U.S. patent application number 16/939848 was filed with the patent office on 2020-11-12 for inhibiting (alpha-v)(beta-6) integrin.
The applicant listed for this patent is Morphic Therapeutic, Inc.. Invention is credited to Andrea Bortolato, Matthew G. Bursavich, Tyler Day, James E. Dowling, Aleksey I. Gerasyuto, Kristopher N. Hahn, Bryce A. Harrison, Eugene Hickey, Byungchan Kim, Kyle D. Konze, Fu-Yang Lin, Blaise S. Lippa, Qi Qiao, Bruce N. Rogers, Brian Sosa, Mats A. Svensson, Dawn M. Troast, Cheng Zhong.
Application Number | 20200354359 16/939848 |
Document ID | / |
Family ID | 1000004978216 |
Filed Date | 2020-11-12 |
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United States Patent
Application |
20200354359 |
Kind Code |
A1 |
Harrison; Bryce A. ; et
al. |
November 12, 2020 |
INHIBITING (ALPHA-V)(BETA-6) INTEGRIN
Abstract
Disclosed are small molecule inhibitors of .alpha.v.beta.6
integrin, and methods of using them to treat a number of diseases
and conditions.
Inventors: |
Harrison; Bryce A.;
(Framingham, MA) ; Dowling; James E.; (Lexington,
MA) ; Bursavich; Matthew G.; (Needham, MA) ;
Troast; Dawn M.; (Bedford, MA) ; Lippa; Blaise
S.; (Newton, MA) ; Rogers; Bruce N.; (Belmont,
MA) ; Hahn; Kristopher N.; (Medford, MA) ;
Zhong; Cheng; (Belmont, MA) ; Qiao; Qi;
(Natick, MA) ; Lin; Fu-Yang; (Sudbury, MA)
; Sosa; Brian; (Cambridge, MA) ; Gerasyuto;
Aleksey I.; (Flemington, NJ) ; Bortolato; Andrea;
(Metuchen, NJ) ; Svensson; Mats A.; (New York,
NY) ; Hickey; Eugene; (Danbury, CT) ; Konze;
Kyle D.; (Brooklyn, NY) ; Day; Tyler; (New
York, NY) ; Kim; Byungchan; (West New York,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Morphic Therapeutic, Inc. |
Waltham |
MA |
US |
|
|
Family ID: |
1000004978216 |
Appl. No.: |
16/939848 |
Filed: |
July 27, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16555589 |
Aug 29, 2019 |
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16939848 |
|
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|
|
62724423 |
Aug 29, 2018 |
|
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62859457 |
Jun 10, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
C07D 471/04 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 9/00 20060101 A61K009/00 |
Claims
1-30. (canceled)
31. A compound of formula (I): A-B--C (I) wherein: A is
##STR00498## wherein each R.sub.1 is independently H, alkyl,
halide, alkoxy, CF.sub.3, OH, alkylene-OH, NO.sub.2, --N(H)R.sub.a,
or NH.sub.2; wherein R.sub.a in A is H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; B is
alkylene, -alkylene-O--, or -alkylene-O-alkylene-; C is
##STR00499## wherein each R.sub.3 is independently selected from H,
halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl, cycloalkyl,
-alkylene-alkoxy, aryl, hydroxyl, and alkoxy; and n with respect to
R.sub.3 is 0, 1, 2, 3, or 4; R.sub.a in C is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; R.sub.2
is ##STR00500## and n in R.sub.2 is 0, 1, 2, 3, or 4; R.sub.4 is
independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl, --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; each R.sub.5 is independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; the
absolute configuration at any stereocenter is R, S, or a mixture
thereof; or a pharmaceutically acceptable salt thereof; provided
that the compound is not selected from the group consisting of:
##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505##
##STR00506## ##STR00507##
32. The compound of claim 31, wherein each R.sub.1 is independently
H, alkyl, halide, alkoxy, CF.sub.3, OH, alkylene-OH, --N(H)R.sub.a,
or NH.sub.2; and R.sub.a in C is H, (C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O(C.sub.1-C.sub.6)alkyl; and R.sub.a in
A is (C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl.
33. The compound of claim 32, wherein each R.sub.3 is independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, hydroxyl, and alkoxy; and n with
respect to R.sub.3 is 0 or 1.
34. The compound of claim 33, wherein each R.sub.5 is independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, hydroxyl, and alkoxy.
35. The compound of claim 34, wherein R.sub.4 is selected from the
group consisting of: ##STR00508## ##STR00509## ##STR00510##
36. The compound of claim 31, wherein: a. each R.sub.1 is
independently H, alkyl, halide, or alkoxy; b. each R.sub.3 is
independently selected from the group consisting of: halide, alkyl,
and alkoxy; and n with respect to R.sub.3 is 0 or 1; and c. each
R.sub.5 is independently selected from H, halide, CF.sub.3,
C(H)F.sub.2, C(F)H.sub.2, alkyl, cycloalkyl, -alkylene-alkoxy,
hydroxyl, and alkoxy.
37. The compound of claim 36, wherein R.sub.4 is independently
selected from cycloalkyl, and heterocycloalkyl; and R.sub.a in C is
H.
38. The compound of claim 37, wherein B is selected from the group
consisting of: ##STR00511## q is 0, 1, 2, or 3; and p is 0, 1, or
2.
39. The compound of claim 38, wherein a. each R.sub.3 is
independently selected from H, and F; and b. each R.sub.a is H.
40. The compound of claim 36, wherein R.sub.4 is selected from the
group consisting of: ##STR00512## ##STR00513## ##STR00514##
41. The compound of claim 31, wherein: a. all instances of R.sub.1
are H; b. B is alkylene-O--; c. each R.sub.3 is independently
selected from H, halide, alkyl and alkoxy; and n with respect to
R.sub.3 is 0 or 1; d. R.sub.4 is selected from cycloalkyl and
heterocycloalkyl; e. each R.sub.5 is independently selected from H,
halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl, cycloalkyl,
-alkylene-alkoxy, hydroxyl, and alkoxy; f. R.sub.a in C is H; and
the absolute configuration at any stereocenter is R, S, or a
mixture thereof; or a pharmaceutically acceptable salt thereof.
42. The compound of claim 41, wherein R.sub.3 is independently
selected from H and F.
43. The compound of claim 41, wherein B is ##STR00515## and q is 0,
1, 2, or 3.
44. The compound of claim 43, wherein: a. q is 0, 1, or 2; b.
R.sub.3 is H or F; and c. each R.sub.5 is independently selected
from H, F, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, methyl, cyclopropyl,
methylene-cyclopropyl, hydroxyl, and methoxy.
45. A pharmaceutical composition formulated for oral delivery of an
.alpha.v.beta.6 integrin inhibitor, the composition comprising the
.alpha.v.beta.6 integrin inhibitor compound of claim 31 as an
active compound and a pharmaceutically acceptable carrier
formulated for oral therapeutic administration of the
.alpha.v.beta.6 integrin inhibitor compound.
46. A compound of formula (I): A-B--C (I) wherein: A is
##STR00516## wherein each R.sub.1 is independently H, alkyl,
halide, alkoxy, CF.sub.3, OH, alkylene-OH, NO.sub.2, --N(H)R.sub.a,
or NH.sub.2; wherein R.sub.a in A is H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; B is
alkylene, -alkylene-O--, or -alkylene-O-alkylene-; C is
##STR00517## wherein each R.sub.3 is independently selected from H,
halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl, cycloalkyl,
-alkylene-alkoxy, aryl, hydroxyl, and alkoxy; and n with respect to
R.sub.3 is 0, 1, 2, 3, or 4; R.sub.a in C is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; R.sub.2
is ##STR00518## and m in R.sub.2 is 0, 1, 2, 3, or 4; R.sub.4 is
independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl, --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; each R.sub.5 is independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; and the
absolute configuration at any stereocenter is R, S, or a mixture
thereof; or a pharmaceutically acceptable salt thereof; provided
that the compound is not a compound of the formula:
##STR00519##
47. The compound of claim 46, wherein a. each R.sub.1 is
independently selected from the group consisting of: H, methyl, F,
methoxy, CF.sub.3, OH, and alkylene-OH; b. each R.sub.3 in C is
independently selected from H, halide, alkyl or alkoxy; and n with
respect to R.sub.3 is 0 or 1; c. R.sub.a in C is H; and d. each
R.sub.5 is independently selected from the group consisting of H,
halide, cyclopropyl, methylene-cyclopropyl, and methoxy.
48. The compound of claim 47, wherein a. B is selected from the
group consisting of: ##STR00520## q is 0, 1, 2, or 3; and p is 0,
1, or 2; and b. each R.sub.1 is H.
49. The compound of claim 48, wherein a. g is 0, 1, or 2; and p is
0 or 1; b. n with respect to R.sub.3 is 0; C. R.sub.4 is selected
from the group consisting of: cycloalkyl and heterocycloalkyl; and
d. each R.sub.5 is independently selected from the group consisting
of H, F, cyclopropyl, methylene-cyclopropyl, and methoxy.
50. A pharmaceutical composition formulated for oral delivery of an
.alpha.v.beta.6 integrin inhibitor, the composition comprising the
.alpha.v.beta.6 integrin inhibitor compound of claim 46 as an
active compound and a pharmaceutically acceptable carrier
formulated for oral therapeutic administration of the
.alpha.v.beta.6 integrin inhibitor compound.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Patent Application No. 62/724,423, filed Aug. 29, 2018;
and U.S. Provisional Patent Application No. 62/859,457, filed Jun.
10, 2019.
TECHNICAL FIELD
[0002] This disclosure relates to novel chemical compounds and
methods useful for inhibiting .alpha.v.beta.6 integrin.
BACKGROUND
[0003] The heterodimeric integrin family of receptors modulate
cellular shape and cell adhesion to the extracellular matrix in
response to extrinsic and intrinsic cues.
[0004] Integrin signaling controls cell survival, cell cycle
progression, cell differentiation, and cell migration.
[0005] The integrin receptor exclusively can signal a cell
bi-directionally, both "inside-out" and "outside-in." Thus, they
mediate cell migration by transmitting forces from the
extracellular matrix to the cytoskeleton and regulate cytoskeletal
organization to achieve shape changes needed during cell migration.
RGD-binding integrins can bind to and activate TGF-.beta., and have
recently been implicated in fibrotic disease.
[0006] Integrins are expressed on the surface of most of human
cells. Their pathology contributes to a diverse set of human
diseases, including platelet disorders, atherosclerosis, cancer,
osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular
degeneration and various autoimmune and chronic inflammation
diseases.
[0007] The role of integrins as drug targets has long been
recognized, and a total of six injectable integrin inhibitors have
been approved by the Food and Drug Administration for the treatment
of various therapeutic indications: inflammatory bowel disease
(Entyvio.RTM., Tysabri.RTM.), multiple sclerosis (Tysabri.RTM.),
psoriasis (Raptiva.RTM.), and acute coronary syndrome (Reopro.RTM.,
Aggrastat.RTM., Integrilin.RTM.). Of the 24 known integrin
heterodimers, as least half have relevance in inflammation,
fibrosis, oncology and vascular disease.
[0008] There exists a need for new classes of integrin inhibitors.
There has been a notable absence of therapeutic success with orally
bioavailable integrin inhibitors. Accordingly, there remains a need
for a small molecule integrin inhibitor of .alpha.v.beta.6 suitable
for oral administration. The oral administration route is preferred
for small-molecule delivery as it allows a wide range of doses to
be administered, allows convenient patient self-administration, is
adaptable to varying dosage regimens and needs no special
equipment. Therefore, it is important to identify of
.alpha.v.beta.6 integrin inhibitor compounds that are not only
potent at the intended biological target, but are also
demonstrating other characteristics relating to the ability of the
compound to be absorbed in the body (e.g., after oral delivery) in
a therapeutically effective manner. For example, .alpha.v.beta.6
integrin inhibitor compounds can be selected based on both potency
and based on performance in an in vitro permeability assay (e.g.,
evaluating the ability of compounds to cross a layer of Madin-Darby
Canine Kidney (MDCK) cells from the apical to basolateral side
(A->B)).
SUMMARY
[0009] Applicants have discovered novel .alpha.v.beta.6 integrin
inhibitor compounds and evaluated the possession, performance and
utility of representative examples of such compounds, both for
biochemical potency (e.g., using the assay of Example 35 to
evaluate fluorescence polarization assays of compounds for
.alpha.v.beta.6 binding) and in vitro permeability properties
(e.g., using the assay of Example 36 to evaluate MDCK
permeability).
[0010] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0011] wherein: [0012] A is
[0012] ##STR00001## [0013] B is alkylene,
-alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-,
-cycloalkylene, -alkylene-O--, -cycloalkylene-O--, or
-alkylene-O-alkylene-; [0014] C is
[0014] ##STR00002## [0015] R.sub.1 is independently H, alkyl,
halide, alkoxy, CF.sub.3, OH, alkylene-OH, NO.sub.2, --N(H)R, or
NH.sub.2; [0016] R.sub.2 is
[0016] ##STR00003## [0017] R.sub.3 and R.sub.5 are independently
selected from H, CN, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2,
alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy;
[0018] R.sub.4 is independently selected from alkyl,
--C(F.sub.2)CH.sub.3, cycloalkyl, heterocycloalkyl,
-alkylene-cycloalkyl, --O-alkylene-cycloalkyl; --O-cycloalkyl,
--O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0019] R.sub.a is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; [0020]
n is independently 0, 1, 2, 3, or 4; [0021] m is 0, 1, 2, or 3; and
[0022] the absolute configuration at any stereocenter is R, S, or a
mixture thereof; [0023] or a pharmaceutically acceptable salt
thereof.
[0024] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0025] wherein: [0026] A is
[0026] ##STR00004## [0027] B is selected from the group consisting
of:
##STR00005##
[0027] wherein [0028] q is 0, 1, 2, or 3; and p is 0, 1, or 2;
[0029] C is
[0029] ##STR00006## [0030] all instances of R.sub.1 are H; [0031]
R.sub.2 is
[0031] ##STR00007## [0032] R.sub.3 is H, halide, Me, OMe, or Ph.
[0033] R.sub.4 is independently selected from alkyl,
--C(F.sub.2)CH.sub.3, cycloalkyl, heterocycloalkyl,
-alkylene-cycloalkyl, --O-alkylene-cycloalkyl; --O-cycloalkyl,
--O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0034] R.sub.5 is F; [0035]
R.sub.a is H; [0036] n is independently 0 or 1; [0037] m is 0 or 1;
and [0038] the absolute configuration at any stereocenter is R, S,
or a mixture thereof; [0039] or a pharmaceutically acceptable salt
thereof.
[0040] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0041] wherein: [0042] A is
[0042] ##STR00008## [0043] B is selected from the group consisting
of:
##STR00009##
[0043] wherein [0044] q is 0, 1, 2, or 3; and p is 0, 1, or 2;
[0045] C is
[0045] ##STR00010## [0046] all instances of R.sub.1 are H; [0047]
R.sub.2 is
[0047] ##STR00011## [0048] R.sub.3 is H, halide, Me, OMe, or Ph;
[0049] R.sub.4 is independently selected from alkyl,
--C(F.sub.2)CH.sub.3, cycloalkyl, heterocycloalkyl,
-alkylene-cycloalkyl, --O-alkylene-cycloalkyl; --O-cycloalkyl,
--O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0050] R.sub.5 is F; [0051]
R.sub.a is H; [0052] n is 0 or 1; [0053] m is 0 or 1; and [0054]
the absolute configuration at any stereocenter is R, S, or a
mixture thereof; [0055] or a pharmaceutically acceptable salt
thereof.
[0056] In certain embodiments, the invention relates to a method of
treating a disease or a condition selected from the group
consisting of idiopathic pulmonary fibrosis, diabetic nephropathy,
focal segmental glomerulosclerosis, chronic kidney disease,
nonalcoholic steatohepatitis, primary biliary cholangitis, primary
sclerosing cholangitis, solid tumors, hematological tumors, organ
transplant, Alport syndrome, interstitial lung disease
radiation-induced fibrosis, bleomycin-induced fibrosis,
asbestos-induced fibrosis, flu-induced fibrosis,
coagulation-induced fibrosis, vascular injury-induced fibrosis,
aortic stenosis, and cardiac fibrosis comprising the step of:
administering to a subject in need thereof a therapeutically
effective amount of any one of the compounds described herein.
BRIEF DESCRIPTION OF THE FIGURES
[0057] FIG. 1 is a table summarizing inhibition of .alpha.v.beta.6
integrin by exemplary compounds, as measured in a fluorescence
polarization assay.
[0058] FIG. 2 is a table summarizing inhibition of .alpha.v.beta.6
integrin by exemplary compounds, as measured in a fluorescence
polarization assay.
[0059] FIG. 3 is a table summarizing permeability properties of
exemplary compounds from FIG. 1 measured in a MDCK in vitro assay
of Example 36.
[0060] FIG. 4 is a table summarizing permeability properties of
exemplary compounds from FIG. 2 measured in a MDCK in vitro assay
of Example 36.
DETAILED DESCRIPTION
[0061] In certain embodiments, the invention relates to compounds
that inhibit .alpha.v.beta.6 integrin. In certain embodiments, the
compounds are selective for .alpha.v.beta.6 integrin.
[0062] The compounds will be useful for the treatment of idiopathic
pulmonary fibrosis, diabetic nephropathy, focal segmental
glomerulosclerosis, chronic kidney disease, nonalcoholic
steatohepatitis, primary biliary cholangitis, primary sclerosing
cholangitis, solid tumors, hematological tumors, organ transplant,
Alport syndrome, interstitial lung disease, radiation-induced
fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis,
flu-induced fibrosis, coagulation-induced fibrosis, vascular
injury-induced fibrosis, aortic stenosis, or cardiac fibrosis.
Definitions
[0063] For convenience, before further description of the present
invention, certain terms employed in the specification, examples
and appended claims are collected here. These definitions should be
read in light of the remainder of the disclosure and understood as
by a person of skill in the art. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood by a person of ordinary skill in the art.
[0064] In order for the present invention to be more readily
understood, certain terms and phrases are defined below and
throughout the specification.
[0065] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0066] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0067] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e., "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of" "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0068] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0069] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0070] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
[0071] Certain compounds contained in compositions of the present
invention may exist in particular geometric or stereoisomeric
forms. In addition, polymers of the present invention may also be
optically active. The present invention contemplates all such
compounds, including cis- and trans-isomers, R- and S-enantiomers,
diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures
thereof, and other mixtures thereof, as falling within the scope of
the invention. Additional asymmetric carbon atoms may be present in
a substituent such as an alkyl group. All such isomers, as well as
mixtures thereof, are intended to be included in this
invention.
[0072] If, for instance, a particular enantiomer of compound of the
present invention is desired, it may be prepared by asymmetric
synthesis, or by derivation with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts are formed with an appropriate
optically-active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0073] Structures depicted herein are also meant to include
compounds that differ only in the presence of one or more
isotopically enriched atoms. For example, compounds produced by the
replacement of a hydrogen with deuterium or tritium, or of a carbon
with a .sup.13C- or .sup.14C-enriched carbon are within the scope
of this invention.
[0074] The term "prodrug" as used herein encompasses compounds
that, under physiological conditions, are converted into
therapeutically active agents. A common method for making a prodrug
is to include selected moieties that are hydrolyzed under
physiological conditions to reveal the desired molecule. In other
embodiments, the prodrug is converted by an enzymatic activity of
the host animal.
[0075] The phrase "pharmaceutically acceptable excipient" or
"pharmaceutically acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such
as a liquid or solid filler, diluent, excipient, solvent or
encapsulating material, involved in carrying or transporting the
subject chemical from one organ or portion of the body, to another
organ or portion of the body. Each carrier must be "acceptable" in
the sense of being compatible with the other ingredients of the
formulation, not injurious to the patient, and substantially
non-pyrogenic. Some examples of materials which can serve as
pharmaceutically acceptable carriers include: (1) sugars, such as
lactose, glucose, and sucrose; (2) starches, such as corn starch
and potato starch; (3) cellulose, and its derivatives, such as
sodium carboxymethyl cellulose, ethyl cellulose, and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as cocoa butter and suppository waxes; (9)
oils, such as peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil, and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol, and polyethylene glycol; (12) esters, such as ethyl
oleate and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations. In certain embodiments, pharmaceutical compositions
of the present invention are non-pyrogenic, i.e., do not induce
significant temperature elevations when administered to a
patient.
[0076] The term "pharmaceutically acceptable salts" refers to the
relatively non-toxic, inorganic and organic acid addition salts of
the compound(s). These salts can be prepared in situ during the
final isolation and purification of the compound(s), or by
separately reacting a purified compound(s) in its free base form
with a suitable organic or inorganic acid, and isolating the salt
thus formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,
valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. (See, for example, Berge et
al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)
[0077] In other cases, the compounds useful in the methods of the
present invention may contain one or more acidic functional groups
and, thus, are capable of forming pharmaceutically acceptable salts
with pharmaceutically acceptable bases. The term "pharmaceutically
acceptable salts" in these instances refers to the relatively
non-toxic inorganic and organic base addition salts of a
compound(s). These salts can likewise be prepared in situ during
the final isolation and purification of the compound(s), or by
separately reacting the purified compound(s) in its free acid form
with a suitable base, such as the hydroxide, carbonate, or
bicarbonate of a pharmaceutically acceptable metal cation, with
ammonia, or with a pharmaceutically acceptable organic primary,
secondary, or tertiary amine. Representative alkali or alkaline
earth salts include the lithium, sodium, potassium, calcium,
magnesium, and aluminum salts, and the like. Representative organic
amines useful for the formation of base addition salts include
ethylamine, diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine, and the like (see, for example, Berge
et al., supra).
[0078] A "therapeutically effective amount" (or "effective amount")
of a compound with respect to use in treatment, refers to an amount
of the compound in a preparation which, when administered as part
of a desired dosage regimen (to a mammal, preferably a human)
alleviates a symptom, ameliorates a condition, or slows the onset
of disease conditions according to clinically acceptable standards
for the disorder or condition to be treated or the cosmetic
purpose, e.g., at a reasonable benefit/risk ratio applicable to any
medical treatment.
[0079] The term "prophylactic or therapeutic" treatment is
art-recognized and includes administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic, (i.e., it protects the host against developing the
unwanted condition), whereas if it is administered after
manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, ameliorate, or
stabilize the existing unwanted condition or side effects
thereof).
[0080] The term "patient" refers to a mammal in need of a
particular treatment. In certain embodiments, a patient is a
primate, canine, feline, or equine. In certain embodiments, a
patient is a human.
[0081] An aliphatic chain comprises the classes of alkyl, alkenyl
and alkynyl defined below. A straight aliphatic chain is limited to
unbranched carbon chain moieties. As used herein, the term
"aliphatic group" refers to a straight chain, branched-chain, or
cyclic aliphatic hydrocarbon group and includes saturated and
unsaturated aliphatic groups, such as an alkyl group, an alkenyl
group, or an alkynyl group.
[0082] "Alkyl" refers to a fully saturated cyclic or acyclic,
branched or unbranched carbon chain moiety having the number of
carbon atoms specified, or up to 30 carbon atoms if no
specification is made. For example, alkyl of 1 to 8 carbon atoms
refers to moieties such as methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, and octyl, and those moieties which are positional
isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes
decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl,
docosyl, tricosyl and tetracosyl. In certain embodiments, a
straight chain or branched chain alkyl has 30 or fewer carbon atoms
in its backbone (e.g., C.sub.1-C.sub.30 for straight chains,
C.sub.3-C.sub.30 for branched chains), and more preferably 20 or
fewer. Alkyl groups may be substituted or unsubstituted.
[0083] As used herein, the term "alkylene" refers to an alkyl group
having the specified number of carbons, for example from 2 to 12
carbon atoms, that contains two points of attachment to the rest of
the compound on its longest carbon chain. Non-limiting examples of
alkylene groups include methylene --(CH.sub.2)--, ethylene
--(CH.sub.2CH.sub.2)--, n-propylene --(CH.sub.2CH.sub.2CH.sub.2)--,
isopropylene --(CH.sub.2CH(CH.sub.3))--, and the like. Alkylene
groups can be cyclic or acyclic, branched or unbranched carbon
chain moiety, and may be optionally substituted with one or more
substituents.
[0084] "Cycloalkyl" means mono- or bicyclic or bridged or
spirocyclic, or polycyclic saturated carbocyclic rings, each having
from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have
from 3-10 carbon atoms in their ring structure, and more preferably
have 3-6 carbons in the ring structure. Cycloalkyl groups may be
substituted or unsubstituted.
[0085] Unless the number of carbons is otherwise specified, "lower
alkyl," as used herein, means an alkyl group, as defined above, but
having from one to ten carbons, more preferably from one to six
carbon atoms in its backbone structure such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
Likewise, "lower alkenyl" and "lower alkynyl" have similar chain
lengths. Throughout the application, preferred alkyl groups are
lower alkyls. In certain embodiments, a substituent designated
herein as alkyl is a lower alkyl.
[0086] "Alkenyl" refers to any cyclic or acyclic, branched or
unbranched unsaturated carbon chain moiety having the number of
carbon atoms specified, or up to 26 carbon atoms if no limitation
on the number of carbon atoms is specified; and having one or more
double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is
exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl,
undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl,
hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl,
heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their
various isomeric forms, where the unsaturated bond(s) can be
located anywhere in the moiety and can have either the (Z) or the
(E) configuration about the double bond(s).
[0087] "Alkynyl" refers to hydrocarbyl moieties of the scope of
alkenyl, but having one or more triple bonds in the moiety.
[0088] The term "alkylthio" refers to an alkyl group, as defined
above, having a sulfur moiety attached thereto. In certain
embodiments, the "alkylthio" moiety is represented by one of
--(S)-alkyl, --(S)-alkenyl, --(S)-alkynyl, and
--(S)--(CH.sub.2).sub.m--R.sup.1, wherein m and R.sup.1 are defined
below. Representative alkylthio groups include methylthio,
ethylthio, and the like. The terms "alkoxyl" or "alkoxy" as used
herein refers to an alkyl group, as defined below, having an oxygen
moiety attached thereto. Representative alkoxyl groups include
methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is
two hydrocarbons covalently linked by an oxygen. Accordingly, the
substituent of an alkyl that renders that alkyl an ether is or
resembles an alkoxyl, such as can be represented by one of
--O-alkyl, --O-alkenyl, --O-- alkynyl,
--O--(CH.sub.2).sub.m--R.sub.10, where m and R.sub.10 are described
below.
[0089] The terms "amine" and "amino" are art-recognized and refer
to both unsubstituted and substituted amines, e.g., a moiety that
can be represented by the formulae:
##STR00012##
wherein R.sub.11, R.sub.12 and R.sub.13 each independently
represent a hydrogen, an alkyl, an alkenyl,
--(CH.sub.2).sub.m--R.sub.10, or R.sub.11 and R.sub.12 taken
together with the N atom to which they are attached complete a
heterocycle having from 4 to 8 atoms in the ring structure;
R.sub.10 represents an alkenyl, aryl, cycloalkyl, a cycloalkenyl, a
heterocyclyl, or a polycyclyl; and m is zero or an integer in the
range of 1 to 8. In certain embodiments, only one of R.sub.11 or
R.sub.12 can be a carbonyl, e.g., R.sub.11, R.sub.12, and the
nitrogen together do not form an imide. In even more certain
embodiments, R.sub.11 and R.sub.12 (and optionally R.sub.13) each
independently represent a hydrogen, an alkyl, an alkenyl, or
--(CH.sub.2).sub.m--R.sub.10. Thus, the term "alkylamine" as used
herein means an amine group, as defined above, having a substituted
or unsubstituted alkyl attached thereto, i.e., at least one of
R.sub.11 and R.sub.12 is an alkyl group. In certain embodiments, an
amino group or an alkylamine is basic, meaning it has a conjugate
acid with a pK.sub.a>7.00, i.e., the protonated forms of these
functional groups have pK.sub.as relative to water above about
7.00.
[0090] The term "amide", as used herein, refers to a group
##STR00013##
wherein each R.sub.14 independently represent a hydrogen or
hydrocarbyl group, or two R.sub.14 are taken together with the N
atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure.
[0091] The term "aryl" as used herein includes 3- to 12-membered
substituted or unsubstituted single-ring aromatic groups in which
each atom of the ring is carbon (i.e., carbocyclic aryl) or where
one or more atoms are heteroatoms (i.e., heteroaryl). Preferably,
aryl groups include 5- to 12-membered rings, more preferably 6- to
10-membered rings The term "aryl" also includes polycyclic ring
systems having two or more cyclic rings in which two or more
carbons are common to two adjoining rings wherein at least one of
the rings is aromatic, e.g., the other cyclic rings can be
cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls,
and/or heterocyclyls. Carboycyclic aryl groups include benzene,
naphthalene, phenanthrene, phenol, aniline, and the like.
Heteroaryl groups include substituted or unsubstituted aromatic 3-
to 12-membered ring structures, more preferably 5- to 12-membered
rings, more preferably 5- to 10-membered rings, whose ring
structures include one to four heteroatoms. Heteroaryl groups
include, for example, pyrrole, furan, thiophene, imidazole,
oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine,
pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be
monocyclic, bicyclic, or polycyclic. Each instance of an aryl group
may be independently optionally substituted, i.e., unsubstituted
(an "unsubstituted aryl") or substituted (a "substituted aryl")
with one or more substituents; e.g., for instance from 1 to 5
substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2
substituents or just 1 substituent. The aromatic ring may be
substituted at one or more ring positions with one or more
substituents, such as halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl,
imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl
(such as trifluromethyl), cyano, or the like. For example, in
certain embodiments, the aryl group can be an unsubstituted
C.sub.5-C.sub.12 aryl and in certain embodiments, the aryl group
can be a substituted C.sub.5-C.sub.10 aryl.
[0092] The term "halo", "halide", or "halogen" as used herein means
halogen and includes, for example, and without being limited
thereto, fluoro, chloro, bromo, iodo and the like, in both
radioactive and non-radioactive forms. In a preferred embodiment,
halo is selected from the group consisting of fluoro, chloro and
bromo.
[0093] The terms "heterocyclyl" or "heterocyclic group" refer to 3-
to 12-membered ring structures, more preferably 5- to 12-membered
rings, more preferably 5- to 10-membered rings, whose ring
structures include one to four heteroatoms. Heterocycles can be
monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl
groups include, for example, thiophene, thianthrene, furan, pyran,
isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole,
imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,
pyrimidine, pyridazine, indolizine, isoindole, indole, indazole,
purine, quinolizine, isoquinoline, quinoline, phthalazine,
naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine,
carbazole, carboline, phenanthridine, acridine, pyrimidine,
phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,
phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,
piperazine, morpholine, lactones, lactams such as azetidinones and
pyrrolidinones, sultams, sultones, and the like. The heterocyclic
ring can be substituted at one or more positions with such
substituents as described above, as for example, halogen, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,
sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate,
carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio,
sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic moiety, --CF.sub.3, --CN, and the like.
[0094] The term "carbonyl" is art-recognized and includes such
moieties as can be represented by the formula:
##STR00014##
wherein X' is a bond or represents an oxygen or a sulfur, and
R.sub.15 represents a hydrogen, an alkyl, an alkenyl,
--(CH.sub.2).sub.m--R.sub.10 or a pharmaceutically acceptable salt,
R.sub.16 represents a hydrogen, an alkyl, an alkenyl or
--(CH.sub.2).sub.m--R.sub.10, where m and R.sub.10 are as defined
above. Where X' is an oxygen and R.sub.15 or R.sub.16 is not
hydrogen, the formula represents an "ester." Where X' is an oxygen,
and R.sub.15 is as defined above, the moiety is referred to herein
as a carboxyl group, and particularly when R.sub.15 is a hydrogen,
the formula represents a "carboxylic acid". Where X' is an oxygen,
and R.sub.16 is a hydrogen, the formula represents a "formate." In
general, where the oxygen atom of the above formula is replaced by
a sulfur, the formula represents a "thiocarbonyl" group. Where X'
is a sulfur and R.sub.15 or R.sub.16 is not hydrogen, the formula
represents a "thioester" group. Where X' is a sulfur and R.sub.15
is a hydrogen, the formula represents a "thiocarboxylic acid"
group. Where X' is a sulfur and R.sub.16 is a hydrogen, the formula
represents a "thioformate" group. On the other hand, where X' is a
bond, and R.sub.15 is not hydrogen, the above formula represents a
"ketone" group. Where X' is a bond, and R.sub.15 is a hydrogen, the
above formula represents an "aldehyde" group.
[0095] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
herein above. The permissible substituents can be one or more and
the same or different for appropriate organic compounds. For
purposes of this invention, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. This invention is not intended to be limited in
any manner by the permissible substituents of organic compounds. It
will be understood that "substitution" or "substituted with"
includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc.
[0096] As used herein, the term "nitro" means --NO.sub.2; the term
"halogen" designates --F, --Cl, --Br, or --I; the term "sulfhydryl"
means --SH; the term "hydroxyl" means --OH; the term "sulfonyl"
means --SO.sub.2--; the term "azido" means --N.sub.3; the term
"cyano" means --CN; the term "isocyanato" means --NCO; the term
"thiocyanato" means --SCN; the term "isothiocyanato" means --NCS;
and the term "cyanato" means --OCN.
[0097] The term "sulfamoyl" is art-recognized and includes a moiety
that can be represented by the formula:
##STR00015##
in which R.sub.11 and R.sub.12 are as defined above.
[0098] The term "sulfate" is art recognized and includes a moiety
that can be represented by the formula:
##STR00016##
in which R.sub.15 is as defined above.
[0099] The term "sulfonamide" is art recognized and includes a
moiety that can be represented by the formula:
##STR00017##
in which R.sub.11 and R.sub.16 are as defined above.
[0100] The term "sulfonate" is art-recognized and includes a moiety
that can be represented by the formula:
##STR00018##
in which R.sub.54 is an electron pair, hydrogen, alkyl, cycloalkyl,
or aryl.
[0101] The terms "sulfoxido" or "sulfinyl", as used herein, refers
to a moiety that can be represented by the formula:
##STR00019##
in which R.sub.17 is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aralkyl, or aryl.
[0102] The term "urea" is art-recognized and may be represented by
the general formula
##STR00020##
[0103] wherein each R.sub.18 independently represents hydrogen or a
hydrocarbyl, such as alkyl, or any occurrence of R.sub.18 taken
together with another and the intervening atom(s) complete a
heterocycle having from 4 to 8 atoms in the ring structure.
[0104] As used herein, the definition of each expression, e.g.,
alkyl, m, n, etc., when it occurs more than once in any structure,
is intended to be independent of its definition elsewhere in the
same structure.
[0105] The term "substituted" refers to moieties having
substituents replacing a hydrogen on one or more carbons of the
backbone. It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term "substituted" is contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
non-aromatic substituents of organic compounds. The permissible
substituents can be one or more and the same or different for
appropriate organic compounds. For purposes of this invention, the
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valences of the heteroatoms. Substituents can
include any substituents described herein, for example, a halogen,
a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a
formyl, or an acyl), a thiocarbonyl (such as a thioester, a
thioacetate, or a thioformate), an alkoxy, a phosphoryl, a
phosphate, a phosphonate, a phosphinate, an amino, an amido, an
amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an
alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
heteroaromatic moiety. In preferred embodiments, the substituents
on substituted alkyls are selected from C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more
preferred embodiments, the substituents on substituted alkyls are
selected from fluoro, carbonyl, cyano, or hydroxyl. It will be
understood by those skilled in the art that substituents can
themselves be substituted, if appropriate. Unless specifically
stated as "unsubstituted," references to chemical moieties herein
are understood to include substituted variants. For example,
reference to an "aryl" group or moiety implicitly includes both
substituted and unsubstituted variants.
[0106] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
Exemplary Compounds of the Invention
[0107] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0108] wherein: [0109] A is
[0109] ##STR00021## [0110] B is alkylene,
-alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-,
-cycloalkylene, -alkylene-O--, -cycloalkylene-O--, or
-alkylene-O-alkylene-; [0111] C is
[0111] ##STR00022## [0112] R.sub.1 is independently H, alkyl,
halide, alkoxy, CF.sub.3, OH, alkylene-OH, NO.sub.2, --N(H)R, or
NH.sub.2; [0113] R.sub.2 is
[0113] ##STR00023## [0114] R.sub.3 and R.sub.5 are independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; [0115]
R.sub.4 is independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl; --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0116] R.sub.a is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; [0117]
n is independently 0, 1, 2, 3, or 4; [0118] m is 0, 1, 2, or 3; and
[0119] the absolute configuration at any stereocenter is R, S, or a
mixture thereof; [0120] or a pharmaceutically acceptable salt
thereof.
[0121] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0122] wherein: [0123] A is
[0123] ##STR00024## [0124] B is alkylene,
-alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-,
-cycloalkylene, -alkylene-O--, -cycloalkylene-O--, or
-alkylene-O-alkylene-; [0125] C is
[0125] ##STR00025## [0126] R.sub.1 is H, or alkoxy; [0127] R.sup.2
is
[0127] ##STR00026## [0128] R.sub.3 and R.sub.5 are independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; [0129]
R.sub.4 is independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl; --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0130] R.sub.a is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; [0131]
n is independently 0, 1, 2, 3, or 4; [0132] m is 0, 1, 2, or 3; and
[0133] the absolute configuration at any stereocenter is R, S, or a
mixture thereof; [0134] or a pharmaceutically acceptable salt
thereof.
[0135] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0136] wherein: [0137] A is
[0137] ##STR00027## [0138] B is alkylene, -alkylene-O--, or
-alkylene-O-alkylene-; [0139] C is
[0139] ##STR00028## [0140] R.sub.1 is H; [0141] R.sub.2 is
[0141] ##STR00029## [0142] R.sub.3 and R.sub.5 are independently
selected from H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl,
cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; [0143]
R.sub.4 is independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl; --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0144] R.sub.a is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; [0145]
n is independently 0, 1, 2, 3, or 4; [0146] m is 0, 1, 2, or 3; and
[0147] the absolute configuration at any stereocenter is R, S, or a
mixture thereof; [0148] or a pharmaceutically acceptable salt
thereof.
[0149] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C (I)
[0150] wherein: [0151] A is
[0151] ##STR00030## [0152] B is alkylene, or -alkylene-O--; [0153]
C is
[0153] ##STR00031## [0154] R.sub.1 is H; [0155] R.sub.2 is
[0155] ##STR00032## [0156] R.sub.5 is independently selected from
H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl, cycloalkyl,
-alkylene-alkoxy, aryl, hydroxyl, and alkoxy; [0157] R.sub.4 is
independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl; --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0158] R.sub.a is H; [0159] n is
0; [0160] m is 0, 1, 2, or 3; and [0161] the absolute configuration
at any stereocenter is R, S, or a mixture thereof; [0162] or a
pharmaceutically acceptable salt thereof.
[0163] In certain embodiments, the invention relates to a compound
of Formula I:
A-B--C(I)
[0164] wherein: [0165] A is
[0165] ##STR00033## [0166] B is
##STR00034##
[0166] wherein q is 0, 1, 2, or 3; [0167] C is
[0167] ##STR00035## [0168] R.sub.1 is independently H, alkyl,
halide, alkoxy, CF.sub.3, OH, alkylene-OH, NO.sub.2, --N(H)R, or
NH.sub.2; [0169] R.sub.2 is
[0169] ##STR00036## [0170] R.sub.5 is independently selected from
H, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2, alkyl, cycloalkyl,
-alkylene-alkoxy, aryl, hydroxyl, and alkoxy; [0171] R.sub.4 is
independently selected from alkyl, --C(F.sub.2)CH.sub.3,
cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl; --O-cycloalkyl, --O-alkyl,
-alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0172] R.sub.a is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; [0173]
n is 0; [0174] m is 0, 1, 2, or 3; and [0175] the absolute
configuration at any stereocenter is R, S, or a mixture thereof;
[0176] or a pharmaceutically acceptable salt thereof.
[0177] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is
##STR00037##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein A is
##STR00038##
[0178] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein B is alkylene. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein B is -alkylene-(heterocyclyl)-alkylene-. In
certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein B is -(heterocyclyl)-alkylene-.
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein B is --cycloalkylene. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein B is -alkylene-O--. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein B is -cycloalkylene-O--. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein B is -alkylene-O-alkylene-. In some embodiments,
-alkylene-O-alkylene- is -methylene-O-propylene,
-ethylene-O-ethylene, or -propylene-O-methylene. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein B is selected from the group consisting of:
##STR00039##
q is 0, 1, 2, or 3; and p is 0, 1, or 2.
[0179] In some embodiments, B is
##STR00040##
In some embodiments, B is
##STR00041##
In some embodiments, q is 0. In some embodiments, q is 1. In some
embodiments, q is 2. In some embodiments, q is 3. In some
embodiments, p is 0. In some embodiments, p is 1. In some
embodiments, p is 2.
[0180] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.1 is H. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.1 is alkyl. In certain embodiments,
R.sub.1 is methyl. In certain embodiments, the invention relates to
any one of the aforementioned compounds, wherein R.sub.1 is halide.
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.1 is alkoxy. In some
embodiments, alkoxy is methoxy, ethoxy, iso-propyloxy,
iso-butyloxy, or tert-butyloxy. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.1 is CF.sub.3. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein R.sub.1
is OH. In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.1 is alkylene-OH. In
certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.1 is NO.sub.2. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.1 is --N(H)R.sub.a. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.1 is NH.sub.2. In some embodiments, at
least one instance of R.sub.1 is alkyl, halide, OMe, OH,
alkylene-OH, or NH.sub.2. In some embodiments, at least one
instance of R.sub.1 is OMe. In some embodiments, all instances of
R.sub.1 are H.
[0181] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.2 is
##STR00042##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.2 is
##STR00043##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.2 is
##STR00044##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.2 is
##STR00045##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.2 is
##STR00046##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.2 is
##STR00047##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.2 is
##STR00048##
[0182] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein n is 0. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein n is 1. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein n is 2.
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein n is 3. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein n is 4.
[0183] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein m is 0. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein m is 1. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein m is 2.
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein m is 3.
[0184] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.3 is H. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.3 is halide. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.3 is CN. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein R.sub.3
is CF.sub.3. In certain embodiments, the invention relates to any
one of the aforementioned compounds, wherein R.sub.3 is
C(H)F.sub.2. In certain embodiments, the invention relates to any
one of the aforementioned compounds, wherein R.sub.3 is
C(F)H.sub.2. In certain embodiments, the invention relates to any
one of the aforementioned compounds, wherein R.sub.3 is alkyl. In
some embodiments, alkyl is methyl, ethyl, iso-propyl, or
tert-butyl. In certain embodiments, the invention relates to any
one of the aforementioned compounds, wherein R.sub.3 is cycloalkyl.
In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,
cylcopentyl, or cyclohexyl. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein R.sub.3
is -alkylene-alkoxy. In certain embodiments, the invention relates
to any one of the aforementioned compounds, wherein R.sub.3 is
aryl. In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.3 is hydroxyl. In
certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.3 is alkoxy. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.3 is H, halide, Me, OMe, or Ph.
[0185] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.4 is alkyl. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.4 is --C(F.sub.2)CH.sub.3. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.4 is cycloalkyl. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein R.sub.4 is heterocycloalkyl. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.4 is -alkylene-cycloalkyl. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein R.sub.4 is --O-- alkylene-cycloalkyl. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.4 is --O-cycloalkyl. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.4 is --O-alkyl. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein R.sub.4 is -alkylene-O-alkyl. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.4 is -alkylene-O-cycloalkyl. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein R.sub.4 is -alkylene-O-alkylene-cycloalkyl. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.4 is selected from -alkylene-cycloalkyl,
--O-- alkylene-cycloalkyl; -alkylene-O-alkyl,
-alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl. In
some embodiments, alkylene R.sub.4 is methylene or ethylene.
[0186] In certain embodiments, the invention relates to any one of
the aforementioned compounds, R.sub.4 is selected from
##STR00049## ##STR00050##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, R.sub.4 is selected from optionally
substituted
##STR00051##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, R.sub.4 is
##STR00052##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, R.sub.4 is
##STR00053##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, R.sub.4 is
##STR00054##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, R.sub.4 is
##STR00055##
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.4 is selected from
##STR00056## ##STR00057##
[0187] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sub.5 is H. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.5 is halide. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.5 is F. In certain embodiments, the invention relates
to any one of the aforementioned compounds, wherein R.sub.5 is CN.
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein R.sub.5 is CF.sub.3. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.5 is C(H)F.sub.2. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein R.sub.5 is C(F)H.sub.2. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.5 is alkyl. In some embodiments, alkyl is methyl,
ethyl, iso-propyl, or tert-butyl. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.5 is cycloalkyl. In some embodiments, cycloalkyl is
cyclopropyl, cyclobutyl, cylcopentyl, or cyclohexyl. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.5 is -alkylene-alkoxy. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein R.sub.5 is aryl. In certain embodiments, the
invention relates to any one of the aforementioned compounds,
wherein R.sub.5 is hydroxyl. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein R.sub.5
is alkoxy. In certain embodiments, the invention relates to any one
of the aforementioned compounds, wherein R.sub.5 is H, halide, Me,
OMe, or Ph.
[0188] In certain embodiments, the invention relates to any one of
the aforementioned compounds, R.sub.a is H. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
R.sub.a is (C.sub.1-C.sub.6)alkyl. In some embodiments,
(C.sub.1-C.sub.6)alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl. In certain embodiments, the invention
relates to any one of the aforementioned compounds, R.sub.a is
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, R.sub.a is
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl;
[0189] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein the absolute configuration at
any stereocenter is R. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein the
absolute configuration at any stereocenter is S. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein the absolute configuration at any stereocenter
is a mixture of R and S.
[0190] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein the compound is a
pharmaceutically acceptable salt.
[0191] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065##
[0192] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00066## ##STR00067## ##STR00068## ##STR00069##
[0193] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00070## ##STR00071##
[0194] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00072##
[0195] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00073##
[0196] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081##
[0197] In certain embodiments, the invention relates to a compound
of formula:
##STR00082##
[0198] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087##
##STR00088## ##STR00089##
[0199] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095##
[0200] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00096## ##STR00097##
[0201] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00098##
[0202] In certain embodiments, the invention relates to a compound
of formula:
##STR00099##
[0203] In certain embodiments, the invention relates to a compound
of formula:
##STR00100##
[0204] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00101##
[0205] In certain embodiments, the invention relates to a compound
of formula:
##STR00102##
[0206] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107##
##STR00108## ##STR00109## ##STR00110## ##STR00111##
##STR00112##
[0207] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00113## ##STR00114## ##STR00115##
[0208] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120##
##STR00121## ##STR00122## ##STR00123## ##STR00124##
##STR00125##
[0209] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00126## ##STR00127##
[0210] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00128## ##STR00129## ##STR00130## ##STR00131##
[0211] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00132##
[0212] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00133## ##STR00134## ##STR00135##
[0213] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00136##
[0214] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00137## ##STR00138##
[0215] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00139##
[0216] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00140##
[0217] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00141##
[0218] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00142## ##STR00143##
[0219] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00144##
[0220] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00145##
[0221] In some embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00146##
Exemplary Pharmaceutical Compositions
[0222] In certain embodiments, the invention relates to a
pharmaceutical composition comprising any one of the aforementioned
compounds and a pharmaceutically acceptable carrier.
[0223] Patients, including but not limited to humans, can be
treated by administering to the patient an effective amount of the
active compound or a pharmaceutically acceptable prodrug or salt
thereof in the presence of a pharmaceutically acceptable carrier or
diluent. The active materials can be administered by any
appropriate route, for example, orally, parenterally,
intravenously, intradermally, subcutaneously, or topically, in
liquid or solid form.
[0224] The concentration of active compound in the drug composition
will depend on absorption, inactivation and excretion rates of the
drug as well as other factors known to those of skill in the art.
It is to be noted that dosage values will also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
composition. The active ingredient can be administered at once, or
can be divided into a number of smaller doses to be administered at
varying intervals of time.
[0225] In certain embodiments, the mode of administration of the
active compound is oral. Oral compositions will generally include
an inert diluent or an edible carrier. They can be enclosed in
gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches or capsules. Pharmaceutically compatible binding agents,
and/or adjuvant materials can be included as part of the
composition.
[0226] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a
disintegrating agent such as alginic acid, Primogel or corn starch;
a lubricant such as magnesium stearate or Sterotes; a glidant such
as colloidal silicon dioxide; a sweetening agent such as sucrose or
saccharin; or a flavoring agent such as peppermint, methyl
salicylate, or orange flavoring. When the dosage unit form is a
capsule, it can contain, in addition to material of the above type,
a liquid carrier such as a fatty oil. In addition, unit dosage
forms can contain various other materials that modify the physical
form of the dosage unit, for example, coatings of sugar, shellac,
or other enteric agents.
[0227] The compound can be administered as a component of an
elixir, suspension, syrup, wafer, chewing gum or the like. A syrup
can contain, in addition to the active compound(s), sucrose or
sweetener as a sweetening agent and certain preservatives, dyes and
colorings and flavors.
[0228] The compound or a pharmaceutically acceptable prodrug or
salts thereof can also be mixed with other active materials that do
not impair the desired action, or with materials that supplement
the desired action, such as antibiotics, antifungals,
anti-inflammatories or other antivirals, including but not limited
to nucleoside compounds. Solutions or suspensions used for
parenteral, intradermal, subcutaneous, or topical application can
include the following components: a sterile diluent such as water
for injection, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents, such as ethylenediaminetetraacetic acid; buffers, such as
acetates, citrates or phosphates, and agents for the adjustment of
tonicity, such as sodium chloride or dextrose. The parental
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic.
[0229] If administered intravenously, carriers include
physiological saline and phosphate buffered saline (PBS).
[0230] In certain embodiments, the active compounds are prepared
with carriers that will protect the compound against rapid
elimination from the body, such as a controlled release
formulation, including but not limited to implants and
microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters and
polylactic acid. For example, enterically coated compounds can be
used to protect cleavage by stomach acid. Methods for preparation
of such formulations will be apparent to those skilled in the art.
Suitable materials can also be obtained commercially.
[0231] Liposomal suspensions (including but not limited to
liposomes targeted to infected cells with monoclonal antibodies to
viral antigens) are also preferred as pharmaceutically acceptable
carriers. These can be prepared according to methods known to those
skilled in the art, for example, as described in U.S. Pat. No.
4,522,811 (incorporated by reference). For example, liposome
formulations can be prepared by dissolving appropriate lipid(s)
(such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl
choline, arachadoyl phosphatidyl choline, and cholesterol) in an
inorganic solvent that is then evaporated, leaving behind a thin
film of dried lipid on the surface of the container. An aqueous
solution of the active compound is then introduced into the
container. The container is then swirled by hand to free lipid
material from the sides of the container and to disperse lipid
aggregates, thereby forming the liposomal suspension.
Exemplary Methods of the Invention
[0232] In certain embodiments, the invention relates to a method of
treating a disease or a condition selected from the group
consisting of idiopathic pulmonary fibrosis, diabetic nephropathy,
focal segmental glomerulosclerosis, chronic kidney disease,
nonalcoholic steatohepatitis, primary biliary cholangitis, primary
sclerosing cholangitis, solid tumors, hematological tumors, organ
transplant, Alport syndrome, interstitial lung disease,
radiation-induced fibrosis, bleomycin-induced fibrosis,
asbestos-induced fibrosis, flu-induced fibrosis,
coagulation-induced fibrosis, vascular injury-induced fibrosis,
aortic stenosis, and cardiac fibrosis comprising the step of:
administering to a subject in need thereof a therapeutically
effective amount of any one of the aforementioned compounds.
[0233] In certain embodiments, the invention relates to any one of
the aforementioned methods, wherein the disease or condition is a
solid tumor (sarcomas, carcinomas, and lymphomas). Exemplary tumors
that may be treated in accordance with the invention include e.g.,
Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, myelosarcoma,
chondrosarcoma, liposarcoma, leiomyosarcoma, soft tissue sarcoma,
non-small cell lung cancer, small cell lung cancer, bronchus
cancer, prostate cancer, breast cancer, pancreatic cancer,
gastrointestinal cancer, colon cancer, rectum cancer, colon
carcinoma, colorectal adenoma, thyroid cancer, liver cancer,
intrahepatic bile duct cancer, hepatocellular cancer, adrenal gland
cancer, stomach cancer, gastric cancer, glioma (e.g., adult,
childhood brain stem, childhood cerebral astrocytoma, childhood
visual pathway and hypothalamic), glioblastoma, endometrial cancer,
melanoma, kidney cancer, renal pelvis cancer, urinary bladder
cancer, uterine corpus, uterine cervical cancer, vaginal cancer,
ovarian cancer, multiple myeloma, esophageal cancer, brain cancer
(e.g., brain stem glioma, cerebellar astrocytoma, cerebral
astrocytoma/malignant glioma, ependymoma, meduloblastoma,
supratentorial primitive neuroectodermal tumors, visual pathway and
hypothalamic glioma), lip and oral cavity and pharynx, larynx,
small intestine, melanoma, villous colon adenoma, a neoplasia, a
neoplasia of epithelial character, lymphomas (e.g., AIDS-related,
Burkitt's, cutaneous T-cell, Hodgkin, non-Hodgkin, and primary
central nervous system), a mammary carcinoma, basal cell carcinoma,
squamous cell carcinoma, actinic keratosis, tumor diseases,
including solid tumors, a tumor of the neck or head, polycythemia
vera, essential thrombocythemia, myelofibrosis with myeloid
metaplasia, Waldenstrom's macroglobulinemia, adrenocortical
carcinoma, AIDS-related cancers, childhood cerebellar astrocytoma,
childhood cerebellar astrocytoma, basal cell carcinoma,
extrahepatic bile duct cancer, malignant fibrous histiocytoma bone
cancer, bronchial adenomas/carcinoids, carcinoid tumor,
gastrointestinal carcinoid tumor, primary central nervous system,
cerebellar astrocytoma, childhood cancers, ependymoma, extracranial
germ cell tumor, extragonadal germ cell tumor, extrahepatic bile
duct cancer, intraocular melanoma eye cancer, retinoblastoma eye
cancer, gallbladder cancer, gastrointestinal carcinoid tumor, germ
cell tumors (e.g., extracranial, extragonadal, and ovarian),
gestational trophoblastic tumor, hepatocellular cancer,
hypopharyngeal cancer, hypothalamic and visual pathway glioma,
islet cell carcinoma (endocrine pancreas), laryngeal cancer,
malignant fibroushistiocytoma of bone/osteosarcoma, meduloblastoma,
mesothelioma, metastatic squamous neck cancer with occult primary,
multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell
neoplasm, mycosis fungoides, nasal cavity and paranasal sinus
cancer, nasopharyngeal cancer, neuroblastoma, oral cancer,
oropharyngeal cancer, ovarian epithelial cancer, ovarian germ cell
tumor, ovarian low malignant potential tumor, islet cell pancreatic
cancer, parathyroid cancer, pheochromocytoma, pineoblastoma,
pituitary tumor, pleuropulmonary blastoma, ureter transitional cell
cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer,
Sezary syndrome, non-melanoma skin cancer, Merkel cell carcinoma,
squamous cell carcinoma, testicular cancer, thymoma, gestational
trophoblastic tumor, and Wilms' tumor.
[0234] In certain embodiments, the invention relates to any one of
the aforementioned methods, wherein the disease is disease or
condition is a hematological tumor. Exemplary homatological tumors
that may be treated in accordance with the invention include e.g.,
acute lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin
lymphoma, non-Hodgkin lymphoma, and multiple myeloma.
[0235] In certain embodiments, the invention relates to any one of
the aforementioned methods, wherein the disease or condition is
selected from the group consisting of idiopathic pulmonary
fibrosis, systemic sclerosis associated interstitial lung disease,
myositis associated interstitial lung disease, systemic lupus
erythematosus associated interstitial lung disease, rheumatoid
arthritis, and associated interstitial lung disease.
[0236] In certain embodiments, the invention relates to any one of
the aforementioned methods, wherein the disease or condition is
selected from the group consisting of diabetic nephropathy, focal
segmental glomerulosclerosis, and chronic kidney disease.
[0237] In certain embodiments, the invention relates to any one of
the aforementioned methods, wherein the disease or condition is
selected from the group consisting of nonalcoholic steatohepatitis,
primary biliary cholangitis, and primary sclerosing
cholangitis.
[0238] In certain embodiments, the invention relates to any one of
the aforementioned methods, wherein the subject is a mammal. In
certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the subject is human.
Additional Numeric Embodiments
[0239] 1. A compound of formula (I):
[0239] A-B--C (I)
[0240] wherein: [0241] A is
[0241] ##STR00147## [0242] B is alkylene,
-alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-,
-cycloalkylene, -alkylene-O--, -cycloalkylene-O--, or
-alkylene-O-alkylene-; [0243] C is
[0243] ##STR00148## [0244] R.sub.1 is independently H, alkyl,
halide, alkoxy, CF.sub.3, OH, alkylene-OH, NO.sub.2, or
--N(H)R.sub.a; [0245] R.sub.2 is
[0245] ##STR00149## [0246] R.sub.3 and R.sub.5 are independently
selected from H, --CN, halide, CF.sub.3, C(H)F.sub.2, C(F)H.sub.2,
alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy;
[0247] R.sub.4 is independently selected from alkyl,
--C(F.sub.2)CH.sub.3, cycloalkyl, heterocycloalkyl,
-alkylene-cycloalkyl, --O-alkylene-cycloalkyl, --O-cycloalkyl,
--O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and
-alkylene-O-alkylene-cycloalkyl; [0248] R.sub.a is H,
(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylene-O--(C.sub.1-C.sub.6)alkyl, or
--(C.sub.1-C.sub.6)alkylene-O--C(O)O(C.sub.1-C.sub.6)alkyl; [0249]
n is independently 0, 1, 2, 3, or 4; [0250] m is 0, 1, 2, or 3; and
[0251] the absolute configuration at any stereocenter is R, S, or a
mixture thereof; [0252] or a pharmaceutically acceptable salt
thereof. [0253] 2. The compound of embodiment 1, wherein B is
selected from the group consisting of:
[0253] ##STR00150## [0254] q is 0, 1, 2, or 3; and [0255] p is 0,
1, or 2. [0256] 3. The compound of embodiment 1, wherein B is
-alkylene-O-alkylene-. [0257] 4. The compound of embodiment 3,
wherein -alkylene-O-alkylene- is -methylene-O-propylene,
-ethylene-O-ethylene, or -propylene-O-methylene. [0258] 5. The
compound of anyone of embodiments 1-4, wherein at least one
instance of R.sub.1 is alkyl, halide, OMe, OH, alkylene-OH, or
NH.sub.2. [0259] 6. The compound of embodiment 5, wherein the at
least one instance of R.sub.1 is OMe. [0260] 7. The compound of
anyone of embodiments 1-4, wherein all instances of R.sub.1 are H.
