedure that is administered once or
infrequently, such as surgery, along with a compound of Formula I
administered within a short time or longer time before or after the
other therapy or procedure. In some embodiments, the present
invention provides for delivery of a compound of Formula I and one
or more other drug therapeutics delivered by a different route of
administration or by the same route of administration. The use in
combination for any route of administration includes delivery of a
compound of Formula I and one or more other drug therapeutics
delivered by the same route of administration together in any
formulation, including formulations where the two compounds are
chemically linked in such a way that they maintain their
therapeutic activity when administered. In one aspect, the other
drug therapy may be co-administered with a compound of Formula I.
Use in combination by co-administration includes administration of
co-formulations or formulations of chemically joined compounds, or
administration of two or more compounds in separate formulations
within a short time of each other (e.g. within an hour, 2 hours, 3
hours, up to 24 hours), administered by the same or different
routes. Co-administration of separate formulations includes
co-administration by delivery via one device, for example the same
inhalant device, the same syringe, etc., or administration from
separate devices within a short time of each other. Co-formulations
of a compound of Formula I and one or more additional drug
therapies delivered by the same route includes preparation of the
materials together such that they can be administered by one
device, including the separate compounds combined in one
formulation, or compounds that are modified such that they are
chemically joined, yet still maintain their biological activity.
Such chemically joined compounds may have a linkage that is
substantially maintained in vivo, or the linkage may break down in
vivo, separating the two active components.
EXAMPLES
[1245] Examples related to the present invention are described
below. In most cases, alternative techniques can be used. The
examples are intended to be illustrative and are not limiting or
restrictive to the scope of the invention. For example, where
additional compounds are prepared following a protocol of a Scheme
for a particular compound, it is understood that conditions may
vary, for example, any of the solvents, reaction times, reagents,
temperatures, work up conditions, or other reaction parameters may
be varied employing alternate solvents, reagents, reaction times,
temperatures, work up conditions, and the like, as are readily
available to one skilled in the art. In some examples, the mass
spectrometry result indicated for a compound may have more than one
value due to the isotope distribution of an atom in the molecule,
such as a compound having a bromo or chloro substituent.
[1246] Unless specifically indicated otherwise, the Formula
enumeration and R group enumeration used in the following examples
is not related to such enumeration in other sections of this
application. The reagents and solvents used in these examples can
be readily substituted with appropriate alternatives as are known
in the art and isolation of products is readily achieved by methods
known in the art, including, but not limited to, extraction,
crystallization, and chromatographic methods.
[1247] Ring numbering for the 1H-pyrrolo[2,3-b]pyridine in the
following Examples is as follows:
##STR00061##
[1248] Ring numbering for the 7H-pyrrolo[2,3-d]pyrimidine in the
following Examples is as follows:
##STR00062##
Example 1: Synthesis of
5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine
4
[1249]
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4
is prepared in two steps from 5-chloro-1H-pyrrolo[2,3-b]pyridine 1
as shown in Scheme 1.
##STR00063##
Step 1--Preparation of 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine
(2)
[1250] To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (1,
15.00 g, 98.31 mmol) in 300 mL of dichloromethane under an
atmosphere or nitrogen, pyridine (7.951 mL, 98.31 mmol) and iodine
monochloride (110 mL, 1.0 M in dichloromethane, 110 mmol) are added
slowly over 20 minutes. The reaction is stirred at room temperature
for 2 hours, then quenched with 100 mL of 1 M aqueous sodium
thiosulfate pentahydrate. The layers are separated, solids
collected from the aqueous layer by filtration and combined with
the organic layer. The aqueous layer is extracted with ethyl
acetate, and the organic layers are combined and washed with brine,
then concentrated under vacuum. The resulting solid is washed with
20% ethyl acetate in hexane to provide the desired compound.
Step 2--Preparation of
5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine
(4)
[1251] To 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2, 16.50 g,
59.25 mmol) in 250.0 mL of N,N-dimethylformamide, sodium hydride
(3.10 g, 77.5 mmol) is added. The reaction is stirred at room
temperature for 90 minutes, then triisopropylsilyl chloride (3,
13.00 mL, 61.36 mmol) is added slowly. The reaction is stirred at
room temperature overnight, then poured into water and extracted
with ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography, eluting
with 20-100% ethyl acetate in hexane. Appropriate fractions are
combined and concentrated under vacuum to provide the desired
compound (4, 10.0 g).
Example 2: Synthesis of 3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine
7
[1252] 3-Iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 7 is prepared in
two steps from
5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 5 as shown
in Scheme 2.
##STR00064##
Step 1--Preparation of
5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6)
[1253] In a round bottom flask,
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) 1:1
complex with dichloromethane (0.04 g, 0.05 mmol) is combined with
10 mL of toluene under an atmosphere of nitrogen, and
5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5, 0.3 g,
0.8 mmol) in 1 mL of toluene is added dropwise. The reaction is
stirred at 60.degree. C. for 1 hour, then at 90.degree. C. for 30
minutes. The reaction is cooled to room temperature, an ice/water
solution of 0.1 N citric acid at pH 4 is added, and the mixture
extracted with ethyl acetate. The organic layer is washed with
brine, de-colored with charcoal, filtered through celite and the
filtrate dried over sodium sulfate. The sodium sulfate is removed
by filtration and the filtrate concentrated under vacuum to provide
the desired compound (6, 218 mg).
Step 2--Preparation of 3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine
(7)
[1254] To a solution of
5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 1 g,
2.0 mmol) in 10 mL of tetrahydrofuran, iodine (0.43 g, 1.7 mmol) in
5 mL of tetrahydrofuran is added. The reaction is stirred at room
temperature overnight, then quenched with 20 mL of 1M aqueous
sodium thiosulfate and extracted with ethyl acetate. The organic
layers are combined and washed with water and brine, dried over
sodium sulfate, filtered and the filtrate concentrated under
vacuum. The resulting material is purified by silica gel column
chromatography, eluting with ethyl acetate and hexanes. Appropriate
fractions are combined and concentrated under vacuum to provide the
desired compound as a white solid (7, 20 mg). MS (ESI)
[M+H.sup.+].sup.+=258.70.
Example 3: Synthesis of
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine
8
[1255]
3-Iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8
is prepared in one step from
5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 6 as shown
in Scheme 3.
##STR00065##
Step 1--Preparation of
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine
(8)
[1256] 5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6,
1.1 g, 3.8 mmol) and 10 mL of dichloromethane are combined in a
round bottom flask and stirred for 10 minutes. A slurry of
N-iodosuccinimide (1.0 g, 4.6 mmol) in 5 mL of dichloromethane is
added and stirred at room temperature overnight. The reaction is
quenched with sodium thiosulfate (20 mL, 1M in water) and the
aqueous layer is extracted with ethyl acetate. The combined organic
layer is washed with water and brine, dried with sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography, eluting
with ethyl acetate and hexanes. Appropriate fractions are combined
and concentrated under vacuum to provide the desired compound as a
light yellow oil (8, 1.2 g, 75%). MS (ESI)
[M+H.sup.+].sup.+=415.08.
Example 4: Synthesis of
4-ethoxy-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
13
[1257]
4-Ethoxy-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
13 is prepared in three steps from
4-chloro-7H-pyrrolo[2,3-d]pyrimidine 9 as shown in Scheme 4.
##STR00066##
Step 1--Preparation of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine
(11)
[1258] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 300 mg, 1.95 mmol)
is combined with 3.00 mL of ethanol (10, 51.4 mmol), then potassium
hydroxide (0.226 g, 4.03 mmol) is added. The reaction is heated at
120.degree. C. for 3 hours in a microwave, then extracted with
ethyl acetate and aqueous saturated ammonium chloride. The organic
layer is washed with brine, dried with magnesium sulfate, filtered
and the filtrate concentrated under vacuum. The resulting material
is recrystallized from methanol to provide the desired compound
(11, 213 mg). MS (ESI) [M+H.sup.+].sup.+=164.9.
Step 2--Preparation of 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
(12)
[1259] To 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine (11, 1.60 g, 9.8
mmol) in 50.0 mL of dichloromethane, N,N-dimethylformamide (2.0 mL,
26 mmol) and N-iodosuccinimide (2.40 g, 10.7 mmol) are added and
the reaction stirred at room temperature for 2 hours. The reaction
is poured into water and extracted with ethyl acetate. The organic
layer is dried with sodium sulfate, filtered and the filtrate
concentrated under vacuum to provide the desired compound (12, 2.70
g).
Step 3--Preparation of
4-ethoxy-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
(13)
[1260] To 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (12, 2.70 g,
9.34 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of
nitrogen, sodium hydride (411.0 mg, 10.27 mmol) is added. The
reaction is stirred at room temperature for 20 minutes, then
triisopropylsilyl chloride (3, 2.177 mL, 10.27 mmol) is added. The
reaction is stirred at room temperature for 2 hours, then poured
into water and extracted with ethyl acetate. The organic layer is
dried over sodium sulfate, filtered and the filtrate concentrated
under vacuum. The resulting material is purified by silica gel
column chromatography, eluting with 5-100% ethyl acetate in hexane.
Appropriate fractions are combined and concentrated under vacuum to
provide the desired compound (13, 3.90 g).
[1261]
5-Iodo-4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
14
##STR00067##
is prepared similarly to the protocol of Scheme 4, replacing
ethanol with methanol in step 1.
[1262]
5-Iodo-4-methyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
16
##STR00068##
is prepared similarly to the protocol of Scheme 4, where step 1 is
replaced by the following step 1a:
##STR00069##
Step 1a--Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine
(15)
[1263] To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.03 g, 32.8
mmol) in 100 mL of toluene,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1
complex with dichloromethane (0.627 g, 0.328 mmol) is added under
an atmosphere of nitrogen. After stirring for 10 minutes,
methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) is
added slowly. The reaction is heated at 55.degree. C. overnight,
then cooled to -70 to -80.degree. C. and quenched by adding
ammonium chloride dropwise. Then 1N hydrochloric acid is added and
the pH is adjusted to 7-8 with the addition of saturated sodium
bicarbonate. This is extracted 3.times. with ethyl acetate. The
combined organic layer is washed with saturated ammonium chloride
and brine, then dried with magnesium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography, eluting with ethyl
acetate and dichloromethane, then methanol and dichloromethane.
Appropriate fractions are combined and concentrated under vacuum to
provide the desired compound as a tan solid (15). MS (ESI)
[M+H.sup.+].sup.+=134. This is reacted similarly to steps 2 and 3
of Scheme 4 to provide the desired compound 16.
[1264]
4-Cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimid-
ine 19
##STR00070##
is prepared similarly to the protocol of Scheme 4, where step 1 is
replaced by the following step 1b:
##STR00071##
Step 1b--Preparation of 4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine
(18)
[1265] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 0.452 g, 2.94
mmol), cyclopropylmagnesium bromide (17, 31.4 mL, 0.50 M in
tetrahydrofuran, 15.7 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1
complex with dichloromethane (0.240 g, 0.294 mmol) are combined
with 15.4 mL of toluene. The reaction is heated at 60.degree. C.
overnight, then quenched with 1 M aqueous hydrochloric acid to pH 4
and filtered through a bed of celite. The layers of the filtrate
are separated and the aqueous layer extracted with ethyl acetate.
The combined organic layers are washed with brine, dried over
sodium sulfate, filtered and the filtrate concentrated under
vacuum. The resulting material is purified by silica gel column
chromatography, eluting with ethyl acetate and hexane. Appropriate
fractions are combined and concentrated under vacuum to provide the
desired compound (18, 0.465 g). MS (ESI) [M+H.sup.+].sup.+=160.1.
This is reacted similarly to steps 2 and 3 of Scheme 4 to provide
the desired compound 19.
[1266] Cyclopropyl-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
22
##STR00072##
is prepared similarly to the protocol of scheme 4, steps 1 and 2,
where step 1 is replaced by the following step 1c:
##STR00073##
Step 1c--Preparation of
cyclopropyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (21)
[1267] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 1.06 g, 6.90 mmol)
is dissolved in cyclopropylamine (20, 2.42 mL, 34.5 mmol) and
heated to reflux overnight. The reaction mixture is cooled and
poured into water, then extracted with ethyl acetate. The organic
layer is washed with brine, dried over sodium sulfate, filtered and
the filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography, eluting with ethyl
acetate and dichloromethane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (21, 337
mg). MS (ESI) [M+H.sup.+].sup.+=174.9. This is reacted similarly to
step 2 of Scheme 4 to provide the desired compound 22.
Example 5: Synthesis of
7-benzenesulfonyl-5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine
27
[1268]
7-Benzenesulfonyl-5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyri-
midine 27 is prepared in three steps from
4-chloro-7H-pyrrolo[2,3-d]pyrimidine 9 as shown in Scheme 5.
##STR00074##
Step 1--Preparation of
4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (24)
[1269] To 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.00 g, 32.6
mmol) in 12.5 mL of 2-methoxy-ethanol (23, 158 mmol), potassium
hydroxide (3.3 g, 59 mmol) is added. The reaction is heated at
100.degree. C. overnight, then poured into water and extracted with
ethyl acetate. The organic layer is dried with sodium sulfate,
filtered and the filtrate concentrated under vacuum to provide the
desired compound (24, 5.70 g).
Step 2--Preparation of
5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25)
[1270] To 4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (24,
5.70 g, 29.5 mmol) in 150.0 mL of dichloromethane,
N,N-dimethylformamide (6.0 mL, 78 mmol) and N-iodosuccinimide (7.22
g, 32.1 mmol) are added and the reaction stirred at room
temperature for 2 hours. The reaction is poured into water and
extracted with ethyl acetate. The organic layer is dried with
sodium sulfate, filtered and the filtrate concentrated under
vacuum. The resulting material is washed with ethyl acetate and
hexane to provide the desired compound (25, 6.75 g).
Step 3--Preparation of
7-benzenesulfonyl-5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine
(27)
[1271] To 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine
(25, 3.67 g, 11.5 mmol) in 60.0 mL of tetrahydrofuran under an
atmosphere of nitrogen, sodium hydride (506.0 mg, 12.65 mmol) is
added. The reaction is stirred at room temperature for 20 minutes,
then benzenesulfonyl chloride (26, 1.614 mL, 12.65 mmol) is added.
The reaction is stirred at room temperature for 30 minutes, then
poured into water and extracted with ethyl acetate. The organic
layer is dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum. The resulting material is purified by
silica gel column chromatography, eluting with 15-100% ethyl
acetate in hexane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (27, 4.50
g). MS (ESI) [M+H.sup.+].sup.+=460.0.
[1272] 1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine
28, 1-benzenesulfonyl-3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 29,
and 7-benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
30,
##STR00075##
are prepared following the protocol of scheme 5 step 3 or steps 2
and 3, replacing
5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine 25 with
5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 2 and
3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 7, respectively in step
3, or by reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 9 directly
in step 2.
[1273]
7-Benzenesulfonyl-5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine 31
and
7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
32,
##STR00076##
are prepared following the protocol of scheme 5 steps 2 and 3,
replacing 4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine 24 with
4-methyl-7H-pyrrolo[2,3-d]pyrimidine 15 and
4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine 18, respectively, in step
2.
[1274]
4-Cyclopropyl-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimi-
dine 33,
##STR00077##
is synthesized similarly to compound 32, where
4-methylbenzenesulfonyl chloride is used in place of
benzenesulfonyl chloride 26 in step 3 of Scheme 5.
Example 6: Synthesis of
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H--
pyrrolo[2,3-b]pyridine 37
[1275]
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethy-
l)-1H-pyrrolo[2,3-b]pyridine 37 is prepared in three steps from
1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 28 and
2-methylsulfanyl-pyrimidine-5-carbaldehyde 34 as shown in Scheme
6.
##STR00078##
Step 1--Preparation of
(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfa-
nyl-pyrimidin-5-yl)-methanol (35)
[1276] To a solution of
1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (28,
8.40 g, 20.1 mmol) in 96.3 mL of tetrahydrofuran at -40.degree. C.
under nitrogen, isopropylmagnesium chloride (10.1 mL, 2.0 M in
tetrahydrofuran, 20.3 mmol) is added slowly. The reaction is
allowed to warm to 5.degree. C. over 60 minutes, then cooled to
-40.degree. C., followed by addition of
2-methylsulfanyl-pyrimidine-5-carbaldehyde (34, 2.50 g, 16.2 mmol)
in 15.0 mL of tetrahydrofuran. The reaction is allowed to warm to
10.degree. C. over 2 hours, then poured into aqueous ammonium
chloride and extracted with ethyl acetate. The organic layer is
dried over sodium sulfate, filtered and the filtrate is
concentrated under vacuum. The resulting material is purified by
silica gel column chromatography eluting with 40-100% ethyl acetate
in hexane. Appropriate fractions are combined and the solvents
removed under vacuum to provide the desired compound as an
off-white solid (35, 4.0 g). MS (ESI) [M+H.sup.+].sup.+=447.2.
Step 2--Preparation of
1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-p-
yrrolo[2,3-b]pyridine (36)
[1277] To
(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-me-
thylsulfanyl-pyrimidin-5-yl)-methanol (35, 4.70 g, 10.5 mmol) in
120.0 mL of acetonitrile, triethylsilane (22.0 mL, 138 mmol) and
trifluoroacetic acid (11.0 mL, 143 mmol) are added. The reaction is
stirred at 80.degree. C. for 3 hours, then concentrated under
vacuum, mixed with aqueous potassium carbonate and extracted with
ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography eluting
with 20-100% ethyl acetate in hexane. Appropriate fractions are
combined and solvents removed under vacuum to provide the desired
compound (36, 2.90 g).
Step 3--Preparation of
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H--
pyrrolo[2,3-b]pyridine (37)
[1278] To
1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmet-
hyl)-1H-pyrrolo[2,3-b]pyridine (36, 4.40 g, 10.2 mmol) in 100.0 mL
of dichloromethane, meta-chloroperoxybenzoic acid (max. 77%, 4.90
g, 21.9 mmol) is added at 0.degree. C. The reaction is stirred at
0.degree. C. for 40 minutes, then poured into water and extracted
with ethyl acetate. The organic layer is dried over sodium sulfate,
filtered, and the filtrate is concentrated under vacuum. The
resulting material is purified by silica gel column chromatography
eluting with 20% ethyl acetate in hexane. Appropriate fractions are
combined and solvents removed under vacuum to provide the desired
compound (37, 3.76 g). MS (ESI) [M+H.sup.+].sup.+=463.0.
[1279]
1-Benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-5-meth-
yl-1H-pyrrolo[2,3-b]pyridine 38
##STR00079##
is prepared following the protocol of Scheme 6, replacing
1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 28 with
1-benzenesulfonyl-3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 29 in
step 1.
