U.S. patent application number 17/221859 was filed with the patent office on 2021-08-12 for carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists.
The applicant listed for this patent is BRISTOL-MYERS SQUIBB COMPANY. Invention is credited to PETER TAI WAH CHENG, James R. Corte, Suresh Dhanusu, Tianan Fang, Sutjano Jusuf, Robert F. Kaltenbach, III, Lawrence J. Kennedy, Jun Li, Ramesh Babu Reddigunta, Kumaravel Selvakumar, Jun Shi, Yan Shi, Shiwei Tao, Steven J. Walker, Hao Zhang.
Application Number | 20210244711 17/221859 |
Document ID | / |
Family ID | 1000005495301 |
Filed Date | 2021-08-12 |
United States Patent
Application |
20210244711 |
Kind Code |
A1 |
CHENG; PETER TAI WAH ; et
al. |
August 12, 2021 |
CARBAMOYLOXYMETHYL TRIAZOLE CYCLOHEXYL ACIDS AS LPA ANTAGONISTS
Abstract
The present invention provides compounds of Formula (I):
##STR00001## or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates or prodrugs thereof, wherein all the
variables are as defined herein. These compounds are selective LPA
receptor inhibitors.
Inventors: |
CHENG; PETER TAI WAH;
(Princeton, NJ) ; Kaltenbach, III; Robert F.;
(Holland, PA) ; Li; Jun; (Pittsburgh, PA) ;
Shi; Jun; (San Diego, CA) ; Shi; Yan;
(Flourtown, PA) ; Tao; Shiwei; (Hillsborough,
NJ) ; Zhang; Hao; (Belle Mead, NJ) ; Dhanusu;
Suresh; (Tamil Nadu, IN) ; Selvakumar; Kumaravel;
(Bangalore, IN) ; Reddigunta; Ramesh Babu;
(Chittoor District, IN) ; Walker; Steven J.;
(Portage, MI) ; Kennedy; Lawrence J.; (Titusville,
NJ) ; Corte; James R.; (Yardley, PA) ; Fang;
Tianan; (Newtown, PA) ; Jusuf; Sutjano;
(Princeton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRISTOL-MYERS SQUIBB COMPANY |
Princeton |
NJ |
US |
|
|
Family ID: |
1000005495301 |
Appl. No.: |
17/221859 |
Filed: |
April 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16732387 |
Jan 2, 2020 |
11007180 |
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17221859 |
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16038739 |
Jul 18, 2018 |
10576062 |
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16732387 |
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15628104 |
Jun 20, 2017 |
10071078 |
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16038739 |
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62352792 |
Jun 21, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4192 20130101;
C07D 401/14 20130101; A61K 31/41 20130101; A61K 31/454 20130101;
A61K 31/27 20130101; C07C 62/10 20130101; C07D 401/04 20130101;
C07D 249/06 20130101 |
International
Class: |
A61K 31/4192 20060101
A61K031/4192; C07D 401/14 20060101 C07D401/14; C07D 249/06 20060101
C07D249/06; A61K 31/27 20060101 A61K031/27; A61K 31/454 20060101
A61K031/454; C07D 401/04 20060101 C07D401/04 |
Claims
1. A compound according to Formula (I): ##STR00476## or
stereoisomers, tautomers, a pharmaceutically acceptable salts,
solvates or prodrugs thereof, wherein R.sub.2 is independently
selected from H and C.sub.1-4 alkyl substituted with 1-5 R.sub.9;
R.sub.13 is independently selected from H, D, and C.sub.1-4 alkyl
substituted with 1-3 R.sub.9; R.sub.3 and R.sub.4 are independently
selected from H, C.sub.1-7 alkyl substituted with 1-3 R.sub.9,
--(CR.sub.7R.sub.7).sub.r--C.sub.3-8 cycloalkyl substituted with
1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3
R.sub.8, C.sub.2-7alkenyl substituted with 1-3 R.sub.9,
--(CR.sub.7R.sub.7).sub.r-5-6 membered heterocyclic ring
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-5-6
membered heteroaryl ring substituted with 1-3 R.sub.8, or R.sub.3
and R.sub.4 combine with the N to which they are attached to form a
4-9 membered heterocyclic ring substituted with 1-3 R.sub.8;
X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently selected
from CR.sub.5 and N; provided no more than two of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 are N; R.sub.5 is independently selected from
H, F, Cl, OR.sub.7, CN, N(R.sub.7).sub.2, C.sub.1-4 alkyl
substituted with 1-5 R.sub.9, C.sub.1-4 alkoxy substituted with 1-5
R.sub.9, and C.sub.1-4 heteroalkyl substituted with 1-5 R.sub.9;
R.sub.6 is C.sub.3-8 cycloalkyl which is substituted with R.sub.10
and (--CH.sub.2).sub.0-1R.sub.11; R.sub.7 is independently selected
from H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or R.sub.7 and
R.sub.7, together with the carbon atom to which they both attach,
form a C.sub.3-6 cycloalkyl ring; R.sub.8 is independently selected
from H, D, C.sub.1-6 alkyl substituted with 1-5 R.sub.9, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, phenyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, F, Cl, Br, CN, COOH, and C.sub.1-4 alkoxy; R.sub.9 is
independently selected from H, D, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.1-5 heteroalkyl C.sub.3-6
cycloalkyl, and phenyl, wherein when R.sub.9 is Cl, NH.sub.2 or OH
it is not substituted on C.sub.1 of the the alkyl to which it is
attached; R.sub.10 is independently selected from H, D, C.sub.1-4
alkyl, F, Cl, Br, OR.sub.7, NHC(.dbd.O)OR.sub.7, and
NHC(.dbd.O)OR.sub.7; R.sub.11 is independently selected from H, CN,
--C(.dbd.O)R.sub.12, tetrazolyl, ##STR00477## R.sub.12 is
independently selected from OH, OC.sub.1-4 alkyl, NH.sub.2,
NHCH.sub.2CH.sub.2SO.sub.3H, and NHSO.sub.2C.sub.1-4alky; r is
independently selected from zero, 1, 2, 3, and 4, and n is slected
from 1, 2, 3, or 4.
2. The compound of claim 1, wherein R.sub.3 and R.sub.4 are
independently selected from H, C.sub.1-7 alkyl substituted with 1-3
R.sub.9, --(CR.sub.7R.sub.7).sub.r--C.sub.3-8 cycloalkyl
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-aryl
substituted with 1-3 R.sub.8, C.sub.2-7alkenyl substituted with 1-3
R.sub.9, --(CR.sub.7R.sub.7).sub.r-5-6 membered heterocyclic ring
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-5-6
membered heteroaryl ring substituted with 1-3 R.sub.8, and R.sub.3
and R.sub.4 combine with the N to which they are attached to form
the following: ##STR00478## each of which may be substituted with
1-3 R.sub.8, and n equals 1 or 2.
3. The compound according to claim 1 wherein, R.sub.3 and R.sub.4
are independently selected from H, C.sub.1-7 alkyl substituted with
1-3 R.sub.9, --(CR.sub.7R.sub.7).sub.r--C.sub.3-8 cycloalkyl
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-aryl
substituted with 1-3 R.sub.8, C.sub.2-7alkenyl substituted with 1-3
R.sub.9, ##STR00479## each of which can be substituted with 1-3
R.sub.8, and R.sub.3 and R.sub.4 combine with the N to which they
are attached to form a 4-9 membered heterocyclic ring substituted
with 1-3 R.sub.8; and n equals 1 or 2.
4. A compound according to Formula (II): ##STR00480## or an
enantiomer, a diastereomer, a stereoisomer, a pharmaceutically
acceptable salt thereof, wherein R.sub.2 is independently selected
from H and C.sub.1-4 alkyl substituted with 1-5 R.sub.9; R.sub.13
is independently selected from H, D, and C.sub.1-4 alkyl
substituted with 1-3 R.sub.9; R.sub.3 and R.sub.4 are independently
selected from H, C.sub.1-7 alkyl substituted with 1-3 R.sub.9,
--(CR.sub.7R.sub.7).sub.r--C.sub.3-6 cycloalkyl substituted with
1-3 R.sub.8, and --(CR.sub.7R.sub.7).sub.r-aryl substituted with
1-3 R.sub.8; X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are
independently selected from CR.sub.5 and N; provided no more than
two of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 are N; R.sub.5 is
independently selected from H, F, Cl, OR.sub.7, CN,
N(R.sub.7).sub.2, C.sub.1-4 alkyl substituted with 1-5 R.sub.9,
C.sub.1-4 alkoxy substituted with 1-5 R.sub.9, and C.sub.1-4
heteroalkyl substituted with 1-5 R.sub.9; R.sub.6 is ##STR00481##
R.sub.7 is independently selected from H, C.sub.1-4 alkyl, and
C.sub.3-6 cycloalkyl; or R.sub.7 and R.sub.7, together with the
carbon atom to which they both attach, form a C.sub.3-6 cycloalkyl
ring; R.sub.8 is independently selected from H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.9, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, F, Cl, Br, CN, and COOH;
R.sub.9 is independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.1-5 heteroalkyl C.sub.3-6
cycloalkyl, and phenyl wherein when R.sub.9 is Cl, NH.sub.2 or OH
it is not substituted on C.sub.1 of the the alkyl to which it is
attached; R.sub.10 is independently selected from H, D, C.sub.1-4
alkyl, F, Cl, Br, ORS, NHC(.dbd.O)OR.sub.7, and
NHC(.dbd.O)OR.sub.7; R.sub.11 is independently selected from CN,
--C(.dbd.O)R.sub.12, tetrazolyl, ##STR00482## R.sub.12 is
independently selected from OH, OC.sub.1-4 alkyl, NH.sub.2,
NHCH.sub.2CH.sub.2SO.sub.3H, and NHSO.sub.2C.sub.1-4alky; r is
independently selected from zero, 1, 2, 3, and 4.
5. The compound of claim 4 having Formula (VII): ##STR00483## or an
enantiomer, a diastereomer, a stereoisomer, a pharmaceutically
acceptable salt thereof, wherein R.sub.2 is independently selected
from CH.sub.3 and CD.sub.3; R.sub.13 is independently selected from
H and C.sub.1-4 alkyl; R.sub.3 is independently selected from H and
C.sub.1-4 alkyl; R.sub.4 is independently selected from C.sub.1-6
alkyl substituted with 1-3 R.sub.9,
(CR.sub.7R.sub.7).sub.r--C.sub.3-6 cycloalkyl substituted with 1-3
R.sub.8, and --(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3
R.sub.8; R.sub.5 is independently selected from H, F, Cl, CN, and
C.sub.1-4 alkyl; R.sub.6 is ##STR00484## R.sub.7 is independently
selected from H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or
R.sub.7 and R.sub.7, together with the carbon atom to which they
both attach, form a C.sub.3-6 cycloalkyl ring; R.sub.8 is
independently selected from H, C.sub.1-6 alkyl substituted with 1-5
R.sub.9, C.sub.3-6 cycloalkyl, F, Cl, Br, CN, .dbd.O, and COOH;
R.sub.9 is independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and phenyl,
wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not substituted on
C.sub.1 of the the alkyl to which it is attached; R.sub.10 is
independently selected from H, C.sub.1-4 alkyl, and F; R.sub.11
independently selected from --C(.dbd.O)R.sub.12 and tetrazolyl;
R.sub.12 is independently selected from OH and
NHSO.sub.2C.sub.1-4alky; and r is independently selected from zero,
1, 2, 3, and 4.
6. The compound of claim 5, or an enantiomer, a diastereomer, a
stereoisomer, a pharmaceutically acceptable salt thereof, wherein
R.sub.2 is independently selected from CH.sub.3 and CD.sub.3;
R.sub.13 is independently selected from H and CH.sub.3; R.sub.3 is
independently selected from H and CH.sub.3; R.sub.4 is
independently selected from C.sub.1-6 alkyl, ##STR00485## R.sub.5
is independently selected from H, F, Cl, and C.sub.1-4 alkyl;
R.sub.6 is ##STR00486## R.sub.7 is independently selected from H,
C.sub.1-4 alkyl, and C.sub.1-6 cycloalkyl; and R.sub.8 is
independently selected from H, F, Cl, Br, CN, and C.sub.1-4
alkyl.
7. The compound of claim 5 having Formula (VIII): ##STR00487## or
an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically
acceptable salt thereof, wherein R.sub.2 is independently selected
from CH.sub.3 and CD.sub.3; R.sub.13 is independently selected from
H and CH.sub.3; R.sub.3 is independently selected from H and
CH.sub.3; R.sub.4 is independently selected from ##STR00488##
R.sub.5 is independently selected from H, F, and CH.sub.3; and
R.sub.8 is independently selected from H, F, Cl, Br, CN, and
C.sub.1-4 alkyl.
8. The compound of claim 4 having Formula (IX): ##STR00489## or an
enantiomer, a diastereomer, a stereoisomer, a pharmaceutically
acceptable salt thereof, wherein R.sub.2 is independently selected
from CH.sub.3 and CD.sub.3; R.sub.13 is independently selected from
H and C.sub.1-4 alkyl; R.sub.13 is independently selected from H
and C.sub.1-4 alkyl; R.sub.4 is independently selected from
C.sub.1-6 alkyl substituted with 1-3 R.sub.9,
(CR.sub.7R.sub.7).sub.r--C.sub.3-6 cycloalkyl substituted with 1-3
R.sub.8, and --(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3
R.sub.8; R.sub.5 is independently selected from H, F, Cl, CN, and
C.sub.1-4 alkyl; R.sub.6 is ##STR00490## R.sub.7 is independently
selected from H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or
R.sub.7 and R.sub.7, together with the carbon atom to which they
both attach, form a C.sub.3-6 cycloalkyl ring; R.sub.8 is
independently selected from H, C.sub.1-6 alkyl substituted with 1-5
R.sub.9, C.sub.3-6 cycloalkyl, F, Cl, Br, CN, .dbd.O, and COOH;
R.sub.9 is independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and phenyl,
wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not substituted on
C.sub.1 of the the alkyl to which it is attached; R.sub.10 is
independently selected from H and F; R.sub.11 is independently
selected from --C(.dbd.O)R.sub.12 and tetrazolyl; R.sub.12 is
independently selected from OH and --C(.dbd.O)NHSO.sub.2Me; and r
is independently selected from zero, 1, 2, 3, and 4.
9. A pharmaceutical composition comprising one or more compounds
according to claim 1 and a pharmaceutically acceptable carrier or
diluent.
10. A method of treating fibrosis in a mammal comprising
administering a therapeutically effective amount of a compound
according to claim 1 or a pharmaceutically acceptable salt thereof
to the mammal in need thereof.
11. A method of treating a disease, disorder, or condition in a
mammal comprising administering a therapeutically effective amount
of a compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, to the mammal in need thereof; wherein the
disease, disorder or condition is selected from pulmonary fibrosis,
asthma, chronic obstructive pulmonary disease (COPD), hepatic
fibrosis, renal fibrosis, arterial fibrosis, systemic sclerosis,
liver fibrosis, skin fibrosis, fibrosis of the gut, and ocular
fibrosis.
12. The method of claim 11, wherein the disease, disorder, or
condition is pulmonary fibrosis, hepatic fibrosis, renal fibrosis,
arterial fibrosis, or systemic sclerosis.
13. The method of claim 11, wherein the disease, disorder, or
condition is idiopathic pulmonary fibrosis (IPF).
14. The method of claim 11, wherein the disease, disorder, or
condition is non-alcoholic steatohepatitis (NASH).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/732,387, filed Jan. 2, 2020, now allowed,
which is a divisional application of U.S. patent application Ser.
No. 16/038,739, filed Jul. 18, 2018, now U.S. Pat. No. 10,576,062,
issued Mar. 3, 2020, which is a divisional application of U.S.
patent application Ser. No. 15/628,104, filed on Jun. 20, 2017, now
U.S. Pat. No. 10,071,078, issued Sep. 11, 2018, which claims
priority to U.S. Provisional Application Ser. No. 62/352,792, filed
Jun. 21, 2016, the entire content of which is incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel substituted triazole
compounds, compositions containing them, and methods of using them,
for example, for the treatment or prophylaxis of disorders
associated with one or more of the lysophosphatidic acid (LPA)
receptors.
BACKGROUND OF THE INVENTION
[0003] Lysophospholipids are membrane-derived bioactive lipid
mediators, of which one of the most medically important is
lysophosphatidic acid (LPA). LPA is not a single molecular entity
but a collection of endogenous structural variants with fatty acids
of varied lengths and degrees of saturation (Fujiwara et al., J
Biol. Chem., 2005, 280, 35038-35050). The structural backbone of
the LPAs is derived from glycerol-based phospholipids such as
phosphatidylcholine (PC) or phosphatidic acid (PA).
[0004] The LPAs are bioactive lipids (signaling lipids) that
regulate various cellular signaling pathways by binding to the same
class of 7-transmembrane domain G protein-coupled (GPCR) receptors
(Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors,
Lysophospholipid Receptors: Signaling and Biochemistry, 2013,
Wiley; ISBN: 978-0-470-56905-4 & Zhao, Y. et al, Biochim.
Biophys. Acta (BBA)--Mol. Cell Biol. Of Lipids, 2013, 1831, 86-92).
The currently known LPA receptors are designated as LPA1,
LPA.sub.2, LPA.sub.3, LPA.sub.4, LPA5 and LPA.sub.6 (Choi, J. W.,
Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186).
[0005] The LPAs have long been known as precursors of phospholipid
biosynthesis in both eukaryotic and prokaryotic cells, but the LPAs
have emerged only recently as signaling molecules that are rapidly
produced and released by activated cells, notably platelets, to
influence target cells by acting on specific cell-surface receptors
(see, e.g., Moolenaar et al., BioEssays, 2004, 26, 870-881, and van
Leewen et al., Biochem. Soc. Trans., 2003, 31, 1209-1212). Besides
being synthesized and processed to more complex phospholipids in
the endoplasmic reticulum, LPAs can be generated through the
hydrolysis of pre-existing phospholipids following cell activation;
for example, the sn-2 position is commonly missing a fatty acid
residue due to deacylation, leaving only the sn-1 hydroxyl
esterified to a fatty acid. Moreover, a key enzyme in the
production of LPA, autotaxin (lysoPLD/NPP2), may be the product of
an oncogene, as many tumor types up-regulate autotaxin (Brindley,
D., J. Cell Biochem. 2004, 92, 900-12). The concentrations of LPAs
in human plasma & serum as well as human bronchoalveolar lavage
fluid (BALF) have been reported, including determinations made
using sensitive and specific LC/MS & LC/MS/MS procedures (Baker
et al. Anal. Biochem., 2001, 292, 287-295; Onorato et al., J. Lipid
Res., 2014, 55, 1784-1796).
[0006] LPA influences a wide range of biological responses, ranging
from induction of cell proliferation, stimulation of cell migration
and neurite retraction, gap junction closure, and even slime mold
chemotaxis (Goetzl, et al., Scientific World J., 2002, 2, 324-338;
Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors,
Lysophospholipid Receptors: Signaling and Biochemistry, 2013,
Wiley; ISBN: 978-0-470-56905-4). The body of knowledge about the
biology of LPA continues to grow as more and more cellular systems
are tested for LPA responsiveness. For instance, it is now known
that, in addition to stimulating cell growth and proliferation,
LPAs promote cellular tension and cell-surface fibronectin binding,
which are important events in wound repair and regeneration
(Moolenaar et al., BioEssays, 2004, 26, 870-881). Recently,
anti-apoptotic activity has also been ascribed to LPA, and it has
recently been reported that PPAR.gamma. is a receptor/target for
LPA (Simon et al., J. Biol. Chem., 2005, 280, 14656-14662).
[0007] Fibrosis is the result of an uncontrolled tissue healing
process leading to excessive accumulation and insufficient
resorption of extracellular matrix (ECM) which ultimately results
in end-organ failure (Rockey, D. C., et al., New Engl. J. Med.,
2015, 372, 1138-1149). Recently it was reported that the LPA.sub.1
receptor was over-expressed in idiopathic pulmonary fibrosis (IPF)
patients. LPA.sub.1 receptor knockout mice were also protected from
bleomycin-induced lung fibrosis (Tager et al., Nature Med., 2008,
14, 45-54).
[0008] Thus, antagonizing the LPA.sub.1 receptor may be useful for
the treatment of fibrosis such as pulmonary fibrosis, hepatic
fibrosis, renal fibrosis, arterial fibrosis and systemic sclerosis,
and thus the diseases that result from fibrosis (pulmonary
fibrosis-Idiopathic Pulmonary Fibrosis [IPF], hepatic
fibrosis-Non-alcoholic Steatohepatitis [NASH], renal
fibrosis-diabetic nephropathy, systemic sclerosis-scleroderma,
etc.)
SUMMARY OF THE INVENTION
[0009] The present invention provides novel substituted triazole
compounds including stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates or prodrugs thereof, which are useful as
antagonists against one or more of the lysophosphatidic acid (LPA)
receptors, especially the LPA.sub.1 receptor.
[0010] The present invention also provides processes and
intermediates for making the compounds of the present
invention.
[0011] The present invention also provides pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and
at least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates or prodrugs thereof.
[0012] The compounds of the invention may be used in the treatment
and/or prophylaxis of conditions in which LPA plays a role.
[0013] The compounds of the present invention may be used in
therapy.
[0014] The compounds of the present invention may be used for the
manufacture of a medicament for the treatment and/or prophylaxis of
a condition in which inhibition of the physiological activity of
LPA is useful, such as diseases in which an LPA receptor
participates, is involved in the etiology or pathology of the
disease, or is otherwise associated with at least one symptom of
the disease.
[0015] In another aspect, the present invention is directed to a
method of treating fibrosis of organs (liver, kidney, lung, heart
and the like as well as skin), liver diseases (acute hepatitis,
chronic hepatitis, liver fibrosis, liver cirrhosis, portal
hypertension, regenerative failure, non-alcoholic steatohepatitis
(NASH), liver hypofunction, hepatic blood flow disorder, and the
like), cell proliferative disease [cancer (solid tumor, solid tumor
metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's
sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like)
and invasive metastasis of cancer cell, and the like], inflammatory
disease (psoriasis, nephropathy, pneumonia and the like),
gastrointestinal tract disease (irritable bowel syndrome (IBS),
inflammatory bowel disease (IBD), abnormal pancreatic secretion,
and the like), renal disease, urinary tract-associated disease
(benign prostatic hyperplasia or symptoms associated with
neuropathic bladder disease, spinal cord tumor, hernia of
intervertebral disk, spinal canal stenosis, symptoms derived from
diabetes, lower urinary tract disease (obstruction of lower urinary
tract, and the like), inflammatory disease of lower urinary tract,
dysuria, frequent urination, and the like), pancreas disease,
abnormal angiogenesis-associated disease (arterial obstruction and
the like), scleroderma, brain-associated disease (cerebral
infarction, cerebral hemorrhage, and the like), neuropathic pain,
peripheral neuropathy, and the like, ocular disease (age-related
macular degeneration (AMD), diabetic retinopathy, proliferative
vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma
filtration surgery scarring, and the like).
[0016] In another aspect, the present invention is directed to a
method of treating diseases, disorders, or conditions in which
activation of at least one LPA receptor by LPA contributes to the
symptomology or progression of the disease, disorder or
condition.
[0017] These diseases, disorders, or conditions may arise from one
or more of a genetic, iatrogenic, immunological, infectious,
metabolic, oncological, toxic, surgical, and/or traumatic
etiology.
[0018] In another aspect, the present invention is directed to a
method of treating renal fibrosis, pulmonary fibrosis, hepatic
fibrosis, arterial fibrosis and systemic sclerosis comprising
administering to a patient in need of such treatment a compound of
the present invention as described above.
[0019] In one aspect, the present invention provides methods,
compounds, pharmaceutical compositions, and medicaments described
herein that comprise antagonists of LPA receptors, especially
antagonists of LPA1.
[0020] The compounds of the invention can be used alone, in
combination with other compounds of the present invention, or in
combination with one or more, preferably one to two other
agent(s).
[0021] These and other features of the invention will be set forth
in expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE INVENTION
I. COMPOUNDS OF THE INVENTION
[0022] In one aspect, the present invention provides, inter alia,
compounds of Formula (I):
##STR00002##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates or prodrugs thereof, wherein [0023] R.sub.2 is
independently selected from H and C.sub.1-4 alkyl substituted with
1-5 R.sub.9; [0024] R.sub.13 is independently selected from H, D,
and C.sub.1-4 alkyl substituted with 1-3 R.sub.9; [0025] R.sub.3
and R.sub.4 are independently selected from H, C.sub.1-7 alkyl
substituted with 1-3 R.sub.9, --(CR.sub.7R.sub.7).sub.r--C.sub.3-8
cycloalkyl substituted with 1-3 R.sub.8,
--(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3 R.sub.8,
C.sub.2-7alkenyl substituted with 1-3 R.sub.9,
--(CR.sub.7R.sub.7).sub.r-5-6 membered heterocyclic ring
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-5-6
membered heteroaryl ring substituted with 1-3 R.sub.8, or R.sub.3
and R.sub.4 combine with the N to which they are attached to form a
4-9 membered heterocyclic ring substituted with 1-3 R.sub.8; [0026]
X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently selected
from CR.sub.5 and N; provided no more than two of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 are N; [0027] R.sub.5 is independently selected
from H, F, Cl, OR.sub.7, CN, N(R.sub.7).sub.2, C.sub.1-4 alkyl
substituted with 1-5 R.sub.9, C.sub.1-4 alkoxy substituted with 1-5
R.sub.9, and C.sub.1-4 heteroalkyl substituted with 1-5 R.sub.9;
[0028] R.sub.6 is C.sub.3-8 cycloalkyl which is substituted with
R.sub.10 and (--CH.sub.2).sub.0-1R.sub.11; [0029] R.sub.7 is
independently selected from H, C.sub.1-4 alkyl, and C.sub.3-6
cycloalkyl; or R.sub.7 and R.sub.7, together with the carbon atom
to which they both attach, form a C.sub.3-6 cycloalkyl ring; [0030]
R.sub.8 is independently selected from H, D, C.sub.1-6 alkyl
substituted with 1-5 R.sub.9, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
phenyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, F, Cl, Br, CN,
COOH, and C.sub.1-4 alkoxy; [0031] R.sub.9 is independently
selected from H, D, F, Cl, NH.sub.2, OH, OC.sub.1-5alkyl,
C.sub.1-5alkyl, C.sub.1-5 heteroalkyl C.sub.3-6 cycloalkyl, and
phenyl, wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not
substituted on C.sub.1 of the the alkyl to which it is attached;
[0032] R.sub.10 is independently selected from H, D, C.sub.1-4
alkyl, F, Cl, Br, OR.sub.7, NHC(.dbd.O)OR.sub.7, and
NHC(.dbd.O)OR.sub.7; [0033] R.sub.11 is independently selected from
H, CN, --C(.dbd.O)R.sub.12, tetrazolyl,
[0033] ##STR00003## [0034] R.sub.12 is independently selected from
OH, OC.sub.1-4 alkyl, NH.sub.2, NHCH.sub.2CH.sub.2SO.sub.3H, and
NHSO.sub.2C.sub.1-4alkyl; [0035] r is independently selected from
zero, 1, 2, 3, and 4, [0036] and n is slected from 1, 2, 3, or
4.
[0037] In another embodiment, the present invention includes
compounds of Formula (I), wherein
[0038] R.sub.3 and R.sub.4 are independently selected from H,
C.sub.1-7 alkyl substituted with 1-3 R.sub.9,
--(CR.sub.7R.sub.7).sub.r--C.sub.3-8 cycloalkyl substituted with
1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3
R.sub.8, C.sub.2-7alkenyl substituted with 1-3 R.sub.9,
--(CR.sub.7R.sub.7).sub.r-5-6 membered heterocyclic ring
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-5-6
membered heteroaryl ring substituted with 1-3 R.sub.8, and R.sub.3
and R.sub.4 combine with the N to which they are attached to form
the following:
##STR00004##
each of which may be substituted with 1-3 R.sub.8, and [0039] n
equals 1 or 2.
[0040] In another embodiment, the present invention includes
compounds of Formula (I) wherein, R.sub.3 and R.sub.4 are
independently selected from H, C.sub.1-7 alkyl substituted with 1-3
R.sub.9, --(CR.sub.7R.sub.7).sub.r--C.sub.3-8 cycloalkyl
substituted with 1-3 R.sub.8, --(CR.sub.7R.sub.7).sub.r-aryl
substituted with 1-3 R.sub.8, C.sub.2-7alkenyl substituted with 1-3
R.sub.9,
##STR00005##
each of which can be substituted with 1-3 R.sub.8, and R.sub.3 and
R.sub.4 combine with the N to which they are attached to form a 4-9
membered heterocyclic ring substituted with 1-3 R.sub.8; and [0041]
n equals 1 or 2.
[0042] In another embodiment, the present invention includes
compounds of Formula (II):
##STR00006##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0043] R.sub.2 is
independently selected from H and C.sub.1-4 alkyl substituted with
1-5 R.sub.9; [0044] R.sub.13 is independently selected from H, D,
and C.sub.1-4 alkyl substituted with 1-3 R.sub.9; [0045] R.sub.3
and R.sub.4 are independently selected from H, C.sub.1-7 alkyl
substituted with 1-3 R.sub.9, --(CR.sub.7R.sub.7).sub.r--C.sub.3-6
cycloalkyl substituted with 1-3 R.sub.8, and
--(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3 R.sub.8; [0046]
X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently selected
from CR.sub.5 and N; provided no more than two of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 are N; [0047] R.sub.5 is independently selected
from H, F, Cl, OR.sub.7, CN, N(R.sub.7).sub.2, C.sub.1-4 alkyl
substituted with 1-5 R.sub.9, C.sub.1-4 alkoxy substituted with 1-5
R.sub.9, and C.sub.1-4 heteroalkyl substituted with 1-5 R.sub.9;
[0048] R.sub.6 is
[0048] ##STR00007## [0049] R.sub.7 is independently selected from
H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or R.sub.7 and
R.sub.7, together with the carbon atom to which they both attach,
form a C.sub.3-6 cycloalkyl ring; [0050] R.sub.8 is independently
selected from H, C.sub.1-6 alkyl substituted with 1-5 R.sub.9,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, F, Cl, Br, CN, .dbd.O, and CO.sub.2H; [0051] R.sub.9 is
independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.1-5 heteroalkyl C.sub.3-6
cycloalkyl, and phenyl, wherein when R.sub.9 is Cl, NH.sub.2 or OH
it is not substituted on C.sub.1 of the the alkyl to which it is
attached; [0052] R.sub.10 is independently selected from H, D,
C.sub.1-4 alkyl, F, Cl, Br, OR.sub.7, NHC(.dbd.O)OR.sub.7, and
NHC(.dbd.O)R.sub.7; [0053] R.sub.11 is independently selected from
CN, --C(.dbd.O)R.sub.12, tetrazolyl,
[0053] ##STR00008## [0054] R.sub.12 is independently selected from
OH, OC.sub.1-4 alkyl, NH.sub.2, NHCH.sub.2CH.sub.2SO.sub.3H, and
NHSO.sub.2C.sub.1-4alkyl; and [0055] r is independently selected
from zero, 1, 2, 3, and 4.
[0056] In another aspect, the present invention provides compounds
of Formula (III):
##STR00009##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0057] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0058] R.sub.13
is independently selected from H and C.sub.1-4 alkyl; [0059]
R.sub.3 is independently selected from H and C.sub.1-4 alkyl;
[0060] R.sub.4 is independently selected from C.sub.1-6 alkyl
substituted with 1-3 R.sub.9, --(CR.sub.7R.sub.7).sub.r--C.sub.3-6
cycloalkyl substituted with 1-3 R.sub.8, and
--(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3 R.sub.8; [0061]
R.sub.5 is independently selected from H, F, Cl, CN and C.sub.1-4
alkyl; provided one of R.sub.5 is H; [0062] R.sub.6 is
[0062] ##STR00010## [0063] R.sub.7 is independently selected from
H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or R.sub.7 and
R.sub.7, together with the carbon atom to which they both attach,
form a C.sub.3-6 cycloalkyl ring; [0064] R.sub.8 is independently
selected from H, C.sub.1-6 alkyl substituted with 1-5 R.sub.9,
C.sub.3-6 cycloalkyl, F, Cl, Br, CN, .dbd.O, and COOH; [0065]
R.sub.9 is independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and phenyl,
wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not substituted on
C.sub.1 of the the alkyl to which it is attached; [0066] R.sub.10
is independently selected from H, D, C.sub.1-4 alkyl, and F; [0067]
R.sub.11 is independently selected from CN, --C(.dbd.O)R.sub.12,
and tetrazolyl; [0068] R.sub.12 is independently selected from OH,
OC.sub.1-4 alkyl, NH.sub.2, and NHSO.sub.2C.sub.1-4alkyl; and
[0069] r is independently selected from zero, 1, 2, 3, and 4.
[0070] In another aspect, the present invention provides compounds
of Formula (IV):
##STR00011##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0071] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0072] R.sub.13
is independently selected from H and C.sub.1-4 alkyl; [0073]
R.sub.3 is independently selected from H and C.sub.1-4 alkyl;
[0074] R.sub.4 is independently selected from C.sub.1-6 alkyl,
[0074] ##STR00012## [0075] R.sub.5 is independently selected from
H, F, Cl, and C.sub.1-4 alkyl; provided one of R.sub.5 is H; [0076]
R.sub.7 is independently selected from H, C.sub.1-4 alkyl, and
C.sub.3-6 cycloalkyl; [0077] R.sub.8 is independently selected from
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.9, C.sub.3-6
cycloalkyl, F, Cl, Br, CN, .dbd.O, and COOH; [0078] R.sub.9 is
independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and phenyl,
wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not substituted on
C.sub.1 of the the alkyl to which it is attached; [0079] R.sub.10
is independently selected from H, D, C.sub.1-4 alkyl, and F; [0080]
R.sub.11 is independently selected from CN, --C(.dbd.O)R.sub.12,
and
##STR00013##
[0080] and [0081] R.sub.12 is independently selected from OH,
NH.sub.2 and NHSO.sub.2C.sub.1-4alkyl.
[0082] In another aspect, the present invention provides compounds
of Formula (III) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein [0083]
R.sub.4 is independently selected from
##STR00014##
[0083] and [0084] R.sub.8 is independently selected from H, F, Cl,
Br, CN, and C.sub.1-4 alkyl; and
[0085] other variables are as defined in Formula (IV).
[0086] In another aspect, the present invention provides compounds
of Formula (V):
##STR00015##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0087] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0088] R.sub.13
is independently selected from H and CH.sub.3; [0089] R.sub.3 is
independently selected from H and CH.sub.3; [0090] R.sub.4 is
independently selected from
##STR00016##
[0090] and [0091] R.sub.5 is independently selected from H, F, and
C.sub.1-4 alkyl; [0092] R.sub.8 is independently selected from H,
F, Cl, Br, CN, and C.sub.1-4 alkyl; [0093] R.sub.10 is
independently selected from H, D, and F; and [0094] R.sub.11 is
independently selected from --C(.dbd.O)OH, and
--C(.dbd.O)NHSO.sub.2Me.
[0095] In another aspect, the present invention provides compounds
of Formula (VI):
##STR00017##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0096] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0097] R.sub.13
is independently selected from H and CH.sub.3; [0098] R.sub.3 is
independently selected from H and CH.sub.3; [0099] R.sub.4 is
independently selected from
[0099] ##STR00018## [0100] R.sub.5 is independently selected from H
and CH.sub.3; and [0101] R.sub.8 is independently selected from H,
F, Cl, Br, CN, and C.sub.1-4 alkyl.
[0102] In another aspect, the present invention provides compounds
of Formula (VII):
##STR00019##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0103] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0104] R.sub.13
is independently selected from H and C.sub.1-4 alkyl; [0105]
R.sub.3 is independently selected from H and C.sub.1-4 alkyl;
[0106] R.sub.4 is independently selected from C.sub.1-6 alkyl
substituted with 1-3 R.sub.9, (CR.sub.7R.sub.7).sub.r--C.sub.3-6
cycloalkyl substituted with 1-3 R.sub.8, and
--(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3 R.sub.8; [0107]
R.sub.5 is independently selected from H, F, Cl, CN, and C.sub.1-4
alkyl; [0108] R.sub.6 is
[0108] ##STR00020## [0109] R.sub.7 is independently selected from
H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or R.sub.7 and
R.sub.7, together with the carbon atom to which they both attach,
form a C.sub.3-6 cycloalkyl ring; [0110] R.sub.8 is independently
selected from H, C.sub.1-6 alkyl substituted with 1-5 R.sub.9,
C.sub.3-6 cycloalkyl, F, Cl, Br, CN, .dbd.O, and COOH; [0111]
R.sub.9 is independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and phenyl,
wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not substituted on
C.sub.1 of the the alkyl to which it is attached; [0112] R.sub.10
is independently selected from H, C.sub.1-4 alkyl, and F; [0113]
R.sub.11 is independently selected from CN, --C(.dbd.O)R.sub.12,
tetrazolyl,
[0113] ##STR00021## [0114] R.sub.12 is independently selected from
OH, OC.sub.1-4 alkyl, NH.sub.2, NHCH.sub.2CH.sub.2SO.sub.3H, and
NHSO.sub.2C.sub.1-4alkyl; and [0115] r is independently selected
from zero, 1, 2, 3, and 4.
[0116] In another aspect, the present invention provides compounds
of Formula (VI) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein [0117]
R.sub.1 is independently selected from CH.sub.3 and CD.sub.3;
[0118] R.sub.2 is independently selected from H and CH.sub.3;
[0119] R.sub.3 is independently selected from H and CH.sub.3;
[0120] R.sub.4 is independently selected from C.sub.1-6 alkyl,
[0120] ##STR00022## [0121] R.sub.5 is independently selected from
H, F, Cl, and C.sub.1-4 alkyl; [0122] R.sub.6 is
[0122] ##STR00023## [0123] R.sub.7 is independently selected from
H, C.sub.1-4 alkyl, and C.sub.1-6 cycloalkyl; and [0124] R.sub.8 is
independently selected from H, F, Cl, Br, CN, and C.sub.1-4
alkyl.
[0125] In another aspect, the present invention provides compounds
of Formula (VIII):
##STR00024##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0126] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0127] R.sub.13
is independently selected from H and CH.sub.3; [0128] R.sub.3 is
independently selected from H and CH.sub.3; [0129] R.sub.4 is
independently selected from
[0129] ##STR00025## [0130] R.sub.5 is independently selected from
H, F, and CH.sub.3; and [0131] R.sub.8 is independently selected
from H, F, Cl, Br, CN, and C.sub.1-4 alkyl.
[0132] In another aspect, the present invention provides compounds
of Formula (IX):
##STR00026##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein [0133] R.sub.2 is
independently selected from CH.sub.3 and CD.sub.3; [0134] R.sub.13
is independently selected from H and C.sub.1-4 alkyl; [0135]
R.sub.3 is independently selected from H and C.sub.1-4 alkyl;
[0136] R.sub.4 is independently selected from C.sub.1-6 alkyl
substituted with 1-3 R.sub.9, (CR.sub.7R.sub.7).sub.r--C.sub.3-6
cycloalkyl substituted with 1-3 R.sub.8, and
--(CR.sub.7R.sub.7).sub.r-aryl substituted with 1-3 R.sub.8; [0137]
R.sub.5 is independently selected from H, F, Cl, CN, and C.sub.1-4
alkyl; [0138] R.sub.6 is independently selected from
[0138] ##STR00027## [0139] R.sub.7 is independently selected from
H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; or R.sub.7 and
R.sub.7, together with the carbon atom to which they both attach,
form a C.sub.3-6 cycloalkyl ring; [0140] R.sub.8 is independently
selected from H, C.sub.1-6 alkyl substituted with 1-5 R.sub.9,
C.sub.3-6 cycloalkyl, F, Cl, Br, CN, .dbd.O, and COOH; [0141]
R.sub.9 is independently selected from H, F, Cl, NH.sub.2, OH,
OC.sub.1-5alkyl, C.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and phenyl,
wherein when R.sub.9 is Cl, NH.sub.2 or OH it is not substituted on
C.sub.1 of the the alkyl to which it is attached; [0142] R.sub.10
is independently selected from H, and F, [0143] R.sub.11 is
independently selected from CN, --C(.dbd.O)R.sub.12,
tetrazolyl,
[0143] ##STR00028## [0144] R.sub.12 is independently selected from
OH, OC.sub.1-4 alkyl, NH.sub.2, NHCH.sub.2CH.sub.2SO.sub.3H, and
NHSO.sub.2C.sub.1-4alkyl; and [0145] r is independently selected
from zero, 1, 2, 3, and 4.
[0146] In yet another embodiment, the present invention includes a
compound of Formula (I) or (II) selected from the group of:
##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033##
or an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0147] In yet another embodiment, the present invention includes a
compound of Formula (I) or (II) selected from the group of:
##STR00034## ##STR00035## ##STR00036##
or an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0148] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00037##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0149] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00038##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0150] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00039##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0151] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00040##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0152] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00041##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0153] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00042##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0154] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00043##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0155] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00044##
or an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0156] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00045##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0157] In yet another embodiment, the present invention includes
compound of Formula (I) or (II) wherein said compound has the
formula:
##STR00046##
an enantiomer, a diastereomer, a stereoisomer, or a
pharmaceutically acceptable salt thereof.
[0158] For any and all of the embodiments, substituents are
selected from among from a subset of the listed alternatives. For
example, in some embodiments, R.sub.12 is --OH, --OC.sub.1-4 alkyl,
or --NHSO.sub.2C.sub.1-4 alkyl. In some embodiments, R.sub.12 is
--OH or --OC.sub.1-4 alkyl. In some embodiments, R.sub.12 is --OH.
In some embodiments, R.sub.12 is --OC.sub.1-4 alkyl. In some
embodiments, R.sub.12 is --OCH.sub.3 or --OCH.sub.2CH.sub.3. In
some embodiments, R.sub.12 is --NHSO.sub.2C.sub.1-4alkyl.
[0159] In some embodiments, R.sub.3 is C.sub.1-4 alkyl; R.sub.5 is
H or C.sub.1-4 alkyl. In some embodiments, R.sub.12 is --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3 or
--NHSO.sub.2CH.sub.2CH.sub.3; R.sub.3 is --CH.sub.3, CD.sub.3 or
--CH.sub.2CH.sub.3. In some embodiments, R.sub.12 is --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3 or
--NHSO.sub.2CH.sub.2CH.sub.3; R.sub.3 is --CH.sub.3, CD.sub.3, or
--CH.sub.2CH.sub.3; R.sub.5 is H or C.sub.1-4 alkyl.
[0160] In some embodiments, R.sub.4 is
##STR00047##
wherein
##STR00048##
is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,
3-ethylphenyl, 4-ethylphenyl, 2-deuteromethylphenyl,
3-deuteromethylphenyl, 4-deuteromethylphenyl,
2-monofluoromethylphenyl, 3-monofluoromethylphenyl,
4-monofluoromethylphenyl, 2-difluoromethylphenyl,
3-difluoromethylphenyl, 4-difluoromethylphenyl,
2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropylphenyl,
2-cyclobutylphenyl, 3-cyclobutylphenyl, 4-cyclobutylphenyl,
2-cyclopentylphenyl, 3-cyclopentylphenyl, 4-cyclopentylphenyl,
2-cyclohexylphenyl, 3-cyclohexylphenyl or 4-cyclohexylphenyl.
[0161] In some embodiments, R.sub.4 is
--(CHR.sub.7).sub.r--C.sub.3-6 cycloalkyl and r is 0, 1, or 2, and
R.sub.7 is H or methyl. In some embodiments, r is 0, R.sub.4 is
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and R.sub.7 is
H or methyl. In some embodiments, r is 1, R.sub.4 is cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl, R.sub.7 is H or methyl.
[0162] In some embodiments, R.sub.3 is C.sub.1-4 alkyl, R.sub.4 is
--(CHR.sub.7).sub.r--C.sub.3-6 cycloalkyl, and r is 0, 1, or 2, and
R.sub.7 is H or methyl. In some embodiments, R.sub.3 is --CH.sub.3,
CD.sub.3, or --CH.sub.2CH.sub.3, R.sub.4 is cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl, r is 0 or 1, and R.sub.7 is
H or methyl. In some embodiments, R.sub.3 is --CH.sub.3, R.sub.4 is
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, r is 1, R.sub.7
is H or methyl.
[0163] In some embodiments, R.sub.3 is C.sub.1-4 alkyl, R.sub.4 is
C.sub.1-4 alkyl, and R.sub.7 is H or methyl. In some embodiments,
R.sub.3 is --CH.sub.3, CD.sub.3, or --CH.sub.2CH.sub.3, R.sub.4 is
--CH.sub.3, CD.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
or --CH(CH.sub.3).sub.3, and R.sub.7 is H or methyl. In some
embodiments, R.sub.3 is --CH.sub.3, R.sub.4 is --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
or --CH(CH.sub.3).sub.3, R.sub.7 is H or methyl.
[0164] In some embodiments, R.sub.1 is H or C.sub.1-2 alkyl,
R.sub.2 is H or C.sub.1-2 alkyl, R.sub.3 is C.sub.1-2 alkyl,
R.sub.4 is --(CHR.sub.7).sub.r--C.sub.3-6 cycloalkyl and r is 1,
R.sub.5 is H or C.sub.1-2 alkyl, R.sub.6 is cyclopentyl or
cyclohexyl, R.sub.7 is H or C.sub.1-2 alkyl, R.sub.8 is H, R.sub.9
is H, R.sub.10 is H, and R.sub.11 is --C(.dbd.O)OH.
[0165] In some embodiments, R.sub.1 is H or methyl, R.sub.2 is H or
methyl, R.sub.3 is methyl, R.sub.4 is --CHR.sub.7-cyclopropyl,
--CHR.sub.7-cyclobutyl, --CHR.sub.7-cyclopentyl, or
--CHR.sub.7-cyclohexyl, R.sub.5 is H or methyl, R.sub.6 is
cyclohexyl, R.sub.7 is H or methyl, R.sub.8 is H, R.sub.9 is H,
R.sub.10 is H, and R.sub.11 is --C(.dbd.O)OH.
[0166] In some embodiments, the pharmaceutically acceptable salt of
the compound of Formulas (I)-(IX) is a sodium salt.
[0167] Any combination of the groups described above for the
various variables is contemplated herein. Throughout the
specification, groups and substituents thereof are chosen by one
skilled in the field to provide stable moieties and compounds.
[0168] In another aspect, the present invention provides a compound
selected from any subset list of compounds exemplified in the
present application.
[0169] In another embodiment, the present invention includes
compounds of Formula (X):
##STR00049##
[0170] or an enantiomer, a diastereomer, or a stereoisomer thereof,
wherein
[0171] R.sub.20 is independently selected from C.sub.1-6 alkyl or
H;
[0172] R.sub.21 is independently selected from C.sub.1-6 alkyl or
H;
[0173] X.sup.5 and X.sup.6 are independently selected from CH or N;
and
[0174] X.sup.7 is selected from Cl, Br, or F. [0175] In another
embodiment, the present invention includes compounds of Formula
(XI):
##STR00050##
[0175] or an enantiomer, a diastereomer, or a stereoisomer
thereof.