[0261] 8. The compound of any one of embodiments 1-7, wherein
R.sub.2 is
[0261] ##STR00151## [0262] 9. The compound of embodiment 8, wherein
n in R.sub.2 is 0. [0263] 10. The compound of embodiment 8, wherein
n in R.sub.2 is 1. [0264] 11. The compound of any one of
embodiments 1-7, wherein R.sub.2 is
[0264] ##STR00152## [0265] 12. The compound of embodiment 11,
wherein m in R.sub.2 is 0. [0266] 13. The compound of embodiment
11, wherein m in R.sub.2 is 1. [0267] 14. The compound of
embodiment 1, 8, 10, 11, or 13, wherein R.sub.5 is F. [0268] 15.
The compound of embodiment 1, 8, 10, 11, or 13, wherein R.sub.5 is
CN. [0269] 16. The compound of any one of embodiments 1-7, wherein
R.sub.2 is
[0269] ##STR00153## [0270] 17. The compound of any one of
embodiments 1-16, wherein cycloalkyl is cyclopropyl, cyclobutyl,
cylcopentyl, or cyclohexyl. [0271] 18. The compound of any one of
embodiments 1-16, wherein alkyl is methyl, ethyl, iso-propyl, or
tert-butyl. [0272] 19. The compound of any one of embodiments 1-18,
wherein R.sub.3 is H, halide, Me, OMe, or Ph. [0273] 20. The
compound of any one of embodiments 1-19, wherein R.sub.4 is
independently selected from -alkylene-cycloalkyl,
--O-alkylene-cycloalkyl; -alkylene-O-alkyl, -alkylene-O-cycloalkyl,
and -alkylene-O-alkylene-cycloalkyl. [0274] 21. The compound of
embodiment 20, wherein alkylene in R.sub.4 is methylene or
ethylene. [0275] 22. The compound of any one of embodiments 1-19,
wherein R.sub.4 is selected from
[0275] ##STR00154## ##STR00155## [0276] 23. The compound of any one
of embodiments 1-19, wherein R.sub.4 is selected from
[0276] ##STR00156## ##STR00157## [0277] 24. The compound of any one
of embodiments 1-23, wherein R.sub.a is H.
EXEMPLIFICATION
[0278] The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
General Schemes and Procedures for the Preparation of Compounds of
the Invention
[0279] The moiety R.sub.1 and R.sub.2 represents appropriate
substituents; L represents an appropriate linker, and X represents
an appropriate halogen, such as Br, Cl or I, or another leaving
group such as mesylate or tosylate.
##STR00158##
represents an appropriate optionally substituted pyrrolidine.
##STR00159##
represents an appropriate optionally substituted
tetrahydronaphthyridine.
##STR00160##
represents an appropriate optionally substituted naphthyridine.
General Schemes for the Synthesis of .alpha.v.beta.6 Inhibitors
##STR00161##
General Procedures
9-BBN and Suzuki Reactions
##STR00162##
[0281] Alkene intermediates may be cross-coupled to 2-halo
naphthyridines or tetrahydronaphthyridines by the following
procedure. To a solution of alkene (1 equiv.) in dry THF (2-10
mL/mmol) under Ar was added 9-BBN (0.5M solution in THF, 1-2
equiv.). The reaction was stirred at 40-80.degree. C. for 1-4
hours, then cooled to room temperature. This solution was added to
a mixture of 2-halonaphthyridine or Boc-protected
2-halotetrahydronaphthyridine (1-1.5 equiv.), cesium carbonate (2-5
equiv.) and Pd(PPh3)4 or another appropriate Pd/ligand combination
(0.05 to 0.1 equiv.) in 1,4-Dioxane (2-10 mL/mmol). The reaction
was stirred at 80-100.degree. C. for 12-24 hours. Solvent was
removed in vacuo, and the residue was purified by silica gel column
to give the alkyl linked naphthyridine product.
Ring Annulations
##STR00163##
[0283] Naphthyridines may also be made from methyl ketones by the
following procedure. A mixture of methyl ketone (1 equiv.),
2-aminonicotinaldehyde (1-2 equiv.) and secondary amine such as
pyrrolidine or L-proline (1-2 equiv.) in DMF or EtOH (1-10 mL/mmol)
was stirred at 70-100.degree. C. for 2-10 hours. Solvent was
removed in vacuo, and the residue was purified by silica gel column
to give the desired naphthyridine product.
Naphthyridine Reduction
##STR00164##
[0285] Naphthyridines may be reduced to tetrahydronaphthyridines by
the following procedure. A mixture of an appropriate naphthyridine
(1 equiv.) and Pd/C (5-20 weight percent Pd, 0.05 to 0.2 equiv.) in
ethyl acetate or another appropriate solvent (2-10 mL/mmol) was
stirred under Ha balloon at room temperature to 50.degree. C. for
2-20 hours. The reaction was filtered and concentrated in vacuo to
give the desired tetrahydronaphthyridine product.
Boc Deprotection
##STR00165##
[0287] Boc-protected amine (1 equiv.) was treated with HCl (4-100
equiv.) in 1,4-dioxane (1-50 mL/mmol amine) at room temperature to
50.degree. C. for 1-4 hours. The reaction was concentrated in
vacuo, and the amine product was used crude or after purification
by silica gel column. The amine could be used crude as a
dihydrochloride salt or converted to the free base by dissolving in
an appropriate solvent and washing with aqueous NaHCO.sub.3.
Amine Alkylation:
##STR00166##
[0289] A mixture of amine (1 equiv.), alkylating agent (1-1.5
equiv.) and K.sub.2CO.sub.3 or N,N-diisopropylethylamine (2-10
equiv.) in MeCN or DMF (3-10 mL/mmole amine) was stirred at room
temperature to 80.degree. C. for 4-16 hours. The reaction was
concentrated in vacuo, and the residue was purified by silica gel
column to give the desired amino acetic acid ester. The amine used
may be the free base or a salt such hydrochloride or
dihydrochloride. If the reaction is done with a salt of the amine,
additional equivalents of base may be needed.
Saponification:
##STR00167##
[0291] For certain esters such as R.sub.1=Me or ethyl, the ester
may be saponified under basic conditions. The ester (1 equiv.) was
treated with LiOH--H.sub.2O (3-5 equiv.) in MeOH (3-10 mL/mmol
ester) and water (3-10 mL/mmol ester) at room temperature to
50.degree. C. for 1-16 hours. The reaction was concentrated in
vacuo, and the residue was purified by prep HPLC to give the
desired carboxylic acid product.
[0292] For certain esters such as R.sub.1=tert-butyl, the ester may
be saponified under acidic conditions. The ester (1 equiv.) was
treated with 4 N HCl (4-100 equiv.) in 1,4-dioxane (1-25 mL/mmol
ester) at room temperature to 50.degree. C. for 1-16 hours. The
reaction was concentrated in vacuo, and the residue was purified by
prep HPLC to give the desired carboxylic acid product.
Petasis Reaction:
##STR00168##
[0294] As an alternative to the amine alkylation/saponification
sequence, a Petasis reaction can be used to prepare certain aryl
analogs: A mixture of amine (1 equiv.) aryl boronic acid or aryl
boronate ester (1-1.5 equiv.) and 2-oxoacetic acid (1.5-2 equiv.)
in MeCN or DMF (2-10 mL/mmole amine) was stirred at 50-80.degree.
C. for 2-16 hours. The reaction was concentrated in vacuo, and the
residue was purified by prep HPLC to give the desired amino acetic
acid.
Analytical Methods
Prep-HPLC Methods
[0295] Crude samples were dissolved in MeOH and purified by prep
HPLC using a Gilson 215 instrument, detection wavelength 214
nm:
[0296] Prep HPLC A: column: XBridge C18, 21.2*250 mm, 10 .mu.m;
mobile phase: A water (10 mM ammonium hydrogen carbonate), B
CH.sub.3CN; gradient elution as in text; flow rate: 20 mL/min.
[0297] Prep HPLC B: column: XBridge C18, 21.2*250 mm, 10 .mu.m;
mobile phase: A water (10 mM formic acid), B CH.sub.3CN; gradient
elution as in text; flow rate: 20 mL/min.
[0298] Prep HPLC C: column: XBridge OBD C18, 19*100 mm, 5 .mu.m;
mobile phase: A water, B CH.sub.3CN; gradient elution as in text;
flow rate: 20 mL/min.
Prep Chiral SFC Methods
[0299] Racemic products were separated to individual enantiomers by
chiral Prep SFC using an SFC-80 (Thar, Waters) instrument,
detection wavelength 214 nm:
[0300] Prep chiral SFC A: column: (R,R)-Whelk-O1, 20*250 mm, 5
.mu.m (Decial), column temperature: 35.degree. C., mobile phase:
CO2/methanol (0.2% methanol ammonia)=60/40, flow rate: 80 g/min,
back pressure: 100 bar.
[0301] Prep chiral SFC B: column: AD 20*250 mm, 10 .mu.m (Daicel),
column temperature: 35.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia)=60/40, flow
rate: 80 g/min, back pressure: 100 bar.
[0302] Prep chiral SFC C: column: AS 20*250 mm, 10 .mu.m (Daicel),
column temperature: 35.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia)=60/40, flow
rate: 80 g/min, back pressure: 100 bar.
[0303] Prep chiral SFC D: column: OD 20*250 mm, 10 .mu.m (Daicel),
column temperature: 35.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia)=60/40, flow
rate: 80 g/min, back pressure: 100 bar.
[0304] Prep chiral SFC E: column: Cellulose-SC 20*250 mm, 10 .mu.m
(Daicel), column temperature: 35.degree. C., mobile phase:
CO.sub.2/methanol (0.2% methanol ammonia)=60/40, flow rate: 80
g/min, back pressure: 100 bar.
[0305] Prep chiral SFC F: column: OZ 20*250 mm, 10 .mu.m (Daicel),
column temperature: 35.degree. C., mobile phase: CO.sub.2/methanol
(0.2% methanol ammonia)=60/40, flow rate: 80 g/min, back pressure:
100 bar.
[0306] Prep chiral SFC G: column: IC 20*250 mm, 10 .mu.m (Daicel),
column temperature: 35.degree. C., mobile phase: CO.sub.2/methanol
(0.2% methanol ammonia)=60/40, flow rate: 80 g/min, back pressure:
100 bar.
[0307] Prep chiral SFC H: column: (S,S)-Whelk-O1, 20*250 mm, 5
.mu.m (Decial), column temperature: 35.degree. C., mobile phase:
CO.sub.2/methanol (0.2% methanol ammonia)=60/40, flow rate: 80
g/min, back pressure: 100 bar.
Analytical Chiral SFC Methods
[0308] Chiral products were analyzed by chiral SFC using an SFC-80
(Thar, Waters) instrument, detection wavelength 214 nm:
[0309] Chiral SFC A: column: (R,R)-Whelk-O 1, 4.6*100 mm, 5 .mu.m
(Decial), column temperature: 40.degree. C., mobile phase:
CO.sub.2/methanol (0.2% methanol ammonia), isocratic elution as in
text, flow rate: 4 g/min, back pressure: 120 bar.
[0310] Chiral SFC B: column: AD 4.6*100 mm, 5 .mu.m (Daicel),
column temperature: 40.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia), isocratic
elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
[0311] Chiral SFC C: column: AS 4.6*100 mm, 5 .mu.m (Daicel),
column temperature: 40.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia), isocratic
elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
[0312] Chiral SFC D: column: OD 4.6*100 mm, 5 .mu.m (Daicel),
column temperature: 40.degree. C., mobile phase: CO.sub.2/methanol
(0.2% methanol ammonia), isocratic elution as in text, flow rate: 4
g/min, back pressure: 120 bar.
[0313] Chiral SFC E: column: Cellulose-SC 4.6*100 mm, 5 .mu.m
(Daicel), column temperature: 40.degree. C., mobile phase:
CO.sub.2/methanol (0.2% methanol ammonia), isocratic elution as in
text, flow rate: 4 g/min, back pressure: 120 bar.
[0314] Chiral SFC F: column: OZ 4.6*100 mm, 5 .mu.m (Daicel),
column temperature: 40.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia), isocratic
elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
[0315] Chiral SFC G: column: IC 4.6*100 mm, 5 .mu.m (Daicel),
column temperature: 40.degree. C.,
mobile phase: CO.sub.2/methanol (0.2% methanol ammonia), isocratic
elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
[0316] Chiral SFC H: column: (S,S)-Whelk-O1, 4.6*100 mm, 5 .mu.m
(Decial), column temperature: 40.degree. C., mobile phase:
CO.sub.2/methanol (0.2% methanol ammonia), isocratic elution as in
text, flow rate: 4 g/min, back pressure: 120 bar.
[0317] Chiral SFC I: column: IC 4.6*250 mm, 5 .mu.m (SHIMADZU),
column temperature: 40.degree. C.,
mobile phase: n-Hexane (0.1% DEA):EtOH (0.1% DEA), isocratic
elution as in text, flow rate: 1 mL/min.
[0318] Chiral SFC J: column: (S,S)-Whelk-O1 4.6*250 mm, 5 .mu.m
(SHIMADZU), column temperature: 40.degree. C., mobile phase:
n-Hexane (0.1% DEA):EtOH (0.1% DEA), isocratic elution as in text,
flow rate: 1 mL/min.
[0319] Chiral SFC K: column: OZ--H 4.6*250 mm, 5 .mu.m (SHIMADZU),
column temperature: 40.degree. C., mobile phase: n-Hexane (0.1%
DEA):EtOH (0.1% DEA), isocratic elution as in text, flow rate: 1
mL/min.
[0320] Chiral SFC L: column: chiral PAK IG 4.6*250 mm, 5 .mu.m
(SHIMADZU), column temperature: 35.degree. C., mobile phase:
n-Hexane (0.1% DEA):EtOH (0.1% DEA), isocratic elution as in text,
flow rate: 1 mL/min.
[0321] Chiral SFC M: column: EnantioPak OJ 4.6*250 mm, 5 .mu.m
(Decial), column temperature: 40.degree. C., mobile phase: n-Hexane
(0.1% DEA):EtOH (0.1% DEA), isocratic elution as in text, flow
rate: 1 mL/min.
Synthesis of Intermediates
[0322] The following intermediates were prepared according to the
procedures below for use in synthesizing examples:
Preparation of
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride
Step 1: tert-butyl
(R)-3-(4-(2-methyl-1,3-dioxolan-2-yl)butoxy)pyrrolidine-1-carboxylate
##STR00169##
[0324] A mixture of (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (1.09 g, 5.41 mmol),
2-(4-bromobutyl)-2-methyl-1,3-dioxolane (1.2 g, 5.41 mmol) and
sodium hydride (260 mg, 10.82 mmol) in DMF (5 mL) was stirred at
100.degree. C. for 6 h. Solvent was removed in vacuo, and the
residue was purified by silica gel column (pet ether: EtOAc 10:1)
to give the desired product (R)-tert-butyl 3-(4-(2-methyl-1,3-di
oxolan-2-yl)butoxy)pyrrolidine-1-carboxylate as a colorless oil
(380 mg). Yield 21% (ESI 330.2 (M+H)+).
Step 2:
(R)-tert-butyl3-(5-oxohexyloxy)pyrrolidine-1-carboxylate
##STR00170##
[0326] (R)-tert-butyl3-(4-(2-methyl-1,3-di
oxolan-2-yl)butoxy)pyrrolidine-1-carboxylate (1.3 g, 3.95 mmol) was
treated with a solution of HCl/dioxane (4.0 M, 10 mL) at room
temperature for 2 hours. The solvent was removed in vacuo, and the
residue was diluted with acetone (10 mL) and H.sub.2O (1 mL).
Potassium carbonate was added to adjust the pH to 8.about.9,
followed by Boc.sub.2O (1.24 g, 5.69 mmol). The reaction was
stirred at room temperature for 3, then filtered and concentrated
under vacuum. The residue was purified by silica gel column (pet
ether: EtOAc 15:1) to give the desired product
(R)-tert-butyl3-(5-oxohexyloxy)pyrrolidine-1-carboxylate as a
colorless oil (820 mg). Yield 73% (ESI 186 (M-100).sup.+, 230
(M-56).sup.+).
Step 3: (R)-tert-butyl
3-(4-(1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
##STR00171##
[0328] A mixture of
(R)-tert-butyl3-(5-oxohexyloxy)pyrrolidine-1-carboxylate (820 mg,
2.88 mmol), 2-aminonicotinaldehyde (456 mg, 3.77 mmol) and
pyrrolidine (265 mg, 3.77 mmol) in DMF (5 mL) was stirred at
85.degree. C. for 4 h. Solvent was removed in vacuo, and the
residue was purified by silica gel column (DCM:MeOH 15:1) to give
the desired product (R)-tert-butyl
3-(4-(1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate as a
colorless oil (750 mg). Yield 70% (ESI 372.2 (M+H).sup.+).
Step 4:
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthy-
ridine dihydrochloride
##STR00172##
[0330] A mixture of (R)-tert-butyl
3-(4-(1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate (750
mg, 2.02 mmol), Pd/C (10%, 500 mg) in EtOAc (10 mL) was stirred at
60.degree. C. for 6 hours under hydrogen. The reaction was filtered
and concentrated in vacuo. The residue was treated with a solution
of HCl/dioxane (4.0 M, 4 mL) at room temperate for 2 hours, and the
solvent was removed in vacuo to give the desired product
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride as a white solid (600 mg). Yield 96% (ESI 276.2
(M+H)+).
Preparation of
(R)-5-methoxy-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naph-
thyridine dihydrochloride
Step 1: (R)-tert-butyl
3-(4-bromobutoxy)pyrrolidine-1-carboxylate
##STR00173##
[0332] To a solution of tert-butyl
(R)-3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in
n-Heptane (10 mL) was added sodium hydroxide 50% solution in water
(5 mL, 31.2 mmol), tetrabutylammonium bromide (43.0 mg, 0.13 mmol)
and 1,4-dibromobutane (1.595 mL, 13.35 mmol). The mixture was
stirred at 80.degree. C. for 2 hours, then cooled to room
temperature, diluted with water (10 mL) and extracted with diethyl
ether (3.times.10 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated in vacuo. The residue was
purified by silica gel column (pet ether:EtOAc=4:1) to give the
desired product (R)-tert-butyl
3-(4-bromobutoxy)pyrrolidine-1-carboxylate as a colorless oil (686
mg). Yield 80% (ESI 314 (M+H-Boc)+).
Step 2: (R)-tert-butyl
3-(but-3-enyloxy)pyrrolidine-1-carboxylate
##STR00174##
[0334] To a solution of tert-butyl
(R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylate (512 mg, 1.58 mmol)
in THE (10 mL) at 0.degree. C. was added t-BuOK (446 mg, 3.97
mmol). The reaction was stirred at room temperature for 1 hour,
then diluted with water (20 mL) and extracted with diethyl ether
(3.times.20 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated in vacuo to give the desired
product (R)-tert-butyl 3-(but-3-enyloxy)pyrrolidine-1-carboxylate
as a colorless oil (355 mg). Yield 90% (ESI 186 (M+H-Boc)+).
Step 3: (R)-tert-butyl
3-(4-(4-chloro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
##STR00175##
[0336] To a solution of tert-butyl (R)-tert-butyl
3-(but-3-enyloxy)pyrrolidine-1-carboxylate (486 mg, 1.8 mmol) in
THF (dry, 2 mL) under Ar was added 9-BBN (0.5 M solution in THF,
7.2 mL, 3.6 mmol). The reaction was stirred at 50.degree. C. for 2
hours, then cooled to room temperature. This solution was added to
a mixture of 2,4-dichloro-1,8-naphthyridine (360 mg, 1.8 mmol),
cesium carbonate (1730 mg, 5.4 mmol) and Pd(PPh3)4 (208 mg, 0.18
mmol) in 1,4-dioxane (7 mL). The reaction was stirred at 90.degree.
C. for 1.5 hours. Solvent was removed in vacuo, and the residue was
purified by silica gel column (pet ether: EtOAc 1:1 to 1:10) to
give the desired product (R)-tert-butyl
3-(4-(4-chloro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
as a yellow oil (300 mg). Yield 41% (ESI 406 (M+H)+).
Step 4: (R)-tert-butyl
3-(4-(4-methoxy-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
##STR00176##
[0338] To a solution of (R)-tert-butyl
3-(4-(4-chloro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
(76 mg, 0.13 mmol) in MeOH (5 mL) was added NaOMe (45 mg, 0.26
mmol). The reaction was stirred under reflux overnight, then
concentrated in vacuo, diluted with ethyl acetate (30 mL), washed
with water (2.times.20 mL), dried over MgSO4, filtered and
concentrated in vacuo to give the desired product (R)-tert-butyl
3-(4-(4-methoxy-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
as a colorless oil (60 mg). Yield 80% (ESI 402 (M+H)+).
Step 5:
(R)-5-methoxy-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1-
,8-naphthyridine dihydrochloride
##STR00177##
[0340] A mixture of (R)-tert-butyl
3-(4-(4-methoxy-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate
(60 mg, 0.15 mmol) and Pd/C (10%, 30 mg) in EtOAc (10 mL) was
stirred under balloon hydrogen at 30.degree. C. for 17 hours. The
mixture was filtered and concentrated in vacuo. The residue was
treated with 4M HCl in dioxane (3 mL, 12 mmol) at room temperature
for 2 hours. Solvent was removed in vacuo to give the desired
product
(R)-5-methoxy-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naph-
thyridine dihydrochloride as a colorless oil (45 mg). Yield 88%
(ESI 306 (M+H).sup.+).
Preparation of
(R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride
Step 1: (R)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate
##STR00178##
[0342] A solution of PPh3 (5.11 g, 19.5 mmol) and 1H-imidazole
(1.33 g, 19.5 mmol) in DCM (50 mL) was cooled to 0.degree. C., and
then slowly treated with I.sub.2 (4.95 g, 19.5 mmol). After stirred
at 0.degree. C. for 30 mins, a solution of (R)-tert-butyl
3-(hydroxymethyl)pyrrolidine-1-carboxylate in DCM (10 mL) was added
and the reaction was stirred at room temperature overnight. The
reaction was diluted with water (50 mL), extracted with DCM (30
mL*3). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and removed in vacuo. The residue was purified by silica
gel column (pet ether: EtOAc 10:1) to give the desired product
(R)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate as a
colorless oil (3.7 g). Yield 80%. (ESI 256 (M+H-56)+).
Step 2:
(R)-((1-(tert-butoxycarbonyl)_pyrrolidin-3-yl)methyl)triphenylphos-
phonium
##STR00179##
[0344] A solution of (R)-tert-butyl
3-(iodomethyl)pyrrolidine-1-carboxylate (3.7 g, 12 mmol) and PPh3
(4.1 g, 15.5 mmol) in DMF (50 mL) was stirred at room temperature
overnight. Solvent was removed in vacuo, and the residue was
purified by silica gel column (DCM: MeOH 10:1) to give the crude
product. Diethyl ether (30 mL) was added to the crude product and
stirred at r.t for 30 mins, filtered. The filter cake was dried
under vacuum to give the desired product
(R)-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)triphenylphosphonium
as a white solid (5.6 g). Yield 84%. (ESI N/A).
Step 3: ethyl 4-(2-methyl-1,3-dioxolan-2-yl)butanoate
##STR00180##
[0346] A solution of ethyl 5-oxohexanoate (2 g, 13.9 mmol),
ethylene glycol (2.6 g, 42 mmol) and p-Toluene sulfonic acid (478
mg, 2.78 mmol) in toluene (50 mL) was stirred under reflux to
remove water by Dean-stark trap for 6 hours. Solvent was removed in
vacuo, and the residue was purified by silica gel column (pet
ether: EtOAc 10:1) to give the desired product ethyl
4-(2-methyl-1,3-dioxolan-2-yl)butanoate as a colourless oil (1.4 g,
50% yield). (ESI 203 (M+H)+).
Step 4: 4-(2-methyl-1,3-dioxolan-2-yl)butanal
##STR00181##
[0348] To a solution of ethyl
4-(2-methyl-1,3-dioxolan-2-yl)butanoate (500 mg, 2.48 mmol) in DCM
(10 mL) at -78.degree. C. under Ar, was added DIBAL-H (1 M, 3.7 mL,
3.7 mmol) slowly. The reaction was stirred at -78.degree. C. for 30
mins, then 20 mL of water was added, warmed to r.t, extracted with
DCM (20 mL*3). The combined organic layer was dried over Na2SO4,
filtered and concentrated under vacuum. The residue was purified by
silica gel column (pet ether: EtOAc 2:1) to give the desired
product 4-(2-methyl-1,3-dioxolan-2-yl)butanal as a colorless oil
(220 mg). Yield 56%. (ESI 159 (M+H)+).
Step 5: (S)-tert-butyl
3-(5-(2-methyl-1,3-dioxolan-2-yl)pent-1-enyl)pyrrolidine-1-carboxylate
##STR00182##
[0350] To a solution of
(R)-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)triphenylphosphonium
(2.0 g, 3.6 mmol) in DCM (30 mL) at 0.degree. C. under N2, was
added LiHMDS (1 M, 5.4 mL, 5.4 mmol). The mixture was stirred at
0.degree. C. for 30 mins, then
4-(2-methyl-1,3-dioxolan-2-yl)butanal (565 mg, 3.6 mmol) was added.
The reaction was stirred at r.t for 4 hours, then MeOH (20 mL) was
added. Solvent was removed in vacuo, and the residue was purified
by silica gel column (pet ether: EtOAc 3:1) to give the desired
product (S)-tert-butyl
3-(5-(2-methyl-1,3-dioxolan-2-yl)pent-1-enyl)pyrrolidine-1-carboxylate
as a yellow oil (500 mg). Yield 43%. (ESI 226 (M+H-100)+).
Step 6: (R)-tert-butyl 3-(6-oxoheptyl)pyrrolidine-1-carboxylate
##STR00183##
[0352] To a solution of (S)-tert-butyl 3-(5-(2-methyl-1,3-di
oxolan-2-yl)pent-1-enyl)pyrrolidine-1-carboxylate (500 mg, 1.54
mmol) in EtOAc (20 mL), was added Pd/C (10%, 50 mg) and the mixture
was stirred at 40.degree. C. overnight under H2. The reaction was
filtered and the filtrate was concentrated in vacuo. The residue
was treated with TsOH (264 mg, 1.54 mmol) in acetone (5 mL). The
mixture was stirred at r.t for 6 hours, then EtOAc (20 mL) was
added, washed with sat. NaHCO3 solution (20 mL) and brine. The
organic layer was dried over Na2SO4, filtered and concentrated in
vacuo to give the desired product (R)-tert-butyl
3-(6-oxoheptyl)pyrrolidine-1-carboxylate as a yellow oil (200 mg).
Yield 46% (ESI 184 (M+H-100)+).
Step 7: (R)-tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyl)pyrrolidine-1-carboxylate
##STR00184##
[0354] To a solution of (R)-tert-butyl
3-(6-oxoheptyl)pyrrolidine-1-carboxylate (300 mg, 1.06 mmol) in
EtOH (10 mL), was added 2-aminonicotinaldehyde (155 mg, 1.27 mmol)
and pyrrolidine (90 mg, 1.27 mmol). The reaction was heated to
reflux overnight. Solvent was removed in vacuo, and the residue was
purified by silica gel column (DCM:MeOH=20:1) to give the desired
product (R)-tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyl)pyrrolidine-1-carboxylate as a
yellow oil (220 mg). Yield 56%. (ESI 370 (M+H)+).
Step 8:
(R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyri-
dine dihydrochloride
##STR00185##
[0356] To a solution of (R)-tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyl)pyrrolidine-1-carboxylate (220
mg, 0.60 mmol) in EtOAc (10 mL) was added Pd/C (10%, 30 mg). The
mixture was stirred at 40.degree. C. under H2 overnight. The
reaction was filtered and the filtrate was concentrated in vacuo.
The residue was treated with a solution of HCl/dioxane (4.0 M, 5
mL) at room temperate for 2 hours, then the solvent was removed in
vacuo to give the desired product
(R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride as a yellow oil (160 mg). Yield 86%. (ESI 274
(M+H)+).
Preparation of
(R)-7-(3-(pyrrolidin-3-yloxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride
Step 1: 2-(3-bromopropyl)-2-methyl-1,3-dioxolane
##STR00186##
[0358] In a flame dried round-bottomed flask equipped with a
magnetic stir bar and a Dean-Stark trap under N.sub.2, a solution
of 5-bromopentan-2-one (2.0 g, 12.12 mmol) in toluene (40 mL) was
treated with ethylene glycol (6.93 g, 111.7 mmol) and TsOH (384 mg,
0.22 mmol). The reaction mixture was heated to reflux for 1 h,
allowed to cool to room temperature, diluted with saturated aqueous
NaHCO.sub.3 (60 mL) and extracted with ethyl acetate (100 mL). The
organic layer was washed with water (2.times.100 mL), dried over
MgSO4, filtered and concentrated in vacuo. The residue was purified
by silica gel column (pet ether:EtOAc 4:1) to give the desired
product as a colorless oil (1.5 g). Yield 59%.
Step 2: (R)-tert-butyl
3-(3-(2-methyl-1,3-dioxolan-2-yl)propoxy)pyrrolidine-1-carboxylate
##STR00187##
[0360] A mixture of (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (894 mg, 4.78 mmol) and NaH (287
mg, 7.18 mmol) in DMF (10 mL) was stirred at 0.degree. C. for 1
hour. A solution of 2-(3-bromopropyl)-2-methyl-1,3-dioxolane (1 g,
4.78 mmol) in DMF (5 mL) was added dropwise at 0.degree. C., and
the reaction mixture was stirred at 100.degree. C. overnight.
Solvent was removed in vacuo, and the residue was purified by
silica gel column (pet ether:EtOAc 1:1) to give the desired product
as a colorless oil (500 mg). Yield 33% (ESI 216
(M+H-100).sup.+).
Step 3: (R)-tert-butyl
3-(4-oxopentyloxy)pyrrolidine-1-carboxylate
##STR00188##
[0362] A mixture of (R)-tert-butyl
3-(3-(2-methyl-1,3-dioxolan-2-yl)propoxy)pyrrolidine-1-carboxylate
(500 mg, 1.59 mmol) and p-toluenesulfonic acid monohydrate (151 mg
0.79 mmol) in acetone (10 mL) and H2O (5 mL) was stirred at room
temperature for 4 hours. The reaction was diluted with H2O (10 mL)
and extracted with EtOAc (3.times.10 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated in vacuo
to give the desired product as a colorless oil (380 mg). Yield 88%
(ESI 172 (M+H-100).sup.+).
Step 4: (R)-tert-butyl 3-(3-(1,8-naphthyridin-2
yl)propoxy)pyrrolidine-1-carboxylate
##STR00189##
[0364] A mixture of (R)-tert-butyl
3-(4-oxopentyloxy)pyrrolidine-1-carboxylate (380 mg, 1.40 mmol),
2-aminonicotinaldehyde (171 mg, 1.40 mmol) and pyrrolidine (99 mg,
1.40 mmol) in ethanol (8 mL) was refluxed overnight. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(DCM:MeOH 40:1) to give the desired product as a colorless oil (310
mg). Yield 62% (ESI 358 (M+H)+).
Step 5:
(R)-7-(3-(pyrrolidin-3-yloxy)propyl)-1,2,3,4-tetrahydro-1,8-naphth-
yridine dihydrochloride
##STR00190##
[0366] A mixture of (R)-tert-butyl
3-(3-(1,8-naphthyridin-2-yl)propoxy)pyrrolidine-1-carboxylate (310
mg, 0.87 mmol) and Pd/C (10%, 30 mg) in EtOAc (30 mL) was stirred
under balloon hydrogen at room temperature for 16 hours. The
mixture was filtered and concentrated in vacuo. The residue was
treated with HCl in 1,4-dioxane (4M, 5 mL) at 25.degree. C. for 2
hours. Solvent was removed in vacuo to give
(R)-7-(3-(pyrrolidin-3-yloxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride as a colorless oil (240 mg). Yield 83% (ESI 262
(M+H)+).
Preparation of
(R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride
Step 1: 2-(5-bromopentyl)-2-methyl-1,3-dioxolane
##STR00191##
[0368] To a solution of 7-bromoheptan-2-one (14 g, 73 mmol) in
toluene (150 mL) in a three-necked flask equipped with Dean-Stark
trap was added ethane-1,2-diol (15 g, 255 mmol) and
p-toluenesulfonic acid (251 mg, 1.46 mmol). The reaction mixture
was stirred at reflux for 20 h. The reaction mixture was cooled to
room temperature and washed with sat NaHCO.sub.3 solution, water
and brine. The organic phase was concentrated, and the residue was
separated by silica gel column (7% EtOAc in petroleum ether) to
give 2-(5-bromopentyl)-2-methyl-1,3-dioxolane (16 g, 92%).
Step 2: (R)-tert-butyl
3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate
##STR00192##
[0370] To a solution of (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (3.5 g, 18.7 mmol) in DMF (25
mL) was added NaH (830 mg, 20.6 mmol) in portions at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 1 h.
2-(5-bromopentyl)-2-methyl-1,3-dioxolane (4.9 g, 20.6 mmol) was
added and the reaction mixture was stirred at 100.degree. C. for 16
h. The reaction mixture was poured into ice water and extracted
with EtOAc (150 mL.times.3). The combined organic phase was washed
with brine, dried over Na.sub.2SO.sub.4. The organic phase was
concentrated, and the residue was chromatographed on silica gel
(20% EtOAc in pet. Ether) to give the product (R)-tert-butyl 3
(5-(2-methyl-1,3-di oxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate
as yellow oil (3.7 g, 57%); (ESI 344.3 (M+H)+).
Step 3: (R)-tert-butyl
3-(6-oxoheptyloxy)pyrrolidine-1-carboxylate
##STR00193##
[0372] To a solution of (R)-tert-butyl
3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate
(3.7 g, 10.8 mmol) in acetone (70 mL) and water (7 mL) was added
p-toluenesulfonic acid (927 mg, 5.4 mmol). The reaction mixture was
stirred at room temperature for 16 h. The reaction mixture was
neutralized with saturated aqueous NaHCO.sub.3 solution and
concentrated under reduced pressure. The residue was extracted with
EtOAc (100 mL.times.3). The combined organic phase was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated to give the
product (R)-tert-butyl 3-(6-oxoheptyloxy)pyrrolidine-1-carboxylate
as yellow oil (2.99 g, 92%); (ESI 300.1 (M+H).sup.+).
Step 4: (R)-tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyloxy)pyrrolidine-1-carboxylate
##STR00194##
[0374] To a solution of (R)-tert-butyl
3-(6-oxoheptyloxy)pyrrolidine-1-carboxylate (2.9 g, 9.7 mmol) in
EtOH (40 mL) was added 2-aminonicotinaldehyde (1.2 g, 9.7 mmol) and
L-proline (558 mg, 4.8 mmol). The reaction mixture was stirred at
reflux for 16 h. Then the reaction mixture was concentrated, and
the residue was separated by silica gel column (5% MeOH in EtOAc)
to give (R)-tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyloxy)pyrrolidine-1-carboxylate as
a yellow solid (2.4 g, 64%); (95% purity, UV=214 nm, ESI 386.0
(M+H).sup.+).
Step 5: (R)-tert-butyl
3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)pyrrolidine-1-ca-
rboxylate
##STR00195##
[0376] To a solution of (R)-tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyloxy)pyrrolidine-1-carboxylate
(2.4 g, 6.2 mmol) in EtOH (30 mL) was added Pd/C (10%, 300 mg). The
reaction mixture was degassed and purged with H.sub.2 for 3 times
and stirred at 45.degree. C. under H.sub.2 for 20 h. The reaction
mixture was filtered and the filtrate was concentrated to give
(R)-tert-butyl
3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)pyrrolidine-1-ca-
rboxylate as a yellow oil (2.5 g, 100%); (ESI 390.5 (M+H)+).
Step 6:
(R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphth-
yridine dihydrochloride
##STR00196##
[0378] To a solution of (R)-tert-butyl
3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)pyrrolidine-1-ca-
rboxylate (2.4 g, 6.2 mmol) in DCM (10 mL) was added
HCl/1,4-dioxane (4 mol/L, 30 mL). The reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was concentrated
to give
(R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride as a yellow oil (2.9 g, 100%); (ESI 290.4
(M-55).sup.+).
Preparation of
7-(5-(3-fluoropyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e dihydrochloride
Step 1: tert-butyl
3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate
##STR00197##
[0380] To a mixture of ((4-bromobutoxy)methyl)benzene (9.45 g,
38.87 mmol) and Mg (1.89 g, 77.74 mmol) in Et.sub.2O (20 mL) was
added I.sub.2 (202 mg, 1.09 mmol). The reaction mixture was stirred
at 40.degree. C. for 1 h. After cooled to room temperature, the
mixture was added to a solution of tert-butyl
3-oxopyrrolidine-1-carboxylate (2.4 g, 12.96 mmol) in 30 mL of
Et.sub.2O at 5.degree. C. The reaction was stirred at room
temperature overnight, then quenched with aq. NH.sub.4Cl (10 mL)
and extracted with EtOAc (30 mL.times.3). The combined organic
layer was dried over sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by silica gel column (pet
ether:EtOAc 5:12:1) to give the desired product tert-butyl
3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate as a
yellow oil (1.7 g). Yield 38% (ESI 294 (M+H-56).sup.+).
Step 2: tert-butyl
3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate
##STR00198##
[0382] A mixture of tert-butyl
3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylates (1.7 g,
4.86 mmol) and BAST (10.76 g, 48.6 mmol) in DCM (30 mL) was stirred
at 40.degree. C. for 24 h. The reaction was diluted with MeOH (2
mL), washed with water (20 mL), dried over sodium sulfate, filtered
and concentrated in vacuo. The residue was purified by silica gel
column (pet ether:EtOAc 20:1.about.10:1) to give the desired
product tert-butyl
3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate as a light
yellow oil (1.1 g). Yield 64% (ESI 296 (M+H-56).sup.+).
Step 3: (tert-butyl
3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate
##STR00199##
[0384] A mixture of tert-butyl
3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate (1.1 g,
3.13 mmol) and Pd/C (5%, 1.1 g) in EtOAc (100 mL) was stirred under
hydrogen at 45.degree. C. overnight. The mixture was filtered and
concentrated in vacuo to give the desired product tert-butyl
3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate as a light
yellow oil (780 mg). Yield 95% (ESI 206 (M+H-56).sup.+).
Step 4: tert-butyl
3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate
##STR00200##
[0386] To a solution of triphenylphosphine (1.58 g, 6.04 mmol) and
imidazole (411 mg, 6.04 mmol) in DCM (40 mL) at 5.degree. C. was
added I.sub.2 (835 mg, 3.29 mmol). The reaction mixture was stirred
at 5.degree. C. for 15 min, and then a solution of (tert-butyl
3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate (780 mg, 2.99
mmol) in DCM (15 mL) was added. The reaction mixture was stirred at
5.degree. C. for 1 h, then concentrated in vacuo at 15.degree. C.,
and the residue was purified by silica gel column (pet ether:EtOAc
20:1.about.10:1) to give the desired product tert-butyl
3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate as a light yellow
oil (700 mg). Yield 63% (ESI 316 (M+H-56).sup.+).
Step 5: tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate
##STR00201##
[0388] To a solution of (R)-tert-butyl
3-(1,1-difluoro-4-iodobutyl)pyrrolidine-1-carboxylate (700 mg, 1.88
mmol) and 2-methyl-1,8-naphthyridine (407 mg, 2.82 mmol) in THE (12
mL) at 0.degree. C. was added LiHMDS (2.82 mL, 1M, 2.82 mmol). The
reaction mixture was stirred at 0.degree. C. for 3 h, then quenched
with saturated ammonium chloride solution (6 mL), diluted with
water (15 mL) and extracted with EtOAc (30 mL.times.2). The
combined organic layers were dried over sodium sulfate, filtered
and concentrated in vacuo. The residue was purified by prep-TLC to
give the desired product tert-butyl
3-(5-(1,8-naphthyridin-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate
as a light yellow solid (350 mg). Yield 48% (ESI 388
(M+H).sup.+).
Step 6:
7-(5-(3-fluoropyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-napht-
hyridine dihydrochloride
##STR00202##
[0390] A mixture of
3-(5-(1,8-naphthyridin-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate
(200 mg, 0.516 mmol) and Pd/C (5%, 200 mg) in EtOAc (20 mL) under
hydrogen was stirred at 45.degree. C. overnight. The reaction
mixture was filtered and concentrated in vacuo. To the residue was
added 1,4-dioxane (2 mL) and HCl/dioxane (2 mL, 4M) at room
temperature. The reaction mixture was stirred at room temperature
for 3 h, then concentrated in vacuo to give the desired product
7-(5-(3-fluoropyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e dihydrochloride as a light yellow solid (140 mg). Yield 93% (ESI
292 (M+H).sup.+).
Preparation of
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e dihydrochloride
Step 1: Tert-butyl
(R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate
##STR00203##
[0392] To a suspension of tert-butyl
(R)-3-hydroxypyrrolidine-1-carboxylate (12.8 g, 68.4 mmol),
tetrabutylammonium bromide (1.102 g, 3.42 mmol) and
6-bromo-1-hexene (13.71 mL, 103 mmol) in heptane (256 mL) was added
sodium hydroxide (128 mL, 68.4 mmol, 50 wt % solution in water).
The mixture was vigourously stirred at 80.degree. C. for 2 hours,
then cooled to room temperature, diluted with water and extracted
with heptane and twice with diethyl ether/heptane. The combined
organic layers were washed with brine, dried over sodium sulfate
and concentrated in vacuo. Purification by column chromatography
(600 g silica, 5->14% ethyl acetate in heptane) afforded the
desired product tert-butyl
(R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate (14.93 g). Yield
81%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.5.87-5.74 (m, 1H),
5.05-4.91 (m, 2H), 4.04-3.95 (m, 1H), 3.48-3.27 (m, 6H), 2.07 (q,
J=7.2 Hz, 2H), 2.02-1.84 (m, 2H), 1.60-1.51 (m, 2H), 1.51-1.38 (m,
11H).
Step 2: tert-butyl
(R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate
##STR00204##
[0394] To a solution of tert-butyl
(R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate (14.93 g, 55.4
mmol) in THE (420 mL) and water (140 mL) was added sodium periodate
(26.1 g, 122 mmol) and osmium tetroxide (1.5 mL, 0.232 mmol, 4%
solution in water). After 1 hour, additional sodium periodate (5 g,
23.38 mmol) was added. After 30 minutes, the mixture was diluted
with water and extracted three times with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated in vacuo. The residue was purified by
flash column chromatography (.about.600 g silica, 20->50% ethyl
acetate in heptane). This afforded the desired product tert-butyl
(R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (10.97 g). Yield
72%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 9.77 (s, 1H),
4.03-3.94 (m, 1H), 3.50-3.27 (m, 6H), 2.47 (t, J=7.2 Hz, 2H),
2.02-1.84 (m, 2H), 1.77-1.65 (m, 2H), 1.65-1.54 (m, 2H), 1.46 (s,
9H).
Step 3: tert-butyl
(3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate
##STR00205##
[0396] To a solution of tert-butyl
(R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (10.97 g, 40.4
mmol) in THF (70 mL) at 0.degree. C. was added dropwise
vinylmagnesium bromide (66.4 mL, 46.5 mmol, 0.7 M solution in THF).
After 16 hours, the mixture was quenched with aqueous saturated
ammonium chloride and extracted with ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate and
concentrated, and the residue was purified by flash column
chromatography (20->50% EtOAc in heptane) to give the desired
product tert-butyl
(3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate
(7.68 g). Yield 63%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
5.93-5.80 (m, 1H), 5.28-5.17 (m, 1H), 5.15-5.06 (m, 1H), 4.17-4.05
(m, 1H), 3.99 (s, 1H), 3.52-3.23 (m, 6H), 2.03-1.83 (m, 2H),
1.65-1.50 (m, 5H), 1.50-1.33 (m, 11H).
Step 4: tert-butyl
(R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylat-
e
##STR00206##
[0398] Tert-butyl
(3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate
(10.48 g, 35.0 mmol), 2-chloro-3-iodopyridine (4.19 g, 17.50 mmol),
tetrabutylammonium chloride (0.486 g, 1.750 mmol) and sodium
hydrogencarbonate (3.68 g, 43.8 mmol) were dissolved/suspended
under argon in DMF (35 mL), and argon was bubbled through this
mixture for 15 minutes. Palladium(II) acetate (0.393 g, 1.750 mmol)
was added, and the mixture was heated to 50.degree. C. for 24
hours, then cooled to room temperature, diluted with water and
extracted three times with ethyl acetate. The combined organic
layers were washed three times with brine, dried over sodium
sulfate and concentrated, and the residue was purified by column
chromatography (silica, 20->55% EtOAc in heptane) to afford the
desired product tert-butyl
(R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylat-
e (3.05 g). Yield 42%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
8.25 (dd, J=4.7, 1.9 Hz, 1H), 7.62 (dd, J=7.5, 1.9 Hz, 1H), 7.17
(dd, J=7.5, 4.7 Hz, 1H), 4.04-3.93 (m, 1H), 3.51-3.25 (m, 6H), 2.99
(t, J=7.3 Hz, 2H), 2.79 (t, J=7.3 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H),
2.01-1.83 (m, 2H), 1.72-1.48 (m, 4H), 1.30 (s, 9H).
Step 5: tert-butyl
(R)-3-((5-(((R)-tert-butylsulfinyl)imino)-7-(2-chloropyridin-3-yl)heptyl)-
oxy)pyrrolidine-1-carboxylate
##STR00207##
[0400] To a solution of (R)-(+)-2-methyl-2-propanesulfinamide
(1.799 g, 14.84 mmol) and tert-butyl
(R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylat-
e (3.05 g, 7.42 mmol) in THE (30 mL) was added titanium(IV)
ethoxide (7.24 mL, 22.27 mmol). The resulting mixture was heated to
50.degree. C. for 20 hours, then poured out on half-saturated
aqueous sodium hydrogencarbonate, stirred for 10 minutes,
transferred to 2 centrifuge vials and centrifuged for 5 min at 7800
rpm. The liquids were decanted into a separation funnel. The vials
were then filled with ethyl acetate, shaken vigorously and
centrifuged again for 5 minutes at 7800 rpm. The liquids were
combined in the separation funnel. The layers were separated, and
the aqueous phase was extracted once more with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated, and the residue was purified by flash
column chromatography (300 g silica, 35-65% EtOAc in heptane) to
afford the desired product tert-butyl
(R)-3-((5-(((R)-tert-butylsulfinyl)imino)-7-(2-chloropyridin-3-yl)heptyl)-
oxy)pyrrolidine-1-carboxylate (3.15 g). Yield 78% (ESI 514/516
(M+H)+). .sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.27 (dd,
J=4.7, 1.9 Hz, 1H), 7.64 (dd, J=62.5, 7.4 Hz, 1H), 7.19 (dd, J=7.5,
4.8 Hz, 1H), 3.99 (s, 1H), 3.54-3.24 (m, 6H), 3.16-2.87 (m, 2H),
2.87-2.60 (m, 2H), 2.60-2.35 (m, 1H), 1.94 (s, 2H), 1.77-1.53 (m,
5H), 1.45 (s, 9H), 1.35-1.11 (m, 9H).
Step 6: tert-butyl
(3R)-3-((5-(((R)-tert-butylsulfinyl)amino)-7-(2-chloropyridin-3-yl)heptyl-
)oxy)pyrrolidine-1-carboxylate
##STR00208##
[0402] To a solution of tert-butyl
(R)-3-((5-(((R)-tert-butylsulfinyl)imino)-7-(2-chloropyridin-3-yl)heptyl)-
oxy)pyrrolidine-1-carboxylate (3.15 g, 6.13 mmol) in methanol (20
mL) was added sodium borohydride (0.278 g, 7.35 mmol). After 2
hours, the mixture was quenched with saturated aqueous ammonium
chloride and extracted three times with ethyl acetate. The combined
organic layers were washed with brine, dried over sodium sulfate
and concentrated, and the residue was purified by flash column
chromatography (50->100% EtOAc in heptane) afford the desired
product tert-butyl (3R)-3-((5-(((R)-tert-butyl
sulfinyl)amino)-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxyl-
ate (3.05 g). Yield 85%. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 8.28-8.22 (m, 1H), 7.72-7.51 (m, 1H), 7.22-7.15 (m, 1H),
4.03-3.95 (m, 1H), 3.49-3.22 (m, 7H), 3.16-3.06 (m, 1H), 2.96-2.64
(m, 2H), 2.00-1.83 (m, 4H), 1.80-1.70 (m, 1H), 1.65-1.51 (m, 3H),
1.51-1.37 (m, 11H), 1.25 (s, 9H).
Step 7: tert-butyl
(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
-2-yl)butoxy)pyrrolidine-1-carboxylate
##STR00209##
[0404] To a solution of tert-butyl
(3R)-3-((5-(((R)-tert-butylsulfinyl)amino)-7-(2-chloropyridin-3-yl)heptyl-
)oxy)pyrrolidine-1-carboxylate (3.05 g, 5.20 mmol) in 1,4-dioxane
(25 mL) was added Xantphos (0.602 g, 1.040 mmol) and cesium
carbonate (3.39 g, 10.40 mmol). The mixture was bubbled through
with argon for 15 minutes. Palladium(II) acetate (0.117 g, 0.520
mmol) was added, and the reaction was bubbled through with argon
for 1 minute and stirred at 100.degree. C. for 16 hours, then
cooled to room temperature, quenched with water and extracted three
times with ethyl acetate. The combined organic layers were washed
with brine, dried over sodium sulfate and concentrated, and the
residue was purified by flash column chromatography (40->100%
EtOAc in heptane) to afford the desired product tert-butyl
(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
-2-yl)butoxy)pyrrolidine-1-carboxylate (928 mg). Yield 36% (ESI 480
(M+H)+). The compound was separated by chiral SFC to give
stereoisomer A and stereoisomer B. Apparatus: Waters Prep 100 SFC
UV directed system; Waters 2998 Photodiode Array (PDA) Detector;
Waters 2767 Sample Manager; Masslynx.TM. Software; FractionLynx.TM.
Application Manager, Acq. Method: Cell-2_f70_10_50_8mn_SW_120 bar,
Loading: 50 mg, Column: Phenomenex Lux Cellulose-2 (250.times.21.2
mm, 5 .mu.m), Flow: 70 mL/min, Column temp: 35.degree. C.; ABPR:
120 bar; Eluent A: CO.sub.2, Eluent B: 20 mM ammonia in methanol,
Linear gradient: t=0 min 10% B, t=5 min 50% B, t=7.5 min 50% B, t=8
min 10% B. Injection: Sandwich 100 .mu.l methanol, Detection PDA:
210-320 nm, Collection: Based on PDA TIC.
tert-butyl (3R)-3-(4-(1-((R)-tert-butyl
sulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-c-
arboxylate stereoisomer A: 0.58 grams, LC/MS ESI 480 (M+H)+.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.06-7.98 (m, 1H),
7.37-7.29 (m, 1H), 6.73-6.63 (m, 1H), 4.20-4.09 (m, 1H), 4.03-3.93
(m, 1H), 3.50-3.25 (m, 6H), 2.94-2.79 (m, 1H), 2.77-2.65 (m, 1H),
2.20-2.08 (m, 1H), 2.00-1.49 (m, 7H), 1.46 (s, 9H), 1.43-1.27 (m,
2H), 1.21 (s, 9H). tert-butyl (3R)-3-(4-(1-((R)-tert-butyl
sulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-c-
arboxylate stereoisomer B: 0.45 grams, LC/MS ESI 480 (M+H)+.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.20-8.09 (m, 1H),
7.39-7.31 (m, 1H), 6.90-6.80 (m, 1H), 4.25-4.12 (m, 1H), 4.04-3.92
(m, 1H), 3.51-3.24 (m, 6H), 2.87-2.62 (m, 2H), 2.11-1.83 (m, 3H),
1.76-1.49 (m, 6H), 1.46 (s, 9H), 1.40-1.27 (m, 10H).
Step 8:
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-napht-
hyridine stereoisomer A dihydrochloride
##STR00210##
[0406] To a solution of tert-butyl (3R)-3-(4-(1-((R)-tert-butyl
sulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-c-
arboxylate stereoisomer A (0.58 g, 1.209 mmol) in methanol (5 mL)
was added hydrochloric acid (5 mL, 20.00 mmol, 4N solution in
dioxane). The mixture was stirred at room temperature for 3 hours,
then concentrated in vacuo and coevaporated with methanol. Diethyl
ether was added which started a slow crystallisation of the
product. After standing overnight the crystallised material was
scratched loose, and the material was triturated with diethyl
ether. After a few hours the solids were collected by filtration,
rinsed with fresh diethyl ether and dried under vacuum to afford
the desired product
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e stereoisomer A dihydrochloride (438 mg) as a beige solid. Yield
100%. LC/MS ESI 276 (M-2HCl+H)+. .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.75-7.66 (m, 2H), 6.80 (t, J=6.8 Hz, 1H), 4.30-4.23 (m,
1H), 3.67-3.56 (m, 1H), 3.56-3.44 (m, 2H), 3.44-3.33 (m, 3H), 3.25
(dd, J=12.5, 4.2 Hz, 1H), 2.96-2.78 (m, 2H), 2.26-2.16 (m, 1H),
2.13-1.99 (m, 2H), 1.77-1.46 (m, 7H), 1.23-1.12 (m, 1H). Specific
Optical Rotation: 33.9.degree. c.=0.5, MeOH, 22.7.degree. C., 589
nm.
Step 9:
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-napht-
hyridine stereoisomer B dihydrochloride
##STR00211##
[0408] To a solution of tert-butyl (3R)-3-(4-(1-((R)-tert-butyl
sulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-c-
arboxylate stereoisomer B (0.45 g, 0.938 mmol) in methanol (5 mL)
was added hydrochloric acid (5 mL, 20.00 mmol, 4N solution in
dioxane). The mixture was stirred at room temperature for 3 hours,
then concentrated in vacuo and coevaporated with methanol. Diethyl
ether was added which started a slow crystallisation of the
product. After standing overnight the crystallised material was
scratched loose, and the material was triturated with diethyl
ether. After a few hours, the solids were collected by filtration,
rinsed with fresh diethyl ether and dried under vacuum to afford
the desired product
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e stereoisomer B dihydrochloride (289 mg) as a beige solid. Yield
85%. LC/MS ESI 276 (M-2HCl+H)+. .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.74-7.66 (m, 2H), 6.80 (t, J=6.8 Hz, 1H), 4.30-4.23 (m,
1H), 3.66-3.57 (m, 1H), 3.57-3.45 (m, 2H), 3.45-3.33 (m, 3H),
3.29-3.21 (m, 1H), 2.96-2.78 (m, 2H), 2.26-2.16 (m, 1H), 2.13-1.97
(m, 2H), 1.76-1.44 (m, 7H). Specific Optical Rotation:
-48.3.degree. c.=0.5, MeOH, 22.7.degree. C., 589 nm.
[0409] The following methods were used to prepare compounds
1-21:
Example 1: Preparation of
2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 1-E1 and
1-E2)
Step 1: ethyl 2-(2-cyclopropylphenyl)acetate
##STR00212##
[0411] A mixture of ethyl 2-(2-bromophenyl)acetate (5.0 g, 20.57
mmol), cyclopropylboronic acid (3.54 g, 41.14 mmol), Pd(OAc).sub.2
(922 mg, 4.12 mmol), tricyclohexylphosphine (1.73 g, 6.17 mmol) and
tripotassium phosphate (15.3 g, 72.01 mmol) in toluene (60 mL) and
water (7.5 mL) was stirred at 120.degree. C. overnight. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(pet ether: EtOAc 20:1) to give the desired product ethyl
2-(2-cyclopropylphenyl) acetate as a colorless oil (4.0 g). Yield
95%. .sup.1H NMR (400 MHz, CDCl3) .delta.7.21-7.18 (m, 4H),
4.18-4.16 (q, 2H), 3.83 (s, 2H), 1.52-1.48 (m, 1H), 1.29-1.18 (t,
3H), 0.94-0.64 (m, 4H).
Step 2: ethyl 2-bromo-2-(2-cyclopropylphenyl)acetate
##STR00213##
[0413] To a solution of ethyl 2-(2-cyclopropylphenyl) acetate (1 g,
4.9 mmol) in THE (16 mL) at -78.degree. C. was added lithium
diisopropylamide solution 2.0 M in THF/hexanes (6.2 mL, 12.4 mmol)
dropwise. The reaction was stirred at -78.degree. C. for 30 min.