Example 7: Synthesis of
6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylami-
ne 49
[1280]
6-fluoro-5-(5-methyl-1H-pyrrolo[2,3]pyridin-3-ylmethyl)-pyridin-2-y-
lamine 49 is prepared in seven steps from 2,6-difluoro-pyridine 39
and 4-methoxy-benzylamine 40 as shown in Scheme 7.
##STR00080## ##STR00081##
Step 1--Preparation of
(6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (41)
[1281] To 2,6-difluoro-pyridine (39, 100 g, 869 mmol) in 500 mL of
N-methylpyrrolidinone, 4-methoxy-benzylamine (40, 136 mL, 1.043
mol) and N,N-diisopropylethylamine (304 mL, 1.738 mol) are added.
The reaction is stirred at 90.degree. C. overnight, then poured
into 8 L of water. The resulting precipitate is collected by
filtration and washed with water, then taken up in ethyl acetate
and washed with water. The organic layer is dried over sodium
sulfate, filtered and the filtrate concentrated under vacuum. The
resulting material is triturated with heptane and collected by
filtration to provide the desired compound (41, 151 g, 650 mmol,
74.8% yield).
Step 2--Preparation of
(5-bromo-6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (42)
[1282] To (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (41, 151
g, 650 mmol) in 4 L of acetonitrile under an atmosphere of
nitrogen, N-bromosuccinimide (116 g, 650 mmol) is added in
portions. After reacting for 2 hours, the solvent is removed under
vacuum and the residue is taken up in ethyl acetate, then poured
into aqueous sodium thiosulfate. The organic layer is washed with
warm water, dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum. The resulting material is crystallized
from heptane to provide the desired compound (42, 172 g, 553 mmol,
85% yield).
Step 3--Preparation of 2-fluoro-6-(4-methoxy-benzylamino)-nicotinic
acid methyl ester (43)
[1283] To (5-bromo-6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine
(42, 85 g, 273 mmol) in 1.5 L of methanol in a 2 L Parr flask,
triethylamine (77 mL, 546 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (5.80
g, 7.10 mmol) are added. The reaction is heated at 100.degree. C.
under 100 psi of carbon monoxide overnight. The reaction is cooled
and filtered through celite and the filtrate is concentrated under
vacuum. The resulting material is dissolved in dichloromethane and
passed through a plug of silica gel, eluting with ethyl acetate.
The solvent is removed under vacuum to provide the desired compound
as a peach colored solid (43, 70 g, 241 mmol, 88% yield).
Step 4--Preparation of
[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-3-yl]-methanol (44)
[1284] To 2-fluoro-6-(4-methoxy-benzylamino)-nicotinic acid methyl
ester (43, 70 g, 241 mmol) in 350 mL of tetrahydrofuran, lithium
aluminum hydride (362 mL, 1 M in tetrahydrofuran, 362 mmol) is
added dropwise while cooling. The reaction is stirred at room
temperature for 2 hours, then quenched with dropwise addition of 14
mL of water, 14 mL of 15% aqueous sodium hydroxide, and 42 mL of
water, sequentially. Then 500 mL of methyl tert-butyl ether is
added and solids are removed by filtration. The filtrate is
concentrated under vacuum and the resulting solid is dissolved in
dichloromethane, passed through a plug of silica gel and eluted
with 50-100% ethyl acetate in heptane. The solvent is removed under
vacuum to provide the desired compound as an off-white solid (44,
63 g, 240 mmol, 100% yield).
Step 5--Preparation of
2-fluoro-6-(4-methoxy-benzylamino)-pyridine-3-carbaldehyde (45)
[1285] To
[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-3-yl]-methanol (44, 63
g, 240 mmol) in 1.25 L of ethyl acetate, manganese(IV) oxide (210
g, 2.416 mol) is added. The reaction is stirred overnight at room
temperature, then filtered through celite and the celite rinsed
with ethyl acetate. The combined filtrates are concentrated under
vacuum and the resulting solid is triturated with heptane and
collected by filtration to provide the desired compound as a white
solid (45, 62 g, 238 mmol, 99% yield).
Step 6--Preparation of
(6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid
tert-butyl ester (47)
[1286] 2-Fluoro-6-(4-methoxy-benzylamino)-pyridine-3-carbaldehyde
(45, 62 g, 238 mmol), 600 mL of tert-butyl alcohol,
di-tert-butyldicarbonate (46, 83 mL, 357 mmol) and
dimethylaminopyridine (2.91 g, 23.82 mmol) are combined in a round
bottom flask. The reaction is stirred at 30.degree. C. overnight
and then concentrated under vacuum. The resulting material is
purified by silica gel column chromatography, eluting with 0-20%
ethyl acetate in hexane. Appropriate fractions are combined and the
solvents removed under vacuum to provide the desired compound (47,
54 g, 150 mmol, 62.9% yield).
Step 7--Preparation of
{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyr-
idin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid
tert-butyl ester (48)
[1287] To
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8,
40 g, 97.0 mmol) in 400 mL of tetrahydrofuran under an atmosphere
of nitrogen at -20.degree. C., isopropylmagnesium chloride (54.8
mL, 2 M in tetrahydrofuran, 110 mmol) is added and the reaction
allowed to warm to 0.degree. C. over 30 minutes. The reaction is
cooled to -40.degree. C. and
(6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid
tert-butyl ester (47, 15.81 g, 43.9 mmol) in tetrahydrofuran is
added. The reaction is allowed to warm to 0.degree. C. over an
hour, then quenched with brine and extracted with ethyl acetate.
The organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography, eluting with 0-40%
ethyl acetate in hexane. Appropriate fractions are combined and the
solvents removed under vacuum to provide the desired compound (48,
21 g, 32.4 mmol, 73.8% yield).
Step 8--Preparation of
6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylami-
ne (49)
[1288] To
{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[-
2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic
acid tert-butyl ester (48, 21 g, 32.4 mmol) in 500 mL of
acetonitrile, triethylsilane (51.7 mL, 324 mmol) and
trifluoroacetic acid (24.93 mL, 324 mmol) are added. The reaction
is stirred at 50.degree. C. for several hours, then concentrated
under vacuum, and the residue is taken up in 250 mL of
dichloromethane and 250 mL of trifluoroacetic acid is added. The
mixture is stirred at reflux for several hours, then concentrated
under vacuum. The residue is taken up in ethyl acetate and poured
into aqueous potassium carbonate. The organic layer is separated,
concentrated under vacuum and purified by silica gel column
chromatography, eluting with 0-5% methanol in dichloromethane.
Appropriate fractions are combined and the solvents removed under
vacuum to provide the desired compound (49, 5.2 g, 20.29 mmol,
62.7% yield).
[1289]
5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-
-ylamine 50
##STR00082##
is prepared following the protocol of Scheme 7, replacing
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8
with
5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4
in step 7.
Example 8: Synthesis of Aldehyde Reagents
[1290] Aldehyde reagents that are used in making compounds are
prepared according to the following protocols. In these reactions,
the unprotected aldehyde isolated after step 5, or the subsequently
Boc-protected aldehyde may be used in preparation of compounds.
[1291]
(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 57 is prepared in six steps from
2,6-difluoro-pyridine 39 as shown in Scheme 8.
##STR00083## ##STR00084##
Step 1--Preparation of 2, 6-difluoro-nicotinic acid (51)
[1292] In a round bottom flask, to 2,6-difluoro-pyridine (39, 7.10
g, 61.7 mmol) in 150.0 mL of tetrahydrofuran under an atmosphere of
nitrogen at -78.degree. C., n-butyllithium (26.0 mL, 2.50 M in
hexane, 65.0 mmol) is slowly added. After 30 minutes, 3.0 g of dry
ice is added and an hour later the reaction is allowed to warm to
room temperature. The reaction is poured into water, extracted with
ethyl acetate and the aqueous layer is adjusted to pH 4-5 with 1 N
hydrochloric acid. This is extracted with ethyl acetate and the
organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum to provide the desired compound
(51, 5.6 g).
Step 2--Preparation of 2,6-difluoro-nicotinic acid methyl ester
(52)
[1293] In a round bottom flask, 2,6-difluoro-nicotinic acid (51,
5.60 g, 35.2 mmol), 60.0 mL of methanol and sulfuric acid (1.0 mL,
19.0 mmol) are combined and heated to reflux overnight. The
reaction is poured into water, adjusted to pH around 9 with 1M
aqueous potassium carbonate, and extracted with ethyl acetate. The
organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum to provide the desired compound
as a yellow oil (52, 3.5 g).
Step 3--Preparation of
2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-nicotinic acid methyl
ester (54)
[1294] To a round bottom flask, 2,6-difluoro-nicotinic acid methyl
ester (52, 2.00 g, 11.6 mmol) is combined with 20.0 mL of
N,N-dimethylformamide under an atmosphere of nitrogen at
-40.degree. C. To this, 5-amino-2-methoxypyridine (53, 1.55 g, 12.5
mmol) and triethylamine (5.0 mL, 36.0 mmol) are added and the
reaction stirred at -40.degree. C., then warmed to room temperature
and reacted overnight. The reaction is then heated to 50.degree. C.
over the weekend, then at 70.degree. C. for 3 hours. The reaction
is poured into water and extracted with ethyl acetate. The organic
layer is dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum. The resulting material is purified by
silica gel column chromatography eluting with 20-100% ethyl acetate
in hexane. Appropriate fractions are combined and concentrated
under vacuum to provide the desired compound (54, 1.20 g).
Step 4--Preparation of
[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanol
(55)
[1295] To 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-nicotinic acid
methyl ester (54, 1.20 g, 4.33 mmol) in 50.0 mL of tetrahydrofuran,
lithium tetrahydroaluminate (8.66 mL, 1.00 M in tetrahydrofuran,
8.66 mmol) is added and the reaction is stirred at room temperature
for 3 hours. Sodium sulfate decahydrate (5 g) is added and after 1
hour, the reaction is filtered and the filtrate concentrated under
vacuum. The resulting material is purified by silica gel column
chromatography eluting with 20-100% ethyl acetate in hexane.
Appropriate fractions are combined and concentrated under vacuum to
provide the desired compound (55, 700 mg). MS (ESI)
[M+H.sup.+].sup.+=250.1.
Step 5--Preparation of
2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde
(56)
[1296] To
[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanol
(55, 0.700 g, 2.81 mmol) in 20.0 mL of tetrahydrofuran, Dess-Martin
periodinane (1.44 g, 3.40 mmol) is added and the reaction stirred
at room temperature for 30 minutes. The reaction is poured into
aqueous potassium carbonate and extracted with ethyl acetate. The
organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography eluting with 20-100%
ethyl acetate in hexane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (56, 450
mg). MS (ESI) [M+H.sup.+].sup.+=248.0.
Step 6--Preparation of
(6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic
acid tert-butyl ester (57)
[1297] To
2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde
(56, 2.21 g, 8.94 mmol) in 50 mL of tetrahydrofuran,
di-tert-butyldicarbonate (46, 2.82 g, 12.9 mmol) and
4-dimethylaminopyridine (0.30 g, 2.4 mmol) are added and the
reaction stirred at room temperature overnight. The reaction is
concentrated under vacuum and the resulting material is purified by
silica gel column chromatography eluting with 20-100% ethyl acetate
in hexane. Appropriate fractions are combined and concentrated
under vacuum to provide the desired compound (57, 1.39 g).
[1298] Additional aldehydes are prepared similarly to the protocol
of scheme 8, as shown in the following table, replacing
5-amino-2-methoxypyridine 53 with a suitable amine compound in step
3. While the table indicates the Boc-protected aldehyde, the
non-Boc protected aldehyde may be isolated after step 5.
TABLE-US-00002 TABLE 3 Step 3 amine compound Final aldehyde
##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098##
Example 9: Synthesis of
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
xyl-amine P-3001
[1299]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-c-
yclohexyl-amine P-3001 is prepared in one step from
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H--
pyrrolo[2,3-b]pyridine 37 and cyclohexanamine 62 as shown in Scheme
9.
##STR00099##
Step 1--Preparation of
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
xyl-amine (83001)
[1300] In a microwave vial, to
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H--
pyrrolo[2,3-b]pyridine (37, 60 mg, 0.13 mmol) in 1.0 mL of
N-methylpyrrolidinone, cyclohexanamine (62, 0.20 g, 2.0 mmol) is
added. The reaction is heated at 155.degree. C. for 25 minutes in a
microwave, then potassium hydroxide (1.0 mL, 1.00 M in water, 1.0
mmol) is added and the reaction heated at 95.degree. C. for 15
minutes in a microwave. The reaction is poured into water and
extracted with ethyl acetate. The organic layer is dried over
sodium sulfate, filtered and the filtrate concentrated under
vacuum. The resulting material is purified by silica gel column
chromatography, eluting with 20-100% ethyl acetate in hexane.
Appropriate fractions are collected and concentrated under vacuum
to provide the desired compound (P-3001, 11.4 mg). MS (ESI)
[M+H.sup.+].sup.+=341.9.
[1301]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(-
4-methyl-cyclohexyl)-amine P-3009 was prepared similarly to Scheme
9, replacing step 1 with the following steps 1a and 2:
##STR00100##
Step 1a--Preparation of
[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-(4-methyl-cyclohexyl)-amine (64)
[1302] In a microwave vial, to
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H--
pyrrolo[2,3-b]pyridine (37, 0.140 g, 0.302 mmol) in 2.0 mL of
N-methylpyrrolidinone, 4-methylcyclohexylamine (63, 0.30 g, 2.6
mmol) is added. The reaction is heated at 160.degree. C. for 20
minutes in a microwave, then poured into water and extracted with
ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography, eluting
with 20-100% ethyl acetate in hexane. Appropriate fractions are
combined and concentrated under vacuum to provide the desired
compound (64, 0.120 g). MS (ESI) [M+H.sup.+].sup.+=496.4.
Step 2--Preparation of
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-meth-
yl-cyclohexyl)-amine (P-3009)
[1303] To
[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmeth-
yl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine (64, 0.120 g, 0.242
mmol) in 5.0 mL of tetrahydrofuran, tetrabutylammonium fluoride
trihydrate (0.20 g, 0.63 mmol) is added. The reaction is stirred at
room temperature overnight, then poured into water and extracted
with ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography, eluting
with 20-100% ethyl acetate in hexane. Appropriate fractions are
collected and concentrated under vacuum to provide the desired
compound (P-3009, 1.4 mg). MS (ESI) [M+H.sup.+].sup.+=355.95.
[1304] Additional compounds are prepared following the protocol of
Scheme 9. Compounds are made substituting cyclohexanamine 62 with a
suitable amine and optionally substituting
1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H--
pyrrolo[2,3-b]pyridine 37 with
1-benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-5-methyl-1H--
pyrrolo[2,3-b]pyridine 38. The following compounds are made using
this procedure: [1305]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclope-
ntyl-amine (P-3003), [1306]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-di-
fluoro-cyclohexyl)-amine (P-3004), [1307]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopr-
opyl-amine (P-3005), [1308]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohe-
ptyl-amine (P-3006), [1309]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclobu-
tyl-amine (P-3007), [1310]
(4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3010), [1311]
(4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3011), [1312]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluo-
ro-phenyl)-amine (P-3012), [1313]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluo-
ro-phenyl)-amine (P-3014), [1314]
(2-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3015), [1315]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-meth-
oxy-phenyl)-amine (P-3016), [1316]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluo-
ro-phenyl)-amine (P-3017), [1317]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trif-
luoromethyl-pyridin-3-yl)-amine (P-3018), [1318]
(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-
)-pyrimidin-2-yl]-amine (P-3020), [1319]
(4-Methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyri-
midin-2-yl]-amine (P-3021), [1320]
(4-Fluoro-3-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-yl]-amine (P-3022), [1321]
(3-Fluoro-4-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-yl]-amine (P-3023), [1322]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-prop-
oxy-phenyl)-amine (P-3024), [1323]
(4-Ethyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimi-
din-2-yl]-amine (P-3025), [1324]
(4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-amine (P-3026), [1325]
(6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
-pyrimidin-2-yl]-amine (P-3027), [1326]
[5-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-[5-(5-methyl-1H-pyrrolo[2,3-b]pyrid-
in-3-ylmethyl)-pyrimidin-2-yl]-amine (P-3028), [1327]
(5-tert-Butyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
methyl)-pyrimidin-2-yl]-amine (P-3029), [1328]
(4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p-
yrimidin-2-yl]-amine amine (P-3030), [1329]
1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmet-
hyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol (P-3031), [1330]
(5-Cyclopropyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyrimidin-2-yl]-amine (P-3032), [1331]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-meth-
ylsulfanyl-phenyl)-amine (P-3033), [1332]
(1-Ethyl-1H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyrimidin-2-yl]-amine (P-3035), [1333]
(1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyrimidin-2-yl]-amine (P-3036), [1334]
[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-trif-
luoromethyl-2H-pyrazol-3-yl)-amine (P-3037), and [1335]
(5-Isopropoxy-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
methyl)-pyrimidin-2-yl]-amine (P-3038).
[1336] The following table indicates the
2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine
(column 2) and amine compound (column 3) used in step 1 to afford
the desired compound (column 4). The compound number is provided in
column 1, and the observed mass is in column 5.