[0176] In another aspect, the present invention provides a compound
selected from the list below:
[0177]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (1)
[0178]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (2)
[0179]
(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxyli-
c acid (3)
[0180]
trans-3-(4-(5-(((cyclopentyl(methypcarbamoyl)oxy)methyl)-1-methyl-1-
H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (4)
[0181]
(1S,3S)-3-(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid (5)
[0182]
(1R,3R)-3-(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid (6)
[0183]
(1-Methyl-4-(4-((1S,3S)-3-((methylsulfonyl)carbamoyl)cyclohexyl)oxy-
)phenyl)-1H-1,2,3-triazol-5-yl)methyl cyclopentyl(methyl)carbamate
(7)
[0184] No names for (8) and (9)
[0185]
(1S,3S)-3-(4-(1-Methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)ox-
y)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid
(10)
[0186]
3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-c-
arboxylic acid (11)
[0187]
(1S,3S)-3-(4-(5-(1-(((cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (12)
[0188]
3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-c-
arboxylic acid (13)
[0189]
(4-(5-(((1S,3S)-3-carbamoylcyclohexyl)oxy)-6-methylpyridin-2-yl)-1--
methyl-1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate (14)
[0190]
(4-(5-(((1S,3S)-3-cyanocyclohexyl)oxy)-6-methylpyridin-2-yl)-1-meth-
yl-1H-1,2,3-triazol-5-yl)methyl (cyclobutylmethyl)(methyl)carbamate
(15)
[0191]
(4-(5-(((1S,3S)-3-(1H-tetrazol-5-yl)cyclohexyl)oxy)-6-methylpyridin-
-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate (16)
[0192]
(1-methyl-4-(6-methyl-5-(((1S,3S)-3-((methylsulfonyl)carbamoyl)cycl-
ohexyl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate (17)
[0193]
3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,-
2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(18),
[0194]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((R)-1-phenylethyl)carb-
amoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-car-
boxylic acid (19),
[0195]
(1S,3S)-3-((6-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (20),
[0196]
(1S,3S)-3-((6-(1-methyl-5-(((methyl((R)-1-phenylethyl)carbamoyl)oxy-
)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (21),
[0197]
(1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(22),
[0198]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (23),
[0199]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)methy-
l)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (24),
[0200]
(1S,3S)-3-((6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (25),
[0201]
(1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic acid
(26),
[0202]
(1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic
acid (27),
[0203]
(1S,3S)-3-(2-fluoro-4-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (28),
[0204]
(1S,3S)-3-((6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (29),
[0205]
(1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (30),
[0206]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)-
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxyli-
c acid (31),
[0207]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (32),
[0208]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxyli-
c acid (33),
[0209]
(1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (34),
[0210]
(1S,3S)-3-((6-(5-(4(4-chlorobenzyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (35),
[0211]
(1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)me-
thyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carbox-
ylic acid (36),
[0212]
(1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic
acid (37),
[0213]
(1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic acid
(38),
[0214]
(1S,3S)-3-(2-methyl-4-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (39),
[0215]
(1S,3S)-3-(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1-
,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic acid
(40),
[0216]
(1S,3S)-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic
acid (41),
[0217]
(1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)-4-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (42),
[0218]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(43),
[0219]
(1S,3S)-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic
acid (44),
[0220]
(1S,3S)-3-(4-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic
acid (45),
[0221]
(1S,3S)-3-(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1-
,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic acid
(46),
[0222]
(1S,3S)-3-(2-fluoro-4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (47),
[0223]
(1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (isomer 1) (48),
[0224]
(1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (isomer 2) (49),
[0225]
(1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (50),
[0226]
(1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)me-
thyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (51),
[0227]
(1S,3S)-3-(4-(5-(((((S)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)me-
thyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (52),
[0228]
(1S,3S)-3-(4-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1-
H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(53),
[0229]
(1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (54),
[0230]
(1S,3S)-3-(4-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (55),
[0231]
(1S,3S)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic
acid (56),
[0232]
(1S,3S)-3-(4-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)methyl-
)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(57),
[0233]
(1S,3S)-3-(4-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H--
1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (58),
[0234]
(1S,3S)-3-(4-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H--
1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (59),
[0235]
(1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (60),
[0236]
(1S,3S)-3-(4-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (61),
[0237]
(1R,3R)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(62),
[0238]
(1R,3R)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic
acid (63),
[0239]
(1S,3S)-3-(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1-
,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (64),
[0240]
(1S,3S)-3-(4-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (65),
[0241]
(1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (66),
[0242]
(1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (67),
[0243]
(1S,3S)-3-(4-(5-(((sec-butyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(68),
[0244]
(3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic-1-d acid (69),
[0245]
(1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)me-
thyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carbox-
ylic acid (70),
[0246]
(1S,3S)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(71),
[0247]
(1-Methyl-4-(4-(((1R,3R)-3-((methylsulfonyl)carbamoyl)cyclohexyl)ox-
y)phenyl)-1H-1,2,3-triazol-5-yl)methyl cyclopentyl(methyl)carbamate
(72),
[0248]
(1S,3S)-3-(4-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(73),
[0249]
(1S,3S)-3-(4-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic
acid (74),
[0250]
(1S,3S)-3-(4-(1-methyl-5-(((methyl(1-propylcyclopropyl)carbamoyl)ox-
y)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic
acid (75),
[0251]
(1S,3S)-3-(4-(1-methyl-5-(((methyl(pentan-3-yl)carbamoyl)oxy)methyl-
)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(76),
[0252]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(pentan-3-yl)carbamoyl)oxy)methy-
l)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (77),
[0253]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (78),
[0254]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(1-methylcyclopropyl)carbamoyl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (79),
[0255]
(1S,3S)-3-((6-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)meth-
yl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic
acid (80),
[0256]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(1-propylcyclopropyl)carbamoyl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (81, 82),
[0257]
(1S,3S)-3-((2-Methyl-6-(1-methyl-5-(((methyl(pentan-3-yl)carbamoyl)-
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic
acid (83),
[0258]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(2-methylpentan-2-yl)ca-
rbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarb-
oxylic acid (84),
[0259]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-methylcyclopropyl)ca-
rbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (85),
[0260]
(1S,3S)-3-((6-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)meth-
yl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexaneca-
rboxylic acid (86),
[0261]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-propylcyclopropyl)ca-
rbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (87),
[0262]
(rac)-trans-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexan-
e-1-carboxylic acid (88),
[0263]
trans-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic
acid (89),
[0264]
trans-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)-1-fluorocyclohexane-1-carb-
oxylic acid (90),
[0265]
trans-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (91),
[0266]
cis-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-m-
ethyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (92),
[0267]
cis-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-m-
ethyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclopentane-1-carbo-
xylic acid (93),
[0268]
(1S,3S)-3-(4-(5-(1-((cyclopentyl(methyl)carbamoyl)oxy)ethyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(94),
[0269]
(Cis)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (Enantiomer A, 95),
[0270]
(Cis)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (Enantiomer B, 96),
[0271]
(1R,3R)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (97),
[0272]
(1S,3S)-3-((6-(5-((((2-fluorobenzyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (98),
[0273]
(1S,3S)-3-((6-(5-((((1-cyclobutylpropyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (99),
[0274]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-phenylcyclopropyl)ca-
rbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (100),
[0275]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)-
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-
-carboxylic acid (101),
[0276]
(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)-
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexa-
ne-1-carboxylic acid (102),
[0277]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(phenethyl)carbamoyl)ox-
y)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (103),
[0278]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)m-
ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (104),
[0279]
(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-car-
boxylic acid (105),
[0280]
(1S,3S)-3-((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (Enantiomer A, 106)
[0281]
(1S,3S)-3-((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (Enantiomer B, 107),
[0282]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (108),
[0283]
(1S,3S)-3-((6-(5-((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (109),
[0284]
(1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (110),
[0285]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-(met-
hyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (111),
[0286]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3-
)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (112),
[0287]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (113),
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl-d3)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (114),
[0288]
(3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic-1-d acid (115),
[0289]
(1S,3S)-3-((6-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (116),
[0290]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((tetrahydro-2H-pyran-4-
-yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cy-
clohexane-1-carboxylic acid (117),
[0291]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-2-ylmethyl)car-
bamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (118),
[0292]
(1S,3S)-3-((6-(5-(((ethyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (119),
[0293]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-3-ylmethyl)car-
bamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (120),
[0294]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyrimidin-2-ylmethyl)c-
arbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (121),
[0295]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-4-ylmethyl)car-
bamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (122),
[0296]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyrazin-2-ylmethyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (123),
[0297]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((1-methyl-1H-pyrazol-5-
-yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cy-
clohexane-1-carboxylic acid (124),
[0298]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(morpholin-3-ylmethyl)c-
arbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (125),
[0299]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((tetrahydrofuran-3-yl)-
methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cycloh-
exane-1-carboxylic acid (126),
[0300]
(1S,3S)-3-((6-(5-(((butyhethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,-
2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (127),
[0301]
(1S,3S)-3-((6-(5-(((ethyl(propyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (128),
[0302]
(1S,3S)-3-((6-(5-((((1-isopropylcyclopropyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (129),
[0303]
(1S,3S)-3-((6-(5-((((1-isobutylcyclopropyl)(methyl)carbamoyl)oxy)me-
thyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-
-1-carboxylic acid (130),
[0304]
(1S,3S)-3-((6-(5-((((1-ethylcyclopropyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (131),
[0305]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-propylcyclobutyl)car-
bamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (132),
[0306]
(1S,3S)-3-((6-(5-((((1-ethylcyclobutyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (133),
[0307]
(1S,3S)-3-((6-(5-(((2-azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (134),
[0308]
(1S,3S)-3-((6-(5-(46-azaspiro[3.4]octane-6-carbonyl)oxy)methyl)-1-m-
ethyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (135),
[0309]
(1S,3S)-3-((6-(5-(((cyclobutyhmethyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (136),
[0310]
(1S,3S)-3-((6-(5-(((3,3-dimethylpiperidine-1-carbonyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (137),
[0311]
(1S,3S)-3-((6-(5-(((isopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (138),
[0312]
(1S,3S)-3-((6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (139),
[0313]
(1S,3S)-3-((6-(5-(((3,3-dimethylpyrrolidine-1-carbonyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-car-
boxylic acid (140),
[0314]
(1R,3S)-3-((6-(5-((((3,3-difluoro-cyclobutyl)(methyl)carbamoyl)oxy)-
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid; cis isomer from epimerization in
final ester hydrolysis (141),
[0315]
(1S,3S)-3-((6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxyli-
c acid (142),
[0316]
(1S,3S)-3-((6-(5-(((3,3-difluoro-pyrrolidine-1-carbonyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (143),
[0317]
(1S,3S)-3-((6-(5-(((5-azaspiro[2.4]heptane-5-carbonyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (144),
[0318]
(1S,3S)-3-((6-(5-(((((3,3-difluoro-cyclobutyl)methyl)(methyl)carbam-
oyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)c-
yclohexane-1-carboxylic acid (145),
[0319]
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[2.3]hexan-1-yl)c-
arbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (cis isomer from epimerization in final ester
hydrolysis) (146),
[0320] (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-methylpy
rrolidine-1-carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)c-
yclohexane-1-carboxylic acid (mixture of diastereomers) (147),
[0321]
(1S,3S)-3-((6-(5-(((-2-azabicyclo[2.2.1]heptane-2-carbonyl)oxy)meth-
yl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-
-carboxylic acid (mixture of diastereomers) (148),
[0322] (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((octahy
drocyclopenta[b]pyrrole-1-carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyri-
din-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of
diastereomers) (149),
[0323]
(1S,3S)-3-((6-(5-(((3-(cyclopropylmethyl)pyrrolidine-1-carbonyl)oxy-
)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohex-
ane-1-carboxylic acid (mixture of diastereomers) (150),
[0324]
(1S,3S)-3-((6-(5-(((3-isobutylpyrrolidine-1-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (mixture of diastereomers) (151),
[0325]
(1S,3S)-3-((6-(5-(((2-ethylpyrrolidine-1-carbonyl)oxy)methyl)-1-met-
hyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxyl-
ic acid (mixture of diastereomers) (152),
[0326]
(1S,3S)-3-((6-(5-(((2-isobutylpyrrolidine-1-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (mixture of diastereomers) (153),
[0327]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((2-(trifluoromethyl)pyrrolidin-
e-1-carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (mixture of diastereomers) (154),
[0328]
(1S,3S)-3-((6-(5-(((3,3-dimethylazetidine-1-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (155),
[0329]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-methylazetidine-1-carbonyl)-
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxyli-
c acid (156),
[0330]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((2-methylazetidine-1-carbonyl)-
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine-3-yl)oxy)cyclohexane-1-carboxyl-
ic acid (mixture of diastereomers) (157),
[0331]
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[3.3]heptan-2-yl)-
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-
-carboxylic acid (158),
[0332]
(1S,3S)-3-((6-(5-(((2-azaspiro[3.4]octane-2-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (159),
[0333]
(1R,3S)-3-((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (cis isomer from epimerization in final ester
hydrolysis step) (160),
[0334]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-methylpiperidine-1-carbonyl-
)oxy)methyl)-1H-1,2,3-triazol
-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of
diastereomers) (161),
[0335]
(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (162),
[0336]
(1S,3S)-3-((6-(5-(((3-isopropylpyrrolidine-1-carbonyl)oxy)methyl)-1-
-methyl
-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-car-
boxylic acid (mixture of diastereomers) (163),
[0337]
(1S,3S)-3-((6-(5-(((3-cyclopropylpyrrolidine-1-carbonyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (mixture of diastereomers) (164),
[0338] (1S,3S)-3-((6-(5-(((3-ethylpyrrolidine-1-carbonyl)
oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cycl-
ohexane-1-carboxylic acid (mixture of diastereomers) (165),
[0339]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-propylpyrrolidine-1-carbony-
l)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (mixture of diastereomers) (166),
[0340]
(1S,3S)-3-((6-(5-(((-7-azabicyclo[2.2.1]heptane-7-carbonyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (167),
[0341]
(1S,3S)-3-((6-(5-((((3,3-dimethyl-cyclobutyl)(methyl)carbamoyl)oxy)-
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (168),
[0342]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-phenylpyrrolidine-1-carbony-
l)
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (mixture of diastereomers) (169),
[0343] (1S,3S)-3-((6-(5-(((tert-butyl
(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyr-
idin-3-yl)oxy)cyclohexane-1-carboxylic acid (170),
[0344]
(1S,3S)-3-((6-(5-(((6-azaspiro[2.5]octane-6-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (171),
[0345]
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3-methylbut-2-en-1-yl)-
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (cis isomer from epimerization during
final hydrolysis step) (172),
[0346]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-
-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(173),
[0347]
(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (174),
[0348]
(1S,3S)-3-((6-(5-(((6-azaspiro[3.4]octane-6-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (175),
[0349]
(1S,3S)-3-((6-(5-(((2-azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (176),
[0350]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3-methylbut-2-en-1-yl)-
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (177),
[0351] (1S,3S)-3-((6-(5-((((1-fluoro-2-methylpropan-2-yl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3--
yl)oxy)cyclohexane-1-carboxylic acid (178),
[0352]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[2.3]hexan-5-yl)c-
arbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (179),
[0353]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(spiro[3.3]heptan-2-yl)carbamoyl-
)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (180),
[0354]
(1S,3S)-3-((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (181),
[0355]
(1S,3S)-3-((6-(5-((((3-fluorocyclobutyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (mixture of diastereomers) (182),
[0356]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(spiro[2.3]hexan-5-yl)carbamoyl)-
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxyli-
c acid (183),
[0357]
(1S,3S)-3-((6-(5-(((((2,2-dimethylcyclopropyl)methyl)(methyl)carbam-
oyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)c-
yclohexane-1-carboxylic acid (mixture of diastereomers) (184),
[0358]
(1S,3S)-3-((6-(5-(((((2,2-dimethylcyclopropyl)methyl)(methyl)carbam-
oyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (mixture of diastereomers) (185),
[0359]
(1S,3S)-3-((6-(5-(((((2,2-difluorocyclopropyl)methyl)(methyl)carbam-
oyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (mixture of diastereomers) (186),
[0360]
(1S,3S)-3-((6-(5-((((3-fluoro-3-methylbutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (187),
[0361]
(1S,3S)-3-((6-(5-((((3-fluoro-3-methylbutyl)(methyl)carbamoyl)oxy)m-
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (188),
[0362]
(1S,3S)-3-((6-(5-(((((1-fluorocyclobutyl)methyl)(methyl)carbamoyl)o-
xy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cycloh-
exane-1-carboxylic acid (189),
[0363]
(1S,3S)-3-((6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (190),
[0364]
(1S,3S)-3-((6-(5-((((4-fluorobutyl)carbamoyl)oxy)methyl)-1-methyl-1-
H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (191),
[0365]
(1S,3S)-3-((6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (192),
[0366]
(1R,3R)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)m-
ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (193),
[0367] (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl-
)oxy)cyclohexane-1-carboxylic acid (194),
[0368]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (195),
[0369]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-car-
boxylic acid (196),
[0370] (1S,3S)-3-((2-ethyl-6-(5-(((isobutyl(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-
-carboxylic acid (197),
[0371]
(1S,3S)-3-((6-(5-(((benzylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-t-
riazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(198),
[0372]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (199),
[0373]
(1S,3S)-3-((2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)me-
thyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (200),
[0374]
(1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (201),
[0375]
(1S,3S)-3-((2-ethyl-6-(5-(((ethyl(methyl)carbamoyl)oxy)methyl)-1-me-
thyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (202),
[0376]
(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (203),
[0377]
(1S,3S)-3-((6-(5-(((3,3-dimethylazetidine-1-carbonyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (204),
[0378]
(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (205),
[0379]
(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)-
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexan-
e-1-carboxylic acid (206),
[0380]
(1S,3S)-3-((2-ethyl-6-(1-methyl-5-(((methyl(1-propylcyclopropyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (207),
[0381]
(1S,3S)-3-((2-ethyl-6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)--
1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (208),
[0382]
(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (209),
[0383]
(1S,3S)-3-((6-(5-(((2-azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (210),
[0384]
(1S,3S)-3-((6-(5-(((5-azaspiro[2.4]heptane-5-carbonyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (211),
[0385]
(1S,3S)-3-((5-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid
(212),
[0386]
(1S,3S)-3-((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid (213),
[0387]
(1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid (214),
[0388]
(1S,3S)-3-((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic
acid (215),
[0389]
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)m-
ethyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic
acid (216),
[0390] (1S,3S)-3-((5-(5-(((butyl
(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyr-
azin-2-yl)oxy) cyclohexane-1-carboxylic acid (219),
[0391] (1S,3S)-3-((5-(5-((((cyclopropyl-methyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methyl-pyrazin-2-yl)oxy)cyc-
lohexane-1-carboxylic acid (220),
[0392]
(1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-ca-
rboxylic acid (221),
[0393] (1S,3S)-3-((5-(5-(((isopentyl
(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyr-
azin-2-yl)oxy) cyclohexane-1-carboxylic acid (222),
[0394]
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(pentyl)carbamoyl)
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxyl-
ic acid (223),
[0395]
(1S,3S)-3-((5-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid (224),
[0396]
(1S,3S)-3-((5-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)
oxy)cyclohexane-1-carboxylic acid (225),
[0397]
(1S,3S)-3-((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxyli-
c acid (226),
[0398]
(1S,3S)-3-((5-(5-((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-c-
arboxylic acid (227),
[0399]
(1S,3S)-3-((5-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid (228),
[0400]
(1S,3S)-3-((5-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)
oxy)cyclohexane-1-carboxylic acid (229),
[0401]
(1S,3S)-3-((5-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)
oxy)cyclohexane-1-carboxylic acid (230),
[0402]
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(neopentyl)carbamoyl)
oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxyl-
ic acid (231),
[0403]
(1S,3S)-3-((5-(5-((((2-fluoro-2-methylpropyl)(methyl)carbamoyl)oxy)-
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)
oxy)cyclohexane-1-carboxylic acid (232),
[0404]
(1S,3S)-3-((5-(5-(((((1-fluoro-cyclobutyl)methyl)(methyl)carbamoyl)-
oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclo-
hexane-1-carboxylic acid (233),
[0405]
(1S,3S)-3-((5-(5-(((((1-fluorocyclopentypmethyl)(methyl)carbamoyl)o-
xy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cycloh-
exane-1-carboxylic acid (234),
[0406]
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclo-
propyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy-
)cyclohexane-1-carboxylic acid (235),
[0407]
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(((1S,2S)-2-methyl
cyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2--
yl)oxy)cyclohexane-1-carboxylic acid (236),
[0408]
(1S,3S)-3-((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cycl-
ohexane-1-carboxylic acid (237),
[0409]
(1S,3S)-3-((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane--
1-carboxylic acid (238),
[0410]
(1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclo-
hexane-1-carboxylic acid (239),
[0411]
(1S,3S)-3-((5-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-
-carboxylic acid (240),
[0412]
(1S,3S)-3-((6-(5-(2-(((Cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid (241),
[0413]
(1S,3S)-3-((2-Methyl-6-(1-methyl-5-(2-((methyl(propyl)carbamoyl)oxy-
)-ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid, TFA salt (242),
[0414]
(1S,3S)-3-((6-(5-(2-((Cyclopentyl-(methyl)carbamoyl)oxy)ethyl)-1-me-
thyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxy-
lic acid (243),
[0415]
(1S,3S)-3-((6-(5-(2-((Benzyl(methyl)-carbamoyl)oxy)ethyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (244),
[0416]
(1S,3S)-3-((6-(5-(2-((Isobutyl-(methyl)carbamoyl)oxy)ethyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (245),
[0417]
(1S,3S)-3-((2-Methyl-6-(1-methyl-5-(2-((pyrrolidine-1-carbonyl)oxy)-
-ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid, TFA salt (246),
[0418]
(1S,3S)-3-((6-(5-(2-((Cyclobutyl(methyl)carbamoyl)oxy)ethyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclo-hexane-1-carboxyl-
ic acid, TFA salt (247),
[0419]
(1S,3S)-3-((6-(5-(2-(((Cyclobutyl-methyl)carbamoyl)oxy)ethyl)-1-met-
hyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxyl-
ic acid, TFA salt (248),
[0420]
(1S,3S)-3-((6-(5-(3-((Benzyl(methyl)carbamoyl)oxy)propyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (249),
[0421]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(2-propoxyethyl)carbamo-
yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (250),
[0422]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)me-
thyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohex-
ane-1-carboxylic acid (251),
[0423]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclopropyl)me-
thyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohex-
ane-1-carboxylic acid (252),
[0424]
(1S,3S)-3-((6-(5-((((2-fluoro-2-methylpropyl)(methyl)carbamoyl)oxy)-
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (253),
[0425]
(1S,3S)-3-((5-(5-((((2-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carbo-
xylic acid; mixture of diastereomers (254),
[0426]
(1S,3S)-3-((6-(5-((((2-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid; mixture of diastereomers (255),
[0427]
(1S,3S)-3-((6-(5-((((4-fluoropentyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (256),
[0428]
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclo-
propyl)methyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane--
1-carboxylic acid (257),
[0429]
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclo-
propyl)methyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane--
1-carboxylic acid (258),
[0430]
(1S,3S)-3-((6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methy-
l)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid (259),
[0431]
(1S,3S)-3-((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1--
methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (260),
[0432]
(1S,3S)-3-((6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-
-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (261),
[0433] (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((2-methyl
cyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)
pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid; mixture of
diastereomers (262),
[0434] (1S,3S)-3-((2-methyl-6-(1-methyl
-5-(((methyl((1-methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-t-
riazol-4-yl) pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(263),
[0435] (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(neopentyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (264),
[0436]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)pyridin-3-yl)oxy)cyclohe-
xane-1-carboxylic acid (265),
[0437]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-(fluoromethyl)pyridin-3-yl)oxy)cyclohex-
ane-1-carboxylic acid (266),
[0438]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cycloh-
exane-1-carboxylic acid (267),
[0439]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohe-
xane-1-carboxylic acid (268),
[0440]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclo-
hexane-1-carboxylic acid (269),
[0441]
(1S,3S)-3-((2-cyano-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)me-
thyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (270),
[0442]
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)-2-(2-hydroxypropan-2-yl)pyridin-3-yl)oxy)-
cyclohexane-1-carboxylic acid (271),
[0443]
(1S,3S)-3-((2-Methoxy-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)-
methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (272),
[0444]
(1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cycl-
ohexane-1-carboxylic acid (273),
[0445]
(1S,3S)-3-((6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-
-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)
oxy)cyclohexane-1-carboxylic acid (274),
[0446]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (275),
[0447]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(trifluoro methyl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (276),
[0448]
(1S,3S)-3-((2-(difluoromethyl)-6-(1-methyl-5-(((methyl(propyl)carba-
moyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (277),
[0449]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carbo-
xylic acid (278),
[0450]
(1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (279),
[0451]
(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methy-
l-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)
pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (280),
[0452]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)
pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (281),
[0453]
(1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carb-
oxylic acid (282),
[0454]
(1S,3S)-3-((2-(methoxymethyl)-6-(1-methyl-5-(((methyl(propyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane--
1-carboxylic acid (283),
[0455]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carbox-
ylic acid (284),
[0456] (1S,3S)-3-((6-(5-((((cyclopropyl
methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(m-
ethoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(285),
[0457] (1S,3S)-3-((6-(5-(((cyclobutyl
(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxym-
ethyl) pyridin-3-yl) oxy)cyclohexane-1-carboxylic acid (286),
[0458]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)
pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (287),
[0459] (1S,3S)-3-((2-methyl-6-(1-methyl-5-((((methyl-d3)(propyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (288),
[0460]
(1S,3S)-3-((2-cyano-6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)ox-
y)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-ca-
rboxylic acid (289),
[0461]
(1S,3S)-3-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3--
triazol-4-yl)-2-cyanopyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
(290),
[0462]
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)-2-cyanopyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (291),
[0463]
(1S,3S)-3-((2-cyano-6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy-
)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-car-
boxylic acid (292),
[0464]
(1S,3S)-3-((2-cyano-6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-
-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid (293),
[0465]
(1S,3S)-3-((2-cyano-6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl-
)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid (294).
[0466] In another embodiment, the compounds of the present
invention have LPA.sub.1 IC.sub.50 values.ltoreq.10 .mu.M.
[0467] In another embodiment, the compounds of the present
invention have LPA.sub.1 IC.sub.50 values.ltoreq.1 .mu.M.
[0468] In another embodiment, the compounds of the present
invention have LPA.sub.1 IC.sub.50 values.ltoreq.0.1 .mu.M.
[0469] In another embodiment, the compounds of the present
invention have LPA.sub.1 IC.sub.50 values.ltoreq.0.05 .mu.M.
[0470] In another embodiment, the compounds of the present
invention have LPA.sub.1 IC.sub.50 values.ltoreq.0.01 .mu.M.
II. OTHER EMBODIMENTS OF THE INVENTION
[0471] In some embodiments, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is an antagonist of at
least one LPA receptor. In some embodiments, the compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
is an antagonist of LPA.sub.1. In some embodiments, the compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
is an antagonist of LPA.sub.2. In some embodiments, the compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
is an antagonist of LPA.sub.3.
[0472] In some embodiments, presented herein are compounds selected
from active metabolites, tautomers, pharmaceutically acceptable
salts, solvates or prodrugs of a compound of Formulas (I)-(IX).
[0473] In another embodiment, the present invention provides a
composition comprising at least one of the compounds of the present
invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof.
[0474] In another embodiment, the present invention provides a
pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of at
least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof.
[0475] In another embodiment, the present invention provides a
process for making a compound of the present invention.
[0476] In another embodiment, the present invention provides an
intermediate for making a compound of the present invention.
[0477] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s).
[0478] In another embodiment, the present invention provides a
method for the treatment and/or prophylaxis of a condition
associated with LPA receptor mediated fibrosis, comprising
administering to a patient in need of such treatment and/or
prophylaxis a therapeutically effective amount of at least one of
the compounds of the present invention or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
As used herein, the term "patient" encompasses all mammalian
species.
[0479] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) inhibiting the disease-state, i.e., arresting it
development; and/or (b) relieving the disease-state, i.e., causing
regression of the disease state.
[0480] As used herein, "prophylaxis" is the protective treatment of
a disease state to reduce and/or minimize the risk and/or reduction
in the risk of recurrence of a disease state by administering to a
patient a therapeutically effective amount of at least one of the
compounds of the present invention or a or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
Patients may be selected for prophylaxis therapy based on factors
that are known to increase risk of suffering a clinical disease
state compared to the general population. For prophylaxis
treatment, conditions of the clinical disease state may or may not
be presented yet. "Prophylaxis" treatment can be divided into (a)
primary prophylaxis and (b) secondary prophylaxis. Primary
prophylaxis is defined as treatment to reduce or minimize the risk
of a disease state in a patient that has not yet presented with a
clinical disease state, whereas secondary prophylaxis is defined as
minimizing or reducing the risk of a recurrence or second
occurrence of the same or similar clinical disease state.
[0481] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. This invention encompasses all combinations of preferred
aspects of the invention noted herein. It is understood that any
and all embodiments of the present invention may be taken in
conjunction with any other embodiment or embodiments to describe
additional embodiments. It is also to be understood that each
individual element of the embodiments is its own independent
embodiment. Furthermore, any element of an embodiment is meant to
be combined with any and all other elements from any embodiment to
describe an additional embodiment.
III. CHEMISTRY
[0482] Throughout the specification and the appended claims, a
given chemical formula or name shall encompass all stereo and
optical isomers and racemates thereof where such isomers exist.
Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms are within the scope of the
invention. Many geometric isomers of C.dbd.C double bonds, C.dbd.N
double bonds, ring systems, and the like can also be present in the
compounds, and all such stable isomers are contemplated in the
present invention. Cis- and trans- (or E- and Z-) geometric isomers
of the compounds of the present invention are described and may be
isolated as a mixture of isomers or as separated isomeric forms.
The present compounds can be isolated in optically active or
racemic forms. Optically active forms may be prepared by resolution
of racemic forms or by synthesis from optically active starting
materials. All processes used to prepare compounds of the present
invention and intermediates made therein are considered to be part
of the present invention. When enantiomeric or diastereomeric
products are prepared, they may be separated by conventional
methods, for example, by chromatography or fractional
crystallization. Depending on the process conditions the end
products of the present invention are obtained either in free
(neutral) or salt form. Both the free form and the salts of these
end products are within the scope of the invention. If so desired,
one form of a compound may be converted into another form. A free
base or acid may be converted into a salt; a salt may be converted
into the free compound or another salt; a mixture of isomeric
compounds of the present invention may be separated into the
individual isomers. Compounds of the present invention, free form
and salts thereof, may exist in multiple tautomeric forms, in which
hydrogen atoms are transposed to other parts of the molecules and
the chemical bonds between the atoms of the molecules are
consequently rearranged. It should be understood that all
tautomeric forms, insofar as they may exist, are included within
the invention.
[0483] The term "stereoisomer" refers to isomers of identical
constitution that differ in the arrangement of their atoms in
space. Enantiomers and diastereomers are examples of stereoisomers.
The term "enantiomer" refers to one of a pair of molecular species
that are mirror images of each other and are not superimposable.
The term "diastereomer" refers to stereoisomers that are not mirror
images. The term "racemate" or "racemic mixture" refers to a
composition composed of equimolar quantities of two enantiomeric
species, wherein the composition is devoid of optical activity.
[0484] The symbols "R" and "S" represent the configuration of
substituents around a chiral carbon atom(s). The isomeric
descriptors "R" and "S" are used as described herein for indicating
atom configuration(s) relative to a core molecule and are intended
to be used as defined in the literature (IUPAC Recommendations
1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
[0485] The term "chiral" refers to the structural characteristic of
a molecule that makes it impossible to superimpose it on its mirror
image. The term "homochiral" refers to a state of enantiomeric
purity. The term "optical activity" refers to the degree to which a
homochiral molecule or nonracemic mixture of chiral molecules
rotates a plane of polarized light.
[0486] As used herein, the term "alkyl" or "alkylene" is intended
to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, "C.sub.1 to C.sub.10 alkyl" or "C.sub.1-10 alkyl" (or
alkylene), is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10
alkyl groups. Additionally, for example, "C.sub.1 to C.sub.6 alkyl"
or "C.sub.1-C.sub.6 alkyl" denotes alkyl having 1 to 6 carbon
atoms. Alkyl group can be unsubstituted or substituted with at
least one hydrogen being replaced by another chemical group.
Example alkyl groups include, but are not limited to, methyl (Me),
ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g.,
n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl,
neopentyl).
[0487] "Alkenyl" or "alkenylene" is intended to include hydrocarbon
chains of either straight or branched configuration having the
specified number of carbon atoms and one or more, preferably one to
two, carbon-carbon double bonds that may occur in any stable point
along the chain. For example, "C.sub.2 to C.sub.6 alkenyl" or
"C.sub.2-6 alkenyl" (or alkenylene), is intended to include
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkenyl groups.
Examples of alkenyl include, but are not limited to, ethenyl,
1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
2-methyl-2-propenyl, and 4-methyl-3-pentenyl.
[0488] "Alkynyl" or "alkynylene" is intended to include hydrocarbon
chains of either straight or branched configuration having one or
more, preferably one to three, carbon-carbon triple bonds that may
occur in any stable point along the chain. For example, "C.sub.2 to
C.sub.6 alkynyl" or "C.sub.2-6 alkynyl" (or alkynylene), is
intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6
alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and
hexynyl.
[0489] The term "alkoxy" or "alkyloxy" refers to an --O-alkyl
group. "C.sub.1 to C.sub.6 alkoxy" or "C.sub.1-6 alkoxy" (or
alkyloxy), is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6 alkoxy groups. Example alkoxy groups
include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or
"thioalkoxy" represents an alkyl group as defined above with the
indicated number of carbon atoms attached through a sulphur bridge;
for example, methyl-S-- and ethyl-S--.
[0490] "Halo" or "halogen" includes fluoro (F), chloro (Cl), bromo
(Br), and iodo (I). "Haloalkyl" is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more halogens. Examples of haloalkyl include, but are not limited
to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl,
pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,
heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include "fluoroalkyl" that is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more fluorine atoms.
[0491] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group
as defined above with the indicated number of carbon atoms attached
through an oxygen bridge. For example, "C.sub.1 to C.sub.6
haloalkoxy" or "C.sub.1-6 haloalkoxy", is intended to include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 haloalkoxy
groups. Examples of haloalkoxy include, but are not limited to,
trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a
haloalkyl group as defined above with the indicated number of
carbon atoms attached through a sulphur bridge; for example,
trifluoromethyl-S--, and pentafluoroethyl-S--.
[0492] The term "cycloalkyl" refers to cyclized alkyl groups,
including mono-, bi- or poly-cyclic ring systems. "C.sub.3 to
C.sub.8 cycloalkyl" or "C.sub.3-8 cycloalkyl" is intended to
include C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8
cycloalkyl groups, including monocyclic, bicyclic, and polycyclic
rings. Example cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
Branched cycloalkyl groups such as 1-methylcyclopropyl and
2-methylcyclopropyl and spiro and bridged cycloalkyl groups are
included in the definition of "cycloalkyl".
[0493] As used herein, "carbocycle", "carbocyclyl" or "carbocyclic
residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or
8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or
13-membered bicyclic or tricyclic hydrocarbon ring, any of which
may be saturated, partially unsaturated, unsaturated or aromatic.
Examples of such carbocycles include, but are not limited to,
cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,
cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,
adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown
above, bridged rings are also included in the definition of
carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles,
unless otherwise specified, are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term
"carbocyclyl" is used, it is intended to include "aryl". A bridged
ring occurs when one or more carbon atoms link two non-adjacent
carbon atoms. Preferred bridges are one or two carbon atoms. It is
noted that a bridge always converts a monocyclic ring into a
tricyclic ring. When a ring is bridged, the substituents recited
for the ring may also be present on the bridge.
[0494] As used herein, the term "bicyclic carbocyclyl" or "bicyclic
carbocyclic group" is intended to mean a stable 9- or 10-membered
carbocyclic ring system that contains two fused rings and consists
of carbon atoms. Of the two fused rings, one ring is a benzo ring
fused to a second ring; and the second ring is a 5- or 6-membered
carbon ring which is saturated, partially unsaturated, or
unsaturated. The bicyclic carbocyclic group may be attached to its
pendant group at any carbon atom which results in a stable
structure. The bicyclic carbocyclic group described herein may be
substituted on any carbon if the resulting compound is stable.
Examples of a bicyclic carbocyclic group are, but not limited to,
naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and
indanyl.
[0495] "Aryl" groups refer to monocyclic or polycyclic aromatic
hydrocarbons, including, for example, phenyl, naphthyl, and
phenanthranyl. Aryl moieties are well known and described, for
example, in Lewis, R. J., ed., Hawley's Condensed Chemical
Dictionary, 13th Edition, John Wiley & Sons, Inc., New York
(1997). "C.sub.6 or C.sub.10 aryl" or "C.sub.6-10 aryl" refers to
phenyl and naphthyl. Unless otherwise specified, "aryl", "C.sub.6
or C.sub.10 aryl" or "C.sub.6-10 aryl" or "aromatic residue" may be
unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3
groups, OH, OCH.sub.3, Cl, F, Br, I, CN, NO.sub.2, NH.sub.2,
N(CH.sub.3)H, N(CH.sub.3).sub.2, CF.sub.3, OCF.sub.3,
C(.dbd.O)CH.sub.3, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CO.sub.2H, and
CO.sub.2CH.sub.3.
[0496] The term "benzyl", as used herein, refers to a methyl group
on which one of the hydrogen atoms is replaced by a phenyl group,
wherein said phenyl group may optionally be substituted with 1 to 5
groups, preferably 1 to 3 groups, OH, OCH.sub.3, Cl, F, Br, I, CN,
NO.sub.2, NH.sub.2, N(CH.sub.3)H, N(CH.sub.3).sub.2, CF.sub.3,
OCF.sub.3, C(.dbd.O)CH.sub.3, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CO.sub.2H, and
CO.sub.2CH.sub.3.
[0497] As used herein, the term "heterocycle", "heterocyclyl", or
"heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or
7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-,
13-, or 14-membered polycyclic heterocyclic ring that is saturated,
partially unsaturated, or fully unsaturated, and that contains
carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected
from the group consisting of N, O and S; and including any
polycyclic group in which any of the above-defined heterocyclic
rings is fused to a benzene ring. The nitrogen and sulfur
heteroatoms may optionally be oxidized (i.e., N.fwdarw.O and
S(O).sub.p, wherein p is 0, 1 or 2). The nitrogen atom may be
substituted or unsubstituted (i.e., N or NR wherein R is H or
another substituent within the definition of the substitution of
the heterocyclic ring). The heterocyclic ring may be attached to
its pendant group at any heteroatom or carbon atom that results in
a stable structure. The heterocyclic rings described herein may be
substituted on carbon or on a nitrogen atom if the resulting
compound is stable. A nitrogen in the heterocycle may optionally be
quaternized. It is preferred that when the total number of S and O
atoms in the heterocycle exceeds 1, then these heteroatoms are not
adjacent to one another. It is preferred that the total number of S
and O atoms in the heterocycle is not more than 1. When the term
"heterocyclyl" is used, it is intended to include heteroaryl.
[0498] Bridged rings are also included in the definition of
heterocycle. A bridged ring occurs when one or more atoms (i.e., C,
O, N, or S) link two non-adjacent carbon or nitrogen atoms.
Examples of bridged rings include, but are not limited to, one
carbon atom, two carbon atoms, one nitrogen atom, two nitrogen
atoms, and a carbon-nitrogen group. It is noted that a bridge
always converts a monocyclic ring into a tricyclic ring. When a
ring is bridged, the substituents recited for the ring may also be
present on the bridge.
[0499] Examples of heterocycles include, but are not limited to,
acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl,
isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl,
pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl,
2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Also included are fused ring and spiro compounds containing, for
example, the above heterocycles.
[0500] Examples of 5- to 10-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,
1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,
isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,
imidazolopyridinyl, and pyrazolopyridinyl.
[0501] Examples of 5- to 6-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[0502] As used herein, the term "bicyclic heterocycle" or "bicyclic
heterocyclic group" is intended to mean a stable 9- or 10-membered
heterocyclic ring system which contains two fused rings and
consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, O and S. Of
the two fused rings, one ring is a 5- or 6-membered monocyclic
aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered
heteroaryl ring or a benzo ring, each fused to a second ring. The
second ring is a 5- or 6-membered monocyclic ring which is
saturated, partially unsaturated, or unsaturated, and comprises a
5-membered heterocycle, a 6-membered heterocycle or a carbocycle
(provided the first ring is not benzo when the second ring is a
carbocycle).
[0503] The bicyclic heterocyclic group may be attached to its
pendant group at any heteroatom or carbon atom which results in a
stable structure. The bicyclic heterocyclic group described herein
may be substituted on carbon or on a nitrogen atom if the resulting
compound is stable. It is preferred that when the total number of S
and O atoms in the heterocycle exceeds 1, then these heteroatoms
are not adjacent to one another. It is preferred that the total
number of S and O atoms in the heterocycle is not more than 1.
[0504] Examples of a bicyclic heterocyclic group are, but not
limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,
1,2,3,4-tetrahydro-quinoxalinyl, and
1,2,3,4-tetrahydro-quinazolinyl.
[0505] As used herein, the term "aromatic heterocyclic group,"
"heteroaryl," or "heteroaryl ring" refers to substituted and
unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or
10-membered bicyclic groups, and 11- to 14-membered tricyclic
groups which have at least one heteroatom (O, S or N) in at least
one of the rings, said heteroatom-containing ring preferably having
1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the
heteroaryl group containing a heteroatom can contain one or two
oxygen or sulfur atoms and/or from one to four nitrogen atoms
provided that the total number of heteroatoms in each ring is four
or less and each ring has at least one carbon atom. Heteroaryl
groups can be substituted or unsubstituted. The nitrogen atom may
be substituted or unsubstituted (i.e., N or NR wherein R is H or
another substituent within the definition of the substitution of
the heterocyclic ring). The nitrogen and sulfur heteroatoms may
optionally be oxidized (i.e., N.fwdarw.O and S(O).sub.p) and the
nitrogen atoms may optionally be quaternized.
[0506] Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any ring.
The heteroaryl ring system may contain zero, one, two or three
substituents. Heteroaryl groups include, without limitation,
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl,
quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,
pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl,
isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,
1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl,
benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane.
[0507] The term "counterion" is used to represent a negatively
charged species such as chloride, bromide, hydroxide, acetate, and
sulfate.
[0508] When a dotted ring is used within a ring structure, this
indicates that the ring structure may be saturated, partially
saturated or unsaturated.
[0509] As referred to herein, the term "substituted" means that at
least one hydrogen atom is replaced with a non-hydrogen group,
provided that normal valencies are maintained and that the
substitution results in a stable compound. When a substituent is
keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced.
Keto substituents are not present on aromatic moieties. When a ring
system (e.g., carbocyclic or heterocyclic) is said to be
substituted with a carbonyl group or a double bond, it is intended
that the carbonyl group or double bond be part (i.e., within) of
the ring. Ring double bonds, as used herein, are double bonds that
are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N,
or N.dbd.N).
[0510] In cases wherein there are nitrogen atoms (e.g., amines) on
compounds of the present invention, these may be converted to
N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or
hydrogen peroxides) to afford other compounds of this invention.
Thus, shown and claimed nitrogen atoms are considered to cover both
the shown nitrogen and its N-oxide (N.fwdarw.O) derivative.
[0511] When any variable occurs more than one time in any
constituent or formula for a compound, its definition at each
occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-3 R groups, then said group may optionally be
substituted with up to three R groups, and at each occurrence R is
selected independently from the definition of R. Also, combinations
of substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0512] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom in which such substituent is bonded to the rest
of the compound of a given formula, then such substituent may be
bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0513] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms that are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
and/or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0514] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic groups such as amines; and
alkali or organic salts of acidic groups such as carboxylic acids.
The pharmaceutically acceptable salts include the conventional
non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, and isethionic.
[0515] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound that contains
a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
18th Edition, Mack Publishing Company, Easton, Pa. (1990), the
disclosure of which is hereby incorporated by reference.
[0516] In addition, compounds of formulas (I)-(IX) may have prodrug
forms. Any compound that will be converted in vivo to provide the
bioactive agent (i.e., a compound of formula I) is a prodrug within
the scope and spirit of the invention. Various forms of prodrugs
are well known in the art. For examples of such prodrug
derivatives, see:
[0517] a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985),
and Widder, K. et al., eds., Methods in Enzymology, 112:309-396,
Academic Press (1985);
[0518] b) Bundgaard, H., Chapter 5, "Design and Application of
Prodrugs", A Textbook of Drug Design and Development, pp. 113-191,
Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers
(1991);
[0519] c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);
[0520] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);
and
[0521] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).
[0522] Compounds containing a carboxy group can form
physiologically hydrolyzable esters that serve as prodrugs by being
hydrolyzed in the body to yield formulas (I)-(IX) compounds per se.
Such prodrugs are preferably administered orally since hydrolysis
in many instances occurs principally under the influence of the
digestive enzymes. Parenteral administration may be used where the
ester per se is active, or in those instances where hydrolysis
occurs in the blood. Examples of physiologically hydrolyzable
esters of compounds of formulas (I)-(IX)include C.sub.1-6alkyl,
C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,
methoxymethyl, C.sub.1-6 alkanoyloxy-C.sub.1-6alkyl (e.g.,
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl),
C.sub.1-6alkoxycarbonyloxy-C.sub.1-6alkyl (e.g.,
methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well-known
physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
conventional techniques known in the art.
[0523] Preparation of prodrugs is well known in the art and
described in, for example, King, F. D., ed., Medicinal Chemistry:
Principles and Practice, The Royal Society of Chemistry, Cambridge,
UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug
Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and
Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C. G., ed., The
Practice of Medicinal Chemistry, Academic Press, San Diego, Calif.
(1999).
[0524] The present invention is intended to include all isotopes of
atoms occurring in the present compounds. Isotopes include those
atoms having the same atomic number but different mass numbers. By
way of general example and without limitation, isotopes of hydrogen
include deuterium and tritium. Deuterium has one proton and one
neutron in its nucleus and that has twice the mass of ordinary
hydrogen. Deuterium can be represented by symbols such as ".sup.2H"
or "D". The term "deuterated" herein, by itself or used to modify a
compound or group, refers to replacement of one or more hydrogen
atom(s), which is attached to carbon(s), with a deuterium atom.
Isotopes of carbon include .sup.13C and .sup.14C.
[0525] Isotopically-labeled compounds of the invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described
herein, using an appropriate isotopically-labeled reagent in place
of the non-labeled reagent otherwise employed. Such compounds have
a variety of potential uses, e.g., as standards and reagents in
determining the ability of a potential pharmaceutical compound to
bind to target proteins or receptors, or for imaging compounds of
this invention bound to biological receptors in vivo or in
vitro.
[0526] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent. It is preferred
that compounds of the present invention do not contain a N-halo,
S(O).sub.2H, or S(O)H group.
[0527] The term "solvate" means a physical association of a
compound of this invention with one or more solvent molecules,
whether organic or inorganic. This physical association includes
hydrogen bonding. In certain instances the solvate will be capable
of isolation, for example, when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid. The
solvent molecules in the solvate may be present in a regular
arrangement and/or a non-ordered arrangement. The solvate may
comprise either a stoichiometric or nonstoichiometric amount of the
solvent molecules. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include, but are not limited
to, hydrates, ethanolates, methanolates, and isopropanolates.
Methods of solvation are generally known in the art.
IV. BIOLOGY
[0528] Lysophospholipids are membrane-derived bioactive lipid
mediators. Lysophospholipids include, but are not limited to,
lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate;
LPA), sphingosine 1-phosphate (S1P), lysophosphatidylcholine (LPC),
and sphingosylphosphorylcholine (SPC). Lysophospholipids affect
fundamental cellular functions that include cellular proliferation,
differentiation, survival, migration, adhesion, invasion, and
morphogenesis. These functions influence many biological processes
that include neurogenesis, angiogenesis, wound healing, immunity,
and carcinogenesis.
[0529] LPA acts through sets of specific G protein-coupled
receptors (GPCRs) in an autocrine and paracrine fashion. LPA
binding to its cognate GPCRs (LPA.sub.1, LPA.sub.2, LPA.sub.3,
LPA.sub.4, LPA.sub.5, LPA.sub.6) activates intracellular signaling
pathways to produce a variety of biological responses.
[0530] Lysophospholipids, such as LPA, are quantitatively minor
lipid species compared to their major phospholipid counterparts
(e.g., phosphatidylcholine, phosphatidylethanolamine, and
sphingomyelin). LPA has a role as a biological effector molecule,
and has a diverse range of physiological actions such as, but not
limited to, effects on blood pressure, platelet activation, and
smooth muscle contraction, and a variety of cellular effects, which
include cell growth, cell rounding, neurite retraction, and actin
stress fiber formation and cell migration. The effects of LPA are
predominantly receptor mediated.
[0531] Activation of the LPA receptors (LPA.sub.1, LPA.sub.2,
LPA.sub.3, LPA.sub.4, LPA.sub.5, LPA.sub.6) with LPA mediates a
range of downstream signaling cascades. These include, but are not
limited to, mitogen-activated protein kinase (MAPK) activation,
adenylyl cyclase (AC) inhibition/activation, phospholipase C (PLC)
activation/Ca.sup.2+ mobilization, arachidonic acid release,
Akt/PKB activation, and the activation of small GTPases, Rho, ROCK,
Rac, and Ras. Other pathways that are affected by LPA receptor
activation include, but are not limited to, cyclic adenosine
monophosphate (cAMP), cell division cycle 42/GTP-binding protein
(Cdc42), proto-oncogene serine/threonine-protein kinase Raf
(c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src),
extracellular signal-regulated kinase (ERK), focal adhesion kinase
(FAK), guanine nucleotide exchange factor (GEF), glycogen synthase
kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin
light chain II (MLC II), nuclear factor kB (NF-kB),
N-methyl-D-aspartate (NMDA) receptor activation,
phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA),
protein kinase C (PKC), ras-related C3 botulinum toxin substrate 1
(RAC1). The actual pathway and realized end point are dependent on
a range of variables that include receptor usage, cell type,
expression level of a receptor or signaling protein, and LPA
concentration. Nearly all mammalian cells, tissues and organs
co-express several LPA-receptor subtypes, which indicates that LPA
receptors signal in a cooperative manner. LPA.sub.1, LPA.sub.2, and
LPA.sub.3 share high amino acid sequence similarity.
[0532] LPA is produced from activated platelets, activated
adipocytes, neuronal cells, and other cell types. Serum LPA is
produced by multiple enzymatic pathways that involve
monoacylglycerol kinase, phospholipase A.sub.1, secretory
phospholipase A.sub.2, and lysophospholipase D (lysoPLD), including
autotaxin. Several enzymes are involved in LPA degradation:
lysophospholipase, lipid phosphate phosphatase, and LPA acyl
transferase such as endophilin. LPA concentrations in human serum
are estimated to be 1-5 .mu.M. Serum LPA is bound to albumin,
low-density lipoproteins, or other proteins, which possibly protect
LPA from rapid degradation. LPA molecular species with different
acyl chain lengths and saturation are naturally occurring,
including 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl
(18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonyl
(20:4) LPA. Quantitatively minor alkyl LPA has biological
activities similar to acyl LPA, and different LPA species activate
LPA receptor subtypes with varied efficacies.
[0533] LPA Receptors
[0534] LPA.sub.1 (previously called VZG-1/EDG-2/mrec1.3) couples
with three types of G proteins, G.sub.i/o, G.sub.q, and
G.sub.12/13. Through activation of these G proteins, LPA induces a
range of cellular responses through LPA.sub.1 including but not
limited to: cell proliferation, serum-response element (SRE)
activation, mitogen-activated protein kinase (MAPK) activation,
adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation,
Ca.sup.2+ mobilization, Akt activation, and Rho activation.
[0535] Wide expression of LPA.sub.1 is observed in adult mice, with
clear presence in testis, brain, heart, lung, small intestine,
stomach, spleen, thymus, and skeletal muscle. Similarly, human
tissues also express LPA.sub.1; it is present in brain, heart,
lung, placenta, colon, small intestine, prostate, testis, ovary,
pancreas, spleen, kidney, skeletal muscle, and thymus.
[0536] LPA.sub.2 (EDG-4) also couples with three types of G
proteins, G.sub.i/o, G.sub.q, and G.sub.12/13, to mediate
LPA-induced cellular signaling. Expression of LPA.sub.2 is observed
in the testis, kidney, lung, thymus, spleen, and stomach of adult
mice and in the human testis, pancreas, prostate, thymus, spleen,
and peripheral blood leukocytes. Expression of LPA.sub.2 is
upregulated in various cancer cell lines, and several human
LPA.sub.2 transcriptional variants with mutations in the
3'-untranslated region have been observed. Targeted deletion of
LPA.sub.2 in mice has not shown any obvious phenotypic
abnormalities, but has demonstrated a significant loss of normal
LPA signaling (e.g., PLC activation, Ca.sup.2+ mobilization, and
stress fiber formation) in primary cultures of mouse embryonic
fibroblasts (MEFs). Creation of lpa1(-/-)lpa2 (-/-) double-null
mice has revealed that many LPA-induced responses, which include
cell proliferation, AC inhibition, PLC activation, Ca.sup.2+
mobilization, JNK and Akt activation, and stress fiber formation,
are absent or severely reduced in double-null MEFs. All these
responses, except for AC inhibition (AC inhibition is nearly
abolished in LPA.sub.1 (-/-) MEFs), are only partially affected in
either LPA.sub.1 (-/-) or LPA.sub.2 (-/-) MEFs. LPA.sub.2
contributes to normal LPA-mediated signaling responses in at least
some cell types (Choi et al, Biochemica et Biophysica Acta 2008,
1781, p 531-539).
[0537] LPA.sub.3 (EDG-7) is distinct from LPA.sub.1 and LPA.sub.2
in its ability to couple with G.sub.i/o and G.sub.q but not
G.sub.12/13 and is much less responsive to LPA species with
saturated acyl chains. LPA.sub.3 can mediate pleiotropic
LPA-induced signaling that includes PLC activation, Ca.sup.2+
mobilization, AC inhibition/activation, and MAPK activation.
Overexpression of LPA.sub.3 in neuroblastoma cells leads to neurite
elongation, whereas that of LPA.sub.1 or LPA.sub.2 results in
neurite retraction and cell rounding when stimulated with LPA.
Expression of LPA.sub.3 is observed in adult mouse testis, kidney,
lung, small intestine, heart, thymus, and brain. In humans, it is
found in the heart, pancreas, prostate, testis, lung, ovary, and
brain (frontal cortex, hippocampus, and amygdala).
[0538] LPA.sub.4 (p2y.sub.9/GPR23) is of divergent sequence
compared to LPA.sub.1, LPA.sub.2, and LPA.sub.3 with closer
similarity to the platelet-activating factor (PAF) receptor.
LPA.sub.4 mediates LPA induced Ca.sup.2+ mobilization and cAMP
accumulation, and functional coupling to the G protein Gs for AC
activation, as well as coupling to other G proteins. The LPA.sub.4
gene is expressed in the ovary, pancreas, thymus, kidney and
skeletal muscle.
[0539] LPA.sub.5 (GPR92) is a member of the purinocluster of GPCRs
and is structurally most closely related to LPA.sub.4. LPA.sub.5 is
expressed in human heart, placenta, spleen, brain, lung and gut.
LPA.sub.5 also shows very high expression in the CD8+ lymphocyte
compartment of the gastrointestinal tract.