Then a solution of chlorotrimethylsilane (1.3 g, 12.25 mmol) in THF
(5 mL) was added, and the reaction was stirred at -78.degree. C.
for another 30 min. Then a solution of NB (1.5 g, 12.25 mmol) in
THF (10 mL) was added and the reaction was stirred at -78.degree.
C. for 1 hour. The reaction was quenched with MeOH (2 mL) and
concentrated in vacuo, and the residue was purified by silica gel
column (pet ether: EtOAc 10:1) to give the desired product ethyl
2-bromo-2-(2-cyclopropylphenyl)acetate as a yellow oil (350 mg).
Yield 25%.
Step 3: ethyl
2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00214##
[0415] A mixture of ethyl 2-bromo-2-(2-cyclopropylphenyl)acetate
(350 mg, 1.24 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(341 mg, 1.24 mmol) and K.sub.2CO.sub.3 (513 mg, 3.72 mmol) in
acetonitrile (8 mL) was stirred 60.degree. C. for 16 h. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(DCM: MeOH 20:1) to give the desired product ethyl
2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)butoxy)pyrrolidin-1-yl)acetate as a yellow oil (150 mg). Yield
25% (ESI 478 (M+H)+).
Step 4:
2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 1-E1 and
1-E2)
##STR00215##
[0417] Ethyl
2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)butoxy)pyrrolidin-1-yl)acetate (150 mg, 0.31 mmol) was treated
with LiOH--H2O (52 mg, 1.24 mmol) in MeOH (4 mL) and H2O (1 mL) at
60.degree. C. for 2 hours. Solvent was removed in vacuo, and the
residue was purified by Prep-HPLC A (30-65% MeCN) to give compound
1 as a white solid (110 mg, 77% yield). The racemic product was
separated by Prep chiral SFC A to give diastereomeric products
compound 1-E1 (25 mg) and compound 1-E2 (26 mg) as white
solids.
[0418] Compound 1-E1 LC/MS ESI 450.6 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 7.60 (d, J=7.6 Hz, 1H), 7.28 (m, 2H), 7.15 (d, J=7.3 Hz,
2H), 6.37 (d, J=7.3 Hz, 1H), 5.31 (s, 1H), 4.21 (s, 1H), 3.72-3.32
(m, 6H), 3.24-3.02 (m, 2H), 2.71 (t, J=6.3 Hz, 2H), 2.54 (t, J=7.5
Hz, 2H), 2.31-1.95 (m, 3H), 1.94-1.79 (m, 2H), 1.77-1.66 (m, 2H),
1.58 (m, 2H), 1.05-0.87 (m, 3H), 0.67-0.38 (m, 1H). Chiral SFC A
(45% MeOH): ee 98%, Rt=1.97 min
[0419] Compound 1-E2 LC/MS ESI 450.6 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 7.60 (d, J=7.6 Hz, 1H), 7.28 (m, 2H), 7.15 (d, J=7.3 Hz,
2H), 6.37 (d, J=7.3 Hz, 1H), 5.31 (s, 1H), 4.21 (s, 1H), 3.72-3.32
(m, 6H), 3.24-3.02 (m, 2H), 2.71 (t, J=6.3 Hz, 2H), 2.54 (t, J=7.5
Hz, 2H), 2.31-1.95 (m, 3H), 1.94-1.79 (m, 2H), 1.77-1.66 (m, 2H),
1.58 (m, 2H), 1.05-0.87 (m, 3H), 0.67-0.38 (m, 1H). Chiral SFC A
(45% MeOH): ee 98%, Rt=2.59 min
Example 2: Preparation of
2-(2-cyclopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-
-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 2-E1 and
2-E2)
Step 1: 1-bromo-2-cyclopropoxybenzene
##STR00216##
[0421] A mixture of 2-bromophenol (2.0 g, 11.6 mmol),
bromocyclopropane (4.6 g, 38.1 mmol) and K2CO3 (5.2 g, 38.1 mmol)
in dry DMF (10 mL) was sealed in a tube and heated by microwave at
140.degree. C. for 2 hours. The reaction mixture was cooled to room
temperature, diluted with water and extracted with diethyl ether
(3.times.100 mL). The combined organic layer was washed with brine
and concentrated in vacuo. The residue was purified by silica gel
column (eluting with 0-10 percent EtOAc/hexanes) to afford the
desired product as colorless oil (400 mg). Yield 17% 1H NMR (400
MHz, CDCL3) .delta. 7.52 (d, J=7.2 Hz, 1H), 7.30-7.27 (m, 2H),
6.88-6.84 (m, 1H), 3.83-3.80 (m, 1H), 0.90-0.82 (m, 4H).
Step 2: 2-cyclopropoxyphenylboronic Acid
##STR00217##
[0423] To a solution of 1-bromo-2-cyclopropoxybenzene (800 mg, 3.75
mmol) in THF (20 mL) was added n-BuLi (2.5M, 4.5 mmol) dropwise.
The reaction was stirred for 1 h at -78.degree. C. under Ar. A
solution of trimethyl borate (779 mg, 7.5 mmol) in THF (5 mL) was
added dropwise, and the reaction stirred for another 1 hour at
-78.degree. C., then slowly warmed to room temperature and stirred
overnight. Aqueous HCl (1N, 20 mL) was added, and the reaction was
stirred at room temperature for 30 min, then extracted with DCM
(3.times.20 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column (pet ether:EtOAc=1:1) to give the
desired product as a white solid (400 mg). Yield: 60% (ESI: 178
[M-H]-).
Step 3:
2-(2-cyclopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 2-E1 and
2-E2)
##STR00218##
[0425] A mixture of 2-cyclopropoxyphenylboronic acid (400 mg, 2.25
mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(476 mg, 1.73 mmol) and 2-oxoacetic acid (304 mg 3.45 mmol) in DCM
(5 mL) was stirred at room temperature for 8 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 2 as a white solid (205 mg, 26%
yield). The racemic product was separated by Prep chiral SFC A to
give diastereomeric products compound 2-E1 (110 mg) and compound
2-E2 (79 mg) as white solids.
[0426] Compound 2-E1 LC/MS ESI 466 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.48 (d, J=7.6 Hz, 1H), 7.41-7.40 (m, 2H), 7.13 (d, J=7.6
Hz, 1H), 7.04-7.00 (m, 1H), 6.38 (d, J=7.6 Hz, 1H), 4.92 (s, 1H),
4.18-4.16 (m, 1H), 3.90-3.85 (m, 1H), 3.56-3.36 (m, 5H), 3.27-3.01
(m, 3H), 2.70 (t, J=6.0 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.09-1.55
(m, 8H), 0.85-0.70 (m, 4H). Chiral SFC A (40% MeOH): ee 85.4%,
Rt=2.39 min
[0427] Compound 2-E2 LC/MS ESI 466 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.52 (d, J=7.6 Hz, 1H), 7.41-7.40 (m, 2H), 7.13 (d, J=7.2
Hz, 1H), 7.03-6.99 (m, 1H), 6.37 (d, J=7.2 Hz, 1H), 4.86 (s, 1H),
4.15-4.12 (m, 1H), 3.92-3.75 (m, 1H), 3.56-3.36 (m, 5H), 3.27-3.14
(m, 3H), 2.70 (t, J=6.0 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.20-1.55
(m, 8H), 0.85-0.70 (m, 4H). Chiral SFC A (40% MeOH): ee 95.4%,
Rt=3.27 min
Example 3: Preparation of
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compounds 3-E1 and
3-E2)
Step 1: 3-bromo-2-cyclopropylpyridine
##STR00219##
[0429] To a solution of 2,3-dibromopyridine (3 g, 12.8 mmol) and
cyclopropylzinc(II) bromide (76 mL, 0.5 M in THF) in THF (30 mL)
was added Pd(PPh3)4 (740 mg, 0.64 mmol). The mixture was stirred at
70.degree. C. under N2 for 4 hours, then diluted with water (50 mL)
and extracted with EtOAc (3.times.50 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column (pet ether: EtOAc
10:1) to give the desired product 3-bromo-2-cyclopropylpyridine as
a yellow oil (1.2 g). Yield 48% (ESI 198 (M+H)+).
Step 2: ethyl 2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate
##STR00220##
[0431] To a solution of EtMgBr (1 M, 3.65 mL, 3.65 mmol) in THF (20
mL) at 0.degree. C. under N.sub.2, was added n-BuLi (2.9 mL, 7.3
mmol). The solution was stirred at 0.degree. C. for 30 min, then a
solution of 3-bromo-2-cyclopropylpyridine (1.2 g, 6.1 mmol) in THF
(5 mL) was added at -10.degree. C. The mixture was stirred at that
temperature for 30 min, and ethyl 2-oxoacetate (50% in toluene, 5
g, 24.4 mmol) was added. The reaction was stirred at 0.degree. C.
for 2 hours, then quenched with saturated K2CO3 solution (20 mL)
and extracted with EtOAc (3.times.50 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel (pet
ether: EtOAc 2:1) to give the desired product ethyl
2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate as a yellow oil (700
mg). Yield 52% (ESI 222 (M+H)+).
Step 3: ethyl
2-(2-cyclopropylpyridin-3-yl)-2-(methylsulfonyloxy)acetate
##STR00221##
[0433] To a solution of ethyl
2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate (300 mg, 1.36 mmol)
and triethylamine (411 mg, 4.1 mmol) in DCM (5 mL) at 0.degree. C.
was added MsCl (232 mg, 2 mmol). The reaction was stirred at room
temperature for 2 hours, then concentrated in vacuo and purified by
silica gel column (pet ether: EtOAc 4:1) to get the desired product
ethyl 2-(2-cyclopropylpyridin-3-yl)-2-(methylsulfonyloxy)acetate as
a yellow oil (190 mg). Yield 47% (ESI 300 (M+H)+).
Step 4: ethyl
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)pentyl)pyrrolidin-1-yl)acetate
##STR00222##
[0435] A mixture of
(R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
hydrochloride (300 mg, 0.87 mmol), ethyl
2-(2-cyclopropylpyridin-3-yl)-2-(methylsulfonyloxy)acetate (286 mg,
0.96 mmol) and diisopropylethylamine (337 mg, 2.6 mmol) in
acetonitrile (10 mL) was stirred at 50.degree. C. overnight.
Solvent was removed in vacuo, and the residue was purified by
silica gel column (DCM: MeOH=0%-20%) to give the desired product as
a yellow oil (245 mg). Yield 54% (ESI 477 (M+H)+).
Step 2:
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8--
naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compounds
3-E1 and 3-E2)
##STR00223##
[0437] Ethyl
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)pentyl)pyrrolidin-1-yl)acetate (245 mg, 0.51 mmol) was
treated with LiOH--H.sub.2O (210 mg, 5.0 mmol) in MeOH (4 mL) and
H.sub.2O (1 mL) at room temperature for 2 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-60% MeCN) to give compound 3 as a white solid (110 mg, 48%
yield). The racemic product was separated by Prep chiral SFC H to
give diastereomeric products compound 3-E1 (42 mg) and compound
3-E2 (45 mg) as white solids.
[0438] Compound 3-E1 LC/MS ESI 449 (M+H).sup.+1H NMR (400 MHz,
MeOD) .delta. 8.39 (t, J=6.1 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H),
7.19-7.10 (m, 2H), 6.35 (d, J=7.3 Hz, 1H), 5.06 (s, 1H), 3.40-3.31
(m, 3H), 3.15-3.08 (m, 2H), 2.84-2.81 (m, 1H), 2.70-2.67 (m, 2H),
2.59-2.56 (m, 1H), 2.55-2.47 (m, 2H), 2.36-2.26 (m, 1H), 2.21-2.13
(m, 1H), 1.90-1.84 (m, 2H), 1.66-1.57 (m, 3H), 1.44-1.26 (m, 7H),
1.08-1.05 (m, 2H), 0.93-0.90 (m, 1H). Chiral SFC H (45% MeOH): ee
92%, Rt=2.11 min
[0439] Compound 3-E2 LC/MS ESI 449 (M+H).sup.+1H NMR (400 MHz,
MeOD) .delta. 8.36 (t, J=6.1 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H),
7.20-7.11 (m, 2H), 6.35 (d, J=8 Hz, 1H), 4.91 (s, 1H), 3.51-3.36
(m, 3H), 3.20-2.91 (m, 2H), 2.71-2.29 (m, 7H), 2.14-2.09 (m, 1H),
1.90-1.84 (m, 2H), 1.64-1.57 (m, 3H), 1.433-1.23 (m, 7H), 1.06-1.01
(m, 2H), 0.92-0.88 (m, 1H). Chiral SFC H (45% MeOH): ee 100%,
Rt=3.77 min
Example 4: Preparation of
2-(2-cyclopropyl-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 4-E1
and 4-E2)
Step 1: 2-cyclopropyl-5-fluoroaniline
##STR00224##
[0441] A mixture of 2-bromo-5-fluoroaniline (3.0 g, 15.8 mmol),
cyclopropylboronic acid (2.7 g, 31.4 mmol), PCy3 (440 mg, 1.57
mmol), Pd(OAc)2 (352 mg, 1.57 mmol) and K3PO4 (20 g, 94.3 mmol) in
toluene (50 mL) and H2O (10 mL) was stirred at 100.degree. C. for 4
hours. The reaction mixture was cooled to room temperature, diluted
with H2O (10 mL) and extracted with EtOAc (3.times.100 mL). The
combined organic layer was washed with brine and concentrated in
vacuo. The residue was purified by silica gel column (pet ether:
EtOAc 2:1) to afford the desired product as a colorless oil (1.8
g). Yield 75% (ESI: 152[M+H]+).
Step 2: 1-cyclopropyl-4-fluoro-2-iodobenzene
##STR00225##
[0443] 2-cyclopropyl-5-fluoroaniline (1.8 g, 11.9 mmol) was added
to a solution of para-toluene sulfonic acid monohydrate (6.8 g,
35.8 mmol) in acetonitrile (60 mL). The reaction was stirred for 10
minutes at room temperature and then cooled to 10.degree. C. A
solution of sodium nitrite (2.0 g, 29.0 mmol) and potassium iodide
(4.0 g, 24.1 mmol) in water (20 mL) was added dropwise over 30
minutes. The reaction mixture was stirred at room temperature for 4
hours, then basified to pH 9-10 with aqueous sodium bicarbonate,
then diluted with EtOAc (100 mL) and 10% aqueous sodium
metabisulphite (20 mL). The phases were separated, and the aqueous
layer was extracted with EtOAc (2.times.100 mL). Organics were
combined, washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by silica gel
column (pet ether: EtOAc 10:1) to afford the desired product as a
colorless oil (1.3 g). Yield 42% (ESI: N/A).
Step 3: 2-cyclopropyl-5-fluorophenylboronic acid
##STR00226##
[0445] To a solution of 1-cyclopropyl-4-fluoro-2-iodobenzene (1.3
g, 4.96 mmol) in THF (50 mL) was added n-BuLi (2.5M, 2.2 mL, 5.5
mmol) dropwise. The reaction was stirred for 1 h at -78.degree. C.
under Ar. A solution of trimethyl borate (1.0 g, 9.62 mmol) in THF
(10 mL) was added dropwise, and the reaction was stirred for
another 1 hour at -78.degree. C., then slowly warmed to room
temperature and stirred overnight. Aqueous HCl (1N, 20 mL) was
added, and the mixture was stirred at room temperature for 30 min,
then extracted with DCM (3.times.20 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column (pet ether:EtOAc=1:1)
to give the desired product as a white solid (500 mg). Yield: 56%
(ESI: 179[M-H]-).
Step 4:
2-(2-cyclopropyl-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds
4-E1 and 4-E2)
##STR00227##
[0447] A mixture of 2-cyclopropyl-5-fluorophenylboronic acid (200
mg, 1.11 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthy-
ridine (306 mg, 1.11 mmol) and 2-oxoacetic acid (123 mg 1.66 mmol)
in MeCN (5 mL) was stirred at 60.degree. C. for 15 hours. Solvent
was removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 4 as a white solid (120 mg, 23%
yield). The racemic product was separated by Prep chiral SFC A to
give diastereomeric products compound 4-E1 (34 mg) and compound
4-E2 (41 mg) as white solids.
[0448] Compound 4-E1 LC/MS ESI 468 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.41 (d, J=10.0 Hz, 1H), 7.20-7.01 (m, 3H), 6.38 (d, J=7.2
Hz, 1H), 5.28 (s, 1H), 4.21 (s, 1H), 3.55-3.05 (m, 8H), 2.71 (t,
J=6.4 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.19-2.05 (m, 3H), 1.92-1.55
(m, 6H), 0.95-0.80 (m, 3H), 0.55-0.50 (m, 1H). Chiral SFC A (35%
MeOH): ee 100%, Rt=2.69 min
[0449] Compound 4-E2 LC/MS ESI 468 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.41 (d, J=10.0 Hz, 1H), 7.20-7.01 (m, 3H), 6.38 (d, J=7.2
Hz, 1H), 5.19 (s, 1H), 4.18 (s, 1H), 3.54-3.19 (m, 8H), 2.71 (t,
J=6.0 Hz, 2H), 2.59-2.53 (m, 2H), 2.22-2.14 (m, 3H), 1.92-1.55 (m,
6H), 0.98-0.85 (m, 3H), 0.55-0.50 (m, 1H). Chiral SFC A (35% MeOH):
ee 97%, Rt=3.26 min
Example 5: Preparation of
2-(2-cyclopropylphenyl)-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)propoxy)pyrrolidin-1-yl)acetic acid (compounds 5-E1 and
5-E2)
Step 1:
2-(2-cyclopropylphenyl)-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)propoxy)pyrrolidin-1-yl)acetic acid (compounds 5-E1 and
5-E2)
##STR00228##
[0451] A mixture of 2-cyclopropylphenylboronic acid (102 mg, 0.63
mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(140 mg, 0.42 mmol) and 2-oxoacetic acid (47 mg 0.63 mmol) in DCM
(5 mL) was stirred at room temperature for 8 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 5 as a white solid (95 mg, 52%
yield). The racemic product was separated by Prep chiral SFC H to
give diastereomeric products compound 5-E1 (15 mg) and compound
5-E2 (9 mg) as white solids.
[0452] Compound 5-E1 LC/MS ESI 436.4 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 7.64 (d, J=7.6 Hz, 1H), 7.33-7.12 (m, 4H), 6.36 (d,
J=7.2 Hz, 1H), 5.26 (s, 1H), 4.18 (s, 1H), 3.55-3.22 (m, 8H), 2.69
(t, J=6.4 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.30-2.13 (m, 3H),
1.92-1.84 (m, 4H), 1.08-0.90 (m, 3H), 0.65-0.55 (m, 1H). Chiral SFC
H (35% MeOH): ee 98%, Rt=2.74 min
[0453] Compound 5-E2 LC/MS ESI 436.4 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 7.61 (d, J=7.6 Hz, 1H), 7.32-7.12 (m, 4H), 6.36 (d,
J=7.2 Hz, 1H), 5.33 (s, 1H), 4.21 (s, 1H), 3.55-3.09 (m, 8H), 2.70
(t, J=6.4 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.25-2.00 (m, 3H),
1.93-1.84 (m, 4H), 1.08-0.90 (m, 3H), 0.65-0.55 (m, 1H). Chiral SFC
H (35% MeOH): ee 99%, Rt=3.55 min
Example 6: Preparation of
2-(2,6-dicyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-nap-
hthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 6-E1
and 6-E2)
Step 1: 2,6-dicyclopropylpyridin-3-amine
##STR00229##
[0455] A mixture of ethyl 2,6-dibromopyridin-3-amine (6.0 g, 23.8
mmol), cyclopropylboronic acid (6.14 g, 71.4 mmol), Pd(OAc)2 (267
mg, 2.38 mmol), tricyclohexylphosphine (668 mg, 6.17 mmol) and
tripotassium phosphate (17.7 g, 83.3 mmol) in toluene (80 mL) and
water (10 mL) was stirred at 120.degree. C. overnight. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(pet ether: EtOAc 4:1) to give the desired product
2,6-dicyclopropylpyridin-3-amine as a colorless oil (3.0 g). Yield
95% (ESI 175.0 (M+H)+).
Step 2: 2,6-dicyclopropylpyridin-3-amine
##STR00230##
[0457] A mixture of ethyl 2,6-dicyclopropylpyridin-3-amine (3.0 g,
17.2 mmol), tert-butyl nitrite (2.66 g, 25.8 mmol) and
cuprousbromide (17.7 g, 25.8 mmol) in acetonitrile (20 mL) was
stirred at 65.degree. C. for 2 hours. Solvent was removed in vacuo,
and the residue was purified by silica gel column (pet ether: EtOAc
6:1) to give the desired product 3-bromo-2,6-dicyclopropylpyridine
as a yellow oil (820 mg). Yield 20% (ESI 239.0 (M+H)+).
Step 3: tert-butyl 2-(2,6-dicyclopropylpyridin-3-yl)acetate
##STR00231##
[0459] A mixture of 3-bromo-2,6-dicyclopropylpyridine (800 mg, 3.36
mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution 0.5 M in
THF (26.9 mL, 13.44 mmol), Pd2(dba)3 (156 mg, 0.17 mmol) and Qphos
(121 mg, 0.17 mmol) in THF (12 mL) was stirred at 65.degree. C. for
2 hours. Solvent was removed in vacuo, and the residue was purified
by silica gel column (pet ether: EtOAc 4:1) to give the desired
product tert-butyl 2-(2,6-dicyclopropylpyridin-3-yl)acetate as a
yellow oil (550 mg). Yield 60% (ESI 274.0 (M+H)+).
Step 4: tert-butyl
2-bromo-2-(2,6-dicyclopropylpyridin-3-yl)acetate
##STR00232##
[0461] To a solution of tert-butyl
2-(2,6-dicyclopropylpyridin-3-yl)acetate (300 mg, 1.1 mmol) in THF
(10 mL) at -78.degree. C. was added lithium diisopropylamide
solution 2.0 M in THF/hexanes (1.4 mL, 2.8 mmol) dropwise. The
reaction was stirred at -78.degree. C. for 30 min, and then a
solution of chlorotrimethylsilane (297 mg, 2.75 mmol) in THF (5 mL)
was added. The reaction was stirred at -78.degree. C. for another
30 min. Then a solution of NBS (325 mg, 2.75 mmol) in THF (5 mL)
was added, and the reaction was stirred at -78.degree. C. for 1
hour. The reaction was quenched with MeOH (2 mL), concentrated in
vacuo and purified by silica gel column (pet ether: EtOAc 4:1) to
give the desired product tert-butyl
2-bromo-2-(2,6-dicyclopropylpyridin-3-yl)acetate as a yellow oil
(80 mg). Yield 21% (ESI 353 (M+H)+).
Step 5: tert-butyl
2-(2,6-dicyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-nap-
hthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00233##
[0463] A mixture of tert-butyl
2-bromo-2-(2,6-dicyclopropylpyridin-3-yl)acetate (80 mg, 0.23
mmol),
((R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(64 mg, 0.23 mmol) and K2CO3 (96 mg, 0.69 mmol) in acetonitrile (8
mL) was stirred 60.degree. C. for 16 hours. Solvent was removed in
vacuo, and the residue was purified by silica gel column (DCM: MeOH
20:1) to give the desired product tert-butyl
2-(2,6-dicyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-nap-
hthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate as a yellow oil (90
mg). Yield 72% (ESI 547 (M+H)+).
Step 6:
2-(2,6-dicyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro--
1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds
6-E1 and 6-E2)
##STR00234##
[0465] Tert-butyl
2-(2,6-dicyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-nap-
hthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (90 mg, 0.16 mmol)
was treated with HCl in 1,4-dioxane (4M, 4 mL) at 25.degree. C. for
2 hours. Solvent was removed in vacuo, and the residue was purified
by Prep-HPLC A (30-65% MeCN) to give diastereomeric products
compound 6-E1 (11 mg) and compound 6-E2 (38 mg) as white
solids.
[0466] Compound 6-E1 LC/MS ESI 491.6 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 8.52 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.67-7.44 (m, 1H),
7.03 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.3 Hz, 1H), 5.18 (s, 1H), 4.22
(s, 1H), 3.76-3.40 (m, 6H), 3.31-3.28 (m, 2H), 2.79-2.66 (m, 4H),
2.39 (d, J=5.6 Hz, 1H), 2.19 (s, 2H), 1.98-1.93 (m, 3H), 1.76-1.74
(m, 2H), 1.64-1.62 (m, 2H), 1.25-1.14 (m, 1H), 1.06-0.72 (m,
8H).
[0467] Compound 6-E2 LC/MS ESI 491.6 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 8.52 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.67-7.44 (m, 1H),
7.03 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.3 Hz, 1H), 5.27 (s, 1H), 4.23
(s, 1H), 3.76-3.40 (m, 6H), 3.31-3.28 (m, 2H), 2.79-2.66 (m, 4H),
2.39 (d, J=5.6 Hz, 1H), 2.19 (s, 2H), 1.98-1.93 (m, 3H), 1.76-1.74
(m, 2H), 1.64-1.62 (m, 2H), 1.25-1.14 (m, 1H), 1.06-0.72 (m,
8H).
Example 7: Preparation of
2-(2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 7-E1 and
7-E2)
Step 1: 1-bromo-2-(isopropoxymethyl)benzene
##STR00235##
[0469] To a solution of isopropanol (0.72 g, 12 mmol) in DMF (15
mL) at 0.degree. C. was added NaH (480 mg, 12 mmol). The reaction
was stirred at 0.degree. C. for 0.5 hour, then
1-bromo-2-(bromomethyl)benzene (3.0 g, 12 mmol) in DMF (5 mL) was
added dropwise. The reaction was stirred at room temperature for 16
hours, then quenched with H2O (10 mL) and extracted with EtOAc
(2.times.20 mL). The combined organic layer was concentrated in
vacuo, and the residue was purified by silica gel column (pet
ether:EtOAc=10:1) to give the desired product
1-bromo-2-(isopropoxymethyl)benzene (1.6 g). Yield 58% (ESI 229
(M+H)+).
Step 2: 2-(isopropoxymethyl)phenylboronic acid
##STR00236##
[0471] To a solution of 1-bromo-2-(isopropoxymethyl)benzene (300
mg, 1.32 mmol) in THF (5 mL) at -78.degree. C., was added nBuLi
(2.5M, 0.6 mL, 1.45 mmol) dropwise. The reaction was stirred at
-78.degree. C. for 1 hour, and trimethyl borate (500 mg, 2.64 mmol)
in THF (2 mL) was added dropwise. The reaction was stirred at room
temperature for 1 hour, then quenched with aqueous HCl (1N, 10 mL)
and extracted with EtOAc (3.times.10 mL). The combined organic
layer was concentrated in vacuo, and the residue was purified by
silica gel column (pet ether:EtOAc=2:1) to give the desired product
2-(isopropoxymethyl)phenylboronic acid as a white solid (120 mg).
Yield: 47% (ESI 193 (M-H)-.
Step 3:
2-(2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-
-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds
7-E1 and 7-E2)
##STR00237##
[0473] A mixture of (3R)-tert-butyl
3-(4-(5-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-
e-1-carboxylate (131 mg, 0.48 mmol),
2-(isopropoxymethyl)phenylboronic acid (120 mg, 0.62 mmol) and 50%
2-oxoacetic acid (92 mg, 0.62 mmol) in MeCN (5 mL) was stirred at
70.degree. C. for 16 hours. Solvent was removed in vacuo, and the
residue was purified by Prep-HPLC B (30-65% MeCN) to give
diastereomeric products compound 7-E1 (40 mg) and compound 7-E2 (34
mg) as HCOOH salts.
[0474] Compound 7-E1 LC/MS ESI 482 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 8.33 (s, 2H), 7.68-7.66 (m, 1H), 7.52-7.50 (m, 1H),
7.46-7.42 (m, 3H), 6.56 (d, J=7.2 Hz, 1H), 5.09 (s, 1H), 4.90-4.88
(m, 1H), 4.52-4.50 (m, 1H), 4.23-4.21 (m, 1H), 3.82-3.80 (m, 1H),
3.66-3.44 (m, 7H), 3.21-3.19 (m, 1H), 2.81-1.60 (m, 12H), 1.25-1.23
(m, 6H).
[0475] Compound 7-E2 LC/MS ESI 482 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 8.33 (s, 2H), 7.65-7.63 (m, 1H), 7.52-7.50 (m, 1H),
7.44-7.42 (m, 3H), 6.56 (d, J=7.2 Hz, 1H), 4.97 (s, 1H), 4.86-4.50
(m, 2H), 4.26-4.24 (m, 1H), 3.85-3.82 (m, 1H), 3.61-3.40 (m, 5H),
3.26-3.22 (m, 3H), 2.81-1.60 (m, 12H), 1.28-1.23 (m, 6H).
Example 8: Preparation of
2-(2-(tert-butoxymethyl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro--
1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound
8)
Step 1: 1-bromo-2-(tert-butoxymethyl)-4-fluorobenzene
##STR00238##
[0477] NaH (60%, 600 mg, 15 mmol) was added to a solution of
2-methylpropan-2-ol (7.4 g, 100 mmol) in THE (30 mL) at 0.degree.
C. The mixture was stirred at 0.degree. C. for 0.5 hour, and
2-bromo-1-(bromomethyl)-4-fluorobenzene (2.68 g, 10 mmol) was
added. The mixture was stirred at 80.degree. C. overnight, then
cooled to room temperature, quenched with water (50 mL) and
extracted with EtOAc (50 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by silica gel column (pet ether:EtOAc 15:1) to give
the desired product as a yellow oil (300 mg). Yield 11% (ESI 261
(M+H)+).
Step 2: 2-(tert-butoxymethyl)-4-fluorophenylboronic acid
##STR00239##
[0479] n-BuLi (0.4 mL, 2.5 M in hexane, 1 mmol) was added dropwise
to a solution of 1-bromo-2-(tert-butoxymethyl)-4-fluorobenzene (150
mg, 0.57 mmol) and triisopropyl borate (188 mg, 1 mmol) in THE (5
mL) at -78.degree. C. The mixture was stirred at -78.degree. C. for
1 hour, then stirred at 25.degree. C. for another 1 hour. The
mixture was quenched with aqueous HCl (2N) to pH=5, then extracted
with EtOAc (10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by silica gel column (pet ether:EtOAc 2:1) to give the
desired product as a colorless oil (70 mg). Yield 54% (ESI 225
(M-H)-).
Step 3:
2-(2-(tert-butoxymethyl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 8)
##STR00240##
[0481] A mixture of 2-(tert-butoxymethyl)-4-fluorophenylboronic
acid (75 mg, 0.33 mmol), 2-oxoacetic acid (88 mg, 50% in water, 0.6
mmol) and
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(91 mg, 0.33 mmol) in CH.sub.3CN (5 mL) was stirred at 60.degree.
C. overnight. Solvent was removed in vacuo, and the residue was
purified by Prep-HPLC A (33-65% MeCN) to give compound 8 as a white
solid (22 mg, 13% yield).
[0482] Compound 8 LC/MS ESI 514 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 7.50-7.42 (m, 2H), 7.17-7.08 (m, 2H), 6.37 (d, J=7.2 Hz,
1H), 4.81-4.74 (m, 2H), 4.55-4.43 (m, 1H), 4.17 (s, 1H), 3.55-3.32
(m, 6H), 3.20-2.95 (m, 2H), 2.72-2.52 (m, 4H), 2.25-1.55 (m, 8H),
1.34-1.28 (m, 9H).
Example 9: Preparation of
2-(2-cyclopropylpyridin-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compounds 9-E1
and 9-E2)
Step 1: ethyl 2-chloro-2-(2-cyclopropylpyridin-3-yl)acetate
##STR00241##
[0484] A solution of ethyl
2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate (500 mg, 2.26 mmol)
in SOCl2 (5 mL) was stirred at rt for 17 hours. Solvent was removed
in vacuo, and the residue was purified by silica gel column (pet
ether: EtOAc 4:1) to get the desired product ethyl
2-chloro-2-(2-cyclopropylpyridin-3-yl)acetate as a yellow oil (210
mg). Yield 39% (ESI 240 (M+H)+).
Step 2: ethyl
2-(2-cyclopropylpyridin-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetate
##STR00242##
[0486] A mixture of
7-(5-(3-fluoropyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e (230 mg, 0.632 mmol), ethyl
2-chloro-2-(2-cyclopropylpyridin-3-yl)acetate (378 mg, 1.580 mmol)
and K.sub.2CO.sub.3 (262 mg, 1.896 mmol) in acetonitrile (8 mL) was
stirred at 60.degree. C. for 16 hours. Solvent was removed in
vacuo, and the residue was purified by silica gel column (DCM: MeOH
20:1) to give the desired product ethyl
2-(2-cyclopropylpyridin-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetate as a yellow oil (120
mg). Yield 38% (ESI 495 (M+H)+).
Step 3:
2-(2-cyclopropylpyridin-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-
-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid
(compounds 9-E1 and 9-E2)
##STR00243##
[0487] ethyl ethyl
2-(2-cyclopropylpyridin-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahy
dro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetate (120 mg,
0.24 mmol) was treated with LiOH--H2O (40 mg, 0.97 mmol) in MeOH (4
mL) and H2O (1 mL) at 60.degree. C. for 2 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 9 as a white solid (60 mg, 53%
yield). The racemic product was separated by Prep chiral SFC F to
give diastereomeric products compound 9-E1 (10 mg) and compound
9-E2 (10 mg) as white solids, each as a mixture of 2
stereoisomers.
[0488] Compound 9-E1 (mixture of 2 stereoisomers) LC/MS ESI 467.4
(M+H)+. 1H NMR (400 MHz, MeOD) .delta. 8.32 (s, 1H), 8.03 (d, J=7.3
Hz, 1H) 7.28 (m, 2H), 6.41 (d, J=7.3 Hz, 1H), 4.81 (s, 1H),
3.40-2.95 (m, 6H), 2.80-2.50 (m, 5H), 2.25-1.20 (m, 12H), 1.10-0.85
(m, 4H). Chiral SFC F (45% MeOH): ee 76%, Rt=2.72 min
[0489] Compound 9-E1 (mixture of 2 stereoisomers) LC/MS ESI 467.4
(M+H)+. 1H NMR (400 MHz, MeOD) .delta. 8.39 (s, 1H), 8.01 (d, J=7.3
Hz, 1H) 7.33 (m, 2H), 6.47 (d, J=7.3 Hz, 1H), 4.96 (s, 1H),
3.45-2.95 (m, 6H), 2.80-2.50 (m, 5H), 2.25-1.20 (m, 12H), 1.10-0.85
(m, 4H). Chiral SFC F (45% MeOH): ee 53%, Rt=3.36 min
Example 10: Preparation of
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound
10)
Step 1: ethyl
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00244##
[0491] A mixture of
(R)-5-methoxy-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naph-
thyridine hydrochloride (215 mg, 0.63 mmol), ethyl
2-chloro-2-(2-cyclopropylpyridin-3-yl)acetate (150 mg, 0.63 mmol)
and diisopropylethylamine (245 mg, 1.89 mmol) in acetonitrile (8
mL) was stirred under reflux for 24 hours. Solvent was removed in
vacuo, and the residue was purified by silica gel column (DCM: MeOH
20:1) to give the desired product ethyl
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate as a yellow oil
(80 mg). Yield 25% (ESI 509 (M+H)+).
Step 2:
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetra-
hydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 10) POP-224 C.sub.3
##STR00245##
[0493] Ethyl
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (105 mg, 0.21
mmol) was treated with LiOH--H2O (87 mg, 2.1 mmol) in MeOH (4 mL)
and H2O (1 mL) at room temperature for 17 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 10 as a white solid (25 mg, 25%
yield).
[0494] Compound 10 LC/MS ESI 481 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 8.26-8.25 (m, 1H), 8.08-8.06 (m, 1H), 7.15-7.11 (m, 1H),
6.26-6.24 (m, 1H), 4.57-4.52 (m, 1H), 4.08-4.07 (m, 1H), 3.85 (s,
1H), 3.46-3.41 (m, 2H), 3.25-2.50 (m, 7H), 2.10-1.50 (m, 8H),
1.10-0.80 (m, 4H).
Example 11: Preparation of
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 11-E1 and
11-E2)
Step 1: 3-bromo-2-cyclobutylpyridine
##STR00246##
[0496] A mixture of magnesium turnings (612 mg, 25.5 mmol) and
cyclobutyl bromide (3.4 g, 25.5 mmol) in anhydrous THF (50 mL) was
heated for 3 hours at 60.degree. C. until complete dissolution of
the magnesium. The solution was cooled to -78.degree. C. and
treated with ZnCl2 (3.48 g, 25.5 mmol) in THF (50 mL). The
resulting white suspension was warmed gradually to room temperature
and stirred for 1 hour. Then a solution of 2,3-dibromopyridine (4
g, 17 mmol) and Pd(PPh3)4 (983 mg, 0.85 mmol) in THF (30 mL) was
added to the reaction. The mixture was stirred at 60.degree. C. for
1 hour under N2, then diluted with water (100 mL) and extracted
with EtOAc (3.times.50 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated in vacuo, and the residue
was purified by silica gel column (pet ether:EtOAc=10:1) to give
the desired product 3-bromo-2-cyclopropylpyridine as a yellow oil
(2.3 g). Yield 94% (ESI 212 (M+H)+).
Step 2: ethyl 2-(2-cyclobutylpyridin-3-yl)-2-hydroxyacetate
##STR00247##
[0498] To a solution of EtMgBr (1 M, 6.54 mL, 6.54 mmol) in THF (20
mL) at 0.degree. C. under N2 was added n-BuLi (2.5M, 5.2 mL, 13.08
mmol). The solution was stirred at 0.degree. C. for 30 min, then a
solution of 3-bromo-2-cyclobutylpyridine (2.3 g, 10.9 mmol) in THF
(5 mL) was added at -10.degree. C. The mixture was stirred at that
temperature for 30 min. Then ethyl 2-oxoacetate (50% in toluene,
8.9 g, 43.6 mmol) was added, and the reaction was stirred at
0.degree. C. for 2 hours, then poured into 20 mL of a saturated
K2CO3 solution and extracted with EtOAc (3.times.50 mL). The
combined organic layers were dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by silica gel
column (pet ether:EtOAc=2:1) to give the desired product ethyl
2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate as a yellow oil (1.1
g). Yield 43% (ESI 236 (M+H)+).
Step 3: ethyl 2-chloro-2-(2-cyclobutylpyridin-3-yl)acetate
##STR00248##
[0500] A solution of ethyl
2-(2-cyclobutylpyridin-3-yl)-2-hydroxyacetate (480 mg, 2 mmol) in
SOCl2 (5 mL) was stirred at room temperature overnight. The mixture
was concentrated in vacuo, adjusted to pH=8 with aq NaHCO3 and
extracted with EtOAc (3.times.20 mL). The combined organic layers
were dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel column (pet ether:EtOAc=10:1) to
give the desired product ethyl
2-chloro-2-(2-cyclobutylpyridin-3-yl)acetate as a yellow oil (310
mg). Yield 47% (ESI 254 (M+H)+).
Step 4: ethyl
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00249##
[0502] A mixture of ethyl
2-chloro-2-(2-cyclobutylpyridin-3-yl)acetate (310 mg, 1.2 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(370 mg, 1.35 mmol) and diisopropylethylamine (464 mg, 3.6 mmol) in
acetonitrile (10 mL) was stirred at 50.degree. C. overnight.
Solvent was removed in vacuo, and the residue was purified by
silica gel column (DCM: MeOH=0%-10%) to give the desired product
ethyl
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)butoxy)pyrrolidin-1-yl)acetate as a colorless oil (165
mg, 0.36 mmol). Yield 28% (ESI 493 (M+H)+).
Step 5:
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-n-
aphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds
11-E1 and 11-E2)
##STR00250##
[0504] Ethyl
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)butoxy)pyrrolidin-1-yl)acetate (165 mg, 0.36 mmol) was
treated with LiOH--H.sub.2O (70 mg, 1.8 mmol) in MeOH (4 mL) and
H.sub.2O (1 mL) at room temperature for 2 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-60% MeCN) to give compound 11 as a white solid (110 mg, 70%
yield). The racemic product was separated by Prep chiral SFC A to
give diastereomeric products compound 11-E1 (35 mg) and compound
11-E2 (35 mg) as white solids.
[0505] Compound 11-E1 LC/MS ESI 465 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 8.54 (d, J=4.5 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H),
7.29-7.23 (m, 2H), 6.43 (d, J=7.0 Hz, 1H), 4.71 (s, 1H), 4.26-4.15
(m, 2H), 3.54-3.38 (m, 4H), 3.22-3.07 (m, 4H), 2.75-2.55 (m, 5H),
2.44-2.33 (m, 3H), 2.13-2.05 (m, 3H), 1.92-1.87 (m, 3H), 1.79-1.74
(m, 2H), 1.67-1.63 (m, 2H). Chiral SFC E (45% MeOH): ee 100%,
Rt=2.99 min.
[0506] Compound 11-E2 LC/MS ESI 465 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 8.55 (d, J=4.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H),
7.30-7.22 (m, 2H), 6.44 (d, J=6.0 Hz, 1H), 4.80 (s, 1H), 4.20-4.16
(m, 2H), 3.51-3.39 (m, 5H), 3.24-3.22 (m, 1H), 3.01-2.91 (m, 2H),
2.75-2.59 (m, 5H), 2.42-2.30 (m, 3H), 2.08-2.02 (m, 3H), 1.92-1.64
(m, 7H). Chiral SFC E (45% MeOH): ee 100%, Rt=5.21 min.
Example 12: Preparation of
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compound
12)
Step 1: methyl 2-(2-iodophenyl)acetate
##STR00251##
[0508] To a solution of 2-(2-iodophenyl)acetic acid (3.67 g, 14
mmol) in MeOH (35 mL) was added 2 mL of concentrated H2SO4. The
reaction was stirred at 85.degree. C. for 2 hours, then
concentrated in vacuo, adjusted to pH=7.about.8 with sat.NaHCO3
solution and extracted with EtOAc (2.times.30 mL). The combined
organic phase was washed with brine, dried over Na2SO4 and
concentrated to give the desired product methyl
2-(2-iodophenyl)acetate (3.7 g) as an orange oil. Yield 96% (ESI
277 (M+H)+).
Step 2: methyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)acetate
##STR00252##
[0510] A mixture of methyl 2-(2-iodophenyl)acetate (828 mg, 3.0
mmol),
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(945 mg, 4.5 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (89 mg, 0.12 mmol)
and Na2CO3 (636 mg, 6. mmol) in 1,4-dioxane (30 mL) and water (6
mL) was stirred under N2 at 90.degree. C. overnight. The mixture
was diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The
organic phase was concentrated in vacuo, and the residue was
purified by silica gel column (pet ether:EtOAc 10:1) to give the
desired product tert-butyl
2-(3-(2-methoxypropan-2-yl)isochroman-5-yl)acetate as a pale orange
oil (488 mg). Yield 70% (ESI 255.1 (M+Na)+).
Step 3: methyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate
##STR00253##
[0512] A mixture of tert-butyl
2-(3-(2-methoxypropan-2-yl)isochroman-5-yl)acetate (488 mg, 2.1
mmol) and Pd(OH)2/C (20%, 120 mg) in MeOH (20 mL) was stirred under
balloon hydrogen at 35.degree. C. for 6 hours. The reaction was
filtered and concentrated in vacuo to provide the desired product
methyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (460 mg) as a
colorless oil. Yield 95% (ESI 235.2 (M+H)+).
Step 4: tert-butyl
2-bromo-2-(3-(2-methoxypropan-2-yl)isochroman-5-yl)acetate
##STR00254##
[0514] To a solution of
2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (234 mg, 1.0 mmol) in
THF (10 mL) at -78.degree. C. was added lithium diisopropylamide
solution 2.0 M in THF/hexanes (1.0 mL, 2.0 mmol) dropwise. The
reaction was stirred at -78.degree. C. for 20 min. Then a solution
of chlorotrimethylsilane (218 mg, 2.0 mmol) in THF (0.5 mL) was
added, and the reaction was stirred at -78.degree. C. for another
10 min. Then a solution of NBS (356 mg, 2.0 mmol) in THF (4 mL) was
added, and the reaction was stirred at -78.degree. C. for 10 min,
then poured into water (10 mL) and extracted with EtOAc (20 mL).
The organic phase was washed with sat.NaHCO3 solution and water and
concentrated in vacuo to give the crude product as a yellow oil
(320 mg). Yield 48% (ESI 315.1 (M+H)+).
Step 5: methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate
##STR00255##
[0516] A mixture of tert-butyl
2-bromo-2-(3-(2-methoxypropan-2-yl)isochroman-5-yl)acetate (320 mg,
47% purity, 0.48 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(132 mg, 0.48 mmol) and diisopropylethylamine (186 mg, 1.44 mmol)
in acetonitrile (12 mL) was stirred at room temperature for 1 hour.
The mixture was diluted with water (8 mL) and extracted with EtOAc
(25 mL). The organic phase was washed with brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by Prep-HPLC
(NH4HCO3, H2O/MeCN) to give methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate as a white solid
(135 mg). Yield 55% (ESI 508.1 (M+H)+).
Step 6: Preparation of
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compound
12)
##STR00256##
[0518] A solution of methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (115 mg) in THE
(5 mL) was treated with LiOH (1 M in H2O, 2.7 mL) at room
temperature overnight. Solvent was removed in vacuo, and the
residue was purified by prep HPLC A (30-64% MeCN/H2O) to give
compound 12 as white solid (82 mg).
[0519] Compound 12 LC/MS ESI 494.2 (M+H)+. 1H NMR (500 MHz, MeOD)
.delta.7.64 (m, 1H), 7.41 (m, 2H), 7.28 (m, 1H), 7.16 (m, 1H), 6.39
(m, 1H), 4.94 (m, 1H), 4.22 (m, 1H), 4.01 (m, 2H), 3.55-3.64 (m,
4H), 3.40 (m, 3H), 3.33-3.37 (m, 3H), 2.72 (t, J=6.5 Hz, 2H), 2.57
(t, J=6.5 Hz, 2H), 2.01-2.24 (m, 2H), 1.88-1.98 (m, 4H), 1.61-1.77
(m, 6H).
Example 13: Preparation of
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compounds
13-E1 and 13-E2)
Step 1: methyl 2-(2-chloropyridin-3-yl)acetate
##STR00257##
[0521] To a solution of 2-(2-chloropyridin-3-yl)acetic acid (1.71
g, 10 mmol) in MeOH (35 mL) was added concentrated H2SO4 (2 mL).
The reaction was stirred at 85.degree. C. for 2 hours, then
concentrated in vacuo, adjusted to pH=7.about.8 with sat. NaHCO3
solution and extracted with EtOAc (2.times.30 mL). The combined
organic phase was washed with brine, dried over Na2SO4 and
concentrated to give the desired product methyl
2-(2-chloropyridin-3-yl)acetate as an orange oil (1.51 g, Yield
81%). (ESI 186 (M+H)+).
Step 2: methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)acetate
##STR00258##
[0523] A mixture of methyl 2-(2-chloropyridin-3-yl)acetate (372 mg,
2.0 mmol),
2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborol-
ane (420 mg, 2.0 mmol), X-Phos Pd G4 (68 mg, 0.08 mmol) and K2CO3
(552 mg, 4 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was
heated at 115.degree. C. by microwave for 2 hours. The mixture was
diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The
organic phase was concentrated in vacuo, and the residue was
purified by silica gel column (pet ether:EtOAc 10:1) to give the
desired product methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)acetate as a pale
orange oil (308 mg). Yield 66% (ESI 234.1 (M+H)+).
Step 3: methyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate
##STR00259##
[0525] A mixture of methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)acetate (302 mg, 1.3
mmol) and Pd(OH).sub.2/C (20%, 100 mg) in MeOH (16 mL) was stirred
under balloon H2 at 35.degree. C. for 4 hours. The reaction was
filtered and concentrated in vacuo to give the desired product
methyl 2-(2-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)acetate as an
orange oil (301 mg). Yield 94% (ESI 236.2 (M+H)+).
Step 4: methyl
2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)acetate
##STR00260##
[0527] To a solution of
2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate methyl
2-(2-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)acetate (301 mg, 1.28
mmol) in THF (8 mL) at -78.degree. C., was added lithium
diisopropylamide solution 2.0 M in THF/hexanes (1.28 mL, 2.56 mmol)
dropwise. The reaction was stirred at -78.degree. C. for 20 min.
Then a solution of chlorotrimethylsilane (278 mg, 2.56 mmol) in THF
(0.5 mL) was added, and the reaction was stirred at -78.degree. C.
for another 10 min. Then a solution of NB (456 mg, 2.56 mmol) in
THF (4 mL) was added, and the reaction was stirred at -78.degree.
C. for 10 min, then poured into water (10 mL) and extracted with
EtOAc (20 mL). The organic phase was washed with sat.NaHCO3
solution and water and concentrated in vacuo to give the crude
product as a yellow oil (390 mg, purity 40%). Yield 39%. (ESI 315.1
(M+H)+).
Step 5: methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)acetate
##STR00261##
[0529] A mixture of methyl
2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)acetate (390
mg, 40% purity),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-napht-
hyridine (137 mg, 0.50 mmol) and diisopropylethylamine (194 mg,
1.50 mmol) in acetonitrile (10 mL) was stirred at room temperature
for 2 hours. The mixture was diluted with water (8 mL) and
extracted with EtOAc (25 mL). The organic phase was washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by Prep-HPLC A (40-75% MeCN) to give the
desired product methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)acetate (105 mg)
as a white sold. Yield 41% (ESI 509.2 (M+H)+).
Step 6: Preparation of
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compounds
13-E1 and 13-E2).sub.
##STR00262##
[0531] A solution of ethyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (71 mg, 0.14
mmol) in THE (5 mL) was treated with LiOH (1 M in H.sub.2O, 2.1 mL)
at room temperature overnight. The mixture was adjusted to
pH=5.about.6 with aqueous HCl (1N) and concentrated in vacuo, and
the residue was purified by preparatory HPLC A (30-64% MeCN) to
give diastereomeric products compound 13-E1 (23 mg) and compound
13-E2 (12 mg) as white solids, each as a mixture of 2
stereoisomers.
[0532] Compound 13-E1 (mixture of 2 stereoisomers) LC/MS ESI 495.3
(M+H)+. 1H NMR (500 MHz, MeOD) .delta. 8.46 (m, 1H), 8.21 (m, 1H),
7.33 (m, H), 7.16 (m, 1H), 6.38 (m, 1H), 5.12 (m, 1H), 4.41 (m,
1H), 4.05 (m, 2H), 3.75 (m, 1H), 3.75-3.37 (m, 4H), 3.30-2.80 (m,
2H), 2.73-2.69 (m, 4H), 2.64-2.54 (m, 2H), 1.96 (m, 1H), 1.91-1.87
(m, 6H), 1.78-1.58 (m, 7H).
[0533] Compound 13-E2 (mixture of 2 stereoisomers) LC/MS ESI 495.3
(M+H)+. 1H NMR (500 MHz, MeOD) .delta. 8.46 (m, 1H), 8.14 (m, 1H),
7.34 (m, 1H), 7.16 (m, 1H), 6.38 (m, 1H), 5.04 (m, 1H), 4.11 (m,
2H), 3.68 (m, 1H), 3.69-3.37 (m, 5H), 3.11-2.98 (m, 2H), 2.87-2.70
(m, 4H), 2.56-2.54 (m, 2H), 2.06-1.80 (m, 7H), 1.78-1.59 (m,
7H).
Example 14: Preparation of
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 14-E1 and
14-E2)
Step 1: sodium
(2-cyclopropylpyridin-3-yl)(hydroxy)methanesulfonate
##STR00263##
[0535] 2-Bromo-3-pyridinecarboxaldehyde (1 g, 5.38 mmol),
cyclopropylboronic acid (1.385 g, 16.13 mmol) and sodium carbonate
(2.279 g, 21.50 mmol) were dissolved in 1,2-dimethoxyethane (20 mL)
and water (5 mL). The mixture was flushed with argon and
bis(triphenylphosphine)palladium(II) dichloride (0.377 g, 0.538
mmol) was added. The reaction was sealed and heated at 100.degree.
C. for 16 hours, then diluted with water and extracted with diethyl
ether. The organic layer was washed twice with water, and a
solution of sodium bisulfate (1.119 g, 10.75 mmol) in water and
some methanol were added. The diethyl ether was evaporated in
vacuo, and the resulting water/methanol mixture was used as such in
the next step.
Step 2:
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8--
naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetonitrile
##STR00264##
[0537] A water/methanol mixture containing sodium
(2-cyclopropylpyridin-3-yl)(hydroxy)methanesulfonate (1.352 g, 5.38
mmol) was added to
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(0.963 g, 3.50 mmol), followed by potassium cyanide (1.752 g, 26.9
mmol). After 16 hours some methanol was added. After 64 hours, the
reaction mixture was diluted with water and extracted three times
with ethyl acetate. The combined organic layers were dried over
sodium sulfate and concentrated in vacuo to afford the desired
product
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)butoxy)pyrrolidin-1-yl)acetonitrile (1.511 g). Yield 65%
(ESI 430 (M-H).sup.-).
Step 3:
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8--
naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetamide
##STR00265##
[0539] To a solution of
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahy
dro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetonitrile
(1.511 g, 3.5 mmol) in dichloromethane (10 mL) was added sulfuric
acid (25 mL, 469 mmol). The reaction was stirred at room
temperature for 24 hours, then quenched on ice, neutralised using
aqueous ammonia and extracted three times with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated, and the residue was purified by reversed
phase chromatography (10 mM solution of ammonium hydrogen carbonate
in water, 20-60% acetonitrile) to afford the desired product
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-
-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetamide (399 mg). Yield
25% (ESI 450 (M+H)+).
Step 4:
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8--
naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (Compounds
14-E1 and 14-E2)
##STR00266##
[0541] A solution of
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)butoxy)pyrrolidin-1-yl)acetamide (399 mg, 0.887 mmol) in
hydrochloric acid (10 mL, 40 mmol, 4N solution in water) was
stirred at 70.degree. C. for 88 hours. The mixture was
concentrated, and the residue was dissolved in water and then
freeze-dried. The residue was dissolved in water (10 mL) and this
was purified using reversed phase chromatography to afford
2-(2-cyclopropylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthy-
ridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid compound 14 (311 mg)
as a diastereoisomeric mixture. Yield 78% (ESI 451 (M+H).sup.+).
The mixture was separated by chiral SFC to give diastereomeric
products compound 14-E1 (107 mg) and compound 14-E2 (100 mg).
Method: Water Acquity UPC2 (Binary Solvent Manager, Isocratic
Solvent Manager, Sample Manager, Column Manager 30S, Convergence
Manager, PDA Detector, Acquity QDa Detector); Column: Chiralpak IC
for SFC use (100.times.4.6 mm, 5 .mu.m). Temperature: 35.degree. C.
Back Pressure: 170 bar. Flow: 2.5 mL/min. Eluent A: CO2. Eluent B:
Methanol+20 mM Ammonia. Gradient: t0=5% B, t2.5 min=50% B, t30
min=50% B, Post time: 0.5 min. Detection PDA: 210-320 nm. Detection
MS: ESI, Mass Range: 700-1250 (positive) 1 Hz, Cone: 15 V.
[0542] Compound 14-E1: 107 mg, LC/MS ESI 451 (M+H)+. .sup.1H NMR
(400 MHz, Methanol-d4) .delta. 8.37 (dd, J=4.7, 1.7 Hz, 1H), 7.97
(dd, J=8.0, 1.8 Hz, 1H), 7.24-7.08 (m, 2H), 6.40 (d, J=7.3 Hz, 1H),
5.04 (s, 1H), 4.22-4.13 (m, 1H), 3.55-3.33 (m, 5H), 3.23-3.10 (m,
2H), 2.79-2.66 (m, 2H), 2.66-2.46 (m, 3H), 2.22-2.05 (m, 2H),
1.94-1.82 (m, 2H), 1.80-1.45 (m, 5H), 1.27-1.15 (m, 1H), 1.07-0.88
(m, 3H).
[0543] Compound 14-E2: 100 mg, LC/MS ESI 451 (M+H)+. .sup.1H NMR
(400 MHz, Methanol-d4) .delta. 8.38 (dd, J=4.8, 1.7 Hz, 1H), 7.94
(dd, J=7.8, 1.7 Hz, 1H), 7.24-7.13 (m, 2H), 6.40 (d, J=7.3 Hz, 1H),
5.13 (s, 1H), 4.25-4.14 (m, 1H), 3.58-3.32 (m, 6H), 3.27-3.14 (m,
1H), 3.07-2.95 (m, 1H), 2.78-2.66 (m, 2H), 2.64-2.49 (m, 2H),
2.49-2.38 (m, 1H), 2.18-2.02 (m, 2H), 1.95-1.82 (m, 2H), 1.81-1.45
(m, 5H), 1.30-1.15 (m, 1H), 1.06-0.86 (m, 3H).
Example 15: Preparation of
2-(2-cyclopropylphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)pentyloxy)pyrrolidin-1-yl)acetic acid (compounds 15-E1 and
15-E2)
Step 1:
2-(2-cyclopropylphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)pentyloxy)pyrrolidin-1-yl)acetic acid (compounds 15-E1
and 15-E2)
##STR00267##
[0545] To a solution of
(R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
dihydrochloride (200 mg, 0.55 mmol) in DMF (2 mL) was added
2-cyclopropylphenylboronic acid (116 mg, 0.72 mmol) and 2-oxoacetic
acid (56 mg, 0.6 mmol). The reaction was stirred at 80.degree. C.
for 1 h. The reaction mixture was purified by prep-HPLC (40-65%
MeCN) to give 90 mg racemic compound 15. The racemic product was
separated by prep chiral SFC A to give diastereomeric products
compound 15-E1 (23 mg) and compound 15-E2 (22 mg) as white
solids.