TABLE-US-00003 TABLE 4 Comp. Amine MS (ESI) number
pyrrolo[2,3-b]pyridine structure Compound structure [M +
H.sup.+].sup.+ P-3003 ##STR00101## ##STR00102## ##STR00103## 328.0
P-3004 ##STR00104## ##STR00105## ##STR00106## 377.9 P-3005
##STR00107## ##STR00108## ##STR00109## 300.0 P-3006 ##STR00110##
##STR00111## ##STR00112## 356.3 P-3007 ##STR00113## ##STR00114##
##STR00115## 314.2 P-3010 ##STR00116## ##STR00117## ##STR00118##
334.1 P-3011 ##STR00119## ##STR00120## ##STR00121## 370.8 P-3012
##STR00122## ##STR00123## ##STR00124## 354.0 P-3014 ##STR00125##
##STR00126## ##STR00127## 353.9 P-3015 ##STR00128## ##STR00129##
##STR00130## 369.9 P-3016 ##STR00131## ##STR00132## ##STR00133##
365.9 P-3017 ##STR00134## ##STR00135## ##STR00136## 353.9 P-3018
##STR00137## ##STR00138## ##STR00139## 384.9 P-3020 ##STR00140##
##STR00141## ##STR00142## 347.1 P-3021 ##STR00143## ##STR00144##
##STR00145## 346.2 P-3022 ##STR00146## ##STR00147## ##STR00148##
363.9 P-3023 ##STR00149## ##STR00150## ##STR00151## 363.9 P-3024
##STR00152## ##STR00153## ##STR00154## 374.0 P-3025 ##STR00155##
##STR00156## ##STR00157## 344.0 P-3026 ##STR00158## ##STR00159##
##STR00160## 360.0 P-3027 ##STR00161## ##STR00162## ##STR00163##
501.3 P-3028 ##STR00164## ##STR00165## ##STR00166## 399.9 P-3029
##STR00167## ##STR00168## ##STR00169## 362.0 P-3030 ##STR00170##
##STR00171## ##STR00172## 372.0 P-3031 ##STR00173## ##STR00174##
##STR00175## 482.3 P-3032 ##STR00176## ##STR00177## ##STR00178##
346.0 P-3033 ##STR00179## ##STR00180## ##STR00181## 362.1 P-3035
##STR00182## ##STR00183## ##STR00184## 334.2 P-3036 ##STR00185##
##STR00186## ##STR00187## 333.9 P-3037 ##STR00188## ##STR00189##
##STR00190## 374.0 P-3038 ##STR00191## ##STR00192## ##STR00193##
363.9
[1337]
(4-Methanesulfonyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
ylmethyl)-pyrimidin-2-yl]-amine P-3034
##STR00194##
is prepared by oxidizing the product of Scheme 9 step 1a in the
preparation of
[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-meth-
ylsulfanyl-phenyl)-amine (P-3033), prior to reaction of step 2,
according to the following step 1b:
##STR00195##
Step 1b--Preparation of
[5-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-(4-methanesulfonyl-phenyl)-amine (66)
[1338] To
[5-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmeth-
yl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine (65, 80 mg,
0.16 mmol) in 10.0 mL of dichloromethane, meta-chlorperoxybenzoic
acid (78.6 mg, 0.351 mmol) is added at 0.degree. C. The reaction is
stirred at room temperature for 30 minutes, then concentrated under
vacuum to provide
[5-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrim-
idin-2-yl]-(4-methanesulfonyl-phenyl)-amine 66, which is reacted
according to Scheme 9 step 2 to provide the desired compound
(P-3034, 30.7 mg). MS (ESI) [M+H.sup.+].sup.+=393.9.
Example 10: Synthesis of
cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyr-
idin-2-yl]-amine P-3008
[1339]
Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethy-
l)-pyridin-2-yl]-amine P-3008 is prepared in one step from
6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylami-
ne 49 and cyclohexanone 67 as shown in Scheme 10.
##STR00196##
Step 1--Preparation of
cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyr-
idin-2-yl]-amine (83008)
[1340] To
6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridi-
n-2-ylamine (49, 100 mg, 0.39 mmol) and cyclohexanone (67, 0.0465
mL, 0.449 mmol) in 3.00 mL of acetonitrile, triethylsilane (0.400
mL, 2.50 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol) were
added. The reaction was stirred at 80.degree. C. overnight, then
extracting with ethyl acetate and 1N aqueous sodium bicarbonate.
The organic layer was washed with brine, dried with magnesium
sulfate, filtered and the filtrate concentrated under vacuum. The
resulting material was purified by silica gel column
chromatography, eluting with 0-60% ethyl acetate in hexane.
Appropriate fractions were combined and concentrated under vacuum
to provide the desired compound (P-3008, 115 mg). MS (ESI)
[M+H.sup.+].sup.+=339.0.
[1341]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin--
2-yl]-(4,4-difluoro-cyclohexyl)-amine P-3013
##STR00197##
is prepared following the protocol of Scheme 10, replacing
6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylami-
ne 49 with
5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyrid-
in-2-ylamine 50 and replacing cyclohexanone 67 with
4,4-difluoro-cyclohexanone. MS (ESI) [M+H.sup.+].sup.+=394.9 and
396.9.
Example 11: Synthesis of
[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine P-3019
[1342]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin--
2-yl]-(6-methoxy-pyridin-3-yl)-amine P-3019 is prepared in two
steps from
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8
and
2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde 56
as shown in Scheme 11.
##STR00198##
Step 6--Preparation of
[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1-triis-
opropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (68)
[1343] To a solution of
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8,
1.02 g, 2.461 mmol) in 6.0 mL of tetrahydrofuran at -50.degree. C.
under nitrogen, isopropylmagnesium chloride (1.23 mL, 2.00 M in
tetrahydrofuran, 2.46 mmol) is added slowly. The reaction is
allowed to warm to 5.degree. C. over 70 minutes, then cooled to
-45.degree. C., followed by addition of
2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde
(56, 0.165 g, 0.667 mmol) in 2.0 mL of tetrahydrofuran. The
reaction is allowed to warm to room temperature over an hour, then
poured into water and extracted with ethyl acetate. The organic
layer is dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum. The resulting material is purified by
silica gel column chromatography eluting with 20-100% ethyl acetate
in hexane. Appropriate fractions are combined and concentrated
under vacuum to provide the desired compound (68, 330 mg). MS (ESI)
[M+H.sup.+].sup.+=536.2.
Step 7--Preparation of
[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine (83019)
[1344] To
[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methy-
l-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol
(68, 0.220 g, 0.411 mmol) in 20.0 mL of 1,2-dichloroethane,
triethylsilane (2.0 mL, 12 mmol) and trifluoroacetic acid (1.0 mL,
13 mmol) are added and the reaction stirred at 80.degree. C. for 3
hours. The reaction is poured into water and extracted with ethyl
acetate. The organic layer is dried over sodium sulfate, filtered
and the filtrate concentrated under vacuum. The resulting material
is purified by silica gel column chromatography eluting with
20-100% ethyl acetate in hexane. Appropriate fractions are combined
and concentrated under vacuum to provide the desired compound
(P-3019, 105.1 mg). MS (ESI) [M+H.sup.+].sup.+=364.2.
[1345]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyrid-
in-2-yl]-(6-methoxy-pyridin-3-yl)-amine P-4001 and
[6-Fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine P-4002
##STR00199##
are prepared similarly to the protocol of Scheme 11, replacing
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8
with
5-iodo-4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
14 and
5-iodo-4-methyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
16, respectively in step 1.
Example 12: Synthesis of
(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
ylmethyl)-pyridin-2-yl]-amine P-3039 or
[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone P-3045
[1346]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyri-
din-3-ylmethyl)-pyridin-2-yl]-amine P-3039 or
[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone P-3045 are prepared in two steps
or three steps from
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8,
and
(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 69 as shown in Scheme 12.
##STR00200## ##STR00201##
Step 1--Preparation of
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsila-
nyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic
acid tert-butyl ester (70)
[1347] To a solution of
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8,
0.43 g, 1.0 mmol) in 5 mL of tetrahydrofuran at -40.degree. C.
under nitrogen, isopropylmagnesium chloride (0.51 mL, 2.00 M in
tetrahydrofuran, 1.0 mmol) is added slowly. The reaction is allowed
to warm to -5.degree. C. over 60 minutes, then cooled to
-45.degree. C., followed by addition of
(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester (69, 0.06 g, 0.2 mmol) in 2.0 mL of
tetrahydrofuran. The reaction is allowed to warm to room
temperature over 2 hours, then poured into water and extracted with
ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography eluting
with 20-100% ethyl acetate in hexane. Appropriate fractions are
combined and concentrated under vacuum to provide the desired
compound (70, 108.1 mg).
Step 2--Preparation of
(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
ylmethyl)-pyridin-2-yl]-amine (P-3039)
[1348] To
(6-ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisop-
ropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic
acid tert-butyl ester (70, 108.1 mg, 0.166 mmol) in 4.54 mL of
1,2-dichloroethane, triethylsilane (0.454 mL, 2.84 mmol) and
trifluoroacetic acid (0.27 mL, 3.5 mmol) are added and the reaction
stirred at 80.degree. C. for 4 hours. The reaction is poured into
aqueous potassium carbonate and extracted with ethyl acetate. The
organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography eluting with 25-100%
ethyl acetate in hexane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (P-3039),
which is further purified by additional chromatography.
Step 2a--Preparation of
(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1-triisopropylsilanyl-1H-py-
rrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic acid
tert-butyl ester (71)
[1349]
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisoprop-
ylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic
acid tert-butyl ester (70, 0.400 g, 0.616 mmol) is alternatively
dissolved in 11.8 mL of dichloromethane, and Dess-Martin
periodinane (0.100 g, 0.236 mmol) is added. The reaction is stirred
at room temperature for 30 minutes, then concentrated under vacuum.
The resulting material is purified by silica gel column
chromatography, eluting with 20-100% ethyl acetate in hexane.
Appropriate fraction are combined and concentrated under vacuum to
provide the desired compound (71, 0.200 g).
Step 3a--Preparation of
[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3045)
[1350] To
(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1-triisopropylsila-
nyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic
acid tert-butyl ester (71, 0.200 g, 0.309 mmol) in 10 mL of
1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.0 mmol) is
added. The reaction is stirred at 80.degree. C. for 2 hours, then
poured into aqueous potassium carbonate and extracted with ethyl
acetate. The organic layer is dried over sodium sulfate, filtered
and the filtrate concentrated under vacuum. The resulting material
is purified by silica gel column chromatography, eluting with 2-15%
methanol in dichloromethane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (P-3045,
60.7 mg). MS (ESI) [M+H.sup.+].sup.+=391.9.
[1351] Additional compounds are prepared following the protocol of
Scheme 12. Compounds are made substituting either of
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8
with a suitable TIPS-protected 1H-pyrrolo[2,3-b]pyridine or
7H-pyrrolo[2,3-d]pyrimidine and
(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 69 with a suitable Boc-protected aldehyde in
step 1. The following compounds are made using this procedure:
[1352]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methoxy-pyridin-3-yl)-amine (P-3019), [1353]
[2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrr-
olo[2,3-b]pyridin-3-yl)-methanone (P-3040), [1354]
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3041), [1355]
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]--
(6-methyl-pyridin-3-yl)-amine (P-3042), [1356]
[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrro-
lo[2,3-b]pyridin-3-yl)-methanone (P-3043), [1357]
(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3--
ylamino)-pyridin-3-yl]-methanone (P-3044), [1358]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl)-pyridin-2-yl]-amine (P-3048), [1359]
[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrol-
o[2,3-b]pyridin-3-yl)-methanone (P-3049), [1360]
(6-Chloro-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-pyridin-2-yl]-amine (P-4003), [1361]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-pyridin-2-yl]-amine (P-4005), [1362]
(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]-amine (P-4006), [1363]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin--
5-ylmethyl)-pyridin-2-yl]-amine (P-4007), [1364]
(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-pyridin-2-yl]-amine (P-4009), [1365]
[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-y-
l]-(6-methyl-pyridin-3-yl)-amine (P-4010), [1366]
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimid-
in-5-ylmethyl)-pyridin-2-yl]-amine (P-4011), [1367]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4012), [1368]
(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidi-
n-5-ylmethyl)-pyridin-2-yl]-amine (P-4013), [1369]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methyl-pyridin-3-yl)-amine (P-4017), [1370]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-(6-methoxy-pyridin-3-yl)-amine (P-4018), [1371]
(6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl-
)-6-fluoro-pyridin-2-yl]-amine (P-4020),
[1372] The following table indicates the TIPS-protected
1H-pyrrolo[2,3-b]pyridine (column 2) and Boc-protected aldehyde
compound (column 3) used in step 1 to afford the desired compound
(column 4). The compound number is provided in column 1, and the
observed mass is in column 5.
TABLE-US-00004 TABLE 5 pyrrolo[2,3- b]pyridine or Comp.
pyrrolo[2,3- MS (ESI) number d]pyrimidine Aldehyde Compound
structure [M + H.sup.+].sup.+ P-3019 ##STR00202## ##STR00203##
##STR00204## 363.9 P-3040 ##STR00205## 378.0 P-3041 ##STR00206##
##STR00207## ##STR00208## 347.8 P-3043 ##STR00209## 361.9 P-3042
##STR00210## ##STR00211## ##STR00212## 367.9 P-3044 ##STR00213##
382.0 P-3048 ##STR00214## ##STR00215## ##STR00216## 362.0 P-3049
##STR00217## 376.1 P-4003 ##STR00218## ##STR00219## ##STR00220##
385.0 P-4005 ##STR00221## ##STR00222## ##STR00223## 394.95 P-4024
##STR00224## 409.2 P-4006 ##STR00225## ##STR00226## ##STR00227##
378.95 P-4007 ##STR00228## ##STR00229## ##STR00230## 379.0 P-4009
##STR00231## ##STR00232## ##STR00233## P-4010 ##STR00234##
##STR00235## ##STR00236## 365.0 P-4011 ##STR00237## ##STR00238##
##STR00239## 367.9 P-4012 ##STR00240## ##STR00241## ##STR00242##
382.1 P-4013 ##STR00243## ##STR00244## ##STR00245## 351.9 P-4017
##STR00246## ##STR00247## ##STR00248## 379.0 P-4018 ##STR00249##
##STR00250## ##STR00251## 394.8 P-4025 ##STR00252## 409.2 P-4020
##STR00253## ##STR00254## ##STR00255## 442.9 444.9
[1373]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3--
d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine P-4004
##STR00256##
is prepared from the intermediate isolated after step 1 in the
preparation of P-4003 according to the following steps 1b and
2b.
##STR00257##
Step 1b--Preparation of
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7--
triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol
(73)
[1374] To
(6-chloro-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(4-methoxy-7-triiso-
propylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl}-carba-
mic acid tert-butyl ester (72, 105 mg, 0.160 mmol) in 3.8 mL of
toluene, [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II) 1:1 complex with dichloromethane (13.0 mg,
0.016 mmol) is added under an atmosphere of nitrogen. The reaction
is stirred for 5 minutes, then cyclopropylmagnesium bromide (17,
1.60 mL, 1.0 M in tetrahydrofuran, 1.60 mmol) is added slowly. The
reaction is heated at 65.degree. C. for 5 hours, then poured into
water and extracted with ethyl acetate. The organic layer is dried
over sodium sulfate, filtered and the filtrate concentrated under
vacuum. The resulting material is purified by silica gel column
chromatography, eluting with 20-100% ethyl acetate in hexane.
Appropriate fractions are combined and concentrated under vacuum to
provide the desired compound (73, 70 mg). MS (ESI)
[M+H.sup.+].sup.+=563.6.
Step 2b--Preparation of
(6-cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyri-
midin-5-ylmethyl)-pyridin-2-yl]-amine (P-4004)
[1375] To
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-m-
ethoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol
(73, 70 mg, 0.12 mmol) in 10.0 mL of 1,2-dichloroethane,
triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.60
mL, 7.8 mmol) are added and the reaction stirred at 80.degree. C.
for 4 hours. The reaction is poured into aqueous potassium
carbonate and extracted with ethyl acetate. The organic layer is
dried over sodium sulfate, filtered and the filtrate concentrated
under vacuum. The resulting material is purified by silica gel
column chromatography, eluting with 20-100% ethyl acetate in
hexane. Appropriate fractions are combined and concentrated under
vacuum to provide the desired compound (P-4004, 11.8 mg). MS (ESI)
[M+H.sup.+].sup.+=390.9.
[1376]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b-
]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-3050
##STR00258##
is prepared similarly to the protocol of Scheme 12, step 1,
followed by steps 1b and 2b, where
(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 69 is replaced with
(6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester in step 1. MS (ESI)
[M+H.sup.+].sup.+=374.2.
[1377]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-meth-
yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-3051
##STR00259##
is similarly prepared from the intermediate formed from step 1b in
the preparation of P-3050, reacting similarly to step 2a of Scheme
12, and then according to the following step 3b.
##STR00260##
Step 3b--Preparation of
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H--
pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3051)
[1378] To
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-m-
ethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(74, 134 mg, 0.25 mmol) in 10 mL of tetrahydrofuran,
tetrabutylammonium fluoride, trihydrate (85.53 mg, 0.27 mmol) is
added and the reaction stirred at room temperature for 30 minutes.
Water is added and the mixture is extracted with ethyl acetate. The
organic layer is washed with water and brine, dried with magnesium
sulfate, filtered and the filtrate concentrated under vacuum. The
resulting material is purified by silica gel column chromatography,
eluting with ethyl acetate in hexane. Appropriate fractions are
combined and concentrated under vacuum to provide the desired
compound (P-3051, 82 mg). MS (ESI) [M+H.sup.+].sup.+=388.0.
[1379]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyr-
rolo[2,3-b]pyridin-3-yl)-methanone P-3052 and
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylme-
thyl)-pyridin-2-yl]-amine P-3053
##STR00261##
were prepared similarly to the protocols used for P-3051 and
P-3052, respectively, where
3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (prepared
similarly to the protocol of Scheme 1, replacing
5-chloro-1H-pyrrolo[2,3-b]pyridine 1 with 1H-pyrrolo[2,3-b]pyridine
in step 1) was used in place of
3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8
in step 1. P-3052 MS (ESI) [M+H.sup.+].sup.+=374.0. P-3053 MS (ESI)
[M+H.sup.+].sup.+=359.9.
[1380]
[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridi-
n-2-yl]-pyridin-3-yl-amine P-4021
##STR00262##
is prepared from
(6-bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl-
)-6-fluoro-pyridin-2-yl]-amine P-4020 according to the following
step 3c.
##STR00263##
Step 3b--Preparation of
[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl-
]-pyridin-3-yl-amine (P-4021)
[1381] To
(6-bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4020, 0.040 g, 0.090
mmol) in 5.0 mL of tetrahydrofuran under nitrogen at -78.degree.
C., tert-butyllithium (0.531 mL, 1.70 M in hexane, 0.903 mmol) is
added. The reaction is stirred at -78.degree. C. for 30 minutes,
then poured into water and extracted with ethyl acetate. The
organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified with silica gel column chromatography, eluting with
20-100% ethyl acetate in hexane. Appropriate fractions are combined
and concentrated under vacuum to provide the desired compound
(P-4021, 25.7 mg). MS (ESI) [M+H.sup.+].sup.+=364.9.
Example 13: Synthesis of
[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methoxy-pyridin-3-yl)-amine P-4023 or
(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-py-
ridin-3-ylamino)-pyridin-3-yl]-methanone P-4022
[1382]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-p-
yridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine P-4023 or
4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyr-
idin-3-ylamino)-pyridin-3-yl]-methanone P-4022 are prepared in
three steps or four steps from
7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
32 and
(6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic
acid tert-butyl ester 57 as shown in Scheme 13.