[0540] LPA.sub.6 (p2y5) is a member of the purinocluster of GPCRs
and is structurally most closely related to LPA.sub.4. LPA.sub.6 is
an LPA receptor coupled to the G12/13-Rho signaling pathways and is
expressed in the inner root sheaths of human hair follicles.
[0541] Illustrative Biological Activity
[0542] Wound Healing
[0543] Normal wound healing occurs by a highly coordinated sequence
of events in which cellular, soluble factors and matrix components
act in concert to repair the injury. The healing response can be
described as taking place in four broad, overlapping
phases--hemostasis, inflammation, proliferation, and remodeling.
Many growth factors and cytokines are released into a wound site to
initiate and perpetuate wound healing processes.
[0544] When wounded, damaged blood vessels activate platelets. The
activated platelets play pivotal roles in subsequent repair
processes by releasing bioactive mediators to induce cell
proliferation, cell migration, blood coagulation, and angiogenesis.
LPA is one such mediator that is released from activated platelets;
this induces platelet aggregation along with mitogenic/migration
effects on the surrounding cells, such as endothelial cells, smooth
muscle cells, fibroblasts, and keratinocytes.
[0545] Topical application of LPA to cutaneous wounds in mice
promotes repair processes (wound closure and increased
neoepithelial thickness) by increasing cell proliferation/migration
without affecting secondary inflammation.
[0546] Activation of dermal fibroblasts by growth factors and
cytokines leads to their subsequent migration from the edges of the
wound into the provisional matrix formed by the fibrin clot
whereupon the fibroblasts proliferate and start to restore the
dermis by secreting and organizing the characteristic dermal
extracellular matrix (ECM). The increasing number of fibroblasts
within the wound and continuous precipitation of ECM enhances
matrix rigidity by applying small tractional forces to the newly
formed granulation tissue. The increase in mechanical stress, in
conjunction with transforming growth factor .beta. (TGF.beta.),
induces .alpha.-smooth muscle actin (.alpha.-SMA) expression and
the subsequent transformation of fibroblasts into myofibroblasts.
Myofibroblasts facilitate granulation tissue remodeling via
myofibroblast contraction and through the production of ECM
components.
[0547] LPA regulates many important functions of fibroblasts in
wound healing, including proliferation, migration, differentiation
and contraction. Fibroblast proliferation is required in wound
healing in order to fill an open wound. In contrast, fibrosis is
characterized by intense proliferation and accumulation of
myofibroblasts that actively synthesize ECM and proinflammatory
cytokines. LPA can either increase or suppress the proliferation of
cell types important in wound healing, such as epithelial and
endothelial cells (EC), macrophages, keratinocytes, and
fibroblasts. A role for LPA.sub.1 in LPA-induced proliferation was
provided by the observation that LPA-stimulated proliferation of
fibroblasts isolated from LPA.sub.1 receptor null mice was
attenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA
induces cytoskeletal changes that are integral to fibroblast
adhesion, migration, differentiation and contraction.
[0548] Fibrosis
[0549] Tissue injury initiates a complex series of host
wound-healing responses; if successful, these responses restore
normal tissue structure and function. If not, these responses can
lead to tissue fibrosis and loss of function.
[0550] For the majority of organs and tissues the development of
fibrosis involves a multitude of events and factors. Molecules
involved in the development of fibrosis include proteins or
peptides (profibrotic cytokines, chemokines, metalloproteinases
etc.) and phospholipids. Phospholipids involved in the development
of fibrosis include platelet activating factor (PAF), phosphatidyl
choline, sphingosine-1 phosphate (S1P) and lysophosphatidic acid
(LPA).
[0551] A number of muscular dystrophies are characterized by a
progressive weakness and wasting of musculature, and by extensive
fibrosis. It has been shown that LPA treatment of cultured
myoblasts induced significant expression of connective tissue
growth factor (CTGF). CTGF subsequently induces collagen,
fibronectin and integrin expression and induces dedifferentiation
of these myoblasts. Treatment of a variety of cell types with LPA
induces reproducible and high level induction of CTGF (J. P.
Pradere, et al., LPA.sub.1 receptor activation promotes renal
interstitial fibrosis, J. Am. Soc. Nephrol. 18 (2007) 3110-3118; N.
Wiedmaier, et al., Int J Med Microbiol; 298(3-4):231-43, 2008).
CTGF is a profibrotic cytokine, signaling down-stream and in
parallel with TGF.beta..
[0552] CTGF expression by gingival epithelial cells, which are
involved in the development of gingival fibromatosis, was found to
be exacerbated by LPA treatment (A. Kantarci, et al., J. Pathol.
210 (2006) 59-66).
[0553] LPA is associated with the progression of liver fibrosis. In
vitro, LPA induces stellate cell and hepatocyte proliferation.
These activated cells are the main cell type responsible for the
accumulation of ECM in the liver. Furthermore, LPA plasma levels
rise during CCl.sub.4-induced liver fibrosis in rodents, or in
hepatitis C virus-induced liver fibrosis in humans (N. Watanabe, et
al., Plasma lysophosphatidic acid level and serum autotaxin
activity are increased in liver injury in rats in relation to its
severity, Life Sci. 81 (2007) 1009-1015; N. Watanabe, et al., J.
Clin. Gastroenterol. 41 (2007) 616-623).
[0554] An increase of phospholipid concentrations in the
bronchoalveolar lavage fluid in rabbits and rodents injected with
bleomycin has been reported (K. Kuroda, et al., Phospholipid
concentration in lung lavage fluid as biomarker for pulmonary
fibrosis, Inhal. Toxicol. 18 (2006) 389-393; K. Yasuda, et al.,
Lung 172 (1994) 91-102).
[0555] LPA is associated with heart disease and mycocardial
remodeling. Serum LPA levels are increased after myocardial
infarction in patients and LPA stimulates rat cardiac fibroblast
proliferation and collagen production (Chen et al. FEBS Lett. 2006
Aug. 21; 580(19):4737-45).
[0556] Pulmonary Fibrosis
[0557] In the lung, aberrant wound healing responses to injury
contribute to the pathogenesis of fibrotic lung diseases. Fibrotic
lung diseases, such as idiopathic pulmonary fibrosis (IPF), are
associated with high morbidity and mortality.
[0558] LPA is an important mediator of fibroblast recruitment in
pulmonary fibrosis. LPA and LPA.sub.1 play key pathogenic roles in
pulmonary fibrosis. Fibroblast chemoattractant activity plays an
important role in the lungs in patients with pulmonary fibrosis.
Profibrotic effects of LPA.sub.1-receptor stimulation is explained
by LPA.sub.1-receptor-mediated vascular leakage and increased
fibroblast recruitment, both profibrotic events. The LPA-LPA.sub.1
pathway has a role in mediating fibroblast migration and vascular
leakage in IPF. The end result is the aberrant healing process that
characterizes this fibrotic condition.
[0559] The LPA.sub.1 receptor is the LPA receptor most highly
expressed on fibroblasts obtained from patients with IPF.
Furthermore, BAL obtained from IPF patients induced chemotaxis of
human foetal lung fibroblasts that was blocked by the dual
LPA.sub.1-LPA.sub.3 receptor antagonist Ki16425. In an experimental
bleomycin-induced lung injury mouse model, it was shown that LPA
levels were high in bronchoalveolar lavage samples compared with
unexposed controls. LPA.sub.1 knockout mice are protected from
fibrosis after bleomycin challenge with reduced fibroblast
accumulation and vascular leakage. In human subjects with IPF, high
LPA levels were observed in bronchoalveolar lavage samples compared
with healthy controls. Increased fibroblast chemotactic activity in
these samples was inhibited by the Ki16425 indicating that
fibroblast migration is mediated by the LPA-LPA receptor(s) pathway
(Tager et al. Nature Medicine, 2008, 14, 45-54).
[0560] The LPA-LPA.sub.1 pathway is crucial in fibroblast
recruitment and vascular leakage in pulmonary fibrosis.
[0561] Activation of latent TGF-.beta. by the .alpha.v.beta.6
integrin plays a critical role in the development of lung injury
and fibrosis (Munger et al. Cell, vol. 96, 319-328, 1999). LPA
induces .alpha.v.beta.6-mediated TGF-.beta. activation on human
lung epithelial cells (Xu et al. Am. J. Pathology, 2009, 174,
1264-1279). The LPA-induced .alpha.v.beta.6-mediated TGF-.beta.
activation is mediated by the LPA.sub.2 receptor. Expression of the
LPA2 receptor is increased in epithelial cells and mesenchymal
cells in areas of lung fibrosis from IPF patients compared to
normal human lung tissue. The LPA-LPA2 pathway contributes to the
activation of the TGF-.beta. pathway in pulmonary fibrosis. In some
embodiments, compounds that inhibit LPA2 show efficacy in the
treatment of lung fibrosis. In some embodiments, compounds that
inhibit both LPA1 and LPA2 show improved efficacy in the treatment
of lung fibrosis compared to compounds which inhibit only LPA1 or
LPA2.
[0562] Renal Fibrosis
[0563] LPA and LPA.sub.1 are involved in the etiology of kidney
fibrosis. LPA has effects on both proliferation and contraction of
glomerular mesangial cells and thus has been implicated in
proliferative glomerulonephritis (C. N. Inoue, et al., Clin. Sci.
(Colch.) 1999, 96, 431-436). In an animal model of renal fibrosis
[unilateral ureteral obstruction (UUO)], it was found that renal
LPA receptors are expressed under basal conditions with an
expression order of
LPA.sub.2>LPA.sub.3=LPA.sub.1>>LPA.sub.4. This model
mimics in an accelerated manner the development of renal fibrosis
including renal inflammation, fibroblast activation and
accumulation of extracellular matrix in the tubulointerstitium. UUO
significantly induced LPA.sub.1-receptor expression. This was
paralleled by renal LPA production (3.3 fold increase) in
conditioned media from kidney explants. Contra-lateral kidneys
exhibited no significant changes in LPA release and LPA-receptors
expression. This shows that a prerequisite for an action of LPA in
fibrosis is met: production of a ligand (LPA) and induction of one
of its receptors (the LPA.sub.1 receptor) (J. P. Pradere et al.,
Biochimica et Biophysica Acta, 2008, 1781, 582-587).
[0564] In mice where the LPA.sub.1 receptor was knocked out
(LPA.sub.1 (-/-), the development of renal fibrosis was
significantly attenuated. UUO mice treated with the LPA receptor
antagonist Ki16425 closely resembled the profile of LPA.sub.1 (-/-)
mice.
[0565] LPA can participate in intraperitonial accumulation of
monocyte/macrophages and LPA can induce expression of the
profibrotic cytokine CTGF in primary cultures of human fibroblasts
(J .S. Koh, et al., J. Clin. Invest., 1998, 102, 716-727).
[0566] LPA treatment of a mouse epithelial renal cell line, MCT,
induced a rapid increase in the expression of the profibrotic
cytokine CTGF. CTGF plays a crucial role in UUO-induced
tubulointerstitial fibrosis (TIF), and is involved in the
profibrotic activity of TGF.beta.. This induction was almost
completely suppressed by co-treatment with the LPA-receptor
antagonist Ki16425. In one aspect, the profibrotic activity of LPA
in kidney results from a direct action of LPA on kidney cells
involving induction of CTGF.
[0567] Hepatic Fibrosis
[0568] LPA is implicated in liver disease and fibrosis. Plasma LPA
levels and serum autotaxin (enzyme responsible for LPA production)
are elevated in hepatitis patients and animal models of liver
injury in correlation with increased fibrosis. LPA also regulates
liver cell function. LPA.sub.1 and LPA.sub.2 receptors are
expressed by mouse hepatic stellate cells and LPA stimulates
migration of hepatic myofibroblasts.
[0569] Ocular Fibrosis
[0570] LPA is in involved in wound healing in the eye. LPA.sub.1
and LPA.sub.3 receptors are detectable in the normal rabbit corneal
epithelial cells, keratocytes and endothelial cells and LPA.sub.1
and LPA.sub.3 expression are increased in corneal epithelial cells
following injury.
[0571] LPA and its homologues are present in the aqueous humor and
the lacrimal gland fluid of the rabbit eye and these levels are
increased in a rabbit corneal injury model.
[0572] LPA induces actin stress fiber formation in rabbit corneal
endothelial and epithelial cells and promotes contraction corneal
fibroblasts. LPA also stimulates proliferation of human retinal
pigmented epithelial cells
[0573] Cardiac Fibrosis
[0574] LPA is implicated in myocardial infarction and cardiac
fibrosis. Serum LPA levels are increased in patients following
mycocardial infarction (MI) and LPA stimulates proliferation and
collagen production (fibrosis) by rat cardiac fibroblasts. Both
LPA1 and LPA3 receptors are highly expressed in human heart
tissue.
[0575] Treatment of Fibrosis
[0576] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used to treat or
prevent fibrosis in a mammal. In one aspect, a compound of Formulas
(I-(IX)), or a pharmaceutically acceptable salt thereof, is used to
treat fibrosis of an organ or tissue in a mammal. In one aspect is
a method for preventing a fibrosis condition in a mammal, the
method comprising administering to the mammal at risk of developing
one or more fibrosis conditions a therapeutically effective amount
of a compound of Formulas (I-(IX)), or a pharmaceutically
acceptable salt thereof. In one aspect, the mammal has been exposed
to one or more environmental conditions that are known to increase
the risk of fibrosis of an organ or tissue. In one aspect, the
mammal has been exposed to one or more environmental conditions
that are known to increase the risk of lung, liver or kidney
fibrosis. In one aspect, the mammal has a genetic predisposition of
developing fibrosis of an organ or tissue. In one aspect, a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof, is administered to a mammal to prevent or minimize
scarring following injury. In one aspect, injury includes
surgery.
[0577] The terms "fibrosis" or "fibrosing disorder," as used
herein, refers to conditions that are associated with the abnormal
accumulation of cells and/or fibronectin and/or collagen and/or
increased fibroblast recruitment and include but are not limited to
fibrosis of individual organs or tissues such as the heart, kidney,
liver, joints, lung, pleural tissue, peritoneal tissue, skin,
cornea, retina, musculoskeletal and digestive tract.
[0578] Exemplary diseases, disorders, or conditions that involve
fibrosis include, but are not limited to: Lung diseases associated
with fibrosis, e.g., idiopathic pulmonary fibrosis, pulmonary
fibrosis secondary to systemic inflammatory disease such as
rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing
alveolitis, radiation induced fibrosis, chronic obstructive
pulmonary disease (COPD), scleroderma, chronic asthma, silicosis,
asbestos induced pulmonary or pleural fibrosis, acute lung injury
and acute respiratory distress (including bacterial pneumonia
induced, trauma induced, viral pneumonia induced, ventilator
induced, non-pulmonary sepsis induced, and aspiration induced);
Chronic nephropathies associated with injury/fibrosis (kidney
fibrosis), e.g., glomerulonephritis secondary to systemic
inflammatory diseases such as lupus and scleroderma, diabetes,
glomerular nephritis, focal segmental glomerular sclerosis, IgA
nephropathy, hypertension, allograft and Alport; Gut fibrosis,
e.g., scleroderma, and radiation induced gut fibrosis; Liver
fibrosis, e.g., cirrhosis, alcohol induced liver fibrosis,
nonalcoholic steatohepatitis (NASH), biliary duct injury, primary
biliary cirrhosis, infection or viral induced liver fibrosis (e.g.,
chronic HCV infection), and autoimmune hepatitis; Head and neck
fibrosis, e.g., radiation induced; Corneal scarring, e.g., LASIK
(laser-assisted in situ keratomileusis), corneal transplant, and
trabeculectomy; Hypertrophic scarring and keloids, e.g., burn
induced or surgical; and other fibrotic diseases, e.g.,
sarcoidosis, scleroderma, spinal cord injury/fibrosis,
myelofibrosis, vascular restenosis, atherosclerosis,
arteriosclerosis, Wegener's granulomatosis, mixed connective tissue
disease, and Peyronie's disease.
[0579] In one aspect, a mammal suffering from one of the following
non-limiting exemplary diseases, disorders, or conditions will
benefit from therapy with a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof: atherosclerosis,
thrombosis, heart disease, vasculitis, formation of scar tissue,
restenosis, phlebitis, COPD (chronic obstructive pulmonary
disease), pulmonary hypertension, pulmonary fibrosis, pulmonary
inflammation, bowel adhesions, bladder fibrosis and cystitis,
fibrosis of the nasal passages, sinusitis, inflammation mediated by
neutrophils, and fibrosis mediated by fibroblasts.
[0580] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is administered to a
mammal with fibrosis of an organ or tissue or with a predisposition
of developing fibrosis of an organ or tissue with one or more other
agents that are used to treat fibrosis. In one aspect, the one or
more agents include corticosteroids. In one aspect, the one or more
agents include immunosuppressants. In one aspect, the one or more
agents include B-cell antagonists. In one aspect, the one or more
agents include uteroglobin.
[0581] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used to treat a
dermatological disorders in a mammal. The term "dermatological
disorder," as used herein refers to a skin disorder. Such
dermatological disorders include, but are not limited to,
proliferative or inflammatory disorders of the skin such as, atopic
dermatitis, bullous disorders, collagenoses, psoriasis,
scleroderma, psoriatic lesions, dermatitis, contact dermatitis,
eczema, urticaria, rosacea, wound healing, scarring, hypertrophic
scarring, keloids, Kawasaki Disease, rosacea, Sjogren-Larsso
Syndrome, urticaria. In one aspect, a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, is used to
treat systemic sclerosis.
[0582] Pain
[0583] Since LPA is released following tissue injury, LPA.sub.1
plays an important role in the initiation of neuropathic pain.
LPA.sub.1, unlike LPA.sub.2 or LPA.sub.3, is expressed in both
dorsal root ganglion (DRG) and dorsal root neurons. Using the
antisense oligodeoxynucleotide (AS-ODN) for LPA.sub.1 and
LPA.sub.1-null mice, it was found that LPA-induced mechanical
allodynia and hyperalgesia is mediated in an LPA.sub.1-dependent
manner. LPA.sub.1 and downstream Rho-ROCK activation play a role in
the initiation of neuropathic pain signaling. Pretreatment with
Clostridium botulinum C3 exoenzyme (BoTXC3, Rho inhibitor) or
Y-27632 (ROCK inhibitor) completely abolished the allodynia and
hyperalgesia in nerve-injured mice. LPA also induced demyelination
of the dorsal root, which was prevented by BoTXC3. The dorsal root
demyelination by injury was not observed in LPA.sub.1-null mice or
AS-ODN injected wild-type mice. LPA signaling appears to induce
important neuropathic pain markers such as protein kinase C.gamma.
(PKC.gamma.) and a voltage-gated calcium channel .alpha.2.delta.1
subunit (Ca.alpha.2.delta.1) in an LPA.sub.1 and Rho-dependent
manner (M. Inoue, et al., Initiation of neuropathic pain requires
lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004)
712-718).
[0584] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used in the treatment
of pain in a mammal. In one aspect, the pain is acute pain or
chronic pain. In another aspect, the pain is neuropathic pain.
[0585] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used in the treatment
of fibromylagia. In one aspect, fibromyalgia stems from the
formation of fibrous scar tissue in contractile (voluntary)
muscles. Fibrosis binds the tissue and inhibits blood flow,
resulting in pain.
[0586] Cancer
[0587] Lysophospholipid receptor signaling plays a role in the
etiology of cancer. Lysophosphatidic acid (LPA) and its G
protein-coupled receptors (GPCRs) LPA.sub.1, LPA.sub.2, and/or
LPA.sub.3 play a role in the development of several types of
cancers. The initiation, progression and metastasis of cancer
involve several concurrent and sequential processes including cell
proliferation and growth, survival and anti-apoptosis, migration of
cells, penetration of foreign cells into defined cellular layers
and/or organs, and promotion of angiogenesis. The control of each
of these processes by LPA signaling in physiological and
pathophysiological conditions underscores the potential therapeutic
usefulness of modulating LPA signaling pathways for the treatment
of cancer, especially at the level of the LPA receptors or
ATX/lysoPLD. Autotaxin (ATX) is a prometastatic enzyme initially
isolated from the conditioned medium of human melanoma cells that
stimulates a myriad of biological activities, including
angiogenesis and the promotion of cell growth, migration, survival,
and differentiation through the production of LPA (Mol Cancer Ther
2008; 7(10):3352-62).
[0588] LPA signals through its own GPCRs leading to activation of
multiple downstream effector pathways. Such downstream effector
pathways play a role in cancer. LPA and its GPCRs are linked to
cancer through major oncogenic signaling pathways.
[0589] LPA contributes to tumorigenesis by increasing motility and
invasiveness of cells. LPA has been implicated in the initiation or
progression of ovarian cancer. LPA is present at significant
concentrations (2-80 .mu.M) in the ascitic fluid of ovarian cancer
patients. Ovarian cancer cells constitutively produce increased
amounts of LPA as compared to normal ovarian surface epithelial
cells, the precursor of ovarian epithelial cancer. Elevated LPA
levels are also detected in plasma from patients with early-stage
ovarian cancers compared with controls. LPA receptors (LPA2 and
LPA3) are also overexpressed in ovarian cancer cells as compared to
normal ovarian surface epithelial cells. LPA stimulates Cox-2
expression through transcriptional activation and
post-transcriptional enhancement of Cox-2 mRNA in ovarian cancer
cells. Prostaglandins produced by Cox-2 have been implicated in a
number of human cancers and pharmacological inhibition of Cox-2
activity reduces colon cancer development and decreases the size
and number of adenomas in patients with familial adenomatous
polyposis. LPA has also been implicated in the initiation or
progression of prostate cancer, breast cancer, melanoma, head and
neck cancer, bowel cancer (colorectal cancer), thyroid cancer and
other cancers (Gardell et al, Trends in Molecular Medicine, vol.
12, no. 2, p 65-75, 2006; Ishii et al, Annu. Rev. Biochem, 73,
321-354, 2004; Mills et al., Nat. Rev. Cancer, 3, 582-591, 2003;
Murph et al., Biochimica et Biophysica Acta, 1781, 547-557,
2008).
[0590] The cellular responses to LPA are mediated through the
lysophosphatidic acid receptors. For example, LPA receptors mediate
both migration of and invasion by pancreatic cancer cell lines: an
antagonist of LPA.sub.1 and LPA.sub.3 (Ki16425) and
LPA.sub.1-specific siRNA effectively blocked in vitro migration in
response to LPA and peritoneal fluid (ascites) from pancreatic
cancer patients; in addition, Ki16425 blocked the LPA-induced and
ascites-induced invasion activity of a highly peritoneal metastatic
pancreatic cancer cell line (Yamada et al, J. Biol. Chem., 279,
6595-6605, 2004).
[0591] Colorectal carcinoma cell lines show significant expression
of LPA.sub.1 mRNA and respond to LPA by cell migration and
production of angiogenic factors. Overexpression of LPA receptors
has a role in the pathogenesis of thyroid cancer. LPA.sub.3 was
originally cloned from prostate cancer cells, concordant with the
ability of LPA to induce autocrine proliferation of prostate cancer
cells.
[0592] LPA has stimulatory roles in cancer progression in many
types of cancer. LPA is produced from and induces proliferation of
prostate cancer cell lines. LPA induces human colon carcinoma DLD1
cell proliferation, migration, adhesion, and secretion of
angiogenic factors through LPA.sub.1 signaling. In other human
colon carcinoma cells lines (HT29 and WiDR), LPA enhances cell
proliferation and secretion of angiogenic factors. In other colon
cancer cell lines, LPA2 and LPA3 receptor activation results in
proliferation of the cells. The genetic or pharmacological
manipulation of LPA metabolism, specific blockade of receptor
signaling, and/or inhibition of downstream signal transduction
pathways, represent approaches for cancer therapies.
[0593] It has been reported that LPA and other phospholipids
stimulate expression of interleukin-8 (IL-8) in ovarian cancer cell
lines. In some embodiments, high concentrations of IL-8 in ovarian
cancer correlate with poor initial response to chemotherapy and
with poor prognosis, respectively. In animal models, expression of
IL-8 and other growth factors such as vascular endothelial growth
factor (VEGF) is associated with increased tumorigenicity, ascites
formation, angiogenesis, and invasiveness of ovarian cancer cells.
In some aspects, IL-8 is an important modulator of cancer
progression, drug resistance, and prognosis in ovarian cancer. In
some embodiments, a compound of Formulas (I)-(IX) inhibits or
reduces IL-8 expression in ovarian cancer cell lines.
[0594] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used in the treatment
of cancer. In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used in the treatment
of malignant and benign proliferative disease. In one aspect, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, is used to prevent or reduce proliferation of tumor cells,
invasion and metastasis of carcinomas, pleural mesothelioma
(Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal
mesothelioma, cancer pain, bone metastases (Boucharaba et al, J.
Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al, Proc.
Natl. acad. Sci., 2006, 103(25) 9643-9648). In one aspect is a
method of treating cancer in a mammal, the method comprising
administering to the mammal a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, and a second therapeutic
agent, wherein the second therapeutic agent is an anti-cancer
agent.
[0595] The term "cancer," as used herein refers to an abnormal
growth of cells which tend to proliferate in an uncontrolled way
and, in some cases, to metastasize (spread). The types of cancer
include, but is not limited to, solid tumors (such as those of the
bladder, bowel, brain, breast, endometrium, heart, kidney, lung,
lymphatic tissue (lymphoma), ovary, pancreas or other endocrine
organ (thyroid), prostate, skin (melanoma or basal cell cancer) or
hematological tumors (such as the leukemias) at any stage of the
disease with or without metastases.
[0596] Additional non-limiting examples of cancers include, acute
lymphoblastic leukemia, acute myeloid leukemia, adrenocortical
carcinoma, anal cancer, appendix cancer, astrocytomas, atypical
teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer,
bladder cancer, bone cancer (osteosarcoma and malignant fibrous
histiocytoma), brain stem glioma, brain tumors, brain and spinal
cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma,
cervical cancer, chronic lymphocytic leukemia, chronic myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cutaneous T-Cell lymphoma, embryonal tumors, endometrial cancer,
ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma
family of tumors, eye cancer, retinoblastoma, gallbladder cancer,
gastric (stomach) cancer, gastrointestinal carcinoid tumor,
gastrointestinal stromal tumor (GIST), gastrointestinal stromal
cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and
neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma,
hypopharyngeal cancer, intraocular melanoma, islet cell tumors
(endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans
cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic
leukemia, acute myeloid leukemia, chronic lymphocytic leukemia,
chronic myelogenous leukemia, hairy cell leukemia, liver cancer,
non-small cell lung cancer, small cell lung cancer, Burkitt
lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin
lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma,
medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic
myelogenous leukemia, myeloid leukemia, multiple myeloma,
nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,
non-small cell lung cancer, oral cancer, oropharyngeal cancer,
osteosarcoma, malignant fibrous histiocytoma of bone, ovarian
cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian
low malignant potential tumor, pancreatic cancer, papillomatosis,
parathyroid cancer, penile cancer, pharyngeal cancer, pineal
parenchymal tumors of intermediate differentiation, pineoblastoma
and supratentorial primitive neuroectodermal tumors, pituitary
tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary
blastoma, primary central nervous system lymphoma, prostate cancer,
rectal cancer, renal cell (kidney) cancer, retinoblastoma,
rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma
family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer,
small cell Lung cancer, small intestine cancer, soft tissue
sarcoma, squamous cell carcinoma, stomach (gastric) cancer,
supratentorial primitive neuroectodermal tumors, T-cell lymphoma,
testicular cancer, throat cancer, thymoma and thymic carcinoma,
thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma,
vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms
tumor.
[0597] The increased concentrations of LPA and vesicles in ascites
from ovarian cancer patients and breast cancer effussions indicate
that it could be an early diagnostic marker, a prognostic indicator
or an indicator of response to therapy (Mills et al, Nat. Rev.
Cancer., 3, 582-591, 2003; Sutphen et al., Cancer Epidemiol.
Biomarkers Prev. 13, 1185-1191, 2004). LPA concentrations are
consistently higher in ascites samples than in matched plasma
samples.
[0598] Respiratory and Allergic Disorders
[0599] In one aspect, LPA is a contributor to the pathogenesis of
respiratory diseases. In one aspect the respiratory disease is
asthma. Proinflammatory effects of LPA include degranulation of
mast cells, contraction of smooth-muscle cells and release of
cytokines from dendritic cells. Airway smooth muscle cells,
epithelial cells and lung fibroblasts all show responses to LPA.
LPA induces the secretion of IL-8 from human bronchial epithelial
cells. IL-8 is found in increased concentrations in BAL fluids from
patients with asthma, chronic obstructive lung disease, pulmonary
sarcoidosis and acute respiratory distress syndrome and Il-8 has
been shown to exacerbate airway inflammation and airway remodeling
of asthmatics. LPA1, LPA2 and LPA3 receptors have all been shown to
contribute to the LPA-induced IL-8 production. Studies cloning
multiple GPCRs that are activated by LPA allowed the demonstration
of the presence of mRNA for the LPA.sub.1, LPA.sub.2 and LPA.sub.3
in the lung (J. J. A. Contos, et al., Mol. Pharmacol. 58,
1188-1196, 2000).
[0600] The release of LPA from platelets activated at a site of
injury and its ability to promote fibroblast proliferation and
contraction are features of LPA as a mediator of wound repair. In
the context of airway disease, asthma is an inflammatory disease
where inappropriate airway "repair" processes lead to structural
"remodeling" of the airway. In asthma, the cells of the airway are
subject to ongoing injury due to a variety of insults, including
allergens, pollutants, other inhaled environmental agents, bacteria
and viruses, leading to the chronic inflammation that characterizes
asthma.
[0601] In one aspect, in the asthmatic individual, the release of
normal repair mediators, including LPA, is exaggerated or the
actions of the repair mediators are inappropriately prolonged
leading to inappropriate airway remodeling. Major structural
features of the remodeled airway observed in asthma include a
thickened lamina reticularis (the basement membrane-like structure
just beneath the airway epithelial cells), increased numbers and
activation of myofibroblasts, thickening of the smooth muscle
layer, increased numbers of mucus glands and mucus secretions, and
alterations in the connective tissue and capillary bed throughout
the airway wall. In one aspect, LPA contributes to these structural
changes in the airway. In one aspect, LPA is involved in acute
airway hyperresponsiveness in asthma. The lumen of the remodeled
asthmatic airway is narrower due to the thickening of the airway
wall, thus decreasing airflow. In one aspect, LPA contributes to
the long-term structural remodeling and the acute
hyperresponsiveness of the asthmatic airway. In one aspect, LPA
contributes to the hyper-responsiveness that is a primary feature
of acute exacerbations of asthma.
[0602] In addition to the cellular responses mediated by LPA,
several of the LPA signaling pathway components leading to these
responses are relevant to asthma. EGF receptor upregulation is
induced by LPA and is also seen in asthmatic airways (M. Amishima,
et al., Am. J. Respir. Crit. Care Med. 157, 1907-1912, 1998).
Chronic inflammation is a contributor to asthma, and several of the
transcription factors that are activated by LPA are known to be
involved in inflammation (Ediger et al., Eur Respir J 21:759-769,
2003).
[0603] In one aspect, the fibroblast proliferation and contraction
and extracellular matrix secretion stimulated by LPA contributes to
the fibroproliferative features of other airway diseases, such as
the peribronchiolar fibrosis present in chronic bronchitis,
emphysema, and interstitial lung disease. Emphysema is also
associated with a mild fibrosis of the alveolar wall, a feature
which is believed to represent an attempt to repair alveolar
damage. In another aspect, LPA plays a role in the fibrotic
interstitial lung diseases and obliterative bronchiolitis, where
both collagen and myofibroblasts are increased. In another aspect,
LPA is involved in several of the various syndromes that constitute
chronic obstructive pulmonary disease.
[0604] Administration of LPA in vivo induces airway
hyper-responsiveness, itch-scratch responses, infiltration and
activation of eosinophils and neutrophils, vascular remodeling, and
nociceptive flexor responses. LPA also induces histamine release
from mouse and rat mast cells. In an acute allergic reaction,
histamine induces various responses, such as contraction of smooth
muscle, plasma exudation, and mucus production. Plasma exudation is
important in the airway, because the leakage and subsequent
airway-wall edema contribute to the development of airway
hyperresponsiveness. Plasma exudation progresses to conjunctival
swelling in ocular allergic disorder and nasal blockage in allergic
rhinitis (Hashimoto et al., J Pharmacol Sci 100, 82-87, 2006). In
one aspect, plasma exudation induced by LPA is mediated by
histamine release from mast cells via one or more LPA receptors. In
one aspect, the LPA receptor(s) include LPA.sub.1 and/or LPA.sub.3.
In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used in the treatment
of various allergic disorders in a mammal. In one aspect, a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof, is used in the treatment of respiratory diseases,
disorders or conditions in a mammal. In one aspect, a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
is used in the treatment of asthma in a mammal. In one aspect, a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof, is used in the treatment of chronic asthma in a
mammal.
[0605] The term "respiratory disease," as used herein, refers to
diseases affecting the organs that are involved in breathing, such
as the nose, throat, larynx, eustachian tubes, trachea, bronchi,
lungs, related muscles (e.g., diaphram and intercostals), and
nerves. Respiratory diseases include, but are not limited to,
asthma, adult respiratory distress syndrome and allergic
(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe
asthma, chronic asthma, clinical asthma, nocturnal asthma,
allergen-induced asthma, aspirin-sensitive asthma, exercise-induced
asthma, isocapnic hyperventilation, child-onset asthma, adult-onset
asthma, cough-variant asthma, occupational asthma,
steroid-resistant asthma, seasonal asthma, seasonal allergic
rhinitis, perennial allergic rhinitis, chronic obstructive
pulmonary disease, including chronic bronchitis or emphysema,
pulmonary hypertension, interstitial lung fibrosis and/or airway
inflammation and cystic fibrosis, and hypoxia.
[0606] The term "asthma" as used herein refers to any disorder of
the lungs characterized by variations in pulmonary gas flow
associated with airway constriction of whatever cause (intrinsic,
extrinsic, or both; allergic or non-allergic). The term asthma may
be used with one or more adjectives to indicate cause.
[0607] In one aspect, presented herein is the use of a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
in the treatment or prevention of chronic obstructive pulmonary
disease in a mammal comprising administering to the mammal at least
once an effective amount of at least one compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof. In
addition, chronic obstructive pulmonary disease includes, but is
not limited to, chronic bronchitis or emphysema, pulmonary
hypertension, interstitial lung fibrosis and/or airway
inflammation, and cystic fibrosis.
[0608] Nervous System
[0609] The nervous system is a major locus for LPA.sub.1
expression; there it is spatially and temporally regulated
throughout brain development. Oligodendrocytes, the myelinating
cells in the central nervous system (CNS), express LPA.sub.1 in
mammals. In addition,
[0610] Schwann cells, the myelinating cells of the peripheral
nervous system, also express LPA.sub.1, which is involved in
regulating Schwann cell survival and morphology. These observations
identify important functions for receptor-mediated LPA signaling in
neurogenesis, cell survival, and myelination.
[0611] Exposure of peripheral nervous system cell lines to LPA
produces a rapid retraction of their processes resulting in cell
rounding, which was, in part, mediated by polymerization of the
actin cytoskeleton. In one aspect, LPA causes neuronal degeneration
under pathological conditions when the blood-brain barrier is
damaged and serum components leak into the brain (Moolenaar, Curr.
Opin. Cell Biol. 7:203-10, 1995). Immortalized CNS neuroblast cell
lines from the cerebral cortex also display retraction responses to
LPA exposure through Rho activation and actomyosin interactions. In
one aspect, LPA is associated with post-ischemic neural damage (J.
Neurochem. 61, 340, 1993; J. Neurochem., 70:66, 1998).
[0612] In one aspect, provided is a compound of Formulas (I)-(IX),
or a pharmaceutically acceptable salt thereof, for use in the
treatment or prevention of a nervous system disorder in a mammal.
The term "nervous system disorder," as used herein, refers to
conditions that alter the structure or function of the brain,
spinal cord or peripheral nervous system, including but not limited
to Alzheimer's Disease, cerebral edema, cerebral ischemia, stroke,
multiple sclerosis, neuropathies, Parkinson's Disease, those found
after blunt or surgical trauma (including post-surgical cognitive
dysfunction and spinal cord or brain stem injury), as well as the
neurological aspects of disorders such as degenerative disk disease
and sciatica.
[0613] In one aspect, provided is a compound of Formulas (I)-(IX),
or a pharmaceutically acceptable salt thereof, for use in the
treatment or prevention of a CNS disorder in a mammal. CNS
disorders include, but are not limited to, multiple sclerosis,
Parkinson's disease, Alzheimer's disease, stroke, cerebral
ischemia, retinal ischemia, post-surgical cognitive dysfunction,
migraine, peripheral neuropathy/neuropathic pain, spinal cord
injury, cerebral edema and head injury.
[0614] Cardiovascular Disorders
[0615] Cardiovascular phenotypes observed after targeted deletion
of lysophospholipid receptors reveal important roles for
lysophospholipid signaling in the development and maturation of
blood vessels, formation of atherosclerotic plaques and maintenance
of heart rate (Ishii, I. et al. Annu. Rev. Biochem. 73, 321-354,
2004). Angiogenesis, the formation of new capillary networks from
pre-existing vasculature, is normally invoked in wound healing,
tissue growth and myocardial angiogenesis after ischemic injury.
Peptide growth factors (e.g. vascular endothelial growth factor
(VEGF)) and lysophospholipids control coordinated proliferation,
migration, adhesion, differentiation and assembly of vascular
endothelial cells (VECs) and surrounding vascular smooth-muscle
cells (VSMCs). In one aspect, dysregulation of the processes
mediating angiogenesis leads to atherosclerosis, hypertension,
tumor growth, rheumatoid arthritis and diabetic retinopathy
(Osborne, N. and Stainier, D. Y. Annu. Rev. Physiol. 65, 23-43,
2003).
[0616] Downstream signaling pathways evoked by lysophospholipid
receptors include Rac-dependent lamellipodia formation (e.g.
LPA.sub.1) and Rho-dependent stress-fiber formation (e.g.
LPA.sub.1), which is important in cell migration and adhesion.
Dysfunction of the vascular endothelium can shift the balance from
vasodilatation to vasoconstriction and lead to hypertension and
vascular remodeling, which are risk factors for atherosclerosis
(Maguire, J. J. et al., Trends Pharmacol. Sci. 26, 448-454,
2005).
[0617] LPA contributes to both the early phase (barrier dysfunction
and monocyte adhesion of the endothelium) and the late phase
(platelet activation and intra-arterial thrombus formation) of
atherosclerosis, in addition to its overall progression. In the
early phase, LPA from numerous sources accumulates in lesions and
activates its cognate GPCRs (LPA.sub.1 and LPA.sub.3) expressed on
platelets (Siess, W. Biochim. Biophys. Acta 1582, 204-215, 2002;
Rother, E. et al. Circulation 108, 741-747, 2003). This triggers
platelet shape change and aggregation, leading to intra-arterial
thrombus formation and, potentially, myocardial infarction and
stroke. In support of its atherogenic activity, LPA can also be a
mitogen and motogen to VSMCs and an activator of endothelial cells
and macrophages. In one aspect, mammals with cardiovascular disease
benefit from LPA receptor antagonists that prevent thrombus and
neointima plaque formation.
[0618] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used to treat or
prevent cardiovascular disease in mammal.
[0619] The term "cardiovascular disease," as used herein refers to
diseases affecting the heart or blood vessels or both, including
but not limited to: arrhythmia (atrial or ventricular or both);
atherosclerosis and its sequelae; angina; cardiac rhythm
disturbances; myocardial ischemia; myocardial infarction; cardiac
or vascular aneurysm; vasculitis, stroke; peripheral obstructive
arteriopathy of a limb, an organ, or a tissue; reperfusion injury
following ischemia of the brain, heart or other organ or tissue;
endotoxic, surgical, or traumatic shock; hypertension, valvular
heart disease, heart failure, abnormal blood pressure; shock;
vasoconstriction (including that associated with migraines);
vascular abnormality, inflammation, insufficiency limited to a
single organ or tissue.
[0620] In one aspect, provided herein are methods for preventing or
treating vasoconstriction, atherosclerosis and its sequelae
myocardial ischemia, myocardial infarction, aortic aneurysm,
vasculitis and stroke comprising administering at least once to the
mammal an effective amount of at least one compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, or
pharmaceutical composition or medicament which includes a compound
of Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof.
[0621] In one aspect, provided herein are methods for reducing
cardiac reperfusion injury following myocardial ischemia and/or
endotoxic shock comprising administering at least once to the
mammal an effective amount of at least one compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof.
[0622] In one aspect, provided herein are methods for reducing the
constriction of blood vessels in a mammal comprising administering
at least once to the mammal an effective amount of at least one
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof.
[0623] In one aspect, provided herein are methods for lowering or
preventing an increase in blood pressure of a mammal comprising
administering at least once to the mammal an effective amount of at
least one compound of Formulas (I)-(IX), or a pharmaceutically
acceptable salt thereof.
[0624] Inflammation
[0625] LPA has been shown to regulate immunological responses by
modulating activities/functions of immune cells such as
T-/B-lymphocytes and macrophages. In activated T cells, LPA
activates IL-2 production/cell proliferation through LPA.sub.1
(Gardell et al, TRENDS in Molecular Medicine Vol. 12 No. 2 February
2006). Expression of LPA-induced inflammatory response genes is
mediated by LPA.sub.1 and LPA.sub.3 (Biochem Biophys Res Commun.
363(4):1001-8, 2007). In addition, LPA modulates the chemotaxis of
inflammatory cells (Biochem Biophys Res Commun., 1993, 15;193(2),
497). The proliferation and cytokine-secreting activity in response
to LPA of immune cells (J. Immunol. 1999, 162, 2049), platelet
aggregation activity in response to LPA, acceleration of migration
activity in monocytes, activation of NF-.kappa.B in fibroblast,
enhancement of fibronectin-binding to the cell surface, and the
like are known. Thus, LPA is associated with various
inflammatory/immune diseases.
[0626] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used to treat or
prevent inflammation in a mammal. In one aspect, antagonists of
LPA.sub.1 and/or LPA.sub.3 find use in the treatment or prevention
of inflammatory/immune disorders in a mammal. In one aspect, the
antagonist of LPA.sub.1 is a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof.
[0627] Examples of inflammatory/immune disorders include psoriasis,
rheumatoid arthritis, vasculitis, inflammatory bowel disease,
dermatitis, osteoarthritis, asthma, inflammatory muscle disease,
allergic rhinitis, vaginitis, interstitial cystitis, scleroderma,
eczema, allogeneic or xenogeneic transplantation (organ, bone
marrow, stem cells and other cells and tissues) graft rejection,
graft-versus-host disease, lupus erythematosus, inflammatory
disease, type I diabetes, pulmonary fibrosis, dermatomyositis,
Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune
thyroiditis), myasthenia gravis, autoimmune hemolytic anemia,
multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis,
primary biliary cirrhosis, allergic conjunctivitis and atopic
dermatitis.
[0628] Other Diseases, Disorders or Conditions
[0629] In accordance with one aspect, are methods for treating,
preventing, reversing, halting or slowing the progression of
LPA-dependent or LPA-mediated diseases or conditions once it
becomes clinically evident, or treating the symptoms associated
with or related to LPA-dependent or LPA-mediated diseases or
conditions, by administering to the mammal a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof. In certain
embodiments, the subject already has a LPA-dependent or
LPA-mediated disease or condition at the time of administration, or
is at risk of developing a LPA-dependent or LPA-mediated disease or
condition.
[0630] In certain aspects, the activity of LPA.sub.1 in a mammal is
directly or indirectly modulated by the administration of (at least
once) a therapeutically effective amount of at least one compound
of Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof. Such modulation includes, but is not limited to, reducing
and/or inhibiting the activity of LPA.sub.1. In additional aspects,
the activity of LPA in a mammal is directly or indirectly
modulated, including reducing and/or inhibiting, by the
administration of (at least once) a therapeutically effective
amount of at least one compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof. Such modulation includes,
but is not limited to, reducing and/or inhibiting the amount and/or
activity of a LPA receptor. In one aspect, the LPA receptor is
LPA.sub.1.
[0631] In one aspect, LPA has a contracting action on bladder
smooth muscle cell isolated from bladder, and promotes growth of
prostate-derived epithelial cell (J. Urology, 1999, 162, 1779-1784;
J. Urology, 2000, 163, 1027-1032). In another aspect, LPA contracts
the urinary tract and prostate in vitro and increases intraurethral
pressure in vivo (WO 02/062389).
[0632] In certain aspects, are methods for preventing or treating
eosinophil and/or basophil and/or dendritic cell and/or neutrophil
and/or monocyte and/or T-cell recruitment comprising administering
at least once to the mammal an effective amount of at least one
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof.
[0633] In certain aspects, are methods for the treatment of
cystitis, including, e.g., interstitial cystitis, comprising
administering at least once to the mammal a therapeutically
effective amount of at least one compound of Formulas (I)-(IX), or
a pharmaceutically acceptable salt thereof.
[0634] In accordance with one aspect, methods described herein
include the diagnosis or determination of whether or not a patient
is suffering from a LPA-dependent or LPA-mediated disease or
condition by administering to the subject a therapeutically
effective amount of a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, and determining whether
or not the patient responds to the treatment.
[0635] In one aspect provided herein are compounds of Formulas
(I)-(IX), pharmaceutically acceptable salts, pharmaceutically
acceptable prodrugs, and pharmaceutically acceptable solvates
thereof, which are antagonists of LPA.sub.1, and are used to treat
patients suffering from one or more LPA-dependent or LPA-mediated
conditions or diseases, including, but not limited to, lung
fibrosis, kidney fibrosis, liver fibrosis, scarring, asthma,
rhinitis, chronic obstructive pulmonary disease, pulmonary
hypertension, interstitial lung fibrosis, arthritis, allergy,
psoriasis, inflammatory bowel disease, adult respiratory distress
syndrome, myocardial infarction, aneurysm, stroke, cancer, pain,
proliferative disorders and inflammatory conditions. In some
embodiments, LPA-dependent conditions or diseases include those
wherein an absolute or relative excess of LPA is present and/or
observed.
[0636] In any of the aforementioned aspects the LPA-dependent or
LPA-mediated diseases or conditions include, but are not limited
to, organ fibrosis, asthma, allergic disorders, chronic obstructive
pulmonary disease, pulmonary hypertension, lung or pleural
fibrosis, peritoneal fibrosis, arthritis, allergy, cancer,
cardiovascular disease, ult respiratory distress syndrome,
myocardial infarction, aneurysm, stroke, and cancer.
[0637] In one aspect, a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is used to improve the
corneal sensitivity decrease caused by corneal operations such as
laser-assisted in situ keratomileusis (LASIK) or cataract
operation, corneal sensitivity decrease caused by corneal
degeneration, and dry eye symptom caused thereby.
[0638] In one aspect, presented herein is the use of a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
in the treatment or prevention of ocular inflammation and allergic
conjunctivitis, vernal keratoconjunctivitis, and papillary
conjunctivitis in a mammal comprising administering at least once
to the mammal an effective amount of at least one compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof.
[0639] In one aspect, presented herein is the use of a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
in the treatment or prevention of Sjogren disease or inflammatory
disease with dry eyes in a mammal comprising administering at least
once to the mammal an effective amount of at least one compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof.
[0640] In one aspect, LPA and LPA receptors (e.g. LPA.sub.1) are
involved in the pathogenesis of osteoarthritis (Kotani et al, Hum.
Mol. Genet., 2008, 17, 1790-1797). In one aspect, presented herein
is the use of a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in the treatment or prevention of
osteoarthritis in a mammal comprising administering at least once
to the mammal an effective amount of at least one compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof.
[0641] In one aspect, LPA receptors (e.g. LPA.sub.1, LPA.sub.3)
contribute to the pathogenesis of rheumatoid arthritis (Zhao et al,
Mol. Pharmacol., 2008, 73(2), 587-600). In one aspect, presented
herein is the use of a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, in the treatment or
prevention of rheumatoid arthritis in a mammal comprising
administering at least once to the mammal an effective amount of at
least one compound of Formulas (I)-(IX), or a pharmaceutically
acceptable salt thereof.
[0642] In one aspect, LPA receptors (e.g. LPA.sub.1) contribute to
adipogenesis. (Simon et al, J. Biol. Chem., 2005, vol. 280, no. 15,
p. 14656). In one aspect, presented herein is the use of a compound
of Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof, in the promotion of adipose tissue formation in a mammal
comprising administering at least once to the mammal an effective
amount of at least one compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof.
a. In Vitro Assays
[0643] The effectiveness of compounds of the present invention as
LPA1 inhibitors can be determined in an LPA1 functional antagonist
assay as follows:
[0644] Chinese hamster ovary cells overexpressing human LPA1 were
plated overnight (15,000 cells/well) in poly-D-lysine coated
384-well microplates (Greiner bio-one, Cat #781946) in DMEM/F12
medium (Gibco, Cat #11039). Following overnight culture, cells were
loaded with calcium indicator dye (AAT Bioquest Inc, Cat #34601)
for 30 minutes at 37.degree. C. The cells were then equilibrated to
room temperature for 30 minutes before the assay. Test compounds
solubilized in DMSO were transferred to 384 well non-binding
surface plates (Coming, Cat #3575) using the Labcyte Echo acoustic
dispense and diluted with assay buffer [1.times. HBSS with
calcium/magnesium (Gibco Cat #14025-092), 20 mM HEPES (Gibco Cat
#15630-080) and 0.1% fatty acid free BSA (Sigma Cat #A9205)] to a
final concentration of 0.5% DMSO. Diluted compounds were added to
the cells by FDSS6000 (Hamamatsu) at final concentrations ranging
from 0.08 nM to 5 .mu.M. and were then incubated for 20 min at room
temperature at which time LPA (Avanti Polar Lipids Cat #857130C)
was added at final concentrations of 10 nM to stimulate the cells.
The compound IC.sub.50 value was defined as the concentration of
test compound which inhibited 50% of the calcium flux induced by
LPA alone. IC.sub.50 values were determined by fitting data to a
4-parameter logistic equation (GraphPad Prism, San Diego
Calif.).
b. In Vivo Assays LPA Challenge with Plasma Histamine
Evaluation.
[0645] Compound is dosed orally p.o. 2 hours to CD-1 female mice
prior to the LPA challenge. The mice are then dosed via tail vein
(IV) with 0.15 mL of LPA in 0.1% BSA/PBS (2 .mu.g/.mu.L). Exactly 2
minutes following the LPA challenge, the mice are euthanized by
decapitation and the trunk blood is collected. These samples are
collectively centrifuged and individual 75 .mu.L samples are frozen
at -20.degree. C. until the time of the histamine assay.
[0646] The plasma histamine analysis was run by standard EIA
(Enzyme Immunoassay) methods. Plasma samples were thawed and
diluted 1:30 in 0.1% BSA in PBS. The EIA protocol for histamine
analysis as outlined by the manufacturer was followed (Histamine
EIA, Oxford Biomedical Research, EA #31).
[0647] The LPA used in the assay is formulated as follows: LPA
(1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P,
Avanti Polar Lipids) is prepared in 0.1% BSA/PBS for total
concentration of 2 .mu.g/.mu.L. 13 mg of LPA is weighed and 6.5 mL
0.1% BSA added, vortexed and sonicated for .about.1 hour until a
clear solution is achieved.
V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS
[0648] In some embodiments, provided is a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof. In some embodiments, the pharmaceutical composition
also contains at least one pharmaceutically acceptable inactive
ingredient.