[0546] Compound 15-E1 LC/MS ESI 464.2 (M+H)+. .sup.1H NMR (500 MHz,
MeOD) .delta. 7.61 (d, J=7.1 Hz, 1H), 7.31 (m, 2H), 7.16 (dd,
J=21.5, 7.4 Hz, 2H), 6.37 (d, J=7.3 Hz, 1H), 5.35 (s, 1H), 4.23 (s,
1H), 3.65 (m, 1H), 3.49 (t, J=6.4 Hz, 2H), 3.42-3.36 (m, 2H),
3.30-2.99 (m, 3H), 2.70 (t, J=6.3 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H),
2.21 (m, 3H), 1.88 (m, 2H), 1.12-0.94 (m, 3H), 0.70-0.51 (m, 1H).
Chiral SFC A (40% MeOH): ee 98%, Rt=2.46 min.
[0547] Compound 15-E2 LC/MS ESI 464.2 (M+H)+. .sup.1H NMR (500 MHz,
MeOD) .delta. 7.54 (d, J=7.5 Hz, 1H), 7.17 (m, 2H), 7.07-6.97 (m,
2H), 6.26 (d, J=7.3 Hz, 1H), 5.08 (s, 1H), 4.06 (s, 1H), 3.43-3.24
(m, 5H), 3.14-2.98 (m, 2H), 2.59 (t, J=6.2 Hz, 2H), 2.48-2.36 (m,
2H), 2.15 (m, 3H), 1.81-1.70 (m, 2H), 1.63-1.45 (m, 4H), 1.39-1.26
(m, 2H), 0.96-0.77 (m, 3H), 0.55-0.42 (m, 1H). Chiral SFC A (40%
MeOH): ee 98%, Rt=3.5 min.
Example 16: Preparation of
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetic acid (compounds 16-E1
and 16-E2)
Step 1: methyl 2-(2-(furan-2-yl)phenyl) acetate
##STR00268##
[0549] To a solution of methyl 2-(2-iodophenyl)acetate (552 mg, 2
mmol) in 5 mL dry DMF was added furan-2-ylboronic acid (224 mg, 2
mmol), tris(dibenzylideneacetone) dipalladium (0) (91.5 mg, 0.1
mmol), X-Phos (47.6 mg, 0.1 mmol), and potassium phosphate (424 mg,
2 mmol). The mixture was stirred at 60.degree. C. for 1 hour under
N2. The reaction was allowed to cool and diluted with ethyl acetate
(20 mL) and water (20 mL). The organic layer was separated and the
aqueous layer was extracted with ethyl acetate three times (20
mL.times.2). The combined organic layer was washed with brine and
dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the residue was chromatographed (Combiflash), using
5.about.20% EtOAc/petroleum ether as eluent, to give methyl
2-(2-(furan-2-yl)phenyl) acetate 340 mg (78.3%); (ESI 217
(M+H).sup.+).
Step 2: methyl 2-(2-(tetrahydrofuran-2-yl)phenyl)acetate
##STR00269##
[0551] To a solution of methyl 2-(2-(furan-2-yl) phenyl) acetate
(340 mg, 1.57 mmol) in 10 ml anhydrous MeOH was added Pd/C (30 mg).
The mixture was stirred for 3 hours at 40.degree. C. under H2
atmosphere (balloon). After the reaction was over, the catalyst was
removed by filtration and the filtrate was concentrated under
reduced pressure. The residue was chromatographed (Combiflash),
using 5-20% EtOAc/petroleum ether as eluent, to give methyl
2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (290 mg, 84%) as an oil.
(ESI 221 (M+H).sup.+)
Step 3: methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl)
acetate
##STR00270##
[0553] A solution of methyl
2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (220 mg, 1 mmol) in 10 mL
THF under N2 was cooled to -78.degree. C. and treated with LDA
(1.25 mL, 2.5 mmol, 2M in THF). The reaction was stirred for 0.5 h,
treated with TMSCl (324 mg, 3 mmol) and, after 0.25 h, NBS (534 mg,
3 mmol) as a solution in 10 mL dry THF. The mixture was stirred for
0.5 h at -78.degree. C. and water (10 mL) was added to quench the
reaction. The mixture was extracted with ethyl acetate (20
mL.times.2). The combined organic layer was washed with brine and
dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the residue was chromatographed (Combiflash), using
0-20% EtOAc/petroleum ether as eluent, to give methyl
2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl) acetate (210 mg, 70.5%);
(ESI 299 (M+H)+)
Step 4: methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate
##STR00271##
[0555] To a solution of methyl
2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (100 mg, 0.33
mmol) in 5 mL acetonitrile was added
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(92 mg, 0.33 mmol) and diisopropylethylamine (129 mg, 1 mmol). The
reaction was stirred for 2 hours, diluted with water (10 mL) and
extracted with ethyl acetate (20 mL.times.3). The combined organic
layers were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was chromatographed (Combiflash), using 20-80% EtOAc/petroleum
ether as eluent, to give methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrro-
lidin-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (90 mg,
54.4%). (ESI 494 (M+H)+)
Step 5:
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrro-
lidin-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetic acid
(compounds 16-E1 and 16-E2)
##STR00272##
[0557] To a solution of methyl 2-((R)-3-(4-(5,6,7,8-tetrahy
dro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)-2-(2-(tetrahydrofuran-2-
-yl)phenyl)acetate (90 mg, 0.18 mmol) in 5 mL methanol was added
LiOH (9 mg, 0.4 mmol) and water (2 mL). The reaction was stirred
for 5 h, filtered and concentrated under reduced pressure. The
residue was purified using reversed-phase semi-preparative HPLC to
give diastereomeric products compound 16-E1 (40 mg, Yield 45.7%)
and compound 16-E2 (19 mg, Yield 22.7%), each as a mixture of two
stereoisomers.
[0558] Compound 16-E1 (mixture of 2 stereoisomers): LC/MS ESI 480.2
(M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.69 (dd, J=11.4,
7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H),
7.38-7.29 (m, 1H), 7.15 (d, J=7.3 Hz, 1H), 6.39 (dd, J=7.3, 2.7 Hz,
1H), 5.30 (dt, J=33.4, 7.0 Hz, 1H), 4.97 (s, 1H), 4.17 (d, J=21.0
Hz, 1H), 4.08 (dd, J=14.1, 6.9 Hz, 1H), 3.90 (ddt, J=14.0, 9.6, 6.9
Hz, 1H), 3.57 (s, 1H), 3.51-3.35 (m, 4H), 3.29-2.98 (m, 3H), 2.71
(t, J=6.3 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.52-2.42 (m, 1H),
2.18-1.94 (m, 5H), 1.88 (dd, J=11.5, 6.1 Hz, 2H), 1.77-1.69 (m,
2H), 1.62 (dd, J=13.6, 6.7 Hz, 2H).
[0559] Compound 16-E2 (mixture of 2 stereoisomers) LC/MS ESI 480.2
(M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.65 (d, J=5.5 Hz, 1H),
7.46 (d, J=7.6 Hz, 1H), 7.41-7.30 (m, 2H), 7.16 (d, J=7.3 Hz, 1H),
6.39 (dd, J=7.3, 1.6 Hz, 1H), 5.23-5.10 (m, 1H), 4.96 (s, 1H),
4.19-4.06 (m, 2H), 3.93-3.84 (m, 1H), 3.57 (s, 1H), 3.50-3.36 (m,
5H), 3.16-2.96 (m, 2H), 2.75-2.65 (m, 2H), 2.56 (t, J=7.4 Hz, 2H),
2.45-2.35 (m, 1H), 2.16-1.99 (m, 5H), 1.88 (dd, J=11.4, 5.8 Hz,
2H), 1.76-1.68 (m, 2H), 1.65-1.59 (m, 2H).
Example 17: Preparation of
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)
pyrrolidin-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetic acid
(compound 17)
Step 1: methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)phenyl)acetate
##STR00273##
[0561] To a solution of methyl 2-(2-iodophenyl)acetate (1.3 g, 4.8
mmol) in 20 mL dry DME and EtOH (5 mL) were added
3,4-dihydro-2H-pyran-6-boronic acid pinacol ester (1.0 g, 4.8
mmol), tetrakis(triphenylphosphine)palladium (0) (277 mg, 0.24
mmol), and sodium carbonate (1.0 g, 9.6 mmol) and the mixture was
heated at 100.degree. C. for 12 h under N.sub.2. The mixture was
allowed to cool to room temperature and diluted with ethyl acetate
(50 mL) and water (10 mL). The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (50 mL.times.3). The
organic phases were combined, washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. After filtration and concentration, the
residue was chromatographed (Combiflash), using 0-20%
EtOAc/petroleum ether as eluent, to give methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)phenyl)acetate (0.4 g, 36%) as an
oil. (ESI 233.1 (m+1).sup.+).
Step 2: methyl 2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00274##
[0563] A mixture of methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)phenyl)acetate (300 mg, 1.3 mmol)
and Pd(OH)2/C (100 mg) in MeOH (25 mL) was hydrogenated (balloon)
for 3 h at 35.degree. C. The catalyst was removed by filtration and
the filtrate was concentrated under reduced pressure. The resulting
residue was chromatographed (Combiflash), using 0-20%
EtOAc/petroleum ether as eluent, to give methyl
2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (180 mg, 60%) as an
oil. (ESI 235.1 (m+1).sup.+).
Step 3: methyl
2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00275##
[0565] To a stirred solution of methyl
2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (150 mg, 0.64 mmol)
in THF (10 mL) at -78.degree. C. under N.sub.2 was added LDA (1.25
mL, 2.5 mmol, 2M in THF) and the reaction was stirred for 0.5 h,
TMSCl (324 mg, 3.0 mmol) was added, the reaction was stirred for
0.25 h, then NBS (445 mg, 2.5 mmol) was added as a solution in THF
(10 mL). The reaction was stirred for 0.5 h at -78.degree. C. and
quenched by the addition of water (10 mL). The mixture was
extracted with ethyl acetate (30 mL.times.3) and the combined
organic phases were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. After filtration and concentration, was
chromatographed (Combiflash), using 0-20% EtOAc/petroleum ether as
eluent, to give methyl
2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (65 mg, 33%).
(ESI 313.2 (m+1).sup.+).
Step 4: methyl
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-
-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00276##
[0567] A mixture of methyl
2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (65 mg, 0.21
mmol), (57 mg, 0.21 mmol) and diisopropylethylamine (65 mg, 0.5
mmol) in acetonitrile (8 mL) was stirred at 25.degree. C. for 16 h.
The solvent was removed under reduced pressure and the residue was
chromatographed on silica gel (DCM: MeOH 20:1) to give ethyl methyl
2-((R)-3-(4-(5,6,7,8-tetrahy
dro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)-2-(2-(tetrahy
dro-2H-pyran-2-yl)phenyl)acetate (30 mg, 28%) as an oil. (ESI 508.1
(m+1).sup.+)
Step 5:
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrro-
lidin-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetic acid
(compound 17)
##STR00277##
[0569] Methyl
2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl) butoxy) pyrrolidin-1-yl)acetate (30 mg, 0.28 mmol) was
treated with LiOH (52 mg, 1.24 mmol) in MeOH (4 mL) and H.sub.2O (1
mL) at 25.degree. C. for 3 hours. The solvent was removed under
reduced pressure and the residue was separated using
semi-preparative reversed-phase HPLC (Prep HPLC A, 30-65% MeCN) to
give compound 17 as a solid (10 mg, 34%).
[0570] Compound 17: LC/MS ESI 494.2 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta..sup.1H NMR (500 MHz, MeOD) .delta. 7.68 (t, J=8.3 Hz, 1H),
7.57 (d, J=7.8 Hz, 1H), 7.40 (dt, J=13.8, 7.5 Hz, 2H), 7.15 (d,
J=7.3 Hz, 1H), 6.38 (dd, J=7.3, 3.3 Hz, 1H), 4.89-4.76 (m, 2H),
4.18 (d, J=17.9 Hz, 1H), 4.09-3.94 (m, 1H), 3.72 (dd, J=22.4, 10.7
Hz, 1H), 3.54-3.43 (m, 2H), 3.38 (dd, J=10.1, 4.5 Hz, 3H),
2.77-2.65 (m, 2H), 2.55 (t, J=6.7 Hz, 2H), 2.17-1.97 (m, 4H),
1.93-1.85 (m, 2H), 1.81-1.58 (m, 8H), 1.51-1.45 (m, 1H), 1.33 (d,
J=22.7 Hz, 3H).
Example 18: Preparation of
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compounds 18-E1 and 18-E2)
Step 1: methyl 2-(2-bromo-5-fluorophenyl)acetate
##STR00278##
[0572] To a solution of 2-(2-bromo-5-fluorophenyl) acetic acid (10
g, 43 mmol) in 60 mL MeOH was added 0.5 mL H.sub.2SO.sub.4. The
mixture was refluxed for 4 hours, allowed to cool to room
temperature and concentrated under reduced pressure. The resulting
pale yellow oil (10 g, 94.3%) was used without any further
purification. (ESI 246.1 (M+H)+)
Step 2: methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate
##STR00279##
[0574] To solution of methyl 2-(2-bromo-5-fluorophenyl)acetate (6.3
g, 25.6 mmol) in DMF (60 mL) was added
3,4-dihydro-2H-pyran-6-boronic acid pinacol ester (5 g, 23.8 mmol),
tris(dibenzylideneacetone) dipalladium (0) (468 mg, 0.52 mmol),
X-Phos (238 mg, 0.52 mmol), and potassium phosphate (2.1 g, 25.6
mmol). The mixture was stirred at 60.degree. C. for 12 hours under
N2. The mixture was allowed to cool to room temperature an
partitioned between ethyl acetate (120 mL) and water (120 mL). The
organic layer was separated and the aqueous layer was extracted
with ethyl acetate (60 mL.times.3). The combined organic phases
were washed with brine and dried over anhydrous Na.sub.2SO.sub.4.
After filtration and concentration, the residue was chromatographed
(Combiflash), using 0-20% EtOAc/petroleum ether as eluent, to give
methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (5.2
g, 87.4%). (ESI 251.1 (M+H).sup.+)
Step 3: methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00280##
[0576] To a solution of methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (500 mg, 2
mmol) in 25 ml anhydrous MeOH was added diisopropylethylamine (0.5
ml) and Pd/C (100 mg). The mixture was stirred for 3 hours at
40.degree. C. under H.sub.2 (balloon). The catalyst was removed by
filtration and the filtrate was concentrated under reduced
pressure. The residue was chromatographed (Combiflash), using 0-20%
EtOAc/petroleum ether as eluent, to give methyl
2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (260 mg,
52%) as an oil. (ESI 253.1 (M+H).sup.+)
Step 4: methyl
2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00281##
[0578] LDA (1.25 ml, 2.5 mmol, 2M in THF) was added to a solution
of methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
(260 mg, 1.03 mmol) in 10 mL THF at -78.degree. C. under N.sub.2.
The reaction was stirred for 0.5 h and TMSCl (324 mg, 3 mmol) was
added. After an additional 0.25 h a solution of NB S (534 mg, 3
mmol) in 10 mL THF was added and reaction was stirred for 0.5 h at
-78.degree. C. The mixture was allowed to warm to room temperature
and diluted with water (10 mL). The mixture was extracted with
ethyl acetate (30 mL.times.3) and the combined organic phases were
washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After
filtration and concentration, the residue was chromatographed
(Combiflash), using 0-20% EtOAc/petroleum ether as eluent, to give
methyl
2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (280
mg, 84.8%). (ESI 333.1 (M+H).sup.+).
Step 5: methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00282##
[0580] To a solution of methyl
2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (70
mg, 0.21 mmol) in DMF (5 mL) was added
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(57 mg, 0.21 mmol) and diisopropylethylamine (81 mg, 0.63 mmol) and
the reaction was stirred for 2 h. The mixture was diluted with
water (10 mL) and extracted with EtOAc (20 mL, .times.2). The
combined organic phases were washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. After filtration and concentration, the
residue was chromatographed (Combiflash), using 20-80%
EtOAc/petroleum ether as eluent, to give methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
(70 mg, 62.8%). (ESI 526.2 (M+H)+)
Step 6:
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 18-E1 and 18-E2)
##STR00283##
[0582] To a solution of methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (70 mg,
0.13 mmol) in 5 mL MeOH was added LiOH (10 mg, 0.4 mmol) and water
(2 mL). The reaction was stirred for 2 hours, filtered and
concentrated under reduced pressure. The residue was
chromatographed by semi-preparative reversed-phase HPLC to give
diastereomeric products compound 18-E1 (25 mg, 36.7%) and compound
18-E2 (13 mg, yield 18.3%), each as a mixture of 2
stereoisomers.
[0583] Compound 18-E1 (mixture of 2 stereoisomers): LC/MS ESI 512.2
(M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.58 (dd, J=8.8,
5.9 Hz, 1H), 7.52-7.42 (m, 1H), 7.21-7.11 (m, 2H), 6.40 (d, J=7.3
Hz, 1H), 4.80 (dd, J=21.1, 11.7 Hz, 2H), 4.22-4.12 (m, 1H), 4.04
(dd, J=10.4, 5.6 Hz, 1H), 3.76-3.66 (m, 1H), 3.61 (d, J=8.1 Hz,
1H), 3.49 (dtd, J=12.6, 6.3, 3.3 Hz, 2H), 3.42-3.34 (m, 3H),
3.22-2.99 (m, 2H), 2.72 (t, J=6.2 Hz, 2H), 2.60-2.51 (m, 2H),
2.16-1.96 (m, 4H), 1.92-1.82 (m, 2H), 1.70 (dddd, J=28.3, 22.6,
9.4, 4.8 Hz, 9H).
[0584] Compound 18-E2 (mixture of 2 stereoisomers): LC/MS ESI 512.2
(M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.44 (dt, J=8.5,
6.0 Hz, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.10 (qd, J=8.4, 2.6 Hz, 1H),
6.39 (dd, J=7.3, 4.0 Hz, 1H), 5.21 (s, 1H), 4.74 (dd, J=29.6, 11.1
Hz, 1H), 4.10 (dd, J=26.7, 15.4 Hz, 2H), 3.66 (dd, J=20.8, 9.7 Hz,
1H), 3.54-3.37 (m, 6H), 3.15-2.96 (m, 2H), 2.72 (t, J=6.2 Hz, 2H),
2.58 (dt, J=14.9, 6.9 Hz, 2H), 2.10 (dd, J=34.9, 11.9 Hz, 2H),
1.99-1.80 (m, 5H), 1.77-1.66 (m, 4H), 1.63-1.55 (m, 3H).
Example 19: Preparation of
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(Compounds 19-E1, 19-E2, 19-E3 and 19-E4)
Step 1: Methyl 2-(2-bromo-5-fluorophenyl)acetate
##STR00284##
[0586] To a solution of 2-(2-bromo-5-fluorophenyl) acetic acid (10
g, 43 mmol) in MeOH (60 mL) was added 0.5 mL H.sub.2SO.sub.4. The
mixture was refluxed for 4 hours, allowed to cool to room
temperature and the solvent was removed under reduced pressure. The
resulting oil (10 g, 94.3%) was used without further purification.
(ESI 246.1 (M+H)+)
Step 2: Methyl
2-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)acetate
##STR00285##
[0588] To a solution of methyl 2-(2-bromo-5-fluorophenyl)acetate
(492 mg, 2 mmol) in DMF (5 mL) was added
2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(392 mg, 2 mmol), tris(dibenzylideneacetone) dipalladium (0) (91
mg, 0.1 mmol), X-Phos (47.6 mg, 0.1 mmol), and potassium phosphate
(424 mg, 2 mmol). The resulting mixture was stirred at 60.degree.
C. for 2 hours under N.sub.2, allowed to cool to room temperature
and partitioned between ethyl acetate (20 mL) and water (20 mL).
The organic layer was separated and the aqueous layer was extracted
with ethyl acetate (20 mL.times.3). The combined organic phases
were washed with brine and dried over anhydrous Na.sub.2SO.sub.4.
After filtration and concentration, the residue was chromatographed
(Combiflash), using 20-80% EtOAc/petroleum ether as eluent, to give
methyl 2-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)acetate (350 mg,
73%). (ESI 237.2 (M+H).sup.+)
Step 3: Methyl
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate
##STR00286##
[0590] To a solution of methyl
2-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl) acetate (350 mg, 1.48
mmol) in methanol (10 mL) was added Pd/C (50 mg). The mixture was
stirred for 3 hours at 40.degree. C. under H.sub.2 (balloon). The
catalyst was removed by filtration and the filtrate was
concentrated under reduced pressure. The residue was
chromatographed (Combiflash), using 5-20% EtOAc/petroleum ether as
eluent, to give methyl
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate (260 mg, 73%) as
an oil. LCMS: 239 (M+H).sup.+
Step 4: methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate
##STR00287##
[0592] A solution of methyl
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate (260 mg, 1.09
mmol) in THF (10 mL) under N.sub.2 was cooled to -78.degree. C. and
treated with LDA (1.25 mL, 2.5 mmol, 2 M in THF) and the mixture
was stirred for 0.5 h. TMSCl (324 mg, 3 mmol) was added, the
reaction was stirred for 0.25 h and NBS (534 mg, 3 mmol) in THF (10
mL) was added. The reaction was stirred for 0.5 h, diluted with
water and extracted with ethyl acetate (30 mL.times.3). The
combined organic phases were washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. After filtration and concentration, The
residue was chromatographed (Combiflash), using 5-20%
EtOAc/petroleum ether as eluent, to give methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate (250 mg,
71.8%) as an oil. (ESI 317.2) (M+H)+)
Step 5: methyl
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00288##
[0594] To a solution of methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate (100 mg,
0.31 mmol) in 5 mL dry DMF was added
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(87 mg, 0.31 mmol) and diisopropylethylamine (120 mg, 0.93 mmol).
The reaction was stirred for 2 h, diluted with water (10 mL) and
extracted with ethyl acetate (20 mL.times.3). The combined organic
phases were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was chromatographed (Combiflash), using 20-80% EtOAc/petroleum
ether as eluent, to give methyl
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (110
mg, 68%) as a solid. (ESI 512 (M+H).sup.+).
Step 6:
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(Compounds 19-E1, 19-E2, 19-E3 and 19-E4)
##STR00289##
[0596] To a solution of methyl
2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (110 mg,
0.21 mmol) in methanol (5 mL) was added LiOH (20 mg, 0.8 mmol) and
water (4 mL). The reaction was stirred for 2 h, filtered and
concentrated under reduced pressure. The resulting the residue was
chromatographed using semi-preparative reversed-phase HPLC to give
diastereomeric compounds compound 19-E1 (10 mg, yield 9.3%),
compound 19-E2 (10 mg, yield 9.3%), compound 19-E3 (10 mg, yield
9.3%) and compound 19-E4 (10 mg, yield 9.3%).
[0597] Compound 19-E1: LC/MS ESI 498.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, MeOD) .delta. 7.48 (dd, J=8.8, 5.7 Hz, 1H), 7.42 (dd,
J=10.1, 2.7 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.14 (td, J=8.4, 2.8
Hz, 1H), 6.41 (dd, J=20.8, 7.3 Hz, 1H), 4.95 (s, 1H), 4.58-4.46 (m,
1H), 4.18 (d, J=18.9 Hz, 1H), 4.05-3.98 (m, 2H), 3.86 (dd, J=15.5,
7.5 Hz, 2H), 3.79 (dd, J=8.3, 6.3 Hz, 1H), 3.50 (t, J=6.2 Hz, 2H),
3.42 (dd, J=14.2, 8.7 Hz, 3H), 3.28 (s, 1H), 3.12-2.98 (m, 2H),
2.73 (t, J=6.2 Hz, 2H), 2.60 (ddd, J=15.0, 9.5, 5.5 Hz, 2H),
2.51-2.38 (m, 1H), 2.08 (ddd, J=14.9, 8.4, 4.6 Hz, 3H), 1.90 (dd,
J=11.8, 5.7 Hz, 2H), 1.80-1.60 (m, 4H).
[0598] Compound 19-E2: LC/MS ESI 498.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, MeOD) .delta. 7.51-7.46 (m, 1H), 7.42 (dd, J=10.1, 2.7
Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.13 (td, J=8.4, 2.8 Hz, 1H), 6.43
(d, J=7.3 Hz, 1H), 4.94 (s, 1H), 4.17 (dd, J=19.1, 11.5 Hz, 2H),
4.11-4.03 (m, 1H), 3.95-3.80 (m, 3H), 3.76-3.68 (m, 1H), 3.52-3.46
(m, 3H), 3.43-3.37 (m, 2H), 3.26 (d, J=12.5 Hz, 1H), 3.13-2.99 (m,
2H), 2.73 (t, J=6.2 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.42-2.29 (m,
1H), 2.07 (dtd, J=42.5, 12.5, 7.8 Hz, 4H), 1.94-1.86 (m, 2H),
1.78-1.69 (m, 2H), 1.68-1.58 (m, 3H).
[0599] Compound 19-E3: LC/MS ESI 498.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, MeOD) .delta. 7.52-7.39 (m, 2H), 7.23 (d, J=7.3 Hz, 1H),
7.13 (td, J=8.4, 2.8 Hz, 1H), 6.42 (t, J=10.9 Hz, 1H), 4.87-4.81
(m, 1H), 4.17 (s, 1H), 4.04 (ddt, J=33.6, 28.5, 7.3 Hz, 3H), 3.88
(dd, J=15.7, 7.6 Hz, 1H), 3.79 (dd, J=8.2, 6.2 Hz, 1H), 3.56-3.51
(m, 1H), 3.46-3.34 (m, 4H), 3.16 (ddd, J=16.9, 15.7, 6.6 Hz, 3H),
2.73 (t, J=6.2 Hz, 2H), 2.62 (dd, J=16.3, 7.8 Hz, 2H), 2.48 (d,
J=7.6 Hz, 1H), 2.18-2.12 (m, 2H), 2.09-2.01 (m, 1H), 1.92-1.86 (m,
2H), 1.75 (dd, J=12.1, 7.4 Hz, 2H), 1.68-1.60 (m, 2H).
[0600] Compound 19-E4: LC/MS ESI 498.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, MeOD) .delta. 7.46 (ddd, J=13.0, 9.5, 4.3 Hz, 2H), 7.24
(d, J=7.3 Hz, 1H), 7.13 (td, J=8.4, 2.8 Hz, 1H), 6.43 (d, J=7.3 Hz,
1H), 4.86 (s, 1H), 4.23-4.14 (m, 2H), 4.09 (td, J=8.3, 4.6 Hz, 1H),
3.98 (dd, J=14.8, 7.4 Hz, 1H), 3.86 (dd, J=15.9, 7.7 Hz, 1H), 3.71
(dd, J=8.6, 6.5 Hz, 1H), 3.54 (dt, J=9.1, 6.1 Hz, 1H), 3.46-3.35
(m, 4H), 3.25-3.08 (m, 3H), 2.73 (t, J=6.2 Hz, 2H), 2.69-2.54 (m,
2H), 2.39 (d, J=7.8 Hz, 1H), 2.16 (d, J=3.6 Hz, 2H), 2.02 (dq,
J=12.4, 7.8 Hz, 1H), 1.95-1.83 (m, 2H), 1.75 (dd, J=12.3, 7.4 Hz,
2H), 1.62 (dd, J=13.6, 7.0 Hz, 2H).
Example 20: Preparation of
2-(2-cyclopropoxy-5-fluorophenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-nap-
hthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (Compounds 20-E1
and 20-E2)
Step 1: 2-bromo-1-cyclopropoxy-4-fluorobenzene
##STR00290##
[0602] A mixture of 2-bromo-4-fluorophenol (250 mg, 1.31 mmol),
bromocyclopropane (792 mg, 6.54 mmol), NaI (2 mg, 0.013 mmol) and
K.sub.2CO.sub.3 (543 mg, 3.93 mmol) in DMF (4 mL) was stirred and
heated to 150.degree. C. under microwave irradiation (Biotage) for
2 hours. The reaction mixture was diluted with water (10 mL) and
ethyl acetate (10 mL), the organic layer was separated and the
aqueous layer was extracted with ethyl acetate (10 mL.times.3). The
combined organic layers were washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. After filtration and concentration, the
residue was chromatographed (Combiflash), using EtOAc/petroleum
ether (1:10) as eluent, to give
2-bromo-1-cyclopropoxy-4-fluorobenzene (50 mg, 16.5%).sup.1H NMR
(500 MHz, CDCl3) .delta. 7.28-7.22 (m, 1H), 7.18 (dd, J=9.1, 4.9
Hz, 1H), 7.03-6.94 (m, 1H), 3.76 (tt, J=5.9, 3.1 Hz, 1H), 0.87-0.69
(m, 4H).
Step 2: 2-cyclopropoxy-5-fluorophenylboronic acid
##STR00291##
[0604] To a solution of 2-bromo-1-cyclopropoxy-4-fluorobenzene (250
mg, 1.08 mmol) in THF (15 mL) at -78.degree. C. under Ar was added
nBuLi (0.87 mL, 2.16 mmol, 2.5 M in THF). The mixture was stirred
for 0.5 h, then triisopropyl borate (224 mg, 1.19 mmol) was slowly
added via syringe. The mixture was stirred continuously for 2 h at
-78.degree. C., then quenched by the addition of saturated aqueous
NH.sub.4Cl solution (5 mL). The mixture was allowed to warm to room
temperature and partitioned between water (10 mL) and ethyl acetate
(10 mL). The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (15 mL.times.3), washed with brine and
dried over anhydrous Na.sub.2SO.sub.4. The organic phase was
concentrated to dryness to give
2-bromo-1-cyclopropoxy-4-fluorobenzene (70 mg, yield 33.0%)
Step 3
2-(2-cyclopropoxy-5-fluorophenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (Compounds
20-E1 and 20-E2)
##STR00292##
[0606] A mixture of
(R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(60 mg, 0.22 mmol), 2-cyclopropoxy-5-fluorophenylboronic acid (47
mg, 0.24 mmol) and 2-oxoacetic acid (18 mg, 0.24 mmol) in MeCN (4
mL) was stirred for 2 hours. The residue was chromatographed using
semi-preparative reversed-phase HPLC (30-65% MeCN) to give compound
20 (45 mg, 42.6%). The racemic product was separated by chiral SFC
to diastereomeric products compound 20-E1 (9.3 mg) and compound
20-E2 (11.1 mg).
[0607] Compound 20-E1 LC/MS ESI 482.2 (M+H).sup.+. 1H NMR (500 MHz,
MeOD) .delta. 7.42 (dd, J=9.1, 4.5 Hz, 1H), 7.31 (dd, J=8.9, 2.8
Hz, 1H), 7.16 (ddd, J=20.7, 12.9, 5.2 Hz, 2H), 6.35 (d, J=7.3 Hz,
1H), 4.86 (s, 1H), 4.11-3.80 (m, 1H), 3.48-3.35 (m, 3H), 3.17 (dd,
J=23.9, 15.4 Hz, 2H), 2.87 (s, 1H), 2.71 (t, J=6.3 Hz, 2H), 2.50
(t, J=7.6 Hz, 2H), 2.38-2.25 (m, 1H), 2.24-2.08 (m, 1H), 1.89 (dt,
J=12.2, 6.1 Hz, 2H), 1.62 (dd, J=13.5, 7.4 Hz, 3H), 1.41 (s, 2H),
1.32 (dd, J=22.3, 9.5 Hz, 5H), 0.98-0.71 (m, 4H).
[0608] Compound 20-E2 LC/MS ESI 482.2 (M+H).sup.+. 1H NMR (500 MHz,
MeOD) .delta. 7.43 (dd, J=9.1, 4.5 Hz, 1H), 7.33 (dd, J=8.9, 2.9
Hz, 1H), 7.22-7.15 (m, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.36 (t, J=5.8
Hz, 1H), 4.88-4.82 (m, 1H), 4.00-3.87 (m, 1H), 3.60 (s, 1H),
3.44-3.34 (m, 3H), 3.16-3.04 (m, 1H), 2.72 (dd, J=15.9, 9.5 Hz,
3H), 2.56-2.46 (m, 2H), 2.42-2.31 (m, 1H), 2.22-2.07 (m, 1H),
1.94-1.83 (m, 2H), 1.67-1.60 (m, 3H), 1.43 (s, 2H), 1.35 (d, J=4.6
Hz, 5H), 0.95-0.70 (m, 4H).
Example 21: Preparation of
2-(2-cyclobutylpyridin-3-yl)-2-((3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthy-
ridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compounds 21-B-E1,
21-B-E2 and 21-A)
Step 1: ethyl
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naph-
thyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate stereoisomer B
##STR00293##
[0610] A mixture of
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e stereoisomer B (120 mg, 0.44 mmol), ethyl
2-chloro-2-(2-cyclobutylpyridin-3-yl)acetate (110 mg, 0.44 mmol)
and diisopropylethylamine (513 mg, 3.72 mmol) in acetonitrile (8
mL) was stirred at 50.degree. C. for 16 hours. Solvent was removed
in vacuo, and the residue was purified by silica gel column (DCM:
MeOH 20:1) to give the desired product ethyl
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-((R)-1,2,3,4-tetrahy
dro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer B as a yellow oil (95 mg). Yield 44% (ESI 493
(M+H)+).
Step 2:
2-(2-cyclobutylpyridin-3-yl)-2-((3R)-3-(4-(1,2,3,4-tetrahydro-1,8--
naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid stereoisomer B
(compounds 21-B-E1 and 21-B-E2)
##STR00294##
[0612] Ethyl
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naph-
thyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate stereoisomer B (95 mg,
0.19 mmol) was treated with LiOH--H2O (52 mg, 1.24 mmol) in MeOH (4
mL) and H2O (1 mL) at 40.degree. C. for 4 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 21-B as a white solid (68 mg, 77%
yield). The racemic product was separated by Prep chiral SFC F to
give diastereomeric products compound 21-B-E1 (4 mg) and compound
21-B-E2 (6 mg) as white solids.
[0613] Compound 21-B-E1 LC/MS ESI 465 (M+H)+. 1H NMR (500 MHz,
MeOD) .delta. 8.68 (m, 1H), 8.08 (d, J=9.5 Hz, 1H), 7.71 (m, 1H),
7.31 (m, 2H), 6.52 (m, 1H), 4.82 (s, 1H), 4.23 (m, 2H), 3.55-3.35
(m, 4H), 3.20 (m, 3H), 2.76 (m, 2H), 2.63-1.86 (m, 9H), 1.75-1.50
(m, 7H), Chiral SFC F: ee 100%, Rt=7.78 min.
[0614] Compound 21-B-E2 LC/MS ESI 465 (M+H)+. 1H NMR (500 MHz,
MeOD) .delta. 8.58 (m, 1H), 8.08 (d, J=9.5 Hz, 1H), 7.75 (m, 1H),
7.31 (m, 2H), 6.52 (m, 1H), 4.82 (s, 1H), 4.23 (m, 2H), 3.55-3.35
(m, 4H), 3.20 (m, 3H), 2.76 (m, 2H), 2.63-1.86 (m, 9H), 1.75-1.50
(m, 7H), Chiral SFC F: ee 100%, Rt=12.02 min.
Step 3:
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-((S)-1,2,3,4-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
stereoisomer A (compound 21-A)
##STR00295##
[0616]
2-(2-cyclobutylpyridin-3-yl)-2-((R)-3-(4-((S)-1,2,3,4-tetrahydro-1,-
8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid stereoisomer
A (compound 21-A) was synthesized from
2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-
e stereoisomer A by the same procedures as for stereoisomer B.
[0617] Compound 21-A LC/MS ESI 465.3 (M+H)+1H NMR (500 MHz, MeOD)
.delta. 8.56-8.54 (m, 1H), 8.08-8.01 (m, 1H), 7.72-7.70 (m, 1H),
7.32-7.29 (m, 2H), 6.56-6.52 (m, 1H), 4.82-4.73 (m, 1H), 4.30-4.18
(m, 2H), 3.78-3.35 (m, 4H), 3.28-2.95 (m, 3H), 2.81-2.28 (m, 6H),
2.24-1.88 (m, 5H), 1.74-1.48 (m, 7H).
Example 22: Preparation of
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 92-A-E1, 92-A-E2, 92-B-E1 and
92-B-E2)
Step 1: Methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00296##
[0619] To a solution of methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (2.4 g, 9.6
mmol) in 100 mL anhydrous MeOH was added Pd(OH).sub.2 (100 mg) and
TEA (2 mL). The mixture was stirred for 8 hours at 40.degree. C.
under an atmosphere of H.sub.2 (balloon).
[0620] The catalyst was removed by filtration and the filtrate was
concentrated under reduced pressure. The residue was
chromatographed on silica (Combiflash) using 5-20% EtOAc/petroleum
ether as eluent, to give racemic methyl
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (2.2 g,
92%). Chiral separation using SFC (AY-H (250*4.6 mm Sum) Moblie
Phase=Hexane (0.1% DEA): EtOH (0.1% DEA)=95:5) gave stereoisomer A
(identified as methyl
(R)-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate, 960 mg,
43.5%) and stereoisomer B (identified as methyl
(S)-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate, 904 mg,
40.7%); (ESI 253.2 (M+H)+).
Step 2: Methyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(stereoisomer B)
##STR00297##
[0622] LDA (25 mL, 50 mmol, 2M in THF) was added to a solution of
(S)-methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
(stereoisomer B, 4.2 g, 16.7 mmol) in THF (100 mL) under an
atmosphere of N.sub.2 at -78.degree. C. The reaction was stirred
for 0.5 h and TMSCl (5.4 g, 50 mmol) was added. After an additional
15 min, a solution of NB (8.9 g, 50 mmol) in THF (50 mL) was added
and the reaction was stirred for 0.5 h at -78.degree. C. The
reaction was diluted with water (10 mL) and extracted with ethyl
acetate (50 mL.times.2). The combined organic phases were washed
with brine and dried over anhydrous Na.sub.2SO.sub.4. After
filtration and concentration, the residue was chromatographed on
silica (Combiflash) using 0-20% EtOAc/petroleum ether as eluent, to
give methyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(stereoisomer B, 4.1 g, 74.5%); (ESI 331.3 (M+H)+.
Step 3: Methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8--
tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
(stereoisomer B)
##STR00298##
[0624] To a solution of methyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(stereoisomer B, 4.1 g, 12.4 mmol) in acetonitrile (30 mL) was
added
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(3.4 g, 12.4 mmol) and DIPEA (4.8 g, 37.2 mmol). The reaction was
stirred for 1 c, diluted with water (50 mL) and extracted with
ethyl acetate (50 mL.times.3). The combined organic phase was
washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After
filtration and concentration, the residue was chromatographed on
silica (Combiflash) using 20-80% EtOAc/petroleum ether as eluent,
to give methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8--
tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate as
a mixture of diastereomers (stereoisomer B, 4.9 g, 75%); (ESI 526.2
(M+H).sup.+); .sup.1H NMR (500 MHz, MeOD) .delta. 7.51 (ddd,
J=20.9, 8.7, 5.9 Hz, 1H), 7.34 (dt, J=10.3, 3.4 Hz, 1H), 7.11 (d,
J=7.3 Hz, 1H), 7.09-7.03 (m, 1H), 6.36 (d, J=7.3 Hz, 1H), 4.86 (m,
2H), 4.47 (m, 1H), 4.08-3.97 (m, 2H), 3.69-3.61 (m, 4H), 3.39 (m,
3H), 2.87 (m, 1H), 2.75-2.63 (m, 3H), 2.56-2.35 (m, 4H), 2.00 (m,
1H), 1.97-1.75 (m, 5H), 1.72-1.63 (m, 4H), 1.57 (m, 4H).
Step 4:
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5-
,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 92-B-E1 and 92-B-E2)
##STR00299##
[0626] To a solution of methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8--
tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
(stereoisomer B, 4.9 g, 9.3 mmol) in methanol (50 mL) was added
LiOH (480 mg, 20 mmol) and water (20 mL). The reaction was stirred
for 16 h at 25.degree. C., filtered and concentrated under reduced
pressure then purified with semi-preparative reversed-phase HPLC to
give individual diastereomers
(S)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid compound 92-B-E1 (1.88 g), (Yield 39.4%) and
(R)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid compound 92-B-E2 (1.33 g) (Yield 27.9%).
[0627] Compound 92-B-E1: LC/MS ESI 512.3 (M+H).sup.+. 1H NMR (400
MHz, MeOD) .delta. 7.58 (dd, J=8.8, 5.9 Hz, 1H), 7.46 (dd, J=10.0,
2.7 Hz, 1H), 7.22-7.11 (m, 2H), 6.40 (d, J=7.3 Hz, 1H), 4.90 (s,
1H), 4.77 (d, J=10.3 Hz, 1H), 4.20 (m, 1H), 4.04 (dd, J=7.5, 5.6
Hz, 1H), 3.68 (t, J=11.6 Hz, 1H), 3.62 (d, J=9.2 Hz, 1H), 3.49 (t,
J=5.6 Hz, 2H), 3.42-3.35 (m, 3H), 3.23 (d, J=12.6 Hz, 1H), 3.04 (m,
1H), 2.72 (t, J=6.2 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 2.2-1.95 (m,
4H), 1.9-1.8 (m, 2H), 1.8-1.55 (m, 8H).
[0628] Compound 92-B-E2: LC/MS ESI 512.3 (M+H).sup.+. .sup.1H NMR
(500 MHz, MeOD) .delta. 7.47-7.39 (m, 2H), 7.19 (d, J=7.3 Hz, 1H),
7.11 (td, J=8.4, 2.6 Hz, 1H), 6.40 (d, J=7.3 Hz, 1H), 4.75 (d,
J=11.1 Hz, 2H), 4.15 (d, J=9.4 Hz, 1H), 4.08 (s, 1H), 3.67 (t,
J=10.7 Hz, 1H), 3.53-3.42 (m, 3H), 3.38 (d, J=5.3 Hz, 2H), 3.10 (m,
2H), 2.72 (t, J=6.2 Hz, 2H), 2.58 (m, 2H), 2.15 (s, 1H), 2.09 (s,
1H), 1.95 (d, J=7.8 Hz, 2H), 1.92-1.82 (m, 3H), 1.73 (m, 4H), 1.61
(m, 4H).
Step 5:
2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5-
,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 92-A-E1 and 92-A-E2)
##STR00300##
[0630]
(R)-2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-
-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid compound 92-A-E1 and
(S)-2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid compound 92-A-E2 were synthesized from methyl
(R)-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate
(stereoisomer A) by the same procedures as for stereoisomer B.
[0631] Compound 92-A-E1: LC/MS ESI 512.1 (M+H).sup.+, .sup.1H NMR
(500 MHz, MeOD) .delta. 7.58-7.50 (m, 2H), 7.16 (d, J=7.4 Hz, 1H),
7.11-7.04 (m, 1H), 6.38 (d, J=7.3 Hz, 1H), 4.87 (d, J=10.9 Hz, 1H),
4.62 (s, 1H), 4.11 (d, J=2.5 Hz, 1H), 4.04 (m, 1H), 3.72 (m, 1H),
3.47-3.35 (m, 5H), 3.16-3.03 (m, 2H), 2.70 (d, J=6.1 Hz, 2H),
2.58-2.50 (m, 2H), 2.16-1.95 (m, 4H), 1.90-1.85 (m, 2H), 1.73-1.65
(m, 4H), 1.64-1.56 (m, 4H).
[0632] Compound 92-A-E2: LC/MS ESI 512.1 (M+H).sup.+, .sup.1H NMR
(500 MHz, MeOD) .delta. 7.50-7.39 (m, 2H), 7.16 (d, J=7.3 Hz, 1H),
7.09 (td, J=8.4, 2.7 Hz, 1H), 6.38 (d, J=7.3 Hz, 1H), 5.08 (s, 1H),
4.76 (d, J=11.0 Hz, 1H), 4.14 (d, J=3.5 Hz, 1H), 4.07 (d, J=12.2
Hz, 1H), 3.44 (m, 3H), 3.38 (d, J=5.5 Hz, 3H), 2.99-2.92 (m, 1H),
2.71 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.10-2.03 (m, 2H),
1.95-1.81 (m, 5H), 1.73-1.67 (m, 4H), 1.60 (m, 4H).
Example 23: Preparation of
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compounds 93-A-E1, 93-A-E2, 93-B-E1 and 93-B-E2)
Step 1: methyl 2-(2-bromo-5-fluorophenyl)acetate
##STR00301##
[0634] To a solution of 2-(2-bromo-5-fluorophenyl) acetic acid (10
g, 43 mmol) in 60 mL of MeOH was added 0.5 mL H.sub.2SO.sub.4 and
the mixture was heated under reflux for 4 hours. The solvent was
removed under reduced pressure to give methyl
2-(2-bromo-5-fluorophenyl)acetate as an oil (10 g, yield: 94.3%)
that was used without any further purification. (ESI 246.1
(M+H)+)
Step 2: methyl 2-(5-fluoro-2-(furan-2-yl)phenyl)acetate
##STR00302##
[0636] To a solution of methyl 2-(2-bromo-5-fluorophenyl)acetate (5
g, 20.2 mmol) in 100 mL of DMF was added furan-2-ylboronic acid
(2.72 g, 24 mmol), tris(dibenzylideneacetone) dipalladium (0) (915
mg, 1 mmol), X-Phos (476 mg, 1 mmol), and potassium phosphate (8.5
g, 40 mmol). The mixture was stirred at 60.degree. C. for 8 hours
under N.sub.2. The reaction was diluted with 200 mL ethyl acetate
and 200 mL water, and the organic layer was separated. The aqueous
layer was extracted with ethyl acetate three times (200
mL.times.3), and the combined organic layer was washed with brine
and dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the residue was chromatographed on silica
(Combiflash) using 0-20% ethyl acetate/petroleum ether as eluent,
to give methyl 2-(5-fluoro-2-(furan-2-yl)phenyl)acetate (3.9 g,
Yield 82.7%); ESI 237.2 (M+H).sup.+
Step 3: methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
##STR00303##
[0638] To a solution of methyl
2-(5-fluoro-2-(furan-2-yl)phenyl)acetate (2.34 g, 10 mmol) in 30 mL
EtOAC was added Pd/C (1 g) and DIEA (2.58 g, 20 mmol). The mixture
was stirred for 5 hours at 35.degree. C. under H.sub.2 atmosphere
(balloon). After the reaction was over, the catalyst was removed by
filtration, and the filtrate was concentrated under reduced
pressure. The residue was chromatographed on silica (Combiflash)
using 5-20% ethyl acetate/petroleum ether as eluent to give methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate (1.56 g, 66.7%)
as an oil.
[0639] The racemic compound was separated by SFC (SFC (AY-H
(250*4.6 mm Sum) Mobile Phase:Hexane (0.1% DEA): EtOH (0.1%
DEA)=95:5) to give stereoisomer A (950 mg) and stereoisomer B (920
mg) as oils; ESI 239.1 (M+H)+
Step 4: Methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
stereoisomer A
##STR00304##
[0641] To a solution of methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate stereoisomer A
(250 mg, 1.05 mmol) in 10 mL dry THF under N.sub.2 at -78.degree.
C. was added LDA (1.25 mL, 2.5 mmol, 2 M in THF). The reaction was
stirred for 0.5 h and TMSCl (324 mg, 3 mmol) was added. After
stirring for 15 minutes, NBS (534 mg, 3 mmol) in 10 mL THF was
added and the mixture was stirred for 0.5 h at -78.degree. C. The
mixture was diluted with water and extracted with ethyl acetate (30
mL.times.3). The combined organic layer was washed with brine and
dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the residue was chromatographed on silica
(Combiflash) using 5-20% ethyl acetate/petroleum ether as eluent to
give methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
stereoisomer A (240 mg, 71%) as an oil; ESI 317.2 (M+H).sup.+
Step 5: Methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A
##STR00305##
[0643] To a solution of methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
stereoisomer A (240 mg, 0.76 mmol) in 10 mL ACN was added
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(213 mg, 0.76 mmol) and DIPEA (295 mg, 2.28 mmol). The reaction was
stirred for 4 hours, diluted with water (30 mL) water and extracted
with ethyl acetate (50 mL.times.3). The combined organic layer was
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was
chromatographed on silica (Combiflash) using 20-80% ethyl
acetate/petroleum ether as eluent to give methyl
2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A (300 mg, 77%) as a solid; ESI 512 (M+H).sup.+
Step 6:
2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid stereoisomer B (Compounds 93-A-E1 and 93-A-E2)
##STR00306##
[0645] To a solution of methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A (330 mg, 0.59 mmol) in 10 mL methanol was added LiOH
(40 mg, 1.6 mmol) and water (10 mL). The reaction was stirred for
16 hours at 25.degree. C. To the mixture was added 1 N HCl to
adjust the pH to 5-6. The mixture was concentrated under reduced
pressure and the residue was purified with semi-preparative HPLC to
give compound 93-A-E1 (56 mg, 18%) as a solid, and compound 93 A-E2
(45 mg, 15%) as a solid.
[0646] Compound 93-A-E1 ESI 498.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.58 (dd, J=8.8, 5.9 Hz, 1H), 7.45 (dd, J=10.0,
2.7 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.15 (dd, J=8.4, 5.8 Hz, 1H),
6.41 (d, J=7.3 Hz, 1H), 5.22 (t, J=7.0 Hz, 1H), 4.96 (s, 1H), 4.19
(s, 1H), 4.07 (dd, J=14.4, 7.3 Hz, 1H), 3.88 (dt, J=14.1, 7.0 Hz,
1H), 3.60-3.43 (m, 3H), 3.43-3.37 (m, 2H), 3.26 (dd, J=33.4, 10.4
Hz, 2H), 3.04 (t, J=7.6 Hz, 1H), 2.72 (t, J=6.2 Hz, 2H), 2.58 (t,
J=7.6 Hz, 2H), 2.44 (dt, J=12.0, 5.9 Hz, 1H), 2.16-1.93 (m, 5H),
1.92-1.86 (m, 2H), 1.75 (m, 2H), 1.68-1.56 (m, 2H)
[0647] Compound 93-A-E2 ESI 498.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.49 (dd, J=8.7, 5.9 Hz, 1H), 7.46 (d, J=10.3
Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.11 (t, J=6.9 Hz, 1H), 6.42 (d,
J=7.3 Hz, 1H), 5.18 (s, 1H), 4.87-4.81 (m, 1H), 4.16 (s, 1H),
4.16-4.09 (m, 1H), 3.88 (t, J=7.1 Hz, 1H), 3.50 (t, J=6.1 Hz, 3H),
3.42-3.36 (m, 2H), 3.10 (d, J=7.6 Hz, 2H), 2.73 (t, J=6.2 Hz, 2H),
2.67-2.54 (m, 2H), 2.41 (d, J=10.7 Hz, 1H), 2.16-1.96 (m, 5H),
1.93-1.85 (m, 2H), 1.75 (m, 2H), 1.64 (m, 2H).
Step 7: Methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
stereoisomer B
##STR00307##
[0649] To a solution of methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate stereoisomer B
(250 mg, 1.05 mmol) in 10 mL dry THF under N.sub.2 at -78.degree.
C. was added LDA (1.25 mL, 2.5 mmol, 2 M in THF). The reaction was
stirred for 0.5 h and TMSCl (324 mg, 3 mmol) was added. After
stirring for 15 minutes, NBS (534 mg, 3 mmol) in 10 mL, THF was
added and the mixture was stirred for 0.5 h at -78.degree. C. The
mixture was diluted with water and extracted with ethyl acetate (30
mL.times.3). The combined organic layer was washed with brine and
dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the residue was chromatographed on silica
(Combiflash) using 5-20% ethyl acetate/petroleum ether as eluent to
give methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
stereoisomer B (235 mg, 70.8%) as an oil; ESI 317.2) (M+H)+
Step 8: methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer B
##STR00308##
[0651] To a solution of methyl
2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate
stereoisomer B (100 mg, 0.31 mmol) in 5 mL ACN was added
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(87 mg, 0.31 mmol) and DIPEA (120 mg, 0.93 mmol). The reaction was
stirred for 4 hours, diluted with water (10 mL) water and extracted
with ethyl acetate (20 mL.times.3). The combined organic layer was
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was
chromatographed on silica (Combiflash) using 20-80% ethyl
acetate/petroleum ether as eluent to give methyl
2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer B (120 mg, 78%) as a solid; ESI 512.2 (M+H).sup.+
Step 9:
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
stereoisomer B (Compounds 93-B-E1 and 93-B-E2)
##STR00309##
[0653] To a solution of methyl
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahyd-
ro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer B (300 mg, 0.59 mmol) in 10 mL methanol was added LiOH
(40 mg, 1.6 mmol) and water (10 mL). The reaction was stirred for
16 hours at 25.degree. C. To the mixture was added 1 N HCl to
adjust the pH to 5-6. The mixture was concentrated under reduced
pressure, and the residue was purified with semi-preparative HPLC
to give compound 93-B-E1 (27 mg, 9%) as a solid, and compound
93-B-E2 (30 mg, 10%) as a solid.
[0654] Compound 93-B-E1 ESI 498.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.58 (dd, J=8.8, 6.0 Hz, 1H), 7.48 (d, J=10.1
Hz, 1H), 7.17 (dd, J=20.5, 7.7 Hz, 2H), 6.41 (d, J=7.3 Hz, 1H),
5.29 (t, J=7.1 Hz, 1H), 4.9 (s, 1H), 4.17 (s, 1H), 4.08 (dd,
J=14.6, 7.2 Hz, 1H), 3.89 (dd, J=13.8, 7.8 Hz, 1H), 3.60-3.38 (m,
5H), 3.16 (d, J=7.5 Hz, 1H), 2.72 (t, J=6.2 Hz, 2H), 2.59 (dd,
J=14.4, 7.2 Hz, 2H), 2.48 (dd, J=11.9, 5.2 Hz, 1H), 2.18 (s, 2H),
2.12-1.99 (m, 2H), 2.01-1.85 (m, 4H), 1.74 (m, 2H), 1.64 (m,
2H).
[0655] Compound 93-B-E2 ESI 498.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.49 (dd, J=8.7, 5.8 Hz, 1H), 7.44 (d, J=10.1
Hz, 1H), 7.19 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.0 Hz, 1H), 6.41 (d,
J=7.3 Hz, 1H), 5.12 (s, 1H), 4.97 (s, 1H), 4.18 (s, 1H), 4.14-4.08
(m, 1H), 3.86 (t, J=6.9 Hz, 1H), 3.48 (t, J=6.2 Hz, 3H), 3.42-3.38
(m, 3H), 3.19 (s, 1H), 3.04 (s, 1H), 2.73 (t, J=6.3 Hz, 2H), 2.58
(t, J=6.2 Hz, 2H), 2.37 (s, 1H), 2.17-1.99 (m, 5H), 1.94-1.84 (m,
2H), 1.74 (m, 2H), 1.64 (m, 2H).
Example 24: Preparation of
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-1-yl)acetic
acid (compounds 94-E1 and 94-E2)
Step 1: (R)-tert-butyl
3-(allyloxymethyl)pyrrolidine-1-carboxylate
##STR00310##
[0657] A mixture of (R)-tert-butyl
3-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.8 mmol) and NaH
(1.09 g, 27.3 mmol) in DMF (20 mL) was stirred at 0.degree. C. for
1 hour. A solution of 3-bromoprop-1-ene (4.5 g, 37.2 mmol) in DMF
(10 mL) was added dropwise to the above mixture at 0.degree. C.,
and the reaction mixture was stirred at 50.degree. C. overnight.
Solvent was removed in vacuo, and the residue was purified by
silica gel column (pet ether:EtOAc 1:1) to give the desired product
as a colorless oil (5.1 g). Yield 85% (ESI 186 (M+H-56)+).
Step 2: (R)-tert-butyl
3-((3-(1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate
##STR00311##
[0659] To a solution of (R)-tert-butyl
3-(allyloxymethyl)pyrrolidine-1-carboxylate (600 mg, 2.49 mmol) in
THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF,
9.95 mL, 4.97 mmol). The reaction was stirred at 50.degree. C. for
2 hours, then cooled to rt. This solution was added to a mixture of
2-bromo-1,8-naphthyridine (520 mg, 2.49 mmol), cesium carbonate
(2.44 g, 7.47 mmol) and Pd(PPh3)4 (144 mg, 0.125 mmol) in
1,4-Dioxane (10 mL). The reaction was stirred at 90.degree. C. for
1.5 hours. Solvent was removed in vacuo, and the residue was
purified by silica gel column (DCM:MeOH 30:1) to give the desired
product (R)-tert-butyl
3-((3-(1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate
as a yellow oil (200 mg). Yield 22% (ESI 372 (M+H)+).
Step 3: (R)-tert-butyl
3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-
e-1-carboxylate
##STR00312##
[0661] A mixture of (R)-tert-butyl
3-((3-(1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate
(200 mg, 0.54 mmol) and Pd/C (40 mg, 20 Wt %) in ethyl acetate (10
mL) was stirred under H.sub.2 balloon at 40.degree. C. for 16
hours. The solid was removed by filtration, the filtrate was
concentrated in vacuo to give the desired product (R)-tert-butyl
3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-
e-1-carboxylate as a yellow oil (200 mg). Yield 99% (ESI 376
(M+H)+).
Step 4:
(R)-7-(3-(pyrrolidin-3-ylmethoxy)propyl)-1,2,3,4-tetrahydro-1,8-na-
phthyridine
##STR00313##
[0663] (R)-tert-butyl
3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)prop
oxy)methyl)pyrrolidine-1-carboxylate (200 mg, 0.53 mmol) was
treated with HCl in 1,4-dioxane (4M, 10 mL) at rt for 2 hours.
Solvent was removed in vacuo to give the desired product
(R)-7-(3-(pyrrolidin-3-ylmethoxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthyri-
dine as a HCl salt (150 mg). Yield 81% (ESI 276 (M+H)+).