##STR00264## ##STR00265##
Step 1--Preparation of
{5-[(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hyd-
roxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamic
acid tert-butyl ester (75)
[1383] To a solution of
7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
(32, 0.760 g, 1.79 mmol) in 5.43 mL of tetrahydrofuran at
-40.degree. C. under nitrogen, isopropylmagnesium chloride (0.892
mL, 2.0 M in tetrahydrofuran, 1.78 mmol) is added slowly. The
reaction is allowed to warm to -5.degree. C. over 75 minutes, then
cooled to -45.degree. C. and
(6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic
acid tert-butyl ester (57, 0.38 g, 1.1 mmol) in 2.0 mL of
tetrahydrofuran is added. The reaction is allowed to warm to room
temperature over 2 hours, then poured into water and extracted with
ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
material is purified by silica gel column chromatography, eluting
with 20-100% ethyl acetate in hexane. Appropriate fractions are
combined and concentrated under vacuum to provide the desired
compound (75, 0.64 g). MS (ESI) [M+H.sup.+].sup.+=647.2.
Step 2--Preparation of
[5-(7-Benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl-
)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (76)
[1384] To
{5-[(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin--
5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carb-
amic acid tert-butyl ester (75, 0.290 g, 0.448 mmol) in 9.93 mL of
1,2-dichloroethane, triethylsilane (0.31 mL, 2.0 mmol) and
trifluoroacetic acid (0.16 mL, 2.0 mmol) are added and the reaction
stirred at 80.degree. C. for 4 hours. The reaction is poured into
aqueous potassium carbonate and extracted with ethyl acetate. The
organic layer is dried with sodium sulfate, filtered and the
filtrate concentrated under vacuum to provide the desired compound
(76, 170 mg). MS (ESI) [M+H.sup.+].sup.+=530.9.
Step 3--Preparation of
[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4023)
[1385] To
[5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-
-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine
(76, 0.170 g, 0.320 mmol) in 10.0 mL of tetrahydrofuran,
tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is
added and the reaction is stirred at room temperature overnight.
The reaction is poured into water and extracted with ethyl acetate.
The organic layer is dried with sodium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography, eluting with 20-100%
ethyl acetate in hexane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (P-4023,
100.4 mg). MS (ESI) [M+H.sup.+].sup.+=390.8.
Step 2a--Preparation of
[5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbony-
l)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-carbamic acid
tert-butyl ester (77)
[1386]
{5-[(7-Benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-y-
l)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbami-
c acid tert-butyl ester (75, 0.350 g, 0.541 mmol) is alternatively
dissolved in 10.0 mL of dichloromethane, and Dess-Martin
periodinane (0.211 g, 0.498 mmol) is added. The reaction is stirred
at room temperature for 30 minutes, then concentrated under vacuum.
The resulting material is purified by silica gel column
chromatography, eluting with 10-100% ethyl acetate in hexane.
Appropriate fraction are combined and concentrated under vacuum to
provide the desired compound (77, 340 mg). MS (ESI)
[M+H.sup.+].sup.+=645.4.
Step 3a--Preparation of
(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluo-
ro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone (78)
[1387] To
[5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine--
5-carbonyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-carbamic
acid tert-butyl ester (77, 0.340 g, 0.527 mmol) in 10 mL of
1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.4 mmol) is
added. The reaction is stirred at 80.degree. C. for 45 minutes,
then poured into aqueous potassium carbonate and extracted with
ethyl acetate. The organic layer is dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum to provide the
desired compound (78, 235 mg). MS (ESI)
[M+H.sup.+].sup.+=545.4.
Step 4a--Preparation of
(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-py-
ridin-3-ylamino)-pyridin-3-yl]-methanone (P-4022)
[1388] To
(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl-
)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone
(78, 0.235 g, 0.432 mmol) in 10.0 mL of tetrahydrofuran,
tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is
added. The reaction is stirred at room temperature overnight, then
poured into water and extracted with ethyl acetate. The organic
layer is dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum. The resulting material is purified by
silica gel column chromatography, eluting with 20-100% ethyl
acetate in hexane. Appropriate fraction are combined and
concentrated under vacuum to provide the desired compound (P-4022,
104.5 mg). MS (ESI) [M+H.sup.+].sup.+=405.0.
[1389] Additional compounds are prepared following the protocol of
Scheme 13.
4-Cyclopropyl-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidi-
ne 33 may be used in place of
7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
32. Compounds are made substituting either of
7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
32 with a suitable benzenesulfonyl or
4-methylbenzenesulfonyl-protected 7H-pyrrolo[2,3-d]pyrimidine or
1H-pyrrolo[2,3-b]pyridine and
(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 57 with a suitable Boc-protected aldehyde in
step 1. In some instances, a non-Boc protected aldehyde is used as
indicated in the following table (with no step 3a in this case).
The following compounds are made using this procedure: [1390]
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3--
d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4008), [1391]
(1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,-
3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4014), [1392]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methyl-pyridin-3-yl)-amine (P-4015), [1393]
(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4016), [1394]
{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]--
pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine (P-4019), [1395]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethoxy-pyridin-3-yl)-amine (P-4026), [1396]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-yl-
amino)-2-fluoro-pyridin-3-yl]-methanone (P-4027), [1397]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-ethyl-pyridin-3-yl)-amine (P-4028), [1398]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-yla-
mino)-2-fluoro-pyridin-3-yl]-methanone (P-4029), [1399]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4030), [1400]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyr-
idin-3-ylamino)-pyridin-3-yl]-methanone (P-4031), [1401]
[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)-methanone (P-4032), [1402]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4036), [1403]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(1-ethyl-1H-pyrazol-4--
ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4037), [1404]
[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-
-2-yl]-(5-methyl-pyridin-3-yl)-amine (P-4038), [1405]
(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(5-methyl-pyr-
idin-3-ylamino)-pyridin-3-yl]-methanone (P-4039),
[1406] The following table indicates the Benzenesulfonyl-protected
1H-pyrrolo[2,3-b]pyridine (column 2) and Boc-protected aldehyde
compound (column 3) used in step 1 to afford the desired compound
(column 4). The compound number is provided in column 1, and the
observed mass is in column 5.
TABLE-US-00005 TABLE 6 Comp. pyrrolo[2,3- MS (ESI) number
b]pyridine Aldehyde Compound structure [M + H.sup.+].sup.+ P-4008
##STR00266## ##STR00267## ##STR00268## 439.0 P-4014 ##STR00269##
##STR00270## ##STR00271## 412.0 P-4015 ##STR00272## ##STR00273##
##STR00274## 409.0 P-4016 ##STR00275## ##STR00276## ##STR00277##
423.0 P-4019 ##STR00278## ##STR00279## ##STR00280## 424.9 P-4026
##STR00281## ##STR00282## ##STR00283## 404.9 P-4027 ##STR00284##
418.8 P-4028 ##STR00285## ##STR00286## ##STR00287## 389.0 P-4029
##STR00288## 402.9 P-4030 ##STR00289## ##STR00290## ##STR00291##
375.0 P-4031 ##STR00292## 388.9 P-4032 ##STR00293## ##STR00294##
##STR00295## 393.1 P-4036 ##STR00296## ##STR00297## ##STR00298##
378.0 P-4037 ##STR00299## 392.0 P-4038 ##STR00300## ##STR00301##
##STR00302## 375.1 P-4039 ##STR00303## 389.1 P-4042 ##STR00304##
##STR00305## ##STR00306## P-4043 ##STR00307##
Example 14: Synthesis of
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropy-
l-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-4040 and
(6-cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine P-4041
[1407]
[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cycl-
opropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-4040 and
(6-cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine P-4041 are prepared in
three steps from
4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
19 and
(6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 80 as shown in Scheme 14.
##STR00308##
Step 1--Preparation of
(6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamic
acid tert-butyl ester (81)
[1408] To
4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyri-
midine (19, 0.72 g, 1.64 mmol) in 6.0 mL of tetrahydrofuran at
-40.degree. C. under nitrogen, isopropylmagnesium chloride (0.82
mL, 2.01 M in tetrahydrofuran, 1.65 mmol) is added slowly. The
reaction is allowed to warm to -5.degree. C. in 75 minutes, then
cooled to -45.degree. C. and
(6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester (80, 0.48 g, 1.38 mmol) in 5.0 mL is added.
The reaction is allowed to warm to room temperature in 2 hours,
then poured into water and extracted with ethyl acetate. The
organic layer is dried over sodium sulfate, filtered and the
filtrate concentrated under vacuum. The resulting material is
purified by silica gel column chromatography, eluting with 20-100%
ethyl acetate in hexane. Appropriate fractions are combined and
concentrated under vacuum to provide the desired compound (81, 0.51
g). MS (ESI) [M+H.sup.+].sup.+=667.2).
Step 2--Preparation of
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropy-
l-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol
(82)
[1409] To
(6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-
-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-c-
arbamic acid tert-butyl ester (81, 0.51 g, 0.77 mmol) in 12 mL of
toluene, [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) (0.13 g, 0.17 mmol) is added under
nitrogen and the reaction stirred for 5 minutes.
Cyclopropylmagnesium bromide (17, 15.29 mL, 0.50 M in
tetrahydrofuran, 7.65 mmol) is added slowly and the reaction is
heated at 65.degree. C. for 2 hours. The reaction is poured into
water and extracted with ethyl acetate. The organic layer is dried
over sodium sulfate, filtered and the filtrate concentrated under
vacuum. The resulting material is purified by silica gel column
chromatography, eluting with 20-100% ethyl acetate in hexane.
Appropriate fractions are combined and concentrated under vacuum to
provide the desired compound (82, 400 mg).
Step 3--Preparation of
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropy-
l-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4040) and
(6-cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-
-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4041)
[1410] To
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-c-
yclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol
(82, 400 mg, 0.7 mmol) in 30 mL of dichloromethane, triethylsilane
(2.6 mL, 16.28 mmol) and trifluoroacetic acid (1.5 mL, 15.13 mmol)
are added, and the reaction is stirred at 80.degree. C. for 3
hours. The reaction is poured into aqueous potassium carbonate and
extracted with ethyl acetate. The organic layer is washed with
brine, dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum. The resulting material is purified by
silica gel column chromatography, eluting with 20-100% ethyl
acetate in hexane to give a mixture of compounds P-4040 and P-4041.
These are separated by preparative HPLC to provide the isolated
compounds (P-4040, 3.0 mg, MS (ESI) [M+H.sup.+].sup.+=414.9),
(P-4041, 37.9 mg, MS (ESI) [M+H.sup.+].sup.+=401.0).
[1411]
(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d-
]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine P-4044 and
[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-4045
##STR00309##
are prepared similarly to Scheme 14, where
4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
19, is replaced in step 1 with
5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared similarly to
Scheme 4 steps 1 and 2). P-4044, 2.5 mg, MS (ESI) [M+H.sup.+].sup.+
375.0. P-4045, 5.3 mg, MS (ESI) [M+H.sup.+].sup.+=388.9.
Example 15: Synthesis of
[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl]methanone (P-4115)
##STR00310##
[1412] Step 1--Preparation of tert-butyl
N-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-
-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate 85
[1413] To a solution of
7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine (1,
0.43 g, 1.01 mmol) in Tetrahydrofuran (5 mL) at -30.degree. C.
under nitrogen was added 2.0 M Isopropylmagnesium Chloride in
Tetrahydrofuran (0.5 ml) slowly. The reaction was allowed to warm
to -5.degree. C. in 75 minutes. Then, the reaction was cooled to
-45.degree. C., followed by adding tert-butyl
N-(6-fluoro-5-formyl-2-pyridyl)-N-(6-methyl-3-pyridyl)carbamate
(84, 0.24 g, 0.72 mmol) in THF (3.0 mL). The reaction was allowed
to warm to room temperature in around 2 hours. The reaction was
poured in to water, extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate, and filtered. The filtrate
was concentrated, purified with silica gel column chromatography
eluting with 20%-100% ethyl acetate in hexane to give product (85,
0.41 g, 90.6%). MS (ESI) [M+H+]+=625.0.
Step 2--Preparation of tert-butyl
N-[5-[[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-hy-
droxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate
86
[1414] To tert-butyl
N-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-
-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate (85,
75 mg, 0.12 mmol) in Isopropyl alcohol (0.80 mL) was added 2M
methylamine in THF (0.6 ml). The resulting solution was stirred at
40.degree. C. for 6 hours. The reaction was concentrated to give
product (86, 70 mg, 94.2%). MS (ESI) [M+H+]+=620.
Step 3--Preparation of tert-butyl
N-[5-[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidine-5-carbon-
yl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate 87
[1415] To tert-butyl
N-[5-[[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-hy-
droxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate
(86, 0.07 g, 0.11 mmol) in DCM (10 mL) was added DMP (0.06 g, 0.14
mmol). The reaction was stirred at room temperature for 20 minutes.
The reaction was concentrated, and purified with silica gel column
chromatography eluting with 20% to 100% ethyl acetate in hexane to
give product (87, 0.065 g, 93.6%).
Step 4--Preparation of
[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluor-
o-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone;
2,2,2-trifluoroacetic acid 88
[1416] To tert-butyl
N-[5-[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidine-5-carbon-
yl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate (87, 65 mg,
0.11 mmol) in dichloroethane (10 mL) was added TFA (0.65 ml, 8.75
mmol). The reaction was heated 80.degree. C. for 1 hour. The
reaction was concentrated to give crude product (CF.sub.3COOH salt)
around (88, 0.080 g, 86.4%). MS (ESI) [M+H+]+=518. MS is the free
base product.
Step 5--Preparation of
[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-(4-methylamino-7H-pyrr-
olo[2,3-d]pyrimidin-5-yl)methanone P-4115
[1417] To
[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-
-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone;
2,2,2-trifluoroacetic acid (88, 80 mg, 0.09 mmol) in Methanol (6
ml) was added KOH (0.1 g, 1.78 mmol). The reaction was stirred at
room temperature for 1 hour. The reaction mixture was concentrated
and purified with silica gel column chromatography eluting with 2%
to 25% methanol in methylene chloride to give product (P-4115, 9.6
mg, 27.3%). MS (ESI) [M+H+]+=377.9.
[1418] Table 2 below provides compounds prepared according to the
synthetic protocols set forth in Schemes 14 and 15. The structures
were characterized by mass spectroscopy and .sup.1H and .sup.13C
NMR spectroscopies.
TABLE-US-00006 TABLE 2 MS (ESI) No. Compound Structure [M +
H.sup.+].sup.+ P-4046 ##STR00311## 407.2 P-4047 ##STR00312## 461.3
P-4048 ##STR00313## 390.1 P-4049 ##STR00314## 462.1 P-4050
##STR00315## 435.0 P-4051 ##STR00316## 419.0 P-4052 ##STR00317##
472.95 P-4053 ##STR00318## 431.0 P-4054 ##STR00319## 405.0 P-4055
##STR00320## 436.5 P-4056 ##STR00321## 498.5 P-4057 ##STR00322##
489.0 P-4058 ##STR00323## 420.9 P-4059 ##STR00324## 447.1 P-4060
##STR00325## 418.0 P-4061 ##STR00326## 473.0 P-4062 ##STR00327##
431.1 P-4063 ##STR00328## 405.0 P-4064 ##STR00329## 445.0 P-4065
##STR00330## 377.9 P-4066 ##STR00331## 422.0 P-4067 ##STR00332##
434.5 P-4068 ##STR00333## 422.0 P-4069 ##STR00334## 449.5 P-4070
##STR00335## 450.0 P-4071 ##STR00336## 539.5 P-4072 ##STR00337##
502.5 P-4073 ##STR00338## 464.0 P-4074 ##STR00339## 491.5 P-4075
##STR00340## 448.0 P-4076 ##STR00341## 434.5 P-4077 ##STR00342##
450.0 P-4078 ##STR00343## 436.5 P-4079 ##STR00344## 452.0 P-4080
##STR00345## 436.5 P-4081 ##STR00346## 408.5 P-4082 ##STR00347##
462.5 P-4083 ##STR00348## 394.5 P-4084 ##STR00349## 462.5 P-4085
##STR00350## 406.0 P-4086 ##STR00351## 469.5 P-4087 ##STR00352##
455.2 P-4088 ##STR00353## 413.2 P-4089 ##STR00354## 387.2 P-4090
##STR00355## 470.2 P-4091 ##STR00356## 458.0 P-4092 ##STR00357##
432.0 P-4093 ##STR00358## 429.9 P-4094 ##STR00359## 403.9 P-4095
##STR00360## 432.5 P-4096 ##STR00361## 496.5 P-4097 ##STR00362##
500.5 P-4098 ##STR00363## 450.0 P-4099 ##STR00364## 446.5 P-4100
##STR00365## 434.5 P-4101 ##STR00366## 397.5 P-4102 ##STR00367##
369.1 P-4103 ##STR00368## 462.1 P-4104 ##STR00369## 462.1 P-4105
##STR00370## 422.0 P-4106 ##STR00371## 422.2 P-4107 ##STR00372##
420.2 P-4108 ##STR00373## 393.9 P-4109 ##STR00374## 412.9 P-4110
##STR00375## 384.9 P-4111 ##STR00376## 446.1 P-4112 ##STR00377##
446.0 P-4113 ##STR00378## 418.1 P-4114 ##STR00379## 406.0 P-4115
##STR00380## 377.9 P-4116 ##STR00381## 462.1 P-4117 ##STR00382##
420.0 P-4118 ##STR00383## 432.2 P-4119 ##STR00384## 436.1 P-4120
##STR00385## 460.1 P-4121 ##STR00386## 434.1 P-4122 ##STR00387##
420.0 P-4123 ##STR00388## 406.5 P-4124 ##STR00389## 391.9 P-4125
##STR00390## 418.0 P-4126 ##STR00391## 420.0 P-4127 ##STR00392##
417.0 P-4128 ##STR00393## 459.0 P-4129 ##STR00394## 417.0 P-4130
##STR00395## 458.0 P-4131 ##STR00396## 379.0 P-4132 ##STR00397##
502.5 P-4133 ##STR00398## 500.5
[1419] The compounds set forth in Table 7 below are prepared
according to the synthetic protocols set forth in Schemes 14 and
15. The structures are characterized by mass spectroscopy and
.sup.1H and .sup.13C NMR spectroscopies.