[0649] In some embodiments, provided is a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof, and at least one pharmaceutically acceptable inactive
ingredient. In one aspect, the pharmaceutical composition is
formulated for intravenous injection, subcutaneous injection, oral
administration, inhalation, nasal administration, topical
administration, ophthalmic administration or otic administration.
In some embodiments, the pharmaceutical composition is a tablet, a
pill, a capsule, a liquid, an inhalant, a nasal spray solution, a
suppository, a suspension, a gel, a colloid, a dispersion, a
suspension, a solution, an emulsion, an ointment, a lotion, an eye
drop or an ear drop.
[0650] In some embodiments, the pharmaceutical composition further
comprises one or more additional therapeutically active agents
selected from: corticosteroids (e.g., dexamethasone or
fluticasone), immunosuppresants (e.g., tacrolimus &
pimecrolimus), analgesics, anti-cancer agent, anti-inflammatories,
chemokine receptor antagonists, bronchodilators, leukotriene
receptor antagonists (e.g., montelukast or zafirlukast),
leukotriene formation inhibitors, monoacylglycerol kinase
inhibitors, phospholipase A.sub.1 inhibitors, phospholipase A.sub.2
inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin
inhibitors, decongestants, antihistamines (e.g., loratidine),
mucolytics, anticholinergics, antitussives, expectorants,
anti-infectives (e.g., fusidic acid, particularly for treatment of
atopic dermatitis), anti-fungals (e.g., clotriazole, particularly
for atopic dermatitis), anti-IgE antibody therapies (e.g.,
omalizumab), .beta.-2 adrenergic agonists (e.g., albuterol or
salmeterol), other PGD2 antagonists acting at other receptors such
as DP antagonists, PDE4 inhibitors (e.g., cilomilast), drugs that
modulate cytokine production, e.g., TACE inhibitors, drugs that
modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blocking
monoclonal antibodies & soluble receptors), PPAR.gamma.
agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase
inhibitors (e.g., zileuton).
[0651] In some embodiments, the pharmaceutical composition further
comprises one or more additional anti-fibrotic agents selected from
pirfenidone, nintedanib, thalidomide, carlumab, FG-3019,
fresolimumab, interferon alpha, lecithinized superoxide dismutase,
simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-gamma-1b,
IW-001, PRM-151, PXS-25, pentoxifylline/N-acetyl-cysteine,
pentoxifylline/vitamin E, salbutamol sulfate,
[Sar9,Met(O2)11]-Substance P, pentoxifylline, mercaptamine
bitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic
acid ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz,
IMM-124-E, MK-4074, PX-102, RO-5093151. In some embodiments,
provided is a method comprising administering a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
to a human with a LPA-dependent or LPA-mediated disease or
condition. In some embodiments, the human is already being
administered one or more additional therapeutically active agents
other than a compound of Formulas (I)-(IX), or a pharmaceutically
acceptable salt thereof. In some embodiments, the method further
comprises administering one or more additional therapeutically
active agents other than a compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof.
[0652] In some embodiments, the one or more additional
therapeutically active agents other than a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, are
selected from: corticosteroids (e.g,. dexamethasone or
fluticasone), immunosuppresants (e.g., tacrolimus &
pimecrolimus), analgesics, anti-cancer agent, anti-inflammatories,
chemokine receptor antagonists, bronchodilators, leukotriene
receptor antagonists (e.g., montelukast or zafirlukast),
leukotriene formation inhibitors, monoacylglycerol kinase
inhibitors, phospholipase A.sub.1 inhibitors, phospholipase A.sub.2
inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin
inhibitors, decongestants, antihistamines (e.g., loratidine),
mucolytics, anticholinergics, antitussives, expectorants,
anti-infectives (e.g., fusidic acid, particularly for treatment of
atopic dermatitis), anti-fungals (e.g., clotriazole, particularly
for atopic dermatitis), anti-IgE antibody therapies (e.g.,
omalizumab), .beta.-2 adrenergic agonists (e.g., albuterol or
salmeterol), other PGD2 antagonists acting at other receptors such
as DP antagonists, PDE4 inhibitors (e.g., cilomilast), drugs that
modulate cytokine production, e.g. TACE inhibitors, drugs that
modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blocking
monoclonal antibodies & soluble receptors), PPAR.gamma.
agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase
inhibitors (e.g., zileuton).
[0653] In some embodiments, the one or more additional
therapeutically active agents other than a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, are other
anti-fibrotic agents selected from pirfenidone, nintedanib,
thalidomide, carlumab, FG-3019, fresolimumab, interferon alpha,
lecithinized superoxide dismutase, simtuzumab, tanzisertib,
tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25,
pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E,
salbutamol sulfate, [Sar9,Met(O2)11]-Substance P, pentoxifylline,
mercaptamine bitartrate, obeticholic acid, aramchol, GFT-505,
eicosapentyl ethyl ester, metformin, metreleptin, muromonab-CD3,
oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151.
[0654] In some embodiments, the one or more additional
therapeutically active agents other than a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, are
selected from ACE inhibitors, ramipril, AII antagonists,
irbesartan, anti-arrythmics, dronedarone, PPAR.alpha. activators,
PPAR.gamma. activators, pioglitazone, rosiglitazone, prostanoids,
endothelin receptor antagonists, elastase inhibitors, calcium
antagonists, beta blockers, diuretics, aldosterone receptor
antagonists, eplerenone, renin inhibitors, rho kinase inhibitors,
soluble guanylate cyclase (sGC) activators, sGC sensitizers, PDE
inhibitors, PDE5 inhibitors, NO donors, digitalis drugs, ACE/NEP
inhibitors, statins, bile acid reuptake inhibitors, PDGF
antagonists, vasopressin antagonists, aquaretics, NHE1 inhibitors,
Factor Xa antagonists, Factor XIIIa antagonists, anticoagulants,
anti-thrombotics, platelet inhibitors, profibroltics,
thrombin-activatable fibrinolysis inhibitors (TAFI), PAI-1
inhibitors, coumarins, heparins, thromboxane antagonists, serotonin
antagonists, COX inhibitors, aspirin, therapeutic antibodies,
GPIIb/IIIa antagonists, ER antagonists, SERMs, tyrosine kinase
inhibitors, RAF kinase inhibitors, p38 MAPK inhibitors,
pirfenidone, multi-kinase inhibitors, nintedanib, sorafenib.
[0655] In some embodiments, the one or more additional
therapeutically active agents other than a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, are
selected from Gremlin-1 mAb, PA1-1 mAb, Promedior (PRM-151;
recombinant human Pentraxin-2); FGF21, TGF.beta. antagonists,
.alpha.v.beta.6 & .alpha.v.beta. pan-antagonists; FAK
inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors,
MGAT2 inhibitors, GPR120 agonists.
[0656] Pharmaceutical formulations described herein are
administrable to a subject in a variety of ways by multiple
administration routes, including but not limited to, oral,
parenteral (e.g., intravenous, subcutaneous, intramuscular),
intranasal, buccal, topical or transdermal administration routes.
The pharmaceutical formulations described herein include, but are
not limited to, aqueous liquid dispersions, self-emulsifying
dispersions, solid solutions, liposomal dispersions, aerosols,
solid dosage forms, powders, immediate release formulations,
controlled release formulations, fast melt formulations, tablets,
capsules, pills, delayed release formulations, extended release
formulations, pulsatile release formulations, multiparticulate
formulations, and mixed immediate and controlled release
formulations.
[0657] In some embodiments, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is administered
orally.
[0658] In some embodiments, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is administered
topically. In such embodiments, the compound of Formulas (I)-(IX),
or a pharmaceutically acceptable salt thereof, is formulated into a
variety of topically administrable compositions, such as solutions,
suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears,
medicated sticks, medicated bandages, balms, creams or ointments.
Such pharmaceutical compounds can contain solubilizers,
stabilizers, tonicity enhancing agents, buffers and preservatives.
In one aspect, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is administered topically
to the skin.
[0659] In another aspect, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is administered by
inhalation. In one embodiment, the compound of Formulas (I)-(IX),
or a pharmaceutically acceptable salt thereof, is administered by
inhalation that directly targets the pulmonary system.
[0660] In another aspect, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is formulated for
intranasal administration. Such formulations include nasal sprays,
nasal mists, and the like.
[0661] In another aspect, the compound of Formulas (I)-(IX), or a
pharmaceutically acceptable salt thereof, is formulated as eye
drops.
[0662] In another aspect is the use of a compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for treating a disease, disorder or
conditions in which the activity of at least one LPA receptor
contributes to the pathology and/or symptoms of the disease or
condition. In one embodiment of this aspect, the LPA is selected
from LPA.sub.1, LPA.sub.2, LPA.sub.3, LPA.sub.4, LPA.sub.5 and
LPA.sub.6. In one aspect, the LPA receptor is LPA.sub.1. In one
aspect, the disease or condition is any of the diseases or
conditions specified herein.
[0663] In any of the aforementioned aspects are further embodiments
in which: (a) the effective amount of the compound of Formulas
(I)-(IX), or a pharmaceutically acceptable salt thereof, is
systemically administered to the mammal; and/or (b) the effective
amount of the compound is administered orally to the mammal; and/or
(c) the effective amount of the compound is intravenously
administered to the mammal; and/or (d) the effective amount of the
compound is administered by inhalation; and/or (e) the effective
amount of the compound is administered by nasal administration; or
and/or (f) the effective amount of the compound is administered by
injection to the mammal; and/or (g) the effective amount of the
compound is administered topically to the mammal; and/or (h) the
effective amount of the compound is administered by ophthalmic
administration; and/or (i) the effective amount of the compound is
administered rectally to the mammal; and/or (j) the effective
amount is administered non-systemically or locally to the
mammal.
[0664] In any of the aforementioned aspects are further embodiments
comprising single administrations of the effective amount of the
compound, including further embodiments in which (i) the compound
is administered once; (ii) the compound is administered to the
mammal multiple times over the span of one day; (iii) continually;
or (iv) continuously.
[0665] In any of the aforementioned aspects are further embodiments
comprising multiple administrations of the effective amount of the
compound, including further embodiments in which (i) the compound
is administered continuously or intermittently: as in a a single
dose; (ii) the time between multiple administrations is every 6
hours; (iii) the compound is administered to the mammal every 8
hours; (iv) the compound is administered to the mammal every 12
hours; (v) the compound is administered to the mammal every 24
hours. In further or alternative embodiments, the method comprises
a drug holiday, wherein the administration of the compound is
temporarily suspended or the dose of the compound being
administered is temporarily reduced; at the end of the drug
holiday, dosing of the compound is resumed. In one embodiment, the
length of the drug holiday varies from 2 days to 1 year.
[0666] Also provided is a method of inhibiting the physiological
activity of LPA in a mammal comprising administering a
therapeutically effective amount of a compound of Formulas (I)-(IX)
or a pharmaceutically acceptable salt thereof to the mammal in need
thereof.
[0667] In one aspect, provided is a medicament for treating a
LPA-dependent or LPA-mediated disease or condition in a mammal
comprising a therapeutically effective amount of a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt
thereof.
[0668] In some cases disclosed herein is the use of a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for the treatment of a
LPA-dependent or LPA-mediated disease or condition.
[0669] In some cases disclosed herein is the use of a compound of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof,
in the treatment or prevention of a LPA-dependent or LPA-mediated
disease or condition.
[0670] In one aspect, is a method for treating or preventing a
LPA-dependent or LPA-mediated disease or condition in a mammal
comprising administering a therapeutically effective amount of a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof.
[0671] In one aspect, LPA-dependent or LPA-mediated diseases or
conditions include, but are not limited to, fibrosis of organs or
tissues, scarring, liver diseases, dermatological conditions,
cancer, cardiovascular disease, respiratory diseases or conditions,
inflammatory disease, gastrointestinal tract disease, renal
disease, urinary tract-associated disease, inflammatory disease of
lower urinary tract, dysuria, frequent urination, pancreas disease,
arterial obstruction, cerebral infarction, cerebral hemorrhage,
pain, peripheral neuropathy, and fibromyalgia.
[0672] In one aspect, the LPA-dependent or LPA-mediated disease or
condition is a respiratory disease or condition. In some
embodiments, the respiratory disease or condition is asthma,
chronic obstructive pulmonary disease (COPD), pulmonary fibrosis,
pulmonary arterial hypertension or acute respiratory distress
syndrome.
[0673] In some embodiments, the LPA-dependent or LPA-mediated
disease or condition is selected from idiopathic pulmonary
fibrosis; other diffuse parenchymal lung diseases of different
etiologies including iatrogenic drug-induced fibrosis, occupational
and/or environmental induced fibrosis, granulomatous diseases
(sarcoidosis, hypersensitivity pneumonia), collagen vascular
disease, alveolar proteinosis, langerhans cell granulomatosis,
lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak
Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage
disorders, familial interstitial lung disease); radiation induced
fibrosis; chronic obstructive pulmonary disease (COPD);
scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma;
silicosis; asbestos induced pulmonary fibrosis; acute respiratory
distress syndrome (ARDS); kidney fibrosis; tubulointerstitium
fibrosis; glomerular nephritis; focal segmental glomerular
sclerosis; IgA nephropathy; hypertension; Alport; gut fibrosis;
liver fibrosis; cirrhosis; alcohol induced liver fibrosis;
toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholic
steatohepatitis (NASH); biliary duct injury; primary biliary
cirrhosis; infection induced liver fibrosis; viral induced liver
fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic
scarring; Duputren disease, keloids, cutaneous fibrosis; cutaneous
scleroderma; spinal cord injury/fibrosis; myelofibrosis; vascular
restenosis; atherosclerosis; arteriosclerosis; Wegener's
granulomatosis; Peyronie's disease, chronic lymphocytic leukemia,
tumor metastasis, transplant organ rejection, endometriosis,
neonatal respiratory distress syndrome and neuropathic pain.
[0674] In one aspect, the LPA-dependent or LPA-mediated disease or
condition is described herein.
[0675] In one aspect, provided is a method for the treatment or
prevention of organ fibrosis in a mammal comprising administering a
therapeutically effective amount of a compound of Formulas (I)-(IX)
or a pharmaceutically acceptable salt thereof to a mammal in need
thereof.
[0676] In one aspect, the organ fibrosis comprises lung fibrosis,
renal fibrosis, or hepatic fibrosis.
[0677] In one aspect, provided is a method of improving lung
function in a mammal comprising administering a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof to the mammal in need
thereof. In one aspect, the mammal has been diagnosed as having
lung fibrosis.
[0678] In one aspect, compounds disclosed herein are used to treat
idiopathic pulmonary fibrosis (usual interstitial pneumonia) in a
mammal.
[0679] In some embodiments, compounds disclosed herein are used to
treat diffuse parenchymal interstitial lung diseases in mammal:
iatrogenic drug induced, occupational/environmental (Farmer lung),
granulomatous diseases (sarcoidosis, hypersensitivity pneumonia),
collagen vascular disease (scleroderma and others), alveolar
proteinosis, langerhans cell granulonmatosis,
lymphangioleiomyomatosis, Hermansky-Pudlak Syndrome, Tuberous
sclerosis, neurofibromatosis, metabolic storage disorders, familial
interstitial lung disease.
[0680] In some embodiments, compounds disclosed herein are used to
treat post-transplant fibrosis associated with chronic rejection in
a mammal: Bronchiolitis obliterans for lung transplant.
[0681] In some embodiments, compounds disclosed herein are used to
treat cutaneous fibrosis in a mammal: cutaneous scleroderma,
Dupuytren disease, keloids.
[0682] In one aspect, compounds disclosed herein are used to treat
hepatic fibrosis with or without cirrhosis in a mammal: toxic/drug
induced (hemochromatosis), alcoholic liver disease, viral hepatitis
(hepatitis B virus, hepatitis C virus, HCV), nonalcoholic liver
disease (NAFLD, NASH), metabolic and auto-immune disease.
[0683] In one aspect, compounds disclosed herein are used to treat
renal fibrosis in a mammal: tubulointerstitium fibrosis, glomerular
sclerosis.
[0684] In any of the aforementioned aspects involving the treatment
of LPA dependent diseases or conditions are further embodiments
comprising administering at least one additional agent in addition
to the administration of a compound having the structure of
Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof.
In various embodiments, each agent is administered in any order,
including simultaneously.
[0685] In any of the embodiments disclosed herein, the mammal is a
human.
[0686] In some embodiments, compounds provided herein are
administered to a human.
[0687] In some embodiments, compounds provided herein are orally
administered.
[0688] In some embodiments, compounds provided herein are used as
antagonists of at least one LPA receptor. In some embodiments,
compounds provided herein are used for inhibiting the activity of
at least one LPA receptor or for the treatment of a disease or
condition that would benefit from inhibition of the activity of at
least one LPA receptor. In one aspect, the LPA receptor is
LPA.sub.1.
[0689] In other embodiments, compounds provided herein are used for
the formulation of a medicament for the inhibition of LPA.sub.1
activity.
[0690] Articles of manufacture, which include packaging material, a
compound of Formulas (I)-(IX), or a pharmaceutically acceptable
salt thereof, within the packaging material, and a label that
indicates that the compound or composition, or pharmaceutically
acceptable salt, tautomers, pharmaceutically acceptable N-oxide,
pharmaceutically active metabolite, pharmaceutically acceptable
prodrug, or pharmaceutically acceptable solvate thereof, is used
for inhibiting the activity of at least one LPA receptor, or for
the treatment, prevention or amelioration of one or more symptoms
of a disease or condition that would benefit from inhibition of the
activity of at least one LPA receptor, are provided.
VI. GENERAL SYNTHESIS INCLUDING SCHEMES
[0691] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or by variations thereon as appreciated by those skilled in the
art. Preferred methods include, but are not limited to, those
described below. The reactions are performed in a solvent or
solvent mixture appropriate to the reagents and materials employed
and suitable for the transformations being effected. It will be
understood by those skilled in the art of organic synthesis that
the functionality present on the molecule should be consistent with
the transformations proposed. This will sometimes require a
judgment to modify the order of the synthetic steps or to select
one particular process scheme over another in order to obtain a
desired compound of the invention.
[0692] It will also be recognized that another major consideration
in the planning of any synthetic route in this field is the
judicious choice of the protecting group used for protection of the
reactive functional groups present in the compounds described in
this invention. An authoritative account describing the many
alternatives to the trained practitioner is Greene et al.,
(Protective Groups in Organic Synthesis, Fourth Edition,
Wiley-Interscience (2006)).
[0693] The compounds of Formulas (I)-(IX) may be prepared by the
exemplary processes described in the following schemes and working
examples, as well as relevant published literature procedures that
are used by one skilled in the art. Exemplary reagents and
procedures for these reactions appear herein after and in the
working examples. Protection and deprotection in the processes
below may be carried out by procedures generally known in the art
(see, for example, Wuts, P. G. M., Greene's Protective Groups in
Organic Synthesis, 5th Edition, Wiley (2014)). General methods of
organic synthesis and functional group transformations are found
in: Trost, B. M. et al., Eds., Comprehensive Organic Synthesis:
Selectivity, Strategy & Efficiency in Modern Organic Chemistry,
Pergamon Press, New York, N.Y. (1991); Smith, M. B. et al., March's
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure.
7th Edition, Wiley, New York, N.Y. (2013); Katritzky, A. R. et al.,
Eds., Comprehensive Organic Functional Group Transformations II,
2nd Edition, Elsevier Science Inc., Tarrytown, N.Y. (2004); Larock,
R. C., Comprehensive Organic Transformations, 2.sup.nd Edition,
Wiley-VCH, New York, N.Y. (1999), and references therein.
[0694] Scheme 1 describes the synthesis of carbamoyloxymethyl
triazole-aryloxy cyclohexyl acids 14. A dihalo (preferably dibromo)
phenyl or azine (e.g. pyridine) derivative 1 is coupled with an
appropriately protected (e.g. as a tetrahydropyranyl ether)
propargyl alcohol 2 under Sonogashira conditions (e.g. Alper, P. et
al, WO 2008097428) to give the corresponding bromo-aryl or
bromo-heteroaryl protected propargyl alcohol 3. Thermal reaction of
alkyne 3 with an alkyl azide 4 (with or without an appropriate
catalyst; Qian, Y. et al, J. Med. Chem., 2012, 55 , 7920-7939 or
Boren, B. C., et al., J. Am. Chem. Soc., 2008, 130, 8923-8930)
provides the corresponding regioisomeric protected
hydroxylmethyl-triazoles, from which the desired triazole
regioisomer 5 can be isolated. Reaction of the bromoaryl- or
bromoheteroaryl-triazoles 5 with pinacol diboronate in the presence
of an appropriate palladium catalyst (Ishiyama, T. et al, J. Org.
Chem. 1995, 60, 7508-7510) provides the corresponding pinacol
boronate 6, which is then oxidized with hydrogen peroxide to give
the corresponding phenol or hydroxyheteroarene 7 (Fukumoto, S. et
al, WO 2012137982). Reaction of phenol/hydroxyheteroarene 7 with a
3-hydroxy cycloalkyl ester 8 under Mitsunobu reaction conditions
(Kumara Swamy, K. C., Chem. Rev., 2009, 109, 2551-2651) furnishes
the corresponding triazole cycloalkyl ether ester 9. Deprotection
of the hydoxytriazole 9 provides the triazole alcohol 10, which is
then reacted with 4-nitrophenyl chloroformate in the presence of an
appropriate base to give the corresponding triazole 4-nitrophenyl
carbonate 11. The triazole 4-nitrophenyl carbonate 11 is then
reacted with an amine 12 in the presence of an appropriate base to
give the triazole carbamate 13, which then undergoes ester
deprotection to give the desired carbamoyloxymethyltriazole-aryloxy
cycloalkyl acids 14.
##STR00051## ##STR00052## ##STR00053##
[0695] For the specific example of analogs 14, where
R.sub.2.dbd.CH.sub.3 (Scheme 1A), instead of using an alkyl azide
for the cycloaddition to the protected hydroxyalkyl alkyne 3,
trimethylsilyl azide is a viable replacement reagent (Qian, Y. et
al, J. Med. Chem., 2012, 55, 7920-7939) that can be used under
either thermal or transition-metal catalyzed conditions (Boren, B.
C. et. al., J. Am. Chem. Soc., 2008, 130, 8923-8930). Under these
conditions, the desired triazole regioisomer 15 is obtained as the
major product of the 1,3-dipolar cycloaddition reaction, and the
trimethylsilyl group is subsequently removed under standard
desilylation conditions (e.g. Bu.sub.4NF, as in Qian, Y. et al, J.
Med. Chem., 2012, 55, 7920-7939).
##STR00054##
[0696] Scheme 2 describes an alternative synthetic route to the
carbamoyloxymethyl triazole-aryloxy cyclohexyl acids 14. A dihalo
(preferably dibromo) phenyl or azine (e.g. pyridine) derivative 1
is coupled with propargyl alcohol under Sonogashira conditions
(Alper, P. et al, WO 2008097428) to give the corresponding
bromo-aryl or bromo-heteroaryl propargyl alcohol 3. Thermal
reaction of alkyne 3 with an alkyl azide 4 (with or without an
appropriate catalyst, Qian, Y. et al, J. Med. Chem., 2012, 55,
7920-7939; Boren, B. C. et. al., J. Am. Chem. Soc., 2008, 130,
8923-8930) provides the corresponding regioisomeric
hydroxymethyl-triazoles, from which the desired triazole
regioisomer 18 can be isolated. Triazole alcohol 18 is then reacted
with 4-nitrophenyl chloroformate in the presence of an appropriate
base to give the corresponding triazole 4-nitrophenyl carbonate 19,
which is then reacted with an amine 12 in the presence of an
appropriate base to give the aryl/heteroaryl-triazole carbamate 20.
The bromo-aryl/heteroaryl triazole 20 is then converted to the
hydroxyaryl or hydroxy-heteroaryl triazole 21 via the corresponding
boronate using the 2 step sequence [B(pin).sub.2/Pd-catalysis
followed by treatment with H.sub.2O.sub.2] described in Scheme 1.
Hydroxyaryl/heteroaryl triazole 22 is then reacted with a 3-hydroxy
cycloalkylester 8 under Mitsunobu reaction conditions (Kumara
Swamy, K. C., Chem. Rev., 2009, 109, 2551-2651) to furnish the
corresponding triazole cycloalkyl ether ester 13 which is then
deprotected to give the desired carbamoyloxy methyltriazole-aryloxy
cyclohexyl acids 14.
##STR00055## ##STR00056##
[0697] Another alternative synthesis of carbamoyloxymethyl
triazole-aryloxy cyclohexyl acids 14 is described in Scheme 3.
Reaction of an alkoxyphenyl or azine (e.g. pyridine) derivative 1
with trimethylsilyl acetylene under Sonogashira conditions (Alper,
P. et al, WO 2008097428) gives the corresponding alkoxy-aryl or
heteroaryl silyl acetylene 23, which is then desilylated under
standard conditions (e.g. Bu.sub.4NF) to give the alkyne 24.
Thermal reaction of alkyne 24 with sodium azide gives the
corresponding triazole (Roehrig, U. et al, WO 2009127669), which is
then alkylated with an alkyl iodide 25 under basic conditions to
give a mixture of regioisomeric alkylated triazoles, from which the
desired triazole regioisomer 26 can be isolated. Lithiation of
triazole 26 (Hernandez, M. et al, US 20120115844) followed by
reaction with a formylating agent, e.g. dimethyl formamide,
provided the triazole aldehyde 27. Deprotection of the alkoxy group
of arene/heteroarene 27 followed by reprotection of the
phenol/hydroxy-heteroarene with a more labile protecting group
(e.g. t-butyldimethylsilyl ether) gives the protected
aryl/heteroaryl triazole aldehyde 28, which is then reduced by
standard methods (e.g. NaBH.sub.4) to the corresponding triazole
alcohol 29. Triazole alcohol 29 is reacted with 4-nitrophenyl
chloroformate to give the corresponding triazole 4-nitrophenyl
carbonate 30. This triazole carbonate 30 is then reacted with an
amine 12 in the presence of an appropriate base to give the
corresponding triazole carbamate, which subsequently undergoes
deprotection to provide the hydroxy aryl/hetero-aryl triazole
carbamate 21. The hydroxy aryl/heteroaryl triazole carbamate 21
then is subjected to a Mitsunobu reaction with 3-hydroxy cycloalkyl
ester 8 to furnish the corresponding triazole cycloalkyl ether
ester 13, followed by ester deprotection to give the desired
carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.
##STR00057## ##STR00058## ##STR00059##
[0698] A different synthetic route for the preparation of triazole
carbamate acids 14 is described in Scheme 4. The protected
hydroxyaryl/heteroaryl triazole alcohol 29 is reacted with the
intermediate isocyanate generated from a carboxylic acid 31 under
Curtius reaction conditions (Seiders, T. et al, WO 2011041694A2) to
give the monoalkyl NH-carbamate 32. Base-mediated reaction of
NH-carbamate 32 with an appropriate alkyl iodide 33 provides the
corresponding triazole N-disubstituted carbamate, which is then
deprotected to provide the hydroxy aryl/heteroaryl triazole
carbamate 21. Hydroxy aryl/heteroaryl triazole carbamate 21 then is
subjected to a Mitsunobu reaction with 3-hydroxy cycloalkylester 8
to furnish the corresponding triazole cycloalkyl ether ester 13
followed by ester deprotection to give the desired carbamoyloxy
methyltriazole-aryloxy cyclohexyl acids 14. Alternatively, the
triazole monoalkyl NH-carbamate 32 is deprotected to give the
hydroxy aryl/heteroaryl triazole carbamate, which is then reacted
with 3-hydroxy cycloalkylester 8 under Mitsunobu reaction
conditions to provide the triazole-aryloxy cyclohexyl ester
NH-carbamate 34. Intermediate NH-carbamate 34 is then alkylated
with alkyl iodide 33 under basic conditions; subsequent ester
deprotection furnishes the desired carbamoyloxy
methyltriazole-aryloxy cyclohexyl acids 14.
##STR00060## ##STR00061##
[0699] An alternative synthesis of carbamoyloxy
methyltriazole-aryloxy cyclohexyl acids 14 from the protected
hydroxyalkyltriazole cycloalkyl ether ester 9 is described in
Scheme 5. Selective deprotection of the alcohol of 9 followed by
its reaction with the isocyanate generated from the Curtius
rearrangement of an alkyl carboxylic acid 31 provides the triazole
NH monoalkyl carbamate 34. The triazole NH-carbamate 34 is then
alkylated with alkyl iodide 33 under basic conditions, followed by
ester deprotection to give the desired carbamoyloxy
methyltriazole-aryloxy cyclohexyl acids 14.
##STR00062## ##STR00063##
[0700] Scheme 6 decribes the synthesis of carbamoyloxy
methyltriazole-aryloxy .alpha.-F cyclohexyl acids 42. Diels-Alder
reaction of diene 35 and ethyl 2-fluoroacrylate 36 under thermal
conditions (e.g. procedure of Kotikyan et al., Bulletin of the
Academy of Sciences of the USSR, Division of Chemical Science
(Engl.), 1971, 20, 292) gives the .alpha.-F cyclohexyl ester 37.
Hydrolysis of ester 37 under basic condition provides acid 38.
Iodolactonization (e.g. Nolsoe, J. M. J. et al., Eur. J. Org.
Chem., 2014, 3051-3065) of the olefin with the carboxylic acid of
38 gives iodolactone 39. Deiodination under radical condition (e.g.
AIBN/(TMS).sub.3SiH, ref. Chatgilialoglu, C. et al., Molecules,
2012, 17, 527-555) affords lactone 40. Openning of lactone 40 via
acidic condition (e.g. AcCl in iPrOH) gives the .alpha.-F
cyclohexyl ester 41. The carbamoyloxy methyltriazole-aryloxy
.alpha.-F cyclohexyl acids 42 are synthesized from the .alpha.-F
cyclohexyl ester 41 following the general synthetic procedure
described in Schemes 1 or 2.
##STR00064##
[0701] Scheme 7 decribes the synthesis of carbamoyloxy
methyltriazole-aryloxy cyclohexyl acids 44. Addition of an alkyl
organometallic reagent (e.g R.sub.13Li or R.sub.13MgX) to aldehyde
28 gives triazole alcohol 43. The carbamoyloxy
methyltriazole-aryloxy cyclohexyl acids 44 can then be synthesized
from triazole alcohol 43 following the general synthetic procedure
described in Scheme 3.
##STR00065##
[0702] Scheme 8 describes the synthesis of carbamoyloxy
methyltriazole-aryloxy cyclohexyl amides 45, tetrazoles 47 and acyl
sulfonamide 48. Treatment of acid 14 with AcCl followed by ammonia
gives primary amide 45. Dehydration of primary amide 45 with
Burgess reagent (Talibi, P. et al., e-EROS Encyclopedia of Reagents
for Organic Synthesis, published online 15 Sep. 2008, DOI:
10.1002/047084289X.rm095m.pub2) furnishes nitrile 46. Cycloaddition
of azide to nitrile 46 affords the tetrazole 47. In a similar
manner to the preparation of amides 45, acyl sulfonamides 48 can be
synthesized by the reaction of carboxylic acid 14 with methyl
sulfonamide using standard coupling agents (e.g. EDC/DMAP).
##STR00066##
[0703] Scheme 9 describes the synthesis of carbamoyloxyethyl
triazole-aryloxy cyclohexyl acids 53. The protected alcohol
intermediate 9 is deprotected to the corresponding alcohol, which
is then oxidized to the corresponding aldehyde (e.g. Dess-Martin
periodinane or Swern oxidation) which is then subjected to an
olefination reaction (e.g. Witting or Peterson olefination
reaction) which provides the terminal olefin 49. Hydroboration of
olefin 49 at the terminal carbon (e.g. with 9-BBN), followed by
oxidative workup, provides the corresponding triazole ethyl alcohol
50. Triazole ethyl alcohol 50 is reacted with 4-nitrophenyl
chloroformate in the presence of an appropriate base to give the
corresponding triazole 4-nitrophenyl carbonate 51. The triazole
4-nitrophenyl carbonate 51 is then reacted with an amine 12 in the
presence of an appropriate base to give the triazole carbamate 52,
which then undergoes ester deprotection to give the desired
carbamoyloxyethyltriazole-aryloxy cycloalkyl acids 53.
##STR00067## ##STR00068##
[0704] Scheme 10 describes the synthesis of carbamoyloxypropyl
triazole-aryloxy cyclohexyl acids 58. The protected alcohol
intermediate 9 is deprotected to the corresponding alcohol, then is
oxidized to the corresponding aldehyde which is then subjected to
olefination conditions (eg. Wittig reaction with a reagent with an
appropriately protected alcohol such as 2-(benzyloxy) ethylidene)
as shown) which provides olefin 54 as a mixture of cis/trans
isomers. Hydrogenation of the olefin, followed by deprotection of
the alcohol (e.g. using hydrogenolysis with H.sub.2), provides the
corresponding triazole alcohol 55. The triazole alcohol 55 is
reacted with 4-nitrophenyl chloroformate in the presence of an
appropriate base to give the corresponding triazole 4-nitrophenyl
carbonate 56. The triazole 4-nitrophenyl carbonate 56 is then
reacted with an amine 12 in the presence of an appropriate base to
give the triazole carbamate 57, which then undergoes ester
deprotection to give the desired carbamoyloxypropyltriazole-aryloxy
cycloalkyl acids 58.
##STR00069## ##STR00070##
[0705] Abbreviations as used herein, are defined as follows:
"1.times." for once, "2.times." for twice, "3.times." for thrice,
".degree. C." for degrees Celsius, "eq" for equivalent or
equivalents, "g" for gram or grams, "mg" for milligram or
milligrams, "L" for liter or liters, "mL" for milliliter or
milliliters, ".mu.L" for microliter or microliters, "N" for normal,
"M" for molar, "mmol" for millimole or millimoles, "min" for minute
or minutes, "h" for hour or hours, "rt" for room temperature, "RT"
for retention time, "RBF" for round bottom flask, "atm" for
atmosphere, "psi" for pounds per square inch, "conc." for
concentrate, "RCM" for ring-closing metathesis, "sat" or "sat'd"
for saturated, "SFC" for supercritical fluid chromatography "MW"
for molecular weight, "mp" for melting point, "ee" for enantiomeric
excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for
electrospray ionization mass spectroscopy, "HR" for high
resolution, "HRMS" for high resolution mass spectrometry, "LCMS"
for liquid chromatography mass spectrometry, "HPLC" for high
pressure liquid chromatography, "RP HPLC" for reverse phase HPLC,
"TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear
magnetic resonance spectroscopy, "nOe" for nuclear Overhauser
effect spectroscopy, ".sup.1H" for proton, ".delta." for delta, "s"
for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m"
for multiplet, "br" for broad, "Hz" for hertz, and ".alpha.",
".beta.", ".gamma.", "R", "S", "E", and "Z" are stereochemical
designations familiar to one skilled in the art. [0706] Me methyl
[0707] Et ethyl [0708] Pr propyl [0709] i-Pr isopropyl [0710] Bu
butyl [0711] i-Bu isobutyl [0712] t-Bu tert-butyl [0713] Ph phenyl
[0714] Bn benzyl [0715] Boc or BOC tert-butyloxycarbonyl [0716]
Boc.sub.2O di-tert-butyl dicarbonate [0717] AcOH or HOAc acetic
acid [0718] AlCl.sub.3 aluminum trichloride [0719] AIBN
Azobis-isobutyronitrile [0720] BBr.sub.3 boron tribromide [0721]
BCl.sub.3 boron trichloride [0722] BEMP
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine [0723] BOP reagent
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate [0724] Burgess reagent
1-methoxy-N-triethylammoniosulfonyl-methanimidate [0725] CBz
carbobenzyloxy [0726] DCM or CH.sub.2Cl.sub.2 dichloromethane
[0727] CH.sub.3CN or ACN acetonitrile [0728] CDCl.sub.3
deutero-chloroform [0729] CHCl.sub.3 chloroform [0730] mCPBA or
m-CPBA meta-chloroperbenzoic acid [0731] Cs.sub.2CO.sub.3 cesium
carbonate [0732] Cu(OAc).sub.2 copper (II) acetate [0733]
Cy.sub.2NMe N-cyclohexyl-N-methylcyclohexanamine [0734] DBU
1,8-diazabicyclo[5.4.0]undec-7-ene [0735] DCE 1,2 dichloroethane
[0736] DEA diethylamine [0737] Dess-Martin
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxo1-3-(1H)-one [0738]
DIC or DIPCDI diisopropylcarbodiimide [0739] DIEA, DIPEA or
diisopropylethylamine [0740] Hunig's base [0741] DMAP
4-dimethylaminopyridine [0742] DME 1,2-dimethoxyethane [0743] DMF
dimethyl formamide [0744] DMSO dimethyl sulfoxide [0745] cDNA
complementary DNA [0746] Dppp
(R)-(+)-1,2-bis(diphenylphosphino)propane [0747] DuPhos
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene [0748] EDC
N-(3-dimthylaminopropyl)-N'-ethylcarbodiimide [0749] EDCI
N-(3-dimthylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0750]
EDTA ethylenediaminetetraacetic acid [0751] (S,S)-EtDuPhosRh(I)
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rho-
dium(I) trifluoromethanesulfonate [0752] Et.sub.3N or TEA
triethylamine [0753] EtOAc ethyl acetate [0754] Et.sub.2O diethyl
ether [0755] EtOH ethanol [0756] GMF glass microfiber filter [0757]
Grubbs II
(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro
(phenylmethylene)(triycyclohexylphosphine)ruthenium [0758] HCl
hydrochloric acid [0759] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0760] HEPES
4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid [0761] Hex
hexane [0762] HOBt or HOBT 1-hydroxybenzotriazole [0763]
H.sub.2O.sub.2 hydrogen peroxide [0764] IBX 2-iodoxybenzoic acid
[0765] H.sub.2SO.sub.4 sulfuric acid [0766] Jones reagent CrO.sub.3
in aqueous H.sub.2SO.sub.4, 2 M solution [0767] K.sub.2CO.sub.3
potassium carbonate [0768] K.sub.2HPO.sub.4 potassium phosphate
dibasic (potassium hydrogen phosphate) [0769] KOAc potassium
acetate [0770] K.sub.3PO.sub.4 potassium phosphate tribasic [0771]
LAH lithium aluminum hydride [0772] LG leaving group [0773] LiOH
lithium hydroxide [0774] MeOH methanol [0775] MgSO.sub.4 magnesium
sulfate [0776] MsOH or MSA methylsulfonic acid/methanesulfonic acid
[0777] NaCl sodium chloride [0778] NaH sodium hydride [0779]
NaHCO.sub.3 sodium bicarbonate [0780] Na.sub.2CO.sub.3 sodium
carbonate [0781] NaOH sodium hydroxide [0782] Na.sub.2SO.sub.3
sodium sulfite [0783] Na.sub.2SO.sub.4 sodium sulfate [0784] NBS
N-bromosuccinimide [0785] NCS N-chlorosuccinimide [0786] NH.sub.3
ammonia [0787] NH.sub.4Cl ammonium chloride [0788] NH.sub.4OH
ammonium hydroxide [0789] NH.sub.4.sup.+HCO.sub.2.sup.- ammonium
formate [0790] NMM N-methylmorpholine [0791] OTf triflate or
trifluoromethanesulfonate [0792] Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) [0793] Pd(OAc).sub.2
palladium(II) acetate [0794] Pd/C palladium on carbon [0795]
Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) [0796]
Ph.sub.3PCl.sub.2 triphenylphosphine dichloride [0797] PG
protecting group [0798] POCl.sub.3 phosphorus oxychloride [0799]
PPTS pyridinium p-toluenesulfonate [0800] i-PrOH or IPA isopropanol
[0801] PS Polystyrene [0802] RT or rt room temperature [0803]
SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride [0804] SiO.sub.2
silica oxide [0805] SnCl.sub.2 tin(II) chloride [0806] TBAF
tra-n-butylammonium fluoride [0807] TBAI tetra-n-butylammonium
iodide [0808] TFA trifluoroacetic acid [0809] THF tetrahydrofuran
[0810] THP tetrahydropyran [0811] TMSCHN.sub.2
Trimethylsilyldiazomethane [0812] TMSCH.sub.2N.sub.3
Trimethylsilylmethyl azide [0813] T3P propane phosphonic acid
anhydride [0814] TRIS tris (hydroxymethyl) aminomethane [0815]
pTsOH p-toluenesulfonic acid
VII. EXAMPLES
[0816] The following Examples are offered as illustrative, as a
partial scope and particular embodiments of the invention and are
not meant to be limiting of the scope of the invention.
Abbreviations and chemical symbols have their usual and customary
meanings unless otherwise indicated. Unless otherwise indicated,
the compounds described herein have been prepared, isolated and
characterized using the schemes and other methods disclosed herein
or may be prepared using the same.
[0817] As appropriate, reactions were conducted under an atmosphere
of dry nitrogen (or argon). For anhydrous reactions, DRISOLV.RTM.
solvents from EM were employed. For other reactions, reagent grade
or HPLC grade solvents were utilized. Unless otherwise stated, all
commercially obtained reagents were used as received.
HPLC/MS and Preparatory/Analytical HPLC Methods Employed in
Characterization or Purification of Examples
[0818] NMR (nuclear magnetic resonance) spectra were typically
obtained on Bruker or JEOL 400 MHz and 500 MHz instruments in the
indicated solvents. All chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal
standard. .sup.1HNMR spectral data are typically reported as
follows: chemical shift, multiplicity (s=singlet, br s=broad
singlet, d=doublet, dd=doublet of doublets, t=triplet, q=quartet,
sep=septet, m=multiplet, app=apparent), coupling constants (Hz),
and integration.
[0819] In the examples where .sup.1HNMR spectra were collected in
d.sub.6-DMSO, a water-suppression sequence is often utilized. This
sequence effectively suppresses the water signal and any proton
peaks in the same region usually between 3.30-3.65 ppm which will
affect the overall proton integration.
[0820] The term HPLC refers to a Shimadzu high performance liquid
chromatography instrument with one of following methods: [0821]
HPLC-1: Sunfire C18 column (4.6.times.150 mm) 3.5 .mu.m, gradient
from 10 to 100% B:A for 12 min, then 3 min hold at 100% B. [0822]
Mobile phase A: 0.05% TFA in water:CH.sub.3CN (95:5) [0823] Mobile
phase B: 0.05% TFA in CH.sub.3CN:water (95:5) [0824] TFA Buffer
pH=2.5; Flow rate: 1 mL/min; Wavelength: 254 nm, 220 nm. [0825]
HPLC-2: XBridge Phenyl (4.6.times.150 mm) 3.5 .mu.m, gradient from
10 to 100% B:A for 12 min, then 3 min hold at 100% B. [0826] Mobile
phase A: 0.05% TFA in water:CH.sub.3CN (95:5) [0827] Mobile phase
B: 0.05% TFA in CH.sub.3CN:water (95:5) [0828] TFA Buffer pH=2.5;
Flow rate: 1 mL/min; Wavelength: 254 nm, 220 nm. [0829] HPLC-3:
Chiralpak AD-H, 4.6.times.250 mm, 5 .mu.m. [0830] Mobile Phase: 30%
EtOH-heptane (1:1)/70% CO.sub.2 [0831] Flow rate=40 mL/min, 100
Bar, 35.degree. C.; Wavelength: 220 nm [0832] HPLC-4: Waters
Acquity UPLC BEH C18, 2.1.times.50 mm, 1.7-.mu.m particles; [0833]
Mobile Phase A: 5:95 CH.sub.3CN:water with 10 mM NH.sub.4OAc;
[0834] Mobile Phase B: 95:5 CH.sub.3CN:water with 10 mM
NH.sub.4OAc; [0835] Temperature: 50.degree. C.; Gradient: 0-100% B
over 3 min, then a 0.75-min hold at 100% B; [0836] Flow: 1.11
mL/min; Detection: UV at 220 nm. [0837] HPLC-5: Waters Acquity UPLC
BEH C18, 2.1.times.50 mm, 1.7-.mu.m particles; [0838] Mobile Phase
A: 5:95 CH.sub.3CN:water with 0.1% TFA; [0839] Mobile Phase B: 95:5
CH.sub.3CN:water with 0.1% TFA; [0840] Temperature: 50.degree. C.;
Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B;
Flow: 1.11 mL/min; Detection: UV at 220 nm.
Intermediate 1 (.+-.)-cis-isopropyl
1-fluoro-3-hydroxycyclohexanecarboxylate
##STR00071##
[0841] Intermediate 1A (.+-.)-ethyl
1-fluorocyclohex-3-enecarboxylate
##STR00072##
[0843] A mixture of 20% buta-1,3-diene in toluene (13.8 mL, 41.1
mmol) and ethyl 2-fluoroacrylate (3.07 mL, 27.4 mmol) was heated at
120.degree. C. in a sealed tube for 7 days. The reaction was cooled
to rt and concentrated in vacuo. The residue was chromatographed
(80 g SiO.sub.2) with EtOAc/Hexane (continuous gradient from 0% to
10% EtOAc over 20 min) to give Intermediate 1A (3.80 g, 22.1 mmol,
80% yield) as a clear oil. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 5.79 (ddd, J=9.9, 4.7, 2.2 Hz, 1H), 5.64-5.58 (m, 1H), 4.26
(q, J=7.2 Hz, 2H), 2.73-2.57 (m, 1H), 2.45-2.23 (m, 2H), 2.20-1.91
(m, 3H), 1.32 (t, J=7.2 Hz, 3H); .sup.19F NMR (471 MHz, CDCl.sub.3)
.delta. -162.69 (s, 1F).
Intermediate 1B (.+-.)-1-fluorocyclohex-3-ene carboxylic acid
##STR00073##
[0845] A mixture of Intermediate 1A (3.80 g, 22.1 mmol) and aq.
LiOH (55.2 mL of a 2.0 M solution, 110 mmol) in THF (50 mL) was
stirred at rt for 18 h. The reaction was acidified to pH=2 with
conc. HCl (9.19 mL, 110 mmol), and then extracted with EtOAc
(3.times.25 mL). The combined organic extracts were washed with
water and concentrated in vacuo to give Intermediate 1B (3.0 g,
20.8 mmol, 94% yield) as a light yellowish oil. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 5.81 (ddd, J=9.8, 4.6, 2.1 Hz, 1H),
5.66-5.58 (m, 1H), 2.76-2.59 (m, 1H), 2.49-2.37 (m, 1H), 2.35-2.23
(m, 1H), 2.22-1.92 (m, 3H); .sup.19F NMR (471 MHz, CDCl.sub.3)
.delta. -163.02 (s, 1F).
Intermediate 1C
(.+-.)-1-fluoro-4-iodo-6-oxabicyclo[3.2.1]octan-7-one
##STR00074##
[0847] To a mixture of Intermediate 1B (3.0 g, 20.8 mmol) in water
(20 mL) was added NaHCO.sub.3 (5.25 g, 62.4 mmol) portionwise and
the mixture was stirred until it became homogeneous. An aq. 12
solution (prepared by dissolving 12 (5.81 g, 22.0 mmol) and KI
(20.7 g, 125 mmol) in 20 mL water) was added and the reaction was
stirred overnight at rt in the dark. Water (100 mL) was then added
and the mixture was extracted with DCM (3.times.25 mL), washed with
10% aq. Na.sub.2S.sub.2O.sub.3 (20 mL.times.2) and water, dried
(MgSO.sub.4) and concentrated in vacuo. The residual crude oil was
chromatographed (80 g SiO.sub.2) with EtOAc/Hexane (continuous
gradient from 0% to 50% EtOAc over 20 min) to give Intermediate 1C
(3.53 g, 13.1 mmol, 62.8% yield) as a white solid. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 4.89 (dt, J=6.5, 3.5 Hz, 1H), 4.44 (q,
J=4.6 Hz, 1H), 3.08 (dd, J=11.6, 1.9 Hz, 1H), 2.75 (tddd, J=11.3,
6.5, 3.3, 1.1 Hz, 1H), 2.50-2.38 (m, 1H), 2.34-2.17 (m, 2H),
2.11-1.99 (m, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta.
172.2, 172.0, 93.6, 91.9, 78.4, 78.3, 39.2, 39.0, 29.7, 29.6, 28.4,
28.2, 20.2; .sup.19F NMR (471 MHz, CDCl.sub.3) .delta. -167.97 (s,
1F)
Intermediate 1D (.+-.)-1-fluoro-6-oxabicyclo[3.2.1]octan-7-one
##STR00075##
[0849] To a solution of intermediate 1C (350 mg, 1.30 mmol) and
AIBN (21 mg, 0.130 mmol) in benzene (5 mL) was added
tris(trimethylsilyl)silane (0.60 mL, 1.94 mmol) portionwise over 10
min at 60.degree. C. The reaction was stirred at 70.degree. C. for
2 h, cooled to rt and then concentrated in vacuo. The residue was
dissolved in EtOAc, washed with sat. aq. NH.sub.4Cl, dried
(MgSO.sub.4) and concentrated in vacuo. The crude oil was
chromatographed (12 g SiO.sub.2) with EtOAc/Hexane (continuous
gradient from 0% to 30% EtOAc over 10 min) to give Intermediate 1D
(124 mg, 0.860 mmol, 66.4% yield) as a white solid. .sup.19F NMR
(471 MHz, CDCl.sub.3) .delta. -167.01 (s, 1F); .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 4.98-4.81 (m, 1H), 2.75 (dtdd, J=15.9,
6.8, 3.3, 1.7 Hz, 1H), 2.24-1.89 (m, 5H), 1.82-1.65 (m, 1H),
1.60-1.46 (m, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta.
173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9, 31.3, 31.1, 26.7,
17.7, 17.6
Intermediate 1
[0850] Acetyl chloride (0.061 mL, 0.860 mmol) was added portionwise
to isopropanol (3 mL) at 0.degree. C. and then stirred at rt for 30
min. Intermediate 1D (124 mg, 0.860 mmol) was added and the
reaction was stirred overnight at rt, then was concentrated in
vacuo. The residual crude oil was chromatographed (4 g SiO.sub.2)
with EtOAc/Hexane (continuous gradient from 0% to 50% EtOAc over 10
min) to give Intermediate 1 (140 mg, 0.685 mmol, 80% yield) as a
clear oil. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 5.08 (spt,
J=6.3 Hz, 1H), 3.91 (tt, J=10.9, 4.4 Hz, 1H), 2.68 (br. s., 1H),
2.28 (dddt, J=13.5, 9.0, 4.6, 2.1 Hz, 1H), 2.06-1.98 (m, 1H),
1.96-1.87 (m, 1H), 1.82-1.62 (m, 4H), 1.37-1.22 (m, 7H); .sup.19F
NMR (471 MHz, CDCl.sub.3) .delta. -162.93 (s, 1F); .sup.13C NMR
(126 MHz, CDCl.sub.3) .delta. 170.9, 170.7, 95.7, 94.2, 69.3, 66.1,
40.7, 40.5, 33.9, 31.6, 31.4, 21.5, 19.1
Intermediate 2 isopropyl
(3R)-3-hydroxycyclohexane-1-carboxylate-1-d
##STR00076##
[0851] Intermediate 2A isopropyl
(1S,3R)-3-((tert-bulyldimethylsilyl)oxy)cyclohexane-1-carboxylate
##STR00077##
[0853] To a solution of (1S,3R)-isopropyl
3-hydroxycyclohexanecarboxylate (0.5 g, 2.68 mmol) and imidazole
(0.238 g, 3.49 mmol) in DCM (4 mL) was added
tert-butylchlorodimethylsilane (0.486 g, 3.22 mmol) in DCM (1 mL)
dropwise over 5 min, stirred at rt overnight. The reaction was
diluted with Et.sub.2O (20 mL). The mixture was washed with brine
(10 mL); the white aqueous phase was separated and the organic
phase was washed with water (10 mL), dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The crude oil was chromatographed (80 g
SiO.sub.2) using a gradient of EtOAc/Hexane (0% to 20% over 15 min)
to give (1S,3R)-isopropyl
3-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (0.60 g,
1.897 mmol, 70.7% yield) as a clear oil. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 5.08-4.95 (m, 1H), 3.65-3.51 (m, 1H), 2.40-2.21
(m, 1H), 2.09 (d, J=12.7 Hz, 1H), 1.94-1.76 (m, 3H), 1.50-1.35 (m,
1H), 1.34-1.17 (m, 9H), 0.91 (s, 9H), 0.13-0.05 (m, 6H)
Intermediate 2B isopropyl
(1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate
##STR00078##
[0855] A solution of LDA (1.664 ml, 3.33 mmol) was added under Ar
to a solution of intermediate 2A (0.5 g, 1.66 mmol) in THF (6.66
mL) at -78.degree. and the resultant mixture was stirred for 60
min. Then D.sub.2O (0.90 mL, 49.9 mmol) was added and the reaction
was allowed to warm to rt. Saturated aq. NH.sub.4Cl (3 mL) was
added and the solution was allowed to warm to rt. The reaction
mixture was extracted with EtOAc (10 mL), and the combined organic
extracts were washed with aq. HCl (10 mL of a 2 M solution),
saturated aq. NaHCO.sub.3 and then brine. The organic layer was
dried over MgSO.sub.4, filtered, then concentrated in vacuo to give
an oil as the crude product (used in the next step without further
purification) (1S,3R)-isopropyl
3-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (0.50 g,
1.66 mmol). LCMS, [M+H].sup.+=302.1.