Step 5: methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-1-yl)acetate
##STR00314##
[0665] A mixture of
(R)-7-(3-(pyrrolidin-3-ylmethoxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthyri-
dine (150 mg, 0.43 mmol), methyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(142 mg, 0.43 mmol) and DIPEA (166 mg, 1.29 mmol) in acetonitrile
(10 mL) was stirred at rt for 3 hours. Solvent was removed in
vacuo, and the residue was purified by silica gel column (DCM: MeOH
10:1) to give the desired product methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-1-yl)acetate
as a yellow oil (140 mg). Yield 62%. (ESI 526 (M+H)+).
Step 6:
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(-
5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-1-yl)ac-
etic acid (compounds 94-E1 and 94-E2)
##STR00315##
[0667] Methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)propoxy)methyl)pyrrolidin-1-yl)acetate
(140 mg, 0.27 mmol) was treated with LiOH--H.sub.2O (126 mg, 3.0
mmol) in MeOH (4 mL) and H.sub.2O (1 mL) at room temperature for 2
hours. Solvent was removed in vacuo, and the residue was purified
by Prep-HPLC A (30-60% MeCN) to give diastereomeric products
compound 94-E1 (17 mg) and compound 94-E2 (49 mg) as white
solids.
[0668] Compound 94-E1 LC/MS ESI 512 (M+H).sup.+ 1H NMR (500 MHz,
MeOD) .delta. 7.65-7.54 (m, 2H), 7.36-7.21 (m, 2H), 6.62 (d, J=7.5
Hz, 1H), 5.06 (s, 1H), 4.77-4.75 (m, 1H), 4.11-4.08 (m, 1H),
3.81-3.33 (m, 8H), 3.25-3.14 (m, 2H), 2.95-2.66 (m, 5H), 2.37-1.58
(m, 13H).
[0669] Compound 94-E2 LC/MS ESI 512 (M+H).sup.+ 1H NMR (500 MHz,
MeOD) .delta. 7.48-7.39 (m, 2H), 7.15-7.08 (m, 2H), 6.35 (d, J=7.0
Hz, 1H), 5.25 (s, 1H), 4.73-4.71 (m, 1H), 4.14-4.12 (m, 1H),
3.81-3.33 (m, 8H), 3.25-3.14 (m, 2H), 2.73-2.56 (m, 5H), 2.18-1.52
(m, 13H).
Example 25: Preparation of
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidin-1-yl)acetic
acid (compounds 95-E1 and 95-E2)
Step 1: (5)-tert-butyl
3-(2-(3-methoxy-3-oxoprop-1-enyloxy)ethyl)pyrrolidine-1-carboxylate
##STR00316##
[0671] To a solution of (S)-tert-butyl
3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (3.3 g, 15.5 mmol) and
4-methylmorpholine (1.85 g, 18.5 mmol) in DCM (40 mL) at room
temperature, was added methyl propiolate (1.55 g, 18.5 mmol). The
mixture was stirred at room temperature for 15 hours, then
concentrated in vacuo. The residue was purified by silica gel
column (pet ether: EtOAc 4:1) to give (S)-tert-butyl
3-(2-(3-methoxy-3-oxoprop-1-enyloxy)ethyl)pyrrolidine-1-carboxylate
as a colorless oil (4.0 g). Yield 87% (ESI 200 (M+H-Boc)+).
Step 2: (S)-tert-butyl
3-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-1-carboxylate
##STR00317##
[0673] A mixture of (S)-tert-butyl
3-(2-(3-methoxy-3-oxoprop-1-enyloxy)ethyl)pyrrolidine-1-carboxylate
(4.0 g, 16.0 mmol) and Pd/C (10%, 200 mg) in EtOAc (25 mL) was
stirred under H2 at rt overnight. The solid was removed by
filtration, the filtrate was concentrated in vacuo to give the
desired product (S)-tert-butyl
3-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-1-carboxylate as a
yellow oil (4.0 g). Yield 96% (ESI 202 (M+H-Boc)+).
Step 3: (S)-tert-butyl
3-(2-(4-(dimethoxyphosphoryl)-3-oxobutoxy)ethyl)pyrrolidine-1-carboxylate
##STR00318##
[0675] To a solution of (S)-tert-butyl 3-(2-(3-m ethoxy-3-oxoprop
oxy)ethyl)pyrrolidine-1-carboxylate (1.5 g, 5.0 mmol) and dimethyl
methylphosphonate (0.682 g, 5.5 mmol) in dry THF (10 mL) at
0.degree. C. under Ar, LDA (2M in THF, 5.25 mL, 10.5 mmol) was
added dropwise. After stirring at 0.degree. C. for 10 mins, the
reaction was quenched with MeOH (5 mL). The mixture was
concentrated under vacuum, and the residual was purified by silica
gel column (pet ether: EtOAc 2:1) to give the desired product
(S)-tert-butyl
3-(2-(4-(dimethoxyphosphoryl)-3-oxobutoxy)ethyl)pyrrolidine-1-carboxylate
as a yellow oil (1.1 g). Yield 57% (ESI 394 (M+H)+).
Step 4: (S)-tert-butyl
3-(2-(2-(1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidine-1-carboxylate
##STR00319##
[0677] A mixture of 2-aminonicotinaldehyde (128 mg, 1.1 mmol),
(S)-tert-butyl
3-(2-(4-(dimethoxyphosphoryl)-3-oxobutoxy)ethyl)pyrrolidine-1-carboxylate
(400 mg, 1.1 mmol) and NaOH (81 mg, 2.2 mmol) in MeOH (6 mL) and
H2O (2 mL) was stirred at rt overnight. Solvent was removed in
vacuo, and the residue was purified by prep-HPLC A (40-70% MeCN) to
give the desired product (S)-tert-butyl
3-(2-(2-(1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidine-1-carboxylate
as a colorless oil (60 mg). Yield 16% (ESI 372 (M+H)+).
Step 5:
(S)-7-(2-(2-(pyrrolidin-3-yl)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8--
naphthyridine hydrochloride
##STR00320##
[0679] A mixture of (S)-tert-butyl
3-(2-(2-(1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidine-1-carboxylate
(400 mg, 1.08 mmol) and Pd/C (80 mg, 10%) in EtOAc (20 mL) was
stirred under H2 at room temperate overnight. The mixture was
filtered and the filtrate was concentrated in vacuo. The residue
was treated with a solution of HCl/dioxane (4.0 M, 4 mL) at room
temperate for 2 hours, then the solvent was removed in vacuo to
give the desired product
(S)-7-(2-(2-(pyrrolidin-3-yl)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthy-
ridine hydrochloride as a white solid (325 mg). Yield 96% (ESI
276.2 (M+H)+).
Step 6: Methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidin-1-yl)acetate
##STR00321##
[0681] A mixture of
(S)-7-(2-(2-(pyrrolidin-3-yl)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthy-
ridine hydrochloride (226 mg, 0.65 mmol), methyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(240 mg, 0.65 mmol) and DIEA (252 mg, 1.95 mmol) in acetonitrile
(10 mL) was stirred at RT overnight. Solvent was removed in vacuo,
and the residue was purified by silica gel column (DCM: MeOH 20:1)
to give the desired product methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidin-1-yl)acetate
as a yellow oil (310 mg). Yield 84% (ESI 526 (M+H)+).
Step 7:
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-
-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidin-1-yl)ac-
etic acid (compounds 95-E1 and 95-E2)
##STR00322##
[0683] Methyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)ethyl)pyrrolidin-1-yl)acetate
(310 mg, 0.55 mmol) was treated with LiOH--H2O (250 mg, 5.95 mmol)
in MeOH (5 mL) and H.sub.2O (1 mL) at 40.degree. C. overnight.
Solvent was removed in vacuo, and the residue was purified by
Prep-HPLC A (30-60% MeCN) to give diastereomeric products compound
95-E1 (67 mg) and compound 95-E2 (37 mg) as white solids.
[0684] Compound 95-E1 LC/MS ESI 512.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.62-7.55 (m, 1H), 7.54-7.50 (m, 1H), 7.20-7.10 (m,
2H), 6.35 (d, J=7.3 Hz, 1H), 4.88-4.78 (m, 2H), 4.08-4.04 (m, 1H),
3.82-3.75 (m, 1H), 3.70-3.61 (m, 3H), 3.49-3.40 (m, 3H), 3.38-3.31
(m, 2H), 3.06-2.99 (m, 1H), 2.68-2.77 (m, 5H), 2.50-2.39 (m, 1H),
2.20-1.90 (m, 3H), 1.95-1.60 (m, 9H).
[0685] Compound 95-E2 LC/MS ESI 512.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.43-7.36 (m, 2H), 7.18-7.09 (m, 2H), 6.38-6.33 (d,
J=7.3 Hz, 1H), 5.42 (s, 1H), 4.80-4.50 (m, 1H), 4.18-4.04 (m, 1H),
3.65-3.62 (m, 3H), 3.50-3.41 (m, 2H), 3.38-3.31 (m, 3H), 3.20-3.00
(m, 3H), 2.75-2.65 (m, 4H), 2.40-2.30 (m, 1H), 2.20-2.05 (m, 2H),
1.98-1.93 (m, 1H), 1.90-1.58 (m, 9H).
Example 26: Preparation of
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 96-E1 and 96-E2)
Step 1: 1-(2-bromo-4-fluorophenyl)-4-methylpent-4-en-1-ol
##STR00323##
[0687] An oven dried 3-neck round bottom flask equipped with a
magnetic stirring bar, cooler, nitrogen inlet and a septum was
charged with magnesium (0.489 g, 20.1 mmol). The magnesium was
dried using a heat gun under a nitrogen flow while stirring and
then stirred under a nitrogen flow overnight. Next, dry
tetrahydrofuran (12 mL) was added, and the mixture was brought to
reflux using a heat gun. A small amount of 1,2-dibromoethane (0.116
mL, 1.34 mmol) was added, and the mixture was brought to reflux
again. A solution of 4-bromo-2-methylbut-1-ene (1.6 mL, 13.4 mmol)
in dry tetrahydrofuran (10 mL) was added dropwise at such a rate to
keep an exothermic reaction going. Upon complete addition, the
greyish brown reaction mixture was stirred for another 20 minutes
and slowly cooled to room temperature. The Grignard reagent was
drawn into a syringe and added dropwise to a solution of
2-bromo-4-fluorobenzaldehyde (2.72 g, 13.4 mmol) in dry
tetrahydrofuran (15 mL) under argon atmosphere at 0.degree. C. Upon
complete addition, the mixture was allowed to come to room
temperature, stirred for 30 minutes, quenched with saturated
ammonium chloride and extracted twice with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated in vacuo. Purification by column
chromatography (silica, 1% to 15% diisopropyl ether in heptane)
afforded the desired product
1-(2-bromo-4-fluorophenyl)-4-methylpent-4-en-1-ol (1.43 g). Yield
39%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.58-7.51 (m, 1H),
7.30-7.23 (m, 1H), 7.11-7.02 (m, 1H), 5.09-5.01 (m, 1H), 4.76 (s,
2H), 2.29-2.10 (m, 2H), 2.03 (d, J=3.6 Hz, 1H), 1.96-1.83 (m, 1H),
1.83-1.68 (m, 4H).
Step 2: 5-(2-bromo-4-fluorophenyl)-2,2-dimethyltetrahydrofuran
##STR00324##
[0689] To a solution of
1-(2-bromo-4-fluorophenyl)-4-methylpent-4-en-1-ol (1.43 g, 5.24
mmol) in toluene (30 mL) was added p-toluenesulfonic acid
monohydrate (0.996 g, 5.24 mmol). The mixture was stirred at
80.degree. C. for an hour, cooled to room temperature, quenched
with saturated aqueous sodium bicarbonate and extracted three times
with dichloromethane. The combined organic layers were dried over
sodium sulfate and concentrated in vacuo. Purification by column
chromatography (silica, 0% to 8% diisopropylether in heptane)
afforded the desired product
5-(2-bromo-4-fluorophenyl)-2,2-dimethyltetrahydrofuran (1.28 g).
Yield 89%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.60-7.52
(m, 1H), 7.29-7.21 (m, 1H), 7.07-6.98 (m, 1H), 5.19 (t, J=7.2 Hz,
1H), 2.64-2.53 (m, 1H), 1.93-1.77 (m, 2H), 1.74-1.61 (m, 1H), 1.42
(s, 3H), 1.36 (s, 3H).
Step 3: tert-butyl
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate
##STR00325##
[0691] An oven dried flask was charged with zinc dust (1.202 g,
18.4 mmol) and heated with a heat gun under an argon flow. After
cooling to room temperature, dry tetrahydrofuran (26 mL) was added,
followed by 1,2-dibromoethane (0.04 mL, 0.46 mmol). The mixture was
heated to reflux and cooled to room temperature 3 times. Then,
trimethylsilyl chloride (0.059 mL, 0.46 mmol) was added which
caused the mixture to reflux spontaneously and the zinc to change
morphology. After stirring for 20 minutes, tert-butyl bromoacetate
(1.34 mL, 9.19 mmol) was added dropwise, resulting in an exotherm.
The mixture was kept at an elevated temperature (45.degree. C.) for
30 minutes and then allowed to cool to room temperature. A separate
flask was charged with
5-(2-bromo-4-fluorophenyl)-2,2-dimethyltetrahydrofuran (1.26 g,
4.59 mmol), tri-tert-butylphosphine tetrafluoroborate (0.147 g,
0.505 mmol) and bis-(dibenzylideneacetone)palladium (0.264 g, 0.459
mmol). The reaction vessel was flushed with argon, dry
tetrahydrofuran (26 mL) was added and argon was bubbled through for
five minutes. The zincate solution was added by syringe, and the
reaction mixture was heated to reflux for 1 hour. The mixture was
cooled to room temperature overnight, quenched with saturated
aqueous ammonium chloride and extracted three times with
heptane/ethyl acetate (1/1, v/v). The combined organic layers were
dried over sodium sulfate and concentrated in vacuo. Purification
by column chromatography (silica, 1% to 6% acetone in heptane)
afforded the desired product tert-butyl
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate
(1.31 g). Yield 92%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
7.51 (dd, J=8.6, 6.0 Hz, 1H), 7.00-6.88 (m, 2H), 5.10 (dd, J=8.5,
6.2 Hz, 1H), 3.57 (q, J=15.5 Hz, 2H), 2.38-2.28 (m, 1H), 1.92-1.71
(m, 3H), 1.43 (s, 9H), 1.40 (s, 3H), 1.34 (s, 3H).
Step 4: tert-butyl
2-bromo-2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate
##STR00326##
[0693] To a solution of tert-butyl
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate (200
mg, 0.65 mmol) in THF (4 mL) at -78.degree. C., was added lithium
diisopropylamide solution 1.0 M in THF/hexanes (1.3 mL, 1.3 mmol)
dropwise. The reaction was stirred at -78.degree. C. for 30 min,
then chlorotrimethylsilane (141 mg, 1.3 mmol) was added and the
reaction was stirred at -78.degree. C. for another 30 min. Then a
solution of NBS (231 mg, 1.3 mmol) in THF (2 mL) was added and the
reaction was stirred at -78.degree. C. for 1 hour. The reaction was
quenched with MeOH (2 mL), solvent was removed in vacuo, and the
residue was purified by silica gel column (pet ether: EtOAc 10:1)
to give the desired product tert-butyl
2-bromo-2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate
as a colorless oil (180 mg). Yield: 72%. (ESI 387 (M+H)+).
Step 5: tert-butyl
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00327##
[0695] A mixture of tert-butyl
2-bromo-2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate
(650 mg, 1.68 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(584 mg, 1.68 mmol) and DIPEA (650 mg, 5.04 mmol) in acetonitrile
(20 mL) was stirred at rt for 3 hours. Solvent was removed in
vacuo, and the residue was purified by silica gel column (DCM: MeOH
10:1) to give the desired product tert-butyl 2
(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,-
8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
as a yellow oil (550 mg). Yield 56%. (ESI 582 (M+H)+).
Step 6:
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(-
4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 96-E1 and 96-E2)
##STR00328##
[0697] Tert-butyl
2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
(550 mg, 0.95 mmol) was treated with HCl in 1,4-dioxane (4M, 10 mL)
at 25.degree. C. for 2 hours. Solvent was removed in vacuo, and the
residue was purified by Prep-HPLC A (33-65% MeCN) to give 96 as a
white solid (220 mg, 44% yield). The racemic product was separated
by Prep chiral SFC E to give diastereomeric products 96-E1 (44 mg)
and 96-E2 (49 mg) as white solids, each as a mixture of 2
stereoisomers.
[0698] Compound 96-E1 (mixture of 2 stereoisomers) LC/MS ESI 526
(M+H)+. 1H NMR (500 MHz, MeOD) .delta. 7.65-7.61 (m, 1H), 7.48 (dd,
J=10 Hz, 2.5 Hz, 1H), 7.18-7.15 (m, 2H), 6.39 (d, J=7.5 Hz, 1H),
5.42 (m, 1H), 4.85 (s, 1H), 4.20 (s, 1H), 3.49-3.36 (m, 5H),
3.22-3.18 (m, 2H), 2.73-2.52 (m, 5H), 2.21-1.87 (m, 7H), 1.75-1.61
(m, 4H), 1.45-1.36 (m, 7H). Chiral SFC E (45% MeOH): ee 100%,
Rt=3.49 min
[0699] Compound 96-E2 (mixture of 2 stereoisomers) LC/MS ESI 526
(M+H)+. 1H NMR (500 MHz, MeOD) .delta. 7.65-7.61 (m, 1H), 7.45 (dd,
J=10 Hz, 2.5 Hz, 1H), 7.18-7.16 (m, 2H), 6.39 (d, J=7.5 Hz, 1H),
5.35 (m, 1H), 4.97 (s, 1H), 4.20 (s, 1H), 3.54-3.36 (m, 5H),
3.22-3.05 (m, 2H), 2.73-2.50 (m, 5H), 2.22-1.88 (m, 7H), 1.76-1.62
(m, 4H), 1.41-1.36 (m, 7H). Chiral SFC E (45% MeOH): ee 98%,
Rt=4.52 min.
Example 27: Preparation of
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compounds 97-A-E1, 97-A-E2, 97-B-E1 and 97-B-E2)
Step 1: 4,4-dimethyltetrahydro-2H-pyran-2-one
##STR00329##
[0701] To a suspension of Lithium aluminum hydride (220 mg, 5.79
mmol) in THF (dry, 15 mL) at -55.degree. C., was added a solution
of 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (1.42 g, 10.0 mmol)
in THF (10 mL) dropwise. The reaction was gradually warmed to
0.degree. C. and stirred for 20 min, then cooled to -15.degree. C.,
added aqueous HCl (6 N, 4 mL) dropwise to quench the reaction. The
mixture was extracted with ether (3.times.15 mL), and the combined
organic layers were dried over Na2SO4. The solvent was removed in
vacuo to afford the desired product
4,4-dimethyltetrahydro-2H-pyran-2-one as a oil (0.91 g, 71% yield).
.sup.1H NMR (400 MHz, CDCl3) .delta.4.40 (t, J=6.0 Hz, 2H), 2.35
(s, 2H), 1.75 (t, J=6.0 Hz, 2H), 1.10 (s, 6H).
Step 2: 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-ol
##STR00330##
[0703] To a solution of 1-bromo-2-iodobenzene (727 mg, 2.58 mmol)
in THF (15 mL) at -25.degree. C. was added isopropylmagnesium
chloride solution (2M in THF, 1.3 mL, 2.6 mmol) dropwise. The
reaction mixture was stirred at -25.degree. C. for 1 hour, then
added a solution of 4,4-dimethyltetrahydro-2H-pyran-2-one (300 mg,
2.34 mmol) in THF (3 mL) dropwise at -25.degree. C. The reaction
mixture was warmed to RT in 1 hour, quenched with MeOH (5 mL) and
concentrated in vacuum. The residue was purified by silica gel
column (pet ether: EtOAc 4:1) to give the desired product
2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-ol as a yellow
oil (130 mg). Yield 18% (ESI 285/287 [M+H]+).
Step 3: 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran
##STR00331##
[0705] To a solution of
2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-ol (130 mg,
0.46 mmol) and TFA (0.23 mL) in DCM (6 mL) at 0.degree. C., was
added Et3SiH (267 mg, 2.3 mmol) dropwise. The reaction mixture was
stirred at rt for 1 hour, then quenched with sat. NaHCO.sub.3
solution (20 mL), extracted with DCM (3.times.10 mL). The combined
organic layers were dried over Na2SO.sub.4, filtered and
concentrated under vacuum. The residue was purified by silica gel
column (pet ether: EtOAc 10:1) to give the desired product
2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran as a yellow oil
(90 mg). Yield 78% (ESI 269/271 [M+H]+).
Step 4: tert-butyl
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00332##
[0707] A mixture of
2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran (180 mg, 0.68
mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (0.5M in
THF, 6.8 mL, 3.4 mmol), Pd2(dba)3 (35 mg, 0.034 mmol) and Q-phos
(25 mg, 0.034 mmol) in THF (2 mL) was stirred at 80.degree. C. for
2 hours. Then the reaction mixture was poured into sat. NaHCO.sub.3
solution (50 mL), extracted with EtOAc (3.times.20 mL). The
combined organic layers were dried over Na2SO4, filtered and
concentrated under vacuum. The residue was purified by silica gel
column (pet ether: EtOAc 10:1) to give the desired product
tert-butyl
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate as a red
oil (150 mg). Yield 73% (ESI 327 [M+Na]+).
Step 5: tert-butyl
2-bromo-2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00333##
[0709] To a solution of tert-butyl
2-(3-isopropyl-3,4-dihydro-1H-pyrano[3,4-c]pyridin-5-yl)acetate
(600 mg, 2.0 mmol) in THF (10 mL) at -78.degree. C., was added
lithium diisopropylamide solution (2.0 M, 2.5 mL, 5.0 mmol)
dropwise. The reaction was stirred at -78.degree. C. for 30 min,
then a solution of chlorotrimethylsilane (540 mg, 5.0 mmol) in THF
(1 mL) was added and the reaction was stirred at -78.degree. C. for
another 30 min. Then a solution of NBS (890 mg, 5.0 mmol) in THF
(10 mL) was added and the reaction was stirred at -78.degree. C.
for 1 hour. The reaction was quenched with MeOH (2 mL), solvent was
removed in vacuo, and the residue was purified by silica gel column
(pet ether: EtOAc 10:1) to give the desired product tert-butyl
2-bromo-2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
as colorless oil (650 mg). Yield 86% (ESI 327 [M-Bu+H]+).
Step 6: tert-butyl
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00334##
[0711] A mixture of tert-butyl
2-bromo-2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
(375 mg, 1.0 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(306 mg, 1.0 mmol), DIPEA (774 mg, 6.0 mmol) and NaI (50 mg) in
acetonitrile (10 mL) was stirred at 40.degree. C. for 12 hours. The
mixture was diluted with water (8 mL) and EtOAc (25 mL). The
organic phase was washed with brine, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by silica gel
column (DCM:MeOH 20:1) to give the desired product tert-butyl
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate as a
colorless oil (410 mg). Yield 72% (ESI 578 [M+H]+).
Step 7:
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,-
6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 97-A-E1, 97-A-E2, 97-B-E1 and 97-B-E2)
##STR00335##
[0713] Tert-butyl
2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (570
mg, 1.0 mmol) was treated with HCl in 1,4-dioxane (4M, 10 mL) at
25.degree. C. for 6 hours. Solvent was removed in vacuo, and the
residue was purified by prep-HPLC A (40-70% MeCN) to give 97-A (102
mg) and 97-B (130 mg). 97-A was separated by Prep chiral SFC H to
give products 97-A-E1 (36 mg) and 97-A-E2 (31 mg) as white solids.
97-B was separated by Prep chiral SFC H to give products 97-B-E1
(30 mg) and 97-B-E2 (44 mg) as white solids.
[0714] Compound 97-A-E1 LC/MS ESI 522 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.68-7.66 (m, 1H), 7.54-7.52 (m, 1H), 7.41-7.34 (m,
2H), 7.15-7.13 (m, 1H), 6.36 (d, J=7.6 Hz, 1H), 5.02-4.95 (m, 2H),
4.21-4.19 (m, 1H), 3.88-3.86 (m, 2H), 3.62-3.60 (m, 1H), 3.50-3.41
(m, 5H), 3.20-3.18 (m, 1H), 3.05-3.02 (m, 1H), 2.70-2.68 (m, 2H),
2.55-2.52 (m, 2H), 2.10-2.07 (m, 2H), 1.90-1.50 (m, 9H), 1.31-1.29
(m, 1H), 1.20 (s, 3H), 1.05 (s, 3H). Chiral SFC H (40% MeOH): ee
100%, Rt=2.81 min.
[0715] Compound 97-A-E2 LC/MS ESI 522 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.69-7.67 (m, 1H), 7.54-7.52 (m, 1H), 7.41-7.31 (m,
2H), 7.15-7.13 (m, 1H), 6.36 (d, J=7.6 Hz, 1H), 5.02-5.00 (m, 1H),
4.84 (s, 1H), 4.16-4.14 (m, 1H), 3.90-3.88 (m, 2H), 3.62-3.60 (m,
1H), 3.50-3.41 (m, 5H), 3.20-3.18 (m, 2H), 2.70-2.68 (m, 2H),
2.54-2.52 (m, 2H), 2.10-2.07 (m, 2H), 1.90-1.50 (m, 9H), 1.31-1.29
(m, 1H), 1.20 (s, 3H), 1.05 (s, 3H). Chiral SFC H (40% MeOH): ee
100%, Rt=3.78 min.
[0716] Compound 97-B-E1 LC/MS ESI 522 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.68-7.66 (m, 1H), 7.54-7.52 (m, 1H), 7.41-7.34 (m,
2H), 7.15-7.13 (m, 1H), 6.36 (d, J=7.6 Hz, 1H), 5.02-4.90 (m, 2H),
4.16-4.14 (m, 1H), 3.90-3.88 (m, 2H), 3.62-3.60 (m, 1H), 3.50-3.41
(m, 5H), 3.20-3.18 (m, 1H), 3.05-3.02 (m, 1H), 2.70-2.68 (m, 2H),
2.54-2.52 (m, 2H), 2.10-2.07 (m, 2H), 1.90-1.50 (m, 9H), 1.31-1.29
(m, 1H), 1.20 (s, 3H), 1.05 (s, 3H). Chiral SFC H (40% MeOH): ee
100%, Rt=2.76 min.
[0717] Compound 97-B-E2 LC/MS ESI 522 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.68-7.66 (m, 1H), 7.54-7.52 (m, 1H), 7.44-7.34 (m,
3H), 6.49 (d, J=7.2 Hz, 1H), 5.02-4.90 (m, 2H), 4.16-4.14 (m, 1H),
3.92-3.90 (m, 2H), 3.70-3.20 (m, 8H), 2.70-2.68 (m, 2H), 2.54-2.52
(m, 2H), 2.10-2.07 (m, 2H), 1.90-1.50 (m, 9H), 1.31-1.29 (m, 1H),
1.20 (s, 3H), 1.05 (s, 3H). Chiral SFC H (40% MeOH): ee 100%,
Rt=3.85 min.
Example 28: Preparation of
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compounds 98-A-E1, 98-A-E2 and 98-B)
Step 1: cyanomethyl 2-bromo-4-fluorobenzoate
##STR00336##
[0719] To a solution of 2-bromo-4-fluorobenzoic acid (5.0 g, 0.23
mol) in dry DCM (20 mL) at 0.degree. C. was added triethylamine
(9.2 g, 0.69 mol) and chloroacetonitrile (3.5 g, 0.46 mol). The
reaction was then heated to reflux and stirred overnight. After
cooling to room temperature, the reaction mixture was washed
successively with aqueous HCl (2M, 20 mL) and sat. NaHCO.sub.3
solution (20 mL). The organic phase was dried over anhydrous MgSO4
and concentrated in vacuo to afford the desired product cyanomethyl
2-bromo-4-fluorobenzoate as a pale yellow oil (4.0 g). Yield 68%
(ESI 258/260 [M+H]+).
Step 2: 1-(2-bromo-4-fluorophenyl)-5-hydroxypentane-1,4-dione
##STR00337##
[0721] To a solution of cyanomethyl 2-bromo-4-fluorobenzoate (3.4
g, 13.2 mmol) and Ti(OiPr)4 (4.15 g, 14.6 mmol) in Et2O (70 mL) at
0.degree. C. under argon, was added EtMgBr (28 ml, 28 mmol, 1M in
THF) dropwise. After the addition of the Grignard reagent, the
mixture was warmed to RT and stirred for 1 hour. The turbid yellow
mixture was quenched with water (10 mL), then 1M HCl (30 mL) were
added, extracted with EtOAc (3*50 mL). The combined organic phases
were washed with saturated aqueous NaHCO.sub.3 and dried (MgSO4).
After evaporation of the solvents, the residue was purified by
silica gel column (pet ether: EtOAc 3:1) to afford the desired
product 1-(2-bromo-4-fluorophenyl)-5-hydroxypentane-1,4-dione (901
mg) as a colorless oil. Yield 25% (ESI 289/271 [M+H]+).
Step 3: 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol
##STR00338##
[0723] To a solution of
1-(2-bromo-4-fluorophenyl)-5-hydroxypentane-1,4-dione (900 mg, 3.13
mmol) in DCM (40 mL) at 0.degree. C. was added Boron trifluroide
(diethyl ether complex, 1110 mg, 7.8 mmol) dropwise. After the
addition, triethylsilane (910 mg, 7.8 mmol) was added and the
reaction was stirred at 0.degree. C. for 1 hour. The reaction
mixture was quenched with sat. NaHCO.sub.3 (20 mL), extracted with
DCM (2*50 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
purified by silica gel column (pet ether: EtOAc 3:1) to give the
desired product 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol
as a colorless oil (650 mg). Yield 80% (ESI 275/277 [M+H]+).
Step 4: 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one
##STR00339##
[0725] To a solution of
6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol (100 mg, 0.37
mmol) in DCM (5 mL) was added Dess-Martin Periodonane (150 mg, 0.50
mmol) in several portions. After the addition, the reaction mixture
was stirred RT for 2 hours, then quenched with a solution of
saturated NaHCO.sub.3 (5 mL). The organic layer was washed with
brine, dried over sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by silica gel column (pet ether:
EtOAc 10:1) to afford the desired product
6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one as a colorless
oil (20 mg). Yield 20% (ESI 273/275 [M+H]+).
Step 5:
2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran
##STR00340##
[0727] To a solution of methyltriphenylphosphonium bromide (134 mg,
0.52 mmol) in THF (3 mL) at 0.degree. C., n-BuLi (2.5M in hexane,
0.21 mL, 0.52 mmol) was added and the reaction was stirred at
0.degree. C. for 30 minutes, then added a solution of
6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one (70 mg, 0.26
mmol) in THF (2 mL). The reaction was stirred at room temperature
for 12 hours, quenched with sat. aq. NH.sub.4Cl and extracted with
DCM (2*10 mL). The combined organic phase was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
purified by silica gel column (pet ether: EtOAc 10:1) to afford the
desired product
2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran as a
colorless oil (51 mg, 70% yield). 1H NMR (400 MHz, CDCl3) .delta.
7.52-7.50 (m, 1H), 7.27-7.25 (m, 1H), 7.05-7.01 (m, 1H), 4.89-4.88
(m, 2H), 4.75-4.73 (m, 1H), 4.37-4.34 (m, 1H), 4.20-4.17 (m, 1H),
2.50-2.46 (m, 2H), 2.15-2.10 (m, 1H), 1.52-1.50 (m, 1H).
Step 6: 6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2,5]octane
##STR00341##
[0729] To a solution of ZnEt2 (1 M in THF, 6 mL, 6.0 mmol) in DCM
(20 mL) at 0.degree. C. was added TFA (690 mg, 6.0 mmol). The
reaction was stirred at 0.degree. C. for 0.5 hour, then CH2I2 (1.7
g, 6.0 mmol) was added dropwise. The reaction was stirred at
0.degree. C. for 0.5 hour, then
2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran (280 mg,
1.0 mmol) in DCM (1 mL) was added. The reaction mixture was stirred
at rt for 2 hours, quenched with sat. NaHCO.sub.3 solution (20 mL),
and the DCM layer was dried over Na2SO4. The solvent was removed in
vacuo and the residue was purified by silica gel column (pet ether:
EtOAc 50:1) to give the desired product
6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5]octane as a yellow oil
(250 mg). Yield 80% (ESI 267/269 [M+H--H2O]+).
Step 7: tert-butyl
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate
##STR00342##
[0731] A mixture of
6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5]octane (250 mg, 0.88
mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution 0.5 M in
THF (10 mL, 5 mmol), Pd2(dba)3 (40 mg, 0.05 mmol) and Q-phos (31
mg, 0.05 mmol) in THF (2 mL) was stirred at 80.degree. C. for 2
hours. Then the mixture was poured into sat. NaHCO.sub.3 solution
(50 mL) and EtOAc (60 mL). The mixture was filtered, the organic
layer was washed with brine, dried over Na2SO4, concentrated in
vacuo, and the residue was purified by silica gel column (pet
ether: EtOAc 10:1) to give the desired product tert-butyl
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate as a red
oil (160 mg). Yield 53% (ESI 343 [M+Na]+).
Step 8: tert-butyl
2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate
##STR00343##
[0733] To a solution of tert-butyl
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate (160 mg,
0.5 mmol) in THF (5 mL) at -78.degree. C., was added lithium
diisopropylamide solution 2.0 M in THF/hexanes (0.62 mL, 1.25 mmol)
dropwise. The reaction was stirred at -78.degree. C. for 30 min,
then a solution of chlorotrimethylsilane (135 mg, 1.25 mmol) in THF
(1 mL) was added and the reaction was stirred at -78.degree. C. for
another 30 min. Then a solution of NBS (221 mg, 1.25 mmol) in THF
(10 mL) was added and the reaction was stirred at -78.degree. C.
for 1 hour. The reaction was quenched with MeOH (2 mL), solvent was
removed in vacuo, and the residue was purified by silica gel column
(pet ether: EtOAc 10:1) to give the desired product tert-butyl
2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate as
a colorless oil (130 mg). Yield 60% (ESI 419/421 [M+Na]+).
Step 9: tert-butyl
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00344##
[0735] A mixture of tert-butyl
2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate
(130 mg, 0.33 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(101 mg, 0.33 mmol), DIPEA (126 mg, 0.99 mmol) and NaI (50 mg) in
acetonitrile (10 mL) was stirred at 40.degree. C. for 12 hours. The
mixture was diluted with water (8 mL) and EtOAc (25 mL). The
organic phase was washed with brine, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by silica gel
column (DCM:MeOH 20:1) to give the desired product tert-butyl
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate as a
colorless oil (101 mg). Yield=52% (ESI 595 [M+H]+).
Step 10:
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6-
,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 98-A-E1, 98-A-E2 and 98-B)
##STR00345##
[0737] A solution of tert-butyl
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (210
mg, 0.35 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room
temperature for 15 hours. Then it was concentrated and purified by
prep-HPLC A (40-70% MeCN) to give 98-A (106 mg) and 98-B (16 mg).
98-A was separated by Prep chiral SFC C to give products 98-A-E1
(35 mg) and 98 A-E2 (31 mg) as white solids.
[0738] Compound 98-A-E1 LC/MS ESI 538 (M+H)+. 1H NMR (500 MHz,
MeOD) .delta. 7.64-7.61 (m, 1H), 7.49-7.46 (m, 1H), 7.18-7.16 (m,
2H), 6.39 (d, J=7.5 Hz, 1H), 4.93 (s, 1H), 4.82-4.85 (m, 1H), 4.19
(br s, 1H), 4.12-4.10 (m, 1H), 3.61 (m, 1H), 3.49 (t, J=6.5 Hz,
2H), 3.341-3.38 (m, 3H), 3.23 (d, J=12.5H, 1H), 3.11-3.09 (m, 2H),
2.72 (t, J=6.0 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.3-2.2- (m, 1H),
2.11-2.00 (m, 4H), 1.90-1.88 (m, 2H), 1.74-1.72 (m, 2H), 1.65-1.63
(m, 2H), 1.2 (m, 1H), 0.6-0.3 (m, 4H). Chiral SFC C (20% EtOH): ee
100%, Rt=1.29 min.
[0739] Compound 98-A-E2 LC/MS ESI 538 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.63-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.22-7.16 (m,
2H), 6.39 (d, J=7.6 Hz, 1H), 4.82-4.80 (m, 1H), 4.20-4.12 (m, 2H),
3.60-3.32 (m, 6H), 3.30-3.05 (m, 4H), 2.75-2.55 (m, 4H), 2.25-1.58
(m, 12H), 0.58-0.30 (m, 4H). Chiral SFC C (20% EtOH): ee 100%,
Rt=2.17 min.
[0740] Compound 98-B (mixture of 2 stereoisomers) LC/MS ESI 538
(M+H)+. 1H NMR (400 MHz, MeOD) .delta. 7.41-7.32 (m, 2H), 7.08-6.98
(m, 2H), 6.28-6.22 (m, 1H), 4.80-4.75 (m, 1H), 4.05-3.85 (m, 2H),
3.60-3.32 (m, 6H), 3.10-2.85 (m, 4H), 2.62-2.58 (m, 2H), 2.47-2.41
(m, 2H), 2.21-1.40 (m, 12H), 0.55-0.20 (m, 4H).
Example 29: Preparation of
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(-
5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compounds 99-E1 and 99-E2)
Step 1: 1-(2-bromo-4-fluorophenyl)cyclopropanol
##STR00346##
[0742] To a solution of 1-(2-bromo-4-fluorophenyl)ethanone (5.0 g,
23.1 mmol) and Et3N (3.51 g, 34.7 mmol) in DCM (50 mL) at 0.degree.
C. under nitrogen, was added TMSOTf (6.17 g, 27.8 mmol) dropwise
via syringe over a period of 10 min. The reaction mixture was
stirred at RT overnight, then quenched with saturated NaHCO3
aqueous (20 mL), extracted the aqueous with DCM (2.times.30 mL).
The combined organic phase was washed with brine, dried over
Na2SO4, filtered and concentrate in vacuo to obtain crude ether.
The crude ether was dissolved in anhydrous DCM (50 mL), added
diiodomethane (25.0 g, 92.4 mmol), cooled to 0.degree. C., then
added diethyl zinc (1 M in THF, 93 mL, 93 mmol) dropwise. The
reaction was stirred at RT for 16 hours, then quenched with a
saturated solution of NH.sub.4Cl (30 mL), extracted with DCM (2*50
mL). The combined organic phase was washed with brine, dried over
Na2SO4, filtered and concentrate in vacuo to obtain crude material.
The crude material was dissolved in MeOH (20 mL), followed by
addition of K2CO3 (3.2 g, 23.1 mmol), then stirred at RT for 30
min. Solvent was removed under vacuum, added H2O (20 mL), extracted
with EtOAc (2*40 mL). The combined organic phase was dried over
sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by silica gel column (pet ether: EtOAc 5:1) to afford the
desired product 1-(2-bromo-4-fluorophenyl)cyclopropanol as a
colorless oil (3.1 g). Yield 86% (ESI 213/215 [M+H]+).
Step 2: ethyl
5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate
##STR00347##
[0744] A mixture of 1-(2-bromo-4-fluorophenyl)cyclopropanol (100
mg, 0.44 mmol), ethyl 2-bromo-2,2-difluoroacetate (351 mg, 1.74
mmol), CuI (8.2 mg, 0.044 mmol), Phenanthroline (17.2 mg, 0.088
mmol) and K2CO3 (120 mg, 0.88 mmol) in MeCN (5 mL) was stirred at
90.degree. C. for 17 hours. The reaction was quenched with water
(10 mL), extracted with EtOAc (3*10 mL). The combined organic
layers were washed with brine, dried over Na2SO4, concentrated in
vacuo, and the residue was purified by silica gel column (pet
ether: EtOAc 5:1) to afford the desired product ethyl
5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate as a
colorless oil (81 mg). Yield 53% (ESI 353/355 [M+H]+).
Step 3:
2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran
##STR00348##
[0746] To a solution of ethyl
5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate (100 mg,
0.28 mmol) in MeOH (5 mL) at 0.degree. C. was added NaBH4 (44 mg,
1.12 mmol). The reaction solution was stirred at RT for 15 hours.
Solvent was removed under vacuum, added H2O (10 mL), extracted with
DCM (3*10 mL). The combined organic phase was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
dissolved in DCM (3 mL) and triflic acid (100 mg, 0.32 mmol) was
added. The reaction was stirred at RT for 15 hours, then quenched
by sat. aq. NaHCO.sub.3 (5 mL), extracted with DCM (2.times.10 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, concentrated in vacuo, and the residue was purified by
silica gel column (pet ether: EtOAc 10:1) to give the desired
product 2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran
a colorless oil (40 mg). Yield 47% (ESI 297/299 [M+H]+).
Step 4: tert-butyl
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate
##STR00349##
[0748] A mixture of
2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran (800 mg,
2.93 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution
(0.5 M in THF, 30 mL, 15 mmol), Pd2(dba)3 (152 mg, 0.15 mmol) and
Q-phos (105 mg, 0.15 mmol) in THF (2 mL) was stirred at 80.degree.
C. for 2 hours. The reaction mixture was poured into sat. NaHCO3
solution (20 mL) and EtOAc (30 mL). The mixture was filtered, the
organic layer was washed with brine, dried over Na2SO4,
concentrated in vacuo, and the residue was purified by silica gel
column (pet ether: EtOAc 10:1) to give the desired product
tert-butyl
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate
as a red oil (703 mg). Yield 78% (ESI 275 [M+H-tBu]+).
Step 5: tert-butyl
2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetat-
e
##STR00350##
[0750] To a solution of tert-butyl
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate
(703 mg, 2.12 mmol) in THF (5 mL) at -78.degree. C., was added
lithium diisopropylamide solution (2M, 2.65 mL, 5.3 mmol) dropwise.
The reaction was stirred at -78.degree. C. for 30 min, then a
solution of chlorotrimethylsilane (573 mg, 5.3 mmol) in THF (1 mL)
was added and the reaction was stirred at -78.degree. C. for
another 30 min. Then a solution of NBS (944 mg, 5.3 mmol) in THF
(10 mL) was added and the reaction was stirred at -78.degree. C.
for 1 hour. The reaction was quenched with MeOH (2 mL), solvent was
removed in vacuo, and the residue was purified by silica gel column
(pet ether: EtOAc 10:1) to give the desired product tert-butyl
2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetat-
e as a red oil (816 mg). Yield 66% (ESI 352/354 [M+H-tBu]+).
Step 6: tert-butyl
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(-
5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00351##
[0752] A mixture of tert-butyl
2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetat-
e (816 mg, 2.0 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(660 mg, 2.0 mmol), DIPEA (821 mg, 6.0 mmol) and NaI (50 mg) in
acetonitrile (20 mL) was stirred at 40.degree. C. for 6 hours. The
mixture was diluted with water (8 mL) and EtOAc (25 mL). The
organic phase was washed with brine, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by silica gel
column (DCM:MeOH 20:1) to give the desired product tert-butyl
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(-
5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
as a colorless oil (710 mg). Yield 58% (ESI 604 [M+H]+).
Step 7:
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-
-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)ace-
tic acid (compounds 99-E1 and 99-E2)
##STR00352##
[0754] To a solution of tert-butyl
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(-
5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
(710 mg, 1.2 mmol) in DCM (10 mL) was added TFA (10 mL). The
reaction was stirred at RT for 15 hours. Then it was concentrated
and purified by prep-HPLC A (40-70% MeCN) to give 99 as a white
solid (400 mg, 63% yield). The racemic product was separated by
Prep chiral SFC A to give diastereomeric products 99-E1 (74 mg) and
99-E2 (88 mg) as white solids.
[0755] Compound 99-E1 LC/MS ESI 548 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 7.61-7.59 (m, 1H), 7.51-7.48 (m, 1H), 7.22-7.13 (m, 2H),
6.41 (d, J=7.2 Hz, 1H), 4.99-4.90 (m, 1H), 4.80 (s, 1H), 4.19-4.17
(m, 1H), 4.01-3.80 (m, 2H), 3.50-3.35 (m, 6H), 3.20-3.18 (m, 1H),
3.02-2.98 (m, 1H), 2.81-2.79 (m, 2H), 2.62-2.59 (m, 2H), 2.30-2.01
(m, 6H), 1.82-1.80 (m, 2H), 1.75-1.60 (m, 4H). Chiral SFC A (40%
MeOH): ee 100%, Rt=1.92 min.
[0756] Compound 99-E2 LC/MS ESI 548 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 7.62-7.60 (m, 1H), 7.53-7.51 (m, 1H), 7.28 (d, J=7.6 Hz,
1H), 7.17-7.14 (m, 1H), 6.44 (d, J=7.2 Hz, 1H), 4.99-4.90 (m, 1H),
4.79 (s, 1H), 4.19-4.17 (m, 1H), 4.01-3.80 (m, 2H), 3.60-3.35 (m,
6H), 3.20-3.18 (m, 2H), 2.81-2.79 (m, 2H), 2.62-2.59 (m, 2H),
2.30-2.01 (m, 6H), 1.82-1.80 (m, 2H), 1.75-1.60 (m, 4H). Chiral SFC
A (40% MeOH): ee 98%, Rt=2.47 min.
Example 30: Preparation of
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compounds 100-E1 and 100-E2)
Step 1: Ethyl 3-(2-bromophenyl)acrylate
##STR00353##
[0758] To a solution of 2-bromobenzaldehyde (5.00 g, 27.0 mmol) in
THF (30 mL) was added ethyl
2-(triphenyl-15-phosphaneylidene)acetate (9.89 g, 28.4 mmol), then
the mixture was stirred at 60.degree. C. overnight. The solvent was
removed in vacuo and the residue was purified by silica gel column
(pet ether: EtOAc 10:1) to give the desired product as a yellow oil
(6.51 g). Yield 93%. .sup.1H NMR (400 MHz, CDCl3) .delta.8.06 (d,
1H), 7.61 (m, 2H), 7.24-7.19 (m, 2H), 6.40 (d, 1H), 4.31-4.08 (m,
2H), 1.36-1.15 (m, 3H).
Step 2: 3-(2-bromophenyl)prop-2-en-1-ol
##STR00354##
[0760] To a solution of 3-(2-bromophenyl)acrylate (6.5 g, 30.7
mmol) in THF (dry, 50 mL) at 0.degree. C., was added DIBAL-H (1 M,
61.3 mL, 61.3 mmol) dropwise. The mixture was stirred at 0.degree.
C. for 30 min, then warmed to RT for an hour. The reaction solvents
was poured into aqueous HCl (1N, 200 mL) and stirred at rt
overnight. The mixture was extracted with ethyl acetate (50
mL.times.3). The combined organic layer was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
purified by silica gel column (pet ether: EtOAc 10:3) to afford the
desired product as a light yellow oil (5.10 g). Yield 89%. .sup.1H
NMR (400 MHz, CDCl3) .delta.7.59-7.30 (m, 3H), 7.18-7.08 (m, 2H),
6.34-6.30 (m, 1H), 4.37-4.27 (m, 2H).
Step 3: 1-bromo-2-(3-bromoprop-1-enyl)benzene
##STR00355##
[0762] To a solution of 3-(2-bromophenyl)prop-2-en-1-ol (4.80 g,
22.64 mmol) in diethyl ether (dry, 50 mL) at 0.degree. C. was added
phosphorus tribromide (1.27 mL, 9.06 mmol). The reaction was
stirred at 0.degree. C. for 1 hour, then quenched with sat.
NaHCO.sub.3, extracted with diethyl ether (50 mL.times.2). The
combined organic layers were washed with brine, dried over sodium
sulfate, filtered and concentrated in vacuo to afford the desired
product 1-bromo-2-(3-bromoprop-1-enyl)benzene as a yellow oil (5.20
g). Yield 79%. .sup.1H NMR (400 MHz, CDCl3) .delta.7.56-7.46 (m,
2H), 7.34-7.26 (m, 2H), 6.36-6.34 (m, 1H), 4.18-4.03 (m, 2H).
Step 4: methyl 5-(2-bromophenyl)-2,2-dimethylpent-4-enoate
##STR00356##
[0764] To a solution of methyl isobutyrate (2.13 g, 20.88 mmol) in
THF (dry, 40 mL) at -78.degree. C. was added LDA (1 M, 20.88 mL,
20.88 mmol) dropwise. The mixture was stirred at -78.degree. C. for
30 min, then added a solution of
1-bromo-2-(3-bromoprop-1-en-1-yl)benzene (5.20 g, 18.98 mmol) in
THF (10 mL) dropwise. The reaction was stirred at -78.degree. C.
for 30 min, then warmed to RT for another 1 hour. The reaction was
quenched with sat. NH.sub.4Cl and extracted with EtOAc (50
mL.times.3). The combined organic layers were washed with brine,
dried over sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by silica gel column (pet ether: EtOAc 5:1) to
afford the desired product as a yellow oil (4.36 g, 78% yield).1H
NMR (400 MHz, CDCl3) .delta.7.58-7.46 (m, 2H), 7.23-7.09 (m, 2H),
6.74-6.51 (m, 1H), 6.10-6.02 (m, 1H), 3.69-3.64 (m, 3H), 2.48-2.40
(m, 2H), 1.24-1.15 (m, 6H).
Step 5: 5-(2-bromophenyl)-2,2-dimethylpent-4-en-1-ol
##STR00357##
[0766] To a solution of methyl
5-(2-bromophenyl)-2,2-dimethylpent-4-enoate (4.36 g, 14.53 mmol) in
THE (dry, 20 mL) at -78.degree. C., was added dropwise a solution
of lithium aluminium hydride in tetrahydrofuran (2.4 M, 6.66 mL,
11.80 mmol). The mixture was stirred at -78.degree. C. for 3 hours,
then quenched with 1M HCl (.about.100 mL, started dropwise). The
reaction was extracted with EtOAc (50 mL.times.3). The combined
organic layers were washed with brine, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
silica gel column (pet ether: EtOAc 10:3) to afford the desired
product as a yellow oil (3.74 g, 93% yield). ESI: 267
(M+H).sup.+
Step 6: Ethyl 3-(2-bromophenyl)acrylate
##STR00358##
[0768] To a solution of
5-(2-bromophenyl)-2,2-dimethylpent-4-en-1-ol (3.74 g, 13.95 mmol)
in dichloro ethane (20 mL) was added Tetrabutylammonium
Hexafluorophosphate (0.27 g, 0.70 mmol) and Calcium(II)
Bis(trifluoromethanesulfonyl)imide (0.22 g, 0.70 mmol). The mixture
was stirred at 90.degree. C. for 20 hours, concentrated in vacuo
and the residue was purified by silica gel column (pet ether: EtOAc
10:1) to afford the desired product ethyl 3-(2-bromophenyl)acrylate
as a yellow oil (1.50 g, 40% yield). 1H NMR (400 MHz, CDCl3)
.delta.7.54 (d, J=6.8 Hz, 2H), 7.33 (t, J=8.0 Hz, 1H), 7.10 (t,
J=7.2 Hz, 1H), 4.56 (d, J=9.6 Hz, 1H), 3.3 (d, J=11.2 Hz, 1H), 3.38
(d, J=11.2 Hz, 1H), 1.88-1.84 (m, 1H), 1.59-1.53 (m, 4H), 1.13 (s,
3H), 0.88 (s, 3H).
Step 7: butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00359##
[0770] To a mixture of ethyl 3-(2-bromophenyl)acrylate (1.50 g,
5.60 mmol), tris(dibenzylideneacetone)dipalladium (0.29 g, 0.28
mmol) and 1, 2, 3, 4,
5-Pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (0.20 g, 0.28
mmol) in THF (10 mL) was added (2-tert-butoxy-2-oxoethyl)zinc(II)
bromide (1 M in THF, 28 mL, 28 mmol). The reaction was stirred at
60.degree. C. for 2 hours. The reaction mixture was poured into
sat. NaHCO.sub.3 (100 mL), extracted with EtOAc (50 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by silica gel column (pet ether: EtOAc 10:1) to afford the
desired product as a red oil (1.21 g, 71% yield). ESI: 249
(M-C.sub.4H.sub.9+H).sup.+
Step 8: tert-butyl
2-bromo-2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
##STR00360##
[0772] To a solution of tert-butyl butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate (1.21 g,
3.17 mmol) in THF (10 mL) at -78.degree. C., was added lithium
diisopropylamide solution 2.0 M in THF/hexanes (4.0 mL, 8.0 mmol)
dropwise. The reaction was stirred at -78.degree. C. for 30 min,
then chlorotrimethylsilane (864 mg, 8.0 mmol) was added and the
reaction was stirred at -78.degree. C. for another 30 min. Then a
solution of NBS (1.43 g, 8.0 mmol) in THF (10 mL) was added and the
reaction was stirred at -78.degree. C. for 1 hour. The reaction was
quenched with MeOH (2 mL), solvent was removed in vacuo, and the
residue was purified by silica gel column (pet ether: EtOAc 10:1)
to give the desired product tert-butyl
2-bromo-2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
as a yellow oil (1.31 g, 85% yield). ESI: 327
(M-C.sub.4H.sub.9+H).sup.+
Step 9: tert-butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
##STR00361##
[0774] A mixture of
(S)-7-(4,4-difluoro-5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-nap-
hthyridine (200 mg, 0.65 mmol,
2-bromo-2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate
(220 mg, 0.65 mmol), DIEA (252 mg, 1.95 mmol) and NaI (19.5 mg,
0.13 mmol) in acetonitrile (10 mL) was stirred at 50.degree. C. for
6 hours. Solvent was removed in vacuo, and the residue was purified
by silica gel column (DCM: MeOH 20:1) to give the desired product
tert-butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate as a
yellow oil (150 mg, 45% yield). ESI: 578 (M+H).sup.+
Step 10: tert-butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl) acetic acid
(compounds 100-E1 and 100-E2)
##STR00362##
[0776] Tert-butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate (150
mg, 0.26 mmol) was treated with a mixture of DCM (3 mL) and TFA (3
mL) at 25.degree. C. overnight. Solvent was removed in vacuo, and
the residue was purified by Prep-HPLC A (30-65% MeCN) to give the
desired product tert-butyl
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl) acetic acid
(Compound 100) as a white solid (96 mg, 70%). The racemic product
was separated by Prep chiral SFC H to give diastereomeric products
100-E1 (29 mg) and 100-E2 (26 mg) as white solids.
[0777] Compound 100-E1 LC/MS ESI 522.7 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.68 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H),
7.45-7.38 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 6.37 (d, J=7.2 Hz, 1H),
4.93 (s, 1H), 4.73 (d, J=8.0 Hz, 1H), 4.19 (s, 1H), 3.56-3.36 (m,
7H), 3.22-3.05 (m, 3H), 2.70 (t, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz,
2H), 2.14-1.92 (m, 6H), 1.76-1.61 (m, 6H), 1.15 (s, 3H), 0.95 (s,
3H). Chiral SFC H (45% MeOH): ee 98%, Rt=1.54 min.
[0778] Compound 100-E2 LC/MS ESI 522.7 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.68 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H),
7.45-7.38 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 6.37 (d, J=7.2 Hz, 1H),
4.81-4.78 (m, 2H), 4.17 (s, 1H), 3.58-3.32 (m, 8H), 3.22-3.15 (m,
2H), 2.70 (t, J=6.0 Hz, 2H), 2.55 (t, J=6.0 Hz, 2H), 2.18-1.92 (m,
6H), 1.76-1.61 (m, 6H), 1.12 (s, 3H), 0.89 (s, 3H). Chiral SFC H
(45% MeOH): ee 100%, Rt=2.35 min.
Example 31: Preparation of
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 101-A-E1, 101-A-E2, 101-B-E1 and
101-B-E2)
Step 1: 4-(2,6-dichloropyridin-3-yl)but-3-en-2-one
##STR00363##
[0780] A mixture of 2,6-dichloronicotinaldehyde (25 g, 143.5 mmol)
and 1-(triphenylphosphoranylidene)-2-propanone (57.2 g, 179.6 mmol)
in toluene (180 mL) was stirred at 110.degree. C. for 16 hours. The
mixture was cooled to room temperature, added H2O (40 mL),
extracted with ethyl acetate (3.times.50 mL). The combined organic
layer was dried over Na2SO4, filtered, solvent was removed in
vacuo. The residue was purified by silica gel column (pet ether:
EtOAc 1:1) to give the desired product as a yellow solid (13.3 g).
Yield 43% (ESI 216.0 (M+H)+).
Step 2: 4-(2,6-dichloropyridin-3-yl)butan-2-amine
##STR00364##
[0782] A mixture of 4-(2,6-dichloropyridin-3-yl)but-3-en-2-one (12
g, 55.8 mmol), NH4OAc (21.5 g, 279.1 mmol) and NaBH3CN (10.6 g,
167.4 mmol) in MeOH (100 mL) was stirred at 30.degree. C. for 16
hours. The mixture was concentrated in vacuo, and the residue was
purified by silica gel column (DCM: MeOH 40:1) to give the desired
product as a yellow oil (7.94 g). Yield 58% (ESI 219.0 (M+H)+).
Step 3: (R)-7-chloro-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
and (S)-7-chloro-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
##STR00365##
[0784] A mixture of 4-(2,6-dichloropyridin-3-yl)butan-2-amine (7 g,
32.1 mmol) and Cs2CO3 (52 g, 160.6 mmol) in DMF (120 mL) was
stirred at 140.degree. C. for 16 hours. The mixture was cooled to
room temperature, added EtOAc (100 mL) and washed with H2O
(3.times.100 mL). The organic layer was removed in vacuo and the
residue was purified by silica gel column (pet ether: EtOAc 1:1) to
give the desired product as a yellow oil (1.9 g). Yield 32% (ESI
183.0 (M+H)+). The racemic product was separated by Prep chiral SFC
B to give stereoisomer A (870 mg) and stereoisomer B (890 mg) as
yellow oils.