TABLE-US-00007 TABLE 7 No Name Structure P-4134 [2-fluoro-6-[(4-
fluorocyclohexyl)amino]-3-pyridyl]-
[4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone
##STR00399## P-4135 [4-(ethylamino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl]-[2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-
pyridyl]methanone ##STR00400## P-4136 [2-fluoro-6-[(4-
fluorocyclohexyl)amino]-3-pyridyl]- [4-(isopropylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00401## P-4137
[4-(cyclopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[2-
fluoro-6-[(4- fluorocyclohexyl)amino]-3- pyridyl]methanone
##STR00402## P-4138 [2-fluoro-6-[(4-
fluorocyclohexyl)amino]-3-pyridyl]-
[4-(2,2,2-trifluoroethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00403## P-4139 [4-[[(1R)-1-
cyclopropylethyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[2-
fluoro-6-[(4- fluorocyclohexyl)amino]-3- pyridyl]methanone
##STR00404## P-4140 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[2- fluoro-6-[(4-
fluorocyclohexyl)amino]-3- pyridyl]methanone ##STR00405## P-4141
[2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-
[4-(methoxymethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone
##STR00406## P-4142 [2-fluoro-6-[(4-
fluorocyclohexyl)amino]-3-pyridyl]- [4-(3-methoxypropylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00407## P-4143
[2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-
[4-(tetrahydropyran-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00408## P-4144 [4-(cyclobutylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[2- fluoro-6-[(4-
fluorocyclohexyl)amino]-3- pyridyl]methanone ##STR00409## P-4145
[6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-
(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone
##STR00410## P-4146 [6-[(3,3-difluorocyclobutyl)amino]-
2-fluoro-3-pyridyl]-[4-(ethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00411## P-4147
[6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-
(propylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone
##STR00412## P-4148 [6-[(3,3-difluorocyclobutyl)amino]-
2-fluoro-3-pyridyl]-[4- (isopropylamino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl]methanone ##STR00413## P-4149
[6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-(2,2,2-
trifluoroethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone
##STR00414## P-4150 [4-[[(1R)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(3,3-difluorocyclobutyl)amino]-2- fluoro-3-pyridyl]methanone
##STR00415## P-4151 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(3,3-difluorocyclobutyl)amino]-2- fluoro-3-pyridyl]methanone
##STR00416## P-4152 [6-[(3,3-difluorocyclobutyl)amino]-
2-fluoro-3-pyridyl]-[4- (methoxymethylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00417## P-4153
[6-[(3,3- 15difluorocyclobutyl)amino]-2- fluoro-3-pyridyl]-[4-
(tetrahydropyran-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00418## P-4154 [4-(cyclobutylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(3,3-difluorocyclobutyl)amino]-2- fluoro-3-pyridyl]methanone
##STR00419## P-4155 [6-[(3,3-difluorocyclobutyl)amino]-
2-fluoro-3-pyridyl]-[4-(3- methoxypropylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00420## P-4156
[6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-(3-
methoxypropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone
##STR00421## P-4157 [6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-(2- methoxyethylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00422## P-4158
[4-(cyclobutylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(4,4-difluorocyclohexyl)amino]-2- fluoro-3-pyridyl]methanone
##STR00423## P-4159 [6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4- (tetrahydropyran-4-ylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00424## P-4160
[4-[[(1R)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(4,4-difluorocyclohexyl)amino]-2- fluoro-3-pyridyl]methanone
##STR00425## P-4161 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(4,4-difluorocyclohexyl)amino]-2- fluoro-3-pyridyl]methanone
##STR00426## P-4162 [6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-(ethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00427## P-4163 [4-(cyclobutylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(4,4-difluorocyclohexyl)amino]-5- fluoro-3-pyridyl]methanone
##STR00428## P-4164 [6-[(4,4-difluorocyclohexyl)amino]-
5-fluoro-3-pyridyl]-[4- (methoxymethylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00429## P-4165
[6-[(4,4-difluorocyclohexyl)amino]- 5-fluoro-3-pyridyl]-[4-(3-
methoxypropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone
##STR00430## P-4166 [6-[(4,4-difluorocyclohexyl)amino]-
5-fluoro-3-pyridyl]-[4- (tetrahydropyran-4-ylamino)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00431## P-4167
[4-[[(1R)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(4,4-difluorocyclohexyl)amino]-5- fluoro-3-pyridyl]methanone
##STR00432## P-4168 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5-yl]-[6-
[(4,4-difluorocyclohexyl)amino]-5- fluoro-3-pyridyl]methanone
##STR00433## P-4169 [6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[[(1S)-1-methylpropyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00434## P-4170 [6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-3-pyridyl]- [4-[(3-hydroxy-1-methyl-
propyl)amino]-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone
##STR00435## P-4171 [6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-3-pyridyl]- [4-[[(1R)-1-
(hydroxymethyl)propyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00436## P-4172 4-[[5-[6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-pyridine-3- carbonyl]-7H-pyrrolo[2,3-
d]pyrimidin-4-yl]amino]pyrrolidin- 2-one ##STR00437## P-4173
[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[[(1R)-2-hydroxy-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-
d]pyrimidin-5-yl]methanone ##STR00438## P-4174
[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[[(1R,3R)-3- hydroxycyclohexyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00439## P-4175
[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[[(1R,2R)-2- hydroxycyclopentyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00440## P-4176
1-[3-[[5-[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-pyridine-3-
carbonyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]pyrrolidin-
1-yl]ethanone ##STR00441## P-4177 (2R)-2-[[5-[6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-pyridine-3- carbonyl]-7H-pyrrolo[2,3-
d]pyrimidin-4- yl]amino]cyclohexanone ##STR00442## P-4178
[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[(1,1-dioxothiolan-3-yl)amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00443## P-4179 [6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-3-pyridyl]- [4-[[(1R,2R)-2-
hydroxycyclohexyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00444## P-4180 [6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-3-pyridyl]- [4-[[(1R)-2-methoxy-1-methyl-
ethyl]amino]-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone
##STR00445## P-4181 4-[[5-[6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-pyridine-3- carbonyl]-7H-pyrrolo[2,3-
d]pyrimidin-4-yl]amino]piperidin-2- one ##STR00446## P-4182
[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[[(1R)-2,2,2-trifluoro-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-
d]pyrimidin-5-yl]methanone ##STR00447## P-4183
4-[[5-[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-pyridine-3-
carbonyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]-1-methyl-
piperidin-2-one ##STR00448## P-4184 [6-[(6-cyclopropyl-3-
pyridyl)amino]-2-fluoro-3-pyridyl]-
[4-[(1,1-dioxothian-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00449## P-4185 1-cyclopropyl-4-[[5-[6-[(6-
cyclopropyl-3-pyridyl)amino]-2- fluoro-pyridine-3-carbonyl]-7H-
pyrrolo[2,3-d]pyrimidin-4- yl]amino]pyrrolidin-2-one ##STR00450##
P-4186 [6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1S)-1- methylpropyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00451## P-4187
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[(3-hydroxy- 1-methyl-propyl)amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00452## P-4188
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R)-1- (hydroxymethyl)propyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00453## P-4189
4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-
pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-
yl]amino]pyrrolidin-2-one ##STR00454## P-4190
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R)-2- hydroxy-1-methyl-ethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00455## P-4191
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3- hydroxycyclohexyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00456## P-4192
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2- hydroxycyclopentyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00457## P-4193
1-[3-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-
pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-
yl]amino]pyrrolidin-1-yl]ethanone ##STR00458## P-4194
(2R)-2-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-
pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-
yl]amino]cyclohexanone ##STR00459## P-4195
[6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-[(1,1-
dioxothiolan-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00460## P-4196
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2- hydroxycyclohexyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00461## P-4197
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R)-2- methoxy-1-methyl-ethyl]amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00462## P-4198
4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-
pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-
yl]amino]piperidin-2-one ##STR00463## P-4199
[6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2-
trifluoro-1-methyl-ethyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-
yl]methanone ##STR00464## P-4200 4-[[5-[6-[(4,4-
difluorocyclohexyl)amino]-2-fluoro- pyridine-3-carbonyl]-7H-
pyrrolo[2,3-d]pyrimidin-4- yl]amino]-1-methyl-piperidin-2-one
##STR00465## P-4201 [6-[(4,4-difluorocyclohexyl)amino]-
2-fluoro-3-pyridyl]-[4-[(1,1- dioxothian-3-yl)amino]-7H-
pyrrolo[2,3-d]pyrimidin-5- yl]methanone ##STR00466## P-4202
1-cyclopropyl-4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-
pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-
yl]amino]pyrrolidin-2-one ##STR00467##
Example 16: Compound Properties
[1420] While the inhibitory activity of the compounds on any of
Fms, Kit, Flt-3, TrkA, TrkB and TrkC kinase is important to their
activity in treating of disease, the compounds described herein
show favorable properties that provide advantages as a
pharmaceutical as well. In some instances, Fms selectivity relative
to Kit and other kinases provides preferred activity for treating
certain diseases, such as rheumatoid arthritis, Alzheimer's
disease, Parkinson's disease, osteoarthritis, glomerulonephritis,
interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic
nephropathy, or renal hypertrophy. In some instances, Fms
selectivity of compounds in combination with the compounds
inability to cross the blood brain barrier provides preferred
activity for treating certain diseases, such as osteoarthritis,
glomerulonephritis, interstitial nephritis, Lupus nephritis,
tubular necrosis, diabetic nephropathy, or renal hypertrophy. In
some instances, Fms selectivity of compounds in combination with
the compounds ability to effectively cross the blood brain barrier
provides preferred activity for treating certain diseases, such as
rheumatoid arthritis, Alzheimer's disease, or Parkinson's disease.
In some instances, dual Fms/Kit activity provides preferred
activity for treating certain diseases, such as breast cancer,
prostate cancer, multiple myeloma, melanoma, acute myeloid
leukemia, brain metastases, neurofibromatosis, gastrointestinal
stromal tumors, rheumatoid arthritis, or multiple sclerosis. In
some instances, dual Fms/Flt-3 activity provides preferred activity
for treating certain diseases, such as acute myeloid leukemia. In
addition to demonstrating kinase inhibitory activity against Fms,
Kit, Flt-3 or at least both Fms and Kit or at least both Fms and
Flt-3 in both biochemical and cell based assays, compounds have
improved solubility, improved pharmacokinetic properties, and low
Cyp inhibition. The compounds are assessed in the following assays
or similar assays available to one skilled in the art.
[1421] Assays for biochemical and cell based activity are known in
the art, for example, U.S. Patent Application Publication Number
2009/0076046, the disclosure of which is hereby incorporated by
reference as it relates to such assays. For example, in one assay
the biochemical activity IC.sub.50 values are determined with
respect to inhibition of c-Kit kinase activity, where inhibition of
phosphorylation of a peptide substrate is measured as a function of
compound concentration. Compounds to be tested are dissolved in
DMSO to a concentration of 20 mM. These are diluted 30 .mu.L into
120 .mu.L of DMSO (4 mM) and 1 .mu.L is added to an assay plate.
These are then serially diluted 1:2 (50 .mu.L to 100 .mu.L DMSO)
for a total of 8 points. Plates are prepared such that each kinase
reaction is 20 .mu.L in 1.times. kinase buffer (25 mM HEPES, pH
7.5, 2 mM MgCl.sub.2, 2 mM MnCl.sub.2, 0.01% Tween-20, 1 mM DTT,
0.01% BSA), 5% DMSO and 100 .mu.M ATP. Substrate is 30 nM
biotin-(E4Y)10 (Millipore). C-kit kinase (obtained from Millipore
(#14-559) or is prepared as described in U.S. Patent Application
Publication Number 2009/0076046, the disclosure of which is hereby
incorporated by reference as it relates to this assay) is at 0.75
ng per sample. After incubation of the kinase reaction for 1 hour
at room temperature, 5 .mu.L of donor beads (Streptavidin coated
beads (Perkin Elmer Life Science) final concentration 10 .mu.g/mL)
in stop buffer (25 mM Hepes pH 7.5, 100 mM EDTA, 0.01% BSA) is
added, the sample is mixed and incubated for 20 minutes at room
temperature before adding 5 .mu.L of acceptor beads (PY20 coated
beads (Perkin Elmer Life Science) final concentration 10 .mu.g/mL)
in stop buffer. The samples are incubated for 60 minutes at room
temperature and the signal per well is read on Envision reader.
Phosphorylated substrate results in binding of the PY20 antibody
and association of the donor and acceptor beads such that signal
correlates with kinase activity. The signal vs. compound
concentration is used to determine the IC.sub.50.
[1422] In one assay the biochemical activity IC.sub.50 values are
determined with respect to inhibition of Fms kinase activity, where
inhibition of phosphorylation of a peptide substrate is measured as
a function of compound concentration. Compounds to be tested,
dissolved in DMSO (1 .mu.L), are added to a white 384-well plate
(Costar #3705). Working stocks of Fms kinase (Invitrogen #PV3249),
biotin-(E4Y).sub.10 substrate (Upstate Biotech, Cat#12-440), and
ATP (Sigma, Cat#A-3377) are prepared in 25 mM Hepes pH 7.5, 0.5 mM
MgCl.sub.2, 2 mM MnCl.sub.2, 2 mM DTT, 0.01% BSA, and 0.01%
Tween-20. All components are added to the 384-well plate for a
final concentration of 1 ng/well Fms, 30 nM biotin-(E4Y).sub.10
(Upstate Biotechnology) and 100 .mu.M ATP in a volume of 20 .mu.L.
Each sample is at 5% DMSO. The plate is then incubated for 20
minutes at 30.degree. C. Just before use, working stocks of donor
and acceptor beads from the AlphaScreen PY20 Detection Kit
(PerkinElmer, Cat#676601M) are prepared in 25 mM Hepes pH 7.5, pH
7.4, 100 mM EDTA, 0.01% BSA. To stop the reaction, the plate is
uncovered in the dark and 5 .mu.L of Donor Beads solution
(Streptavidin beads) is added to each well. The plate is incubated
at room temperature for 20 minutes. Five microliters of Acceptor
Beads solution (PY20 coated beads) are then added to each well. The
final concentration of each bead is 10 .mu.g/mL. The plates are
incubated at room temperature for 60 minutes. Fluorescence signal
is recorded on the Envision reader. Phosphorylated substrate
results in binding of the PY20 antibody and association of the
donor and acceptor beads such that signal correlates with kinase
activity. The signal vs. compound concentration is used to
determine the IC.sub.50.
[1423] In one assay the biochemical activity IC.sub.50 values are
determined with respect to inhibition of Flt-3 kinase activity,
where inhibition of phosphorylation of a peptide substrate is
measured as a function of compound concentration. Compounds to be
tested, dissolved in DMSO (1 are added to a white 384-well plate
(Costar #3705). Working stocks of Flt-3 kinase (Invitrogen),
biotin-(E4Y).sub.10 substrate (Upstate Biotech, Cat#12-440), and
ATP (Sigma, Cat#A-3377) are prepared in 25 mM Hepes pH 7.5, 5 mM
MgCl.sub.2, 5 mM MnCl.sub.2, 1 mM DTT, and 0.01% Tween-20. All
components are added to the 384-well plate for a final
concentration of 1 ng/well Flt-3, 30 nM biotin-(E4Y).sub.10 and 100
.mu.M ATP in a volume of 20 .mu.L. Each sample is at 5% DMSO. The
plate is then incubated for 1 hour at room temperature. Just before
use, working stocks of donor and acceptor beads from the
AlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601M) are
prepared in 25 mM Hepes pH 7.5, pH 7.4, 100 mM EDTA. 0.3% BSA. To
stop the reaction, the plate is uncovered in the dark and 5 .mu.L
of Donor Beads solution (Streptavidin beads) is added to each well.
The plate is incubated at room temperature for 20 minutes. Five
microliters of Acceptor Beads solution (PY20 coated beads) are then
added to each well. The final concentration of each bead is 10
.mu.g/mL. The plates are incubated at room temperature for 60
minutes. Fluorescence signal is recorded on the Envision reader.
Phosphorylated substrate results in binding of the PY20 antibody
and association of the donor and acceptor beads such that signal
correlates with kinase activity. The signal vs. compound
concentration is used to determine the IC.sub.50.
[1424] In one assay the biochemical activity IC.sub.50 values are
determined with respect to inhibition of TrkA kinase activity,
where inhibition of phosphorylation of a peptide substrate is
measured as a function of compound concentration. Compounds to be
tested, dissolved in DMSO (1 .mu.L), are added to a white 384-well
plate (Costar #3705). Working stocks of TrkA kinase (UBI),
biotin-(E4Y).sub.10 substrate (Upstate Biotech, Cat#12-440), and
ATP (Sigma, Cat#A-3377) are prepared in 25 mM Hepes pH 7.5, 10 mM
MnCl.sub.2, 1 mM DTT, 0.01% BSA, and 0.01% Tween-20. All components
are added to the 384-well plate for a final concentration of 1
ng/well TrkA, 30 nM biotin-(E4Y).sub.10 and 100 .mu.M ATP in a
volume of 20 .mu.L. Each sample is at 5% DMSO. The plate is shaken
for 1 minute at 1200 rpm, spun for 1 minute at 1000 rpm, then
incubated for 40 minutes at room temperature. Just before use,
working stocks of donor and acceptor beads from the AlphaScreen
PY20 Detection Kit (PerkinElmer, Cat#676601M) are prepared in 25 mM
Hepes pH 7.5, 100 mM EDTA. 0.01% BSA. Donor Beads solution
(Streptavidin beads) is added (5 .mu.L) to each well to final bead
concentration of 10 .mu.g/mL. The plate is incubated at room
temperature for 20 minutes. Acceptor Beads solution (PY20 coated
beads) are then added to each well (5 .mu.L) to a final
concentration of bead at 10 .mu.g/mL. The plates are incubated at
room temperature for 60 minutes. Fluorescence signal is recorded on
the Envision reader. Phosphorylated substrate results in binding of
the PY20 antibody and association of the donor and acceptor beads
such that signal correlates with kinase activity. The signal vs.
compound concentration is used to determine the IC.sub.50. Similar
assays are used for TrkB and Trk C kinase.
[1425] Compounds are assessed in a variety of cell based assays.
For example BaF3 cells engineered with any of BCR-FMS, BCR-KIT,
BCR-FLT3, BCR-NTRK1, BCR-NTRK2, and BCR-NTRK3, are used in cell
proliferation assays to assess inhibitory activity of Fms, Kit,
Flt-3, TrkA, TrkB, and TrkC, respectively. An MV-4-11 (leukemia)
cell proliferation assay is used to assess inhibitory activity in
Flt-3, and SKNSH (human neuroblastoma) cell proliferation assay is
used to assess efficacy of Fms/Trk inhibitors. Additional cells may
be assayed similarly to assess the efficacy of Fms/Trk inhibitors,
such as MiaPaCa (human pancreatic cancer) and Capan-1 (human
pancreatic carcinoma) cells. Reagent and assay conditions are as
follows:
[1426] BaF3 Cells: [1427] Maintained in RPMI containing 10% FBS, 1%
PenStrep, 1% NEAA, and 1% L-Glutamine, supplemented with 1 mg/mL
G418 and 5% WEHI-CM (or recombinant murine IL-3). [1428] Confluent
cells are split 1:50 to 1:100 every 3-4 days. [1429] MV-4-11 cells:
[1430] Maintained in Iscove's Modified Dulbecco's Medium containing
10% FBS. [1431] Confluent cells are split 1:4 every 3-4 days.