Intermediate 2
[0856] To a solution of intermediate 2B (0.53 g, 1.758 mmol) in THF
(3 mL) was added Bu.sub.4NF (3.52 mL of a 1 M solution, 3.52 mmol)
at rt and stirred overnight. The reaction was then quenched with
1.5 M aq. potassium phosphate (10 mL) and extracted with EtOAc (10
mL). The organic extract was concentrated in vacuo and
chromatographed (24 g SiO.sub.2, continuous gradient from 0 to 100%
EtOAc/Hexanes over 30 min, then at 100% EtOAc for 10 min) to give
intermediate 2 (0.17 g, 0.908 mmol, 51.6% yield). .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 5.02 (dt, J=12.6, 6.2 Hz, 1H), 4.11 (t,
J=4.3 Hz, 1H), 1.84 (d, J=4.1 Hz, 3H), 1.77-1.68 (m, 1H), 1.65-1.49
(m, 5H), 1.24 (d, J=6.3 Hz, 6H).
EXAMPLE 1
(1S,3S)-3-((6-(5-(((cyclopentyhmethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,-
2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00079##
[0857] 1A
3-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-
-yl)pyridine
##STR00080##
[0859] To a solution of 2,5-dibromo-6-methyl-pyridine (5 g, 21.11
mmol) and 2-(prop-2-yn-1-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7
mmol) in MeCN (42.2 mL) was added Et.sub.3N (8.83 mL, 63.3 mmol).
The solution was degassed under N.sub.2, then trans-dichlorobis
(triphenylphosphine) palladium (II) chloride (0.74 g, 1.06 mmol)
and CuI (0.20 g, 1.06 mmol) were added. The reaction was stirred at
rt for 14 h, after which the reaction mixture was filtered through
a Celite.RTM. plug and the plug was washed with EtOAc (2.times.10
mL). The filtrate was concentrated in vacuo and the residue was
chromatographed (SiO.sub.2; continuous gradient from 0% to 100%
EtOAc in Hexanes for 20 min) to give the title compound as a white
solid (6.0 g, 20.3 mmol, 96% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.3, 2.3
Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t, J=3.3 Hz, 1H),
4.61-4.45 (m, 2H), 3.98-3.81 (m, 1H), 3.66-3.44 (m, 1H), 1.92-1.73
(m, 2H), 1.72-1.52 (m, 2H). LCMS, [M+H].sup.+=298.0.
1B
3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)--
1H-1,2,3-triazol-4-yl)pyridine
##STR00081##
[0861] A solution of 1A (6.0 g, 20.3 mmol) in toluene (20 mL) and
TMSCH.sub.2N.sub.3 (7.85 g, 60.8 mmol) was heated at 90.degree. C.
under Ar for 15 h, then was cooled to rt. Volatiles were removed in
vacuo and the residue was dissolved in THF (20 mL). To the mixture
was added TBAF (20.3 mL of a 1 M solution in THF, 20.3 mmol) at
0.degree. C. After stirring for 10 min, the reaction was complete
as determined by analytical HPLC. Volatiles were removed in vacuo
and the residue was chromatographed (SiO.sub.2, continuous gradient
from 0% to 100% EtOAc in hexanes over 20 min) to give the title
compound (2.1 g, 29% yield) as a white solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.85 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz,
1H), 6.03 (br. s., 1H), 5.39-5.23 (m, 4H), 4.81-4.76 (m, 1H), 4.17
(s, 3H), 3.91 (ddd, J=11.3, 7.9, 3.3 Hz, 1H), 3.65-3.48 (m, 1H),
2.54 (s, 3H), 1.88-1.68 (m, 2H), 1.56 (br. s., 2H)
Alternatively, 1B can be synthesized by the following
procedure:
[0862] To a stirred solution of 1A (4.0 g, 13.5 mmol) in DMF (45
mL) under N.sub.2 was added NaN.sub.3 (2.63 g, 40.5 mmol). The
reaction mixture was stirred at 90.degree. C. for 36 h, then was
cooled to rt and filtered through Celite.RTM.. To the filtrate was
added K.sub.2CO.sub.3 (3.73 g, 27.0 mmol) and the reaction mixture
was stirred at rt for 10 min. CH.sub.3I (1.27 mL, 20.3 mmol) was
added dropwise and the reaction mixture was stirred at rt for 16 h,
then was diluted with water (150 mL) and extracted with EtOAc
(2.times.100 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
residual mixture of products (the 2 N-methyl triazole regioisomers)
were separated by flash chromatography (40 g Redisep.RTM. SiO.sub.2
column, eluting with 21% EtOAc in hexanes). The desired regioisomer
product, title compound 1B, was isolated as a white solid (1.0 g,
21%). LC-MS, [M+2].sup.+=355.2. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.64 (d, J=2.0 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H),
7.83-7.92 (m, 1H), 5.27 (s, 2H), 4.68-4.77 (m, 1H), 4.17 (s, 3H),
3.80-3.90 (m, 1H), 3.49-3.57 (m, 1H), 1.67-1.80 (m, 2H), 1.56-1.62
(m, 2H), 1.49-1.55 (m, 2H).
1C
2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-
-triazol-4-yl)pyridin-3-ol
##STR00082##
[0864] To a degassed solution (sparged with Ar 3.times.) of 1B (213
mg, 0.60 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (230 mg,
0.91 mmol) and KOAc (178 mg, 1.81 mmol) in THF was added
Pd(dppf)Cl.sub.2 (22 mg, 0.03 mmol). The reaction mixture was
heated in a sealed tube at 80.degree. C. for 16 h, then was cooled
to rt and partitioned between water and EtOAc. The aqueous layer
was extracted with EtOAc (3.times.20 mL). The combined organic
extracts were washed with brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The crude boronate product was carried on to
the next step without further purification. To a solution of the
crude product,
2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4--
yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (241
mg, 0.603 mmol) in EtOAc (2 mL) was added H.sub.2O.sub.2 (0.19 mL
of a 30% aqueous solution, 6.0 mmol). The reaction mixture was
stirred at rt for 1 h, then was cooled to 0.degree. C. and quenched
by slowly adding sat. aq. Na.sub.2S.sub.2O.sub.3. The aqueous layer
was extracted with EtOAc (3.times.20 mL). The combined organic
extracts were washed with brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was chromatographed (SiO.sub.2,
continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to
give the title compound (150 mg, 86%) as as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (d, J=2.6 Hz, 1H), 8.06 (d,
J=8.6 Hz, 1H), 7.29-7.21 (m, 1H), 5.33 (s, 1H), 5.28 (d, J=2.4 Hz,
2H), 4.76 (s, 1H), 4.18 (s, 3H), 3.90 (s, 1H), 3.63-3.48 (m, 1H),
1.72 (s, 2H), 1.65-1.51 (m, 2H). LCMS, [M+H].sup.+=291.2.
1D. isopropyl
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl-
)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00083##
[0866] To a solution of 1C (1.18 g, 4.06 mmol) and
(1S,3R)-isopropyl 3-hydroxy cyclohexanecarboxylate (synthesized
according to the procedure described in US2007/0197788A1, 1.51 g,
8.13 mmol) in toluene (81 mL) was added Bu.sub.3P (3.17 mL, 12.2
mmol). To this stirred mixture was added
(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (3.08 g, 12.2
mmol) portionwise, and the reaction mixture was heated at
50.degree. C. for 120 min, then was cooled to rt. At this point an
LC-MS of the reaction mixture showed the presence of the desired
product. The mixture was filtered and the filtrate was concentrated
in vacuo. The residue was chromatographed (SiO.sub.2, continuous
gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the
title compound (1.20 g, 2.62 mmol, 64.4% yield) as a white foam.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95 (d, J=8.6 Hz, 1H),
7.22 (d, J=8.6 Hz, 1H), 5.45-5.24 (m, 2H), 5.04 (dt, J=12.5, 6.3
Hz, 1H), 4.83-4.64 (m, 2H), 4.16 (s, 3H), 3.91 (ddd, J=11.2, 7.9,
3.1 Hz, 1H), 3.64-3.48 (m, 1H), 2.93-2.71 (m, 1H), 2.52 (s, 3H),
2.23-1.45 (m, 14H), 1.26 (dd, J=6.4, 2.0 Hz, 6H).
1E. isopropyl
(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-
pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00084##
[0868] To a solution of 1D (1.7 g, 3.71 mmol) in MeOH (37 mL) added
pyridinium p-toluenesulfonate (0.932 g, 3.71 mmol). The reaction
mixture was heated to 60.degree. C. for 2 h, then was cooled to rt,
diluted with water and sat. aq. NaHCO.sub.3, then extracted with
EtOAc (3.times.10 mL). The combined organic extracts were
concentrated in vacuo and chromatographed (SiO.sub.2; continuous
gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the
title compound as a white foam (1.36 g, 3.63 mmol, 98% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (d, J=8.6 Hz, 1H),
7.46 (d, J=5.1 Hz, 1H), 7.27-7.15 (m, 1H), 4.96 (dt, J=12.5, 6.3
Hz, 1H), 4.74 (s, 2H), 4.66-4.59 (m, 1H), 4.00 (s, 3H), 2.80-2.64
(m, 1H), 2.46 (s, 3H), 2.07-1.50 (m, 8H), 1.18 (dd, J=6.4, 2.2 Hz,
6H).
1F. isopropyl
(1S,3S)-3-((2-methyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl-
)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00085##
[0870] To a solution of 1E (1.36 g, 3.63 mmol) and 4-nitrophenyl
chloroformate (2.20 g, 10.9 mmol) in DCM (36.3 mL) was added
pyridine (1.47 mL, 18.2 mmol). The reaction mixture was stirred at
rt for 2 h. LCMS showed the desired product at this point. The
mixture was filtered and the filtrate was concentrated in vacuo.
The residue was chromatographed (SiO.sub.2, continuous gradient
from 0% to 100% EtOAc in Hexanes, 20 min) to afford the title
compound as a white solid (1.66 g, 3.08 mmol, 85% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.30 (d, J=9.2 Hz, 1H), 8.03 (d,
J=8.4 Hz, 1H), 7.41 (d, J=9.2 Hz, 2H), 7.25 (d, J=8.6 Hz, 1H), 6.07
(s, 2H), 5.05 (quin, J=6.2 Hz, 1H), 4.72 (br. s., 1H), 4.22 (s,
3H), 2.91-2.73 (m, 1H), 2.52 (s, 3H), 2.21-1.61 (m, 9H), 1.27 (dd,
J=6.3, 1.9 Hz, 6H).
1G. isopropyl
(1S,3S)-3-((6-(5-(((cyclopentyhmethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1-
,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00086##
[0872] To a solution of 1F (5 g, 9 .mu.mmol) and DIPEA (1.5 .mu.L,
9 ummol) in THF (0.5 mL) was added N-methylcyclopentanamine (1 mg,
9 ummol). The reaction mixture was stirred at rt overnight, after
which LC-MS showed the desired product. Volatiles were removed in
vacuo and the residue was dissolved in EtOAc and washed with aq. 1N
NaOH (5.times.10 mL) until the yellow color had disappeared. The
organic layer was concentrated in vacuo. The residue was used for
the next step without purification. LCMS, [M+H].sup.+=514.4.
EXAMPLE 1
[0873] To a stirred solution of 1G (4.6 mg, 9 .mu.mol) in THF (0.5
mL), MeOH (0.1 mL) and water (0.1 mL) at rt was added aq
LiOH.H.sub.2O (0.023 mL of a 2.0 M solution, 0.045 mmol). The
reaction mixture was stirred at 50.degree. C. for 2 h, after which
LC-MS showed that all starting material had been consumed. The
mixture was acidified to pH=.about.1 by dropwise addition of 1M aq.
HCl. The mixture was extracted with EtOAc (3.times.15 mL); the
combined organic extracts were concentrated in vacuo. The residue
was purified by preparative HPLC (PHENOMENEX.RTM., Axia 5.mu. C18
30.times.100 mm column; detection at 220 nm; flow rate=40 mL/min;
continuous gradient from 0% B to 100% B over 10 min+2 min hold time
at 100% B, where A=90:10:0.1 H.sub.2O:MeOH:TFA and B=90:10:0.1
MeOH:H.sub.2O:TFA) (to give the title compound as an oil (3.2 mg,
75%). LCMS, [M+H].sup.+=472.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.84 (d, J=8.2 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.64 (br.
s., 2H), 4.79 (br. s., 1H), 4.10 (s, 3H), 2.66 (br. s., 4H), 2.42
(s, 3H), 2.10-1.31 (m, 17H). hLPA.sub.1 IC.sub.50=24 nM. Acute in
vivo histamine assay in CD-1 mice: -97% histamine at a 3 mg/kg dose
of Example 1.
EXAMPLE 2
(1S,3S)-3-((6-(5-(((cyclopentyhmethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,-
2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
##STR00087##
[0874] 2A. 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol
##STR00088##
[0876] To a solution of 3,6-dibromopyridine (25.0 g, 100 mmol)) and
prop-2-yn-1-ol (8.70 mL, 149 mmol) in MeCN (141 mL) was added
Et.sub.3N (33.2 mL, 240 mmol). The solution was degassed under Ar
(sparged with Ar 3.times.), after which
trans-dichlorobis(triphenlyphosphine) palladium (II) chloride (2.96
g, 4.22 mmol) and CuI (0.804 g, 4.22 mmol) were added. The reaction
was stirred at rt under Ar for 14 h; the mixture was filtered
through a Celite.RTM. plug, which was washed with EtOAc (3.times.50
mL). The combined filtrates were concentrated in vacuo. The residue
was chromatographed (SiO.sub.2; continuous gradient from 0% to 100%
EtOAc in Hexanes, 20 min) to give the title compound as a white
solid (16.6 g, 74% yield). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.60 (d, J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.2 Hz, 1H), 7.44
(d, J=8.4 Hz, 1H), 4.41 (s, 2H)
2B
(4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol
##STR00089##
[0878] To a degassed (sparged with Ar 3.times.) solution of 2A (1.9
g, 8.40 mmol) in dioxane (42.0 mL) was added
chloro(pentamethylcyclopentadienyl)bis (triphenyl-phosphine)
ruthenium (II) (0.402 g, 0.504 mmol). The mixture was degassed 3
times under Ar again and TMSCH.sub.2N.sub.3 (1.87 mL, 12.6 mmol)
was added. The reaction was stirred at 50.degree. C. for 15 h under
Ar, then cooled to rt and concentrated in vacuo. The oily residue
was dissolved in THF (90 mL) and cooled to 0.degree. C. TBAF (5.40
mL of a 1.0 M solution in THF; 5.40 mmol) was added and the
reaction was stirred at 0.degree. C. for 10 min, after which solid
NaHCO.sub.3 (4 g) was added. The reaction mixture was stirred for
30 min at rt and then filtered. The filtrate was concentrated in
vacuo. The residue was chromatographed (SiO.sub.2; continuous
gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the
title compound (1.30 g, 4.59 mmol, 102% yield) as a white solid.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.49 (dd, J=2.3, 0.7 Hz,
1H), 8.08 (dd, J=8.5, 0.6 Hz, 1H), 7.83 (dd, J=8.5, 2.2 Hz, 1H),
6.16 (t, J=6.9 Hz, 1H), 4.68 (d, J=6.9 Hz, 2H), 3.95 (s, 3H).
2C
(4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(4-nitrop-
henyl) carbonate
##STR00090##
[0880] To a solution of 2B (1.22 g, 4.31 mmol) in CH.sub.2Cl.sub.2
(50 mL) was added pyridine (1.74 mL, 21.55 mmol) and 4-nitrophenyl
chloroformate (1.74 g, 8.62 mmol). The reaction was stirred at rt
for 1 h, then was concentrated in vacuo. The residual solid was
triturated with CH.sub.2Cl.sub.2 and filtered to give the pure
title compound. The filtrate was concentrated in vacuo and the
residue was chromatographed (SiO.sub.2; continuous gradient from 0%
to 100% EtOAc in DCM, 20 min); this purified material was combined
with the previously triturated compound to give the title compound
as a white solid (1.66 g, 86%). LCMS, [M+H].sup.+=434.1.
2D. (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
cyclopentyl(methyl)carbamate
##STR00091##
[0882] To a solution of 2C (140 mg, 0.31 mmol) in THF (6.2 mL) was
added iPr.sub.2NEt (109 .mu.L, 0.62 mmol) and
1-cyclobutyl-N-methylmethanamine (31 mg, 0.31 mmol). The reaction
was stirred at rt for 2 h, then was concentrated in vacuo. The
residue was chromatographed (SiO.sub.2; continuous gradient from 0%
to 100% EtOAc in Hexanes, 20 min) to give the title compound as a
white solid (100 mg, 78%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.66 (dd, J=2.4, 0.7 Hz, 1H), 8.11 (dd, J=8.6, 0.7 Hz, 1H),
7.89 (dd, J=8.6, 2.4 Hz, 1H), 5.74 (s, 2H), 4.15 (s, 3H), 2.88-2.59
(m, 3H), 1.87-1.38 (m, 9H)
2E.
(4-(5-Hydroxypyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate
##STR00092##
[0884] To a degassed (sparged with Ar 3.times.) solution of 2D (151
mg, 3.70 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.41
g, 5.55 mmol), and potassium acetate (1.45 g, 14.8 mmol) in THF (25
mL) was added Pd(dppf)Cl.sub.2 (0.271 g, 0.370 mmol) and the
reaction was heated at 60.degree. C. overnight under Ar, then
cooled to rt. Water (10 mL) was added and the mixture was extracted
with EtOAc (2.times.20 mL). The combined organic extracts were
washed with water (10 mL) and brine (10 mL), dried (MgSO.sub.4) and
concentrated in vacuo. The residual crude boronate product was
dissolved in EtOAc (15 mL) and H.sub.2O.sub.2 (1.62 mL of a 30% aq.
solution, 18.5 mmol) was carefully added portionwise at 0.degree.
C. The reaction was allowed to warm to rt and stirred at rt for 1
h, then was cooled 0.degree. C. and quenched with sat. aq.
Na.sub.2S.sub.2O.sub.3 (20 mL) and extracted with EtOAc (3.times.20
mL). The combined organic extracts were washed with water (20 mL)
and brine (20 mL), dried (MgSO.sub.4) and concentrated in vacuo.
The residue was chromatographed (SiO.sub.2; continuous gradient
from 0% to 100% EtOAc in Hexanes, 20 min) to give the title
compound as a white solid (962 mg, 75%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.22 (dd, J=3.0, 0.6 Hz, 1H), 7.87 (dd, J=8.6,
0.7 Hz, 1H), 7.30 (dd, J=8.7, 3.0 Hz, 1H), 5.68 (s, 2H), 4.19 (s,
3H), 2.76 (br. s., 3H), 1.92-1.43 (m, 8H). LCMS,
[M+H].sup.+=332.3.
1G. isopropyl
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H--
1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00093##
[0886] To a solution of 2E (962 mg, 2.79 mmol), (1S,3R)-isopropyl
3-hydroxy-cyclohexanecarboxylate (934 mg, 5.01 mmol), and Bu.sub.3P
(1.74 mL, 6.96 mmol) in toluene (55 mL) was added
(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (1.76 g, 6.96
mmol). The reaction was heated at 50.degree. C. for 7 h, then was
cooled to rt. The mixture was diluted with CH.sub.2Cl.sub.2 (20 mL)
and filtered through Celite.RTM., which was washed with additional
CH.sub.2Cl.sub.2 (3.times.20 mL). The combined filtrates were
concentrated in vacuo, and the residue was chromatographed
(SiO.sub.2; continuous gradient from 0% to 100% EtOAc in Hexanes,
20 min) to give the title compound as a white solid (786 mg, 55%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.33 (d, J=2.6 Hz, 1H),
8.12 (d, J=8.6 Hz, 1H), 7.34 (dd, J=8.8, 2.9 Hz, 1H), 5.78 (s, 2H),
5.05 (dt, J=12.5, 6.3 Hz, 1H), 4.77-4.66 (m, 1H), 4.16 (s, 3H),
2.95-2.64 (m, 4H), 2.12-2.08 (m, 1H), 2.03-1.87 (m, 4H), 1.82-1.41
(m, 12H), 1.29-1.19 (m, 6H). LCMS, [M+H].sup.+=500.4.
EXAMPLE 2
[0887] To a solution of 2F (786 mg, 1.53 mmol) in THF (3 mL) and
MeOH (3 mL) added aq. LiOH (3.06 mL of a 2N solution, 6.12 mmol).
The reaction mixture was stirred at rt overnight, after which the
pH was adjusted to .about.5 and water (10 mL) was added. The
mixture was extracted with EtOAc (3.times.30 mL), washed with water
(30 mL) and brine (30 mL), dried (MgSO.sub.4) and concentrated in
vacuo. The resulting solid was dissolved in 3 mL of EtOAc and
allowed to stand overnight to give the title compound as a white
crystalline solid (600 mg, 83%). LCMS, [M+H].sup.+=458.2. .sup.1H
NMR (500 MHz, CD.sub.3CN) .delta. 8.34 (d, J=2.5 Hz, 1H), 8.08-8.00
(m, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 5.66 (s, 2H), 4.88-4.73 (m,
1H), 4.11 (s, 3H), 2.87-2.77 (m, 1H), 2.72 (br. s., 3H), 2.10-2.01
(m, 1H), 1.92-1.80 (m, 3H), 1.79-1.57 (m, 9H), 1.56-1.43 (m, 4H).
HPLC-1: RT=7.99 min, purity=100%; HPLC-2: RT=7.81 min, purity=100%.
hLPA1 IC.sub.50=19 nM.
EXAMPLE 3
(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-me-
thyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00094##
[0888] 3A. Isopropyl
(1S,3S)-3-((6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,-
3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00095##
[0890] The title compound was prepared by the same synthetic
sequence as for Example 1F, except that 2,5-dibromo-pyridine was
used as starting material instead of 2,5-dibromo-6-methyl-pyridine.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.43-8.25 (m, 3H),
8.23-8.10 (m, 1H), 7.47-7.31 (m, 3H), 6.11-5.77 (m, 2H), 5.20-4.95
(m, 1H), 4.79-4.63 (m, 1H), 4.31-4.19 (m, 3H), 2.92-2.71 (m, 1H),
2.12-1.54 (m, 8H), 1.35-1.20 (m, 6H). LCMS, [M+H]+=540.2.
3B. isopropyl
(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00096##
[0892] To a solution of Example 3A (10 mg, 9.3 .mu.mol) and
iPr.sub.2NEt (6.5 pi, 0.037 mmol) in THF (0.5 mL) was added
2-cyclopropyl ethanamine (0.8 mg, 9.3 .mu.mol). The reaction
mixture was stirred at rt overnight, then was concentrated in
vacuo. The residue was chromatographed (SiO.sub.2; continuous
gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the
title compound as a white solid (8 mg, 80%). LCMS,
[M+H]+=486.4.
3B. isopropyl
(1S,3S)-3-((6-(5-((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-met-
hyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00097##
[0894] To a solution of 3A (50 mg, 0.103 mmol) and MeI (0.129 mL,
0.257 mmol) in DMF (0.5 mL) was added NaH (10 mg of a 40%
suspension in oil, 0.25 mmol). The reaction was stirred at rt for 1
h, then was quenched with water (5 mL) and extracted with EtOAc
(3.times.10 mL). The combined organic extracts were washed with
water (10 mL) and brine (10 mL), dried (MgSO.sub.4) and
concentrated in vacuo to give the crude product, which was used in
the next step without further purification. LCMS, [M+H]+=500.4.
EXAMPLE 3
[0895] To a stirred solution of 3B (5 mg, 10 .mu.mol) in THF (1.5
mL), MeOH (0.10 mL) and water (0.15 mL) at rt was added aq. LiOH
(0.015 mL of a 2 M solution, 0.030 mmol). The reaction mixture was
stirred at 50.degree. C. for 1 h, then was cooled to rt. The
mixture was acidified to pH 2.3 by dropwise addition of 1M aq. HCl,
then was concentrated in vacuo. The residue was purified by
preparative HPLC (PHENOMENEX.RTM., Axia 5.mu. C18 30.times.100 mm
column; detection at 220 nm; flow rate=40 mL/min; continuous
gradient from 0% B to 100% B over 10 min+2 min hold time at 100% B,
where A=90:10:0.1 H.sub.2O:MeOH:TFA and B=90:10:0.1
MeOH:H.sub.2O:TFA) (to give the title compound as an oil (4.2 mg,
92%). .sup.1H NMR (500 MHz, DMSO-.delta..sub.6) .delta. 8.13 (br.
s., 1H), 7.78 (d, J=8.2 Hz, 1H), 7.33 (d, J=6.4 Hz, 1H), 5.48-5.30
(m, 2H), 4.57 (br. s., 1H), 3.89 (br. s., 3H), 3.09-2.88 (m, 2H),
2.56 (d, J=16.8 Hz, 4H), 2.46 (br. s., 1H), 1.80-1.53 (m, 5H),
1.51-1.25 (m, 5H), 1.20-0.93 (m, 4H). LCMS, [M+H]+=458.4. HPLC-4:
RT=1.42 min, purity=100%. hLPA1 IC.sub.50=19 nM.
EXAMPLE 4
(rac)-trans-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1-
H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
##STR00098##
[0896] 4A Methyl
4-(4-bromophenyl)-1H-1,2,3-triazole-5-carboxylate
##STR00099##
[0898] To a stirred solution of 4-bromobenzaldehyde (1.0 g, 5.40
mmol), methyl 2-cyanoacetate (0.536 g, 5.40 mmol) and Et.sub.3N.HCl
(2.23 g, 16.2 mmol) in DMF (20 mL) under N.sub.2 was added
NaN.sub.3 (1.12 g, 17.3 mmol) and the reaction mixture was stirred
at 70.degree. C. for 16 h, then was cooled to rt. The reaction
mixture was slowly poured into water (100 mL) and extracted with
EtOAc (2.times.50 mL). The combined organic layer was washed with
brine (100 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The crude product was chromatographed (12 g Redisep.RTM.
SiO.sub.2 column, eluting with 40% EtOAc in n-hexanes) to afford
the title compound (0.24 g, 16%) as a yellow solid. LCMS,
[M+H].sup.+=284.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
15.91 (br. s., 1H), 7.75-7.85 (m, 4H), 3.82 (m, 3H).
4B Methyl
4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylate
##STR00100##
[0900] To a stirred solution of 4A (250 mg, 0.886 mmol) in MeCN (5
mL) was added K.sub.2CO.sub.3 (122 mg, 0.886 mmol) and the reaction
mixture was allowed to stir at rt for 30 min. CH.sub.3I (0.06 mL,
0.886 mmol) was added and the reaction was stirred at rt under
N.sub.2 for 16 h. The reaction mixture was diluted with water,
extracted with EtOAc (3.times.15 mL). The combined organic extracts
were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The residue was chromatographed (12 g Redisep.RTM. SiO.sub.2
column, eluting with 30% EtOAc in n-hexanes) to afford the title
compound (200 mg, 70%) as an off white solid. .sup.1H NMR and LCMS
showed the presence of a 3:1 ratio of a mixture of triazole
regioisomers (with the title compound the as major isomer), which
was carried onto the next step without further purification. LC-MS,
[M+H].sup.+=296.0.
4C (4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol
##STR00101##
[0902] To a solution of mixture of 4B (250 mg, 0.844 mmol) in THF
(10 mL) under nitrogen was added dropwise LiAlH (0.93 mL of a 1M
solution in THF; 0.93 mmol) at 0.degree. C. and the reaction
mixture was allowed to stir at 0.degree. C. for 1 h. The reaction
was slowly quenched with water (0.5 mL) and aq. NaOH (0.5 mL of a
10% solution). The reaction mixture was diluted with water (30 mL)
and extracted with EtOAc (2.times.20 mL). The combined organic
extracts were washed with brine (25 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue was chromatographed
(12 g Redisep.RTM. SiO.sub.2 column, eluting with 55% EtOAc in
n-hexanes) to afford the title compound (60 mg, 26%) as an
off-white solid. The two regioisomers were separated by preparative
HPLC (Column: Symmetry C8 (300.times.19) mm 5 .mu.m; M.Phase A:
0.1% HCO.sub.2H in water; M.Phase B: MeCN, flow rate: 17.0 mL/min;
time(min)/% B: 0/45, 35/60;). The desired triazole N-methyl
regioisomer 4C was isolated as white solid (60 mg 26%) and
structurally identified by proton NMR NOE studies on the N-methyl
group. LC-MS, [M+H].sup.+=270.0. .sup.1H NMR (300 MHz, DMSO-d6)
.delta. ppm 7.80-7.60 (m, 4H), 5.59 (t, J=6.0 Hz, 1H) 4.66 (d, J=3
Hz, 2H), 4.08 (s, 3H).
4D (4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
cyclopentylcarbamate
##STR00102##
[0904] To a stirred solution of cyclopentanecarboxylic acid (63.9
mg, 0.559 mmol) and 4C (150 mg, 0.559 mmol) in toluene (4 mL) were
added Et.sub.3N (0.10 mL, 0.84 mmol) and Ph.sub.2PON.sub.3 (0.2 mL,
0.671 mmol), and the resultant solution was stirred at 110.degree.
C. for 20 h under N.sub.2. The reaction mixture was cooled to rt,
volatiles were removed in vacuo and the crude product was
chromatographed (12 g Redisep.RTM. SiO.sub.2 column, eluting with
38% EtOAc in n-hexanes) to afford the title compound (150 mg, 71%)
as an off white solid. LC-MS, [M+H].sup.+=379.0. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.66 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.8
Hz, 2H), 5.24 (s, 2H), 4.18 (s, 3H), 3.90-4.00 (m, 1H), 2.02-1.90
(m, 2H), 1.50-1.80 (m, 3H), 1.30-1.50 (m, 4H).
4E (4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
cyclopentyl(methyl)carbamate
##STR00103##
[0906] To a stirred solution of 4D (200 mg, 0.527 mmol) and DMF (4
mL) was added NaH (19 mg of a 60% suspension in mineral oil, 0.79
mmol) portionwise at 0.degree. C. and the reaction was stirred at
0.degree. C. for 30 min. Iodomethane (0.049 mL, 0.79 mmol) was
added at 0.degree. C. and the reaction was allowed to warm to rt
and stirred at rt for 1 h. The reaction mixture was slowly quenched
with aq. HCl (5 mL of a 1.5 N solution), diluted with water (25 mL)
and extracted with EtOAc (2.times.25 mL). The combined organic
extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The crude product was
chromatographed (12 g Redisep.RTM. SiO.sub.2 column, eluting with
40% EtOAc in n-hexanes) to afford the title compound (200 mg, 96%)
as a pale yellow oily liquid. LC-MS, [M+H].sup.+=395.0.
4F
(1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H--
1,2,3-triazol-5-yl)methyl cyclopentyl(methyl)carbamate
##STR00104##
[0908] To a stirred solution of 4E (700 mg, 1.78 mmol) and
bis(pinacolato)diboron (678 mg, 2.67 mmol) in 1,4-dioxane (7 mL)
was added KOAc (349 mg, 3.56 mmol) and the reaction mixture was
degassed with N.sub.2 for 5 min. 1,1'-Bis(diphenylphosphino)
ferrocenepalladium (II) dichloride-toluene adduct (73 mg, 0.089
mmol) was added and the reaction mixture was stirred at 90.degree.
C. for 16 h under N.sub.2. The reaction mixture was cooled to rt,
filtered through a Celite.RTM. pad, washed with EtOAc (50 mL) and
the combined organic filtrates were concentrated in vacuo. The
residue was chromatographed (24 g Redisep.RTM. SiO.sub.2 column,
eluting with 75% EtOAc in n-hexanes) to afford the title compound
(700 mg, 89%) as a pale yellow oily liquid. LC-MS,
[M+H].sup.+=441.2.
4G (4-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
cyclopentyl(methyl)carbamate
##STR00105##
[0910] To a solution of 4F (700 mg, 1.590 mmol) in THF (20 mL) and
water (7 mL) mixture was added sodium perborate monohydrate (317
mg, 3.18 mmol) and the reaction mixture was stirred at rt for 30
min. The reaction mixture was diluted with sat'd aq. NH.sub.4Cl (50
mL) and extracted with EtOAc (2.times.50 mL). The combined organic
extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The crude product was chromatographed (12 g Redisep.RTM.
SiO.sub.2 column, eluting with 60% EtOAc in n-hexanes) to afford
the title compound (400 mg, 76%) as a white solid. LC-MS,
[M+H].sup.+=331.2. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
9.63 (s, 1H), 7.55 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.26
(s, 2H), 4.20-4.50 (m, 1 H), 4.09 (s, 3H), 2.67 (s, 3H), 1.60-1.80
(m, 4H), 1.40-1.60 (m, 4H).
4H (rac)-trans-Ethyl
3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-tri-
azol-4-yl)phenoxy)cyclohexanecarboxylate
##STR00106##
[0912] To a stirred solution of 4G (300 mg, 0.908 mmol) and
di-tert-butyl azodicarboxylate (627 mg, 2.72 mmol) and Ph.sub.3P
(714 mg, 2.72 mmol) in THF (10 mL) under N.sub.2 was added ethyl
3-hydroxycyclohexanecarboxylate (racemic cis isomer; 313 mg, 1.82
mmol) and the reaction mixture was stirred at 60.degree. C. for 16
h under N.sub.2, then was cooled to rt and concentrated in vacuo.
The residue was chromatographed (24 g Redisep.RTM. SiO.sub.2
column, eluting with 40% EtOAc in n-hexanes) to afford the title
compound (260 mg, 56%) as a colorless oil. LC-MS,
[M+H].sup.+=485.2. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
7.67 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 5.35 (s, 2H),
4.70-4.80 (m, 1H), 4.18 (s, 3H), 4.12 (q, J=7.2 Hz, 2H), 2.70-2.90
(m, 1H), 2.75 (s, 3H), 1.80-2.10 (m, 4H), 1.40-1.80 (m, 13H),
1.10-1.30 (t, J=7.2 Hz, 3H).
EXAMPLE 4
(rac)-trans-3-(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1-
H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid
##STR00107##
[0914] To a stirred solution of 4H (260 mg, 0.429 mmol) in THF (4
mL) and MeOH (4 mL) was added a solution of LiOH.H.sub.2O (31 mg,
1.29 mmol) in water (4 mL) and the reaction mixture was stirred at
rt for 16 h. The mixture was diluted with water (20 mL) and washed
with Et.sub.2O (20 mL) to remove traces of non-polar impurities.
The aqueous layer was neutralized with aq. HCl (2.0 mL of a 1.5N
solution) and extracted with 5% MeOH in CHCl.sub.3 (25 mL). The
organic layer was washed with brine (25 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude
product was purified by preparative HPLC (Column: Symmetry C8
(300.times.19) mm 10 .mu.m; M.Phase A: 0.1% HCOOH in water; M.Phase
B: MeCN, flow rate: 17.0 mL/min; time(min)/% B: 0/30, 20/100;) to
afford the title compound (120 mg, 45%) as a white solid. LC-MS,
[M+H].sup.+=457.2. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.66
(d, J=8.40 Hz, 2H), 7.09 (d, J=8.80 Hz, 2H), 5.37 (s, 2H),
4.75-4.76 (m, 1H), 4.31-4.50 (m, 1H), 4.20 (s, 3H), 2.77-2.81 (m,
4H), 2.07-2.10 (m, 1H), 1.82-1.97 (m, 3H), 1.49-1.79 (m, 12H).
hLPA1 IC.sub.50=18 nM.
EXAMPLE 5 AND EXAMPLE 6
##STR00108##
[0916] Individual enantiomers of Example 4 was separated by chiral
SFC (Column/dimensions: Chiralpak IC (250.times.21) mm, 5 .mu.m; %
CO.sub.2: 60%; % Co solvent: 40% (0.25% DEA in MeOH); Total Flow:
60 g/min; Back Pressure: 100 bars; Temperature: 25.degree. C.; UV:
250 nm;). Example 5 (37 mg, 18%) was isolated as a white solid.
LC-MS, [M+H].sup.+=457.2. OR [.alpha.].sup.24.8.sub.D=(+)14.0 (c
0.10, MeOH). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 7.66 (d,
J=8.40 Hz, 2H), 7.09 (d, J=8.40 Hz, 2H), 5.37 (s, 2H), 4.75-4.76
(m, 1H), 4.31-4.50 (m, 1H), 4.20 (s, 3H), 2.77-2.81 (m, 4H),
2.07-2.10 (m, 1H), 1.82-1.97 (m, 3H), 1.49-1.79 (m, 12H). hLPA1
IC.sub.50=6 nM. Acute mouse in vivo histamine assay: -90% histamine
at a 3 mg/kg dose of Example 5. Example 6 (35 mg, 17%) was isolated
as a white solid. LC-MS, [M+H].sup.+=457.2. OR
[.alpha.].sup.25.2.sub.D=(-)14.0 (c 0.10, MeOH). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.66 (d, J=8.40 Hz, 2H), 7.09 (d, J=8.40
Hz, 2H), 5.37 (s, 2H), 4.75-4.76 (m, 1H), 4.31-4.50 (m, 1H), 4.20
(s, 3H), 2.77-2.81 (m, 4H), 2.07-2.10 (m, 1H), 1.82-1.97 (m, 3H),
1.49-1.79 (m, 12H). hLPA1 IC.sub.50=1314 nM.
EXAMPLE 7
(1-Methyl-4-(4-(((1S,3S)-3-((methylsulfonyl)carbamoyl)cyclohexyl)oxy)pheny-
l)-1H-1,2,3-triazol-5-yl)methyl cyclopentyl(methyl)carbamate
##STR00109##
[0918] To a stirred solution of Example 5 (10 mg, 0.022 mmol) and
methane sulfonamide (3 mg, 0.033 mmol) in DCM (0.5 mL) and DMF (0.5
mL) mixture was added 4-dimethylaminopyridine (3.21 mg, 0.026 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(6.30 mg, 0.033 mmol) and the reaction mixture was stirred at rt
for 16 h under N.sub.2. The reaction mixture was concentrated in
vacuo and the crude product was purified by preparative HPLC
(Column: Sunfire C18 (150.times.19) mm 5 micron; M.Phase A: 0.1%
HCO.sub.2H in water; M.Phase B: MeCN, flow rate: 16.0 mL/min;
time(min)/% B: 0/30, 30/100;) to afford the title compound (4 mg,
33%) as a white solid. LC-MS, [M+H].sup.+=534.4. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.67 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz,
2H), 5.37 (s, 2H), 4.20 (s, 3H), 3.20 (s, 3H), 2.78-2.89 (m, 5H),
1.59-2.10 (m, 17H). hLPA1 IC.sub.50=3750 nM.
EXAMPLE 8 & EXAMPLE 9
##STR00110##
[0919] 8A
4-(4-Methoxyphenyl)-1-methyl-1-H-1,2,3-triazole-5-carbaxaldehyde
##STR00111##
[0921] To a stirred solution of
4-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazole (35 g, 185 mmol) in
THF (860 mL) under N.sub.2 was added n-BuLi (111 mL of a 2.5 M
solution in hexanes, 277 mmol) dropwise at -78.degree. C. and the
reaction mixture was stirred at -78.degree. C. for lh. DMF (22 mL,
277 mmol) was added at -78.degree. C. and the reaction mixture was
allowed to slowly warm to rt and stirred for 2 h at rt. The
reaction mixture was cooled to 0.degree. C., then was slowly
quenched with sat'd aq. NH.sub.4Cl and extracted with DCM
(3.times.250 mL). The combined organic extracts were washed with
brine (500 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The residue was chromatographed (330 g Redisep.RTM.
SiO.sub.2 column, eluting with 20% EtOAc in n-hexanes) to afford
the title compound (18.0 g, 48%) as a yellow solid. LC-MS,
[M+H].sup.+=218.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.04 (s, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 4.31
(s, 3H), 3.84 (s, 3H).
8B
4-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde
##STR00112##
[0923] To a stirred solution of 8A (8.4 g, 38.7 mmol) in DCM (160
mL) was added dropwise BBr.sub.3 (11 mL, 116 mmol) at 0.degree. C.
and the reaction mixture was stirred at 0.degree. for 1 h. The
reaction mixture was quenched carefully with ice-cold water and
neutralized with 10% aq. NaHCO.sub.3 and extracted with DCM
(3.times.150 mL). The combined organic extracts were washed with
brine (250 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The residue was diluted with DCM and the resulting solid
that formed was filtered and dried in vacuo to afford the title
compound (5.7 g, 73%) as a white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 10.04 (s, 1H), 9.88 (s, 1H), 7.71 (d,
J=13.0 Hz, 2H), 6.92 (d, J=13.0 Hz, 2H), 4.28 (s, 3H).
8C
4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazole-5-
-carbaldehyde
##STR00113##
[0925] To a stirred solution of 8B (1.0 g, 4.92 mmol) and imidazole
(0.670 g, 9.84 mmol) in DMF (20 mL) was added TBSCl (0.890 g, 5.91
mmol) and the reaction mixture was stirred at rt for 16 h under
N.sub.2. Water (100 mL) was added to the mixture, which was
extracted with EtOAc (2.times.75 mL). The combined organic extracts
were washed with brine (150 mL), dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. The crude product was chromatographed
(24 g Redisep.RTM. SiO.sub.2 column, eluting with 25% EtOAc in
n-hexanes) to afford the title compound (1.2 g, 77%) as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 10.07 (s, 1H),
7.63 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.36 (s, 3H), 1.01
(s, 9H), 0.24 (s, 6H).
8D
(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-
-yl)methanol
##STR00114##
[0927] To a 0.degree. C. solution of 8C (1.25 g, 3.94 mmol) in THF
(30 mL) was added NaBH.sub.4 (0.223 g, 5.91 mmol) and the reaction
mixture was stirred at 0.degree. C. for 1 h. The reaction mixture
was diluted with water (75 mL) and extracted with EtOAc (2.times.75
mL). The combined organic extracts were washed with brine (150 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
crude product was chromatographed (24 g Redisep.RTM. SiO.sub.2
column, eluting with 60% EtOAc in n-hexanes) to afford the title
compound (0.7 g, 56%) as a white solid. LC-MS, [M+H].sup.+=320.3.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 7.59 (d, J=8.7 Hz,
2H), 6.97 (d, J=8.7 Hz, 2H), 4.77 (s, 2H), 4.15 (s, 3H), 1.02 (s,
9H), 0.24 (s, 6H).
8E
(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-
-yl)methyl (4-nitrophenyl) carbonate
##STR00115##
[0929] To a stirred solution of 8D (500 mg, 1.565 mmol) and
iPr.sub.2NEt (0.50 mL, 3.13 mmol) in DCM (10 mL) was added
4-nitrophenyl chloroformate (379 mg, 1.88 mmol) at 0.degree. C. and
the resultant pale yellow solution was stirred at rt for 16 h under
N.sub.2. The reaction mixture was diluted with water (50 mL) and
extracted with DCM (2.times.50 mL). The combined organic extracts
were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The crude product was chromatographed (24 g Redisep.RTM. SiO.sub.2
column, eluting with 40% EtOAc in n-hexanes) to afford the title
compound (260 mg, 35%) as a white solid. LC-MS, [M+H].sup.+=485.2.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.30 (d, J=9.0 Hz,
2H), 7.64 (d,
[0930] J=9.0 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H), 6.96 (d, J=8.5 Hz,
2H), 5.47 (s, 2H), 4.22 (s, 3H), 1.00 (s, 9H), 0.23 (s, 6H).
8F
(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-
-yl)methyl isopentylcarbamate
##STR00116##
[0932] To a stirred solution of 8E (240 mg, 0.496 mmol) and
Et.sub.3N (0.20 mL, 1.49 mmol) in THF (10 mL) was added
3-methylbutan-1-amine (86 mg, 0.991 mmol) and the reaction mixture
was stirred at rt for 16 h under N.sub.2, then was concentrated in
vacuo. The crude product was chromatographed (12 g Redisep.RTM.
SiO.sub.2 column, eluting with 65% EtOAc in n-hexanes) to afford
the title compound (150 mg, 70%) as a pale yellow liquid. LC-MS,
[M+H].sup.+=433.4. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.62 (d, J=8.5 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 5.24 (s, 2H), 4.72
(br. s., 1H), 4.16 (s, 3H), 3.27-3.19 (m, 2H), 1.30-1.50 (m, 3H),
0.97-1.00 (s, 9H), 0.91-0.96 (m, 6H), 0.23 (s, 6H).
8G (4-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl
isopentylcarbamate
##STR00117##
[0934] To a stirred solution of 8F (150 mg, 0.347 mmol) in THF (6
mL) was added TBAF (0.52 mL of a 1M solution in THF; 0.52 mmol,) at
0.degree. C. and the reaction mixture was stirred at 0.degree. C.
for 30 min. The reaction mixture was diluted with water (25 mL) and
extracted with EtOAc (2.times.25 mL). The combined organic extracts
were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The crude product was chromatographed (12 g Redisep.RTM. SiO.sub.2
column, eluting with 85% EtOAc in n-hexanes) to afford the title
compound (90 mg, 82%) as a white solid. LC-MS, [M+H].sup.+=319.2.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 7.56 (d, J=8.4 Hz,
2H), 6.91 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 4.19 (s, 3H), 3.15 (t,
J=7.3 Hz, 2H), 1.55-1.70 (m, 1H), 1.40 (q, J=7.0 Hz, 2H), 0.94 (d,
J=6.4 Hz, 6H).
8H (rac)-trans-(Ethyl
3-(4-(5-(((isopentylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
phenoxy)cyclohexanecarboxylate
##STR00118##
[0936] To a stirred solution of 8G (100 mg, 0.314 mmol),
di-tert-butyl azodicarboxylate (217 mg, 0.942 mmol) and Ph.sub.3P
(247 mg, 0.942 mmol) in THF (10 mL) under N.sub.2 was added ethyl
3-hydroxycyclohexanecarboxylate (racemic cis isomer; 135 mg, 0.785
mmol) and the reaction mixture was stirred at 60.degree. C. for 16
h under N.sub.2, then was cooled to rt. The reaction mixture was
concentrated in vacuo and the crude product was chromatographed (12
g Redisep.RTM. SiO.sub.2 column, eluting with 22% EtOAc in
n-hexanes) to afford the title compound (90 mg, 60%) as a pale
yellow liquid. LC-MS, [M+H].sup.+=473.2. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 7.66 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz,
2H), 5.29 (s, 2H), 4.75 (br. s., 1H), 4.20 (s, 3H), 4.13 (q, J=6.4
Hz, 2H), 3.15 (t, J=7.3 Hz, 2H), 2.80-2.90 (m, 1H), 1.60-2.00 (m,
6H), 1.20-1.35 (m, 9H), 0.93 (d, J=6.4 Hz, 6H).
8I (rac)-trans-Ethyl
3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triaz-
ol-4-yl)phenoxy)cyclohexanecarboxylate
##STR00119##
[0938] To a stirred solution of 8H (90 mg, 0.190 mmol) in DMF (3
mL) under N.sub.2 was added NaH (9 mg of a 60% mineral suspension,
0.38 mmol) portionwise at 0.degree. C. and stirred at 0.degree. C.
for 30 min. Iodomethane (0.020 mL, 0.29 mmol) was then added and
the reaction mixture was allowed to warm to rt & stirred at rt
for 1 h. The reaction mixture was diluted with water (30 mL) and
extracted with EtOAc (2.times.25 mL). The combined organic extracts
were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), and
filtered. The combined filtrates were concentrated in vacuo. The
crude product was purified by combiflash chromatography (12 g
Redisep.RTM. SiO.sub.2 column, eluting with 75% EtOAc in n-hexanes)
to afford the title compound (60 mg, 64%) as a pale yellow liquid.
LC-MS, [M+H].sup.+=487.2.
EXAMPLE 8 & EXAMPLE 9
[0939] To a stirred solution of 8I (50 mg, 0.103 mmol) in THF (2
mL) and MeOH (2 mL) mixture was added a solution of LiOH.H.sub.2O
(7.0 mg, 0.308 mmol) in water (2 mL) and the reaction mixture was
stirred at rt for 16 h under N.sub.2. The reaction mixture was
diluted with water (20 mL) and washed with Et.sub.2O (20 mL) to
remove non-polar impurities. The aqueous layer was neutralized with
aq. HCl (2.0 mL of a 1.5 N solution) and extracted with MeOH in
CHCl.sub.3 (5% of a 25 mL mixture). The organic layer was washed
with brine (25 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude product was purified by
preparative HPLC (Column: Sunfire C18 (250.times.30) mm 5 .mu.m;
M.Phase A: 10 mM NH.sub.4OAc in water; M.Phase B: MeCN, flow rate:
15.0 mL/min; time(min)/% B: 0/30, 8/40;) followed by separation of
individual enantiomers by chiral SFC. Example 8 (17 mg, 28%) was
obtained as a gummy solid. LC-MS, [M+H].sup.+=459.2. OR
[.alpha.].sup.25.1.sub.D=(+)10.0 (c 0.10, MeOH). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 7.64-7.70 (m, 2H), 7.09 (d, J=8.8 Hz,
2H), 5.36-5.38 (m, 2H), 4.72-4.75 (m, 1H), 4.21 (s, 3H), 3.23-3.26
(m, 1H), 2.82-2.90 (m, 4H), 2.06-2.11 (m, 1H), 1.92-1.94 (m, 3H),
1.57-1.80 (m, 4H), 1.31-1.45 (m, 4H), 0.82-0.96 (m, 6H). hLPA1
IC.sub.50=87 nM. Example 9 (14 mg, 24%) was obtained as a gummy
solid. LC-MS, [M+H].sup.+=459.2. OR [.alpha.].sup.25.1.sub.D=(-)2.0
(c 0.10, MeOH). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
7.64-7.70 (m, 2H), 7.09 (d, J=8.4 Hz, 2H), 5.36-5.38 (m, 2H),
4.72-4.75 (m, 1H), 4.21 (s, 3H), 3.23-3.26 (m, 1H), 2.82-2.90 (m,
4H), 2.06-2.11 (m, 1H), 1.92-1.94 (m, 3H), 1.57-1.80 (m, 4H),
1.31-1.45 (m, 4H), 0.82-0.96 (m, 6H). hLPA1 IC.sub.50=65 nM.