Step 4: (R)-tert-butyl
7-chloro-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
stereoisomer A
##STR00366##
[0786] A mixture of
7-chloro-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine stereoisomer
A (870 mg, 4.75 mmol), (Boc)2O (3.13 g, 14.35 mmol) and DMAP (1.75
g, 14.35 mmol) in THF (40 mL) was stirred at 60.degree. C. for 2
hours. Solvent was removed in vacuo and the residue was purified by
silica gel column (pet ether: EtOAc 10:1) to give the desired
product as a yellow solid (1.2 g). Yield 89% (ESI 283.0
(M+H)+).
Step 5: tert-butyl
7-(4-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy)butyl)-2-methyl-3,4-d-
ihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A
##STR00367##
[0788] To a solution of (R)-tert-butyl
3-(but-3-enyloxy)pyrrolidine-1-carboxylate (512 mg, 2.13 mmol) in
THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF,
8.5 mL, 4.25 mmol). The reaction was stirred at 50.degree. C. for 2
hours, then cooled to rt, added tert-butyl
7-chloro-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
stereoisomer A (600 mg, 2.13 mmol), tricyclohexylphosphine (60 mg,
0.21 mmol), Pd(OAc)2 (47 mg, 0.21 mmol) and NaOH (127 mg, 3.19
mmol). The mixture was stirred at 70.degree. C. for 2 hours.
Solvent was removed in vacuo and the residue was purified by silica
gel column (pet ether: EtOAc 8:1) to give the desired product as a
yellow solid (988 mg). Yield 95% (ESI 490.0 (M+H)+).
Step 6:
2-methyl-7-(4-((R)-pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,-
8-naphthyridine stereoisomer A
##STR00368##
[0790] Tert-butyl 7-(4-((R)-1-(tert-butoxy c arb
onyl)pyrrolidin-3-yloxy)butyl)-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2-
H)-carboxylate stereoisomer A (1.2 g, 2.45 mmol) was treated with
HCl in 1,4-dioxane (4M, 8 mL) at 25.degree. C. for 16 hours.
Solvent was removed in vacuo to give the desired product (781.7 mg)
as a white solid. Yield 88% (ESI 290.0 (M+H)+).
Step 7: tert-butyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A
##STR00369##
[0792] A mixture of
2-methyl-7-(4-((R)-pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-napht-
hyridine stereoisomer A (200 mg, 0.55 mmol), tert-butyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(206 mg, 0.55 mmol) and DIPEA (178 mg, 1.38 mmol) in acetonitrile
(8 mL) was stirred at 50.degree. C. for 4 hours. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(DCM: MeOH 10:1) to give the desired product tert-butyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A as a yellow oil (120 mg). Yield 37% (ESI 582.3
(M+H)+).
Step 8:
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-
-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)ac-
etic acid stereoisomer A (compounds 101-A-E1 and 101-A-E2)
##STR00370##
[0794] To a solution of tert-butyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A (120 mg, 0.21 mmol) in DCM (2.5 mL) was added TFA
(2.5 mL), then the mixture was stirred at rt for 16 hours. Solvent
was removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give diastereomeric products compound 101 A-E1 (40
mg) and compound 101-A-E2 (1.5 mg) as white solids.
[0795] Compound 101-A-E1 LC/MS ESI 526.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.62-7.58 (m, 1H), 7.46-7.43 (m, 1H) 7.28-7.18 (m,
2H), 6.45 (d, J=7.2 Hz, 1H), 5.02 (s, 1H), 4.74 (d, J=10.8 Hz, 1H),
4.21 (s, 1H), 4.01 (d, J=7.2 Hz, 1H), 3.71-3.69 (m, 1H), 3.59-3.40
(m, 5H), 3.15-3.10 (m, 1H), 2.77-2.74 (m, 2H), 2.62-2.58 (m, 2H),
2.05-1.89 (m, 5H), 1.88-1.42 (m, 10H), 1.22 (d, J=10.8 Hz, 3H).
[0796] Compound 101-A-E2 LC/MS ESI 526.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.46-7.41 (m, 2H), 7.31-7.29 (m, 1H) 7.16-7.13 (m,
1H), 6.47 (d, J=7.2 Hz, 1H), 5.32 (s, 1H), 4.70 (d, J=6.8 Hz, 1H),
4.19 (s, 1H), 4.10 (d, J=10.0 Hz, 1H), 3.71-3.40 (m, 4H), 3.19-3.16
(m, 3H), 2.78-2.76 (m, 2H), 2.65-2.61 (m, 2H), 2.25-2.02 (m, 2H),
2.00-1.96 (m, 3H), 1.88-1.42 (m, 10H), 1.22 (d, J=10.8 Hz, 3H).
Step 9:
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-
-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)ac-
etic acid stereoisomer B (compounds 101-B-E1 and 101-B-E2)
##STR00371##
[0798]
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7--
methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)ace-
tic acid stereoisomer B (compounds 101-B-E1 and 101-B-E2) was
synthesized from tert-butyl
7-chloro-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
stereoisomer B by the same methods as stereoisomer A.
[0799] Compound 101-B-E1 LC/MS ESI 526.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.62-7.58 (m, 1H), 7.46-7.43 (m, 1H) 7.26-7.18 (m,
2H), 6.44 (d, J=7.2 Hz, 1H), 4.99 (s, 1H), 4.74 (d, J=10.4 Hz, 1H),
4.21 (s, 1H), 4.03 (d, J=10.8 Hz, 1H), 3.71-3.69 (m, 1H), 3.59-3.40
(m, 5H), 3.10 (s, 1H), 2.76-2.73 (m, 2H), 2.61-2.57 (m, 2H),
2.20-1.89 (m, 5H), 1.81-1.42 (m, 10H), 1.22 (d, J=10.8 Hz, 3H).
[0800] Compound 101-B-E2 LC/MS ESI 526.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.47-7.37 (m, 3H), 7.17-7.12 (m, 1H), 6.49 (d, J=7.2
Hz, 1H), 5.32 (s, 1H), 4.69 (d, J=9.2 Hz, 1H), 4.19 (s, 1H), 4.10
(d, J=10.0 Hz, 1H), 3.71-3.40 (m, 5H), 3.19-3.16 (m, 2H), 2.79-2.76
(m, 2H), 2.68-2.63 (m, 2H), 2.35-2.22 (m, 1H), 2.10-1.96 (m, 4H),
1.86-1.44 (m, 10H), 1.22 (d, J=10.8 Hz, 1H).
Example 32: Preparation of
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
(compounds 102-A-E1, 102-A-E2 and 102-B)
Step 1: ethyl
4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-carboxylate
##STR00372##
[0802] To a solution of diisopropylamine (3.19 mL, 22.8 mmol) in
dry tetrahydrofuran (20 mL) under nitrogen atmosphere at
-78.degree. C. was added n-butyllithium in hexanes (2.5 M, 7.28 mL,
18.2 mmol). This mixture was stirred for 45 minutes at -78.degree.
C., then ethyl tetrahydropyran-4-carboxylate (2.87 mL, 19.0 mmol)
was added dropwise, and the mixture was stirred for 30 minutes at
-78.degree. C. A mixture of 4-bromo-1-butene (2.5 mL, 24.6 mmol)
and HMPA (1.85 mL, 10.6 mmol) in dry tetrahydrofuran (5 mL) was
added dropwise. The mixture was stirred for five minutes at
-78.degree. C., taken out of the acetone/dry ice bath and stirred
in an ice/water bath at 0.degree. C. for 20 minutes, then stirred
for 25 minutes at room temperature. The reaction mixture was
quenched with saturated aqueous ammonium chloride and extracted
three times with diethyl ether. The combined organic layers were
washed with brine, dried over sodium sulfate and concentrated in
vacuo. Purification by column chromatography (silica, 3% to 15%
diethyl ether in pentane) afforded the desired ethyl
4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-carboxylate (3.19 g). Yield
79%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 5.82-5.69 (m, 1H),
5.04-4.91 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.87-3.78 (m, 2H),
3.53-3.39 (m, 2H), 2.14-2.05 (m, 2H), 2.02-1.92 (m, 2H), 1.66-1.59
(m, 2H), 1.55-1.45 (m, 2H), 1.28 (t, J=7.1 Hz, 3H).
Step 2: (4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-yl)methanol
##STR00373##
[0804] To a solution of ethyl
4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-carboxylate (3.17 g, 14.9
mmol) in dry tetrahydrofuran (30 mL) under argon atmosphere at
0.degree. C. was added lithium aluminium hydride in tetrahydrofuran
(2.4 M, 6.22 mL, 14.9 mmol). The mixture was stirred at room
temperature for 1 hour and quenched by slow addition of ethyl
acetate (20 mL). The mixture was washed with 1M hydrochloric acid,
the layers were separated and the water layer was extracted with
ethyl acetate. The combined organic layers were washed with 1M
hydrochloric acid and brine, dried over sodium sulfate and
concentrated in vacuo. Purification by column chromatography
(silica, 15% to 50% ethyl acetate in heptane afforded the desired
product (4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-yl)methanol (2.21
g). Yield 87%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
5.91-5.78 (m, 1H), 5.10-4.92 (m, 2H), 3.76-3.60 (m, 4H), 3.53 (s,
2H), 2.09-1.98 (m, 2H), 1.59-1.48 (m, 4H), 1.48-1.40 (m, 2H), 1.36
(br. s, 1H).
Step 3: (4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-yl)methyl
4-methylbenzenesulfonate
##STR00374##
[0806] To a solution of
(4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-yl)methanol (1.75 g, 10.3
mmol) in dichloromethane (39 mL) at 0.degree. C. was added pyridine
(2.5 mL, 30.9 mmol) and p-toluenesulfonyl chloride (3.14 g, 16.5
mmol). The reaction mixture was stirred at room temperature for 4
days, concentrated in vacuo, diluted saturated aqueous sodium
hydrogen carbonate and extracted three times with ethyl acetate.
The combined organic layers were washed with brine, dried over
sodium sulfate and concentrated in vacuo. Purification by column
chromatography (silica, 10 to 30% ethyl acetate in heptane)
afforded the desired product
(4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-yl)methyl
4-methylbenzenesulfonate (3.15 g). Yield 94%. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.84-7.75 (m, 2H), 7.36 (d, J=8.0 Hz, 2H),
5.78-5.64 (m, 1H), 5.00-4.89 (m, 2H), 3.88 (s, 2H), 3.67-3.47 (m,
4H), 2.46 (s, 3H), 1.90-1.79 (m, 2H), 1.56-1.47 (m, 2H), 1.44 (t,
J=5.6 Hz, 4H).
Step 4: (4-(3-oxopropyl)tetrahydro-2H-pyran-4-yl)methyl
4-methylbenzenesulfonate
##STR00375##
[0808] To a solution of (4-(but-3-en-1-yl)tetrahy
dro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (3.15 g, 9.70
mmol) in tetrahydrofuran (74 mL) and water (24 mL) was added sodium
periodate (5.19 g, 24.3 mmol) and osmium tetroxide solution (4 wt %
in water, 9.9 mg, 0.04 mmol). The mixture was stirred at room
temperature for 1.5 hours, diluted with water and extracted three
times with ethyl acetate. The combined organic layers were washed
with brine, dried over sodium sulfate and concentrated in vacuo.
This afforded the desired product
(4-(3-oxopropyl)tetrahydro-2H-pyran-4-yl)methyl
4-methylbenzenesulfonate (3.17 g). Yield 100%. .sup.1H NMR (400
MHz, Chloroform-d) .delta. 9.73 (d, J=1.7 Hz, 1H), 7.83-7.75 (m,
2H), 7.37 (d, J=8.1 Hz, 2H), 3.87 (s, 2H), 3.70-3.57 (m, 2H),
3.57-3.46 (m, 2H), 2.47 (s, 3H), 2.36-2.25 (m, 2H), 1.84-1.72 (m,
2H), 1.50-1.36 (m, 4H).
Step 5:
(4-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)tetrahydro-2H-pyran-
-4-yl)methyl 4-methylbenzenesulfonate
##STR00376##
[0810] To a solution of 2-bromo-4-fluoroiodobenzene (1.66 mL, 12.8
mmol) in dry toluene (80 mL) at -18.degree. C. under argon
atmosphere was added isopropylmagnesium chloride (2M in THF, 6.37
mL, 12.7 mmol). After stirring for 20 minutes, a solution of
(4-(3-oxopropyl)tetrahydro-2H-pyran-4-yl)methyl
4-methylbenzenesulfonate (3.2 g, 9.8 mmol) in dry tetrahydrofuran
(50 mL) was added. The mixture was allowed to come to room
temperature overnight, then quenched by pouring it into saturated
aqueous ammonium chloride and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated in vacuo. Purification by column
chromatography (silica, 15% to 55% ethyl acetate in heptane)
afforded the desired product
(4-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)tetrahydro-2H-pyran-4-yl)m-
ethyl 4-methylbenzenesulfonate (3.1 g). Yield 63%. .sup.1H NMR (400
MHz, Chloroform-d) .delta. 7.78 (d, J=8.0 Hz, 2H), 7.54-7.46 (m,
1H), 7.34 (d, J=8.0 Hz, 2H), 7.31-7.23 (m, 1H), 7.11-7.01 (m, 1H),
4.98-4.89 (m, 1H), 3.86 (s, 2H), 3.65-3.47 (m, 4H), 2.45 (s, 3H),
2.10 (d, J=4.0 Hz, 1H), 1.80-1.36 (m, 8H).
Step 6: 3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane
##STR00377##
[0812] To a solution of
(4-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)tetrahydro-2H-pyran-4-yl)m-
ethyl 4-methylbenzenesulfonate (3.1 g, 6.2 mmol) in dry
tetrahydrofuran (250 mL) under argon atmosphere at room temperature
was added sodium hydride (60% dispersion in mineral oil, 0.37 g,
9.3 mmol). The mixture was stirred at room temperature overnight,
quenched with saturated aqueous ammonium chloride and extracted
three times with ethyl acetate. The combined organic layers were
washed with brine, dried over sodium sulfate and concentrated in
vacuo. Purification by column chromatography (silica, 2% to 12%
ethyl acetate in heptane) afforded the desired product
3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane (844 mg).
Yield 42%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.54-7.47
(m, 1H), 7.29-7.22 (m, 1H), 7.09-7.00 (m, 1H), 4.64-4.50 (m, 1H),
4.10-4.02 (m, 1H), 3.80-3.57 (m, 4H), 3.36 (d, J=11.5 Hz, 1H),
2.02-1.83 (m, 3H), 1.77-1.67 (m, 1H), 1.60-1.44 (m, 2H), 1.43-1.31
(m, 2H).
[0813] A racemic mixture of
3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane (1.165 gram)
was separated by chiral preparative SFC. Apparatus: Waters Prep 100
SFC UV/MS directed system; Waters 2998 Photodiode Array (PDA)
Detector; Waters Acquity QDa MS detector; Waters 2767 Sample
Manager; Column: Phenomenex Lux Amylose-1 (250.times.21 mm, 51
.mu.m), column temp: 35.degree. C.; flow: 100 mL/min; ABPR: 120
bar; Eluent A: CO.sub.2, Eluent B: 20 mM Ammonia in Isopropanol;
Isocratic method: 5% B for 4 min; Loading: 25 mg; Detection: PDA
(210-400 nm); fraction collection based on PDA TIC.
[0814] The first eluting fraction (stereoisomer A, 0.43 g) was
isolated as a white solid, yield 37%. RT: 1.44 min, 100% ee.
Apparatus: Waters Acquity UPC.sup.2 System; Column: Phenomenex
Amylose-1 (100.times.4.6 mm, 5 .mu.m), column temp: 35.degree. C.;
flow: 2.5 mL/min; BPR: 170 bar; Eluent A: CO.sub.2, Eluent B: 20 mM
Ammonia in Isopropanol; Gradient method: t=0 min 5% B, t=5 min 15%
B, t=6 min 15% B. Detection: PDA (210-320 nm). The second eluting
fraction (stereoisomer B, 0.43 g) was isolated as a white solid,
yield 37%. RT: 1.96 min, 96% ee. Apparatus: Waters Acquity
UPC.sup.2 System; Column: Phenomenex Amylose-1 (100.times.4.6 mm, 5
.mu.m), column temp: 35.degree. C.; flow: 2.5 mL/min; BPR: 170 bar;
Eluent A: CO2, Eluent B: 20 mM Ammonia in Isopropanol; Gradient
method: t=0 min 5% B, t=5 min 15% B, t=6 min 15% B. Detection: PDA
(210-320 nm).
Step 7: (-)-tert-butyl
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate
stereoisomer A
##STR00378##
[0816] An oven dried flask was charged with zinc dust (0.342 g,
5.22 mmol) and heated with a heat gun under an argon flow. After
cooling to room temperature, dry tetrahydrofuran (6 mL) was added
followed by 1,2-dibromoethane (0.011 mL, 0.13 mmol). The mixture
was heated to reflux and cooled to room temperature 3 times. Then,
trimethylsilyl chloride (0.017 mL, 0.13 mmol) was added which
caused the mixture to reflux spontaneously and the zinc to change
morphology. After stirring for 20 minutes, tert-butyl bromoacetate
(0.38 mL, 2.61 mmol) was added dropwise, resulting in an exotherm.
The mixture was kept at an elevated temperature (45.degree. C.) for
30 minutes and then allowed to cool to room temperature. A separate
flask was charged with
3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane stereoisomer
A (0.43 g, 1.31 mmol), tri-tert-butylphosphine tetrafluoroborate
(0.038 g, 0.13 mmol) and bis-(dibenzylideneacetone)palladium (0.075
g, 0.13 mmol). The reaction vessel was flushed with argon, dry
tetrahydrofuran (6 mL) was added and argon was bubbled through for
five minutes. The zincate solution was added by syringe, and the
reaction mixture was heated to reflux for 2 hours. The mixture was
cooled to room temperature overnight, quenched with saturated
aqueous ammonium chloride and extracted with ethyl acetate three
times. The combined organic layers were dried over sodium sulfate
and concentrated in vacuo. Purification by column chromatography
(silica, 0% to 15% ethyl acetate in heptane) afforded the desired
product (-)-tert-butyl
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate
stereoisomer A (251 mg). Yield 53%. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.45-7.38 (m, 1H), 7.01-6.91 (m, 2H), 4.42
(dd, J=11.3, 2.4 Hz, 1H), 4.03 (dd, J=11.4, 2.7 Hz, 1H), 3.78-3.49
(m, 6H), 3.32 (d, J=11.4 Hz, 1H), 2.04-1.58 (m, 5H), 1.53-1.23 (m,
12H). Specific Optical Rotation: -41.2.degree., c=0.3, CHCl.sub.3,
20.3.degree. C., 589 nm.
Step 8: tert-butyl
2-bromo-2-(5-fluoro-2-((S)-2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate
stereoisomer A
##STR00379##
[0818] To a solution of tert-butyl
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate
stereoisomer A (110 mg, 0.32 mmol) in THF (3 mL) at -78.degree. C.,
was added lithium diisopropylamide solution 2.0 M in THF/hexanes
(0.32 mL, 0.64 mmol) dropwise. The reaction was stirred at
-78.degree. C. for 30 min, then chlorotrimethylsilane (70 mg, 0.64
mmol) was added and the reaction was stirred at -78.degree. C. for
another 30 min. Then a solution of NBS (114 mg, 0.64 mmol) in THF
(2 mL) was added and the reaction was stirred at -78.degree. C. for
1 hour. The reaction was quenched with MeOH (2 mL), solvent was
removed in vacuo, and the residue was purified by silica gel column
(pet ether: EtOAc 10:1) to give the desired product tert-butyl
2-bromo-2-(5-fluoro-2-(2,9-di
oxaspiro[5.5]undecan-3-yl)phenyl)acetate stereoisomer A as a yellow
oil (120 mg). Yield 85% (ESI 465.0 (M+Na)+).
Step 9: tert-butyl
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A
##STR00380##
[0820] A mixture of tert-butyl
2-bromo-2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate
stereoisomer A (120 mg, 0.27 mmol),
(R)-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
(94 mg, 0.27 mmol) and DIPEA (95 mg, 0.74 mmol) in acetonitrile (8
mL) was stirred at rt for 3 hours. Solvent was removed in vacuo,
and the residue was purified by silica gel column (DCM: MeOH 10:1)
to give the desired product tert-butyl 2
(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A as a yellow oil (112 mg). Yield 65% (ESI 638.3
(M+H)+).
Step 10:
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(-
4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A (compounds 102-A-E1 and 102-A-E2)
##STR00381##
[0822] To a solution of
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetate
stereoisomer A (112 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5
mL), then the mixture was stirred at RT for 18 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give diastereomeric products 102-A-E1 (20 mg) and
102-A-E2 (11 mg) as white solids.
[0823] Compound 102-A-E1 LC/MS ESI 582.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.61 (dd, J=8.8, 5.9 Hz, 1H), 7.46 (dd, J=10.0, 2.7
Hz, 1H), 7.17 (t, J=7.6 Hz, 2H), 6.41 (d, J=7.3 Hz, 1H), 4.93 (s,
1H), 4.75 (d, J=10.7 Hz, 1H), 4.21 (s, 1H), 3.95 (dd, J=11.2, 2.3
Hz, 1H), 3.74-3.37 (m, 11H), 3.27 (s, 1H), 3.05 (s, 1H), 2.72 (t,
J=6.2 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.14-1.87 (m, 7H), 1.83-1.73
(m, 4H), 1.69-1.64 (m, 2H), 1.56-1.50 (m, 1H), 1.33-1.30 (m,
2H).
[0824] Compound 102-A-E2 LC/MS ESI 582.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.45 (dd, J=12.3, 6.2 Hz, 2H), 7.22 (d, J=7.0 Hz,
1H), 7.17-7.10 (m, 1H), 6.42 (d, J=7.3 Hz, 1H), 5.14 (s, 1H), 4.73
(d, J=12.9 Hz, 1H), 4.17 (s, 1H), 3.96 (d, J=11.8 Hz, 1H),
3.74-3.37 (m, 11H), 3.09-3.05 (m, 2H), 2.73 (t, J=6.3 Hz, 2H),
2.63-2.59 (m, 2H), 2.17-2.07 (m, 4H), 1.92-1.63 (m, 10H), 1.35-1.31
(m, 2H).
Step 11:
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(-
4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid stereoisomer B (compound 102-B)
##STR00382##
[0826]
2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-((R)-3-(4--
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid stereoisomer B (Compound 102-B) was prepared from
3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane stereoisomer
B by the same methods as stereoisomer A.
[0827] Compound 102-B LC/MS ESI 582.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.63-7.60 (m, 1H), 7.50-7.47 (m, 1H), 7.25-7.17 (m,
2H), 6.43 (d, J=7.2 Hz, 1H), 4.93 (s, 1H), 4.87-4.77 (m, 1H), 4.19
(s, 1H), 3.96 (d, J=12.0 Hz, 1H), 3.71-3.39 (m, 11H), 3.21-3.18 (m,
2H), 2.73 (t, J=12.0 Hz, 2H), 2.60 (t, J=12 Hz, 2H), 2.18 (s, 2H),
2.06-2.05 (m, 1H), 1.96-1.91 (m, 4H), 1.89-1.52 (m, 7H), 1.35 (t,
J=8.0 Hz, 2H).
Example 33: Preparation of
2-((R)-3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy-
)pyrrolidin-1-yl)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)aceti-
c acid (compounds 123-E1 and 123-E2)
Step 1: 4-(2,6-dichloropyridin-3-yl)-2-methylbut-3-yn-2-amine
##STR00383##
[0829] A solution of 2,6-dichloro-3-iodopyridine (4.48 g, 16.4
mmol) in anhydrous acetonitrile (36 mL) and triethylamine (36 mL,
259 mmol) was flushed with argon for 15 minutes. Then,
1,1-dimethyl-prop-2-ynylamine (1.78 mL, 18.0 mmol), copper(I)
iodide (94 mg, 0.49 mmol) and bis(triphenylphosphine)palladium(II)
dichloride (345 mg, 0.49 mmol) were added. The mixture was placed
in a preheated oil bath at 60.degree. C. for 1 hour, then cooled to
room temperature, diluted with ethyl acetate, washed twice with
water and with saturated aqueous sodium bicarbonate, dried over
sodium sulfate and concentrated in vacuo. The residue was purified
by column chromatography (silica, gradient 50% to 100% of (3%
triethylamine in ethyl acetate) in heptane). to afford the desired
4-(2,6-dichloropyridin-3-yl)-2-methylbut-3-yn-2-amine (2.95 g) as a
yellow-orange oil. Yield: 79%. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 7.66 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 1.70 (s,
2H), 1.51 (s, 6H).
Step 2: 4-(2,6-dichloropyridin-3-yl)-2-methylbutan-2-amine
##STR00384##
[0831] To a solution of
4-(2,6-dichloropyridin-3-yl)-2-methylbut-3-yn-2-amine (2.95 g, 12.9
mmol) in degassed ethanol (90 mL) was added Wilkinson's catalyst
(1.19 g, 1.29 mmol). The mixture was flushed with hydrogen and
stirred at 35.degree. C. under 5 bar of hydrogen pressure for 3
days. The reaction mixture was concentrated in vacuo, and the
residue was purified by column chromatography (silica, 10% to 15%
ethyl acetate in heptane) to afford the desired
4-(2,6-dichloropyridin-3-yl)-2-methylbutan-2-amine (1.4 g) as a
brown oil. Yield 47%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
7.52 (d, J=7.9 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 2.80-2.71 (m, 2H),
1.67-1.57 (m, 2H), 1.41 (s, 2H), 1.20 (s, 6H).
Step 3:
7-chloro-2,2-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine
##STR00385##
[0833] To a solution of
4-(2,6-dichloropyridin-3-yl)-2-methylbutan-2-amine (1.24 g, 4.2
mmol) in dry N,N-dimethylacetamide (40 mL) was added
N,N-diisopropylethylamine (8.78 mL, 50.4 mmol). The mixture was
heated to 120.degree. C. for 2 days, cooled to room temperature,
diluted with water (400 mL) and extracted with a 1:1 mixture of
heptane and ethyl acetate three times. The combined organic
extracts were washed twice with brine, dried over sodium sulfate
and concentrated in vacuo. The residue was purified by column
chromatography (silica, 5% to 15% ethyl acetate in heptane) to
afford the desired
7-chloro-2,2-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (470 mg)
as a light yellow oil which crystallised upon standing. Yield: 57%.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.12 (d, J=7.5 Hz, 1H),
6.48 (d, J=7.5 Hz, 1H), 4.78 (s, 1H), 2.70 (t, J=6.6 Hz, 2H), 1.67
(t, J=6.6 Hz, 2H), 1.24 (s, 6H).
Step 4: (R)-tert-butyl
3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrol-
idine-1-carboxylate
##STR00386##
[0835] To a solution of (R)-tert-butyl
3-(but-3-enyloxy)pyrrolidine-1-carboxylate (796 mg, 3.3 mmol) in
THF (dry, 3 mL) at room temperature under Ar was added 9-BBN
solution (0.5M in THF, 13.2 mL, 6.6 mmol). The reaction was stirred
at 50.degree. C. for 2 hours, then cooled to room temperature. This
solution was added to a mixture of
7-chloro-2,2-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (433 mg,
2.2 mmol), Pd(OAc)2 (25 mg, 0.11 mmol), PCy3 (62 mg, 0.22 mmol) and
KOH (148 mg, 2.64 mmol) in THF (5 mL). The reaction mixture was
stirred at 70.degree. C. for 3 hours under Ar, then concentrated in
vacuo, and the residue was purified by silica gel column (pet
ether/EtOAc=30%-100%) to give the desired product (R)-tert-butyl
3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrol-
idine-1-carboxylate as a brown oil (764 mg). Yield 86% (ESI 404.2
(M+H)+).
Step 5:
(R)-2,2-dimethyl-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydr-
o-1,8-naphthyridine
##STR00387##
[0837] To a solution of (R)-tert-butyl
3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrol-
idine-1-carboxylate (764 mg, 1.89 mmol) in MeOH (5 mL) was added
HCl/dioxane (4M, 4.7 mL). The reaction was stirred at room
temperature for 2 hours, then quenched with NH3/MeOH (7 N) to
pH=7.about.8. Solvent was removed in vacuo, and the residue was
purified by silica gel column (DCM:MeOH=10:14:1) to give the
desired product
(R)-2,2-dimethyl-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-n-
aphthyridine as an yellow oil (522 mg). Yield 91% (ESI 304.2
(M+H)+).
Step 6: tert-butyl
2-((R)-3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy-
)pyrrolidin-1-yl)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)aceta-
te
##STR00388##
[0839] A mixture of
(R)-2,2-dimethyl-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-n-
aphthyridine (405 mg, 1.33 mmol), tert-butyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(745 mg, 2.0 mmol) and DIPEA (517 mg, 4.0 mmol) in acetonitrile (12
mL) was stirred at room temperature for 2 hours. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(DCM:MeOH=100:120:1) to give the desired product tert-butyl
2-((R)-3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy-
)pyrrolidin-1-yl)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)aceta-
te as a colorless oil (380 mg). Yield 48% (ESI 596.3 (M+H)+).
Step 7:
2-((R)-3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-
)butoxy)pyrrolidin-1-yl)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)pheny-
l)acetic acid (compounds 123-E1 and 123-E2)
##STR00389##
[0841] To a solution of tert-butyl
2-((R)-3-(4-(7,7-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy-
)pyrrolidin-1-yl)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)aceta-
te (380 mg, 0.64 mmol) in DCM (4.0 mL) was added TFA (4.0 mL). The
mixture was stirred at room temperature for 18 hours. Solvent was
removed in vacuo, and the residue was purified by Prep-HPLC A
(30-65% MeCN) to give compound 123-E1 (168 mg) and 123-E2 (25 mg)
as white solids.
[0842] Compound 123-E1 LC/MS ESI 540.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.60-7.56 (m, 1H), 7.48-7.44 (m, 1H), 7.25 (d, J=7.2
Hz, 1H), 7.18-7.14 (m, 1H), 6.42 (d, J=7.2 Hz, 1H), 4.91 (s, 1H),
4.76-4.75 (m, 1H), 4.19 (s, 1H), 4.04-4.02 (m, 1H), 3.71-3.24 (m,
6H), 3.06-3.03 (m, 1H), 2.74-2.74 (m, 2H), 2.60-2.56 (m, 2H),
2.14-1.98 (m, 4H), 1.79-1.62 (m, 10H), 1.26 (s, 6H).
[0843] Compound 123-E2 LC/MS ESI 540.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.46-7.42 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.13-7.10
(m, 1H), 6.42 (d, J=7.2 Hz, 1H), 5.14 (s, 1H), 4.74-4.72 (m, 1H),
4.16-4.08 (m, 2H), 3.69-3.37 (m, 4H), 3.12-3.08 (m, 2H), 2.78-2.74
(m, 2H), 2.61-2.56 (m, 2H), 2.14-2.03 (m, 2H), 1.95-1.82 (m, 3H),
1.75-1.58 (m, 9H), 1.26-1.24 (m, 6H).
Example 34: Preparation of
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4-methox-
y-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl-
)acetic acid Me-stereoisomer A (compounds 124-A-E1, 124-A-E2 and
124-B-E1)
Step 1: 2,6-dichloro-4-methoxynicotinaldehyde
##STR00390##
[0845] To a solution of 2,6-dichloro-4-methoxypyridine (3.49 g,
19.6 mmol) in dry tetrahydrofuran (100 mL) at -78.degree. C. was
added n-butyl lithium (2.5 M solution in hexanes, 8.63 mL, 21.6
mmol). After 30 minutes, ethyl formate (14.2 mL, 177 mmol) was
added, and the mixture was stirred at -78.degree. C. for an
additional 15 minutes. The reaction was quenched with saturated
aqueous ammonium chloride, warmed to room temperature, diluted with
water and extracted three times with ethyl acetate. The combined
organic layers were washed with brine, dried over sodium sulfate
and concentrated in vacuo. Purification by flash column
chromatography (silica, 5% to 40% ethyl acetate in heptane)
afforded the desired product 2,6-dichloro-4-methoxynicotinaldehyde
(1.83 g). Yield 45%. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
10.40 (s, 1H), 6.94 (s, 1H), 4.02 (s, 3H).
Step 2: 4-(2,6-dichloro-4-methoxypyridin-3-yl)but-3-en-2-one
##STR00391##
[0847] A mixture of 2,6-dichloro-4-methoxynicotinaldehyde (4.43 g,
21.5 mmol), acetonyltriphenylphosphonium chloride (8.01 g, 22.6
mmol), potassium carbonate (5.94 g, 43.0 mmol) and 18-crown-6 (5.68
g, 21.5 mmol) in toluene (150 mL) was heated to 80.degree. C. for
2.5 hours. The mixture was allowed to cool to room temperature,
diluted with water and extracted three times with ethyl acetate.
The combined organic layers were washed with water and brine, dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (silica, 5% to 40% ethyl
acetate in heptane) to afford the desired product
4-(2,6-dichloro-4-methoxypyridin-3-yl)but-3-en-2-one (3.68 g).
Yield 69%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.66 (d,
J=16.6 Hz, 1H), 7.07 (d, J=16.6 Hz, 1H), 6.88 (s, 1H), 4.00 (s,
3H), 2.40 (s, 3H).
Step 3: 4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-one
##STR00392##
[0849] A mixture of
4-(2,6-dichloro-4-methoxypyridin-3-yl)but-3-en-2-one (4.4 g, 17.9
mmol) and Wilkinson's catalyst (716 mg, 1.79 mmol) in ethanol (160
mL) was subjected to 4 Bar hydrogen pressure in an autoclave for 6
hours. The solvent was removed in vacuo, and the residue was
purified by flash column chromatography (silica, 5% to 40% ethyl
acetate in heptane) to afford the desired product
4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-one (3.76 g). Yield
85%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 6.76 (s, 1H), 3.90
(s, 3H), 3.05-2.87 (m, 2H), 2.71-2.53 (m, 2H), 2.19 (s, 3H).
Step 4: tert-butyl
(4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-yl)carbamate
##STR00393##
[0851] A mixture of
4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-one (3.74 g, 15.1
mmol) and ammonium acetate (11.64 g, 151 mmol) in methanol (100 mL)
was stirred for 30 minutes. Sodium cyanoborohydride (947 mg, 15.1
mmol) was added. After 2 hours, additional sodium cyanoborohydride
(1.89 g, 30.1 mmol) was added, and the mixture was stirred at room
temperature for 20 hours. The reaction mixture was quenched with
sodium hydroxide (20 mL, 1N solution in water), diluted with water
and extracted with ethyl acetate. The aqueous phase was saturated
with sodium chloride and extracted three more times with ethyl
acetate. The combined organic layers were dried over sodium sulfate
and concentrated in vacuo. The residue was diluted with
hydrochloric acid (1N solution in water) and washed three times
with ethyl acetate. The aqueous layer was concentrated in vacuo,
and the residue was dissolved in 1,4-dioxane (27 mL). A solution of
sodium hydroxide (1.04 g, 26.1 mmol) in water (27 mL) and
di-tertbutyl-dicarbonate (3.03 mL, 13.03 mmol) were added. After 3
hours, the reaction was diluted with water and extracted three
times with ethyl acetate. The combined organic layers were dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (silica, 5% to 40% ethyl
acetate in heptane) to afford the desired product tert-butyl
(4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-yl)carbamate (1.48
g). Yield 28%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 6.75 (s,
1H), 4.38 (s, 1H), 3.89 (s, 3H), 3.71 (s, 1H), 2.84-2.61 (m, 2H),
1.71-1.37 (m, 11H), 1.17 (d, J=6.6 Hz, 3H).
Step 5: 4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-amine
hydrochloride
##STR00394##
[0853] To a solution of tert-butyl
(4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-yl)carbamate (1.48
g, 4.23 mmol) in methanol (15 mL) was added hydrochloric acid in
dioxane (4 M, 30 mL, 120 mmol). After 105 minutes, the mixture was
concentrated in vacuo to afford the desired product
4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-amine hydrochloride
(1.21 g). Yield 100%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.07 (s, 3H), 7.28 (s, 1H), 3.95 (s, 3H), 3.22-3.09 (m, 1H),
2.75-2.59 (m, 2H), 1.88-1.72 (m, 1H), 1.65-1.51 (m, 1H), 1.26 (d,
J=6.5 Hz, 3H).
Step 6:
7-chloro-5-methoxy-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
##STR00395##
[0855] A mixture of
4-(2,6-dichloro-4-methoxypyridin-3-yl)butan-2-amine hydrochloride
(1.59 g, 5.57 mmol) and potassium carbonate (2.31 g, 16.7 mmol) in
2-propanol (50 mL) was heated to 120.degree. C. for 68 hours. The
mixture was cooled to room temperature, diluted with water and
extracted three times with ethyl acetate. The combined organic
layers were dried over sodium sulfate and concentrated in vacuo to
afford the desired product
7-chloro-5-methoxy-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
(1.16 grams). Yield 98%. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 6.19 (s, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 3.55-3.38 (m,
1H), 2.77-2.65 (m, 1H), 2.51-2.35 (m, 1H), 1.99-1.86 (m, 1H),
1.55-1.39 (m, 1H), 1.21 (d, J=6.3 Hz, 3H).
[0856] A racemic mixture of
7-chloro-5-methoxy-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
(1.16 gram) was separated by chiral preparative SFC. Apparatus:
Waters Prep 100 SFC UV/MS directed system; Waters 2998 Photodiode
Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767
Sample Manager; Column: Phenomenex Lux Amylose-1 (250.times.21 mm,
51 .mu.m); Column temp: 35.degree. C.; Flow: 70 mL/min; ABPR: 120
bar; eluent A: CO.sub.2, eluent B: 20 mM ammonia in methanol;
Linear gradient: t=0 min 10% B, t=5 min 50% B; t=7.5 min 50% B;
Detection: PDA (210-400 nm); Fraction collection based on PDA TIC.
The first eluting fraction (stereoisomer A, 425 mg) was isolated as
a white solid, yield 36%. t.sub.R: 2.078 min, 100% ee. Apparatus:
Waters Acquity UPC.sup.2: Waters ACQ-ccBSM Binary Pump; Waters
ACQ-CCM Convergence Manager; Waters ACQ-SM Sample Manager--Fixed
Loop; Waters ACQ-CM Column Manager--30S; Waters ACQ-PDA Photodiode
Array Detector; Waters ACQ-ISM Make Up Pump, Waters Acquity QDa MS
Detector; Column: Phenomenex Lux Amylose-1 (100.times.4.6 mm, 5
.mu.m; Column temp: 35.degree. C.; Flow: 2.5 mL/min; ABPR: 170 bar;
Eluent A: CO.sub.2, Eluent B: 20 mM ammonia in methanol; Linear
gradient: t=0 min 5% B, t=5 min 50% B; t=6 min 50% B; Detection:
PDA (210-400 nm). Specific Optical Rotation: -59.9.degree., c=0.5,
methanol, 21.4.degree. C., 589 nm.
[0857] The second eluting fraction (stereoisomer B, 415 mg) was
isolated as a white solid, yield 35%. t.sub.R: 3.147 min, 99% ee.
Apparatus: Waters Acquity UPC.sup.2: Waters ACQ-ccBSM Binary Pump;
Waters ACQ-CCM Convergence Manager; Waters ACQ-SM Sample
Manager--Fixed Loop; Waters ACQ-CM Column Manager--30S; Waters
ACQ-PDA Photodiode Array Detector; Waters ACQ-ISM Make Up Pump,
Waters Acquity QDa MS Detector; Column: Phenomenex Lux Amylose-1
(100.times.4.6 mm, 5 .mu.m; Column temp: 35.degree. C.; Flow: 2.5
mL/min; ABPR: 170 bar; Eluent A: CO.sub.2, Eluent B: 20 mM ammonia
in methanol; Linear gradient: t=0 min 5% B, t=5 min 50% B; t=6 min
50% B; Detection: PDA (210-400 nm). Specific Optical Rotation:
72.4.degree., c=0.5, methanol, 21.5.degree. C., 589 nm.
Step 7: tert-butyl
7-chloro-5-methoxy-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxyla-
te stereoisomer A
##STR00396##
[0859] To a mixture of
7-chloro-5-methoxy-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
stereoisomer A (190 mg, 0.89 mmol) in THF (8 mL) was added Boc2O
(389 mg, 1.78 mmol) and DMAP (218 mg, 1.78 mmol). The reaction
mixture was stirred at 60.degree. C. for 16 hours, then quenched
with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc
(3.times.20 mL). The combined organic phase was concentrated in
vacuo, and the residue was purified by silica gel column (pet
ether: EtOAc 10:1) to give the desired product tert-butyl
7-chloro-5-methoxy-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxyla-
te stereoisomer A as a yellow oil (260 mg). Yield 93% (ESI 313.0
(M+H)+).
Step 8: tert-butyl
7-(4-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy)butyl)-5-methoxy-2-me-
thyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer
A
##STR00397##
[0861] To a solution of (R)-tert-butyl
3-(but-3-enyloxy)pyrrolidine-1-carboxylate (403 mg, 1.67 mmol) in
THF (dry, 4 mL) was added 9-BBN solution 0.5M in THF (3.34 mL, 1.67
mmol) at room temperature under Ar. The reaction was stirred at
50.degree. C. for 2 hours, then cooled to room temperature. This
solution was added to a mixture of tert-butyl
7-chloro-5-methoxy-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxyla-
te stereoisomer A (260 mg, 0.84 mmol), Pd(OAc)2 (10 mg, 0.042
mmol), PCy3 (23 mg, 0.084 mmol) and K3PO4.H2O (533 mg, 2.51 mmol)
in THF (5 mL). The reaction mixture was stirred at 70.degree. C.
for 3 hours under Ar. Solvent was removed in vacuo, and the residue
was purified by silica gel column (pet ether/EtOAc=10%.about.50%)
to give the desired product tert-butyl
7-(4-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy)butyl)-5-methoxy-2-me-
thyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A
as a yellow oil (350 mg). Yield 80% (ESI 520.0 (M+H)+).
Step 9:
5-methoxy-2-methyl-7-(4-((R)-pyrrolidin-3-yloxy)butyl)-1,2,3,4-tet-
rahydro-1,8-naphthyridine stereoisomer A
##STR00398##
[0863] To a solution of tert-butyl
7-(4-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy)butyl)-5-methoxy-2-me-
thyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A
(350 mg, 0.67 mmol, 1.0 equiv) in DCM (6 mL) was added HCl solution
(4.0 M in 1,4-dioxane, 1.8 mL, 5.36 mmol) dropwise. The reaction
was stirred at 25.degree. C. for 16 hours, then concentrated in
vacuo to give the desired product
5-methoxy-2-methyl-7-(4-((R)-pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-
-1,8-naphthyridine stereoisomer A as a yellow oil (240 mg). Yield
93% (ESI 320.0 (M+H)+).
Step 10: tert-butyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4-methox-
y-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl-
)acetate Me-stereoisomer A
##STR00399##
[0865] A mixture of
5-methoxy-2-methyl-7-(4-((R)-pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-
-1,8-naphthyridine stereoisomer A (240 mg, 0.61 mmol), tert-butyl
2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)acetate
(273 mg, 0.73 mmol) and DIPEA (236 mg, 1.83 mmol) in acetonitrile
(8 mL) was stirred at 60.degree. C. for 2 hours. Solvent was
removed in vacuo, and the residue was purified by silica gel column
(DCM: MeOH 10:1) to give the desired product tert-butyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4-methox-
y-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl-
)acetate Me-stereoisomer A as a yellow oil (160 mg). Yield 42% (ESI
612.0 (M+H)+).
Step 11:
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(-
4-methoxy-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrroli-
din-1-yl)acetic acid Me-stereoisomer A (compounds 124-A-E1 and
124-A-E2)
##STR00400##
[0867] To a solution of tert-butyl
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4-methox-
y-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl-
)acetate Me-stereoisomer A (160 mg, 0.26 mmol) in DCM (5 mL) was
added TFA (1 mL). The reaction was stirred at room temperature for
18 hours. Solvent was removed in vacuo, and the residue was
purified by Prep-HPLC A (30-65% MeCN) to give compound 124-A-E1 (22
mg) and compound 124-A-E2 (2 mg) as white solids.
[0868] Compound 124-A-E1 LC/MS ESI 556.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.59-7.45 (m, 2H), 7.14-7.12 (m, 1H), 6.31 (s,
1H), 4.86 (s, 1H), 4.79 (d, J=9.0 Hz, 1H), 4.18 (s, 1H), 4.03 (d,
J=11.4 Hz, 1H), 3.87 (s, 3H), 3.69-3.67 (m, 1H), 3.56-3.40 (m, 3H),
2.99-2.97 (m, 1H), 2.85-2.42 (m, 4H), 2.25-1.89 (m, 6H), 1.88-1.38
(m, 11H), 1.24 (d, J=6.3 Hz, 3H).
[0869] Compound 124-A-E2 LC/MS ESI 556.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.52-7.44 (m, 2H), 7.12-7.10 (m, 1H), 6.40 (s,
1H), 4.86-4.75 (m, 2H), 4.17-4.08 (m, 2H), 3.92 (s, 3H), 3.69-3.45
(m, 4H), 3.02-2.99 (m, 1H), 2.85-2.42 (m, 4H), 2.25-1.89 (m, 6H),
1.88-1.38 (m, 11H), 1.24 (d, J=6.3 Hz, 3H).
Step 12: Preparation of
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4-methox-
y-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl-
)acetic acid Me-stereoisomer B (compound 124-B-E1)
##STR00401##
[0871]
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4--
methoxy-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidi-
n-1-yl)acetic acid Me-stereoisomer B (compound 124-B-E1) was
synthesized from
7-chloro-5-methoxy-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine
stereoisomer B by the same procedures as for stereoisomer A.
[0872] Compound 124-B-E1 LC/MS ESI 556.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.57-7.54 (m, 1H), 7.49-7.46 (m, 1H), 7.11-7.10
(m, 1H), 6.30 (s, 1H), 4.81 (d, J=8.0 Hz, 1H), 4.73 (s, 1H), 4.15
(s, 1H), 4.05-4.02 (d, J=12.0 Hz, 1H), 3.87 (s, 3H), 3.73-3.68 (m,
1H), 3.51-3.45 (m, 3H), 3.39-3.36 (m, 1H), 3.30-3.22 (m, 1H),
3.12-3.10 (d, J=8.0 Hz, 1H), 2.91-2.86 (m, 1H), 2.76-2.71 (m, 1H),
2.62-2.59 (t, J=12.0 Hz, 2H), 2.52-2.45 (m, 1H), 2.09-1.93 (m, 5H),
1.82-1.60 (m, 8H), 1.51-1.43 (m, 1H), 1.25-1.23 (d, J=8.0 Hz,
3H).
Additional Examples
[0873] Compounds 22-91, 103-122, and 125-129 were prepared using
general procedures based on the method used to prepare compounds
1-21, 92-102, and 123-124.
2-(2-(cyclopropylmethoxy)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)butoxy)pyrrolidin-1-)acetic acid (diastereomeric
compounds 22-E1 and 22-E2)
##STR00402##
[0875] 22-E1 LC/MS ESI 480.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.44 (d, J=7.2 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.01
(d, J=7.2 Hz, 1H), 6.92-6.83 (m, 2H), 6.25 (d, J=7.2 Hz, 1H), 4.89
(s, 1H), 4.04 (s, 1H), 3.82-3.77 (m, 2H), 3.50-3.35 (m, 6H),
2.98-2.80 (m, 2H), 2.59 (t, J=6.4 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H),
1.94-1.17 (m, 9H), 0.49-0.27 (m, 4H). Chiral SFC A (45% MeOH): ee
100%, Rt=2.06 min.
[0876] 22-E2 LC/MS ESI 480.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.44 (d, J=6.4 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.01
(d, J=7.6 Hz, 1H), 6.92-6.83 (m, 2H), 6.24 (d, J=7.6 Hz, 1H), 4.89
(s, 1H), 4.04 (s, 1H), 3.82-3.77 (m, 2H), 3.45-3.35 (m, 6H),
2.98-2.90 (m, 2H), 2.59 (t, J=6.4 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H),
1.94-1.17 (m, 9H), 0.49-0.27 (m, 4H). Chiral SFC A (45% MeOH): ee
100%, Rt=4.49 min.
2-(2-cyclopropyl-4-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 23-E1 and 23-E2)
##STR00403##
[0878] Compound 23-E1 LC/MS ESI 468.6 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.54 (d, J=8.5 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H),
6.93-6.69 (m, 2H), 6.27 (d, J=7.3 Hz, 1H), 5.05 (s, 1H), 4.07 (s,
1H), 3.47-3.25 (m, 5H), 3.21-3.13 (m, 2H), 2.60 (t, J=6.2 Hz, 2H),
2.44 (t, J=7.5 Hz, 2H), 2.23-2.01 (m, 3H), 1.85-1.71 (m, 2H),
1.66-1.44 (m, 4H), 1.02-0.78 (m, 3H), 0.54-0.52 (m, 1H). Chiral SFC
A (45% MeOH): ee 100%, Rt=3.11 min.
[0879] Compound 23-E2 LC/MS ESI 468.6 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.53 (d, J=8.4, 1H), 7.03 (d, J=7.3 Hz, 1H),
6.88-6.64 (m, 2H), 6.27 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.06 (s,
1H), 3.50-3.22 (m, 5H), 3.06-2.71 (m, 3H), 2.60 (t, J=6.2 Hz, 2H),
2.42 (t, J=7.5 Hz, 2H), 2.22-2.04 (m, 1H), 2.05-1.95 (m, 2H),
1.85-1.69 (m, 2H), 1.68-1.39 (m, 4H), 0.96-0.72 (m, 3H), 0.46-0.42
(m, 1H). Chiral SFC A (45% MeOH): ee 100%, Rt=2.31 min.
2-(2-cyclopropylphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
-yl)pentyl)pyrrolidin-1-yl)acetic acid(diastereomeric compounds
24-E1 and 24-E2)
##STR00404##
[0881] Compound 24-E1 LC/MS ESI 447 (M+H).sup.+1H NMR (400 MHz,
MeOD) .delta. 7.61 (d, J=8.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.16-7.10
(m, 2H), 6.33 (d, J=7.2 Hz, 1H), 5.25 (s, 1H), 3.75-3.36 (m, 3H),
3.33-3.31 (m, 2H), 2.71-2.68 (m, 3H), 2.51-2.18 (m, 5H), 1.90-1.84
(m, 2H), 1.68-1.58 (m, 3H), 1.46-1.33 (m, 6H), 1.09-1.07 (m, 3H),
0.59-0.55-(m, 1H).
[0882] Compound 24-E2 LC/MS ESI 447 (M+H).sup.+1H NMR (400 MHz,
MeOD) .delta. 7.61 (d, J=8.0 Hz 1H), 7.33-7.24 (m, 2H), 7.16-7.10
(m, 2H), 6.34 (d, J=7.2 Hz, 1H), 5.24 (s, 1H), 3.85-3.36 (m, 3H),
3.33-3.11 (m, 2H), 2.81-2.68 (m, 3H), 2.52-2.17 (m, 5H), 1.91-1.85
(m, 2H), 1.72-1.3 (m, 9H), 1.11-1.00 (m, 3H), 0.58-0.54 (m,
1H).
2-(2-isopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2--
yl)butoxy) pyrrolidin-1-yl)acetic acid (compound 25)
##STR00405##
[0884] Compound 25 LC/MS ESI 468.2 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.53-7.35 (m, 2H), 7.14 (d, J=7.2 Hz, 1H), 7.08
(d, J=8.4 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.39-6.36 (m, 1H),
5.10-4.90 (m, 1H), 4.74-4.72 (m, 1H), 4.25 (s, 1H), 3.55-3.35 (m,
6H), 3.28-3.02 (m, 2H), 2.71 (t, J=6.0 Hz, 2H), 2.20-1.51 (m, 8H),
1.40-1.35 (m, 6H).
2-(4-cyclopropylpyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compound 26)
##STR00406##
[0886] Compound 26 LC/MS ESI 449.4 (M+H).sup.+. 1H NMR (400 MHz,
MeOD) .delta. 8.73 (d, J=4.4 Hz, 1H), 8.36 (t, J=5.6 Hz, 1H),
7.13-7.10 (m, 1H), 7.01 (d, J=5.2 Hz, 1H), 6.37-6.33 (m, 1H),
5.02-4.95 (m, 1H), 3.65-3.35 (m, 3H), 3.25-2.95 (m, 2H), 2.75-2.65
(m, 3H), 2.55-2.10 (m, 5H), 1.91-1.85 (m, 2H), 1.70-1.60 (m, 3H),
1.50-1.18 (m, 8H), 1.06-1.03 (m, 1H), 0.78-0.74 (m, 1H).
2-(2-cyclopropylphenyl)-2-((S)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric compounds
27-E1 and 27-E2)
##STR00407##
[0888] Compound 27-E1 LC/MS ESI 450.2 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.61 (d, J=7.6 Hz, 1H), 7.31-7.14 (m, 4H), 6.37
(d, J=7.2 Hz, 1H), 5.26 (s, 1H), 4.17 (s, 1H), 3.60-3.25 (m, 8H),
2.71 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.20-1.55 (m, 9H),
1.00-0.90 (m, 3H), 0.58-0.55 (m, 1H). Chiral SFC A (35% MeOH): ee
100%, Rt=3.45 min.
[0889] Compound 27-E2 LC/MS ESI 450.2 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.60 (d, J=7.6 Hz, 1H), 7.33-7.13 (m, 4H), 6.37
(d, J=7.2 Hz, 1H), 5.31 (s, 1H), 4.22 (s, 1H), 3.60-3.05 (m, 8H),
2.71 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.20-1.55 (m, 9H),
1.00-0.92 (m, 3H), 0.58-0.55 (m, 1H). Chiral SFC A (35% MeOH): ee
100%, Rt=4.18 min.
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1--
yl)-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetic acid (compound
28)
##STR00408##
[0891] Compound 28 LC/MS ESI 508.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.64-7.60 (m, 1H), 7.45-7.43 (m, 1H), 7.18-7.12
(m, 3H), 6.38-6.35 (m, 1H), 5.10-4.95 (m, 1H), 4.72-4.60 (m, 2H),
4.17 (s, 1H), 3.60-3.35 (m, 6H), 3.20-3.00 (m, 2H), 2.75-2.68 (m,
2H), 2.56-2.50 (m, 2H), 2.43-1.85 (m, 4H), 1.75-1.50 (m, 4H).
2-(2-isobutoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-
l)butoxy) pyrrolidin-1-yl)acetic acid (diastereomeric compounds
29-E1 and 29-E2)
##STR00409##
[0893] Compound 29-E1 LC/MS ESI 482.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.54 (s, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.46-7.38
(m, 2H), 7.12-7.02 (m, 2H), 6.51 (d, J=7.6 Hz, 1H), 5.25 (s, 1H),
4.18 (s, 1H), 3.87-3.80 (m, 2H), 3.64-3.32 (m, 7H), 3.12-3.06 (m,
1H), 2.82-2.57 (m, 4H), 2.18-1.57 (m, 9H), 1.10-1.02 (m, 6H).
[0894] Compound 29-E2 LC/MS ESI 482.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.54 (s, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.46-7.38
(m, 2H), 7.10-7.01 (m, 2H), 6.49 (d, J=7.6 Hz, 1H), 5.05 (s, 1H),
4.21 (s, 1H), 3.87-3.85 (m, 2H), 3.60-3.22 (m, 8H), 2.82-2.57 (m,
4H), 2.22-1.57 (m, 9H), 1.10-1.02 (m, 6H).
2-(2-isopropoxypyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyri-
din-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 30-E1 and 30-E2)
##STR00410##
[0896] Compound 30-E1 LC/MS ESI 467.2 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.21-8.19 (m, 1H), 7.91-7.88 (m, 1H), 7.12 (d,
J=7.6 Hz, 1H), 7.02-6.98 (m, 1H), 6.34 (d, J=7.2 Hz, 1H), 5.45-5.41
(m, 1H), 3.55-3.36 (m, 3H), 3.25-2.95 (m, 3H), 2.70 (t, J=6.4 Hz,
2H), 2.49 (t, J=7.6 Hz, 2H), 2.45-2.15 (m, 2H), 1.91-1.85 (m, 2H),
1.69-1.59 (m, 3H), 1.42-1.33 (m, 13H).
[0897] Compound 30-E2 LC/MS ESI 467.2 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.21-8.19 (m, 1H), 7.92-7.89 (m, 1H), 7.12 (d,
J=7.6 Hz, 1H), 7.02-6.98 (m, 1H), 6.35 (d, J=7.2 Hz, 1H), 5.45-5.39
(m, 1H), 3.60-3.36 (m, 3H), 3.18-3.13 (m, 1H), 2.85-2.65 (m, 3H),
2.53-2.35 (m, 3H), 2.21-2.17 (m, 1H), 1.91-1.85 (m, 2H), 1.71-1.58
(m, 3H), 1.48-1.32 (m, 13H).
2-(2-cyclopropylphenyl)-2-((S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
-yl)pentyloxy)pyrrolidin-1-yl)acetic acid (diastereomeric compounds
31-E1 and 31-E2)
##STR00411##
[0899] Compound 31-E1 LC/MS ESI 464.3 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.48 (s, 1H), 7.71-7.29 (m, 4H), 7.20 (d, J=7.6
Hz, 1H), 6.53 (d, J=7.2 Hz, 1H), 5.62 (s, 1H), 4.22 (s, 1H),
3.60-3.05 (m, 8H), 2.83-2.65 (m, 4H), 2.38-2.05 (m, 3H), 1.96-1.48
(m, 8H), 1.15-0.90 (m, 3H), 0.58-0.55 (m, 1H).