[1432] SKNSH cells: RPMI containing 10% FBS. On day 1, cells are
counted, then centrifuged in a conical tube for 5 minutes at 1000
rpm. The supernatant is removed and cells are re-suspended as
follows: [1433] BaF3: resuspend in growth media+1 mg/mL G418
(without WEHI/IL-3) to 2.times.10.sup.5 cells/mL. [1434] MV-4-11:
resuspend in growth media to 5.times.10.sup.5 cells/mL. [1435]
SKNSH: resuspend in growth media to 2.times.10.sup.4 cells/mL. The
cells are plated (50 .mu.L, 150 .mu.L for SKNSH cells) in each well
of a 96-well dish (Corning 3610) and incubated at 37.degree. C. in
5% CO.sub.2 overnight, cells plated to a final concentration of
cells as follows:
[1436] BaF3: 10,000 cells per well.
[1437] MV-4-11: 25,000 cells per well.
[1438] SKNSH: 3,000 cells per well.
On day 2, compound at a maximum concentration of 5 mM is serially
diluted 1:3 for a total of 8 point titration with DMSO as a
control. A 1 .mu.L aliquot of each dilution point is added to 249
.mu.L growth media and 50 .mu.L is added to a well containing
cells, providing 10 .mu.M compound for the maximum concentration
point. The cells are incubated for 3 days at 37.degree. C. in 5%
CO.sub.2. For SKNSH cells, a 0.75 .mu.L aliquot of appropriate
dilution in DMSO is added to 150 .mu.L of cells. On day 5, ATPlite
1 step Luminescence Assay System (Perkin Elmer #6016739) is brought
to room temperature along with the cell cultures. ATPlite is added
to each well as follows:
[1439] BaF3: 25 .mu.L per well.
[1440] MV-4-11: 40 .mu.L per well.
[1441] SKNSH: 20 .mu.L per well.
The cells are incubated at room temperature for 10 minutes, then
luminescence is read on Safire reader. The measured luminescence
correlates directly with cell number, such that the reading as a
function of compound concentration is used to determine the
IC.sub.50 value.
[1442] Further, an osteoclast differentiation assay is used to
assess the efficacy of Fms inhibitors for treating bone disease
such as osteoarthritis. On day 0, Osteoclast Medium BulletKit
(Lonza catalog # PT-8001, containing Media, FBS, L-Glutamine,
PenStrep, RANKL, and M-CSF) media is thawed and the FBS,
L-glutamine and PenStrep from the kit is added to 100 mL of
Osteoclast Precursor Basal medium to provide the Osteoclast
Precursor Growth Medium (OPGM). This is warmed to 37.degree. C.
Osteoclast precursor cells (Lonza catalog #2T-110) frozen in
cryovial are warmed to 37.degree. C. and transferred to a 50 mL
conical tube. The cryovial is rinsed with OPGM and added dropwise
to the conical tube of cells with swirling, then the volume is
adjusted to 20-30 mL with addition of OPGM. The cells are
centrifuged at 200.times.g for 15 minutes at room temperature and
all but approximately 3 mL of supernatant is removed to a new
conical tube. The cells are suspended in the remaining supernatant
and the volume is adjusted to 10-15 mL with OPGM added dropwise
with swirling. The cells are centrifuged at 200.times.g for 15
minutes at room temperature and all but approximately 1 mL of
supernatant is removed. The cells are resuspended in the remaining
supernatant, counted, and the volume adjusted with an appropriate
amount of OPGM to provide approximately 1.times.10.sup.5 cells/mL.
A 0.1 mL aliquot of cells is added to each well of a 96-well plate.
Compound to be tested is prepared in DMSO for plating at a high
concentration of 2.5 mM, with 8 point 1:3 serial dilutions. A 1
.mu.L aliquot of each compound dilution is added to a 96 well
v-bottom polypropylene plate and 0.124 mL of OPGM is added to the
compound. Then 50 .mu.L of the compound in OPGM is added to the
osteoclast precursor cells in 96-well plate (providing highest test
concentration of 5 RANKL (2 .mu.g) from the BulletKit is
reconstituted in 1 mL of OPGM, then vortexed and centrifuged
briefly. A 792 .mu.L aliquot of RANKL is added to 6 mL of OPGM and
50 .mu.L is added to low control wells. Then 76.6 .mu.L M-CSF (10
.mu.g/mL) from the BulletKit is added to the remaining 5.8 mL of
OPGM/RANKL solution (4.times.RANKL/M-CSF/OPGM). A 50 .mu.L aliquot
of this is added to the remaining wells, and the remainder is
stored at 4.degree. C. for later use. The plate is incubated at
37.degree. C. for 6 days, then the remaining OPGM/RANKL/M-CSF
solution is warmed to 37.degree. C. The remaining approximately 198
.mu.L is combined with 6 mL of OPGM. The media is aspirated from
the osteoclast wells and 100 .mu.L of RANKL/OPGM is added to the
low controls. The remaining RANKL/OPGM is combined with the
approximately 18.5 .mu.L of remaining M-CSF. The remaining
4.times.RANKL/M-CSF/OPGM from day 0 is diluted to 1.times. and
combined with the freshly prepared solution. A 0.1 mL aliquot of
this is added to each osteoclast well and incubated for 37.degree.
C. for 1 day. The Acid Phosphatase kit (Cayman Chemical catalog
#10008051) is warmed to room temperature. The assay buffer is
diluted 5 mL with 45 mL of water. For each plate, two substrate
tablets are dissolved in 4.5 mL of the assay buffer, mixing by
vortex to break up the tablet. Stop solution is diluted 12 mL with
36 mL of water. In a tissue culture hood, 20 .mu.L of each
osteoclast well supernatant is transferred to a 96 well plate. A 30
.mu.L aliquot of the substrate solution is added to each well and
incubated at 37.degree. C. for 20 minutes, then added 100 .mu.L
stop solution to each well. The absorbance of each well is read at
405 nM on Safire plate reader. The absorbance reading is plotted
vs. concentration to provide the IC.sub.50 for each compound.
[1443] It is understood that the results of these assays may vary
as assay conditions are varied. Inhibition levels determined under
the conditions described herein represent a relative activity for
the compounds tested under the specific conditions employed. The
cell based assays are likely to show variability due to the
complexity of the system and the sensitivity thereof to any changes
in the assay conditions. As such, some level of inhibition in the
cell based assays is indicative of the compounds having some
inhibitory activity for those cells, whereas lack of inhibition at
or below the threshold of the highest concentration tested does not
necessarily indicate that the compound has no inhibitory activity
on the cells, only that under the conditions tested, no inhibition
is observed. Results for compounds that are tested and show
substantially no inhibition below the highest tested concentration
are represented as "-" in the tables below. In some instances, the
compounds were not tested in all of the assays, or assay results
were not valid, as indicated by NA in the tables below.
[1444] The following table indicates the Fms, Kit, Flt3, TrkA, and
TrkC biochemical inhibitory activity for the exemplary compounds
indicated:
TABLE-US-00008 Compound Biochemical Inhibition IC.sub.50 (.mu.M)
number Fms Kit Flt3 TrkA TrkC P-3001 <0.1 <1 NA NA NA P-3003
<1 >1 NA NA NA P-3004 <0.01 <1 >1 NA NA P-3005 <1
>1 NA NA NA P-3006 <0.01 <1 NA NA NA P-3007 <1 >1 NA
NA NA P-3008 <0.1 <1 NA NA NA P-3009 <0.1 NA NA NA NA
P-3010 <0.01 <0.1 <0.1 <1 NA P-3011 <0.01 <0.01
<0.01 >1 NA P-3012 <0.01 <0.01 <0.1 >1 NA P-3013
<0.01 <1 >1 NA NA P-3014 <0.01 <0.1 <1 >1 NA
P-3015 <0.01 <1 <0.1 >1 NA P-3016 <0.1 <0.1
<0.1 >1 NA P-3017 <0.1 <1 <0.1 >1 NA P-3018
<0.01 <0.01 <0.01 <1 NA P-3019 <0.01 <1 <1
<0.1 <0.1 P-3020 <0.01 <0.01 <0.01 <0.1 <1
P-3021 <0.01 <0.01 <0.01 <0.1 <1 P-3022 <0.1
<0.1 <0.1 <1 <1 P-3023 <0.1 <0.1 NA NA NA P-3024
<0.1 <0.01 <0.01 <1 >1 P-3025 <0.1 <0.01
<0.01 <0.1 <0.01 P-3026 <0.01 <0.01 <0.1 >1
<0.1 P-3027 <0.01 <0.01 <0.01 <1 <0.1 P-3028
>1 <1 NA <0.1 <0.1 P-3029 <0.1 <1 NA <1 <1
P-3030 <0.1 <0.1 NA <0.01 <0.01 P-3031 <1 <0.1 NA
<0.1 <0.1 P-3032 >1 <1 NA >1 >1 P-3033 <0.1
<0.01 NA <0.01 <0.1 P-3034 <0.1 <0.1 NA <1 <1
P-3035 <1 <0.1 <0.1 <1 <1 P-3036 <0.01 <0.1
<0.1 <1 <1 P-3037 >1 <1 NA NA NA P-3038 <1 <1
NA NA NA P-3039 <0.01 <0.1 <0.1 <0.1 NA P-3040 <0.1
>1 <0.1 <0.01 NA P-3041 <0.01 <1 <1 <1 NA
P-3042 <0.01 <0.1 <1 <0.1 NA P-3043 <0.01 <1
<1 <0.1 NA P-3044 <0.01 <1 <1 <0.1 NA P-3045
<0.01 <1 <0.1 <0.01 NA P-3048 <0.01 <0.1 NA
<0.01 NA P-3049 <0.01 <0.1 NA <0.01 NA P-3050 <0.1
<0.1 NA <0.1 NA P-3051 <0.01 <0.1 NA <0.01 NA P-3052
<0.1 <0.1 NA <0.01 NA P-3053 <0.01 <0.1 NA <0.1
NA P-4001 <0.01 <1 <1 <0.1 <0.01 P-4002 <0.1
<1 NA <0.1 <1 P-4003 <0.1 <1 <1 <1 NA P-4004
<0.1 <0.1 <0.01 <0.1 NA P-4005 <0.01 <0.1 <0.1
<0.1 NA P-4006 <0.01 <0.1 <0.1 <0.1 NA P-4007
<0.01 <0.1 <0.1 <0.01 NA P-4008 <0.01 <1 <0.1
<0.01 NA P-4009 <0.01 <0.1 <0.1 <0.01 NA P-4010
<0.01 <1 <1 <1 NA P-4011 <0.01 <1 <1 <1 NA
P-4012 <0.01 <1 <1 <0.1 NA P-4013 <0.01 <1 >1
<1 NA P-4014 <0.01 <0.1 <1 >1 NA P-4015 <0.1
<0.1 >1 >1 NA P-4016 <0.01 <0.1 <0.01 <0.01 NA
P-4017 <0.01 <0.1 <0.1 <0.1 NA P-4018 <0.01 <0.1
<0.1 <0.1 NA P-4019 <0.01 <1 <0.1 <0.1 NA P-4020
<0.01 <0.1 <0.1 <0.01 NA P-4021 <0.1 <1 >1
<1 NA P-4022 <0.1 <1 <0.1 <0.01 NA P-4023 <0.01
<1 <1 <0.1 NA P-4024 <1 <1 <0.1 <0.1 NA P-4025
<1 >1 <1 <0.1 NA P-4026 <0.01 <1 <0.1 <0.01
NA P-4027 <0.1 <0.1 <0.01 <0.01 NA P-4028 <0.01
<0.1 <0.1 <0.01 NA P-4029 <0.01 <0.1 <0.01
<0.01 NA P-4030 <0.01 <1 <1 <0.1 NA P-4031 <0.1
<0.1 <0.1 <0.1 NA P-4032 <0.1 <0.1 <0.1 <0.1
NA P-4036 <0.01 <1 >1 <0.1 NA P-4037 <0.1 <1
<1 <0.1 NA P-4038 <0.1 <1 NA <0.1 NA P-4039 <1
<1 NA <0.1 NA P-4040 <0.1 <0.1 NA <0.01 NA P-4041
<0.1 <0.1 NA <0.01 NA P-4046 <0.1 <1 NA <1 NA
P-4047 >1 >1 NA >1 NA P-4048 <0.01 <0.01 NA <0.01
NA P-4049 <0.01 <1 NA <0.01 NA P-4050 <1 <1 NA <1
NA P-4051 <1 <1 NA <0.01 NA P-4052 <1 >1 NA <1 NA
P-4053 <0.01 <1 NA <0.01 NA P-4054 <0.01 >1 NA
<0.1 NA P-4055 <0.1 <1 NA NA NA P-4056 <0.1 <0.1 NA
NA NA P-4057 <0.1 >1 NA <1 NA P-4058 <0.1 >1 NA
<1 NA P-4059 <0.1 <1 NA <0.1 NA P-4060 <0.01 <0.1
NA <0.01 NA P-4061 <0.1 >1 NA <0.1 NA P-4062 <0.01
<0.1 NA <0.01 NA P-4063 <0.01 <1 NA <0.01 NA P-4064
<0.01 <0.1 NA <0.01 NA P-4065 <0.01 <0.1 NA <0.01
NA P-4066 <0.01 <0.1 NA <0.01 NA P-4067 <0.01 <1 NA
<0.01 NA P-4068 <0.01 <0.1 NA <0.01 NA P-4069 <1
>1 NA <0.1 NA P-4070 >1 >1 NA >1 NA P-4071 <1
>1 NA <0.01 NA P-4072 <0.1 >1 NA <0.1 NA P-4073
<0.1 <1 NA <0.01 NA P-4074 <0.1 <1 NA <0.01 NA
P-4075 <0.01 <1 NA <0.01 NA P-4076 <0.01 <0.1 NA
<0.01 NA P-4077 <0.1 <1 NA <0.01 NA P-4078 <0.01
<1 NA <0.01 NA P-4079 <0.01 <0.1 NA <0.01 NA P-4080
<0.01 <1 NA <0.01 NA P-4081 <0.01 <0.1 NA <0.01
NA P-4082 <0.1 <1 NA <0.01 NA P-4083 <0.01 <0.1 NA
<0.01 NA P-4084 <0.01 <0.1 NA <0.01 NA P-4085 <0.01
<1 NA <0.01 NA P-4086 <1 <1 NA <0.1 NA P-4087
<0.1 <0.1 NA <0.01 NA P-4088 <0.1 <1 NA <0.01 NA
P-4089 <0.1 <1 NA <0.1 NA P-4090 <0.1 <1 NA <0.1
NA P-4091 <0.1 <0.1 NA <0.01 NA P-4092 <0.01 <0.1 NA
<0.01 NA P-4093 <0.01 <0.1 NA <0.01 NA P-4094 <0.01
<0.01 NA <0.01 NA P-4095 <0.01 <0.1 NA <0.01 NA
P-4096 <0.1 <1 NA <0.1 NA P-4097 <1 <1 NA <0.1 NA
P-4098 <0.01 <0.1 NA <0.01 NA P-4099 <0.1 <0.1 NA
<0.1 NA P-4100 <0.1 <0.1 NA <0.1 NA P-4101 <0.1
<1 NA <0.1 NA P-4102 <0.1 <1 NA <0.1 NA P-4103 <1
<1 NA <0.1 NA P-4104 <1 <1 NA <0.1 NA P-4105 <0.1
>1 NA <0.1 NA P-4106 <0.1 <1 NA <0.01 NA P-4107
<0.1 <0.1 NA <0.01 NA P-4108 <0.1 <1 NA <0.1 NA
P-4109 <0.1 <1 NA <0.1 NA P-4110 <0.1 <1 NA <1 NA
P-4111 <0.1 <1 NA <0.1 NA P-4112 <0.1 <1 NA <0.1
NA P-4113 <0.01 <0.1 NA <0.01 NA P-4114 <0.01 <0.1
NA <0.01 NA P-4115 <0.01 <0.1 NA <0.01 NA P-4116
<0.1 <0.1 NA <0.01 NA P-4117 <0.01 <0.1 NA <0.01
NA P-4118 <0.1 <0.1 NA <0.01 NA P-4119 <0.01 <0.01
NA <0.01 NA P-4120 <0.1 <0.1 NA <0.1 NA P-4121 <0.1
<0.01 NA <0.1 NA P-4122 <0.01 <0.01 NA <0.01 NA
P-4123 <0.01 <0.01 NA <0.01 NA P-4124 <0.01 <0.01 NA
<0.01 NA P-4125 <0.1 <0.1 NA <0.01 NA P-4126 <0.01
<0.1 NA <0.01 NA P-4127 <0.1 <1 NA <0.1 NA P-4128
<0.1 >1 NA <1 NA P-4129 <0.1 <1 NA <1 NA P-4130
<0.01 <1 NA <0.01 NA
[1445] The following table indicates the inhibition of cell
proliferation for BCR-FMS, BCR-KIT, BCR-FLT3, BCR-NTRK1, BCR-NTRK2
and BCR-NTRK3 BaF3 cells, MV-4-11 cells and SKNSH cells for the
exemplary compounds indicated:
TABLE-US-00009 Inhibition of Cell Proliferation IC.sub.50 (.mu.M)
Comp. BCR/BaF3 number Fms Kit TrkA TrkB TrkC MV-4-11 SKNSH P-3001
<0.1 >1 -- -- -- NA NA P-3003 <1 >1 NA NA NA NA NA
P-3004 <0.1 >1 <10 <10 <10 <10 NA P-3005 <1
>1 -- -- -- NA NA P-3006 <1 >1 <20 -- -- NA NA P-3007
<1 -- -- -- -- NA NA P-3008 <0.1 >1 NA NA NA NA NA P-3009
<1 >1 -- -- -- NA NA P-3010 <0.1 <1 -- -- -- NA NA
P-3011 <0.1 <0.1 <1 <1 <0.1 NA NA P-3012 <0.1