EXAMPLE 10
(1S,3S)-3-(4-(1-Methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)oxy)methy-
l)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid
##STR00120##
[0940] 10A
4-(4-(Benzyloxy)phenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehy-
de
##STR00121##
[0942] To a stirred mixture of compound 8B (5.5 g, 27.1 mmol) and
K.sub.2CO.sub.3 (5.61 g, 40.6 mmol) in MeCN (60 mL) was added
benzyl bromide (3.54 mL, 29.8 mmol) at rt and the reaction mixture
was stirred at 70.degree. C. for 3 h under N.sub.2, then was cooled
to rt. The reaction mixture was filtered through a Celite.RTM. pad,
which was washed with DCM (200 mL). The combined filtrates was
concentrated in vacuo to afford the title compound (7.50 g, 80%) as
a pale yellow solid, which was carried onto to the next step
without further purification. LC-MS, [M+H].sup.+=294.2. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 10.06 (s, 1H), 7.71 (d, J=8.8 Hz,
2H), 7.33-7.49 (m, 5H), 7.12 (d, J=8.8 Hz, 2H), 5.15 (s, 2H), 4.37
(s, 3H).
10B (4-(4-(Benzyloxy)
phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol
##STR00122##
[0944] To a stirred solution of 10A (8 g, 27.3 mmol) in THF (60 mL)
and MeOH (60 mL) was added portionwise NaBH.sub.4 (1.14 g, 30.0
mmol) at 0.degree. C. under N.sub.2 and the reaction mixture was
stirred at rt for 1 h. The reaction mixture was diluted with sat'd.
aq. NH.sub.4Cl (200 mL) and extracted with EtOAc (2.times.200 mL).
The combined organic extracts were washed with brine (400 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
afford the title compound (7.0 g, 83%) as a white solid. This crude
product was carried on to the next step without further
purification. LC-MS, [M+H].sup.+=296.2. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 7.57 (d, J=9.0 Hz, 2H), 7.47-7.33 (m, 5H),
7.04 (d, J=9.0 Hz, 2H), 5.10 (s, 2H), 4.81 (d, J=4.2 Hz, 2H), 4.08
(s, 3H), 2.77 (t, J=5.4 Hz, 1H).
10C 4-(4-(Benzyloxy) phenyl)-5-(((tert butyldimethylsilyl) oxy)
methyl)-1-methyl-1H-1,2,3-triazole
##STR00123##
[0946] To a stirred solution of 10B (7 g, 23.70 mmol) and imidazole
(4.84 g, 71.1 mmol) in DMF (100 mL) was added TBSCl (4.29 g, 28.4
mmol) and the reaction mixture was stirred at rt for 3 h under
N.sub.2. The reaction mixture was diluted with water (200 mL) and
extracted with EtOAc (2.times.200 mL). The combined organic
extracts were washed with brine (400 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo to afford the title compound
(8.0 g, 77%) as a pale yellow solid. This crude product 10c was
used in the next step without further purification. LC-MS,
[M+H].sup.+=410.2. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm
8.03 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.33-7.50 (m, 5H), 7.12 (d,
J=9.0 Hz, 2H), 5.11 (s, 2H), 4.81 (s, 2H), 4.13 (s, 3H), 0.91 (s,
9H), 0.07 (s, 6H).
10D 4-(5-(((tert-Butyldimethylsilyl) oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenol
##STR00124##
[0948] To a degassed (N.sub.2 was bubbled in for 10 min) solution
of 10C (8.0 g, 19.53 mmol) in MeOH (150 mL) was added 10% Pd/C (1
g, 0.940 mmol) at rt. The reaction mixture was degassed with
H.sub.2 for 5 min. then was stirred at rt under 1 atm of H.sub.2
for 5 h, then the H.sub.2 atmosphere was evacuated and replaced
with N.sub.2. The reaction mixture was filtered through a
Celite.RTM. pad and washed with MeOH (200 mL). The combined
filtrates was concentration in vacuo to afford the title compound
(5.0 g, 76%) as a white solid. This crude product 10D was used in
the next step without further purification. LC-MS,
[M+H].sup.+=320.2.
10E (rac)-trans-Ethyl 3-(4-(5-(((tert-butyldimethylsilyl)
oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate
##STR00125##
[0950] To a stirred solution of 10D (2.75 g, 8.61 mmol),
di-tert-butyl azodicarboxylate (7.93 g, 34.4 mmol) and Ph.sub.3P
(9.03 g, 34.4 mmol) in THF (80 mL) was added (rac)-cis-ethyl
3-hydroxycyclohexanecarboxylate (5.93 g, 34.4 mmol) and the
reaction mixture was stirred at 60.degree. C. for 16 h under
N.sub.2, then was cooled to rt. The reaction mixture was
concentrated in vacuo. The crude product was chromatographed (120 g
Redisep.RTM. SiO.sub.2 column, eluting with 40% EtOAc in n-hexanes)
to afford the title compound (2.7 g, 65%) as a colorless liquid.
LC-MS, [M+H].sup.+=474.2.
10F (1S,3S)-ethyl
3-(4-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexan-
ecarboxylate
##STR00126##
[0952] To a stirred solution 10E (200 mg, 0.211 mmol) in THF (6 mL)
was added TBAF (0.317 mL of a 1M solution in THF; 0.317 mmol) at
0.degree. C. and the reaction mixture was stirred at rt under
N.sub.2 for 30 min. The reaction mixture was diluted with water (25
mL) and extracted with EtOAc (2.times.25 mL). The combined organic
extracts were washed with brine (40 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The crude product was
chromatographed (12 g Redisep.RTM. SiO.sub.2 column, eluting with
75% EtOAc in n-hexanes). The racemic product thus obtained was
separated by chiral SFC (Luxcellulose-2 (250.times.21.5) mm, 5
.mu.m; % CO.sub.2: 70%; % Co-solvent: 30% (0.25% DEA in MeOH);
Total Flow: 70 g/min; Back Pressure: 100 bars; Temperature:
35.degree. C.; UV: 230 nm;). The desired S,S enantiomer 10F was
isolated (40 mg, 50%) as an off-white solid: LC-MS,
[M+H].sup.+=360.2. Optical rotation [.alpha.].sup.25.2.sub.D=(+)30
(c 0.10, MeOH). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 7.63
(d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 4.79 (s, 2H), 4.72-4.76
(m, 1H), 4.18 (s, 3H), 4.16 (q, J=7.0 Hz, 2H), 2.80-2.88 (m, 1H),
2.03-2.11 (m, 1H), 1.88-1.98 (m, 3H), 1.57-1.82 (m, 4H), 1.25-1.30
(m, 3H).
10G (1S,3S)-Ethyl-3-(4-(1-methyl-5-((((2-methylpentan-2-yl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylat-
e
##STR00127##
[0954] To a solution of 10F (50 mg, 0.14 mmol),
2,2-dimethylpentanoic acid (18 mg, 0.139 mmol) and Et.sub.3N (0.029
mL, 0.21 mmol) in toluene (3 mL) was added Ph.sub.2PON.sub.3 (0.036
mL, 0.167 mmol) and the resultant pale yellow solution was stirred
at 110.degree. C. for 16 h under N.sub.2, then was cooled to rt.
The reaction mixture was concentrated in vacuo and the crude
product was chromatographed (12 g Redisep SiO.sub.2 column, eluting
with 50% EtOAc in n-hexanes) to afford the title compound (40 mg,
50%) as a white solid. LC-MS, [M+H].sup.+=487.2. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 7.65 (d, J=9.2 Hz, 2H), 7.08 (d, J=9.2
Hz, 2H), 5.24 (s, 2H), 4.75 (br. s., 1H), 4.19 (s, 3H), 4.16 (q,
J=7.2 Hz, 2H), 3.15 (s, 1H), 2.86 (d, J=11.0 Hz, 2H), 2.07 (br. s.,
1H), 1.89-1.99 (m, 3H), 1.60-1.80 (m, 4H), 1.20-1.40 (m, 8H),
0.95-0.88 (m, 6H).
10H (1S,3S)-Ethyl
3-(4-(1-methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)oxy)methyl)-1H-1-
,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate
##STR00128##
[0956] To a stirred solution of 10G (40.0 mg, 0.082 mmol) in DMF (3
mL) under N.sub.2 was added NaH (4 mg of a 60% mineral suspension,
0.16 mmol) portionwise at 0.degree. C. and stirred for 30 min.
Iodomethane (7.71 .mu.l, 0.123 mmol) was then added and the
reaction mixture was stirred at rt for 1 h, then was diluted with
water (20 mL). The mixture was extracted with EtOAc (2.times.20 mL)
and the combined organic extracts were washed with brine (25 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
crude product was chromatographed (12 g Redisep.RTM. SiO.sub.2
column, eluting with 75% EtOAc in n-hexanes) to afford the title
compound (30 mg, 73%) as a pale yellow liquid. LC-MS,
[M+H].sup.+=501.2.
EXAMPLE 10
[0957] To a stirred solution of 10H (30.0 mg, 0.060 mmol) in THF
(1.5 mL) and MeOH (1.5 mL) was added a solution of LiOH.H.sub.2O
(4.3 mg, 0.18 mmol) in water (1.5 mL) and the reaction mixture was
stirred at rt for 16 h under N.sub.2. The reaction mixture was
diluted with water (20 mL) and washed with Et.sub.2O (20 mL) to
remove traces of nonpolar impurities. The aqueous layer was
neutralized with aq. HCl (2.0 mL of a 1.5 N solution) and extracted
with 5% MeOH in CHCl.sub.3 (25 mL). The organic layer was washed
with brine (25 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residual crude product was purified by
preparative HPLC (Kinetex Biphenyl 100A (2500.times.21.1) mm 5
.mu.m; Mobile Phase A: 0.1% HCO.sub.2H in water; Mobile Phase B:
MeCN, flow rate: 18.0 mL/min; time(min)/% B: 0/40, 32/75, 35/95;)
to afford the title compound (8 mg, 28%) as a white solid. LC-MS,
[M+H].sup.+=473.2. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
7.63 (d, J=8.80 Hz, 2H), 7.07 (d, J=8.80 Hz, 2H), 5.31 (s, 2H),
4.83-4.89 (m, 1H), 4.18 (s, 3H), 2.85 (s, 3H), 2.72-2.76 (m, 1H),
2.06-2.10 (m, 1H), 1.82-1.95 (m, 3H), 1.40-1.77 (m, 6H), 1.29 (s,
6H), 1.11-1.24 (m, 2H), 0.08-0.84 (m, 3H). hLPA1 IC.sub.50=23
nM.
EXAMPLE 11
(rac)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-
-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-ca-
rboxylic acid
##STR00129##
[0959] Example 11 was prepared according to the procedure of
Example 2 by using Intermeidate 1 instead of (1S,3R)-isopropyl
3-hydroxy-cyclohexanecarboxylate in the procedure (Mitsunobu
reaction) to synthesize Example 2F. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.15 (d, J=8.8 Hz, 1H), 8.00-7.89 (m, 1H),
5.53-5.32 (m, 2H), 5.00 (br. s., 1H), 4.21 (d, J=2.4 Hz, 3H), 3.32
(dd, J=10.8, 7.5 Hz, 2H), 2.92 (d, J=13.6 Hz, 3H), 2.75 (d, J=2.6
Hz, 3H), 2.55 (dt, J=15.5, 7.8 Hz, 1H), 2.47-2.27 (m, 1H),
2.24-1.77 (m, 10H), 1.76-1.58 (m, 3H); .sup.19F NMR (377 MHz,
CDCl.sub.3) .delta. -76.0 (s, F from TFA), -154.4 (s, 1F). LC-MS,
[M+H].sup.+=490.4. hLPA1 IC.sub.50=12 nM.
EXAMPLE 12
(1S,3S)-3-(4-(5-(1-(((cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid
(diastereomeric mixture)
##STR00130##
[0960] 12A
1-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-
-triazol-5-yl)ethan-1-ol
##STR00131##
[0962] To a -40.degree. C. solution of 8C (279 mg, 0.879 mmol) in
THF (18 mL) was added CH.sub.3MgBr (439 .mu.L of a 3 M solution in
THF, 1.32 mmol). The reaction mixture was allowed to warm to rt and
stirred at rt for 1 h. Water (15 mL) was added and the mixture was
extracted with EtOAc (2.times.30 mL). The combined organic extracts
were concentrated in vacuo and chromatographed (SiO.sub.2;
continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to
give 12A (230 mg, 78%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.42 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.33 (dd,
J=6.8, 3.5 Hz, 1H), 4.23 (s, 3H), 1.96 (d, J=3.3 Hz, 1H), 1.64 (d,
J=6.8 Hz, 3H), 1.00 (s, 9H), 0.22 (s, 6H)
[0963] Example 12 was prepared according to the procedure for the
synthesis of Example 8 by using 12A instead of 8D. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.57 (br. s., 2H), 7.06 (d, J=6.6 Hz,
2H), 6.19-5.87 (m, 1H), 4.69 (br. s., 1H), 4.13 (d, J=5.6 Hz, 3H),
3.21-3.09 (m, 2H), 2.76 (d, J=15.7 Hz, 3H), 2.45-2.37 (m, 1H),
2.01-1.45 (m, 18H). LC-MS, [M+H].sup.+=471.0. hLPA1 IC.sub.50=384
nM.
EXAMPLE 13
3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)
-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocycloh-
exane-1-carboxylic acid (single enantiomer)
##STR00132##
[0965] Example 13 was subjected to chiral SFC (Column: Chiralpak
IC, 21.times.250 mm, 5 micron Mobile Phase: 40% MeOH/60% CO.sub.2
Flow Conditions: 45 mL/min, 150 Bar, 40.degree. C. Detector
Wavelength: 254 nm Injection Details: 0.5 mL of 5 mg/mL solution in
MeOH) to afford Example 13. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.11-7.96 (m, 1H), 7.29 (d, J=8.5 Hz, 1H), 5.75 (d, J=9.6
Hz, 2H), 4.79 (d, J=3.3 Hz, 1H), 4.15 (d, J=7.7 Hz, 3H), 3.38-3.11
(m, 2H), 2.93-2.75 (m, 3H), 2.65-2.51 (m, 1H), 2.25 (br. s., 1H),
2.10-1.47 (m, 7H). LC-MS, [M+H].sup.+=490.4. hLPA1 IC.sub.50=95
nM.
EXAMPLE 14
(4-(5-(((1S,3S)-3-carbamoylcyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl--
1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate
##STR00133##
[0967] To a solution of Example 2 (100 mg, 0.21 mmol) and DMF (0.8
.mu.L, 11 .mu.mol) in CH.sub.2Cl.sub.2 (2 mL) was slowly added
oxalyl chloride (0.21 mL, 0.42 mmol); the mixture was stirred at rt
for 30 min. The mixture was concentrated in vacuo to give the acid
chloride. To the acid chloride in CH.sub.2Cl.sub.2 (1.0 mL) was
added ammonia (6.36 mL of a 0.5 N solution in dioxane, 3.18 mmol).
The mixture was stirred at rt for 30 min, then was concentrated in
vacuo. The residual crude product was chromatographed (SiO.sub.2;
12 g; A=DCM, B=EtOAc; 12 min gradient from 0% B to 100% B; flow
rate=30 mL/min) to afford the title compound (77 mg, 0.17 mmol, 89%
yield) as a white solid. LCMS, [M+H].sup.+=471.2. .sup.1H NMR (500
MHz, DMSO-d.sub.6) [rotamer, ratio 53:47] [major
rotamer--underline; minor rotamer--Italic]: .delta. ppm 7.81 (d,
J=8.5 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H),
5.62 (s, 2H), 5.59 (s, 2H), 4.81 (br-s, 1H), 4.08 (br-s, 3H), 3.21
(br-s, 2H), 3.08 (br-s, 2H), 2.77-2.65 (m, 4H), 2.55 (s, 3H), 2.43
(s, 3H), 2.37-1.36 (m, 12H). HPLC-6: RT=1.36 min, purity=98%. hLPA1
IC.sub.50=824 nM.
EXAMPLE 15
(4-(5-(((1S,3S)-3-cyanocyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1-
,2,3-triazol-5-yl)methyl (cyclobutylmethyl)(methyl)carbamate
##STR00134##
[0969] A mixture of Example 14 (90 mg, 0.19 mmol) and Burgess
reagent (137 mg, 0.57 mmol) in DCM (1 mL) and THF (1 mL) was
stirred at rt for 48 h, then was concentrated in vacuo. The residue
was chromatographed (SiO.sub.2; 12 g; A=DCM, B=EtOAc; 12 min
gradient from 0% B to 100% B; flow rate=30 mL/min) to afford the
title compound (85 mg, 0.18 mmol, 95% yield) as a white solid.
LCMS, [M+H].sup.+=453.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
[rotamer, ratio 53:47] [major rotamer--underline; minor
rotamer--Italic]: .delta. ppm 7.83 (d, J=8.5 Hz, 1H), 7.47 (d,
J=8.7 Hz, 1H), 5.62 (s, 2H), 5.58 (s, 2H), 4.71 (s, 1H), 4.08
(br-s, 3H), 3.22 (br-s, 2H), 3.08 (br-s, 2H), 2.77-2.65 (m, 4H),
2.55 (s, 3H), 2.40 (s, 3H), 2.34-1.34 (m, 12H). HPLC-6: RT=1.68
min, purity=97%. hLPA1 IC.sub.50=3750 nM.
EXAMPLE 16
(4-(5-(((1S,3S)-3-(1H-tetrazol-5-yl)cyclohexyl)oxy)-6-methylpyridin-2-yl)--
1-methyl-1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate
##STR00135##
[0971] A mixture of Example 15 (69 mg, 0.15 mmol), TEA (0.32 mL,
2.3 mmol), NaN.sub.3 (149 mg, 2.3 mmol) and HOAc (0.13 mL, 2.3
mmol) in toluene (1.0 mL) in a sealed tube was stirred at
100.degree. C. for 18 h, then was cooled to rt. The mixture was
diluted with EtOAc (5 mL), quenched with sat'd. aq. NaHCO.sub.3 (3
mL). The mixture was extracted with EtOAc (5.times.5 mL). The
combined organic extracts were dried (MgSO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by
preparative LC/MS using the following conditions: Column: XBridge
C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A: 5:95
MeCN:water with 10 mM NH.sub.4OAc; Mobile Phase B: 95:5 MeCN:water
with 10 mM NH.sub.4OAc; Gradient: 10-60% B over 20 min, then a
5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford the title compound (54 mg, 70% yield) as a white solid.
LCMS, [M+H].sup.+=496.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
[rotamer, ratio 53:47] [major rotamer--underline; minor
rotamer--Italic]: .delta. ppm 7.82 (d, J=8.5 Hz, 1H), 7.49 (d,
J=8.6 Hz, 1H), 5.61 (s, 2H), 5.57 (s, 2H), 4.88 (s, 1H), 4.07
(br-s, 3H), 3.37 (m, 1H), 3.20 (br-s, 2H), 3.06 (br-s, 2H),
2.76-2.65 (m, 3H), 2.54 (s, 3H), 2.44 (s, 3H), 2.37-1.33 (m, 12H).
HPLC-6: RT=1.50 min, purity=96%. hLPA1 IC.sub.50=22 nM.
EXAMPLE 17
(1-methyl-4-(6-methyl-5-(((1S,3S)-3-((methylsulfonyl)carbamoyl)cyclohexyl)-
oxy)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)methyl
(cyclobutylmethyl)(methyl)carbamate
##STR00136##
[0973] To a clear solution of Example 2 (15 mg, 0.032 mmol) and
methanesulfonamide (5 mg, 0.048 mmol) and DMAP (6 mg, 0.048 mmol)
in DMF (0.2 mL) and DCM (1 mL) was added EDC (9.4 mg, 0.048 mmol).
The mixture was stirred at rt for 62 h, then was diluted with water
(2 mL) and DCM (5 mL). The organic layer was washed with brine (5
mL), dried (MgSO.sub.4) and concentrated in vacuo to afford a white
solid, which was purified via preparative LC/MS with the following
conditions: Column: XBridge C18, 19.times.200 mm, 5 .mu.m
particles; Mobile Phase A: 5:95 MeCN:water with 10 mM NH.sub.4OAc;
Mobile Phase B: 95:5 MeCN:water with 10 mM NH.sub.4OAc; Gradient:
20-70% B over 20 min, then a 3-min hold at 100% B; Flow: 20 mL/min.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to afford the title compound (14 mg,
78% yield) as a white solid. LCMS, [M+H].sup.+=549.3. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) [rotamer, ratio 53:47] [major--underlined;
minor--Italic]: .delta. ppm 7.82 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.6
Hz, 1H), 5.62 (s, 2H), 5.58 (s, 2H), 4.85 (s, 1H), 4.08 (br-s, 3H),
3.60 (m, 1H), 3.24-3.08 (m, 2H), 2.79-2.67 (m, 4H), 2.54 (s, 6H),
2.44 (s, 3H), 2.35-1.35 (m, 12H). HPLC-6: RT=1.56 min, purity=97%.
hLPA1 IC.sub.50=352 nM.
TABLE-US-00001 TABLE 1 Analytical & Biology Example Structure
& Name Data Method 18 ##STR00137## LCMS, [M + H].sup.+ = 458.3.
.sup.1H NMR (500 MHz, CD.sub.3CN) .delta. 8.26 (dd, J = 3.0, 0.6
Hz, 1H), 8.00- 7.96 (m, 1H), 7.38 (dd, J = 8.8, 2.8 Hz, 1H), 5.58
(s, 2H), 4.70 (br. s., 1H), 4.03 (s, 3H), 2.79-2.69 (m, 1H), 2.64
(br. s., 3H), 2.01-1.93 (m, 2H), 1.84- 1.73 (m, 3H), 1.71- 1.49 (m,
8H), 1.48-1.36 (m, 4H) hLPA1 IC.sub.50 = 21 nM. Example 2
(rac)-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 19
##STR00138## LCMS, [M + H].sup.+ = 508.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.6
Hz, 1H), 7.38- 6.97 (m, 5H), 5.68 (br s, 2H), 5.36 (br s, 1H), 5.10
(br s, 1H), 4.76 (br s, 1H), 4.14-3.98 (m, 2H), 3.69 (br d, J = 7.7
Hz, 1H), 2.63-2.55 (m, 2H), 2.49-2.44 (m, 1H), 2.38 (br s, 3H),
1.99 (br d, J = 14.4 Hz, 1H), 1.87- 1.70 (m, 3H), 1.67-1.28 (m, 7H)
hLPA1 IC.sub.50 = 17 nM Example 3
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl((R)-1-
phenylethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 20 ##STR00139## LCMS, [M +
H].sup.+ = 486.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83
(br d, J = 8.3 Hz, 1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.85- 5.43 (m,
2H), 4.77 (br s, 1H), 4.28-3.96 (m, 3H), 2.55 (s, 6H), 2.42 (br d,
J = 8.6 Hz, 3H), 1.97 (br s, 1H), 1.87-1.17 (m, 13H), 1.00-0.75 (m,
3H) hLPA1 IC.sub.50 = 28 nM. Example 1 (1S,3S)-3-((6-(5-((((1-
cyclobutylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid (diastereomeric mixture) 21 ##STR00140## LCMS, [M + H].sup.+ =
494.4 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.43-8.29 (m,
1H), 8.07-7.94 (m, 1H), 7.66-7.51 (m, 1H), 7.42-7.04 (m, 5H), 5.78-
5.57 (m, 2H), 5.45- 5.03 (m, 1H), 4.87-4.73 (m, 1H), 4.22-3.95 (m,
3H), 2.74-2.63 (m, 1H), 2.60-2.56 (m, 3H), 2.00- 1.91 (m, 1H),
1.90- 1.71 (m, 3H), 1.70-1.59 (m, 2H), 1.57-1.33 (m, 5H) hLPA1
IC.sub.50 = 21 nM. Example 1 (1S,3S)-3-((6-(1-methyl-5-
(((methyl((R)-1- phenylethyl)carbamoyl)oxy)methyl)-
1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 22 ##STR00141## LCMS, [M + H].sup.+ = 480.1. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.34 (br. s., 1H), 8.01 (d, J = 8.5 Hz,
1H), 7.55 (d, J = 7.0 Hz, 1H), 7.41-6.96 (m, 5H), 5.77-5.56 (m,
2H), 4.78 (br. s., 1H), 4.50-4.25 (m, 2H), 4.18-3.91 (m, 3H), 3.50
(br. s., 1H), 2.84-2.62 (m, 3H), 2.02- 1.74 (m, 4H), 1.71- 1.45 (m,
4H) hLPA1 IC.sub.50 = 18 nM. Example 1 (1S,3S)-3-((6-(5-
(((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 23 ##STR00142##
LCMS, [M + H].sup.+ = 458.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.35 (br. s., 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.57 (d, J =
7.6 Hz, 1H), 5.62 (d, J = 19.2 Hz, 2H), 4.77 (br. s., 1H), 4.11 (d,
J = 6.1 Hz, 3H), 3.56-3.41 (m, 1H), 3.28- 3.04 (m, 2H), 2.80- 2.67
(m, 3H), 2.02-1.40 (m, 15H) hLPA1 IC.sub.50 = 12 nM. Example 1
(1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 24 ##STR00143## LCMS, [M +
H].sup.+ = 460.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.44-8.29 (m, 1H), 8.07-7.95 (m, 1H), 7.55 (br d, J = 7.3 Hz, 1H),
5.73-5.52 (m, 2H), 4.78 (br s, 1H), 4.20- 4.03 (m, 3H), 2.70- 2.59
(m, 2H), 1.99-1.71 (m, 6H), 1.68-1.49 (m, 4H), 1.43-1.09 (m, 4H),
1.06-0.78 (m, 6H), 0.82- 0.58 (m, 1H) hLPA1 IC.sub.50 = 47 nM.
Example 1 (1S,3S)-3-((6-(1-methyl-5- (((methyl(pentan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 25
##STR00144## LCMS, [M + H].sup.+ = 458.3 .sup.1H NMR (400 MHz,
CD.sub.3CN) .delta. 8.24 (br. s., 1H), 8.12 (d, J = 8.1 Hz, 1H),
7.93 (dd, J = 9.1, 2.5 Hz, 1H), 5.17 (br. s., 2H), 4.80-4.59 (m,
1H), 3.97 (d, J = 15.8 Hz, 3H), 3.31- 3.07 (m, 1H), 2.72- 2.54 (m,
4H), 2.02-1.76 (m, 3H), 1.70-1.33 (m, 5H), 1.09-0.87 (m, 3H),
0.84-0.65 (m, 1H), 0.46- 0.13 (m, 4H) hLPA1 IC.sub.50 = 20 nM.
Example 3 (1S,3S)-3-((6-(5-(((((R)-1-
cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 26
##STR00145## LCMS, [M + H].sup.+ = 497.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.73-7.41 (m, 2H), 7.38-6.98 (m, 6H),
5.43-5.26 (m, 2H), 4.72 (br. s., 1H), 4.39 (d, J = 8.9 Hz, 2H),
4.20- 3.95 (m, 3H), 3.67-3.42 (m, 3H), 2.69-2.60 (m, 1H), 1.96 (br.
s., 1H), 1.82 (t, J = 11.1 Hz, 3H), 1.69-1.45 (m, 5H) hLPA1
IC.sub.50 = 34 nM. Example 1 (1S,3S)-3-(4-(5-
(((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
2-fluorophenoxy)cyclohexane-1- carboxylic acid 27 ##STR00146##
LCMS, [M + H].sup.+ = 475.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.70-7.48 (m, 2H), 7.33 (t, J = 8.7 Hz, 1H), 5.32 (d, J =
7.9 Hz, 2H), 4.75 (br. s., 1H), 4.12 (br. s., 3H), 3.65- 3.44 (m,
4H), 3.26-3.07 (m, 2H), 2.69-2.60 (m, 1H), 2.01-1.41 (m, 14H) hLPA1
IC.sub.50 = 14 nM. Example 1 (1S,3S)-3-(4-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-
fluorophenoxy)cyclohexane-1- carboxylic acid 28 ##STR00147## LCMS,
[M + H].sup.+ = 477.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.70-7.43 (m, 2H), 7.32 (br t, J = 8.5 Hz, 1H), 5.33 (br s, 2H),
4.75 (br s, 1H), 4.12 (s, 3H), 3.90 (br s, 1H), 3.52 (br d, J =
16.5 Hz, 2H), 2.71-2.59 (m, 2H), 1.97 (br s, 1H), 1.88-1.76 (m,
3H), 1.71-1.45 (m, 4H), 1.43-1.18 (m, 2H), 1.14- 0.91 (m, 5H), 0.82
(br t, J = 6.9 Hz, 2H), 0.76- 0.66 (m, 1H) hLPA1 IC.sub.50 = 25 nM.
Example 1 (1S,3S)-3-(2-fluoro-4-(1-methyl-5- (((methyl(pentan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomeric
mixture) 29 ##STR00148## LCMS, [M + H].sup.+ = 472.1 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.69 (d, J = 8.2 Hz, 1H), 7.33 (d,
J = 8.2 Hz, 1H), 5.74- 5.34 (m, 2H), 4.64 (br. s., 1H), 3.95 (s,
3H), 3.27 (br. s., 1H), 2.67-2.44 (m, 4H), 2.27 (s, 3H), 1.88 (d, J
= 14.0 Hz, 1H), 1.79-1.59 (m, 3H), 1.56- 1.27 (m, 4H), 1.05- 0.63
(m, 4H), 0.44--0.39 (m, 4H) hLPA1 IC.sub.50 = 41 nM. Example 3
(1S,3S)-3-((6-(5-(((((R)-1- cyclopropylethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 30 ##STR00149## LCMS, [M +
H].sup.+ = 494.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.86
(d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.39- 6.97 (m, 5H),
5.79-5.63 (m, 2H), 4.79 (br. s., 1H), 4.49-4.26 (m, 2H), 4.17- 3.91
(m, 3H), 2.86- 2.69 (m, 3H), 2.68-2.59 (m, 1H), 2.41 (d, J = 14.3
Hz, 3H), 2.07-1.98 (m, 1H), 1.92-1.74 (m, 3H), 1.71-1.45 (m, 4H)
hLPA1 IC.sub.50 = 16 nM. Example 1 (1S,3S)-3-((6-(5-
(((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 31 ##STR00150## LCMS, [M +
H].sup.+ = 474.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84
(d, J = 8.2 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 5.66 (br. s., 2H),
4.79 (br. s., 1H), 4.10 (s, 4H), 2.63 (br. s., 3H), 2.42 (s, 3H),
2.10- 1.97 (m, 1H), 1.91-1.71 (m, 4H), 1.67-1.10 (m, 6H), 1.06-0.80
(m, 4H), 0.64 (br. s., 2H) hLPA1 IC.sub.50 = 36 nM. Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pentan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 32
##STR00151## LCMS, [M + H].sup.+ = 460.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5
Hz, 1H), 5.64 (d, J = 15.9 Hz, 2H), 4.79 (br. s., 1H), 4.10 (s,
3H), 3.53- 3.32 (m, 2H), 3.23- 3.02 (m, 1H), 2.85-2.69 (m, 3H),
2.42 (s, 3H), 1.81 (br. s., 3H), 1.63 (d, J = 9.8 Hz, 6H), 1.31-
0.96 (m, 3H), 0.66 (br. s., 3H) hLPA1 IC.sub.50 = 10 nM. Example 1
(1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 33 ##STR00152## LCMS, [M +
H].sup.+ = 472.4 .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.
7.96-7.79 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 5.67 (br s, 2H),
4.86-4.62 (m, 1H), 4.19- 3.97 (m, 4H), 3.39- 3.01 (m, 2H),
2.88-2.63 (m, 4H), 2.60-2.29 (m, 4H), 2.18-2.04 (m, 1H), 1.91-1.44
(m, 12H), 1.29-1.15 (m, 1H) hLPA1 IC.sub.50 = 7 nM. Example 1
(1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 34 ##STR00153## LCMS, [M +
H].sup.+ = 474.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.85
(d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 5.63 (d, J = 15.3
Hz, 2H), 4.79 (br. s., 1H), 4.10 (br. s., 3H), 3.44 (br. s., 1H),
3.22 (br. s., 1H), 3.06 (br. s., 1H), 2.84-2.69 (m, 3H), 2.63 (t, J
= 10.4 Hz, 1H), 2.42 (s, 3H), 2.09-1.97 (m, 2H), 1.92-1.70 (m, 2H),
1.70-1.42 (m, 4H), 1.40- 1.19 (m, 2H), 1.14 (br. s., 1H), 0.88 (br.
s., 3H), 0.62 (d, J = 4.6 Hz, 3H) hLPA1 IC.sub.50 = 16 nM. Example
1 35 ##STR00154## LCMS, [M + H].sup.+ = 528.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5
Hz, 1H), 7.44- 6.99 (m, 4H), 5.83-5.59 (m, 2H), 4.79 (br. s., 1H),
4.49-4.25 (m, 2H), 4.18- 3.93 (m, 3H), 2.86- 2.68 (m, 3H),
2.67-2.60 (m, 1H), 2.45-2.29 (m, 3H), 2.03 (d, J = 13.7 Hz, 1H),
1.94-1.73 (m, 3H), 1.71-1.44 (m, 4H) hLPA1 IC.sub.50 = 284 nM.
Example 1 (1S,3S)-3-((6-(5-((((4-
chlorobenzyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 36 ##STR00155## LCMS, [M +
H].sup.+ = 471.3 .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.
7.48-7.31 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 5.11 (s,
2H), 4.62 (br. s., 1H), 3.95 (s, 3H), 2.70-2.56 (m, 4H), 2.13 (s,
3H), 2.02-1.92 (m, 1H), 1.65-1.33 (m, 8H), 0.99 (br. s., 3H),
0.83-0.68 (m, 1H), 0.37 (br. s., 1H), 0.26--0.22 (m, 3H) hLPA1
IC.sub.50 = 6 nM. Example 3 (1S,3S)-3-(4-(5-(((((R)-1-
cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2- methylphenoxy)cyclohexane-1- carboxylic acid 37
##STR00156## LCMS, [M - H].sup.+ = 471.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.66-7.42 (m, 2H), 7.06 (d, J = 8.5 Hz, 1H),
5.28 (br. s., 2H), 4.74 (br. s., 1H), 4.10 (br. s., 3H), 3.48-3.34
(m, 2H), 2.76 (br. s., 2H), 2.65-2.58 (m, 1H), 2.22 (br. s., 3H),
2.02-1.40 (m, 15H) hLPA1 IC.sub.50 = 14 nM. Example 1
(1S,3S)-3-(4-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-
methylphenoxy)cyclohexane-1- carboxylic acid 38 ##STR00157## LCMS,
[M - H].sup.+ = 493.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.65-7.39 (m, 2H), 7.37-6.94 (m, 7H), 5.32 (d, J = 19.5 Hz, 2H),
4.72 (br. s., 1H), 4.39 (d, J = 13.4 Hz, 2H), 4.18-3.95 (m, 3H),
2.89- 2.70 (m, 3H), 2.62 (br. s., 1H), 2.24-2.10 (m, 3H), 2.00 (d,
J = 11.9 Hz, 1H), 1.90-1.71 (m, 3H), 1.69-1.39 (m, 4H) hLPA1
IC.sub.50 = 32 nM. Example 1 (1S,3S)-3-(4-(5-
(((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
2-methylphenoxy)cyclohexane-1- carboxylic acid 39 ##STR00158##
LCMS, [M + H].sup.+ = 473.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.62-7.42 (m, 2H), 7.05 (d, J = 8.5 Hz, 1H), 5.27 (br. s.,
2H), 4.74 (br. s., 1H), 4.09 (s, 3H), 3.43 (br. s., 2H), 2.68-2.54
(m, 4H), 2.21 (s, 3H), 2.01 (d, J = 13.7 Hz, 1H), 1.88-1.71 (m,
3H), 1.69-1.18 (m, 6H), 1.16-0.66 (m, 6H) hLPA1 IC.sub.50 = 23 nM.
Example 1 (1S,3S)-3-(2-methyl-4-(1-methyl-5- (((methyl(pentan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomeric
mixture) 40 ##STR00159## LCMS, [M + H].sup.+ = 459.3 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.52 (d, J = 13.1 Hz, 2H), 7.05 (d,
J = 7.6 Hz, 1H), 5.27 (d, J = 5.5 Hz, 2H), 4.74 (br. s., 1H), 4.09
(s, 3H), 3.23- 3.04 (m, 2H), 2.77 (d, J = 6.4 Hz, 3H), 2.61 (br.
s., 1H), 2.22 (s, 3H), 2.00 (d, J = 12.8 Hz, 1H), 1.90- 1.69 (m,
3H), 1.67- 1.04 (m, 8H), 0.91-0.61 (m, 3H) hLPA1 IC.sub.50 = 28 nM.
Example 1 (1S,3S)-3-(4-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylphenoxy)cyclohexane-1-
carboxylic acid 41 ##STR00160## LCMS, [M + H].sup.+ = 471.3,
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.60-7.44 (m, 2H), 7.04
(d, J = 8.5 Hz, 1H), 5.28 (s, 2H), 4.74 (br. s., 1H), 4.09 (s, 3H),
3.42 (br. s., 1H), 2.72-2.58 (m, 4H), 2.27- 2.17 (m, 3H), 2.01 (d,
J = 13.4 Hz, 1H), 1.89- 1.71 (m, 3H), 1.69-1.32 (m, 12H) hLPA1
IC.sub.50 = 14 nM. Example 1 (1S,3S)-3-(4-(5-
(((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-methylphenoxy)cyclohexane- 1-carboxylic acid 42
##STR00161## LCMS, [M + H].sup.+ = 4743. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.32 (s, 1H), 7.90 (s, 1H), 5.62 (d, J = 18.0
Hz, 2H), 4.88 (br. s., 1H), 4.10 (br. s., 3H), 3.26-3.04 (m, 2H),
2.76 (d, J = 17.7 Hz, 3H), 2.65 (br. s., 1H), 2.28 (s, 3H), 2.03
(d, J = 12.8 Hz, 1H), 1.93-1.77 (m, 3H), 1.70-1.06 (m, 7H), 0.88
(d, J = 4.6 Hz, 3H), 0.67 (d, J = 5.2 Hz, 3H) hLPA1 IC.sub.50 =
3750 nM. Example 1 (1S,3S)-3-((6-(5-
(((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-4-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 43 ##STR00162## LCMS, [M +
H].sup.+ = 446.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.35
(d, J = 2.4 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.2 Hz,
1H), 5.62 (d, J = 18.0 Hz, 2H), 4.79 (br. s., 1H), 4.11 (s, 3H),
3.24- 3.04 (m, 2H), 2.82- 2.62 (m, 4H), 1.98 (d, J = 14.0 Hz, 1H),
1.89- 1.73 (m, 3H), 1.72-1.37 (m, 5H), 1.26 (br. s., 2H), 1.05 (br.
s., 1H), 0.88 (br. s., 2H), 0.69 (br. s., 2H) hLPA1 IC.sub.50 = 7
nM. Example 1 (1S,3S)-3-((6-(5-
(((butyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 44 ##STR00163##
LCMS, [M + H].sup.+ = 475.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.61 (d, J = 12.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.35
(t, J = 8.5 Hz, 1H), 5.34 (s, 2H), 4.75 (br. s., 1H), 4.13 (s, 3H),
3.46-3.30 (m, 1H), 2.73-2.59 (m, 4H), 2.01-1.30 (m, 16H) hLPA1
IC.sub.50 = 6 nM. Example 1 (1S,3S)-3-(4-(5-
(((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-fluorophenoxy)cyclohexane- 1-carboxylic acid 45
##STR00164## LCMS, [M + H].sup.+ = 475.4 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.61-7.39 (m, 2H), 7.30-7.19 (m, 1H), 5.23
(s, 2H), 4.66 (br. s., 1H), 4.02 (s, 3H), 3.29 (br. s., 1H), 2.65
(br. s., 3H), 2.60-2.52 (m, 1H), 1.94-1.85 (m, 1H), 1.73 (d, J =
11.0 Hz, 3H), 1.56 (d, J = 8.5 Hz, 2H), 1.44 (br. s., 2H), 0.98 (d,
J = 16.2 Hz, 4H), 0.51- -0.31 (m, 4H) hLPA1 IC.sub.50 = 20 nM.
Example 1 (1S,3S)-3-(4-(5-((((1-
cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2- fluorophenoxy)cyclohexane-1- carboxylic acid
(diastereomeric mixture) 46 ##STR00165## LCMS, [M + H].sup.+ =
463.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.69-7.45 (m,
2H), 7.35 (br. s., 1H), 5.34 (br. s., 2H), 4.75 (br. s., 1H), 4.13
(s, 3H), 3.23- 3.06 (m, 2H), 2.78 (d, J = 8.9 Hz, 3H), 2.63 (br.
s., 1H), 1.99-1.04 (m, 12H), 0.93-0.70 (m, 3H) hLPA1 IC.sub.50 = 6
nM. Example 1 (1S,3S)-3-(4-(5-
(((butyl(methyl)carbamoyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)- 2-fluorophenoxy)cyclohexane-1-
carboxylic acid 47 ##STR00166## LCMS, [M + H].sup.+ = 477.1 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.77-7.43 (m, 2H), 7.33 (br.
s., 1H), 5.34 (d, J = 7.9 Hz, 2H), 4.75 (br. s., 1H), 4.13 (br. s.,
3H), 3.23-3.06 (m, 2H), 2.78 (d, J = 14.6 Hz, 3H), 2.67 (br. s.,
1H), 1.98 (br. s., 1H), 1.89- 1.11 (m, 10H), 0.96- 0.65 (m, 6H)
hLPA1 IC.sub.50 = 3 nM. Example 1 (1S,3S)-3-(2-fluoro-4-(5-
(((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid 48 ##STR00167## LCMS, [M + H].sup.+ = 471.3 .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (br s, 2H), 7.04 (br d, J =
7.5 Hz, 2H), 5.32 (s, 2H), 4.72 (br s, 1H), 4.19 (br s, 3H), 2.94
(br d, J = 3.1 Hz, 1H), 2.67 (s, 3H), 2.47-1.58 (m, 16H), 1.02 (br
s, 3H) hLPA1 IC.sub.50 = 8 nM. Example 1 (1S,3S)-3-(4-(5-((((1-
cyclobutylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (isomer 1) 49
##STR00168## LCMS, [M + H].sup.+ = 471.3 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.85-7.62 (m, 2H), 7.03 (br d, J = 3.3 Hz, 2H),
5.32 (br d, J = 2.9 Hz, 2H), 4.87- 4.56 (m, 1H), 4.19 (br s, 3H),
3.07-2.86 (m, 1H), 2.67 (br s, 3H), 2.49- 1.49 (m, 16H), 1.05- 0.93
(m, 3H) hLPA1 IC.sub.50 = 14 nM. Example 1 (1S,3S)-3-(4-(5-((((1-
cyclobutylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (isomer 2) 50
##STR00169## LCMS, [M + H].sup.+ = 460.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.34 (br. s., 1H), 8.09-7.93 (m, 1H), 7.55
(d, J = 7.9 Hz, 1H), 5.62 (d, J = 16.8 Hz, 2H), 4.78 (br. s., 1H),
4.11 (br. s., 3H), 3.29-3.00 (m, 2H), 2.76 (d, J = 17.7 Hz, 3H),
2.64 (br. s., 1H), 1.97-1.45 (m, 8H), 1.40- 1.14 (m, 2H), 0.88 (d,
J = 4.9 Hz, 3H), 0.67 (d, J = 5.2 Hz, 3H) hLPA1 IC.sub.50 = 12 nM.
Example 1 (1S,3S)-3-((6-(5- (((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 51 ##STR00170##
LCMS, [M + H].sup.+ = 457.3 .sup.1H NMR (400 MHz, CD.sub.3CN)
.delta. 7.64-7.44 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.10 (s, 2H),
4.61-4.49 (m, 1H), 3.94 (s, 3H), 2.70-2.52 (m, 4H), 1.96-1.85 (m,
1H), 1.75-1.35 (m, 8H), 0.97 (br. s., 3H), 0.75 (br. s., 1H),
0.44-0.25 (m, 4H) hLPA1 IC.sub.50 = 24 nM. In vivo acute histamine
assay: -73% histamine at a 3 mg/kg dose of Example 51 Example 1
(1S,3S)-3-(4-(5-(((((R)-1- cyclopropylethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-
carboxylic acid 52 ##STR00171## LCMS, [M + H].sup.+ = 457.2 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.54 (d, J = 8.2 Hz, 2H), 6.96
(d, J = 8.2 Hz, 2H), 5.18 (br. s., 2H), 4.59 (br. s., 1H), 3.99 (s,
3H), 2.62 (br. s., 3H), 2.51 (br. s., 1H), 1.74-1.31 (m, 8H), 1.06-
0.90 (m, 3H), 0.87- 0.71 (m, 1H), 0.43--0.30 (m, 4H) hLPA1
IC.sub.50 = 197 nM. Example 3 (1S,3S)-3-(4-(5-(((((S)-1-
cyclopropylethyl)(methyl)carbamoyl)- oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 53 ##STR00172##
LCMS, [M + H].sup.+ = 445.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.68 (br. s., 2H), 7.08 (d, J = 8.2 Hz, 2H), 5.31 (s, 2H),
4.72 (br. s., 1H), 4.12 (s, 3H), 3.08-2.93 (m, 2H), 2.80 (d, J =
15.3 Hz, 3H), 2.67 (br. s., 1H), 2.03-1.48 (m, 9H), 0.88-0.64 (m,
6H) hLPA1 IC.sub.50 = 440 nM. Example 1 (1S,3S)-3-(4-(5-
(((isobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid (diastereomeric mixture) 54 ##STR00173## LCMS, [M +
H].sup.+ = 471.2 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (t,
J = 9.4 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 5.21 (s, 2H), 4.61 (br.
s., 1H), 4.10 (d, J = 2.2 Hz, 4H), 3.84 (dd, J = 10.3, 6.6 Hz, 1H),
2.98- 2.76 (m, 1H), 2.69- 2.53 (m, 3H), 2.34-2.19 (m, 1H), 2.08 (d,
J = 13.9 Hz, 1H), 2.00-1.40 (m, 12H), 0.90 (dd, J = 17.7, 6.7 Hz,
3H) hLPA1 IC.sub.50 = 19 nM. Example 2 (1S,3S)-3-(4-(5-((((1-
cyclobutylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomeric
mixture) 55 ##STR00174## LCMS, [M + H].sup.+ = 457.2 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.80 (br. s., 2H), 7.20 (d, J = 7.6
Hz, 2H), 5.43 (br. s., 2H), 4.83 (br. s., 1H), 4.24 (s, 3H),
3.54-3.30 (m, 3H), 2.93 (d, J = 9.2 Hz, 3H), 2.79 (br. s., 1H),
2.17- 1.30 (m, 10H), 0.76- -0.06 (m, 4H) hLPA1 IC.sub.50 = 41 nM.
Example 3
(rac)-trans-3-(4-(5-((((2- cyclopropylethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-
carboxylic acid 56 ##STR00175## LCMS, [M + H].sup.+ = 473.2 .sup.1H
NMR (400 MHz, CD.sub.3CN) .delta. 7.61 (d, J = 15.2 Hz, 2H), 7.05
(br. s., 1H), 5.33 (br. s., 2H), 4.79 (br. s., 1H), 4.14 (s, 3H),
3.35-3.13 (m, 2H), 2.91-2.72 (m, 4H), 2.36- 2.26 (m, 3H), 2.14 (d,
J = 13.4 Hz, 1H), 1.89- 1.26 (m, 10H), 1.02- 0.68 (m, 6H) hLPA1
IC.sub.50 = 3 nM. Example 2 (1S,3S)-3-(4-(5-
(((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)-2-methylphenoxy)cyclohexane-1- carboxylic acid 57 ##STR00176##
LCMS, [M + H].sup.+ = 459.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.67 (t, J = 9.6 Hz, 2H), 7.16- 6.98 (m, 2H), 5.31 (s, 2H),
4.72 (br. s., 1H), 4.12 (s, 3H), 2.66 (d, J = 10.1 Hz, 1H), 2.04-
1.47 (m, 10H), 1.46- 1.28 (m, 3H), 1.19-0.65 (m, 9H) hLPA1
IC.sub.50 = 142 nM. Example 2 trans-3-(4-(1-methyl-5-
(((methyl(pentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomeric
mixture) 58 ##STR00177## LCMS, [M + H].sup.+ = 459.1 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.70 (d, J = 8.2 Hz, 2H), 7.08 (d,
J = 7.6 Hz, 2H), 5.31 (br. s., 2H), 4.72 (br. s., 1H), 4.12 (s,
3H), 3.23-3.08 (m, 2H), 2.79 (d, J = 13.7 Hz, 3H), 2.67 (br. s.,
1H), 2.03-1.01 (m, 14H), 0.93-0.69 (m, 3H) hLPA1 IC.sub.50 = 250
nM. Example 2 (rac)-trans-3-(4-(1-methyl-5-
(((methyl(pentyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-
yl)phenoxy)cyclohexane-1- carboxylic acid 59 ##STR00178## LCMS, [M
+ H].sup.+ = 431.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.68
(br. s., 2H), 7.09 (d, J = 8.5 Hz, 2H), 5.31 (s, 2H), 4.72 (br. s.,
1H), 4.12 (s, 3H), 3.20-3.07 (m, 2H), 2.80 (d, J = 9.8 Hz, 3H),
2.67 (br. s., 1H), 2.05-1.31 (m, 10H), 0.84-0.65 (m, 3H) hLPA1
IC.sub.50 = 1880 nM. Example 2 (rac)-trans-3-(4-(1-methyl-5-
(((methyl(propyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-
yl)phenoxy)cyclohexane-1- carboxylic acid 60 ##STR00179## LCMS, [M
+ H].sup.+ = 479.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.80-7.55 (m, 2H), 7.44-6.96 (m, 7H), 5.48-5.16 (m, 2H), 4.70 (br.
s., 1H), 4.41 (d, J = 12.8 Hz, 2H), 4.21- 3.94 (m, 3H), 2.90-2.73
(m, 3H), 2.70-2.61 (m, 1H), 2.04-1.48 (m, 8H) hLPA1 IC.sub.50 = 130
nM. Example 2 (rac)-trans-3-(4-(5- (((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid 61 ##STR00180## LCMS, [M + H].sup.+ = 443.2 .sup.1H
NMR (500 MHz, .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.66-7.46
(m, 2H), 7.08-6.86 (m, 2H), 5.28-5.11 (m, 2H), 4.68-4.59 (m, 1H),
4.10- 3.94 (m, 3H), 3.08- 2.91 (m, 3H), 2.85-2.71 (m, 3H),
2.65-2.54 (m, 1H), 1.97-1.39 (m, 8H), 0.96-0.67 (m, 1H), 0.46- 0.22
(m, 2H), 0.16 to -0.08 (m, 2H) hLPA1 IC.sub.50 = 273 nM. Example 2
(rac)-trans-3-(4-(5- ((((cyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-
yl)phenoxy)cyclohexane-1- carboxylic acid 62 ##STR00181## LCMS, [M
+ H].sup.+ = 459.2 .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.