[0900] Compound 31-E2 LC/MS ESI 464.3 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.48 (s, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.45 (d,
J=7.6 Hz, 1H), 7.39-7.19 (m, 3H), 6.52 (d, J=7.2 Hz, 1H), 5.33 (s,
1H), 4.22 (s, 1H), 3.58-3.05 (m, 8H), 2.81-2.62 (m, 4H), 2.45-1.78
(m, 8H), 1.56-1.42 (m, 3H), 1.15-0.90 (m, 3H), 0.58-0.55 (m,
1H).
2-(4-isopropylpyrimidin-5-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compound 32)
##STR00412##
[0902] Compound 32 LC/MS ESI 452.6 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 8.99-8.94 (m, 2H), 7.26 (d, J=6.8 Hz, 1H), 6.41 (d,
J=7.2 Hz, 1H), 4.67-4.62 (m, 1H), 3.71-3.69 (m, 1H), 3.47-3.32 (m,
4H), 3.16-2.85 (m, 2H), 2.73-2.63 (m, 5H), 2.41-2.03 (m, 2H),
1.96-1.80 (m, 2H), 1.73-1.52 (m, 3H), 1.52-1.24 (m, 12H).
2-(2-cyclobutoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric compounds
33-E1 and 33-E2)
##STR00413##
[0904] Compound 33-E1 LC/MS ESI 480.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.50 (d, J=6.8 Hz, 1H), 7.38-7.33 (m, 1H), 7.13
(d, J=7.2 Hz, 1H), 7.00-6.90 (m, 2H), 6.37 (d, J=7.2 Hz, 1H), 5.08
(s, 1H), 4.82-4.76 (m, 1H), 4.19 (s, 1H), 3.62-3.05 (m, 8H),
2.78-2.40 (m, 6H), 2.25-1.55 (m, 12H). Chiral SFC A (45% MeOH): ee
99%, Rt=1.82 min.
[0905] Compound 33-E2 LC/MS ESI 480.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.42 (d, J=7.2 Hz, 1H), 7.28-7.22 (m, 1H), 7.03
(d, J=7.6 Hz, 1H), 7.90-6.79 (m, 2H), 6.26 (d, J=7.6 Hz, 1H), 4.95
(s, 1H), 4.75-4.66 (m, 1H), 4.06 (s, 1H), 3.52-3.05 (m, 8H), 2.60
(t, J=6.0 Hz, 2H), 2.44-2.30 (m, 4H), 2.20-1.98 (m, 4H), 1.80-1.45
(m, 8H). Chiral SFC A (45% MeOH): ee 94%, Rt=2.77 min.
2-(2-(pyrrolidin-1-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 34-E1 and 34-E2)
##STR00414##
[0907] Compound 34-E1 LC/MS ESI 479.4 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCL3) .delta. 7.50 (d, J=6.8 Hz, 1H), 7.28-7.02 (m, 4H), 6.27
(d, J=7.2 Hz, 1H), 4.68 (s, 1H), 3.94-3.91 (m, 1H), 3.49-3.17 (m,
10H), 2.72-2.49 (m, 6H), 2.06-1.55 (m, 12H).
[0908] Compound 34-E2 LC/MS ESI 479.4 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCL3) .delta. 7.55 (s, 1H), 7.28-7.02 (m, 4H), 6.27 (d, J=7.2
Hz, 1H), 4.55 (s, 1H), 3.98-3.95 (m, 1H), 3.50-3.07 (m, 10H),
2.85-2.49 (m, 6H), 2.06-1.55 (m, 12H).
2-(2-cyclopropylphenyl)-2-((R)-3-(3-((5,6,7,8-tetrahydro-1,8-naphthyridin--
2-yl)methoxy)propyl)pyrrolidin-1-yl)acetic acid (compound 35)
##STR00415##
[0910] Compound 35 LC/MS ESI 450 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 8.50 (brs, 1H), 7.62-7.60 (m, 1H), 7.41-7.21 (m, 4H),
6.60-6.58 (m, 1H), 5.30-5.28 (m, 1H), 4.37-4.35 (m, 2H), 3.36-3.31
(m, 5H), 3.30-3.11 (m, 2H), 2.85-2.75 (m, 3H), 2.50-1.50 (m, 10H),
1.10-0.50 (m, 4H).
2-(2-cyclopropylphenyl)-2-(cis-3-fluoro-4-(4-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 36-E1 and 36-E2)
##STR00416##
[0912] Compound 36-E1 LC/MS ESI 468.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 8.53 (s, 1H), 7.70-7.07 (m, 5H), 6.49 (d, J=8.3 Hz,
1H), 5.32-5.19 (m, 2H), 4.30-4.04 (m, 1H), 3.84-3.36 (m, 6H),
3.33-3.24 (m, 1H), 3.00 (t, J=9.7 Hz, 1H), 2.77-2.64 (m, 4H),
2.36-2.18 (m, 1H), 1.98-1.83 (m, 2H), 1.80-1.52 (m, 4H), 1.16-0.87
(m, 3H), 0.58-0.54 (m, 1H).
[0913] Compound 36-E2 LC/MS ESI 468.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 8.50 (s, 1H), 7.68-7.06 (m, 5H), 6.52 (d, J=7.2 Hz,
1H), 5.42-5.08 (m, 2H), 4.44-4.01 (m, 1H), 3.81-3.33 (m, 6H),
3.33-3.24 (m, 2H), 2.77-2.64 (m, 4H), 2.36-2.18 (m, 1H), 1.98-1.83
(m, 2H), 1.84-1.53 (m, 4H), 1.24-0.85 (m, 3H), 0.58-0.54 (m,
1H).
2-(2-cyclopropyl-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound 37)
##STR00417##
[0915] Compound 37 LC/MS ESI 468.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.52 (s, 1H), 7.48-7.01 (m, 4H), 6.49-6.46 (m, 1H),
5.41-5.28 (m, 1H), 4.24-4.20 (m, 1H), 3.55-3.10 (m, 8H), 2.77-2.61
(m, 4H), 2.29-2.05 (m, 3H), 1.92-1.55 (m, 6H), 1.05-0.80 (m, 3H),
0.55-0.50 (m, 1H).
2-(2-cyclopropyl-6-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound 38)
##STR00418##
[0917] Compound 38 LC/MS ESI 468.4 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.49 (s, 1H), 7.45-7.37 (m, 2H), 7.09-7.03 (m, 2H),
6.54-6.50 (m, 1H), 5.60-5.52 (m, 1H), 4.24-4.20 (m, 1H), 3.59-3.15
(m, 8H), 2.80-2.63 (m, 4H), 2.23-2.13 (m, 3H), 1.92-1.55 (m, 6H),
1.08-0.65 (m, 4H).
2-(2-(methoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrid-
in-2-yl)butoxy)pyrrolidin-hyl)acetic acid (diastereomeric compounds
39-E1 and 39-E2)
##STR00419##
[0919] Compound 39-E1 LC/MS ESI 454.2 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.66-7.64 (m, 1H), 7.43-7.39 (m, 3H), 7.13 (d, J=7.2 Hz,
1H), 6.36 (d, J=7.2 Hz, 1H), 4.89 (s, 1H), 4.44 (d, J=8.0 Hz, 1H),
4.17 (s, 1H), 3.49-3.36 (m, 8H), 3.14-3.13 (m, 2H), 2.70 (t, J=6.4
Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.14-2.13 (m, 2H), 1.96-1.84 (m,
2H), 1.74-1.59 (m, 5H). Chiral SFC A (40% MeOH): ee 100%, Rt=2.64
min.
[0920] Compound 39-E2 LC/MS ESI 454.2 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.67-7.65 (m, 1H), 7.42-7.38 (m, 3H), 7.13 (d, J=7.6 Hz,
1H), 6.36 (d, J=7.2 Hz, 1H), 4.81 (s, 1H), 4.45 (s, 1H), 4.17 (s,
1H), 3.36-3.27 (m, 8H), 3.19-3.13 (m, 2H), 2.70 (t, J=6.4 Hz, 2H),
2.55 (t, J=7.6 Hz, 2H), 2.18-2.14 (m, 2H), 1.90-1.84 (m, 2H),
1.73-1.58 (m, 5H). Chiral SFC A (40% MeOH): ee 100%, Rt=4.68
min.
2-(2-(cyclopropylmethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 40-E1 and 40-E2)
##STR00420##
[0922] Compound 40-E1 LC/MS ESI 464.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.45 (s, 1H), 7.66-7.30 (m, 5H), 6.54 (d, J=7.2
Hz, 1H), 5.18-4.93 (m, 1H), 4.21 (m, 1H), 3.61-3.41 (m, 6H),
3.28-3.24 (m, 2H), 2.94-2.64 (m, 6H), 2.22-2.18 (m, 2H), 1.94-1.65
(m, 6H), 1.17-1.11 (m, 1H), 0.58-0.52 (m, 2H), 0.27-0.24 (m,
2H).
[0923] Compound 40-E2 LC/MS ESI 464.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.46 (s, 1H), 7.63-7.31 (m, 5H), 6.57 (d, J=7.6
Hz, 1H), 5.13 (s, 1H), 4.24 (m, 1H), 3.59-3.42 (m, 6H), 3.18-3.11
(m, 2H), 2.86-2.61 (m, 6H), 2.16-2.13 (m, 2H), 1.93-1.68 (m, 6H),
1.17-1.11 (m, 1H), 0.56-0.51 (m, 2H), 0.27-0.23 (m, 2H).
2-(2-isopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-
l)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric compounds
41-E1 and 41-E2)
##STR00421##
[0925] Compound 41-E1 LC/MS ESI 452.2 (M+H).sup.+1H NMR (400 MHz,
MeOD) .delta. 7.61 (d, J=7.2 Hz, 1H), 7.41 (d, J=6.4 Hz, 1H), 7.38
(t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H),
6.37 (d, J=7.2 Hz, 1H), 4.92 (s, 1H), 4.18 (s, 1H), 3.49-3.36 (m,
6H), 3.32-3.03 (m, 3H), 2.70 (t, J=6.4 Hz, 2H), 2.55 (t, J=7.6 Hz,
2H), 2.21-2.02 (m, 2H), 1.89-1.84 (m, 2H), 1.71-1.69 (m, 2H),
1.62-1.58 (m, 2H), 1.30-1.27 (m, 6H). Chiral SFC F (45% MeOH): ee
100%, Rt=3.67 min.
[0926] Compound 41-E2 LC/MS ESI 452.2 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=6.0 Hz, 1H), 7.38 (t,
J=7.2 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.40
(d, J=7.6 Hz, 1H), 5.03 (s, 1H), 4.20 (s, 1H), 3.56-3.54 (m, 3H),
3.39-3.36 (m, 3H), 3.08-3.01 (m, 3H), 2.72 (t, J=6.4 Hz, 2H), 2.58
(t, J=7.6 Hz, 2H), 2.19-2.02 (m, 2H), 1.91-1.88 (m, 2H), 1.77-1.62
(m, 2H), 1.61-1.58 (m, 2H), 1.31-1.27 (m, 6H). Chiral SFC F (45%
MeOH): ee 96.7%, Rt=8.03 min.
2-(2-cyclopropyl-6-(cyclopropylmethyl)pyridin-3-yl)-2-((R)-3-(3-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)propoxy)pyrrolidin-1-yl)acetic acid
(compound 42)
##STR00422##
[0928] Compound 42 LC/MS ESI 491.6 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.67 (d, J=8.1 Hz, 1H), 6.92 (d, J=7.5 Hz, 2H), 6.16
(d, J=7.3 Hz, 1H), 4.78-4.72 (m, 1H), 4.11-3.81 (m, 1H), 3.39-3.13
(m, 5H), 2.97-2.72 (m, 3H), 2.55-2.47 (m, 2H), 2.43-2.19 (m, 5H),
2.05-1.78 (m, 2H), 1.78-1.58 (m, 4H), 1.14-0.98 (m, 1H), 0.94-0.63
(m, 4H), 0.31-0.27 (m, 2H), 0.22-0.18 (m, 2H).
2-(2-cyclopropoxyphenyl)-2-((3R,4S)-3-fluoro-4-(4-(5,6,7,8-tetrahydro-1,8--
naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 43-E1 and 43-E2)
##STR00423##
[0930] Compound 43-E1 LC/MS ESI 484.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.49 (d, J=7.5 Hz, 1H), 7.40-7.39 (m, 2H),
7.20-7.18 (m, 1H), 7.06-6.96 (m, 1H), 6.39 (d, J=7.3 Hz, 1H), 5.20
(d, J=54.2 Hz, 1H), 4.89 (s, 1H), 4.10-4.02 (m, 1H), 3.90 (s, 1H),
3.80-3.33 (m, 6H), 3.20-3.03 (m, 2H), 2.71 (t, J=6.2 Hz, 2H), 2.56
(t, J=7.6 Hz, 2H), 1.90-1.82 (m, 2H), 1.75-1.55 (m, 4H), 0.96-0.63
(m, 4H).
[0931] Compound 43-E2 LC/MS ESI 484.4 (M+H).sup.+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.51 (d, J=7.5 Hz, 1H), 7.39-7.37 (m, 2H),
7.20-7.18 (m, 1H), 7.06-6.96 (m, 1H), 6.41 (d, J=7.3 Hz, 1H), 5.12
(d, J=54.2 Hz, 1H), 4.84 (s, 1H), 4.10-4.02 (m, 1H), 3.87 (s, 1H),
3.65-3.33 (m, 6H), 3.20-3.01 (m, 2H), 2.72 (t, J=6.2 Hz, 2H), 2.59
(t, J=7.6 Hz, 2H), 1.90-1.82 (m, 2H), 1.75-1.55 (m, 4H), 0.96-0.63
(m, 4H).
2-(5-fluoro-2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,-
8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 44-E1 and 44-E2)
##STR00424##
[0933] Compound 44-E1 LC/MS ESI 500.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.55-7.41 (m, 3H), 7.25-7.19 (m, 1H), 6.61 (d, J=7.2 Hz,
1H), 5.29 (s, 1H), 4.83-4.79 (m, 1H), 4.51-4.47 (m, 1H), 4.26 (s,
1H), 3.83-3.23 (m, 9H), 2.84-2.71 (m, 4H), 2.29-1.55 (m, 8H),
1.35-1.20 (m, 6H). Compound 44-E2 LC/MS ESI 500.3 (M+H)+1H NMR (400
MHz, MeOD) .delta. 7.59-7.41 (m, 3H), 7.25-7.19 (m, 1H), 6.60 (d,
J=7.2 Hz, 1H), 5.19 (s, 1H), 4.83-4.79 (m, 1H), 4.51-4.47 (m, 1H),
4.28 (s, 1H), 3.83-3.23 (m, 9H), 2.84-2.71 (m, 4H), 2.29-1.55 (m,
8H), 1.35-1.20 (m, 6H).
2-(2,4-dicyclopropylpyrimidin-5-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound
45)
##STR00425##
[0935] Compound 45 LC/MS ESI 492 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 8.60-8.57 (m, 1H), 8.46 (bs, 1H), 7.52 (d, J=7.2 Hz, 1H),
6.59 (d, J=7.6 Hz, 1H), 5.21-5.10 (m, 1H), 4.23-4.21 (m, 1H),
3.70-2.50 (m, 12H), 2.50-1.55 (m, 10H), 1.50-1.00 (m, 8H).
2-(2-(cyclobutoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 46-E1 and 46-E2)
##STR00426##
[0937] Compound 46-E1 LC/MS ESI 494.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.51 (s, 1H), 7.68-7.66 (m, 1H), 7.45-7.41 (m, 4H), 6.53
(d, J=7.2 Hz, 1H), 5.06 (s, 1H), 4.82-4.79 (m, 1H), 4.40-4.36 (m,
1H), 4.21-4.09 (m, 2H), 3.63-3.33 (m, 7H), 3.18-3.14 (m, 1H),
2.79-2.68 (m, 4H), 2.24-1.50 (m, 14H).
[0938] Compound 46-E2 LC/MS ESI 494.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.49 (s, 1H), 7.66 (s, 1H), 7.48-7.42 (m, 4H), 6.54 (d,
J=7.2 Hz, 1H), 4.94 (s, 1H), 4.80-4.45 (m, 2H), 4.24-4.10 (m, 2H),
3.58-3.15 (m, 8H), 2.80-2.62 (m, 4H), 2.24-1.50 (m, 14H).
2-(2-(3-fluoro-3-methylbutyl)pyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-
-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound
47)
##STR00427##
[0940] Compound 47 LC/MS ESI 498.9 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.43-8.42 (m, 1H), 8.31-8.08 (m, 1H), 7.32-7.23 (m, 2H),
6.44-6.41 (m, 1H), 4.69-4.57 (m, 1H), 4.13-4.12 (m, 1H), 3.49-3.32
(m, 4H), 3.24-2.90 (m, 6H), 2.75-2.56 (m, 4H), 2.25-1.52 (m, 10H),
1.48-1.35 (m, 6H).
2-(3-cyano-2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphth-
yridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound 48)
##STR00428##
[0942] Compound 48 LC/MS ESI 475.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.85-7.81 (m, 2H), 7.60-7.55 (m, 2H), 6.01 (d, J=7.2 Hz,
1H), 5.90-5.78 (m, 1H), 4.28-4.26 (m, 1H), 3.62-3.46 (m, 7H),
3.28-3.20 (m, 1H), 2.84-2.72 (m, 4H), 2.27-1.67 (m, 9H), 1.26-0.88
(m, 4H).
2-(1-isopentyl-6-oxo-1,6-dihydropyridin-2-yl)-2-((R)-3-(4-(5,6,7,8-tetrahy-
dro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 49)
##STR00429##
[0944] Compound 49 LC/MS ESI 497 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 8.41 (s, 2H), 7.71 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz,
1H), 7.14 (d, J=6.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.55 (d, J=7.6
Hz, 1H), 4.85 (d, J=9.6 Hz, 1H), 4.40-4.21 (m, 3H), 3.70-2.50 (m,
12H), 2.50-1.55 (m, 11H), 0.96-0.94 (m, 6H).
2-(6-cyclopropyl-4-(isopropoxymethyl)pyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-te-
trahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 50-E1 and 50-E2)
##STR00430##
[0946] Compound 50-E1 LC/MS ESI 523.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 8.58 (s, 1H), 8.50 (s, 1H), 7.41 (d, J=7.3 Hz, 1H),
7.32 (s, 1H), 6.51 (d, J=7.3 Hz, 1H), 4.78-4.75 (m, 1H), 4.62-4.59
(m, 1H), 4.20 (s, 1H), 3.84-3.76 (m, 1H), 3.69-3.32 (m, 8H),
3.24-3.07 (m, 1H), 2.83-2.39 (m, 4H), 2.12-2.02 (m, 3H), 1.97-1.87
(m, 2H), 1.84-1.61 (m, 4H), 1.27-1.25 (m, 6H), 1.21-0.83 (m,
4H).
[0947] Compound 50-E2 LC/MS ESI 523.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 8.57-8.49 (m, 2H), 7.40 (d, J=7.3 Hz, 1H), 7.32 (s,
1H), 6.51 (d, J=7.3 Hz, 1H), 4.89-4.69 (m, 2H), 4.23 (s, 1H),
3.81-3.76 (m, 1H), 3.60-3.32 (m, 7H), 3.24-3.10 (m, 2H), 2.78-2.66
(m, 4H), 2.12-2.02 (m, 3H), 1.97-1.87 (m, 2H), 1.74-1.51 (m, 4H),
1.27-1.25 (m, 6H), 1.21-0.83 (m, 4H).
2-(3-fluoro-2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,-
8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound
51)
##STR00431##
[0949] Compound 51 LC/MS ESI 500 (M+H)+. 1H NMR (500 MHz, MeOD)
.delta. 7.52 (d, J=8.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.20-7.15 (m,
1H), 6.39-6.37 (m, 1H), 4.84-4.76 (m, 1H), 4.18 (s, 1H), 3.85-3.81
(m, 1H), 3.49-3.40 (m, 6H), 3.33-3.12 (m, 2H), 2.73-2.70 (m, 2H),
2.56-2.53 (m, 2H), 2.12-2.06 (m, 2H), 1.90-1.58 (m, 6H), 1.26-1.21
(m, 6H).
2-(2,4-dicyclopropylpyrimidin-5-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compound
52)
##STR00432##
[0951] Compound 52 LC/MS ESI 490 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 8.61-8.59 (m, 1H), 8.36 (bs, 2H), 7.51 (d, J=7.2 Hz, 1H),
6.55 (d, J=7.2 Hz, 1H), 5.11-5.10 (m, 1H), 3.50-2.50 (m, 8H),
2.50-1.55 (m, 9H), 1.50-1.00 (m, 15H).
2-(2-((cyclopropylmethoxy)methyl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 53-E1 and 53-E2)
##STR00433##
[0953] Compound 53-E1 LC/MS ESI 512.3 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 8.51 (s, 1H), 7.49-7.41 (m, 3H), 7.20-7.15 (m, 1H),
6.52 (d, J=7.2 Hz, 1H), 5.07 (s, 1H), 4.86-4.84 (m, 1H), 4.48-4.45
(m, 1H), 4.22 (s, 1H), 3.62-3.12 (m, 10H), 2.79-2.65 (m, 4H),
2.24-1.55 (m, 8H), 1.08-1.01 (m, 1H), 0.54-0.49 (m, 2H), 0.27-0.24
(m, 2H).
[0954] Compound 53-E2 LC/MS ESI 512.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.51 (s, 1H), 7.49-7.46 (m, 3H), 7.20-7.16 (m, 1H), 6.54
(d, J=7.2 Hz, 1H), 4.98 (s, 1H), 4.85-4.52 (m, 2H), 4.24 (s, 1H),
3.60-3.12 (m, 10H), 2.81-2.65 (m, 4H), 2.29-1.55 (m, 8H), 1.16-1.13
(m, 1H), 0.54-0.49 (m, 2H), 0.27-0.24 (m, 2H).
2-(5-fluoro-2-((1-methylcyclopropoxy)methyl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 54-E1 and 54-E2)
##STR00434##
[0956] Compound 54-E1 LC/MS ESI 512.3 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 8.51 (s, 1H), 7.49-7.38 (m, 3H), 7.17-7.11 (m, 1H),
6.50 (d, J=7.6 Hz, 1H), 4.93-4.90 (m, 2H), 4.53-4.50 (m, 1H), 4.21
(s, 1H), 3.66-3.09 (m, 8H), 2.78-2.65 (m, 4H), 2.18-1.62 (m, 8H),
1.50 (s, 3H), 0.87-0.84 (m, 2H), 0.49-0.45 (m, 2H).
[0957] Compound 54-E2 LC/MS ESI 512.3 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 8.51 (s, 1H), 7.47-7.36 (m, 3H), 7.15-7.11 (m, 1H),
6.48 (d, J=7.2 Hz, 1H), 4.85-4.80 (m, 2H), 4.60-4.57 (m, 1H), 4.20
(s, 1H), 3.62-3.09 (m, 8H), 2.77-2.64 (m, 4H), 2.20-1.64 (m, 8H),
1.50 (s, 3H), 0.91-0.88 (m, 2H), 0.49-0.47 (m, 2H).
2-(5-fluoro-2-(isopropoxymethyl)phenyl)-2-((3R)-3-(4-(7-methyl-5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 55-E1 and 55-E2)
##STR00435##
[0959] Compound 55-E1 (mixture of 2 stereoisomers) LC/MS ESI 514
(M+H).sup.+ 1H NMR (400 MHz, MeOD) .delta. 8.35 (s, 2H), 7.54-7.47
(m, 3H), 7.19-7.15 (m, 1H), 6.57 (d, J=7.2 Hz, 1H), 5.07-5.05 (m,
1H), 4.85 (d, J=7.6 Hz, 1H), 4.50-3.31 (m, 9H), 3.30-2.00 (m, 8H),
1.96-1.20 (m, 14H).
[0960] Compound 55-E2 (mixture of 2 stereoisomers) LC/MS ESI 514
(M+H).sup.+ 1H NMR (400 MHz, MeOD) .delta. 8.31 (s, 2H), 7.54-7.47
(m, 3H), 7.19-7.15 (m, 1H), 6.58 (d, J=8.8 Hz, 1H), 5.07-5.05 (m,
1H), 4.87-4.35 (m, 3H), 3.80-3.31 (m, 5H), 3.30-2.25 (m, 8H),
2.15-1.20 (m, 16H).
2-(2-((S)-1-isopropoxyethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 56-E1 and 56-E2)
##STR00436##
[0962] Compound 56-E1 LC/MS ESI 496.3 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 8.56 (s, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2
Hz, 1H), 7.24-7.19 (m, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.34 (d, J=7.6
Hz, 1H), 5.44-5.42 (m, 1H), 4.19 (s, 1H), 4.02 (s, 1H), 3.56-3.31
(m, 4H), 2.95-2.48 (m, 8H), 2.14-1.81 (m, 4H), 1.68-1.52 (m, 4H),
1.41-1.02 (m, 9H). Chiral SFC F (45% MeOH): ee 100%, Rt=3.77
min.
[0963] Compound 56-E2 LC/MS ESI 496.3 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 7.65-7.61 (m, 2H), 7.42-7.31 (m, 2H), 7.17 (d, J=7.6
Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 5.06-5.04 (m, 1H), 4.20 (s, 1H),
3.53-3.31 (m, 7H), 3.08-2.98 (m, 2H), 2.72 (t, J=6.4 Hz, 2H), 2.57
(t, J=7.2 Hz, 2H), 2.18-1.82 (m, 4H), 1.78-1.50 (m, 4H), 1.45-1.42
(m, 3H), 1.20-1.08 (m, 6H). Chiral SFC F (45% MeOH): ee 100%,
Rt=5.60 min.
2-(2-((R)-1-isopropoxyethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 57-E1 and 57-E2)
##STR00437##
[0965] Compound 57-E1 LC/MS ESI 496.4 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 8.47 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.0 Hz,
1H), 7.45-7.34 (m, 3H), 6.53 (d, J=7.2 Hz, 1H), 5.11-5.09 (m, 1H),
4.94 (s, 1H), 4.23 (s, 1H), 3.59-3.28 (m, 9H), 2.78 (t, J=6.4 Hz,
2H), 2.69 (t, J=7.6 Hz, 2H), 2.27-2.14 (m, 2H), 1.93-1.65 (m, 6H),
1.49 (d, J=6.4 Hz, 3H), 1.21-1.12 (m, 6H).
[0966] Compound 57-E2 LC/MS ESI 496.4 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 8.46 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.2
Hz, 1H), 7.46-7.34 (m, 3H), 6.53 (d, J=7.2 Hz, 1H), 5.23 (s, 1H),
5.10-5.05 (m, 1H), 4.25 (s, 1H), 3.66-3.20 (m, 9H), 2.80-2.67 (m,
4H), 2.17-2.10 (m, 2H), 1.93-1.65 (m, 6H), 1.50-1.47 (m, 3H),
1.21-1.02 (m, 6H).
2-(5-fluoro-2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(4-fluoro-5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 58)
##STR00438##
[0968] Compound 58 LC/MS ESI 518 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 8.50 (bs, 1H), 7.45-7.43 (m, 2H), 7.18-7.14 (m, 1H), 6.25
(d, J=7.6 Hz, 1H), 4.90-4.80 (m, 2H), 4.52-4.48 (m, 1H), 4.22 (s,
1H), 3.80-3.05 (m, 9H), 2.70-2.55 (m, 4H), 2.22-1.54 (m, 8H),
1.25-1.18 (m, 6H).
2-(5-fluoro-2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 59)
##STR00439##
[0970] Compound 59 LC/MS ESI 530 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 8.54 (bs, 1H), 7.48-7.45 (m, 2H), 7.13-7.12 (m, 1H), 6.40
(d, J=8.8 Hz, 1H), 4.90-4.83 (m, 2H), 4.52-4.48 (m, 1H), 4.19 (s,
1H), 3.81-3.75 (m, 4H), 3.55-3.02 (m, 8H), 2.68-2.52 (m, 4H),
2.20-1.54 (m, 8H), 1.28-1.20 (m, 6H).
2-(5-fluoro-2-((3-methyloxetan-3-yloxy)methyl)phenyl)-2-((R)-3-(4-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compound 60)
##STR00440##
[0972] Compound 60 LC/MS ESI 528.3 (M+H)+1H NMR (400 MHz, MeOD)
.delta. 7.52-7.46 (m, 2H), 7.19-7.11 (m, 2H), 6.39 (d, J=7.2 Hz,
1H), 4.88-4.72 (m, 4H), 4.54-4.42 (m, 3H), 4.17 (s, 1H), 3.48-3.31
(m, 6H), 3.18-3.03 (m, 2H), 2.73-2.55 (m, 4H), 2.20-1.84 (m, 4H),
1.78-1.55 (m, 8H).
2-(3-fluoro-2-(((R)-tetrahydrofuran-3-yloxy)methyl)phenyl)-2-((R)-3-(4-(5,-
6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compound 61)
##STR00441##
[0974] Compound 61 LC/MS ESI 528.3 (M+H).sup.+1H NMR (400 MHz,
MeOD) .delta. 7.56-7.46 (m, 1H), 7.43-7.38 (m, 1H), 7.21-7.18 (m,
2H), 6.41-6.38 (m, 1H), 4.86 (m, 1H), 4.81-4.68 (m, 2H), 4.39-4.35
(m, 1H), 4.30-4.14 (m, 1H), 3.98-3.65 (m, 4H), 3.50-3.39 (m, 5H),
3.18-3.00 (m, 2H), 2.75-2.71 (m, 2H), 2.58-2.55 (m, 2H), 2.21-2.02
(m, 4H), 1.92-1.80 (m, 2H), 1.76-1.65 (m, 2H), 1.62-1.58 (m,
3H).
2-(3-fluoro-2-(((R)-tetrahydrofuran-3-yloxy)methyl)phenyl)-2-((3R)-3-(1-hy-
droxy-5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)a-
cetic acid (compound 62)
##STR00442##
[0976] Compound 62 LC/MS ESI 542.4 (M+H)+1H NMR (500 MHz, MeOD)
.delta. 7.42-7.34 (m, 2H), 7.19-7.08 (m, 2H), 6.36-6.33 (m, 1H),
4.68-4.60 (m, 1H), 4.28-4.23 (m, 1H), 3.98-3.50 (m, 5H), 3.44-3.31
(m, 6H), 3.15-2.84 (m, 2H), 2.64-2.45 (m, 4H), 2.20-1.75 (m, 5H),
1.60-1.22 (m, 8H).
2-(3-fluoro-2-((3-methyloxetan-3-yloxy)methyl)phenyl)-2-((R)-3-(4-(5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compound 63)
##STR00443##
[0978] Compound 63 LC/MS ESI 528.3 (M+H)+.sup.1H NMR (400 MHz,
MeOD) .delta. 7.57-7.45 (m, 2H), 7.24-7.16 (m, 2H), 6.41-6.37 (m,
1H), 4.94-4.71 (m, 4H), 4.47-4.41 (m, 2H), 4.20-4.18 (m, 1H),
3.74-3.02 (m, 8H), 2.72 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H),
2.20-1.84 (m, 4H), 1.78-1.51 (m, 7H).
2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yloxy)methyl)phenyl)-2-((R)-3-(4-(5,-
6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compound 64)
##STR00444##
[0980] Compound 64 LC/MS ESI 528.4 (M+H)+.sup.1H NMR (500 MHz,
MeOD) .delta. 8.43 (s, 1H), 7.52-7.49 (m, 3H), 7.19-7.17 (m, 1H),
6.57 (d, J=7.0 Hz, 1H), 5.03-4.83 (m, 2H), 4.57-4.49 (m, 1H),
4.38-4.28 (m, 2H), 3.98-3.22 (m, 12H), 2.82-2.72 (m, 4H), 2.30-2.04
(m, 4H), 1.98-1.58 (m, 6H).
2-(2-cyclobutylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2--
yl)butoxy)pyrrolidin-1-yl)acetic acid (compound 65)
##STR00445##
[0982] Compound 65 LC/MS ESI 528.4 (M+H)+.sup.1H NMR (500 MHz,
MeOD) .delta. 7.62-7.59 (m, 1H), 7.51-7.27 (m, 4H), 6.59-6.55 (m,
1H), 5.05-4.91 (m, 1H), 4.30-4.28 (m, 1H), 4.02-3.90 (m, 1H),
3.68-3.05 (m, 8H), 2.81-2.70 (m, 4H), 2.44-1.58 (m, 14H).
2-(2-cyclopropyl-3-methoxyphenyl)-2-[(3R)-3-[4-(5,6,7,8-tetrahydro-1,8-nap-
hthyridin-2-yl)butoxy]pyrrolidin-1-yl]acetic acid (diastereomeric
compounds 66-E1 and 66-E2)
##STR00446##
[0984] Compound 66-E1 LC/MS ESI 480 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 7.46 (d, J=7.2 Hz, 1H), 7.32-7.28 (m, 1H), 7.19 (d,
J=7.6 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 5.58
(s, 1H), 4.21-4.18 (m, 1H), 3.86 (s, 3H), 3.61-3.24 (m, 8H),
2.81-2.66 (m, 4H), 2.18-1.61 (m, 9H), 1.11-0.67 (m, 4H).
[0985] Compound 66-E2 LC/MS ESI 480 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 7.47 (d, J=7.2 Hz, 1H), 7.34-7.17 (m, 2H), 7.02 (d,
J=8.4 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 5.76 (s, 1H), 4.21-4.18 (m,
1H), 3.86 (s, 3H), 3.65-3.24 (m, 8H), 2.78-2.54 (m, 4H), 2.22-1.51
(m, 9H), 1.15-0.60 (m, 4H).
2-(2-(cis-2-methoxycyclopropyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-
-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 67-E1 and 67-E2)
##STR00447##
[0987] Compound 67-E1 LC/MS ESI 480.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.69-7.58 (m, 1H), 7.29-7.23 (m, 2H), 7.15-7.09 (m,
2H), 6.37 (d, J=7.3 Hz, 1H), 5.19 (d, J=7.8 Hz, 1H), 4.18-4.17 (m,
1H), 3.70-3.34 (m, 9H), 3.27-3.24 (m, 3H), 2.70 (t, J=6.2 Hz, 2H),
2.61-2.37 (m, 3H), 2.25-2.05 (m, 2H), 1.96-1.79 (m, 2H), 1.79-1.47
(m, 4H), 1.42-0.84 (m, 2H). Chiral K: (45% MeOH): ee 98.4%, Rt=2.78
min.
[0988] Compound 67-E2 LC/MS ESI 480.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.68-7.56 (m, 1H), 7.49-7.26 (m, 4H), 6.51-6.49 (m,
1H), 5.31-5.26 (m, 1H), 4.18-4.17 (m, 1H), 3.72-3.34 (m, 12H),
2.75-2.55 (m, 4H), 2.50-2.42 (m, 1H), 2.25-2.05 (m, 2H), 1.96-1.52
(m, 6H), 1.12-1.04 (m, 2H). Chiral K: (45% MeOH): ee 38%, Rt=5.26
min.
2-(2-(trans-2-methoxycyclopropyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1-
,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 68-E1 and 68-E2)
##STR00448##
[0990] Compound 68-E1 LC/MS ESI 480.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.69-7.58 (m, 1H), 7.29-7.23 (m, 2H), 7.15-7.09 (m,
2H), 6.37 (d, J=7.3 Hz, 1H), 5.24 (d, J=7.8 Hz, 1H), 4.18-4.17 (m,
1H), 3.70-3.34 (m, 9H), 3.27-3.24 (m, 3H), 2.70 (t, J=6.2 Hz, 2H),
2.61-2.37 (m, 3H), 2.25-2.05 (m, 2H), 1.96-1.79 (m, 2H), 1.79-1.47
(m, 4H), 1.42-0.84 (m, 2H). Chiral K: (45% MeOH): ee 98.4%, Rt=2.72
min.
[0991] Compound 68-E1 LC/MS ESI 480.3 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.62-7.59 (m, 1H), 7.33-7.24 (m, 2H), 7.16-7.07 (m,
2H), 6.37 (d, J=7.3 Hz, 1H), 5.30-5.23 (m, 1H), 4.21 (s, 1H),
3.65-3.02 (m, 12H), 2.70 (t, J=6.2 Hz, 2H), 2.56-2.30 (m, 3H),
2.16-1.98 (m, 2H), 1.96-1.80 (m, 2H), 1.79-1.49 (m, 4H), 1.38-1.05
(m, 2H). Chiral K: (45% MeOH): ee 38%, Rt=5.22 min.
2-(3-fluoro-2-((3-methyloxetan-3-yloxy)methyl)phenyl)-2-((R)-3-(4-(4-metho-
xy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (compound 69)
##STR00449##
[0993] Compound 69 LC/MS ESI 558 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 7.62-7.60 (m, 1H), 7.43-7.41 (m, 1H), 7.19-7.14 (m, 1H),
6.28 (s, 1H), 4.90-4.71 (m, 7H), 4.46-4.41 (m, 2H), 4.17-4.12 (m,
1H), 3.87 (s, 3H), 3.55-3.30 (m, 4H), 3.22-2.95 (m, 2H), 2.64-2.52
(m, 4H), 2.20-1.55 (m, 11H).
2-(4-((3-methyloxetan-3-yl)methoxy)pyrimidin-5-yl)-2-((R)-3-(5-(5,6,7,8-te-
trahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid
(compound 70)
##STR00450##
[0995] Compound 70 LC/MS ESI 510.3 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 8.74-8.69 (m, 2H), 7.13-7.11 (m, 1H), 6.36-6.33 (m,
1H), 4.80-4.72 (m, 1H), 4.70-4.50 (m, 6H), 3.50-3.30 (m, 3H),
3.22-3.00 (m, 2H), 2.80-2.60 (m, 3H), 2.50-2.40 (m, 2H), 2.35-2.00
(m, 2H), 1.92-1.82 (m, 2H), 1.62-1.48 (m, 3H), 1.42-1.22 (m,
9H).
2-(4-cyclopropoxypyrimidin-5-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compound 71)
##STR00451##
[0997] Compound 71 LC/MS ESI 466.3 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 8.75 (d, J=8.4 Hz, 1H), 8.69 (d, J=8.4 Hz, 1H),
7.13-7.11 (m, 1H), 6.36-6.33 (m, 1H), 4.54-4.49 (m, 2H), 3.39-3.37
(m, 3H), 3.18-2.90 (m, 2H), 2.71-2.68 (m, 2H), 2.51-2.47 (m, 2H),
2.30-2.20 (m, 1H), 2.19-2.04 (m, 1H), 1.92-1.82 (m, 2H), 1.62-1.24
(m, 10H), 0.94-0.80 (m, 4H).
2-(2-(cyclopropoxyphenyl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 72-E1 and 72-E2)
##STR00452##
[0999] Compound 72-E1 LC/MS ESI 496.3 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 7.42-7.40 (m, 1H), 7.36-7.30 (m, 2H), 6.97-6.95
(m, 1H), 6.20 (s, 1H), 4.91-4.85 (m, 1H), 4.10 (s, 1H), 3.78-3.71
(m, 4H), 3.43-3.38 (m, 4H), 3.22-2.94 (m, 3H), 2.51-2.48 (m, 4H),
2.03-1.57 (m, 8H), 0.73-0.62 (m, 3H).
[1000] Compound 72-E2 LC/MS ESI 496.3 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 7.44-7.42 (m, 1H), 7.35-7.33 (m, 2H), 6.96-6.94
(m, 1H), 6.17 (s, 1H), 4.85-4.82 (m, 1H), 4.09 (s, 1H), 3.86-3.77
(m, 4H), 3.40-3.37 (m, 3H), 3.25-3.13 (m, 5H), 2.52-2.48 (m, 4H),
2.12-1.51 (m, 8H), 0.81-0.64 (m, 4H).
2-(5-fluoro-2-((3-methyloxetan-3-yloxy)methyl)phenyl)-2-((R)-3-(4-(4-metho-
xy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 73-E1 and 73-E2)
##STR00453##
[1002] Compound 73-E1 LC/MS ESI 558.2 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 8.50 (br, 1H), 7.54-7.48 (m, 2H), 7.19-7.15 (m, 1H),
6.52 (s, 1H), 5.00 (s, 1H), 4.87 (d, J=10.8 Hz, 1H), 4.76-4.70 (m,
2H), 4.49-4.40 (m, 3H), 4.22 (s, 1H), 3.97 (s, 3H), 3.66-3.60 (m,
1H), 3.58-3.42 (m, 3H), 3.40-3.37 (m, 3H), 3.13-3.10 (m, 1H),
2.74-2.59 (m, 4H), 2.21-2.15 (m, 2H), 1.92-1.62 (m, 9H).
[1003] Compound 73-E2 LC/MS ESI 558.2 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 8.50 (br, 1H), 7.54-7.48 (m, 2H), 7.20-7.16 (m, 1H),
6.55 (s, 1H), 5.02-5.00 (s, 1H), 4.93-4.76 (m, 3H), 4.57-4.48 (m,
1H), 4.46-4.40 (m, 2H), 4.23 (s, 1H), 3.98 (s, 3H), 3.80-3.19 (m,
6H), 3.15-3.08 (m, 2H), 2.76-2.60 (m, 4H), 2.27-2.05 (m, 2H),
1.89-1.62 (m, 9H).
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1--
yl)-2-(2-(tetrahydrofuran-3-yl)phenyl)acetic acid (Compound 74)
##STR00454##
[1005] Compound 74: LC/MS ESI 480.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.63 (dd, J=13.4, 7.8 Hz, 1H), 7.47 (d, J=7.2
Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.17 (d,
J=7.3 Hz, 1H), 6.40 (dd, J=7.3, 5.4 Hz, 1H), 4.99 (s, 1H),
4.23-4.14 (m, 2H), 4.13-4.06 (m, 1H), 4.06-3.96 (m, 1H), 3.95-3.80
(m, 2H), 3.75 (m, 1H), 3.52 (m, 2H), 3.40 (m, 3H), 3.30-2.99 (m,
3H), 2.72 (t, J=6.2 Hz, 2H), 2.57 (m, 2H), 2.38 (m, 1H), 2.06 (m,
3H), 1.89 (m, 2H), 1.79-1.68 (m, 2H), 1.67-1.57 (m, 2H).
2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1--
yl)-2-(2-(tetrahydro-2H-pyran-3-yl)phenyl)acetic acid (compound
75)
##STR00455##
[1007] Compound 75: LC/MS ESI 494.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.67 (t, J=7.9 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H),
7.35 (t, J=7.5 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.3 Hz,
1H), 6.44-6.35 (m, 1H), 4.84 (s, 1H), 4.17 (d, J=23.7 Hz, 1H), 3.94
(m, 2H), 3.66-3.35 (m, 8H), 3.10 (m, 3H), 2.74-2.67 (m, 2H),
2.61-2.52 (m, 2H), 2.21-2.01 (m, 3H), 1.88 (m, 2H), 1.84-1.59 (m,
7H).
2-(2-(3,3-difluorocyclobutyl)pyridin-2-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-
-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (compound
76)
##STR00456##
[1009] Compound 76 LC/MS ESI 501.2 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 8.62-8.58 (m, 1H), 8.04-7.99 (m, 1H), 7.34-7.29
(m, 2H), 6.48 (d, J=7.3 Hz, 1H), 4.84-4.70 (m, 1H), 4.17 (s, 1H),
4.12-3.95 (m, 1H), 3.45-3.32 (m, 4H), 3.28-2.61 (m, 12H), 2.17-1.62
(m, 8H).
2-(2-(trans-3-methoxycyclobutyl)pyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahy-
dro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 77)
##STR00457##
[1011] Compound 77 LC/MS ESI 495.3 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 8.59-8.57 (m, 1H), 8.03-7.98 (m, 1H), 7.32-7.28
(m, 2H), 6.48 (t, J=7.3 Hz, 1H), 4.84-4.71 (m, 1H), 4.26-4.15 (m,
3H), 3.54-3.40 (m, 5H), 3.28 (s, 3H), 3.13-3.10 (m, 2H), 2.78-2.60
(m, 6H), 2.48-2.36 (m, 2H), 2.17-1.64 (m, 8H).
2-(2-(cis-3-methoxycyclobutyl)pyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydr-
o-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 78)
##STR00458##
[1013] Compound 78 LC/MS ESI 495.3 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 8.58-8.56 (m, 1H), 8.00 (dd, J=17.8, 7.9 Hz,
1H), 7.31-7.29 (m, 2H), 6.49-6.46 (m, 1H), 4.91-4.79 (m, 1H),
4.21-4.18 (m, 1H), 3.90-3.87 (m, 1H), 3.71-3.40 (m, 6H), 3.30-3.00
(m, 6H), 2.78-2.59 (m, 6H), 2.51-1.60 (m, 10H).
2-(2-(tert-butoxymethyl)phenyl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro--
1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 79-E1 and 79-E2)
##STR00459##
[1015] Compound 79-E1 LC/MS ESI 526.2 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 7.67-7.65 (m, 1H), 7.44-7.38 (m, 3H), 6.36 (s, 1H),
4.96 (s, 1H), 4.83 (d, J=10.4 Hz, 1H), 4.47 (d, J=10.4 Hz, 1H),
4.20 (s, 1H), 3.91 (s, 3H), 3.79-3.42 (m, 4H), 3.39-3.36 (m, 2H),
3.35-3.31 (m, 1H), 3.09-3.07 (m, 1H), 2.64-2.58 (m, 4H), 2.20-2.12
(m, 2H), 1.86-1.62 (m, 6H), 1.29 (s, 9H).
[1016] Compound 79-E2 LC/MS ESI 526.2 (M+H).sup.+ 1H NMR (400 MHz,
MeOD) .delta. 7.62 (s, 1H), 7.42 (s, 3H), 6.49 (s, 1H), 4.96 (s,
1H), 4.76-4.75 (m, 1H), 4.61-4.55 (m, 1H), 4.24 (s, 1H), 3.96 (s,
3H), 3.64-3.42 (m, 3H), 3.40-3.30 (m, 3H), 3.25-3.15 (m, 2H),
2.79-2.58 (m, 4H), 2.29-2.21 (m, 1H), 2.13-2.02 (m, 1H), 1.96-1.62
(m, 6H), 1.33 (s, 9H).
2-(5-fluoro-2-((1-methylcyclopropyl)methoxy)phenyl)-2-((R)-3-(4-(4-methoxy-
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 80-E1 and 80-E2)
##STR00460##
[1018] Compound 80-E1 LC/MS ESI 542.2 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.37-7.34 (m, 1H), 7.15-6.93 (m, 2H), 6.31-6.21 (m,
1H), 5.04 (s, 1H), 4.24-3.96 (m, 1H), 3.93-3.74 (m, 5H), 3.56-3.36
(m, 3H), 3.35-3.17 (m, 4H), 3.08-2.88 (m, 1H), 2.59-2.55 (m, 4H),
2.16-1.96 (m, 2H), 1.93-1.48 (m, 6H), 1.24 (s, 3H), 0.79-0.32 (m,
4H).
[1019] Compound 80-E2 LC/MS ESI 542.2 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.35-7.33 (m, 1H), 7.18-7.03 (m, 2H), 6.55 (s, 1H),
5.05 (s, 1H), 4.31 (s, 1H), 3.98-3.81 (m, 5H), 3.58-3.31 (m, 8H),
2.82-2.55 (m, 4H), 2.40-2.06 (m, 2H), 1.98-1.52 (m, 6H), 1.24 (s,
3H), 0.55-0.38 (m, 4H).
2-(2-cyclopropoxy-5-fluorophenyl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydr-
o-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 81)
##STR00461##
[1021] Compound 81 LC/MS ESI 514 (M+H)+. .sup.1H NMR (500 MHz,
MeOD) .delta. 7.41-7.39 (m, 1H), 7.35-7.32 (m, 1H), 7.17-7.13 (m,
1H), 6.28 (s, 1H), 4.81 (s, 1H), 4.16 (s, 3H), 3.91-3.90 (m, 1H),
3.87 (s, 3H), 3.50-3.36 (m, 3H), 3.22-3.30 (m, 3H), 3.18-3.14 (m,
2H), 2.62-2.58 (m, 4H), 2.17-2.10 (m, 2H), 1.78-1.72 (m, 2H),
1.66-1.62 (m, 2H), 0.86-0.77 (m, 4H).
2-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-((R)-3-(4-(5,6,-
7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 82-E1 and 82-E2)
##STR00462##
[1023] Compound 82-E1 LC/MS ESI 523.3 (M+H).sup.+. .sup.1H NMR (500
MHz, MeOD) .delta. 8.52-8.47 (m, 1H), 8.03-8.01 (m, 1H), 7.31-7.24
(m, 2H), 6.46 (t, J=6.8 Hz, 1H), 4.81-4.76 (m, 1H), 4.16 (s, 1H),
3.88-3.72 (m, 3H), 3.56-3.38 (m, 4H), 3.31-2.99 (m, 4H), 2.78-2.60
(m, 4H), 2.11-1.62 (m, 12H), 1.40-1.38 (m, 3H), 1.26 (s, 3H).
[1024] Compound 82-E2 LC/MS ESI 523.3 (M+H)+. .sup.1H NMR (500 MHz,
MeOD) .delta. 8.52-8.46 (m, 1H), 8.08-8.02 (m, 1H), 7.30-7.24 (m,
2H), 6.46-6.44 (m, 1H), 4.76-4.66 (m, 1H), 4.14 (s, 1H), 3.81-3.64
(m, 3H), 3.54-3.37 (m, 4H), 3.15-2.95 (m, 4H), 2.78-2.59 (m, 4H),
2.06-1.59 (m, 12H), 1.39-1.36 (m, 3H), 1.27-1.26 (m, 3H).
2-(5-fluoro-2-((oxetan-3-yloxy)methyl)phenyl)-2-((R)-3-((S)-1-fluoro-5-(5,-
6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic
acid (compound 83)
##STR00463##
[1026] Compound 83 LC/MS ESI 526 (M+H).sup.+ 1H NMR (400 MHz, MeOD)
.delta. 7.49-7.44 (m, 2H), 7.15-7.11 (m, 2H), 6.36-6.33 (m, 1H),
4.85-4.82 (m, 1H), 4.50-4.35 (m, 2H), 4.10-3.39 (m, 8H), 3.22-2.98
(m, 2H), 2.71-2.68 (m, 2H), 2.52-2.02 (m, 6H), 1.90-1.86 (m, 2H),
1.71-1.24 (m, 10H).
2-(2-cyclopropylphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
-yl)pentyloxy) pyrrolidin-1-yl)acetic acid (compound 84)
##STR00464##
[1028] Compound 84 LC/MS ESI 464.2 (M+H).sup.+ 1H NMR (500 MHz,
MeOD) .delta. 7.70-7.57 (m, 2H), 7.35-7.24 (m, 4H), 7.21-7.10 (m,
4H), 6.38 (dd, J=7.3, 5.5 Hz, 2H), 5.35 (s, 1H), 5.21 (s, 1H), 4.20
(d, J=23.0 Hz, 2H), 3.66-3.35 (m, 10H), 3.28-3.01 (m, 6H),
2.75-2.63 (m, 4H), 2.60-2.46 (m, 4H), 2.30-2.01 (m, 6H), 1.93-1.83
(m, 4H), 1.74-1.53 (m, 8H), 1.53-1.36 (m, 4H), 1.08-0.92 (m, 6H),
0.65-0.54 (m, 2H).
2-(4-cyclopropylpyridin-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)pentyloxy)pyrrolidin-1-yl)acetic acid(compound 85)
##STR00465##
[1030] Compound 85 LC/MS ESI 464.9 (M+H).sup.+1H NMR (500 MHz,
MeOD) .delta. 8.74 (d, J=22.7 Hz, 1H), 8.24 (d, J=5.3 Hz, 1H), 7.14
(m, 1H), 6.92 (d, J=4.6 Hz, 1H), 6.35 (m, 1H), 4.55 (d, J=47.6 Hz,
1H), 4.05 (d, J=18.7 Hz, 1H), 3.38 (m, 4H), 2.84-2.37 (m, 8H),
2.15-1.99 (m, 1H), 1.84 (s, 3H), 1.72-1.42 (m, 5H), 1.37 (d, J=6.0
Hz, 2H), 1.18-1.04 (m, 2H), 1.01-0.89 (m, 1H), 0.69-0.57 (m,
1H).
2-(2-(1,1-difluoroethyl)phenyl)-2-((R)-3-((5-(5,6,7,8-tetrahydro-1,8-napht-
hyridin-2-yl)pentyl)oxy)pyrrolidin-1-yl)acetic acid (diastereomeric
compounds 86-E1 and 86-E2)
##STR00466##
[1032] Compound 86-E1 LC/MS ESI 488.2 (M+H).sup.+ 1H NMR (500 MHz,
MeOD) .delta. 7.87 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.55
(m, 2H), 7.16 (d, J=7.3 Hz, 1H), 6.39 (d, J=7.3 Hz, 1H), 5.09 (s,
1H), 4.20 (s, 1H), 3.62 (s, 1H), 3.50-3.42 (m, 2H), 3.38 (m, 2H),
3.21 (m, 2H), 3.03 (s, 1H), 2.71 (m, 2H), 2.61-2.50 (m, 2H), 2.19
(m, 4H), 2.04 (s, 1H), 1.94-1.80 (m, 2H), 1.76-1.53 (m, 4H), 1.44
(m, 2H).
[1033] Compound 86-E2 LC/MS ESI 488.2 (M+H).sup.+ 1H NMR (500 MHz,
MeOD) .delta. 7.95 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.53
(m, 2H), 7.24 (d, J=7.2 Hz, 1H), 6.42 (d, J=7.3 Hz, 1H), 4.17 (s,
1H), 3.59 (s, 1H), 3.49-3.42 (m, 2H), 3.41-3.36 (m, 2H), 3.09 (d,
J=12.7 Hz, 3H), 2.73 (t, J=6.2 Hz, 2H), 2.58 (m, 2H), 2.20 (m, 4H),
2.06 (s, 1H), 1.94-1.84 (m, 2H), 1.80-1.63 (m, 2H), 1.58 (s, 3H),
1.50-1.36 (m, 2H).
2-(2-cyclopropyl-5-methylpyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-
-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid (Compound
87)
##STR00467##
[1035] Compound 87: LC/MS ESI 465.2 (M+H)+, .sup.1H NMR (500 MHz,
MeOD) .delta. 8.21 (dd, J=5.4, 1.7 Hz, 1H), 7.86 (dd, J=15.8, 1.6
Hz, 1H), 7.26-7.16 (m, 1H), 6.40 (d, J=7.3 Hz, 1H), 5.00 (s, 1H),
4.93 (s, 1H), 4.20-4.11 (m, 1H), 3.47 (m, 2H), 3.38 (m, 2H), 3.33
(m, 1H), 3.19-2.88 (m, 3H), 2.72 (t, J=6.1 Hz, 2H), 2.58 (m, 2H),
2.54-2.40 (m, 1H), 2.28 (d, J=5.5 Hz, 3H), 2.20-2.01 (m, 2H),
1.92-1.84 (m, 2H), 1.75-1.66 (m, 2H), 1.59 (m, 2H), 1.20 (m, 1H),
1.04-0.92 (m, 2H), 0.91-0.82 (m, 1H).
2-(5-fluoro-2-(2-methoxyethoxy)phenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-
-naphthyridin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (compound
88)
##STR00468##
[1037] Compound 88 LC/MS A: 95% purity, UV=214 nm, Rt=1.406 min,
ESI 500.7 (M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.32 (td,
J=9.0, 3.0 Hz, 1H), 7.21-7.03 (m, 3H), 6.36 (dd, J=7.3, 4.1 Hz,
1H), 4.98 (s, 1H), 4.29-4.16 (m, 2H), 3.81 (t, J=4.3 Hz, 2H), 3.46
(d, J=2.2 Hz, 3H), 3.41-3.37 (m, 2H), 3.32 (s, 2H), 3.16 (d, J=31.1
Hz, 2H), 2.71 (t, J=6.2 Hz, 2H), 2.51 (td, J=7.6, 4.4 Hz, 2H),
2.45-2.16 (m, 2H), 1.98-1.84 (m, 2H), 1.64 (m, 3H), 1.40 (m,
6H).
2-(2-(2-methoxyethoxy)phenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyr-
idin-2-yl)pentyl)pyrrolidin-1-yl)acetic acid (Compound 89)
##STR00469##
[1039] Compound 89: LC/MS ESI 482.2 (M+H).sup.+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.56 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.48-7.42
(m, 1H), 7.18 (dd, J=8.2, 4.6 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 6.59
(s, 1H), 5.43 (s, 1H), 4.31-4.25 (m, 2H), 4.19-3.96 (m, 1H),
3.82-3.77 (m, 2H), 3.48 (m, 6H), 3.35-3.30 (m, 1H), 3.23-2.92 (m,
2H), 2.81 (d, J=5.3 Hz, 2H), 2.74-2.62 (m, 2H), 2.25 (m, 2H),
1.99-1.90 (m, 2H), 1.80-1.63 (m, 3H), 1.57-1.29 (m, 6H).
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydr-
o-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 90-E1 and 90-E2)
##STR00470##
[1041] Compound 90-E1 (mixture of 2 isomers) LC/MS ESI 498.1
(M+H).sup.+. .sup.1H NMR (500 MHz, MeOD).sup.1H NMR (500 MHz, MeOD)
.delta. 7.46 (dd, J=8.8, 5.9 Hz, 1H), 7.38-7.26 (m, 1H), 7.12-6.97
(m, 2H), 6.30 (d, J=7.3 Hz, 1H), 5.13 (m, 1H), 4.90 (s, 1H), 4.07
(d, J=15.0 Hz, 1H), 3.95 (m, 1H), 3.83-3.70 (m, 1H), 3.46-3.31 (m,
3H), 3.27 (m, 2H), 3.14-2.88 (m, 2H), 2.61 (t, J=6.2 Hz, 2H), 2.47
(m, 2H), 2.33 (m, 1H), 2.08-1.83 (m, 5H), 1.77 (m, 2H), 1.63 (m,
2H), 1.55-1.45 (m, 2H).