<1 <1 <1 <1 NA NA P-3013 <0.1 >1 -- -- -- <10
NA P-3014 <0.1 >1 -- -- -- NA NA P-3015 <1 >1 -- -- --
NA NA P-3016 <1 >1 -- -- -- NA NA P-3017 <1 >1 -- -- --
NA NA P-3018 <0.1 <0.1 <1 <0.1 <0.1 <0.01 NA
P-3019 <0.01 <1 <0.1 <0.1 <0.1 <1 <10 P-3020
<0.01 <0.1 <0.1 <0.1 <0.1 <0.1 <1 P-3021
<0.01 <0.1 <1 <0.1 <0.1 NA <1 P-3022 <0.1
<0.1 <1 <1 <1 <1 NA P-3023 <0.1 <0.1 <1
<1 <1 <0.1 NA P-3024 <0.01 <0.1 <1 <1 <0.1
NA <1 P-3025 <0.01 <0.01 <0.01 <0.01 <0.01 NA
<1 P-3026 <0.01 <0.1 <0.1 <0.1 <0.1 NA -- P-3027
<0.01 <0.1 <0.1 <1 <0.1 <0.01 -- P-3028 <1
<0.1 <0.1 <1 <0.1 NA <20 P-3029 <0.1 <1 >1
>1 <1 NA -- P-3030 <0.01 <0.01 <0.01 <0.01
<0.01 NA <0.1 P-3031 <0.01 <0.01 <0.01 <0.01
<0.01 NA <0.1 P-3032 <1 <1 <1 >1 <1 NA <1
P-3033 <0.01 <0.01 <0.1 <0.1 <0.1 NA <1 P-3034
<0.01 <0.1 <0.1 <1 <0.1 NA <1 P-3035 <0.1
<1 <1 <1 <0.1 <1 <1 P-3036 <0.01 <0.1 <1
<1 <1 <0.1 <20 P-3037 >1 >1 >1 -- >1 NA --
P-3038 <1 <1 <1 >1 <1 >1 -- P-3039 <0.01 <1
<1 <1 <0.1 <1 >1 P-3040 <0.1 >1 <0.1
<0.01 <0.01 NA >1 P-3041 <0.01 <1 <1 <1
<0.1 NA >1 P-3042 <0.1 <1 <1 <0.1 <0.1 NA
>1 P-3043 <0.1 <1 <0.1 <0.1 <0.1 NA <1 P-3044
<0.1 <1 <1 <0.1 <0.1 NA >1 P-3045 <0.1 <1
<0.1 <0.01 <0.1 NA -- P-3048 <0.01 <0.1 <0.1 NA
NA NA NA P-3049 <0.01 <0.1 <0.01 NA NA NA NA P-3050
<0.1 <1 <0.1 NA NA NA NA P-3051 <0.1 <1 <0.1 NA
NA NA NA P-3052 <0.1 NA <0.1 NA <0.01 NA NA P-3053
<0.01 NA <0.1 NA <0.01 NA NA P-4001 <0.01 <1 <0.1
<0.1 <0.01 <1 <1 P-4002 <0.1 <1 <1 <1
<0.1 NA <0.1 P-4003 <0.1 >1 <1 <1 <0.1 <1
>1 P-4004 <0.01 <0.1 <0.01 <0.01 <0.01 <1
<1 P-4005 <0.01 <0.1 <0.1 <0.01 <0.01 <1 <1
P-4006 <0.01 <0.1 <0.1 <0.01 <0.01 <0.1 <0.1
P-4007 <0.01 <1 <0.01 <0.1 <0.01 <1 <1 P-4008
<0.01 <1 <0.1 <0.1 <0.1 <0.1 >1 P-4009
<0.01 <1 <0.1 <0.01 <0.01 <0.1 <0.1 P-4010
<0.01 <1 <1 <0.1 <0.1 <1 <1 P-4011 <0.01
>1 <1 <1 <1 <1 >1 P-4012 <0.01 <1 <1
<0.1 <0.1 <1 >1 P-4013 <0.01 <1 <1 <1 <1
<1 >1 P-4014 <0.1 >1 <1 <1 <1 <1 >10
P-4015 <0.01 >1 <1 <1 <0.1 <1 >1 P-4016
<0.01 <0.1 <0.1 <0.01 <0.01 <0.1 >1 P-4017
<0.01 <1 <1 <1 <0.1 <1 <1 P-4018 <0.01
<1 <0.1 <0.1 <0.01 <1 <1 P-4019 <0.01 <1
<1 <0.1 <0.1 <1 >1 P-4020 <0.1 <1 <1
<0.1 <0.1 NA <1 P-4021 <1 >1 >1 <1 <1 NA
<1 P-4022 <0.1 <1 <0.01 <0.01 <0.01 NA <1
P-4023 <0.01 <1 <0.1 <0.1 <0.01 NA <1 P-4024
<0.1 <1 <0.1 <0.1 <0.1 NA >1 P-4025 <0.1 >1
<0.1 <0.1 <0.1 NA >1 P-4026 <0.01 <1 <0.1
<0.01 <0.01 NA NA P-4027 <0.1 <1 <0.1 <0.01
<0.01 NA NA P-4028 <0.01 <1 <0.01 <0.01 <0.01 NA
NA P-4029 <0.1 <0.1 <0.01 <0.01 <0.01 NA NA P-4030
<0.01 <1 <1 <0.1 <0.1 NA NA P-4031 <0.1 <1
<0.1 <0.01 <0.01 NA NA P-4032 <0.1 <1 <0.1
<0.1 <0.1 NA NA P-4036 <0.1 <1 <1 <0.1 <0.1 NA
NA P-4037 <0.1 <0.1 <0.1 NA NA NA NA P-4038 <0.1 <1
<1 <1 <0.1 NA NA P-4039 <0.1 <1 <0.1 <0.1
<0.1 NA NA P-4040 <0.1 <0.1 <0.01 <0.01 <0.01 NA
NA P-4041 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4046
<0.1 <1 <1 <1 <1 NA <10 P-4047 >1 >1 >1
>1 >1 NA NA P-4048 <0.01 <1 <1 <0.01 <0.01 NA
<1 P-4049 <1 <1 <1 <1 <1 NA <1 P-4050 <1
>1 <1 <1 <1 NA <1 P-4051 <1 >1 <1 <0.01
<0.01 NA <1 P-4052 <1 >1 <1 <1 <0.01 NA >1
P-4053 <1 <1 <0.01 <0.01 <0.01 NA <1 P-4054 <1
<1 <1 <1 <0.01 NA <10 P-4055 <1 >1 <1
<0.01 <0.01 NA <1 P-4056 <1 >1 <1 <0.01
<0.01 NA <1 P-4057 <1 >1 >1 >1 <1 NA <10
P-4058 <0.1 <1 <1 <1 <0.1 NA <10 P-4059 <0.1
>1 <1 <0.1 <0.1 NA <1 P-4060 <0.01 <0.1
<0.01 <0.01 <0.01 NA <0.1 P-4061 <0.1 >1 <0.1
<0.01 <0.01 NA NA P-4062 <0.1 <1 <0.01 <0.01
<0.01 NA <1 P-4063 <0.1 <0.1 <0.01 <0.1 <0.01
NA <1 P-4064 <0.1 <0.1 <0.1 <0.01 <0.01 NA NA
P-4065 <0.1 <0.1 <0.1 <0.01 <0.01 NA <1 P-4066
<0.01 <0.01 <0.01 <0.01 <0.01 NA NA P-4067 <0.01
<0.1 <0.01 <0.01 <0.01 NA NA P-4068 <0.01 <0.1
<0.01 <0.01 <0.01 NA NA P-4069 >1 >1 >1 >1
>1 NA NA P-4070 >1 >1 >1 >1 >1 NA NA P-4071
<0.1 <0.1 <0.1 <0.1 <0.01 NA NA P-4072 <0.1 <1
<0.01 <0.01 <0.01 NA NA P-4073 <0.1 <1 <0.1
<0.01 <0.01 NA NA P-4074 <1 <1 <0.1 <0.1 <0.01
NA NA P-4075 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA
P-4076 <0.1 <0.1 <0.01 <0.01 <0.01 NA NA P-4077
<0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4078 <0.01
<0.1 <0.01 <0.01 <0.01 NA NA P-4079 <0.1 <0.1
<0.01 <0.01 <0.01 NA NA P-4080 <0.1 <0.1 <0.01
<0.01 <0.01 NA NA P-4081 <0.01 <0.1 <0.01 <0.01
<0.01 NA NA P-4082 <0.01 <0.1 <0.01 <0.01 <0.01
NA NA P-4083 <0.1 <0.1 <0.01 <0.01 <0.01 NA NA
P-4084 <0.01 <1 <0.1 <0.01 <0.01 NA <10 P-4085
<1 >1 <1 NA <0.1 NA NA P-4086 NA NA <0.01 NA NA NA
NA P-4087 <1 >1 <1 <0.1 <0.01 NA NA P-4088 <0.1
<1 <0.1 <0.1 <0.01 NA NA P-4089 <0.1 <1 <1
<0.1 <0.01 NA <10 P-4090 <0.1 <1 <0.1 <0.01
<0.01 NA <1 P-4091 <0.01 <0.1 <0.01 <0.01
<0.01 NA <0.1 P-4092 <0.01 <0.1 <0.01 <0.01
<0.01 NA <1 P-4093 <0.01 <0.1 <0.01 <0.01
<0.01 NA NA P-4094 <0.1 <0.1 <0.01 <0.01 <0.01 NA
<1 P-4095 <0.01 <0.1 <0.01 <0.01 <0.01 NA <1
P-4096 <0.01 <1 <0.01 <0.01 NA NA <10 P-4097 <0.1
<1 <0.1 <0.1 NA NA <10 P-4098 <0.1 <0.1 <0.01
<0.01 NA NA <10 P-4099 <0.01 <0.1 <0.01 <0.01 NA
NA <1 P-4100 <0.1 <1 <0.01 <0.01 NA NA <1 P-4101
<0.01 <1 <0.1 <0.01 NA NA <1 P-4102 <0.01 <1
<1 <0.1 NA NA <1 P-4103 <0.1 >1 <1 >1 >1 NA
>1 P-4104 <0.1 >1 <0.1 <0.1 <0.1 NA <1 P-4105
<0.1 >1 <0.1 <1 <1 NA <10 P-4106 <0.1 <1
<0.1 <0.1 <0.01 NA <1 P-4107 <0.1 <1 <0.1
<0.1 <0.01 NA <1 P-4108 <0.1 >1 <1 <1 <0.1
NA >1 P-4109 <0.1 <1 <1 <1 NA NA <10 P-4110
<0.1 <1 >1 >1 NA NA <10 P-4111 <0.1 <1
<0.01 <0.01 <0.01 NA NA P-4112 <0.1 >1 <0.1
<0.1 <0.01 NA <10 P-4113 <0.01 <1 <0.1 NA NA NA
NA P-4114 <0.01 <1 <0.01 NA NA NA NA P-4115 <0.01 <1
<0.1 <0.1 <0.01 NA NA P-4116 <0.01 <0.1 <0.01
<0.01 <0.01 NA NA P-4117 <0.01 <0.1 <0.01 <0.01
<0.01 NA NA P-4118 <0.01 <0.1 <0.01 <0.01 <0.01
NA NA P-4119 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA
P-4120 <0.1 <1 <0.01 <0.01 <0.01 NA <1 P-4121
<0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4122 <0.01
<0.1 <0.01 <0.01 <0.01 NA NA P-4123 <0.01 <0.1
<0.01 <0.01 <0.01 NA <0.1 P-4124 <0.01 <0.1
<0.01 <0.01 <0.01 NA <1 P-4125 <0.01 <0.1
<0.01 <0.01 <0.01 NA NA P-4126 <0.01 <0.1 <0.01
<0.01 <0.01 NA <0.1 P-4127 <0.01 <0.1 <1 <0.1
<0.1 NA <10 P-4128 <0.1 <1 <1 <0.1 <0.1 NA
>1 P-4129 <0.1 <1 <1 <0.1 <0.1 NA >10 P-4130
<0.01 >1 <0.1 <0.01 <0.01 NA <10
[1446] Compounds P-3001, P-3004, P-3006, P-3008, P-3013, P-3019,
P-3027, P-3036, P-3039, P-3040, P-3041, P-3042, P-3043, P-3044,
P-3045, P-4001, P-4004, P-4005, P-4006, P-4007, P-4008, P-4009,
P-4010, P-4011, P-4012, P-4013, P-4014, P-4015, P-4016, P-4017,
P-4022, P-4023, P-4024, P-4025, and P-4026 to P-4130 were assessed
and showed activity in the osteoclast differentiation assay, where
compounds P-3004, P-3006, P-3008, P-3019, P-3027, P-3036, P-3039,
P-3041, P-3042, P-4001, P-4004, P-4005, P-4006, P-4007, P-4008,
P-4009, P-4010, P-4011, P-4012, P-4013, P-4014, P-4015, P-4016, and
P-4023 demonstrated an IC.sub.50 below 0.1 .mu.M in this assay.
[1447] Compounds also demonstrate in vivo activity in a
splenomegaly mouse model, where BaF3 cell growth in the spleens of
nude mice may show inhibition with compound treatment. BaF3 cells
are engineered with any of BCR-FMS, BCR-TRK1 or BCR-TRK2 to assess
in vivo inhibitory effects of Fms, TrkA or TrkB inhibition,
respectively. BaF3 cells are maintained in growth media (RPMI
containing 10% FBS, 1% PenStrep, 1% NEAA, and 1% L-Glutamine,
supplemented with 5% murine IL-3 and 1 mg/mL G418). Four days prior
to start, 2.times.10.sup.6 cells are inoculated into a T150 vented
flask using the growth media and incubated at 37.degree. C. in 5%
CO.sub.2 for three days. One day prior to start, cells are
collected by centrifugation and re suspended in growth media
without IL-3. On the day of cell implant, the cells are collected
by centrifugation, rinsed 3.times.20 mL with RPMI, then re
suspended in 5.4 mL of media and counted, then adjusted with
additional RPMI as needed to give 5.times.10.sup.7 cells/mL. On day
1, female nu/nu mice at 5-6 weeks of age are injected intravenously
with BaF3 cells injected injecting 0.1 mL (5.times.10.sup.6) cells
in the tail vein (mice without cell injected are included as
control group). Compound stocks in dimethylsulfoxide are stored at
room temperature protected from light. Stocks are diluted prior to
dosing, diluting 22 .mu.L of compound stock into 858 .mu.L of
diluent (or 50 .mu.L into 1950 .mu.L) to provide vehicle of 1.0%
Polysorbate 80, 0.5% hydroxypropyl methyl cellulose, with final
dimethylsulfoxide at 2.5% in all dosing suspensions and vehicle
control. Dosing suspension is prepared prior to use, mixing by
inversion and sonication in a water bath to make a uniform
suspension. On days 10-18, mice are treated with vehicle only or
the desired level of compound in vehicle, .about.0.2 mL per 25 gm
mouse, once a day by oral gavage, or in some instances, twice per
day. On day 18, mice are administered a final dose and two hours
later a plasma sample is taken. At four hours following the final
dose, mice are sacrificed, an additional plasma sample is collected
and mouse spleens are removed and weighed. The average spleen
weight of vehicle control group mice is compared to the average
spleen weight of the test compound mice. Percent spleen growth
inhibition is calculated as 100.times.[(spleen weight vehicle
control-spleen weight test compound)/spleen weight vehicle
control]. In some instances, the compounds were not tested in all
of the assays as indicated by NA in the table below.
[1448] The following table provides data indicating the percent
spleen growth inhibition for exemplary compounds indicated (dosed
once per day at 10 mg per kg unless indicated otherwise) in the
splenomegaly mouse model:
TABLE-US-00010 Comp. % spleen growth inhibition number Fms TrkA
TrkB P-3004 43 NA NA P-3010 47 NA NA P-3013 48 NA NA P-3019 40 NA
14 P-3027 42 NA 2 P-3045 11 NA NA P-4004 36 16 41 P-4004* 70 40 91
P-4005 65 25 35 P-4006 55 NA 21 P-4007 28 NA 19 P-4012 24 NA NA
P-4022 42 NA 33 P-4026 41 NA NA P-4027 -1.4 NA NA P-4028 86 NA 88
P-4029 66 NA NA P-4030 58 NA 50 P-4031 29 NA NA P-4053 69 NA NA
P-4090.sup.# 38 NA NA P-4084 6.2 NA NA P-4062 76 NA NA P-4061 48 NA
NA P-4112 9.5 NA NA P-4110 30 NA NA P-4124 20 NA NA P-4120 37 NA NA
P-4123.sup.# 14 NA NA P-4130 70 NA NA P-4128 15 NA NA *Dosed at 30
mg/kg. .sup.#Dosed at 5 mg/kg.
[1449] As an indication of relative solubility, the turbidity of
compounds in aqueous solutions is assessed. To assess possible
compound properties in different physiological compartments, such
as stomach, intestine, and blood, a series of aqueous buffers with
varying pH is used. Thus each compound is diluted into four
different physiologically relevant buffers and solution turbidity
is measured by spectrophotometry. The concentration of compound
that demonstrates turbidity by forming enough insoluble suspension
to raise the average optical density above 0.01 at three
wavelengths (490, 535, and 650 nm) is used to define the limit of
the compound solubility in that buffer.
[1450] Compounds are dissolved at a concentration of 25 mM in
dimethyl sulfoxide, then serially diluted 1:1 into a 96 well plate,
diluting 10 times in pure dimethyl sulfoxide, with the final well
of each row a dimethyl sulfoxide blank. In an assay plate, 99 .mu.L
of appropriate buffer is added to each well, and 1 .mu.L of each
sample dilution is added to the buffer, achieving a range of final
total concentrations in aqueous solutions having different pH. The
buffers used are Simulated Gastric Fluid (SGF-pH 1.5) 0.5M NaCl, pH
1.5; Simulated Intestinal fluid (SIF-pH 4.5 and pH 6.8) 0.05M
NaH.sub.2PO.sub.4, pH 4.5 and 6.8; and Hepes Buffer (HEPES-pH 7.4)
10 mM HEPES, 150 mM NaCl, pH 7.4. Control compounds pyrene, estriol
and propranolol HCl are also assessed. Plates are spun and then
mixed for 1 minute, and the absorbance is read using a Tecan Safire
II to read wavelengths in the visible range (490, 535, and 650 nm)
at four locations per well, reflecting the degree of turbidity
present. The average optical density for each wavelength in each
well is graphed vs. compound concentration, and the concentration
at which the curve crosses a threshold O.D. of 0.01 for each
wavelength is reported as the endpoint turbidity assay result. The
average of the three wavelengths is used to compare turbidity of
compounds. Compounds are considered to have low solubility if the
threshold concentration is <31.3 .mu.M, moderate solubility if
the threshold concentration is 31.3 .mu.M to 250 .mu.M, and high
solubility if the threshold concentration is >250 .mu.M.