7.80-7.65 (m, 2H), 7.12-6.96 (m, 2H), 5.35-5.24 (m, 2H), 4.78-4.70
(m, 1H), 5.07- 4.33 (m, 1H), 4.20- 4.06 (m, 3H), 3.37-3.14 (m, 2H),
2.93-2.72 (m, 4H), 2.13-2.02 (m, 1H), 1.92-1.22 (m, 10H), 0.99-0.74
(m, 6H) hLPA1 IC.sub.50 = 1290 nM. Example 2 (1R,3R)-3-(4-(5-
(((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid 63 ##STR00182## LCMS, [M + H].sup.+ = 473.2 .sup.1H
NMR (400 MHz, CD.sub.3CN) .delta. 7.65-7.46 (m, 2H), 7.04 (d, J =
8.4 Hz, 1H), 5.29 (br. s., 2H), 4.78 (br. s., 1H), 4.13 (s, 3H),
3.30-3.19 (m, 2H), 2.88-2.74 (m, 4H), 2.30 (s, 3H), 2.18-2.09 (m,
1H), 1.80-1.25 (m, 11H), 0.96-0.70 (m, 6H) hLPA1 IC.sub.50 = 701
nM. Example 2 (1R,3R)-3-(4-(5- (((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)-2-methylphenoxy)cyclohexane-1- carboxylic acid 64 ##STR00183##
LCMS, [M + H].sup.+ = 445.2 (500 MHz, DMSO-d.sub.6) .delta.
7.76-7.57 (m, 2H), 7.17- 6.94 (m, 2H), 5.42- 5.23 (m, 2H),
4.77-4.62 (m, 1H), 4.19-4.04 (m, 3H), 3.28-3.06 (m, 2H), 2.88-2.75
(m, 3H), 2.71- 2.59 (m, 1H), 2.01- 1.03 (m, 13H), 0.92- 0.68 (m,
3H) hLPA1 IC.sub.50 = 32 nM. Example 1 (rac)-trans-3-(4-(5-
(((butyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-
yl)phenoxy)cyclohexane-1- carboxylic acid 65 ##STR00184## LCMS, [M
+ H].sup.+ = 457.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.54
(d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 5.19 (br. s., 2H),
4.60 (br. s., 1H), 3.99 (s, 3H), 2.63 (br. s., 4H), 2.60-2.51 (m,
1H), 1.95-1.34 (m, 8H), 1.06- 0.71 (m, 4H), 0.47- 0.29 (m, 4H)
hLPA1 IC.sub.50 = 80 nM. Example 1 trans-3-(4-(5-((((1-
cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomeric
mixture) 66 ##STR00185## LCMS, [M + H].sup.+ = 457.2 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.70 (d, J = 7.9 Hz, 2H), 7.09 (d,
J = 8.5 Hz, 2H), 5.31 (br. s., 2H), 4.72 (br. s., 1H), 4.12 (br.
s., 3H), 3.31- 3.13 (m, 2H), 2.78 (d, J = 11.0 Hz, 3H), 2.67 (br.
s., 1H), 2.03-1.45 (m, 15H) hLPA1 IC.sub.50 = 68 nM. Example 1
(rac)-trans-3-(4-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-
carboxylic acid 67 ##STR00186## LCMS, [M + H].sup.+ = 471.2 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.81-7.58 (m, 2H), 7.12-7.03
(m, 2H), 5.43-5.17 (m, 2H), 4.71 (br. s., 1H), 4.12 (d, J = 12.2
Hz, 3H), 4.06- 3.74 (m, 1H), 3.00 (s, 3H), 2.66 (br. s., 1H),
2.03-1.44 (m, 15H), 0.94-0.81 (m, 3H) hLPA1 IC.sub.50 = 109 nM.
Example 1 trans-3-(4-(5-((((1- cyclobutylethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-
carboxylic acid (diastereomeric mixture) 68 ##STR00187## LCMS, [M +
H].sup.+ = 445.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.75-7.60 (m, 2H), 7.08 (d, J = 8.9 Hz, 2H), 5.31 (s, 2H), 4.71
(br. s., 1H), 4.11 (s, 3H), 4.05-3.73 (m, 1H), 2.73-2.57 (m, 4H),
2.02- 1.27 (m, 10H), 1.08- 0.92 (m, 3H), 0.76-0.57 (m, 3H) hLPA1
IC.sub.50 = 320 nM. Example 1 (trans)-3-(4-(5-(((sec-
butyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-
yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomeric mixture)
69 ##STR00188## LCMS, [M + H].sup.+ = 473.0 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.6
Hz, 1H), 5.62 (d, J = 19.4 Hz, 2H), 4.09 (d, J = 7.2 Hz, 3H), 3.33-
3.04 (m, 2H), 2.82-2.67 (m, 3H), 2.36 (br. s., 3H), 2.45-2.16 (m,
1H), 2.08- 1.15 (m, 14H) hLPA1 IC.sub.50 = 57 nM. Example 2 (using
intermedi- ate 2) (3S)-3-((6-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic-1-d acid (homochiral) 70
##STR00189## LCMS, [M + H].sup.+ = 475.3 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51-7.32 (m, 2H), 7.03 (t, J = 8.5 Hz, 1H),
5.28-5.12 (m, 2H), 4.62 (br. s., 1H), 4.11 (s, 3H), 3.41 (d, J =
9.0 Hz, 1H), 3.19 (br. s., 1H), 2.98-2.69 (m, 4H), 2.11 (d, J =
13.6 Hz, 1H), 2.01- 1.67 (m, 4H), 1.65- 1.49 (m, 3H), 1.11 (d, J =
6.6 Hz, 3H), 0.78 (br. s., 1H), 0.57--0.15 (m, 3H) hLPA1 IC.sub.50
= 10 nM. Example 1 (1S,3S)-3-(4-(5-(((((R)-1-
cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2- fluorophenoxy)cyclohexane-1- carboxylic acid 71
##STR00190## LCMS, [M + H].sup.+ = 459.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.88-7.56 (m, 2H), 7.08 (br. s., 2H), 5.31
(br. s., 2H), 4.71 (br. s., 1H), 4.12 (s, 3H), 3.29- 3.05 (m, 2H),
2.79 (d, J = 17.1 Hz, 3H), 2.70- 2.60 (m, 1H), 2.05-1.19 (m, 11H),
0.93-0.69 (m, 6H) hLPA1 IC.sub.50 = 13 nM. Example 2
(rac)-trans-3-(4-(5- (((isopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid 72 ##STR00191## LCMS, [M + H].sup.+ = 534.4 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 7.67 (d, J = 8.8 Hz, 2H), 7.09
(d, J = 8.8 Hz, 2H), 5.37 (s, 2H), 4.20 (s, 3H), 3.20 (s, 3H),
2.78-2.89 (m, 5H), 1.59- 2.10 (m, 17H). hLPA1 IC.sub.50 = 2780 nM.
Example 7 (1-Methyl-4-(4-(((1R,3R)-3-
((methylsulfonyl)carbamoyl)cyclohexyl)
oxy)phenyl)-1H-1,2,3-triazol-5- yl)methyl cyclopentyl
(methyl)carbamate 73 ##STR00192## LCMS, [M + H].sup.+ = 443.5
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.64 (d, J = 8.00 Hz,
2H), 7.08 (d, J = 8.00 Hz, 2H), 5.33 (s, 2H), 4.72-4.74 (m, 1H),
4.18 (s, 3H), 2.78-2.84 (m, 4H), 2.08-2.14 (m, 5H), 1.82-1.93 (m,
3H), 1.41-1.79 (m, 7H). hLPA1 IC.sub.50 = 62 nM. Example 10
(1S,3S)-3-(4-(5- (((cyclobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid 74 ##STR00193## LCMS, [M + H].sup.+ = 483.2 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 7.66 (d, J = 8.80 Hz, 2H), 7.09
(d, J = 8.80 Hz, 2H), 5.36 (s, 2H), 4.83-4.89 (m, 1H), 4.19 (s,
3H), 2.90-2.97 (m, 3H), 2.70-2.87 (m, 2H), 2.08-2.15 (m, 1H),
1.90-1.99 (m, 3H), 1.62- 1.74 (m, 4H), 1.05- 1.09 (m, 2H),
0.50-0.70 (m, 2H), 0.12-0.43 (m, 6H). hLPA1 IC.sub.50 = 100 nM.
Example 3 (1S,3S)-3-(4-(5- ((((Dicyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-
yl)phenoxy)cyclohexanecarboxylic acid 75 ##STR00194## LCMS, [M +
H].sup.+ = 471.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.70-7.80 (m, 1H), 7.60-7.70 (m, 1H), 7.08 (m, 2H), 5.30- 5.39 (m,
2H), 4.81-4.83 (m, 1H), 4.18-4.21 (m, 3H), 2.89 (s, 3H), 2.79- 2.82
(m, 1H), 2.06-2.12 (m, 1H), 1.80-2.00 (m, 3H), 1.60-1.80 (m, 4H),
1.20-1.50 (m, 4H), 0.80- 0.90 (m, 2H), 0.70- 0.80 (m, 3H),
0.60-0.70 (m, 2H). hLPA1 IC.sub.50 = 20 nM. Example 3
(1S,3S)-3-(4-(1-methyl-5- (((methyl(1-
propylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-
yl)phenoxy)cyclohexane-1- carboxylic acid 76 ##STR00195## LCMS, [M
+ H].sup.+ = 459.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.60-7.70 (m, 2H), 7.10-7.00 (m, 2H), 5.37 (s, 2H), 4.70- 4.80 (m,
1H), 4.18 (s, 3H), 2.75-2.85 (m, 1H), 2.60-2.70 (m, 3H), 2.08- 2.15
(m, 1H), 1.90- 2.00 (m, 3H), 1.60-1.75 (m, 5H), 1.40-1.50 (m, 4H),
0.71-0.81 (m, 6H). hLPA1 IC.sub.50 = 47 nM. Example 3
(1S,3S)-3-(4-(1-methyl-5- (((methyl(pentan-3-
yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 77 ##STR00196##
LCMS, [M + H].sup.+ = 460.4 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.30-8.46 (m, 1H), 7.90-7.97 (m, 1H), 7.51-7.65 (m, 1H),
5.70 (d, J = 10.8 Hz, 1H), 4.50-4.60 (m, 1H), 4.20 (s, 3H),
3.62-3.93 (m, 1H), 2.71-2.82 (m, 1H), 2.60-2.70 (m, 3H), 1.82- 2.10
(m, 4H), 1.57- 1.79 (m, 4H), 1.36-1.49 (m, 5H), 0.82 (t, J = 7.2
Hz, 3H), 0.67 (t, J = 7.6 Hz, 3H). hLPA1 IC.sub.50 = 242 nM.
Example 1 (1S,3S)-3-((6-(1-methyl-5- (((methyl(pentan-3-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 78 ##STR00197## LCMS, [M +
H].sup.+ = 474.4 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.30-8.50 (m, 1H), 7.94-8.05 (m, 1H), 7.53 (d, J = 8.40 Hz, 1H),
5.66 (s, 2H), 4.82- 4.86 (m, 1H), 4.20 (s, 3H), 2.75-2.90 (m, 4H),
1.90-2.20 (m, 4H), 1.60- 1.90 (m, 6H), 1.31 (s, 6H), 1.15-1.21 (m,
2H), 0.80 (t, J = 6.40 Hz, 3H). hLPA1 IC.sub.50 = 27 nM. Example 1
(1S,3S)-3-((6-(1-methyl-5- (((methyl(2-methylpentan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 79 ##STR00198## LCMS, [M +
H].sup.+ = 444.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.35-8.40 (m, 1H), 7.97 (d, J = 9.20 Hz, 1H), 7.53 (dd, J = 8.8
& 2.8 Hz, 1H), 5.70 (s, 2H), 4.80-4.85 (m, 1H), 4.21 (d, J =
16.00 Hz, 3H), 2.81-2.87 (m, 4H), 1.91-2.11 (m, 4H), 1.63- 1.87 (m,
4H), 1.12 (s, 3H), 0.56-0.87 (m, 4H). hLPA1 IC.sub.50 = 45 nM.
Example 1 (1S,3S)-3-((6-(1-methyl-5- (((methyl(1-
methylcyclopropyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-
3-yl)oxy)cyclohexane-1-carboxylic acid 80 ##STR00199## LCMS, [M +
H].sup.+ = 484.4 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.32-8.40 (m, 1H), 7.97-8.04 (m, 1H), 7.53 (d, J = 8.00 Hz, 1H),
5.60-5.80 (m, 2H), 4.82- 4.87 (m, 1H), 4.19 (s, 3H), 2.91 (d, J =
14.80 Hz, 3H), 2.79-2.81 (m, 2H), 2.40-2.50 (m, 1H), 1.91-2.10 (m,
4H), 1.63- 1.79 (m, 4H), 0.99-1.07 (m, 2H), 0.51-0.68 (m, 2H),
0.13-0.41 (m, 5H). hLPA1 IC.sub.50 = 60 nM. Example 3
(1S,3S)-3-((6-(5- ((((Dicyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexanecarboxylic acid 81 ##STR00200## LCMS, [M +
H].sup.+ = 472.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.31-8.39 (m, 1H), 7.94-8.02 (m, 1H), 7.52 (d, J = 8.40 Hz, 1H),
5.67-5.70 (m, 2H), 4.81- 4.89 (m, 1H), 4.40- 4.50, m, 1H), 4.20 (d,
J = 16.40 Hz, 3H), 2.72- 2.87 (m, 3H), 1.85-2.10 (m, 4H), 1.60-1.73
(m, 4H), 1.10-1.40 (m, 4H), 0.84-0.90 (m, 2H), 0.65- 0.76 (m, 4H),
0.56- 0.59 (m, 1H). hLPA1 IC.sub.50 = 61 nM. Example 3
(1S,3S)-3-((6-(1-methyl-5- (((methyl(1-
propylcyclopropyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-
3-yl)oxy)cyclohexane-1-carboxylic acid 82 ##STR00201## LCMS, [M +
H].sup.+ = 460.9 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.35
(br. s., 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 6.6 Hz, 1H),
5.85-5.40 (m, 2H), 4.78 (br. s., 1H), 3.59- 2.83 (m, 2H), 2.79-2.60
(m, 4H), 2.03-1.36 (m, 14H), 1.16 (t, J = 7.2 Hz, 1H) hLPA1
IC.sub.50 = 28 nM. Example 4 (1S,3S)-3-((6-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-(methyl-d3)-1H- 1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 83 ##STR00202## LCMS, [M +
H].sup.+ = 474.4 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.68 (d,
J = 8.0 Hz, 1H), 7.35-7.40 (m, 1H), 5.55-5.65 (m, 2H), 4.20-4.30
(m, 1H), 4.07 (s, 3H), 3.75-3.90 (m, 1H), 3.55-3.70 (m, 1H),
2.50-2.70 (m, 3H), 2.20-2.40 (m, 3H), 1.80- 2.10 (m, 3H), 1.94 (s,
3H), 1.55-1.84 (m, 3H), 1.10-1.40 (m, 3H), 0.70 (t, J = 7.6 Hz,
3H), 0.55 (t, J = 7.2 Hz, 3H). hLPA1 IC.sub.50 = 92 nM. Example 2
(1S,3S)-3-((2-Methyl-6-(1-methyl-5- (((methyl(pentan-3-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexanecarboxylic acid 84 ##STR00203## LCMS, [M +
H].sup.+ = 488.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.70 (d,
J = 8.4, 1H), 7.32 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 4.07 (s, 3H),
2.74 (s, 3H), 2.62-2.69 (m, 1H), 2.40 (s, 3H), 1.98-2.05 (m, 1H),
1.80-1.90 (m, 3H), 1.45-1.70 (m, 5H), 1.20 (s, 6H), 1.01-1.10 (m,
3H), 0.71-0.79 (m, 1H), 0.60-0.70 (m, 3H). hLPA1 IC.sub.50 = 69 nM.
Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl(2-methylpentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3- yl)oxy)cyclohexanecarboxylic acid 85
##STR00204## LCMS, [M + H].sup.+ = 458.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.81 (d, J = 8, 1H) 7.44 (d, J = 8 Hz, 1 H)
5.71 (s, 2 H) 4.79- 4.81 (m, 1 H) 4.13-4.26 (m, 3H) 2.74-2.88 (m, 4
H) 2.51 (s, 3 H) 2.06- 2.18 (m, 1 H) 1.86-1.96 (m, 3 H) 1.62-1.83
(m, 4 H) 1.11 (br. s., 3 H) 0.43-0.85 (m, 4 H) hLPA1 IC.sub.50 = 58
nM. Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-
methylcyclopropyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-
3-yl)oxy)cyclohexane-1-carboxylic acid 86 ##STR00205## LCMS, [M +
H].sup.+ = 498.3 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.79 (d,
J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.60-5.70 (m, 2H), 4.17
(s, 3H), 2.90 (d, J = 13.2 Hz, 3H), 2.60-2.80 (m, 3H), 2.49 (s,
3H), 2.40-2.55 (m, 3H), 2.05-2.15 (m, 1H), 1.60-1.80 (m, 4H), 1.20-
1.40 (m, 2H), 0.90- 1.10 (m, 2H), 0.45-0.65 (m, 2H), 0.30-0.40 (m,
2H), 0.10-0.30 (m, 2H). hLPA1 IC.sub.50 = 54 nM. Example 1
(1S,3S)-3-((6-(5- ((((Dicyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexanecarboxylic
acid 87 ##STR00206## LCMS, [M + H].sup.+ = 486.0 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.77-7.86 (m, 1 H) 7.44 (d, J = 8.4 Hz, 1
H) 5.71 (d, J = 11.6 Hz, 2H) 4.81-4.84 (m, 1 H), 4.2 (d, J = 8.4
Hz, 1 H), 2.74-2.90 (m, 4H), 2.51(s, 3H), 2.10-2.15(m, 1H),
1.91-1.97(m, 3H), 1.66-1.74 (m, 4H), 1.28- 1.37(m, 2H), 1.12-1.20
(m, 2H), 0.84-0.93 (m, 2H), 0.68-0.71(m, 5H), 0.51-0.53 (m, 2H).
hLPA1 IC.sub.50 = 36 nM. Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-
propylcyclopropyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-
3-yl)oxy)cyclohexane-1-carboxylic acid 88 ##STR00207## LCMS, [M +
H].sup.+ = 490.3 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.89 (d,
J = 8.6 Hz, 1H), 7.24-7.17 (m, 1H), 5.71-5.62 (m, 2H), 4.71 (tt, J
= 6.8, 3.7 Hz, 1H), 4.58-4.13 (m, 1H), 4.07 (s, 3H), 2.65 (br. s.,
3H), 2.52-2.38 (m, 4H), 2.24-1.32 (m, 15H); hLPA1 IC.sub.50 = 32
nM. Example 11 (rac)-trans-3-((6-(5-
(((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-methylpyridin-3-yl)oxy)-1- fluorocyclohexane-1-carboxylic
acid 89 ##STR00208## LCMS, [M + H].sup.+ = 476.3 .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.46 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 8.8
Hz, 1H), 7.56 (dd, J = 8.9, 2.6 Hz, 1H), 5.50 (s, 2H), 4.89-4.75
(m, 1H), 4.55- 4.44 (m, 1H), 4.10 (s, 3H), 2.64 (br. s., 3H),
2.56-2.37 (m, 4H), 2.19- 1.37 (m, 15H) hLPA1 IC.sub.50 = 32 nM.
Example 11 (rac)-trans-3-((6-(5-
(((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)pyridin-3-yl)oxy)-1-
fluorocyclohexane-1-carboxylic acid 90 ##STR00209## LCMS, [M +
H].sup.+ = 476.3 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.60 (d,
J = 2.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.8 Hz,
1H), 5.56 (s, 2H), 4.92 (br. s., 1H), 4.65- 4.50 (m, 1H), 4.21 (d,
J = 3.0 Hz, 3H), 2.85 (d, J = 17.1 Hz, 3H), 2.66- 2.41 (m, 4H),
2.29-1.48 (m, 15H) hLPA1 IC.sub.50 = 14 nM. Example 11
(rac)-trans-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)-1-
fluorocyclohexane-1-carboxylic acid 91 ##STR00210## LCMS, [M +
H].sup.+ = 473.4 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.11 (d,
J = 8.8 Hz, 1H), 7.80 (t, J = 8.9 Hz, 1H), 5.70-5.42 (m, 2H), 4.86
(br. s., 1H), 4.20 (d, J = 1.7 Hz, 3H), 3.39-3.26 (m, 3H), 2.90 (d,
J = 7.7 Hz, 3H), 2.77- 2.69 (m, 3H), 2.19-1.63 (m, 15H) hLPA1
IC.sub.50 = 18 nM. Example 2 (rac)-trans-3-((6-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 92 ##STR00211## LCMS, [M +
H].sup.+ = 472.3 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d,
J = 8.6 Hz, 1H), 7.66 (t, J = 8.6 Hz, 1H), 5.72 (d, J = 14.5 Hz,
1H), 5.47 (d, J = 14.3 Hz, 1H), 4.58 (br. s., 1H), 4.21 (s, 3H),
3.40-3.19 (m, 2H), 2.90 (s, 3H), 2.70 (d, J = 2.6 Hz, 3H),
2.64-2.46 (m, 2H), 2.31- 1.48 (m, 14H) hLPA1 IC.sub.50 = 76 nM.
Example 2 (rac)-cis-3-((6-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 93 ##STR00212## LCMS, [M +
H].sup.+ = 475.1 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.10
(br. s., 1H), 7.87 (br. s., 1H), 5.90-5.21 (m, 2H), 4.21 (br. s.,
3H), 3.30 (t, J = 8.0 Hz, 2H), 2.85 (br. s., 1H), 2.73 (br. s.,
3H), 2.63- 2.47 (m, 1H), 2.24-1.52 (m, 16H) hLPA1 IC.sub.50 = 20
nM. Example 4 (1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(methyl-
d3)carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 94
##STR00213## LCMS, [M + H].sup.+ = 471.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.58 (br. S., 2H), 7.05 (d, J = 8.0 Hz, 2H),
6.00 (d, J = 6.9 Hz, 1H), 4.69 (br. S., 1H), 4.40-4.22 (m, 1H),
4.13 (s, 3H), 2.65 (br. S., 4H), 1.98-1.35 (m, 19H) hLPA1 IC.sub.50
= 241 nM. Example 14 (1S,3S)-3-(4-(5-(1-
((cyclopentyl(methyl)carbamoyl)oxy)
ethyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-
carboxylic acid 95 ##STR00214## LCMS, [M + H].sup.+ = 472.3 .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.91 (d, J = 8.1 Hz, 1H), 7.16
(dd, J = 8.3, 3.6 Hz, 1H), 5.74 (br. S., 2H), 4.32-4.18 (m, 1H),
4.13 (br. S., 3H), 3.35- 3.11 (m, 2H), 2.92-2.75 (m, 3H), 2.56-2.24
(m, 5H), 2.17-1.35 (m, 15H) hLPA1 IC.sub.50 = 1152 nM. Example 1
(Cis)-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid; Enantiomer A 96 ##STR00215##
LCMS, [M + H].sup.+ = 472.3 .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.86 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 5.67
(br. s., 2H), 4.23-4.12 (m, 1H), 4.06 (br. s., 3H), 3.31-3.01 (m,
2H), 2.86-2.65 (m, 3H), 2.42-2.30 (m, 4H), 2.16-1.31 (m, 15H) hLPA1
IC.sub.50 = 20 nM. Example 1 (Cis)-3-((6-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid Enantiomer B 97 ##STR00216##
LCMS, [M + H].sup.+ = 472.3 .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.03-7.90 (m, 1H), 7.23 (d, J = 8.6 Hz, 1H), 5.77 (br d, J
= 5.3 Hz, 2H), 4.72 (br s, 1H), 4.16 (br s, 3H), 3.38- 3.15 (m,
2H), 2.90 (br s, 3H), 2.80 (br s, 2H), 2.59 (br s, 1H), 2.45-2.36
(m, 1H), 2.23-2.10 (m, 1H), 2.08-1.52 (m, 14H) hLPA1 IC.sub.50 = 10
nM. Example 1 (1R,3R)-3-((6-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 98 ##STR00217## LCMS, [M +
H].sup.+ = 512.3 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.84
(d, J = 5.2 Hz, 1H), 7.46 (br. s., 1H), 7.41-6.79 (m, 4H),
5.87-5.59 (m, 2H), 4.78 (br. s., 1H), 4.51- 4.26 (m, 2H), 4.15-3.91
(m, 3H), 3.53-3.37 (m, 1H), 2.87-2.69 (m, 3H), 2.67-2.58 (m, 1H),
2.46- 2.30 (m, 3H), 2.07- 1.44 (m, 8H) hLPA1 IC.sub.50 = 19 nM.
Example 1 (1S,3S)-3-((6-(5-((((2-
fluorobenzyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 99 ##STR00218## LCMS, [M +
H].sup.+ = 486.3 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.47
(d, J = 8.5 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 5.65 (br. s., 2H),
4.77 (br. s., 1H), 4.07 (s, 3H), 3.51 (br. s., 4H), 2.66-2.57 (m,
1H), 2.40 (br. s., 3H), 2.29- 2.19 (m, 1H), 2.05-1.97 (m, 1H),
1.89-1.43 (m, 14H), 1.25 (d, J = 7.3 Hz, 3H), 0.76 (t, J = 7.3 Hz,
3H) hLPA1 IC.sub.50 = 144 nM. Example 1 (1S,3S)-3-((6-(5-((((1-
cyclobutylpropyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid (diastereomeric mixture) 100 ##STR00219## LCMS, [M + H].sup.+
= 520.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.60-7.69 (m, 1
H) 7.01-7.34 (m, 5 H) 6.78-6.88 (m, 1H) 5.60-5.68 (m, 2 H) 4.08-
4.14 (m, 1 H) 3.76- 3.86 (m, 3 H) 2.88-2.94 (m, 3 H) 2.80-2.83 (m,
1 H) 2.32-2.44 (m, 3H) 1.86-1.92 (m, 4 H) 1.54- 1.67 (m, 4 H) 1.18-
1.27 (m, 4 H) hLPA1 IC.sub.50 = 70 nM. Example 5
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-
phenylcyclopropyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-
3-yl)oxy)cyclohexane-1-carboxylic acid 101 ##STR00220## LCMS, [M +
H].sup.+ = 500.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.60-7.69 (m, 1 H) 7.01-7.34 (m, 5 H) 6.78-6.88 (m, 1 H) 5.60-5.68
(m, 2 H) 4.08- 4.14 (m, 1 H) 3.76- 3.86 (m, 3 H) 2.88-2.94 (m, 3 H)
2.80-2.83 (m, 1 H) 2.32-2.44 (m, 3H) 1.86-1.92 (m, 4 H) 1.54- 1.67
(m, 4 H) 1.18- 1.27 (m, 4 H) hLPA1 IC.sub.50 = 49 nM. Example 5
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(3,3,3-
trifluoropropyl)carbamoyl)oxy)methyl)-
1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 102 ##STR00221## LCMS, [M + H].sup.+ = 469.9 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.83 (d, J = 8.4 Hz, 1H), 7.48 (d, J =
8.6 Hz, 1H), 5.61 (s, 2H), 4.87-4.69 (m, 1H), 4.10 (s, 3H), 2.71
(br. S., 3H), 2.55 (s, 3H), 2.40 (s, 3H), 2.07-1.47 (m, 15H) hLPA1
IC.sub.50 = 53 nM. Example 1 (1S,3S)-3-((6-(5-
(((bicyclo[1.1.1]pentan-1- yl(methyl)carbamoyl)oxy)methyl)-1-
methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 103
##STR00222## LCMS, [M + H].sup.+ = 508.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.84-7.88 (m, 1 H) 7.46 (br. s., 1 H) 7.12-7.31
(m, 4 H) 6.97- 7.01 (m, 1 H) 5.60- 5.73 (m, 2H) 4.80 (br. s., 1 H)
4.12 (br. s., 3 H) 3.46-3.53 (m, 3 H) 2.74- 2.85 (m, 4 H) 2.63 (d,
J = 7.03 Hz, 1 H) 2.46 (br. s., 3 H) 2.09 (br. s., 1 H) 1.94 (br.
s., 3 H) 1.61- 1.73 (m, 4 H) hLPA1 IC.sub.50 = 119 nM. Example 5
(1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl(phenethyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 104 ##STR00223##
LCMS, [M + H].sup.+ = 446.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.81 (d, J = 8.53 Hz, 1 H) 7.44 (d, J = 8.53 Hz, 1 H) 5.71
(br. s., 2 H) 4.81 (br. s., 1 H) 4.19 (s, 3 H) 3.09-3.17 (m, 2 H)
2.81-2.90 (m, 4 H) 2.51 (s, 3 H) 2.14 (br. s., 1 H) 1.88-1.92 (m, 3
H) 1.68-1.71 (m, 4 H) 1.56 (br. s., 2 H) 0.88 (d, J = 7.03 Hz, 3 H)
hLPA1 IC.sub.50 = 19 nM Example 5
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 105 ##STR00224## LCMS, [M +
H].sup.+ = 456.3 hLPA1 IC.sub.50 = 576 nM. Example 3
(1S,3S)-3-((6-(5- (((bicyclo[1.1.1]pentan-1-
ylcarbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 106
##STR00225## LCMS, [M + H].sup.+ = 486.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.79 (d, J = 8.53 Hz, 1 H) 7.44 (d, J = 8.53
Hz, 1 H) 5.66 (s, 2 H) 4.19 (s, 3H) 2.68 (d, J = 6.02 Hz, 1 H) 2.52
(s, 3 H) 2.12 (d, J = 13.05 Hz, 3 H) 1.94 (br. s., 3H) 1.58-1.79
(m, 5H) 1.31 (br. s., 6 H) 1.13 (br. s., 3 H) 0.93-0.96 (m, 3 H)
hLPA1 IC.sub.50 = 67 nM. Example 5 (1S,3S)-3-((6-(5-((((1,3-
dimethylcyclobutyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid Enantiomer A 107 ##STR00226##
LCMS, [M + H].sup.+ = 486.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 7.79 (d, J = 8.53 Hz, 1 H) 7.44 (d, J = 8.53 Hz, 1 H)
5.66 (s, 2 H) 4.19 (s, 3H) 2.68 (d, J = 6.02 Hz, 1 H) 2.52 (s, 3 H)
2.12 (d, J = 13.05 Hz, 3 H) 1.94 (br. s., 3H) 1.58-1.79 (m, 5H)
1.31 (br. s., 6 H) 1.13 (br. s., 3 H) 0.93-0.96 (m, 3 H) hLPA1
IC.sub.50 = 70 nM. Example 5 (1S,3S)-3-((6-(5-((((1,3-
dimethylcyclobutyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid Enantiomer B 108 ##STR00227##
LCMS, [M + H].sup.+ = 458.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.83 (d, J = 8.2 Hz, 1H), 7.58- 7.37 (m, 1H), 7.29 (br. s.,
1H), 5.64 (s, 2H), 4.77 (br. s., 1H), 4.07 (s, 3H), 3.01 (t, J =
6.0 Hz 2H), 2.44-2.31 (m, 4H), 2.05- 1.40 (m, 15H) hLPA1 IC.sub.50
= 108 nM. Example 1 (1S,3S)-3-((6-(5-
((((cyclobutylmethyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 109 ##STR00228## LCMS, [M +
H].sup.+ = 486.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
6.97-7.04 (m, 1 H) 6.60-6.67 (m, 1 H) 4.89 (s, 2 H) 3.99- 4.01 (m,
1 H) 3.38 (s, 3 H) 2.39-2.43 (m, 1 H) 2.26-2.30 (m, 1 H) 2.08 (s, 3
H) 1.70 (s, 3 H) 1.28- 1.33 (m, 1 H) 1.10- 1.19 (m, 4 H) 0.46-0.98
(m, 12 H) 0.39-0.42 (m, 1 H) hLPA1 IC.sub.50 = 22 nM. Example 5
(1S,3S)-3-((6-(5- ((((cyclopentylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 110 ##STR00229## LCMS, [M +
H].sup.+ = 447.4 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.34
(br. s., 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H),
7.36-6.86 (m, 1H), 6.03-5.43 (m, 2H), 4.77 (br. s., 1H), 3.26-2.57
(m, 6H), 2.19-1.31 (m, 8H), 1.07-0.65 (m, 1H), 0.62--0.21 (m, 4H)
hLPA1 IC.sub.50 = 31 nM. Example 4 (1S,3S)-3-((6-(5-
((((cyclopropylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-(methyl-d3)-1H- 1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 111 ##STR00230## LCMS, [M +
H].sup.+ = 461.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.33
(d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 6.3 Hz,
1H), 5.60 (br. s., 2H), 4.77 (br. s., 1H), 3.59 (br. s., 1H), 2.63
(br. s., 4H), 1.94 (br. s., 1H), 1.86-1.69 (m, 3H), 1.68- 1.25 (m,
12H) hLPA1 IC.sub.50 = 23 nM. Example 4 (1S,3S)-3-((6-(5-
(((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-(methyl-d3)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 112 ##STR00231## LCMS, [M +
H].sup.+ = 449.4 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.34
(d, J = 2.3 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.6 Hz,
1H), 5.83- 5.25 (m, 2H), 4.77 (br. s., 1H), 3.29-2.97 (m, 2H),
2.85-2.59 (m, 4H), 1.94 (br. s., 1H), 1.88-1.71 (m, 3H), 1.68-1.33
(m, 5H), 1.31-1.14 (m, 2H), 1.08-0.55 (m, 4H) hLPA1 IC.sub.50 = 17
nM. Example 4 (1S,3S)-3-((6-(5-
(((butyl(methyl)carbamoyl)oxy)methyl)-
1-(methyl-d3)-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 113 ##STR00232##
LC/MS: [M + H].sup.+ = 486.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.99-7.72 (m, 1H), 7.48 (br d, J = 7.4 Hz, 1H), 5.62 (br s,
3H), 4.79 (br s, 1H), 4.10 (br s, 4H), 3.31-2.96 (m, 5H), 2.71-2.59
(m, 1H), 2.41 (br s, 3H), 1.97-1.77 (m, 6H), 1.59-1.34 (m, 6H),
1.07-0.76 (m, 4H) hLPA.sub.1 IC.sub.50 = 15 nM Example 1
(1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(ethyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 114 ##STR00233## LC/MS: [M + H].sup.+ = 460.2 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.80 (br d, J = 8.6 Hz, 1H), 7.45 (br d,
J = 8.7 Hz, 1H), 5.65 (s, 2H), 4.76 (br s, 1H), 4.06 (s, 2H),
3.93-3.84 (m, 2H), 3.61-3.17 (m, 7H), 2.66-2.58 (m, 1H), 2.39 (s,
3H), 2.12-1.29 (m, 8H) hLPA.sub.1 IC.sub.50 = 643 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((morpholine-4-
carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 115 ##STR00234## LC/MS: [M +
H].sup.+ = 458.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84
(br d, J = 8.2 Hz, 1H), 7.48 (br d, J = 7.7 Hz, 1H), 5.86-5.45 (m,
2H), 4.78 (br s, 1H), 4.10 (s, 3H), 3.12-2.92 (m, 2H), 2.89-2.76
(m, 3H), 2.62 (br s, 1H), 2.41 (s, 3H), 2.09-1.42 (m, 8H),
0.97-0.64 (m, 1H), 0.55--0.10 (m, 4H) hLPA.sub.1 IC.sub.50 = 18 nM
Example 1 (1S,3S)-3-((6-(5- ((((cyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 116 ##STR00235## LC/MS: [M +
H].sup.+ = 460.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.03-7.74 (m, 1H), 7.47 (br d, J = 7.7 Hz, 1H), 6.06-5.43 (m, 2H),
4.78 (br s, 1H), 4.10 (s, 3H), 3.02 (br d, J = 6.8 Hz, 1H), 2.88
(br d, J = 6.9 Hz, 1H), 2.81-2.69 (m, 3H), 2.62 (br t, J = 10.2 Hz,
1H), 2.41 (s, 3H), 2.12-1.42 (m, 9H), 0.81 (br d, J = 6.1 Hz, 3H),
0.62 (br d, J = 5.8 Hz, 3H) hLPA.sub.1 IC.sub.50 = 29 nM Example 1
(1S,3S)-3-((6-(5- (((isobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 117 ##STR00236## LC/MS: [M +
H].sup.+ = 502.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.85
(br d, J = 6.1 Hz, 1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.73- 5.48 (m,
2H), 4.78 (br s, 1H), 4.10 (br d, J = 7.7 Hz, 3H), 3.82 (br d, J =
8.8 Hz, 1H), 3.62 (br d, J = 12.5 Hz, 1H), 3.24 (br s, 1H), 3.17
(s, 1H), 3.09 (br d, J = 6.3 Hz, 1H), 3.04-2.92 (m, 2H), 2.84-2.72
(m, 3H), 2.41 (s, 3H), 2.05-1.10 (m, 13H) hLPA1 IC.sub.50 = 17 nM
Example 1 118 ##STR00237## LC/MS: [M + H].sup.+ = 495.0 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.69-7.72 (m, 2H), 7.72-7.03 (m,
4H), 5.79-5.58 (m, 2H), 4.78 (br s, 1H), 4.45 (s, 2H), 4.27-3.82
(m, 2H), 3.17 (s, 1H), 2.97-2.75 (m, 3H), 2.63 (br s, 1H),
2.44-2.29 (m, 3H), 2.02 (br d, J = 12.7 Hz, 1H), 1.93-1.40 (m, 7H)
hLPA1 IC.sub.50 = 211 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pyridin-2-
ylmethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 119 ##STR00238## LC/MS: [M +
H].sup.+ = 432.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84
(d, J = 8.5 Hz, 1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.64 (br d, J =
13.1 Hz, 2H), 4.78 (br s, 1H), 4.09 (s, 3H), 3.31-3.04 (m, 2H),
2.84-2.70 (m, 3H), 2.62 (br s, 1H), 2.41 (s, 3H), 2.01 (br d, J =
14.1 Hz, 1H), 1.92-1.72 (m, 3H), 1.69-1.43 (m, 4H), 1.08- 0.78 (m,
3H) hLPA.sub.1 IC.sub.50 = 878 nM Example 1 (1S,3S)-3-((6-(5-
(((ethyl(methyl)carbamoyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 120 ##STR00239## LC/MS: [M +
H].sup.+ = 495.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.64-8.27 (m, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.70-7.31 (m, 2H),
6.59 (s, 1H), 5.81- 5.57 (m, 2H), 4.79 (br s, 1H), 4.52-4.27 (m,
2H), 4.20-3.96 (m, 2H), 3.39 (br s, 1H), 2.98-2.70 (m, 3H), 2.63
(br d, J = 9.8 Hz, 1H), 2.38 (br d, J = 17.8 Hz, 2H), 2.10- 1.96
(m, 1H), 1.91-1.04 (m, 8H) hLPA.sub.1 IC.sub.50 = 809 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pyridin-3-
ylmethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 121 ##STR00240## LC/MS: [M +
H].sup.+ = 496.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76
(br d, J = 4.9 Hz, 1H), 8.61 (d, J = 4.9 Hz, 1H), 7.95- 7.68 (m,
1H), 7.50-7.20 (m, 2H), 5.85-5.44 (m, 2H), 4.77 (br s, 1H), 4.67-
4.49 (m, 2H), 4.13 (s, 1H), 2.95-2.75 (m, 4H), 2.64 (br s, 1H),
2.44- 2.33 (m, 4H), 2.09-1.97 (m, 1H), 1.91-1.74 (m, 4H), 1.68-1.48
(m, 4H) hLPA1 IC.sub.50 = 1087 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pyrimidin-2-
ylmethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 122 ##STR00241## LC/MS: [M +
H].sup.+ = 495.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.85-8.33 (m, 1H), 8.06-7.72 (m, 1H), 7.58-7.39 (m, 2H), 7.37-6.99
(m, 2H), 6.04- 5.53 (m, 2H), 4.87- 4.31 (m, 2H), 4.23-3.84 (m, 3H),
3.17 (s, 1H), 2.93-2.73 (m, 3H), 2.67- 2.57 (m, 1H), 2.43- 2.29 (m,
3H), 2.02 (br d, J = 13.9 Hz, 1H), 1.90- 1.73 (m, 2H), 1.66-1.47
(m, 2H), 1.37-1.14 (m, 2H), 1.00 (br d, J = 6.1 Hz, 1H), 0.85 (br
d, J = 6.3 Hz, 1H) hLPA1 IC.sub.50 = 873 nM Example 1 123
##STR00242## LC/MS: [M + H].sup.+ = 496.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.63-8.51 (m, 1H), 8.47-8.30 (m, 1H),
7.96-7.59 (m, 1H), 7.56-7.27 (m, 1H), 6.05- 5.37 (m, 2H), 4.77 (br
s, 1H), 4.62-4.39 (m, 2H), 4.24-3.84 (m, 3H), 3.45 (br s, 1H),
2.98-2.76 (m, 3H), 2.63 (br s, 1H), 2.41- 2.24 (m, 3H), 2.15- 1.35
(m, 8H) hLPA1 IC.sub.50 = 618 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pyrazin-2-ylmethyl)
carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid 124 ##STR00243## LC/MS: [M + H].sup.+
= 498.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (d, J =
8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.41- 7.12 (m, 1H), 6.14 (br
s, 1H), 5.70 (br s, 2H), 5.13- 3.29 (m, 7H), 2.71 (br s, 3H),
2.59-2.55 (m, 2H), 2.39 (s, 3H), 2.14-1.31 (m, 9H) hLPA1 IC.sub.50
= 982 nM Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl((1-methyl-1H-pyrazol-5- yl)methyl)carbamoyl)oxy)methyl)-
1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 125 ##STR00244## LC/MS: [M + H].sup.+ = 504.0 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.5 Hz, 2H), 7.49 (br d,
J = 8.5 Hz, 1H), 6.00- 5.25 (m, 3H), 4.75 (br s, 2H), 4.10 (br s,
4H), 2.90- 2.72 (m, 3H), 2.41 (s, 4H), 2.14-1.31 (m, 13H) hLPA1
IC.sub.50 = 668 nM Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl(morpholin-3- ylmethyl)carbamoyl)oxy)methyl)-
1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 126 ##STR00245## LC/MS: [M + H].sup.+ = 488.1 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.94 (br d, J = 8.9 Hz, 1H), 7.83 (d, J
= 8.5 Hz, 1H), 7.48 (br d, J = 8.5 Hz, 1H), 6.52 (br d, J = 8.2 Hz,
1H), 5.65 (br s, 2H), 4.76 (br s, 1H), 4.09 (s, 3H), 3.55- 2.96 (m,
3H), 2.85- 2.70 (m, 3H), 2.60-2.56 (m, 1H), 2.40 (s, 3H), 2.33-2.23
(m, 1H), 2.03- 1.19 (m, 11H) hLPA1 IC.sub.50 = 346 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl((tetrahydrofuran-3-
yl)methyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 127 ##STR00246## LC/MS: [M +
H].sup.+ = 474.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.81
(br d, J = 8.5 Hz, 1H), 7.44 (br d, J = 8.5 Hz, 1H), 5.58 (s, 2H),
4.75 (br s, 1H), 4.08 (s, 3H), 3.23-2.91 (m, 4H), 2.60 (br s, 1H),
2.39 (s, 3H), 2.05-1.93 (m, 1H), 1.89-1.71 (m, 3H) 1.66-1.37 (m,
4H), 1.25- 1.12 (m, 4H), 1.06- 0.77 (m, 5H), 0.58 (br s, 2H) hLPA1
IC.sub.50 = 33 nM Example 1 (1S,3S)-3-((6-(5-
(((butyl(ethyl)carbamoyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 128
##STR00247## LC/MS: [M + H].sup.+ = 460.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5
Hz, 1H), 5.61 (s, 2H), 4.78 (br s, 1H), 4.09 (s, 3H), 3.42-3.33 (m,
1H), 3.23-2.96 (m, 4H), 2.62 (br t, J = 10.4 Hz, 1H), 2.41 (s, 3H),
2.01 (br d, J = 13.7 Hz, 1H), 1.91-1.73 (m, 3H), 1.68- 1.41 (m,
5H), 1.28 (br s, 1H), 1.00 (br d, J = 6.1 Hz, 1H), 0.92-0.76 (m,
3H), 0.62 (br s, 1H) hLPA1 IC.sub.50 = 158 nM Example 3 129
##STR00248## LCMS, [M + H].sup.+ = 486 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.81 (br d, J = 8.2 Hz, 1H), 7.46 (br d, J =
8.5 Hz, 1H), 5.60 (br s, 2H), 4.78 (br s, 1H), 4.15-4.03 (m, 3H),
3.53 (br s, 1H), 2.80- 2.70 (m, 3H), 2.65-2.57 (m, 1H), 2.41 (s,
3H), 2.05-1.96 (m, 1H), 1.89- 1.72 (m, 3H), 1.66- 1.46 (m, 4H),
0.86-0.82 (m, 2H), 0.76-0.48 (m, 8H) hLPA1 IC.sub.50 = 352 nM
Example 3 (1S,3S)-3-((6-(5-((((1- isopropylcyclopropyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 130 ##STR00249## LCMS, [M +
H].sup.+ = 500 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.82 (br
d, J = 8.5 Hz, 1H), 7.46 (br d, J = 8.5 Hz, 1H), 5.59 (br s, 2H),
4.77 (br s, 1H), 4.15-4.02 (m, 3H), 3.59 (br s, 1H), 2.79- 2.66 (m,
3H), 2.63-2.56 (m, 1H), 2.39 (s, 3H), 2.04-1.94 (m, 1H), 1.88- 1.71
(m, 3H), 1.66- 1.44 (m, 4H), 1.15-1.08 (m, 1H), 0.90-0.85 (m, 2H),
0.83-0.32 (m, 9H) hLPA1 IC.sub.50 = 243 nM Example 10
(1S,3S)-3-((6-(5-((((1- isobutylcyclopropyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 131 ##STR00250## LCMS, [M +
H].sup.+ = 472 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.80 (br
d, J = 7.9 Hz, 1H), 7.46 (br d, J = 8.2 Hz, 1H), 5.60 (s, 2H),
4.81-4.71 (m, 1H), 4.15-4.01 (m, 3H), 3.66 (br s, 3H), 2.78-2.66
(m, 3H), 2.61-2.55 (m, 1H), 2.40 (s, 3H), 2.02-1.93 (m, 1H),
1.85-1.73 (m, 3H), 1.64-1.44 (m, 5H), 0.85-0.76 (m, 1H), 0.67- 0.57
(m, 4H), 0.44 (br s, 1H) hLPA1 IC.sub.50 = 187 nM Example 10
(1S,3S)-3-((6-(5-((((1- ethylcyclopropyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 132 ##STR00251## LCMS, [M +
H].sup.+ = 500 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.01-7.78 (m, 1H), 7.49 (br d, J = 4.6 Hz, 1H), 5.58 (br s, 2H),
4.78 (br s, 1H), 4.09 (br s, 3H), 3.54-3.32 (m, 2H), 2.63-2.58 (m,
3H), 2.46-2.32 (m, 3H), 2.08- 1.97 (m, 3H), 1.91- 1.74 (m, 4H),
1.70-1.47 (m, 8H), 1.28-1.19 (m, 1H), 1.07-0.79 (m, 3H), 0.62-0.56
(m, 1H) hLPA1 IC.sub.50 = 180 nM Example 10
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-
propylcyclobutyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 133 ##STR00252## LCMS, [M +
H].sup.+ = 486 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.81 (br
d, J = 7.3 Hz, 1H), 7.48 (br d, J = 8.5 Hz, 1H), 5.57 (br s, 2H),
4.82-4.73 (m, 1H), 4.08 (s, 3H), 2.64- 2.57 (m, 3H), 2.41 (s, 3H),
2.23-1.74 (m, 9H), 1.70-1.44 (m, 8H), 0.92- 0.41 (m, 3H) hLPA1
IC.sub.50 = 174 nM Example 10
(1S,3S)-3-((6-(5-((((1- ethylcyclobutyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 134 ##STR00253## LCMS, [M +
H].sup.+ = 470 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (d,
J = 8.5 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 5.62 (s, 2H), 4.77 (br
s, 1H), 4.06 (s, 3H), 3.90 (s, 1H), 3.81 (br s, 3H), 2.64-2.58 (m,
1H), 2.41 (s, 3H), 2.10- 1.97 (m, 5H), 1.88-1.75 (m, 3H), 1.74-1.50
(m, 6H) hLPA1 IC.sub.50 = 76 nM Example 1 (1S,3S)-3-((6-(5-(((2-
azaspiro[3.3]heptane-2- carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 135 ##STR00254## LCMS, [M +
H].sup.+ = 484 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.79 (br
d, J = 8.2 Hz, 1H), 7.44 (br d, J = 8.5 Hz, 1H), 5.62- 5.56 (m,
2H), 4.74 (br s, 1H), 4.08-4.04 (m, 2H), 3.86-3.61 (m, 2H), 3.18
(s, 3H), 3.04 (s, 1H), 2.62- 2.56 (m, 1H), 2.38 (s, 3H), 2.01-1.92
(m, 1H), 1.90-1.71 (m, 10H), 1.65-1.41 (m, 4H) hLPA1 IC.sub.50 = 47
nM Example 1 (1S,3S)-3-((6-(5-(((6- azaspiro[3.4]octane-6-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 136 ##STR00255## LCMS, [M +
H].sup.+ = 458 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.98 (d, J
= 8.5 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 5.77 (s, 2H), 4.76-4.71
(m, 1H), 4.17- 4.13 (m, 4H), 2.93- 2.82 (m, 3H), 2.53 (s, 3H), 2.07
(s, 10H), 1.68 (br s, 5H) hLPA1 IC.sub.50 = 36 nM Example 1
(1S,3S)-3-((6-(5- (((cyclobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 137 ##STR00256## LCMS, [M +
H].sup.+ = 586 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (br
d, J = 8.5 Hz, 1H), 7.47 (br d, J = 8.9 Hz, 1H), 5.62 (br s, 2H),
4.77 (br s, 1H), 4.09 (s, 3H), 3.30- 2.86 (m, 4H), 2.61-2.57 (m,
1H), 2.41 (s, 3H), 2.03-1.92 (m, 1H), 1.88- 1.72 (m, 3H), 1.62 (br
d, J = 9.2 Hz, 5H), 1.31- 1.19 (m, 4H), 0.89-0.75 (m, 3H),
0.73-0.60 (m, 3H) hLPA1 IC50 = 292 nM Example 1
(1S,3S)-3-((6-(5-(((3,3- dimethylpiperidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 138 ##STR00257## LCMS, [M +
H].sup.+ = 446 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br
d, J = 8.3 Hz, 1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.63 (br s, 2H),
4.79 (br s, 1H), 4.09 (s, 3H), 3.91- 3.90 (m, 1H), 2.69-2.61 (m,
3H), 2.41 (s, 3H), 1.62 (br s, 9H), 1.03 (br s, 3H), 0.93 (br s,
3H) hLPA1 IC.sub.50 = 98 nM Example 3 (1S,3S)-3-((6-(5-