[1042] Compound 90-E2 (mixture of 2 isomers) LC/MS ESI 498.1
(M+H).sup.+. .sup.1H NMR (500 MHz, MeOD .sup.1H NMR (500 MHz, MeOD)
.delta. 7.46-7.31 (m, 2H), 7.00 (dd, J=30.9, 7.6 Hz, 1H), 6.87 (d,
J=7.7 Hz, 1H), 6.27 (d, J=7.3 Hz, 1H), 5.22 (m, 1H), 4.53 (m, 1H),
4.29 (m, 1H), 4.05-3.92 (m, 1H), 3.77 (d, J=6.5 Hz, 1H), 3.71-3.55
(m, 2H), 3.32 (m, 5H), 3.06 (t, J=9.7 Hz, 1H), 2.63 (m, 5H),
2.48-2.26 (m, 3H), 1.93 (m, 2H), 1.85-1.73 (m, 4H), 1.52-1.48 (m,
2H).
2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(4-methoxy-5,6-
,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 91-A-E1, 91-A-E2, 91-B-E1 and
91-B-E2)
##STR00471##
[1044] Compound 91-A-E1 LC/MS A: 99% purity, UV=214 nm, Rt=1.64
min, ESI 542.7 (M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.53 (m,
2H), 7.09 (d, J=2.6 Hz, 1H), 6.30 (s, 1H), 4.87 (s, 1H), 4.60 (s,
1H), 4.12 (s, 1H), 4.03 (s, 1H), 3.87 (s, 3H), 3.72 (d, J=2.5 Hz,
1H), 3.55-3.40 (m, 2H), 3.30 (m, 4H), 3.07-2.95 (m, 2H), 2.74-2.53
(m, 4H), 2.18-2.09 (m, 1H), 2.08-1.93 (m, 3H), 1.74 (m, 10H).
[1045] Compound 91-B-E1 LC/MS A: 100% purity, UV=214 nm, Rt=1.62
min, ESI 542.7 (M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta. 7.52 (m,
2H), 7.11 (d, J=2.7 Hz, 1H), 6.30 (s, 1H), 4.89-4.72 (m, 3H), 4.16
(d, J=2.7 Hz, 1H), 4.02 (s, 1H), 3.87 (s, 3H), 3.70 (d, J=2.2 Hz,
1H), 3.48 (m, 3H), 3.25 (m, 1H), 3.13 (d, J=12.2 Hz, 1H), 2.99-2.85
(m, 1H), 2.60 (m, 4H), 2.08-1.96 (m, 4H), 1.88-1.60 (m, 11H).
[1046] Compound 91-B-E2 LC/MS A: 95% purity, UV=214 nm, Rt=1.66
min, ESI 542.7 (M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta.
7.47-7.41 (m, 2H), 7.06 (m, 1H), 6.33 (s, 1H), 4.86 (dd, J=13.9,
10.6 Hz, 3H), 4.15-4.06 (m, 2H), 3.73-3.64 (m, 1H), 3.55-3.39 (m,
3H), 3.29 (m, 2H), 3.09-2.92 (m, 3H), 2.71-2.56 (m, 4H), 2.19-1.56
(m, 16H).
2-(2-(6,6-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-te-
trahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 103-E1 and 103-E2)
##STR00472##
[1048] Compound 103-E1 (mixture of 2 stereoisomers) LC/MS ESI 522
(M+H)+. 1H NMR (500 MHz, MeOD) .delta. 7.72-7.70 (m, 1H), 7.62-7.59
(m, 1H), 7.45-7.35 (m, 2H), 7.21-7.19 (m, 1H), 6.38-6.35 (m, 1H),
5.21-5.19 (m, 1H), 4.92-4.90 (m, 1H), 4.23-4.21 (m, 1H), 3.81-3.61
(m, 1H), 3.51-2.91 (m, 7H), 2.62-2.59 (m, 2H), 2.51-2.49 (m, 2H),
2.18-1.48 (m, 14H), 1.31-1.29 (m, 3H), 1.23-1.21 (m, 3H).
[1049] Compound 103-E2 (mixture of 2 stereoisomers) LC/MS ESI 522
(M+H)+. 1H NMR (500 MHz, MeOD) .delta. 7.70-7.65 (m, 1H), 7.35-7.32
(m, 3H), 7.14 (d, J=7.2 Hz, 1H), 6.37-6.35 (m, 1H), 5.51-5.49 (m,
1H), 4.98-4.92 (m, 1H), 4.18-4.16 (m, 1H), 3.51-3.31 (m, 4H),
3.29-2.81 (m, 4H), 2.72-2.68 (m, 2H), 2.54-2.51 (m, 2H), 2.18-1.48
(m, 14H), 1.34-1.31 (m, 6H).
2-(2-(4,4-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 104-E1 and 104-E2)
##STR00473##
[1051] Compound 104-E1 (mixture of 2 stereoisomers) LC/MS ESI 526
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.63-7.59 (m, 1H),
7.48-7.45 (dd, J=2.8 Hz, J=10.4 Hz 1H), 7.18-7.14 (m, 2H), 6.38 (d,
J=7.1 Hz, 1H), 5.46-5.42 (m, 1H), 4.82 (m, 1H), 4.15-4.14 (m, 1H),
3.75-3.73 (m, 1H), 3.63-3.61 (m, 1H), 3.49-3.32 (m, 5H), 3.23-3.12
(m, 2H), 2.75-2.71 (m, 2H), 2.57-2.54 (m, 2H), 2.37-2.33 (m, 1H),
2.14 (m, 2H), 1.89-1.85 (m, 2H), 1.79-1.60 (m, 6H), 1.21 (s, 3H),
1.16 (s, 3H). Chiral SFC E (45% MeOH): ee 100%, Rt=3.86 min.
[1052] Compound 104-E2 (mixture of 2 stereoisomers) LC/MS ESI 526
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.61-7.58 (m, 1H),
7.47-7.44 (dd, J=2.8 Hz, J=10.4 Hz 1H), 7.16-7.11 (m, 2H), 6.38 (d,
J=7.1 Hz, 1H), 5.46-5.42 (m, 1H), 4.81 (m, 1H), 4.16-4.15 (m, 1H),
3.75-3.73 (m, 1H), 3.63-3.61 (m, 1H), 3.47-3.31 (m, 5H), 3.22-3.11
(m, 2H), 2.94 (m, 1H), 2.72-2.69 (m, 1H), 2.56-2.53 (m, 2H),
2.35-2.31 (m, 1H), 2.09-2.07 (m, 2H), 1.91-1.77 (m, 2H), 1.75-1.69
(m, 3H), 1.65-1.60 (m, 2H), 1.20 (s, 3H), 1.16 (s, 3H). Chiral SFC
E (45% MeOH): ee 98%, Rt=4.89 min.
2-(4-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 105-E1 and 105-E2)
##STR00474##
[1054] Compound 105-E1 (mixture of 2 stereoisomers) LC/MS ESI 512.3
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.80-7.70 (m, 1H),
7.27-7.24 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.10-7.05 (m, 1H),
6.38-6.36 (m, 1H), 4.87-4.65 (m, 2H), 4.16-4.03 (m, 2H), 3.70-3.67
(m, 1H), 3.49-3.36 (m, 5H), 3.25-3.15 (m, 1H), 3.10-2.85 (m, 2H),
2.70 (t, J=6.4 Hz, 2H), 2.54 (t, J=8.0 Hz, 2H), 2.20-1.80 (m, 6H),
1.78-1.55 (m, 8H).
[1055] Compound 105-E2 (mixture of 2 stereoisomers) LC/MS ESI 512.3
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.75-7.60 (m, 1H),
7.22-7.18 (m, 2H), 7.17-7.00 (m, 1H), 6.39-6.36 (m, 1H), 5.25-4.94
(m, 1H), 4.81-4.58 (m, 1H), 4.20-4.05 (m, 2H), 3.80-3.36 (m, 7H),
3.25-2.95 (m, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.56 (t, J=3.6 Hz, 2H),
2.20-2.00 (m, 2H), 1.99-1.80 (m, 5H), 1.98-1.54 (m, 7H).
2-(2-fluoro-6-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetra-
hydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 106-E1 and 106-E2)
##STR00475##
[1057] Compound 106-E1 (mixture of 2 stereoisomers) LC/MS ESI 512.3
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.35-7.29 (m, 2H),
7.13-7.05 (m, 2H), 6.35 (d, J=8.0 Hz, 1H), 5.18-5.12 (m, 1H), 4.74
(s, 1H), 4.70 (s, 1H), 4.01 (d, J=12.0 Hz, 1H), 3.78-3.61 (m, 1H),
3.54-3.36 (m, 4H), 3.24-2.82 (m, 3H), 2.71-2.68 (m, 2H), 2.53-2.48
(m, 2H), 2.19-2.17 (m, 2H), 2.03-2.00 (m, 1H), 1.94-1.84 (m, 4H),
1.72-1.52 (m, 8H).
[1058] Compound 106-E2 (mixture of 2 stereoisomers) LC/MS ESI 512.3
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.35-7.29 (m, 2H),
7.13-7.05 (m, 2H), 6.35 (d, J=8.0 Hz, 1H), 5.18-5.12 (m, 1H), 4.72
(s, 1H), 4.05-3.99 (m, 2H), 3.78-3.61 (m, 1H), 3.44-3.36 (m, 4H),
3.24-2.82 (m, 2H), 2.71-2.68 (m, 3H), 2.53-2.48 (m, 2H), 2.19-2.18
(m, 2H), 2.03-2.00 (m, 1H), 1.90-1.86 (m, 4H), 1.69-1.54 (m,
8H).
2-(5-fluoro-2-(5-oxaspiro[2.4]heptan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 107-E1 and 107-E2)
##STR00476##
[1060] Compound 107-E1 (mixture of 2 stereoisomers) LC/MS ESI 524
(M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta. 8.30 (bs, 1H),
7.58-7.54 (m, 1H), 7.40-7.35 (m, 2H), 7.11-7.06 (m, 1H), 6.46 (d,
J=7.2 Hz, 1H), 5.43-5.40 (m, 1H), 4.95 (s, 1H), 4.13-4.11 (m, 1H),
3.86-3.84 (m, 1H), 3.66-3.64 (m, 1H), 3.50-3.31 (m, 6H), 3.31-3.20
(m, 2H), 2.72-2.51 (m, 4H), 2.18-2.03 (m, 4H), 1.81-1.59 (m, 6H),
0.60-0.48 (m, 4H). Chiral SFC E (45% MeOH): ee 100%, Rt=4.74
min.
[1061] Compound 107-E2 (mixture of 2 stereoisomers) LC/MS ESI 524
(M+H)+. .sup.1H NMR (500 MHz, MeOD) .delta. 8.53 (bs, 1H),
7.70-7.67 (m, 1H), 7.52-7.46 (m, 2H), 7.24-7.20 (m, 1H), 6.58 (d,
J=7.2 Hz, 1H), 5.49-5.45 (m, 1H), 5.20 (s, 1H), 4.23-4.21 (m, 1H),
3.96-3.91 (m, 1H), 3.75-3.71 (m, 1H), 3.71-3.31 (m, 7H), 3.31-3.20
(m, 1H), 2.82-2.61 (m, 4H), 2.18-2.03 (m, 4H), 1.81-1.59 (m, 6H),
0.70-0.58 (m, 4H). Chiral SFC E (45% MeOH): ee 100%, Rt=6.51
min.
2-(5-fluoro-2-(6-oxaspiro[2.5]octan-5-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetr-
ahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 108-E1 and 108-E2)
##STR00477##
[1063] Compound 108-E1 (mixture of 2 stereoisomers) LC/MS ESI 538.2
(M+H)+, .sup.1H NMR (400 MHz, MeOD) .delta. 7.55-7.40 (m, 1H),
7.39-7.31 (m, 1H), 7.15-7.01 (m, 2H), 6.28 (d, J=7.2 Hz, 1H), 4.84
(s, 1H), 4.18-4.14 (m, 1H), 4.00-3.85 (m, 1H), 3.80-3.60 (m, 1H),
3.58-3.43 (m, 1H), 3.42-3.35 (m, 2H), 3.33-3.23 (m, 3H), 3.20-3.11
(m, 1H), 2.95-2.90 (m, 1H), 2.60 (t, J=6.4 Hz, 2H), 2.45 (t, J=7.6
Hz, 2H), 2.20-1.85 (m, 4H), 1.83-1.73 (m, 2H), 1.70-1.40 (m, 4H),
1.25-1.15 (m, 2H), 0.80-0.60 (m, 1H), 0.50-0.40 (m, 1H), 0.39-0.20
(m, 3H). Chiral SFC H (40% EtOH): ee 100%, Rt=2.10 min.
[1064] Compound 108-E2 (mixture of 2 stereoisomers) LC/MS ESI 538.2
(M+H)+, .sup.1H NMR (400 MHz, MeOD) .delta. 7.55-7.43 (m, 1H),
7.41-7.30 (m, 1H), 7.20-6.90 (m, 2H), 6.40-6.20 (m, 1H), 4.70 (s,
1H), 4.20-4.05 (m, 1H), 4.00-3.85 (m, 1H), 3.80-3.60 (m, 1H),
3.58-3.22 (m, 6H), 3.20-2.90 (m, 2H), 2.70-2.55 (m, 2H), 2.50-2.38
(m, 2H), 2.20-1.90 (m, 4H), 1.83-1.73 (m, 2H), 1.70-1.40 (m, 4H),
1.25-1.15 (m, 2H), 0.80-0.60 (m, 1H), 0.50-0.40 (m, 1H), 0.39-0.20
(m, 3H). Chiral SFC H (40% EtOH): ee 100%, Rt=2.51 min.
2-(2-(1,4-dioxan-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-
-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 109-E1 and 109-E2)
##STR00478##
[1066] Compound 109-E1 (mixture of 2 stereoisomers) LC/MS ESI 514
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.61-7.59 (m, 1H),
7.52-7.48 (m, 1H), 7.22-7.20 (m, 1H), 7.16-7.14 (m, 1H), 6.42-6.40
(m, 1H), 5.21-5.02 (m, 1H), 4.78-4.75 (m, 1H), 4.30-4.26 (m, 1H),
4.20-4.17 (m, 1H), 3.81-3.75 (m, 2H), 3.73-3.68 (m, 2H), 3.50-3.31
(m, 6H), 3.20-2.98 (m, 3H), 2.72-2.68 (m, 2H), 2.54-2.51 (m, 2H),
2.18-2.03 (m, 2H), 1.81-1.59 (m, 6H).
[1067] Compound 109-E2 (mixture of 2 stereoisomers) LC/MS ESI 514
(M+H)+. .sup.1H NMR (400 MHz, MeOD) .delta. 7.51-7.49 (m, 2H),
7.32-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.42-6.39 (m, 1H), 5.30-4.96
(m, 2H), 4.20-4.17 (m, 1H), 3.91-3.70 (m, 6H), 3.52-3.31 (m, 6H),
3.20-2.98 (m, 3H), 2.72-2.68 (m, 2H), 2.54-2.51 (m, 2H), 2.18-2.03
(m, 2H), 1.81-1.56 (m, 6H).
2-(2-(4,4-difluorotetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 110-E1 and 110-E2)
##STR00479##
[1069] Compound 110-E1 (mixture of 2 stereoisomers) LC/MS ESI 534.2
(M+H)+, .sup.1H NMR (400 MHz, MeOD) .delta. 7.80-7.60 (m, 1H),
7.55-7.45 (m, 1H), 7.35-7.15 (m, 2H), 6.43 (d, J=7.2 Hz, 1H),
5.75-5.60 (m, 1H), 4.77 (s, 1H), 4.30-4.05 (m, 2H), 4.04-3.90 (m,
1H), 3.60-3.50 (m, 1H), 3.45-3.30 (m, 4H), 3.25-2.95 (m, 4H),
2.80-2.70 (m, 2H), 2.65-2.30 (m, 3H), 2.25-2.05 (m, 2H), 1.95-1.85
(m, 2H), 1.80-1.55 (m, 4H). Chiral SFC F (30% MeOH): ee 100%,
Rt=4.16 min.
[1070] Compound 110-E2 (mixture of 2 stereoisomers) LC/MS ESI 534.2
(M+H)+, .sup.1H NMR (400 MHz, MeOD) .delta. 7.75-7.68 (m, 1H),
7.65-7.40 (m, 1H), 7.35-7.15 (m, 2H), 6.50-6.40 (m, 1H), 5.70-5.40
(m, 1H), 4.78 (s, 1H), 4.40-4.10 (m, 2H), 4.05-3.80 (m, 1H),
3.60-3.45 (m, 2H), 3.42-3.38 (m, 3H), 3.30-2.80 (m, 4H), 2.78-2.70
(m, 2H), 2.65-2.40 (m, 3H), 2.20-2.00 (m, 2H), 1.95-1.85 (m, 2H),
1.80-1.55 (m, 4H). Chiral SFC F (30% MeOH): ee 100%, Rt=5.04
min.
2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 111-E1 and 111-E2)
##STR00480##
[1072] Compound 111-E1 LC/MS ESI 512.3 (M+H)+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.62-7.58 (m, 1H), 7.48-7.46 (m, 1H), 7.22-7.15
(m, 2H), 6.41 (d, J=7.0 Hz, 1H), 4.85-4.79 (m, 2H), 4.18 (s, 1H),
4.05-4.02 (m, 1H), 3.75-3.71 (m, 1H), 3.56-3.31 (m, 6H), 3.21-3.16
(m, 2H), 2.74-2.57 (m, 4H), 2.18-1.62 (m, 14H).
[1073] Compound 111-E2 LC/MS ESI 512.3 (M+H)+, .sup.1H NMR (500
MHz, MeOD) .delta. 7.62-7.58 (m, 1H), 7.48-7.46 (m, 1H), 7.22-7.15
(m, 2H), 6.62-6.60 (m, 1H), 6.00 (br, 1H), 4.65-4.61 (m, 1H),
4.25-4.12 (m, 2H), 3.55-3.31 (m, 8H), 2.84-2.65 (m, 5H), 2.18-1.62
(m, 14H).
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-
-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (THF stereoisomer A, diastereomeric compounds 112-A-E1 and
112-A-E2)
##STR00481##
[1075] Compound 112-A-E1 LC/MS ESI 528.2 (M+H)+, .sup.1H NMR (400
MHz, MeOD) .delta. 8.53 (s, 1H), 7.60-7.58 (m, 1H), 7.47-7.45 (m,
1H), 7.19-7.15 (m, 1H), 6.49 (s, 1H), 5.20-5.09 (m, 2H), 4.20 (s,
1H), 4.10-4.05 (m, 1H), 3.96 (s, 3H), 3.90-3.81 (m, 1H), 3.56-3.31
(m, 6H), 3.16-3.10 (m, 1H), 2.74-2.69 (m, 4H), 2.40 (s, 1H),
2.08-1.62 (m, 12H).
[1076] Compound 112-A-E2 LC/MS ESI 528.2 (M+H)+, .sup.1H NMR (400
MHz, MeOD) .delta. 8.59 (s, 4H), 7.50-7.40 (m, 2H, 7.19-7.15 (m,
1H), 6.49 (s, 1H), 5.16-5.12 (m, 1H), 4.20-4.10 (m, 2H), 3.96 (s,
3H), 3.90-3.81 (m, 1H), 3.56-3.31 (m, 4H), 3.19-3.01 (m, 4H),
2.75-2.69 (m, 4H), 2.40 (s, 1H), 2.20 (s, 1H), 2.09-1.98 (m, 4H),
1.92-1.62 (m, 7H).
2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 113-E1 and 113-E2)
##STR00482##
[1078] Compound 113-E1 LC/MS ESI 512.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 8.45 (s, 1H), 7.63-7.59 (m, 1H), 7.46 (d, J=8.0
Hz, 2H), 7.21-7.19 (m, 1H), 6.55 (d, J=8.0 Hz, 1H), 5.11 (s, 1H),
4.74 (d, J=8.0 Hz, 1H), 4.34 (s, 1H), 4.06 (d, J=8.0 Hz, 1H),
3.72-3.71 (m, 1H), 3.58-3.33 (m, 6H), 3.15 (s, 1H), 2.81-2.67 (m,
4H), 2.18 (s, 2H), 2.03-1.58 (m, 13H).
[1079] Compound 113-E2 LC/MS ESI 512.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 8.45 (s, 1H), 7.47-7.45 (m, 2H), 7.21-7.19 (m, 1H),
7.16-7.11 (m, 1H), 6.43 (d, J=8.0 Hz, 1H), 5.25 (s, 1H), 4.89 (d,
J=8.0 Hz, 1H), 4.19 (s, 1H), 4.10 (d, J=8.0 Hz, 1H), 3.58-3.33 (m,
6H), 3.15-3.12 (m, 2H), 2.75-2.72 (m, 2H), 2.63-2.59 (m, 2H),
2.18-2.16 (m, 2H), 2.03-1.58 (m, 13H).
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-5,6,7,8--
tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(THF stereoisomer A, Me stereoisomers A and B, diastereomeric
compounds 114-A-E1, 114-A-E2, 114-B-E1 and 114-B-E2)
##STR00483##
[1081] Compound 114-A-E1 LC/MS ESI 512.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.56-7.49 (m, 2H), 7.18 (d, J=8.0 Hz, 1H)
7.08-7.06 (m, 1H), 6.41 (d, J=8.0 Hz, 1H), 5.33-5.30 (m, 1H), 4.95
(s, 2H), 4.59 (s, 1H), 4.16-4.05 (m, 2H), 3.92-3.85 (m, 1H),
3.59-3.40 (m, 3H), 3.03-2.82 (m, 2H), 2.75-2.72 (m, 3H), 2.57-2.42
(m, 3H), 2.07-2.01 (m, 3H), 2.00-1.82 (m, 3H), 1.75-1.65 (m, 2H),
1.62-1.59 (m, 2H), 1.57-1.55 (m, 1H), 1.22 (d, J=10.8 Hz, 3H).
[1082] Compound 114-A-E2 LC/MS ESI 512.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.51-7.41 (m, 2H), 7.22 (d, J=8.0 Hz, 1H)
7.11-7.08 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.23-5.21 (m, 1H), 4.95
(s, 1H), 4.79 (s, 1H), 4.16-4.05 (m, 2H), 3.92-3.85 (m, 1H),
3.59-3.40 (m, 3H), 3.13-3.03 (m, 3H), 2.75-2.72 (m, 2H), 2.64-2.58
(m, 2H), 2.47-2.42 (m, 1H), 2.07-1.82 (m, 6H), 1.75-1.65 (m, 2H),
1.62-1.59 (m, 2H), 1.57-1.55 (m, 1H), 1.22 (d, J=10.8 Hz, 3H).
[1083] Compound 114-B-E1 LC/MS ESI 512.3 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.56-7.49 (m, 2H), 7.18 (d, J=8.0 Hz, 1H) 7.08-7.06
(m, 1H), 6.41 (d, J=8.0 Hz, 1H), 5.33-5.30 (m, 1H), 4.95 (s, 2H),
4.59 (s, 1H), 4.16-4.05 (m, 2H), 3.92-3.85 (m, 1H), 3.59-3.40 (m,
3H), 3.03-2.82 (m, 2H), 2.75-2.72 (m, 3H), 2.57-2.42 (m, 3H),
2.07-2.01 (m, 3H), 2.00-1.82 (m, 3H), 1.75-1.65 (m, 2H), 1.62-1.59
(m, 2H), 1.57-1.55 (m, 1H), 1.22 (d, J=10.8 Hz, 3H).
[1084] Compound 114-B-E2 LC/MS ESI 512.3 (M+H)+. .sup.1H NMR (400
MHz, MeOD) .delta. 7.51-7.41 (m, 2H), 7.22 (d, J=8.0 Hz, 1H)
7.11-7.08 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.23-5.21 (m, 1H), 4.95
(s, 1H), 4.79 (s, 1H), 4.16-4.05 (m, 2H), 3.92-3.85 (m, 1H),
3.59-3.40 (m, 3H), 3.13-3.03 (m, 3H), 2.75-2.72 (m, 2H), 2.64-2.58
(m, 2H), 2.47-2.42 (m, 1H), 2.07-1.82 (m, 6H), 1.75-1.65 (m, 2H),
1.62-1.59 (m, 2H), 1.57-1.55 (m, 1H), 1.22 (d, J=10.8 Hz, 3H).
2-(2-(2,2-difluoro-6-oxaspiro[3.5]nonan-7-yl)-5-fluorophenyl)-2-((R)-3-(4--
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 115-A-E1, 115-A-E2, 115-B-E1 and
115-B-E2)
##STR00484##
[1086] Compound 115-A-E1 LC/MS ESI 588.3 (M+H)+, 1H NMR (400 MHz,
MeOD) .delta. 7.60-7.55 (m, 1H), 7.50-7.20 (m, 1H), 7.20-7.05 (m,
2H), 6.39 (d, J=7.2 Hz, 1H), 4.88-4.80 (m, 1H), 4.75 (s, 1H),
4.25-4.15 (m, 1H), 3.90-3.75 (m, 1H), 3.70-3.60 (m, 1H), 3.58-3.45
(m, 3H), 3.42-3.38 (m, 2H), 3.35-3.18 (m, 1H), 3.17-3.05 (m, 1H),
3.00-2.85 (m, 1H), 2.80-2.70 (m, 2H), 2.65-2.50 (m, 3H), 2.45-2.38
(m, 1H), 2.35-2.15 (m, 2H), 2.10-1.85 (m, 7H), 1.83-1.55 (m,
5H).
[1087] Compound 115-A-E2 LC/MS ESI 588.3 (M+H)+, 1H NMR (400 MHz,
MeOD) .delta. 7.60-7.40 (m, 2H), 7.30-7.20 (m, 1H), 7.18-7.05 (m,
1H), 6.42 (d, J=7.2 Hz, 1H), 5.04 (s, 1H), 4.75 (d, J=10.4 Hz, 1H),
4.20-4.10 (m, 1H), 3.95-3.85 (m, 1H), 3.75-3.60 (m, 1H), 3.59-3.50
(m, 2H), 3.48-3.38 (m, 3H), 3.20-3.18 (m, 2H), 2.80-2.70 (m, 2H),
2.68-2.40 (m, 4H), 2.38-2.20 (m, 2H), 2.18-2.00 (m, 3H), 1.98-1.58
(m, 10H).
[1088] Compound 115-B-E1 LC/MS ESI 588 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.58-7.48 (m, 2H), 7.19-7.14 (m, 2H), 6.40 (d, J=7.2
Hz, 1H), 4.91-4.77 (m, 2H), 4.16-4.15 (m, 1H), 3.82-3.80 (m, 1H),
3.72-3.70 (m, 1H), 3.50-3.31 (m, 6H), 3.31-3.20 (m, 2H), 2.72-2.41
(m, 6H), 2.31-2.25 (m, 2H), 2.20-1.60 (m, 12H).
[1089] Compound 115-B-E2 LC/MS ESI 588 (M+H)+. 1H NMR (400 MHz,
MeOD) .delta. 7.46-7.43 (m, 2H), 7.19-7.14 (m, 2H), 6.39 (d, J=7.2
Hz, 1H), 5.21-5.19 (m, 1H), 4.71-4.69 (m, 1H), 4.19-4.17 (m, 1H),
3.87-3.84 (m, 1H), 3.66-3.64 (m, 1H), 3.40-3.31 (m, 4H), 3.31-2.98
(m, 2H), 2.76-2.50 (m, 6H), 2.28-2.25 (m, 2H), 2.20-1.60 (m,
14H).
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-te-
trahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 116-E1 and 116-E2)
##STR00485##
[1091] Compound 116-E1 (mixture of 2 stereoisomers) LC/MS ESI 530.2
(M+H)+, 1H NMR (400 MHz, MeOD) .delta. 7.70-7.55 (m, 1H), 7.50-7.40
(m, 1H), 7.38-7.20 (m, 2H), 7.10-7.00 (m, 1H), 6.26 (d, J=7.6 Hz,
1H), 4.90 (d, J=10.8 Hz, 1H), 4.72 (s, 1H), 4.10-4.00 (m, 1H),
3.98-3.85 (m, 1H), 3.80-3.65 (m, 1H), 3.60-3.25 (m, 5H), 3.18-3.05
(m, 2H), 2.65-2.55 (m, 2H), 2.50-2.38 (m, 2H), 2.35-1.40 (m, 13H).
Chiral SFC F (45% EtOH): ee 100%, Rt=1.89 min.
[1092] Compound 116-E2 (mixture of 2 stereoisomers) LC/MS ESI 530.2
(M+H)+, 1H NMR (400 MHz, MeOD) .delta. 7.70-7.55 (m, 1H), 7.50-7.40
(m, 1H), 7.38-7.20 (m, 2H), 7.10-7.00 (m, 1H), 6.26 (d, J=7.2 Hz,
1H), 5.05-4.82 (m, 2H), 4.10-4.00 (m, 1H), 3.98-3.85 (m, 1H),
3.80-3.65 (m, 1H), 3.60-3.43 (m, 1H), 3.42-3.35 (m, 2H), 3.30-3.25
(m, 2H), 3.18-3.08 (m, 1H), 3.05-2.85 (m, 1H), 2.59 (t, J=6.0 Hz,
2H), 2.44 (t, J=7.6 Hz, 2H), 2.35-1.40 (m, 13H). Chiral SFC F (45%
EtOH): ee 100%, Rt=4.45 min.
2-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetra-
hydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 117-E1 and 117-E2)
##STR00486##
[1094] Compound 117-E1: (ESI 512.63 (M+H).sup.+), .sup.1H NMR (500
MHz, MeOD) .delta. 7.39-7.26 (m, 2H), 7.10 (d, J=7.3 Hz, 1H), 7.01
(m, 1H), 6.31 (d, J=7.3 Hz, 1H), 4.80 (s, 1H), 4.09 (s, 1H),
3.95-3.85 (m, 2H), 3.49-3.33 (m, 5H), 3.31-3.26 (m, 2H), 3.20-3.13
(m, 2H), 2.97-2.86 (m, 2H), 2.62 (t, J=6.2 Hz, 2H), 2.49 (m, 2H),
2.03-1.93 (m, 2H), 1.87-1.74 (m, 4H), 1.59 (m, 6H).
[1095] Compound 117-E2: (ESI 512.63 (M+H)+), .sup.1H NMR (500 MHz,
MeOD) .delta. 7.49-7.39 (m, 2H), 7.22 (d, J=7.3 Hz, 1H), 7.12 (m,
1H), 6.42 (d, J=7.3 Hz, 1H), 4.84 (s, 1H), 4.17 (d, J=3.3 Hz, 1H),
4.05-3.96 (m, 2H), 3.66-3.49 (m, 3H), 3.46-3.34 (m, 5H), 3.26-3.12
(m, 3H), 2.73 (t, J=6.2 Hz, 2H), 2.61 (m, 2H), 2.21-2.10 (m, 2H),
1.96-1.85 (m, 4H), 1.78-1.59 (m, 6H).
2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(5-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)pentyloxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 118-E1 and 118-E2)
##STR00487##
[1097] Compound 118-E1: (ESI 526.65 (M+H).sup.+), .sup.1H NMR (500
MHz, MeOD) .delta. 7.57 (m, 1H), 7.51 (m, 1H), 7.19 (d, J=7.3 Hz,
1H), 7.13 (m, 1H), 6.39 (d, J=7.3 Hz, 1H), 4.87-4.78 (m, 2H), 4.17
(d, J=2.7 Hz, 1H), 4.07 (m, 1H), 3.74 (m, 1H), 3.55 (m, 1H), 3.45
(m, 2H), 3.40-3.35 (m, 2H), 3.24 (m, 1H), 3.13 (d, J=12.5 Hz, 1H),
3.01-2.93 (m, 1H), 2.69 (t, J=6.2 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H),
2.10-1.99 (m, 4H), 1.92-1.83 (m, 2H), 1.74 (m, 2H), 1.64 (m, 6H),
1.43 (m, 2H).
[1098] Compound 118-E2: (ESI 526.65 (M+H).sup.+), .sup.1H NMR (500
MHz, MeOD) .delta. 7.51-7.41 (m, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.08
(m, 1H), 6.40 (d, J=7.3 Hz, 1H), 4.89 (s, 2H), 4.12 (m, 2H), 3.70
(t, J=10.6 Hz, 1H), 3.54-3.45 (m, 2H), 3.44-3.36 (m, 3H), 3.09 (s,
1H), 3.00-2.88 (m, 2H), 2.72 (t, J=6.2 Hz, 2H), 2.66-2.51 (m, 2H),
2.17 (m, 1H), 2.03-1.93 (m, 2H), 1.88 (m, 4H), 1.74 (t, J=10.4 Hz,
3H), 1.69-1.50 (m, 5H), 1.48-1.35 (m, 1H).
2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydr-
o-1,8-naphthyridin-2-yl)pentyloxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 119 A-E1, 119-A-E2, 119-B-E1 and
119-B-E2)
##STR00488##
[1100] Compound 119-A-E1: (ESI 512.63 (M+H).sup.+), .sup.1H NMR
(500 MHz, MeOD) .delta. 7.55-7.41 (m, 2H), 7.18 (d, J=7.3 Hz, 1H),
7.10 (m, 1H), 6.39 (d, J=7.3 Hz, 1H), 5.22-5.16 (m, 1H), 4.88 (s,
1H), 4.15 (m, 2H), 3.91 (m, 1H), 3.53-3.42 (m, 3H), 3.41-3.37 (m,
2H), 3.25 (d, J=8.8 Hz, 1H), 3.06 (d, J=12.2 Hz, 1H), 3.00-2.94 (m,
1H), 2.71 (t, J=6.2 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.42 (m, 1H),
2.16-1.98 (m, 5H), 1.91-1.85 (m, 2H), 1.70-1.59 (m, 4H), 1.44 (m,
2H).
[1101] Compound 119-A-E2: (ESI 512.63 (M+H).sup.+), .sup.1H NMR
(500 MHz, MeOD) .delta. 7.55 (m, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.12
(m, 1H), 6.41 (d, J=7.3 Hz, 1H), 5.37 (t, J=7.0 Hz, 1H), 4.68 (s,
1H), 4.12 (m, 2H), 3.94 (m, 1H), 3.51-3.36 (m, 5H), 3.17 (s, 1H),
3.06-2.94 (m, 2H), 2.73 (t, J=6.2 Hz, 2H), 2.57 (m, 3H), 2.18 (m,
1H), 2.12-2.01 (m, 3H), 1.97-1.86 (m, 3H), 1.78-1.55 (m, 5H),
1.48-1.40 (m, 1H).
[1102] Compound 119-B-E1: (ESI 512.63 (M+H).sup.+), .sup.1H NMR
(500 MHz, MeOD) .delta. 7.58 (m, 1H), 7.47 (m, 1H), 7.22-7.09 (m,
2H), 6.39 (d, J=7.3 Hz, 1H), 5.25 (t, J=7.2 Hz, 1H), 4.93 (s, 1H),
4.18 (d, J=3.4 Hz, 1H), 4.11 (m, 1H), 3.94 (m, 1H), 3.56-3.42 (m,
3H), 3.41-3.36 (m, 2H), 3.27-3.11 (m, 2H), 3.07-2.97 (m, 1H), 2.71
(t, J=6.2 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.49 (m, 1H), 2.14-2.02
(m, 4H), 2.02-1.92 (m, 1H), 1.91-1.83 (m, 2H), 1.71-1.57 (m, 4H),
1.49-1.38 (m, 2H).
[1103] Compound 119-B-E2: (ESI 512.63 (M+H).sup.+), .sup.1H NMR
(500 MHz, MeOD) .delta. 7.51 (m, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.07
(m, 1H), 6.41 (d, J=7.3 Hz, 1H), 5.34 (t, J=7.5 Hz, 1H), 4.58 (s,
1H), 4.15 (m, 2H), 3.92 (m, 1H), 3.49 (m, 1H), 3.45-3.35 (m, 4H),
2.96 (d, J=7.2 Hz, 2H), 2.89 (m, 1H), 2.73 (t, J=6.2 Hz, 2H),
2.66-2.52 (m, 2H), 2.46 (m, 1H), 2.10 (m, 3H), 1.97 (m, 1H), 1.90
(m, 3H), 1.78-1.64 (m, 2H), 1.63-1.51 (m, 3H), 1.44 (m, 1H).
2-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-((R)-3-(5-(5,6,7,8-tetra-
hydro-1,8-naphthyridin-2-yl)pentyloxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 120-E1 and 120-E2)
##STR00489##
[1105] Compound 120-E1: (ESI 526.65 (M+H).sup.+), .sup.1H NMR (500
MHz, MeOD) .delta. 7.44 (m, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.10 (m,
1H), 6.40 (d, J=7.3 Hz, 1H), 4.81 (s, 1H), 4.18 (s, 1H), 4.09-4.00
(m, 2H), 3.62 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.44-3.35 (m, 4H),
3.11 (d, J=12.0 Hz, 1H), 2.94 (t, J=7.8 Hz, 2H), 2.71 (t, J=6.2 Hz,
2H), 2.56 (t, J=7.6 Hz, 2H), 2.12-2.00 (m, 2H), 1.96-1.86 (m, 4H),
1.80-1.60 (m, 6H), 1.44 (m, 2H).
[1106] Compound 120-E2: (ESI 526.65 (M+H).sup.+), .sup.1H NMR (500
MHz, MeOD) .delta. 7.51 (d, J=10.3 Hz, 1H), 7.41 (m, 1H), 7.26 (d,
J=7.3 Hz, 1H), 7.09 (m, 1H), 6.42 (d, J=7.3 Hz, 1H), 4.61 (s, 1H),
4.14 (s, 1H), 4.04 (d, J=7.5 Hz, 2H), 3.65 (m, 2H), 3.52 (m, 2H),
3.45-3.37 (m, 4H), 3.19 (s, 1H), 3.02 (s, 1H), 2.92 (s, 1H), 2.73
(t, J=6.2 Hz, 2H), 2.69-2.52 (m, 2H), 2.16 (m, 1H), 2.05 (s, 1H),
1.94-1.86 (m, 4H), 1.81-1.66 (m, 4H), 1.57 (d, J=18.6 Hz, 3H), 1.44
(m, 1H).
(2S)-2-(4-cyano-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(diastereomeric compounds 121-E1 and 121-E2)
##STR00490##
[1108] Compound 121-E1 (mixture of 2 stereoisomers) (ESI 519.2
(M+H).sup.+), .sup.1H NMR (500 MHz, MeOD) .delta. 7.89 (dd, J=12.0,
8.2 Hz, 2H), 7.76-7.58 (m, 1H), 7.24 (m, 1H), 6.43 (d, J=7.3 Hz,
1H), 4.81 (m, 2H), 4.16 (m, 1H), 4.09 (m, 1H), 3.77-3.67 (m, 1H),
3.52-3.37 (m, 5H), 3.30-2.88 (m, 3H), 2.73 (m, 2H), 2.68-2.53 (m,
2H), 2.21-1.54 (m, 15H).
[1109] Compound 121-E2 (mixture of 2 stereoisomers) (ESI 519.2
(M+H)+), .sup.1H NMR (500 MHz, MeOD) .delta. 7.84 (dd, J=8.1, 2.7
Hz, 1H), 7.81 (t, J=1.9 Hz, 1H), 7.64 (m, 1H), 7.27 (m, 1H), 6.43
(t, J=6.8 Hz, 1H), 5.02 (d, J=58.4 Hz, 1H), 4.86 (m, 1H), 4.21-4.05
(m, 2H), 3.67 (m, 1H), 3.57-3.34 (m, 5H), 3.30-2.84 (m, 3H), 2.74
(m, 2H), 2.62 (m, 2H), 2.21-1.51 (m, 15H).
(S)-2-(3-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7-
,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (122-E1)
##STR00491##
[1111] Compound 122-E1: LC/MS ESI 512.2 (M+H)+. .sup.1H NMR (400
MHz, DMSO) .delta.8.18 (s, 1H), .delta.7.26-7.33 (m, 2H),
.delta.7.03-7.10 (m, 2H), .delta.6.58 (s, 1H), .delta.6.25 (d, J=6
Hz, 1H), .delta.4.96 (d, J=14 Hz, 1H), .delta. 4.53 (s, 1H),
.delta.3.95-3.99 (m, 1H), .delta.3.91 (d, J=10.8 Hz, 1H),
.delta.3.44 (t, J=11.2 Hz, 1H), .delta.3.30 (t, J=6.4 Hz, 2H),
.delta.3.22 (t, J=6 Hz, 2H), .delta.2.95 (dd, J=6, 12 Hz, 1H),
.delta.2.69-2.80 (m, 2H), .delta.2.60 (t, J=6 Hz, 2H),
.delta.2.53-2.55 (m, 1H), .delta.2.43 (t, J=5.6, 2H),
.delta.1.90-1.98 (m, 2H), .delta. 1.47-1.82 (m, 12H).
2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(4-methoxy-5,-
6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 129-E1 and 129-E2)
##STR00492##
[1113] Compound 129-E1: LC/MS ESI 568 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.63-7.48 (m, 2H), 7.18-7.15 (m, 1H), 6.30 (s, 1H),
4.92-4.85 (m, 3H), 4.77 (s, 1H), 4.20-4.14 (m, 2H), 3.87 (s, 3H),
3.50-3.32 (m, 3H), 3.30-2.85 (m, 4H), 2.62-2.55 (m, 4H), 2.21-1.60
(m, 12H), 0.60-0.30 (m, 4H). Chiral SFC C (20% EtOH): ee 100%,
Rt=1.35 min.
[1114] Compound 129-E2: LC/MS ESI 568 (M+H)+. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.46-7.40 (m, 2H), 6.95-6.92 (m, 1H), 6.14 (s, 1H),
4.85-4.80 (m, 3H), 4.37 (s, 1H), 4.02-3.96 (m, 2H), 3.74 (s, 3H),
3.40-3.22 (m, 2H), 2.98-2.65 (m, 5H), 2.52-2.41 (m, 4H), 2.20-1.40
(m, 12H), 0.44-0.20 (m, 4H). Chiral SFC C (20% EtOH): ee 100%,
Rt=2.02 min.
2-(2-(5,5-dimethyl-1,4-dioxan-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-t-
etrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic acid
(compound 125)
##STR00493##
[1116] Compound 125 (mixture of 4 stereoisomers) LC/MS ESI 542
(M+H)+. 1H NMR (400 MHz, MeOD) .delta. 8.42 (s, 1H), 7.76-7.69 (m,
1H), 7.60-7.45 (m, 2H), 7.29-7.19 (m, 1H), 6.62-6.57 (m, 1H), 5.18
(s, 1H), 4.90-4.81 (m, 1H), 4.28-4.24 (m, 1H), 4.18-3.98 (m, 1H),
3.81-3.38 (m, 10H), 3.32-3.16 (m, 1H), 2.82-2.61 (m, 4H), 2.31-2.20
(m, 2H), 1.98-1.55 (m, 6H), 1.49-1.35 (m, 3H)), 1.20-1.08 (m,
3H).
2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(4-
-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)a-
cetic acid (diastereomeric compounds 126-E1 and 126-E2)
##STR00494##
[1118] Compound 126-E1 (mixture of 2 stereoisomers) LC/MS ESI 578
(M+H)+, 1H NMR (400 MHz, MeOD) .delta. 7.60-7.49 (m, 2H), 7.10 (t,
J=8.0 Hz, 1H), 6.32 (s, 1H), 5.04 (d, J=10.8 Hz, 1H), 4.59 (s, 1H),
4.12 (s, 1H), 4.02-3.79 (m, 5H), 3.52-3.35 (m, 4H), 3.30-2.75 (m,
6H), 2.68-2.52 (m, 4H), 2.35-1.55 (m, 12H). Chiral SFC A (35% IPA):
ee 100%, Rt=4.39 min.
[1119] Compound 126-E2 (mixture of 2 stereoisomers) LC/MS ESI 578
(M+H)+, 1H NMR (400 MHz, MeOD) .delta. 7.62-7.49 (m, 2H), 7.12-7.06
(m, 1H), 6.36 (s, 1H), 5.12-5.04 (m, 1H), 4.50 (s, 1H), 4.13 (s,
1H), 4.02-3.78 (m, 5H), 3.57-3.35 (m, 4H), 3.27-2.83 (m, 6H),
2.79-2.52 (m, 4H), 2.38-1.52 (m, 12H). Chiral SFC A (35% IPA): ee
100%, Rt=5.12 min.
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5-
,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)acetic
acid (diastereomeric compounds 127-E1, 127-E2 and 127-E3)
##STR00495##
[1121] Compound 127-E1 LC/MS ESI 540 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 7.64-7.61 (m, 1H), 7.49-7.47 (m, 1H), 7.19-7.15 (m, 2H),
6.41-6.39 (m, 1H), 4.92-4.90 (m, 1H), 4.72-4.70 (m, 1H), 4.19-4.17
(m, 1H), 3.52-3.32 (m, 8H), 3.16-3.14 (m, 1H), 3.02-3.01 (m, 1H),
2.73-2.70 (m, 2H), 2.59-2.56 (m, 2H), 2.11-1.50 (m, 12H), 1.20 (s,
3H), 0.90 (s, 3H). Chiral SFC H (45% IPA): ee 100%, Rt=2.35
min.
[1122] Compound 127-E2 LC/MS ESI 540 (M+H)+. 1H NMR (400 MHz, MeOD)
.delta. 7.65-7.63 (m, 1H), 7.52-7.49 (m, 1H), 7.21-7.16 (m, 2H),
6.41-6.39 (m, 1H), 4.82-4.70 (m, 2H), 4.17-4.16 (m, 1H), 3.52-3.32
(m, 8H), 3.20-3.16 (m, 2H), 2.73-2.70 (m, 2H), 2.59-2.56 (m, 2H),
2.24-2.08 (m, 2H), 2.01-1.55 (m, 10H), 1.20 (s, 3H), 0.90 (s, 3H).
Chiral SFC H (45% IPA): ee 100%, Rt=3.66 min.
[1123] Compound 127-E3 (mixture of 2 stereoisomers) LC/MS ESI 540
(M+H)+. 1H NMR (400 MHz, MeOD) .delta. 7.66-7.62 (m, 1H), 7.51-7.49
(m, 1H), 7.41-7.17 (m, 2H), 6.48-6.46 (m, 1H), 4.92-4.90 (m, 1H),
4.72-4.70 (m, 1H), 4.19-4.17 (m, 1H), 3.52-3.32 (m, 8H), 3.16-3.10
(m, 2H), 2.73-2.70 (m, 2H), 2.59-2.56 (m, 2H), 2.11-1.50 (m, 12H),
1.20-1.18 (m, 3H), 0.90-0.84 (m, 3H).
2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(4-
-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidin-1-yl)a-
cetic acid (diastereomeric compounds 128-E1, 128-E2 and 128-E3)
##STR00496##
[1125] Compound 128-E1 (mixture of 2 stereoisomers) LC/MS ESI 570
(M+H)+, 1H NMR (400 MHz, MeOD) .delta. 7.65-7.58 (m, 1H), 7.53-7.46
(m, 1H), 7.15-7.11 (m, 1H), 6.32-6.30 (m, 1H), 4.83-4.64 (m, 2H),
4.20-4.12 (m, 1H), 3.88-3.85 (m, 3H), 3.58-3.35 (m, 6H), 3.32-2.91
(m, 4H), 2.75-2.54 (m, 4H), 2.20-1.55 (m, 12H), 1.12 (s, 3H), 0.87
(d, J=4.8 Hz, 3H).
[1126] Compound 128-E2 LC/MS ESI 570 (M+H)+, 1H NMR (400 MHz, MeOD)
.delta. 7.47-7.44 (m, 2H), 7.12-7.08 (m, 1H), 6.30 (s, 1H), 5.18
(s, 1H), 4.65 (d, J=8.0 Hz, 1H), 4.13 (s, 1H), 3.87 (s, 3H),
3.61-3.36 (m, 7H), 3.28-2.94 (m, 3H), 2.69-2.56 (m, 4H), 2.19-1.53
(m, 12H), 1.16 (s, 3H), 0.87 (s, 3H).
[1127] Compound 128-E3 LC/MS ESI 570 (M+H)+, 1H NMR (400 MHz, MeOD)
.delta. 7.51-7.40 (m, 2H), 7.09-7.05 (m, 1H), 6.35 (s, 1H), 4.79
(d, J=8.0 Hz, 1H), 4.13 (s, 1H), 3.90 (s, 3H), 3.62-3.38 (m, 5H),
3.31-3.20 (m, 2H), 3.02-2.52 (m, 8H), 2.21-1.52 (m, 12H), 1.15 (s,
3H), 0.87 (s, 3H).
Example 35: Fluorescence Polarization Assays of Compounds for
.alpha.v.beta.6 Binding
[1128] Fluorescence Polarization (FP) assays were used to measure
compound activity through binding competition with the
fluorescein-labeled peptide GRGDLGRL. In the assay, 10 nM of
integrin .alpha.v.beta.6 was incubated with the test compound in 2
mM manganese chloride, 0.1 mM calcium chloride, 20 mM HEPES buffer
at pH 7.3, 150 mM sodium chloride, 0.01% Triton X 100, 2% DMSO, and
3 nM of the fluorescein-labeled peptide. The assays were run in
384-well plates. For both assay versions, the integrin protein was
pre-incubated with the test compounds for 15 minutes at 22.degree.
C. before the fluorescein-labeled peptide was added. After the
fluorescein-labeled peptide was added, the assay was incubated at
22.degree. C. for 1 hour and fluorescence polarization was
measured. IC.sub.50 values were determined by nonlinear regression,
4-parameter curve fitting (FIGS. 1 and 2).
Example 36: MDCK Permeability Assays
[1129] Compounds were tested for permeability in an MDCK
permeability assay. This assay measures the ability of compounds to
cross a layer of Madin-Darby Canine Kidney (MDCK) cells from the
apical to basolateral side (A->B). This measurement is
predictive of the ability of compounds to be absorbed in the gut
following oral dosing, an essential characteristic of an orally
administered small molecule integrin inhibitor drug.
[1130] The assay is run in two formats. One uses wild type MDCK
cells with no inhibitor. This method works well in determining the
passive permeability of compounds with low efflux by P-glyocprotein
(Pgp), and was used to assess permeability of a Reference Compound
having the chemical formula shown below. The MDCK value of less
than 1 (i.e., less than about 0.23) was obtained for the Reference
Compound using this method; an IC50 value of about 96.5 nM was
obtained for the Reference Compound using the fluorescence
polarization assay of Example 35.
TABLE-US-00001 ##STR00497## avb6. (IC50) [nM] MDCK (A->B) 96.5
<0.23
[1131] However, for compounds with Pgp efflux, it is necessary to
include a Pgp inhibitor order to determine passive permeability for
A->B transmission. In this case, a MDCK-MDR1 cell line
overexpressing Pgp is used, and PGP inhibitor GF120918 is included
at sufficient concentration (10 .mu.M) to block activity of Pgp.
This procedure (MDCK-MDR1 with PGP inh (A->B) [10{circumflex
over ( )}cm/s]) was used to obtain the data presented in Tables
shown in FIGS. 3 and 4. MDCK permeability values of less than 5
10{circumflex over ( )}6 cm/s predict low absorption in the gut,
while permeability values greater than 5 10{circumflex over ( )}6
cm/s predict sufficient absorption in the gut for oral dosing of a
small molecule drug.
[1132] The detailed experimental procedure is as follows:
TABLE-US-00002 EQUIPMENT REAGENTS 24-well Cell Culture Plate
GF120918 (Pgp inhibitor) (PET membrane): Millipore Lucifer Yellow #
PSHT 010 R5 Reference compounds: Quinidine, 24-well feeder tray:
Metoprolol, Atenolol Millipore #PSMW 010 R5 Cell line: MDCK (ATCC)
or MDCK Millicell ERS System- MDR1 (NKI) Millipore # MERS 000 01
Cell culture growth medium (MEM + 96-well U-shape plates (BH 10%
FBS + 1% NEAA): Bio# BH-04ML-96U) Trypsin-EDTA (Invitrogen, Cat#
96-well microplates 25200-072) (Greiner#655209) Assay and dosing
solution buffer: 37.quadrature. CO.sub.2 Incubator Hanks Balanced
Salt Solution (HBSS, Infinite F2000pro (TECAN) Invitrogen, Cat#
14025-092) with 25 mM HEPES, pH 7.4 Test article and reference
compound stock solutions were prepared in DMSO, Lucifer Yellow (LY)
stock solution was prepared in the assay buffer.
Cell Culture and Maintenance:
[1133] Cell stock cultures (MDCK or MDCK MDR1) are maintained in
MEM+10% FBS+1% NEAA, grown in 75 cm.sup.2 tissue culture treated
flasks and split (passed) 2 times weekly to maintain desired
confluence. [1134] For maintenance passage: trypsinized cells are
routinely distributed into new flasks at a standard passage ratio
of 1:20.
Seeding Assay Plates:
[1135] MDCK assay plates are seeded with MDCK or MDCK MCR1 cells
3-4 days prior to running the assay. 24-well plates are seeded at a
cell density of 0.88.times.10.sup.5/well in a 400 .mu.L apical
chamber volume (2.2.times.10.sup.5/mL) with a 25 mL volume of
growth medium to the 24-well basal chamber. Assay plates are
generally provided with a growth medium change 24 hours prior to
the assay.
Preparation of the Assay Plates and Trans-Epithelial Electrical
Resistance (TEER) Measurement:
[1136] MDCK assay plates are rinsed with HBSS+ prior to running the
assay. After rinsing, fresh HBSS+ is added to the assay plate in a
400 .mu.L apical chamber volume and a 0.8 mL HBSS+ basal chamber
volume. Measure the electrical resistance across the monolayer
using the Millicell ERS system ohm meter. (The cells will be used
if TEER is higher than 100 ohm*cm.sup.2).
Preparation of Dosing Solution.
[1137] Donor solutions are prepared in HBSS+ with 0.4% DMSO and 5
.mu.M test compound. The donor solution contains 5 .mu.M lucifer
yellow for apical dosing, but no lucifer yellow for basolateral
dosing. The donor solution may also contain 10 .mu.M GF120918 for
Pgp inhibition. Receiver solutions are prepared with HBSS+ with
0.4% DMSO. Donor and receiver solutions were centrifuged at 4000
rpm, 5 min, and supernatants were used for compound dosing.
Preparation of the Cell Plates:
[1138] Remove the buffer from the apical side and basolateral side.
Add 600 .mu.L of donor solution (for A-to-B) or 500 .mu.L of
receiver solution (for B-to-A) to the apical wells based on plate
map. [1139] A fresh basolateral plate is prepared by adding 800
.mu.L of receiver solution (for A-to-B) or 900 .mu.L of donor
solution (B-to-A) to the well of a new 24-well plate. [1140] Put
the apical plate and basolateral plate into a 37 .quadrature.
CO.sub.2 incubator.
Preparation of Analytical Plate:
[1140] [1141] After 5 min, transfer 100 .mu.L of samples from all
donors (for both A-to-B and B-to-A) into appropriate wells of a
sample plate for D0. And transfer 100 .mu.L of samples from all
apical chambers (the donor of A-to-B and receiver of B-to-A) into
appropriate wells of a microplate for Lucifer Yellow D0 (D0 LY)
[1142] Lay the apical plate to the basolateral plate to start
transport process. [1143] At 90 min, separate the apical and
basolateral plates and transfer 100 .mu.L of samples from all
donors (for both A-to-B and B-to-A) into appropriate wells of a new
sample plate for D90, and transfer 200 .mu.L of samples from all
receivers into appropriate wells of a sample plate for R90.
Transfer 100 .mu.L of samples from all basolateral chambers
(receiver of A-to-B and donor of B-to-A) into appropriate wells of
a new microplate for Lucifer Yellow R90 (R90 LY). [1144] Determine
LY permeability by reading D0 LY and R90 LY at an excitation
wavelength of 485 nm and an emission wavelength of 535 nm using a
fluorescent plate reader. [1145] LC/MS/MS Sample preparation:
[1146] For receiver solution: 60 .mu.L of sample+60 .mu.L ACN with
IS (200 ng/mL Osalmid) [1147] For donor solution: 6 of sample+54
.mu.L 0.4% DMSO/HBSS+60 .mu.L ACN with IS (200 ng/mL Osalmid)
[1148] The compound standard curve 20.times. solutions (0.1-60
.mu.M range) are prepared in MeOH:H.sub.2O (1:1). 1.times.
concentrated solutions (0.005-3 .mu.M range) are prepared by mixing
3 of 20.times. solution with 57 .mu.L 0.4% DMSO HBSS and 60 .mu.L
ACN with IS (200 ng/mL Osalmid).
Calculations
[1149] Transepithelial electrical
resistance(TEER)=(Resistance.sub.sample-Resistance.sub.blank).times.Effec-
tive Membrane Area
Lucifer Yellow permeability:
P.sub.app=(V.sub.A/(Area.times.time)).times.([RFU].sub.accepter-[RFU].su-
b.blank)/(([RFU].sub.initial,donor-[RFU].sub.blank).times.Dilution
Factor).times.100
Plate drug transport assays using the following equation:
Transepithelial electrical
resistance(TEER)=(Resistance.sub.sample-Resistance.sub.blank).times.Effec-
tive Membrane Area
Drug permeability:
P.sub.app=(V.sub.R/(Area.times.time)).times.([drug].sub.receiver/(([drug-
].sub.initial,donor).times.Dilution Factor)
Where V.sub.R is the volume in the receiver well (0.8 mL for A-to-B
and 0.4 mL for B-to-A), area is the surface area of the membrane
(0.7 cm.sup.2 for Millipore-24 Cell Culture Plates), and time is
the total transport time in seconds.
Percentage Recovery=100.times.(Total compound in donor at 90
min.times.Dilution Factor+Total compound in receiver at 90
min)/(Total compound in donor at 0 min.times.Dilution Factor)
INCORPORATION BY REFERENCE
[1150] All of the U.S. patents and U.S. patent application
publications cited herein are hereby
INCORPORATED BY REFERENCE
Equivalents
[1151] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are encompassed by the following
claims.
* * * * *