[1451] The following table indicates the relative solubility
(L=low, M=moderate, H=high) based on turbidity threshold
concentration at each pH for exemplary compounds according to the
invention as indicated:
TABLE-US-00011 Compound turbidity threshold (L, M, H) number 1.4
4.5 6.8 7.4 P-3001 H L L L P-3004 H L L L P-3010 H L L M P-3011 L L
L L P-3012 M M M M P-3013 L L L L P-3014 H M M M P-3018 H M M M
P-3019 H L L L P-3039 H M M M P-3040 M M M M P-3043 M M M M P-3044
L L L M P-3045 M M M L P-4001 M M M M P-4002 H M M M P-4003 M M M M
P-4004 M M L L P-4005 M L L L P-4006 H L L L P-4007 M L L L P-4008
M M M M P-4009 H M L L P-4010 H M L L P-4011 M M M M P-4012 M L L L
P-4013 H M M M P-4014 M M M M P-4015 M M M M P-4016 M H M M P-4017
M M M L P-4018 M L L L P-4019 M L L L P-4022 H M L L P-4023 H M L L
P-4024 M L M M P-4025 M L L L P-4036 H M L L P-4037 H M M M P-4048
H M M M P-4049 H L L L P-4050 H L L L P-4051 H M M L P-4052 L L L L
P-4053 H M M M P-4054 H M M M P-4055 M M L L P-4056 M M M L P-4057
L L L M P-4058 M L L L P-4059 M L L L P-4060 H M M M P-4061 M L M M
P-4062 H L M L P-4063 M M M M P-4064 H M L L P-4065 H M M M P-4066
M L L M P-4067 H M M M P-4068 H M M M P-4069 M L M M P-4070 H M M M
P-4071 M M M M P-4072 M L L L P-4073 M L L L P-4074 H M M M P-4075
M L L L P-4076 M M M L P-4077 M L L L P-4078 M L L L P-4079 H M M M
P-4080 M M H M P-4081 H M H M P-4082 M L L L P-4083 M M M H P-4084
M M M H P-4087 H M M M P-4088 H M M M P-4089 H M M M P-4090 M M M M
P-4091 H M M M P-4092 M M M M P-4093 H L L L P-4094 H L M M P-4095
M M M M P-4096 H L L L P-4097 M L L L P-4098 H L M M P-4099 H L L L
P-4100 H M M M P-4101 M L L L P-4102 H M M M P-4103 L M M M P-4104
M L L L P-4105 M M M M P-4106 M M L M P-4107 M M M M P-4108 H M M M
P-4109 L L L L P-4110 M L L L P-4111 H L L L P-4112 M M M H P-4114
H L L L P-4115 H M M M P-4116 H M M M P-4117 H L L L P-4118 H M M L
P-4119 H M M L P-4120 L M M M P-4121 H H H H P-4122 H L M L P-4123
H L L L P-4124 M L L M P-4125 H L L L P-4127 H M M M P-4128 H M M M
P-4129 H M M M P-4130 H M M M
[1452] CYP (Cytochrome P450) enzymes are the major drug
metabolizing enzymes present in the liver. The inhibition of CYP
enzyme activity (IC.sub.50) for each of CYP1A2, CYP2C19, CYP2C9,
CYP2D6, CYP3A4(BFC) and CYP3A4(BQ) is determined for compounds,
where inhibition of metabolism of a known substrate leads to a
decrease in the fluorescence of the metabolized product. The
fluorescence of the product is monitored as a function of compound
concentration.
[1453] Compounds are dissolved in DMSO to a concentration of 100
mM. These are diluted 1 into 82 .mu.L of acetonitrile. An 11 .mu.L
aliquot of this solution is then added to 204 .mu.L of cofactor mix
(1.3% NADPH Regeneration system Solution A, 1.04% NADPH
Regeneration system Solution B from BD Biosciences, 5% acetonitrile
and 0.05% DMSO). These are then serially diluted 1:1 (160 .mu.L to
160 .mu.L co-factor mix) for a total of 10 points. A 10 .mu.L
aliquot of this final mixture is dispensed into 384 well assay
plates and incubated for 10 minutes at 37.degree. C. Enzyme and
substrate mix (10 .mu.L; 0.5 pmol CYP1A2/5 .mu.M CEC; 1.0 pmol
CYP2C9/75 MFC; 0.5 pmol CYP2C19/25 .mu.M CEC; 1.5 pmol CYP2D6/1.5
.mu.M AMMC; 1.0 pmol CYP3A4/50 .mu.M BFC; or 1.0 pmol CYP3A4/40
.mu.M BQ) is added to these assay plates. Assay plates are
incubated at 37.degree. C. (CYP1A2-15 min; CYP2C9-45 min; CYP2C19,
2D6 and 3A4-30 min) and read in a Tecan Safire 2 plate reader
(CYP1A2, 2C19 and 3A4 409 ex/460 em; CYP2C9 and 2D6 409 ex/530 em).
The signal versus compound concentration is used to determine the
IC.sub.50. The enzymes and substrates for this assay are obtained
from BD Biosciences. While other factors are involved in
determining CYP effects in vivo, compounds preferably have
IC.sub.50 values of >5 .mu.M, more preferably IC.sub.50 values
of >10 .mu.M.
[1454] The following table indicates the Cyp inhibition for
exemplary compounds according to the invention as indicated:
TABLE-US-00012 Compound Cyp IC.sub.50 (.mu.M) number 1A2 2C19 2C9
2D6 3A4(BFC) 3A4(BQ) P-3001 >10 >10 >10 >10 >10
>10 P-3004 >10 5-10 >10 >10 >10 >10 P-3006 >10
>10 >10 >10 >10 NA P-3008 >10 <5 5-10 >10 5-10
NA P-3009 >10 <5 >10 >10 5-10 NA P-3010 >10 >10
>10 >10 >10 >10 P-3011 >10 >10 >10 >10
>10 >10 P-3012 >10 >10 >10 >10 >10 >10
P-3013 5-10 <5 >10 >10 >10 >10 P-3018 >10 >10
>10 >10 <5 >10 P-3019 >10 <5 >10 >10 >10
>10 P-3039 >10 >10 >10 >10 >10 NA P-3040 >10
>10 >10 >10 >10 >10 P-3041 >10 >10 >10
>10 5-10 >10 P-3043 >10 >10 >10 >10 >10 >10
P-3044 >10 >10 >10 >10 >10 >10 P-3048 >10
<5 >10 >10 >10 >10 P-3049 >10 >10 >10
>10 >10 >10 P-3050 >10 >10 >10 >10 >10
>10 P-3051 >10 >10 >10 >10 >10 >10 P-3052
>10 5-10 5-10 >10 >10 >10 P-3053 >10 >10 >10
>10 >10 >10 P-4001 >10 <5 >10 >10 >10 NA
P-4002 >10 >10 >10 >10 >10 >10 P-4003 >10
>10 >10 >10 >10 >10 P-4004 >10 >10 >10
>10 >10 >10 P-4005 >10 >10 >10 >10 >10
>10 P-4006 >10 >10 >10 >10 >10 >10 P-4007
>10 >10 >10 >10 >10 >10 P-4008 >10 >10
>10 >10 5-10 >10 P-4009 >10 5-10 >10 >10 >10
>10 P-4010 >10 >10 >10 >10 >10 >10 P-4011
>10 >10 5-10 >10 5-10 >10 P-4012 >10 >10 >10
>10 >10 >10 P-4013 >10 >10 <5 >10 >10
>10 P-4014 >10 >10 5-10 <5 5-10 >10 P-4015 >10
>10 >10 >10 >10 >10 P-4016 >10 >10 >10
>10 >10 >10 P-4017 >10 >10 >10 >10 >10
>10 P-4018 >10 <5 >10 >10 5-10 >10 P-4019 >10
5-10 >10 >10 5-10 >10 P-4022 >10 5-10 >10 5-10 5-10
>10 P-4023 >10 <5 >10 5-10 <5 >10 P-4024 >10
>10 >10 >10 <5 >10 P-4025 >10 5-10 >10 >10
<5 >10 P-4028 >10 5-10 5-10 >10 >10 >10 P-4029
>10 >10 >10 >10 >10 >10 P-4030 >10 5-10 >10
>10 >10 >10 P-4031 >10 >10 >10 <5 >10
>10 P-4036 5-10 5-10 5-10 >10 5-10 5-10 P-4037 >10 >10
5-10 >10 5-10 5-10 P-4041 5-10 <5 5-10 >10 >10 5-10
P-4047 >10 >10 >10 >10 >10 >10 P-4048 >10
>10 >10 >10 >10 >10 P-4049 >10 5-10 5-10 >10
>10 >10 P-4050 >10 >10 >10 >10 >10 >10
P-4051 >10 >10 >10 >10 >10 >10 P-4052 >10
>10 >10 >10 >10 >10 P-4053 >10 >10 >10
>10 >10 >10 P-4054 >10 >10 >10 >10 >10
>10 P-4055 <10 <10 >10 >10 >10 >10 P-4056
>10 5-20 >10 >10 >10 >10 P-4057 >10 >10 >10
>10 >10 >10 P-4058 >10 >10 >10 >10 >10
>10 P-4059 >10 >10 5-10 >10 >10 >10 P-4060 >10
>10 >10 >10 >10 >10 P-4061 >10 >10 >10
>10 >10 >10 P-4062 >10 >10 >10 >10 >10
>10 P-4063 >10 >10 >10 >10 >10 >10 P-4064
>10 >10 >10 >10 >10 >10 P-4065 >10 >10
>10 >10 >10 >10 P-4066 >10 >10 >10 >10
>10 5-10 P-4067 >10 5-10 >10 >10 >10 >10 P-4068
>10 >10 >10 >10 >10 >10 P-4069 >10 5-10 >10
>10 5-10 >10 P-4070 >10 >10 >10 >10 >10 >10
P-4071 >10 >10 >10 >10 >10 >10 P-4072 >10
<10 5-10 5-10 >10 >10 P-4073 >10 5-10 >10 >10
>10 >10 P-4074 >10 5-10 >10 >10 >10 >10 P-4075
>10 5-10 >10 >10 >10 >10 P-4076 >10 5-10 >10
>10 >10 >5 P-4077 5-10 5-10 >10 >10 >10 >10
P-4078 5-10 >10 >10 >10 >10 >10 P-4079 >10 5-10
>10 >10 >10 >10 P-4080 >10 >10 >10 >10
>10 >10 P-4081 >10 >10 >10 >10 >10 >10
P-4082 >10 >10 >10 >10 >10 5-10 P-4083 >10 >10
>10 >10 >10 >10 P-4084 >10 5-10 >10 >10 >10
>10 P-4087 >10 >10 >10 >10 >10 >10 P-4088
>10 >10 >10 >10 >10 >10 P-4089 >10 >10
>10 >10 >10 >10 P-4090 >10 >10 >10 >10
>10 >10 P-4091 >10 >10 >10 >10 >10 >10
P-4092 <5 <5 <5 <5 >10 >10 P-4093 >10 >10
>10 >10 >10 >10 P-4094 <5 <5 <5 <5 >10
>10 P-4095 >10 >10 >10 >10 >10 >10 P-4096
<5 <5 <5 <5 >10 5-10 P-4097 <5 <5 <5 <5
>10 >10 P-4098 <5 <5 <5 <5 >10 >10 P-4099
<5 <5 <5 <5 >10 <5 P-4100 <5 <5 <5 <5
>10 >10 P-4101 >10 5-10 5-10 >10 >10 >10 P-4102
<5 <5 <5 <5 >10 >10 P-4103 <5 >10 >10
>10 >10 >10 P-4104 >10 5-10 >10 >10 >10 >10
P-4105 >10 >10 >10 >10 >10 >10 P-4106 <5 <5
<5 <5 >10 >10 P-4107 <5 <5 <5 <5 >10
>10 P-4108 <5 <5 <5 <5 >10 >10 P-4109 >10
5-10 5-10 >10 >10 >10 P-4110 <5 <5 <5 <5
>10 >10 P-4111 >10 5-10 5-10 >10 >10 5-10 P-4112
<5 <5 <5 <5 >10 >10 P-4113 >10 >10 >10
>10 >10 >10 P-4114 >10 >10 >10 >10 >10
>10 P-4115 <5 <5 <5 <5 >10 >10 P-4116 >10
>10 >10 >10 >10 >10 P-4117 5-10 >10 5-10 >10
>10 >10 P-4118 >10 >10 >10 >10 >10 >10
P-4119 >10 >10 >10 >10 >10 >10 P-4120 <5 <5
<5 <5 >10 >10 P-4121 >10 5-10 >10 >10 >10
>10 P-4122 >10 >10 5-10 >10 >10 >10 P-4123 >10
>10 >10 >10 >10 >10 P-4124 <5 <5 <5 <5
>10 >10 P-4125 >10 >10 >10 >5 >10 >10
P-4126 <5 >10 >10 >10 <10 5-10 P-4127 >10 5-10
>10 >10 <5 <5 P-4128 >10 >10 >10 >10 >10
>10 P-4129 >10 >10 5-10 5-10 <5 <5 P-4130 >10
<5 >10 >10 <5 >10
[1455] Pharmacokinetic properties of compounds (including any solid
forms or formulations thereof) are assessed in male Sprague Dawley
rats or male Beagle dogs. Rats are dosed daily with compound either
by IV injections via surgically implanted jugular catheters or by
oral gavage (P0). Each compound is prepared as a 20 mg/mL stock
solution in dimethyl sulfoxide, which is further diluted to provide
the dosing stock at the desired concentration for the IV or PO
formulations. For IV dosing, the dosing stock is diluted into a
1:1:8 mixture of Solutol.RTM.:ethanol:water. For PO dosing, the
dosing stock is diluted into 1% methylcellulose. In a cassette
format (or each compound, solid form thereof or formulation thereof
is done individually), compounds are diluted to 0.5 mg/mL each for
IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2
mL/kg) or 2 mg/kg (5 mL/kg), respectively. For IV dosed animals,
tail vein blood samples are collected with lithium heparin
anticoagulant at 5, 15, 30, and 60 minutes and 4, 8, and 24 hours
post dosing each day. For PO dosed animals, tail vein blood samples
are collected with lithium heparin anticoagulant at 30 minutes, 1,
2, 4, 8 and 24 hours post dosing each day. Dogs are dosed daily by
oral capsules in a suitable formulation at 50 mg/mL. Cephalic vein
blood samples are collected with lithium heparin anticoagulant at
30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day. All
samples are processed to plasma and frozen for later analysis of
each compound by LC/MS/MS. Plasma levels as a function of time are
plotted to assess the AUC (ng*hr/mL). Compounds according to the
present invention preferably show improved pharmacokinetic
properties relative to previously described compounds, i.e. they
have substantially higher values for one or more of AUC, Cmax and
half-life relative to previously described compounds.
[1456] Analysis of penetration of compound into the brain can be
assessed similarly. Each compound is prepared as a 100 mg/mL stock
solution in dimethyl sulfoxide, as well as control compounds
atenolol at 100 mg/mL and antipyrine at 50 mg/mL. In a cassette
format, up to three test compounds, along with atenolol and
antipyrine, are combined, 180 .mu.L each, and added to 17.1 mL of
1% methylcellulose. The compounds are in a suspension that is
administered in a single dose (10 mL per kg body weight) to 2
groups of CD rats (8-9 weeks, n=3 per group) by oral gavage, an
additional group of rats dosed with vehicle only. One group of
compound treated rats is sacrificed at 2 hours post dosing, the
other group at 6 hours. Plasma is collected in Li-heparin and the
brains are collected, cut into right and left hemispheres, weighed
and flash frozen. Brain homogenate (30%) and plasma samples are
assessed by equilibrium dialysis using a 96 well equilibrium
dialysis apparatus with a 5K MW cut off membrane (The Nest Group,
Inc.) as per the vendor's protocol with the samples on one side of
the dialysis membrane and an equal volume of 1.times.PBS on the
other side. The apparatus is incubated overnight at 37.degree. C.
on a plate rotator (The Nest Group, Inc.). The compound
concentrations on both sides are analyzed by LC/MS/MS to calculate
the mass balance recovery. The concentration in the PBS side is
calculated using a standard curve generated for each compound. The
PBS concentration is the free compound concentration, while the
side with the biological sample provides the concentration in
plasma or brain.
Example 17: Efficacy of Compounds in Combination with
Standard-of-Care Chemotherapeutic Agents in Four Human Cancer Cell
Lines
[1457] Compounds of the invention, such as compounds of Formula I,
in combination with a standard chemotherapeutic agent, such as
5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,
paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed
for their effectiveness in killing human tumor cells. Such assays
are known in the art, for example, as described in U.S. patent
application Ser. No. 11/473,347, the disclosure of which are hereby
incorporated by reference with respect to such assays.
[1458] All patents and other references cited in the specification
are indicative of the level of skill of those skilled in the art to
which the invention pertains, and are incorporated by reference in
their entireties, including any tables and figures, to the same
extent as if each reference had been incorporated by reference in
its entirety individually.
[1459] One skilled in the art would readily appreciate that the
present invention is well adapted to obtain the ends and advantages
mentioned, as well as those inherent therein. The methods,
variances, and compositions described herein as presently
representative of preferred embodiments are exemplary and are not
intended as limitations on the scope of the invention. Changes
therein and other uses will occur to those skilled in the art,
which are encompassed within the spirit of the invention, are
defined by the scope of the claims.
[1460] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations which is not specifically disclosed herein. Thus,
for example, in each instance herein any of the terms "comprising",
"consisting essentially of" and "consisting of" may be replaced
with either of the other two terms. Thus, for an embodiment of the
invention using one of the terms, the invention also includes
another embodiment wherein one of these terms is replaced with
another of these terms. In each embodiment, the terms have their
established meaning. Thus, for example, one embodiment may
encompass a method "comprising" a series of steps, another
embodiment would encompass a method "consisting essentially of" the
same steps, and a third embodiment would encompass a method
"consisting of" the same steps. The terms and expressions which
have been employed are used as terms of description and not of
limitation, and there is no intention that in the use of such terms
and expressions of excluding any equivalents of the features shown
and described or portions thereof, but it is recognized that
various modifications are possible within the scope of the
invention claimed. Thus, it should be understood that although the
present invention has been specifically disclosed by preferred
embodiments and optional features, modification and variation of
the concepts herein disclosed may be resorted to by those skilled
in the art, and that such modifications and variations are
considered to be within the scope of this invention as defined by
the appended claims.
[1461] In addition, where features or aspects of the invention are
described in terms of Markush groups or other grouping of
alternatives, those skilled in the art will recognize that the
invention is also thereby described in terms of any individual
member or subgroup of members of the Markush group or other
group.
[1462] Also, unless indicated to the contrary, where various
numerical values are provided for embodiments, additional
embodiments are described by taking any 2 different values as the
endpoints of a range. Such ranges are also within the scope of the
described invention.
[1463] Thus, additional embodiments are within the scope of the
invention and within the following claims.
* * * * *