(((isopropyl)methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 139 ##STR00258## LCMS, [M +
H].sup.+ = 494 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.85 (d,
J = 8.2 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 5.66 (br s, 2H), 4.78
(br s, 1H), 4.10 (s, 3H), 2.82-2.68 (m, 5H), 2.67-2.59 (m, 2H),
2.41 (s, 3H), 2.06-1.97 (m, 1H), 1.94-1.71 (m, 3H), 1.68-1.42 (m,
4H), 1.24 (s, 2H) hLPA1 IC.sub.50 = 70 nM Example 10
(1S,3S)-3-((6-(5-((((3,3- difluorocyclobutyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 140 ##STR00259## LCMS, [M +
H].sup.+ = 472 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (br
d, J = 8.5 Hz, 1H), 7.47 (br d, J = 8.5 Hz, 1H), 5.65 (br d, J =
4.6 Hz, 2H), 4.78 (br s, 1H), 4.08 (br d, J = 4.6 Hz, 3H), 3.36-
3.21 (m, 1H), 3.02 (s, 1H), 2.90 (s, 1H), 2.62 (br s, 1H), 2.41 (s,
3H), 2.06-1.96 (m, 1H), 1.80 (br s, 3H), 1.57 (br t, J = 7.2 Hz,
6H), 1.23 (s, 2H), 0.99 (s, 3H), 0.94 (s, 3H) hLPA1 IC.sub.50 = 148
nM Example 1 (1S,3S)-3-((6-(5-(((3,3- dimethylpyrrolidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 141 ##STR00260## LCMS, [M +
H].sup.+ = 494 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (d,
J = 8.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 5.65 (br s, 2H),
4.45-4.38 (m, 1H), 4.10 (s, 3H), 2.79-2.74 (m, 4H), 2.70-2.62 (m,
1H), 2.49-2.40 (m, J = 11.7, 11.7 Hz, 2H), 2.37-2.34 (m, 3H), 2.30-
2.20 (m, 1H), 2.11- 2.00 (m, 1H), 1.90-1.78 (m, 2H), 1.47-1.23 (m,
6H) hLPA1 IC.sub.50 = 283 nM Example 10
(1R,3S)-3-((6-(5-((((3,3-difluoro-
cyclobutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid; cis isomer from epimerization in
final ester hydrolysis 142 ##STR00261## LCMS, [M + H].sup.+ = 444
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.5 Hz,
1H), 7.47 (br d, J = 8.2 Hz, 1H), 5.65 (s, 2H), 4.81-4.73 (m, 1H),
4.10 (s, 3H), 3.72-3.52 (m, 1H), 2.74 (br s, 3H), 2.65-2.57 (m,
1H), 2.41 (s, 3H), 2.04-1.94 (m, 1H), 1.92-1.70 (m, 3H), 1.68-1.41
(m, 4H), 0.57 (br s, 2H), 0.48 (br s, 2H) hLPA1 IC.sub.50 = 252 nM
Example 10 (1S,3S)-3-((6-(5- (((cyclopropyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 143 ##STR00262## LCMS, [M +
H].sup.+ = 480 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.82 (br
d, J = 7.6 Hz, 1H), 7.49 (br d, J = 7.6 Hz, 1H), 5.70 (s, 2H), 4.75
(br s, 1H), 4.09 (s, 3H), 3.73-3.54 (m, 1H), 2.42-2.38 (m, 3H),
2.38-2.31 (m, 2H), 1.99- 1.46 (m, 8H), 1.23 (s, 2H) hLPA1 IC.sub.50
= 518 nM Example 1 (1S,3S)-3-((6-(5-(((3,3-difluoro-
pyrrolidine-1-carbonyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 144
##STR00263## LCMS, [M + H].sup.+ = 470 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.6
Hz, 1H), 5.67 (s, 2H), 4.77 (br s, 1H), 4.09 (br s, 3H), 2.72-2.60
(m, 1H), 2.43 (s, 3H), 2.08- 1.97 (m, 1H), 1.83 (br d, J = 10.9 Hz,
3H), 1.75- 1.45 (m, 7H), 1.25 (s, 2H), 0.63-0.44 (m, 4H) hLPA1
IC.sub.50 = 89 nM Example 1 (1S,3S)-3-((6-(5-(((5-
azaspiro[2.4]heptane-5- carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 145 ##STR00264## LCMS, [M +
H].sup.+ = 508 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br
d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 5.65 (br s, 2H), 4.77
(br s, 1H), 4.10 (s, 3H), 2.79 (br s, 3H), 2.70-2.62 (m, 1H), 2.43
(s, 3H), 2.39-2.19 (m, 4H), 2.09-1.97 (m, 2H), 1.92-1.76 (m, 3H),
1.71- 1.60 (m, 2H), 1.59- 1.47 (m, 2H), 1.25 (s, 2H) hLPA1
IC.sub.50 = 94 nM Example 3 (1S,3S)-3-((6-(5-(((((3,3-difluoro-
cyclobutyl)methyl)(methyl)carba- moyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 146 ##STR00265## LCMS, [M +
H].sup.+ = 484 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (d,
J = 8.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 5.98- 5.48 (m, 2H),
4.45-4.36 (m, 1H), 4.13 (s, 3H), 3.53-3.14 (m, 1H), 2.72 (s, 2H),
2.47-2.39 (m, 1H), 2.35 (s, 3H), 2.27- 2.20 (m, 1H), 2.08-1.99 (m,
1H), 1.93-1.58 (m, 7H), 1.50-1.20 (m, 6H), 0.75-0.65 (m, 1H), 0.58-
0.50 (m, 1H) hLPA1 IC.sub.50 = 1816 nM Example 3
(1R,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(spiro[2.3]hexan-1-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (cis isomer from epimerization
in final ester hydrolysis) 147 ##STR00266## LCMS, [M + H].sup.+ =
458 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (d, J = 8.6
Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 5.65 (s, 2H), 4.81-4.74 (m, 1H),
4.08 (s, 3H), 3.82-3.59 (m, 1H), 3.45-3.10 (m, 3H), 2.81-2.66 (m,
1H), 2.65-2.58 (m, 1H), 2.41 (s, 3H), 2.08-1.95 (m, 1H), 1.93-1.73
(m, 4H), 1.67-1.33 (m, 5H), 1.26- 1.18 (m, 1H), 0.99- 0.86 (m, 3H)
hLPA1 IC.sub.50 = 250 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-methylpyrrolidine-1-
carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 148
##STR00267## LCMS, [M + H].sup.+ = 470 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85-7.78 (m, 1H), 7.46 (d, J = 8.7 Hz, 1H),
5.67-5.54 (m, 2H), 4.77 (br s, 1H), 4.13- 4.03 (m, 3H), 3.98- 3.85
(m, 1H), 3.77-3.66 (m, 1H), 3.20-3.05 (m, 1H), 2.93-2.77 (m, 1H),
2.66-2.57 (m, 1H), 2.48- 2.42 (m, 1H), 2.40 (s, 3H), 2.04-1.96 (m,
1H), 1.88-1.72 (m, 3H), 1.65- 1.52 (m, 4H), 1.50- 1.44 (m, 2H),
1.37-1.24 (m, 3H) hLPA1 IC.sub.50 = 325 nM Example 1 149
##STR00268## LCMS, [M + H].sup.+ = 484 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.5 Hz, 1H), 7.47 (br d, J =
8.5 Hz, 1H), 5.68- 5.57 (m, 2H), 4.78 (br s, 1H), 4.13-4.06 (m,
3H), 4.04-3.86 (m, 1H), 3.58- 3.47 (m, 3H), 2.68- 2.57 (m, 2H),
2.41 (s, 3H), 2.05-1.96 (m, 1H), 1.89-1.74 (m, 4H), 1.69- 1.59 (m,
3H), 1.54- 1.45 (m, 4H), 1.26-1.22 (m, 2H) hLPA1 IC.sub.50 = 180 nM
Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((octahydrocyclopenta[b]pyrrole-1- carbonyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid
(mixture of diastereomers) 150 ##STR00269## LCMS, [M + H].sup.+ =
498 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.2
Hz, 1H), 7.48 (br d, J = 8.5 Hz, 1H), 5.66 (br s, 2H), 4.82-4.75
(m, 1H), 4.09 (s, 3H), 3.63- 3.33 (m, 1H), 3.32-3.08 (m, 2H),
2.97-2.72 (m, 1H), 2.68-2.60 (m, 1H), 2.42 (s, 3H), 2.20-2.08 (m,
1H), 2.07-1.98 (m, 1H), 1.98-1.90 (m, 1H), 1.90-1.73 (m, 3H), 1.68-
1.38 (m, 5H), 1.29- 1.11 (m, 2H), 0.70-0.54 (m, 1H), 0.42-0.30 (m,
2H), 0.04--0.11 (m, 2H) hLPA1 IC.sub.50 = 91 nM Example 1 151
##STR00270## LCMS, [M + H].sup.+ = 500 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.2 Hz, 1H), 7.47 (br d, J =
8.3 Hz, 1H), 5.66 (br s, 2H), 4.80-4.74 (m, 1H), 4.10 (s, 3H),
3.64- 3.33 (m, 1H), 2.86-2.77 (m, 1H), 2.74-2.64 (m, 1H), 2.43 (s,
3H), 2.16- 2.08 (m, 1H), 2.08-2.00 (m, 1H), 1.98-1.77 (m, 5H),
1.71-1.32 (m, 7H), 1.29-1.12 (m, 2H), 0.92- 0.81 (m, 6H) hLPA1
IC.sub.50 = 101 nM Example 1 (1S,3S)-3-((6-(5-(((3-
isobutylpyrrolidine-1- carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 152
##STR00271## LCMS, [M + H].sup.+ = 471 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br s, 1H), 7.48 (br d, J = 8.5 Hz, 1H),
5.64 (br s, 2H), 4.79 (br s, 1H), 4.09 (br s, 3H), 3.61-3.12 (m,
3H), 2.67-2.59 (m, 1H), 2.42 (s, 3H), 2.06-1.94 (m, 1H), 1.92-1.42
(m, 12H), 0.86-0.75 (m, 2H), 0.64-0.54 (m, 1H) hLPA1 IC.sub.50 =
157 nM Example 1
(1S,3S)-3-((6-(5-(((2- ethylpyrrolidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 153
##STR00272## LCMS, [M + H].sup.+ = 500 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.5 Hz, 1H), 7.48 (br d, J =
7.3 Hz, 1H), 5.74- 5.48 (m, 2H), 4.78 (br s, 1H), 4.10 (br s, 3H),
3.66- 3.11 (m, 3H), 2.41 (br s, 3H), 2.09-1.41 (m, 14H), 1.36-1.07
(m, 2H), 0.89 (br s, 3H), 0.59- 0.42 (m, 3H) hLPA1 IC.sub.50 = 163
nM Example 1 (1S,3S)-3-((6-(5-(((2- isobutylpyrrolidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 154
##STR00273## LCMS, [M + H].sup.+ = 511 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.2 Hz, 1H), 7.55 (br d, J =
8.5 Hz, 1H), 5.82- 5.65 (m, 2H), 4.78-4.68 (m, 1H), 4.10 (br s,
3H), 3.29-3.13 (m, 3H), 2.39 (s, 2H), 2.14-2.00 (m, 1H), 1.98-1.46
(m, 12H) hLPA1 IC.sub.50 = 321 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((2-(trifluoromethyl)pyrrolidine-1- carbonyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid
(mixture of diastereomers) 155 ##STR00274## LCMS, [M + H].sup.+ =
458 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.2
Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H),
4.07 (s, 3H), 3.64-3.45 (m, 1H), 3.32-3.09 (m, 1H), 2.70-2.59 (m,
1H), 2.43 (s, 3H), 2.30-2.15 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.73
(m, 3H), 1.67- 1.45 (m, 4H), 1.16 (s, 6H) hLPA1 IC.sub.50 = 175 nM
Example 1 (1S,3S)-3-((6-(5-(((3,3- dimethylazetidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 156 ##STR00275## LCMS, [M +
H].sup.+ = 444 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br
d, J = 8.5 Hz, 1H), 7.48 (br d, J = 8.9 Hz, 1H), 5.64 (s, 2H), 4.79
(br s, 1H), 4.07 (s, 3H), 4.00-3.92 (m, 2H), 3.31-3.09 (m, 1H),
2.68-2.58 (m, 2H), 2.43 (s, 3H), 2.02 (br d, J = 13.4 Hz, 1H),
1.94- 1.73 (m, 3H), 1.63 (br d, J = 10.1 Hz, 4H), 1.12 (d, J = 6.7
Hz, 3H) hLPA1 IC.sub.50 = 231 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-methylazetidine-1-
carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 157 ##STR00276## LCMS, [M +
H].sup.+ = 444 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br
d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 5.63 (s, 2H), 4.79
(br s, 1H), 4.08 (s, 3H), 3.81-3.69 (m, 2H), 3.64-3.50 (m, 1H),
3.31-3.10 (m, 1H), 2.67- 2.59 (m, 1H), 2.43 (s, 3H), 2.33-2.21 (m,
1H), 2.12-1.96 (m, 1H), 1.64 (br s, 7H), 1.00 (d, J = 6.1 Hz, 3H)
hLPA1 IC.sub.50 = 529 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((2-methylazetidine-1-
carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridine-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 158
##STR00277## LCMS, [M + H].sup.+ = 498 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.5
Hz, 1H), 5.62 (br s, 2H), 4.78 (br s, 1H), 4.09 (s, 3H), 3.32-3.12
(m, 1H), 2.74-2.58 (m, 4H), 2.41 (s, 3H), 2.10-1.70 (m, 14H),
1.68-1.44 (m, 4H) hLPA1 IC.sub.50 = 32 nM Example 10
(1R,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(spiro[3.3]heptan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 159 ##STR00278## LCMS, [M +
H].sup.+ = 484 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (br
d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 5.64 (s, 2H), 4.78
(br s, 1H), 4.07 (s, 3H), 3.69 (br s, 3H), 3.63-3.51 (m, 1H), 3.31-
3.11 (m, 2H), 2.42 (s, 3H), 1.91-1.77 (m, 3H), 1.71-1.58 (m, 6H),
1.57- 1.47 (m, 6H) hLPA1 IC.sub.50 = 162 nM Example 1
(1S,3S)-3-((6-(5-(((2- azaspiro[3.4]octane-2-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 160 ##STR00279## LCMS, [M +
H].sup.+ = 486 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (d,
J = 8.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 5.63 (br s, 2H),
4.49-4.36 (m, 1H), 4.10 (s, 3H), 2.77-2.69 (m, 3H), 2.48-2.39 (m,
1H), 2.37 (s, 3H), 2.31- 2.23 (m, 1H), 2.12-2.02 (m, 1H), 1.92-1.59
(m, 6H), 1.50-1.20 (m, 4H), 1.14-0.95 (m, 6H) hLPA1 IC.sub.50 = 61
nM Example 3 (1R,3S)-3-((6-(5-((((3,3-
dimethylcyclobutyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (cis isomer from epimerization
in final ester hydrolysis step) 161 ##STR00280## LCMS, [M +
H].sup.+ = 472 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br
d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 5.65 (s, 2H), 4.77
(br s, 1H), 4.09 (s, 3H), 3.81-3.66 (m, 1H), 2.82-2.70 (m, 1H),
2.69-2.62 (m, 1H), 2.43 (s, 3H), 2.06-1.97 (m, 1H), 1.92-1.76 (m,
3H), 1.66 (br s, 6H), 1.46- 1.18 (m, 3H), 1.03 (s, 2H), 0.86-0.71
(m, 3H) hLPA1 IC.sub.50 = 178 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-methylpiperidine-1-
carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 162
##STR00281## LCMS, [M + H].sup.+ = 472 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.6
Hz, 1H), 5.63 (s, 2H), 4.82-4.71 (m, 1H), 4.09 (s, 3H), 3.62-3.53
(m, 2H), 3.34-3.18 (m, 1H), 2.79 (br s, 3H), 2.70- 2.61 (m, 1H),
2.42 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 3H), 1.70- 1.47 (m,
4H), 1.31- 1.15 (m, 2H), 0.42-0.16 (m, 2H), 0.03--0.26 (m, 2H)
hLPA1 IC.sub.50 = 34 nM Example 1 (1S,3S)-3-((6-(5-((((2-
cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 163 ##STR00282## LCMS, [M + H].sup.+ = 486 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.5 Hz, 1H), 7.48 (d, J
= 8.5 Hz, 1H), 5.66 (br d, J = 9.5 Hz, 2H), 4.83- 4.75 (m, 1H),
4.10 (s, 3H), 3.18 (br s, 1H), 2.93- 2.81 (m, 1H), 2.74 (s, 1H),
2.68-2.60 (m, 1H), 2.42 (s, 3H), 2.07-1.98 (m, 1H), 1.94-1.73 (m,
6H), 1.67-1.34 (m, 6H), 0.93-0.75 (m, 6H) hLPA1 IC.sub.50 = 104 nM
Example 1 (1S,3S)-3-((6-(5-(((3- isopropylpyrrolidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 164
##STR00283## LCMS, [M + H].sup.+ = 484 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.82 (br d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5
Hz, 1H), 5.65 (br s, 2H), 4.80-4.74 (m, 1H), 4.08 (s, 3H),
3.33-3.08 (m, 2H), 2.88 (s, 2H), 2.65-2.58 (m, 1H), 2.40 (s, 3H),
2.04-1.95 (m, 1H), 1.90 (s, 4H), 1.62 (br s, 6H), 0.71-0.54 (m,
1H), 0.42-0.26 (m, 2H), 0.16-0.02 (m, 2H) hLPA1 IC.sub.50 = 83 nM
Example 1 (1S,3S)-3-((6-(5-(((3- cyclopropylpyrrolidine-1-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 165
##STR00284## LCMS, [M + H].sup.+ = 472 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.9
Hz, 1H), 5.67 (br s, 2H), 4.83-4.76 (m, 1H), 4.10 (s, 3H),
3.24-3.09 (m, 1H), 2.98-2.78 (m, 1H), 2.77-2.69 (m, 1H), 2.67-2.61
(m, 1H), 2.42 (s, 3H), 2.06-1.79 (m, 6H), 1.67-1.23 (m, 8H),
0.93-0.79 (m, 3H) hLPA1 IC.sub.50 = 102 nM Example 1
(1S,3S)-3-((6-(5-(((3- ethylpyrrolidine-1-carbonyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 166
##STR00285## LCMS, [M + H].sup.+ = 486 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5
Hz, 1H), 5.66 (br s, 2H), 4.82-4.74 (m, 1H), 4.09 (s, 3H),
3.24-3.07 (m, 1H), 2.90 (s, 1H), 2.76-2.67 (m, 1H), 2.67- 2.60 (m,
1H), 2.42 (s, 3H), 2.10-1.97 (m, 2H), 1.92 (s, 5H), 1.68-1.34 (m,
5H), 1.32-1.19 (m, 4H), 0.92-0.80 (m, 3H) hLPA1 IC.sub.50 = 109 nM
Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((3-propylpyrrolidine-1- carbonyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid
(mixture of diastereomers) 167 ##STR00286## LCMS, [M + H].sup.+ =
470 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.85 (d, J = 8.5
Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H),
4.09 (s, 3H), 3.31-3.13 (m, 1H), 2.67-2.59 (m, 1H), 2.42 (s, 3H),
2.06-1.98 (m, 1H), 1.91-1.74 (m, 3H), 1.67-1.46 (m, 8H), 1.39-1.33
(m, 4H) hLPA1 IC.sub.50 = 317 nM Example 1
(1S,3S)-3-((6-(5-(((-7-azabicyclo [2.2.1]heptane-7-carbonyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid 168 ##STR00287## LCMS, [M + H].sup.+
= 486 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (d, J = 8.5
Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 5.63 (br s, 2H), 4.78 (br s,
1H), 4.10 (s, 3H), 2.72 (br s, 3H), 2.68-2.58 (m, 1H), 2.41 (s,
3H), 2.00 (br s, 1H), 1.93-1.71 (m, 6H), 1.64 (br s, 5H), 1.07-0.95
(m, 6H) hLPA1 IC.sub.50 = 29 nM Example 3
(1S,3S)-3-((6-(5-((((3,3-dimethyl-
cyclobutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid 169 ##STR00288## LCMS, [M + H].sup.+
= 520 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.91-7.81 (m,
1H), 7.52-7.45 (m, 1H), 7.37-7.19 (m, 5H), 5.72 (br s, 2H), 4.83-
4.75 (m, 1H), 4.11 (br d, J = 13.7 Hz, 3H), 3.81- 3.63 (m, 1H),
3.39-3.10 (m, 3H), 2.67-2.61 (m, 1H), 2.43 (br d, J = 4.9 Hz, 3H),
2.24-2.16 (m, 1H), 2.07-1.99 (m, 1H), 1.97-1.73 (m, 4H), 1.70- 1.47
(m, 4H) hLPA1 IC.sub.50 = 336 nM Example 1
(1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((3-phenylpyrrolidine-1-carbonyl) oxy)methyl)-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid (mixture of
diastereomers) 170 ##STR00289## LCMS, [M + H].sup.+ = 460 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.5 Hz, 1H),
7.48 (br d, J = 8.5 Hz, 1H), 5.60 (s, 2H), 4.79 (br s, 1H), 4.10
(s, 3H), 2.77 (s, 3H), 2.68- 2.58 (m, 1H), 2.42 (s, 3H), 2.09-1.97
(m, 1H), 1.93-1.73 (m, 3H), 1.69- 1.43 (m, 4H), 1.27 (s, 9H) hLPA1
IC.sub.50 = 183 nM Example 1 (1S,3S)-3-((6-(5-(((tert-butyl
(methyl)carbamoyl)oxy)methyl)-1- methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid
171 ##STR00290## LCMS, [M + H].sup.+ = 484 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5
Hz, 1H), 5.66 (s, 2H), 4.79 (br s, 1H), 4.09 (s, 3H), 3.59-3.16 (m,
2H), 2.69-2.60 (m, 1H), 2.42 (s, 3H), 2.06-1.95 (m, 1H), 1.91-1.71
(m, 3H), 1.68-1.44 (m, 4H), 1.31-1.11 (m, 4H), 0.28 (s, 4H) hLPA1
IC.sub.50 = 162 nM Example 1 (1S,3S)-3-((6-(5-(((6-azaspiro
[2.5]octane-6-carbonyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 172
##STR00291## LCMS, [M + H].sup.+ = 472 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.5
Hz, 1H), 5.68- 5.59 (m, 2H), 5.16-4.91 (m, 1H), 4.47-4.36 (m, 1H),
4.09 (s, 3H), 3.87- 3.60 (m, 2H), 2.80-2.64 (m, 3H), 2.45-2.39 (m,
1H), 2.37 (s, 3H), 2.30- 2.22 (m, 1H), 2.09-2.02 (m, 1H), 1.93-1.78
(m, 3H), 1.72-1.49 (m, 4H), 1.47-1.28 (m, 5H) hLPA1 IC.sub.50 = 312
nM Example 3 (1R,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl(3-methylbut-2-en-1- yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid (cis
isomer from epimerization during final hydrolysis step) 173
##STR00292## LCMS, [M + H].sup.+ = 432 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.35 (d, J = 2.4 Hz, 1H), 7.99 (br d, J = 8.2
Hz, 1H), 7.58- 7.52 (m, 1H), 5.67-5.58 (m, 2H), 4.79 (br s, 1H),
4.10 (s, 3H), 3.20-3.01 (m, 2H), 2.77 (br d, J = 15.9 Hz, 3H),
2.71- 2.62 (m, 1H), 2.00-1.72 (m, 4H), 1.72-1.41 (m, 5H), 1.40-1.28
(m, 1H), 0.86-0.61 (m, 3H) hLPA1 IC.sub.50 = 131 nM Example 1
(1S,3S)-3-((6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 174 ##STR00293## LCMS, [M +
H].sup.+ = 444 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.35 (d,
J = 2.4 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.9, 2.7
Hz, 1H), 5.63 (s, 2H), 4.79 (br s, 1H), 4.57-4.17 (m, 1H), 4.10 (s,
3H), 2.80-2.63 (m, 4H), 2.12-1.94 (m, 4H), 1.90-1.74 (m, 4H), 1.72-
1.48 (m, 5H), hLPA1 IC.sub.50 = 58 nM Example 1 (1S,3S)-3-((6-(5-
(((cyclobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 175 ##STR00294##
LCMS, [M + H].sup.+ = 470 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.43-8.26 (m, 1H), 8.08-7.91 (m, 1H), 7.64-7.44 (m, 1H),
5.63 (br s, 2H), 4.78 (br s, 1H), 4.08 (br s, 3H), 3.30-3.11 (m,
3H), 2.71- 2.60 (m, 1H), 2.00- 1.88 (m, 2H), 1.88-1.73 (m, 9H),
1.70-1.44 (m, 4H) hLPA1 IC.sub.50 = 703 nM Example 1
(1S,3S)-3-((6-(5-(((6- azaspiro[3.4]octane-6-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid
176 ##STR00295## LCMS, [M + H].sup.+ = 456 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.35 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 8.9
Hz, 1H), 7.55 (dd, J = 8.7, 2.6 Hz, 1H), 5.60 (s, 2H), 4.79 (br s,
1H), 4.08 (s, 3H), 3.84 (s, 4H), 2.72-2.63 (m, 1H), 2.13- 2.02 (m,
4H), 2.01- 1.92 (m, 1H), 1.90-1.76 (m, 3H), 1.76-1.60 (m, 4H),
1.60-1.48 (m, 2H) hLPA1 IC.sub.50 = 400 nM Example 1
(1S,3S)-3-((6-(5-(((2- azaspiro[3.3]heptane-2-
carbonyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid
177 ##STR00296## LCMS, [M + H].sup.+ = 472 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5
Hz, 1H), 5.69- 5.61 (m, 2H), 5.17-4.91 (m, 1H), 4.78 (br s, 1H),
4.09 (s, 3H), 3.85-3.61 (m, 2H), 2.80-2.66 (m, 3H), 2.65-2.59 (m,
1H), 2.41 (s, 3H), 2.06-1.96 (m, 1H), 1.90-1.74 (m, 3H), 1.73-1.60
(m, 4H), 1.59-1.47 (m, 4H), 1.46- 1.37 (m, 2H) hLPA1 IC.sub.50 = 21
nM Example 3 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl(3-methylbut-2-en-1- yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 178
##STR00297## LCMS, [M + H].sup.+ = 478 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5
Hz, 1H), 5.62 (s, 2H), 4.81-4.74 (m, 1H), 4.57 (s, 1H), 4.47 (s,
1H), 4.11 (s, 3H), 2.82 (s, 3H), 2.65-2.58 (m, 1H), 2.42 (s, 3H),
2.05-1.96 (m, 1H), 1.89-1.74 (m, 3H), 1.64 (br s, 4H), 1.28 (br s,
6H) hLPA1 IC.sub.50 = 156 nM Example 3
(1S,3S)-3-((6-(5-((((1-fluoro-2- methylpropan-2-yl)(methyl)
carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-methyl-
pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 179 ##STR00298##
LCMS, [M + H].sup.+ = 484 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.82 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 5.63
(s, 2H), 4.75 (br s, 1H), 4.09 (s, 3H), 2.88-2.72 (m, 3H),
2.70-2.59 (m, 1H), 2.41 (s, 3H), 2.38-2.28 (m, 2H), 2.08-1.75 (m,
7H), 1.70-1.45 (m, 4H), 0.47-0.26 (m, 4H) hLPA1 IC.sub.50 = 14 nM
Example 3 (1S,3S)-3-((2-methyl-6-(1-methyl-5-
(((methyl(spiro[2.3]hexan-5- yl)carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 180
##STR00299## LCMS, [M + H].sup.+ = 484 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.34 (br s, 1H), 7.99 (br d, J = 8.9 Hz, 1H),
7.59-7.51 (m, 1H), 5.60 (br s, 2H), 4.82- 4.74 (m, 1H), 4.09 (s,
3H), 2.72-2.61 (m, 4H), 2.05-1.70 (m, 15H), 1.70-1.60 (m, 2H),
1.60- 1.44 (m, 2H) hLPA1 IC.sub.50 = 62 nM Example 10
(1S,3S)-3-((6-(1-methyl-5- (((methyl(spiro[3.3]heptan-2-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid 181 ##STR00300## LCMS, [M + H].sup.+
= 472 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.34 (br d, J =
2.1 Hz, 1H), 7.98 (br d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.9, 2.7
Hz, 1H), 5.60 (br s, 2H), 4.78 (br s, 1H), 4.61-4.23 (m, 1H), 4.10
(s, 3H), 2.71 (s, 3H), 2.68-2.61 (m, 1H), 2.08-1.71 (m, 7H), 1.66
(br d, J = 8.9 Hz, 2H), 1.60-1.46 (m, 2H), 1.14- 0.90 (m, 6H) hLPA1
IC.sub.50 = 101 nM Example 10 (1S,3S)-3-((6-(5-((((3,3-
dimethylcyclobutyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 182 ##STR00301## LCMS, [M +
H].sup.+ = 476 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (d,
J = 8.5 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 5.63 (s, 2H), 5.17-4.99
(m, 1H), 4.79-4.71 (m, 1H), 4.09 (s, 3H), 3.69-3.51 (m, 1H), 3.46
(br s, 1H), 2.75 (s, 3H), 2.67-2.57 (m, 1H), 2.41 (s, 4H), 2.32-
2.17 (m, 2H), 2.03-1.95 (m, 1H), 1.88-1.75 (m, 3H), 1.69-1.45 (m,
4H) hLPA1 IC.sub.50 = 61 nM Example 10 (1S,3S)-3-((6-(5-((((3-
fluorocyclobutyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid (mixture of diastereomers) 183 ##STR00302## LCMS, [M +
H].sup.+ = 470 .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.34 (d,
J = 2.5 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 2.8
Hz, 1H), 5.76 (s, 2H), 4.79- 4.69 (m, 1H), 4.16 (s, 3H), 3.01-2.82
(m, 4H), 2.47-2.32 (m, 2H), 2.18- 1.87 (m, 7H), 1.85- 1.56 (m, 4H),
0.61-0.27 (m, 4H) hLPA1 IC.sub.50 = 20 nM Example 3
(1S,3S)-3-((6-(1-methyl-5- (((methyl(spiro[2.3]hexan-5-
yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 184 ##STR00303## LCMS, [M +
H].sup.+ = 486 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.94-7.76 (m, 1H), 7.55-7.40 (m, 1H), 5.75-5.53 (m, 2H), 4.77 (br
s, 1H), 4.09 (s, 3H), 3.30-3.02 (m, 1H), 2.90-2.72 (m, 3H), 2.70-
2.58 (m, 1H), 2.45- 2.32 (m, 3H), 2.06-1.94 (m, 1H), 1.90-1.72 (m,
3H), 1.67-1.43 (m, 4H), 1.08-0.93 (m, 3H), 0.92- 0.77 (m, 3H),
0.75- 0.49 (m, 1H), 0.46-0.14 (m, 1H), 0.14 to-0.15 (m, 1H) hLPA1
IC.sub.50 = 37 nM Example 3 185 ##STR00304## LCMS, [M + H].sup.+ =
472 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.34 (br s, 1H),
7.99 (br d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.6, 2.5 Hz, 1H), 5.63
(s, 2H), 4.84-4.73 (m, 1H), 4.11 (s, 3H), 2.82 (br s, 3H),
2.73-2.63 (m, 1H), 2.03- 1.93 (m, 1H), 1.91- 1.74 (m, 3H),
1.72-1.49 (m, 4H), 1.26 (s, 1H), 0.97 (br s, 6H), 0.66 (br s, 1H),
0.38 (br s, 1H), 0.02 (br s, 1H) hLPA1 IC.sub.50 = 86 nM Example 3
(1S,3S)-3-((6-(5-(((((2,2- dimethylcyclopropyl)methyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 186
##STR00305## LCMS, [M + H].sup.+ = 480 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.34 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 8.7
Hz, 1H), 7.53 (dd, J = 8.7, 2.7 Hz, 1H), 5.64 (br s, 2H), 4.82-4.73
(m, 1H), 4.10 (s, 3H), 2.83 (br s, 3H), 2.72-2.64 (m, 1H),
2.01-1.93 (m, 1H), 1.90-1.73 (m, 4H), 1.71- 1.48 (m, 5H), 1.25 (s,
1H), 1.23-1.09 (m, 1H) hLPA1 IC50 = 67 nM Example 3
(1S,3S)-3-((6-(5-(((((2,2- difluorocyclopropyl)methyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 187
##STR00306## LCMS, [M + H].sup.+ = 492 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.90-7.73 (m, 1H), 7.51-7.42 (m, 1H),
5.64-5.58 (m, 2H), 4.76 (br s, 1H), 4.08 (br s, 3H), 3.81-3.74 (m,
2H), 3.31-3.22 (m, 1H), 3.15-3.09 (m, 1H), 2.66- 2.57 (m, 1H), 2.38
(br s, 3H), 1.98-1.72 (m, 5H), 1.67-1.39 (m, 6H), 1.32- 1.24 (m,
3H), 1.09- 1.01 (m, 3H) hLPA1 IC.sub.50 = 50 nM Example 3
(1S,3S)-3-((6-(5-((((3-fluoro-3- methylbutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 188 ##STR00307## LCMS, [M +
H].sup.+ = 478 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.39-8.25 (m, 1H), 8.08-7.93 (m, 1H), 7.54 (br s, 1H), 5.66- 5.53
(m, 2H), 4.76 (br s, 1H), 4.09 (br s, 2H), 3.86- 3.74 (m, 2H),
3.31- 3.24 (m, 1H), 3.16-3.12 (m, 1H), 2.68-2.60 (m, 1H), 1.97-1.73
(m, 5H), 1.63 (br s, 6H), 1.33- 1.25 (m, 3H), 1.14-1.07 (m, 3H)
hLPA1 IC.sub.50 = 32 nM Example 3 (1S,3S)-3-((6-(5-((((3-fluoro-3-
methylbutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 189 ##STR00308##
LCMS, [M + H].sup.+ = 490 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.84 (br d, J = 8.4 Hz, 1H), 7.46 (br d, J = 8.6 Hz, 1H),
5.69 (s, 2H), 4.77 (br s, 1H), 4.11 (s, 3H), 3.72-3.23 (m, 1H),
2.85 (br s, 3H), 2.72- 2.60 (m, 1H), 2.42 (s, 3H), 2.20-1.73 (m,
9H), 1.65 (br d, J = 9.8 Hz, 5H) hLPA1 IC.sub.50 = 120 nM Example 3
(1S,3S)-3-((6-(5-(((((1- fluorocyclobutyl)methyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyndin-3-
yl)oxy)cyclohexane-1-carboxylic acid 190 ##STR00309## LCMS, [M +
H].sup.+ = 464.1 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.12 (d,
J = 8.8 Hz, 1H), 7.86 (br t, J = 7.8 Hz, 1H), 5.64-5.57 (m, 1H),
5.55-5.47 (m, 1H), 4.86 (br s, 1H), 4.53 (dt, J = 10.4, 5.4 Hz,
1H), 4.43 (dt, J = 10.5, 5.3 Hz, 1H), 4.22 (s, 3H), 3.45 (q, J =
7.1 Hz, 2H), 2.97 (d, J = 12.9 Hz, 3H), 2.88 (br s, 1H), 2.74
(d,
J = 2.2 Hz, 3H), 2.18-1.76 (m, 9H), 1.68 (br d, J = 6.3 Hz, 1H)
.sup.19F-NMR: -221.9 ppm hLPA1 IC.sub.50 = 81 nM
(1S,3S)-3-((6-(5-((((3- fluoropropyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 191 ##STR00310## LCMS, [M +
H].sup.+ = 464.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84
(d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.33 (br t, J = 5.6
Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.47 (t, J = 6.1 Hz, 1H),
4.37 (t, J = 6.0 Hz, 1H), 4.08 (s, 3H), 3.02 (q, J = 6.0 Hz, 2H),
2.71-2.59 (m, 1H), 2.42 (s, 3H), 2.11-1.98 (m, 1H), 1.90-1.75 (m,
3H), 1.72-1.41 (m, 8H) hLPA1 IC.sub.50 = 553 nM
(1S,3S)-3-((6-(5-((((4- fluorobutyl)carbamoyl)oxy)methyl)-
1-methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 192
##STR00311## LCMS, [M + H].sup.+ = 478.4 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 11.11 (br s, 1H), 8.18 (d, J = 8.8 Hz, 1H),
8.00 (d, J = 8.8 Hz, 1H), 5.58-5.39 (m, 2H), 4.90 (br s, 1H), 4.57-
4.49 (m, 1H), 4.46-4.35 (m, 1H), 4.23 (d, J = 4.2 Hz, 3H), 3.35 (br
d, J = 7.0 Hz, 2H), 3.03- 2.69 (m, 7H), 2.24-1.57 (m, 12H) .sup.19F
NMR: 219 ppm hLPA1 IC.sub.50 = 36 nM (1S,3S)-3-((6-(5-((((4-
fluorobutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 193 ##STR00312## LCMS, [M +
H].sup.+ = 446.1 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95 (d,
J = 8.6 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 5.77 (br d, J = 5.3 Hz,
2H), 4.38- 4.21 (m, 1H), 4.15 (s, 3H), 3.34-3.06 (m, 2H), 2.98-2.79
(m, 3H), 2.60- 2.38 (m, 5H), 2.21- 1.94 (m, 3H), 1.81-1.66 (m, 1H),
1.63-1.33 (m, 7H), 0.97-0.70 (m, 2H) hLPA1 IC.sub.50 = 1696 nM
(1R,3R)-3-((2-methyl-6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)
methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid
[0974] The following analogs were synthesized according to the
methods described for the preparation of Example 1 except that the
intermediate 3 was used (instead of Example 1F).
##STR00313##
[0975] Intermediate 3 was prepared from
2,5-dibromo-6-ethyl-pyridine using the same synthetic sequence as
described for the preparation of Example 1.
TABLE-US-00002 Example Structure & Name Analytical &
Biology Data Method 194 ##STR00314## LCMS, [M + H].sup.+ = 472.0
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.87 (br d, J = 7.9 Hz,
1H), 7.50 (br d, J = 8.5 Hz, 1H), 5.69 (br d, J = 16.2 Hz, 2H),
4.81 (br s, 1H), 4.14 (s, 3H), 3.56 (br s, 1H), 3.10 (br s, 1H).
2.99 (br s, 1H), 2.89-2.78 (m, 5H), 2.10- 2.02 (m, 1H), 1.90 (br d,
J = 11.6 Hz, 1H), 1.86-1.78 (m, 2H), 1.69-1.48 (m, 4H), 1.31-1.20
(m, 3H), 1.03-0.86 (m, 1H), 0.85-0.66 (m, 1H), 0.45 (br s, 1H),
0.28 (br s, 1H), 0.22 (br s, 1H), 0.00 (br s, 1H) hLPA1 IC.sub.50 =
14 nM Example 1 195 ##STR00315## LCMS, [M + H].sup.+ = 485.9
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.94-7.76 (m, 1H),
7.60- 7.41 (m, 1H), 5.66 (s, 2H), 4.88- 4.62 (m, 1H), 2.80 (q, J =
7.3 Hz, 2H), 2.64 (br s, 3H), 2.01- 1.92 (m, 1H), 1.92-1.86 (m,
1H), 1.85-1.72 (m, 4H), 1.67- 1.58 (m, 5H), 1.54 (br s, 5H), 1.43
(br s, 5H), 1.24 (br t, J = 7.4 Hz, 3H) hLPA1 IC.sub.50 = 11 nM 196
##STR00316## LCMS, [M + H]+ = 486.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.2 Hz, 1H), 7.50 (br d, J =
8.6 Hz, 1H), 5.66 (br d, J = 16.0 Hz, 2H), 4.75 (br s, 1H), 4.10
(br d, J = 9.4 Hz, 3H), 2.80 (br d, J = 6.4 Hz, 2H), 2.73 (br d, J
= 17.7 Hz, 3H), 1.91 (br d, J = 14.9 Hz, 2H), 1.84 (s, 6H), 1.76
(s, 4H), 1.71-1.57 (m, 4H), 1.54 (br s, 2H), 1.43 (br d, J = 8.1
Hz, 1H), 1.25 (br d, J = 6.8 Hz, 3H) hLPA1 IC.sub.50 = 12 nM 197
##STR00317## LCMS, [M + H].sup.+ = 474.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.80 (br t, J = 8.1 Hz, 1H), 7.45 (br d, J =
8.2 Hz, 1H), 5.63 (br d, J = 18.3 Hz, 2H), 4.75 (br s, 1H), 4.08
(br s, 3H), 2.99 (br d, J = 7.0 Hz, 1H), 2.85 (br d, J = 6.7 Hz,
1H), 2.81-2.70 (m, 5H), 1.97 (br d, J = 13.7 Hz, 1H), 1.86 (s, 1H),
1.79 (br d, J = 12.5 Hz, 3H), 1.60 (br d, J = 8.9 Hz, 3H),
1.57-1.45 (m, 2H), 1.23 (br d, J = 7.6 Hz, 3H), 0.78 (br d, J = 5.5
Hz, 3H), 0.59-0.54 (m, 3H) hLPA1 IC.sub.50 = 27 nM 198 ##STR00318##
LCMS, [M + H].sup.+ = 494.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.84 (br d, J = 8.3 Hz, 2H), 7.47 (br d, J = 8.5 Hz, 1H),
7.32- 7.27 (m, 2H), 7.22 (br d, J = 7.2 Hz, 3H), 5.69 (s, 2H), 4.76
(br s, 1H), 4.18 (br d, J = 5.9 Hz, 2H), 4.08 (s, 3H), 3.50 (br s,
1H), 2.78 (q, J = 7.3 Hz, 2H), 1.98 (br d, J = 13,0 Hz, 1H), 1.80
(br d, J = 11.8 Hz, 3H), 1.61 (br s, 2H), 1.54 (br s, 1H), 1.50 (br
s, 1H), 1.22 (br t, J = 7.4 Hz, 3H) hLPA1 IC.sub.50 = 46 nM 199
##STR00319## LCMS, [M + H].sup.+ = 474.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.3 Hz, 1H), 7.46 (br d, J =
8.3 Hz, 1H), 5.64 (br d, J = 12.4 Hz, 2H), 4.76 (br s, 1H), 4.09
(br s, 3H), 3.53 (br s, 1H), 3.17 (br s, 1H), 3.03 (br s, 1H),
2.82-2.69 (m, 5H), 1.98 (br d, J = 13.8 Hz, 1H), 1.79 (br d, J =
11.0 Hz, 3H), 1.60 (br s, 2H), 1.57-1.45 (m, 2H), 1.41 (br s, 1H),
1.26-1.16 (m, 5H), 1.01-0.93 (m, 1H), 0.86 (br s, 1H), 0.61 (br s,
2H) hLPA1 IC.sub.50 = 7 nM 200 ##STR00320## LCMS, [M + H].sup.+ =
460.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.92-7.70 (m,
1H), 7.62- 7.30 (m, 1H), 5.80-5.48 (m, 2H), 4.89-4.58 (m, 1H),
4.24- 3.82 (m, 3H), 3.60-3.25 (m, 1H), 3.21-2.93 (m, 2H), 2.85-
2.67 (m, 5H), 2.66-2.56 (m, 1H), 2.07-1.94 (m, 1H), 1.90- 1.69 (m,
3H), 1.68-1.36 (m, 5H), 1.33-1.14 (m, 3H), 0.86- 0.67 (m, 2H),
0.67-0.40 (m, 2H) hLPA1 IC.sub.50 = 11 nM 201 ##STR00321## LCMS, [M
+ H].sup.+ = 474.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83
(br d, J = 8.3 Hz, 1H), 7.46 (br d, J = 8.3 Hz, 1H), 5.64 (br d, J
= 12.4 Hz, 2H), 4.76 (br s, 1H), 4.09 (br s, 3H), 3.53 (br s, 1H),
3.17 (br s, 1H), 3.03 (br s, 1H), 2.82-2.69 (m, 5H), 1.98 (br d, J
= 13.8 Hz, 1H), 1.79 (br d, J = 11.0 Hz, 3H), 1.60 (br s, 2H),
1.57-1.45 (m, 2H), 1.41 (br s, 1H), 1.26-1.16 (m, 5H), 1.01-0.93
(m, 1H), 0.86 (br s, 1H), 0.61 (br s, 2H) hLPA1 IC.sub.50 = 25 nM
202 ##STR00322## LCMS, [M + H].sup.+ = 446.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (br d, J = 8.5 Hz, 1H), 7.47 (br d, J =
8.5 Hz, 1H), 5.66 (br s, 2H), 4.76 (br s, 1H), 4.09 (s, 3H),
3.56-3.37 (m, 1H), 3.19 (br d, J = 18.6 Hz, 1H), 3.11 (br s, 1H),
2.82-2.75 (m, 3H), 2.73 (br s, 2H), 2.60-2.53 (m, 1H), 1.98 (br d,
J = 13.4 Hz, 1H), 1.80 (br d, J = 11.0 Hz, 2H), 1.61 (br s, 2H),
1.53 (br d, J = 16.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 1.00 (br d,
J = 6.1 Hz, 2H), 0.86 (br s, 2H) hLPA1 IC.sub.50 = 160 nM 203
##STR00323## LCMS, [M + H].sup.+ = 472.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.81 (br d, J = 8.2 Hz, 1H), 7.46 (br d, J =
8.9 Hz, 1H), 5.62 (s, 2H), 4.74 (br s, 1H), 4.07 (s, 3H), 3.77-3.70
(m, 4H), 2.77 (q, J = 7.3 Hz, 2H), 2.70 (br s, 2H), 2.03 (br s,
1H), 1.93 (br d, J = 13.1 Hz, 2H), 1.88-1.72 (m, 5H), 1.63-1.41 (m,
6H), 1.21 (br t, J = 7.3 Hz, 3H) hLPA1 IC.sub.50 = 8 nM 204
##STR00324## LCMS, [M + H].sup.+ = 472.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.81 (br d, J = 8.5 Hz, 1H), 7.46 (br d, J =
8.5 Hz, 1H), 5.62 (s, 2H), 4.74 (br s, 1H), 4.05 (s, 3H), 3.79-3.70
(m, 4H), 2.78 (q, J = 7.3 Hz, 2H), 1.91 (br s, 1H), 1.86-1.73 (m,
5H), 1.64- 1.44 (m, 4H), 1.22 (t, J = 7.5 Hz, 3H), 1.13 (s, 6H)
hLPA1 IC.sub.50 = 102 nM 205 ##STR00325## LCMS, [M + H].sup.+ =
470.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.82 (br d, J =
7.3 Hz, 1H), 7.48 (br s, 1H), 5.62 (br s, 2H), 4.99-4.53 (m, 1H),
4.07 (br s, 2H), 3.58 (br s, 1H), 3.17 (s, 1H), 2.89 (s, 1H), 2.82
(br s, 1H), 2.73 (s, 1H), 2.35 (br s, 1H), 2.05 (br s, 1H), 1.90
(br s, 7H), 1.64 (br s, 4H), 1.25 (br s, 3H), 1.00 (d, J = 6.1 Hz,
1H) hLPA1 IC.sub.50 = 842 nM 206 ##STR00326## LCMS, [M + H].sup.+ =
484.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.88-7.75 (m, J =
8.2 Hz, 1H), 7.54-7.41 (m, J = 8.2 Hz, 1H), 5.63 (s, 2H), 4.88-4.67
(m, 1H), 4.09 (s, 2H), 3.69-3.53 (m, 1H), 3.17 (s, 1H), 2.89 (s,
1H), 2.80 (br d, J = 7.3 Hz, 2H), 2.76-2.63 (m, 3H), 2.05 (br s,
1H), 1.79 (br s, 8H), 1.61 (br s, 4H), 1.22 (br t, J = 7.3 Hz, 3H),
1.00 (d, J = 6.4 Hz, 1H) hLPA1 IC.sub.50 = 34 nM 207 ##STR00327##
LCMS, [M + H].sup.+ = 500.4 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.83 (br d, J = 8.5 Hz, 1H), 7.47 (br d, J = 8.5 Hz, 1H),
5.64 (br d, J = 8.5 Hz, 2H), 4.78 (br s, 1H), 4.12 (s, 2H), 4.08
(br s, 1H), 2.83-2.73 (m, 4H), 2.73- 2.65 (m, 1H), 2.60 (br s, 1H),
2.12-1.94 (m, 1H), 1.86 (br d, J = 12.2 Hz, 1H), 1.82-1.70 (m, 2H),
1.66-1.52 (m, 3H), 1.52- 1.37 (m, 2H), 1.31-1.22 (m, 4H), 1.20 (br
s, 1H), 1.06 (br d, J = 8.2 Hz, 1H), 1.00 (d, J = 6.1 Hz, 1H), 0.84
(br s, 1H), 0.74 (br s, 1H), 0.68-0.54 (m, 4H), 0.44 (br s, 1H)
hLPA1 IC.sub.50 = 133 nM 208 ##STR00328## LCMS, [M + H].sup.+ =
488.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.89-7.77 (m, J =
8.5 Hz, 1H), 7.53-7.41 (m, J = 8.5 Hz, 1H), 5.64 (br s, 2H), 4.76
(br s, 1H), 4.09 (s, 3H), 3.27-3.10 (m, 1H), 3.04 (br s, 1H), 2.89
(s, 1H), 2.82-2.67 (m, 5H), 1.98 (br d, J = 12.8 Hz, 1H), 1.89 (s,
3H), 1.80 (br d, J = 11.6 Hz, 2H), 1.61 (br d, J = 8.5 Hz, 2H),
1.54 (br s, 1H), 1.49 (br d, J = 11.3 Hz, 1H), 1.30 (br d, J = 5.8
Hz, 1H), 1.24 (br t, J = 7.5 Hz, 3H), 1.12 (br s, 1H), 0.86 (br s,
3H), 0.60 (br s, 3H) hLPA1 IC.sub.50 = 26 nM 209 ##STR00329## LCMS,
[M + H].sup.+ = 486.4 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.83 (br d, J = 7.6 Hz, 1H), 7.46 (br d, J = 8.5 Hz, 1H), 5.65 (br
d, J = 10.7 Hz, 2H), 4.77 (br s, 1H), 4.09 (br s, 3H), 3.24 (br s,
1H), 3.12 (br s, 1H), 2.95- 2.85 (m, 1H), 2.83-2.71 (m, 5H), 2.61
(br t, J = 10.5 Hz, 1H), 2.08-1.95 (m, 1H), 1.92-1.82 (m, 2H),
1.82-1.73 (m, 2H), 1.66-1.45 (m, 4H), 1.33 (br s, 1H), 1.28-1.11
(m, 4H), 0.35 (br s, 1H), 0.16 (br s, 1H), -0.01 (br s, 1H), -0.27
(br s, 1H) hLPA1 IC.sub.50 = 22 nM 210 ##STR00330## LCMS, [M +
H].sup.+ = 484.4 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83
(d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 5.64 (s, 2H), 4.77
(br s, 1H), 4.07 (s, 3H), 2.93-2.86 (m, 1H), 2.80 (q, J = 7.3 Hz,
2H), 2.73 (s, 1H), 2.61 (br t, J = 10.7 Hz, 1H), 2.09- 1.99 (m,
5H), 1.93-1.82 (m, 3H), 1.82-1.67 (m, 4H), 1.65- 1.52 (m, 3H), 1.50
(br s, 1H), 1.28-1.14 (m, 3H) hLPA1 IC.sub.50 = 67 nM 211
##STR00331## LCMS, [M + H]+ = 484.4 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.87-7.80 (m, 1H), 7.46 (br d, J = 8.9 Hz,
1H), 5.69 (br d. J = 5.8 Hz, 2H), 4.77 (br s, 1H), 4.09 (br d, J =
15.3 Hz, 3H), 3.15 (s, 1H), 3.07 (s, 1H), 2.89 (s, 1H), 2.80 (q, J
= 7.6 Hz, 2H), 2.73 (s, 1H), 2.61 (br t, J = 10.5 Hz, 1H),
2.16-1.96 (m, 1H), 1.91-1.74 (m, 3H), 1.70 (t, J = 6.9 Hz, 2H),
1.65-1.45 (m, 4H), 1.29-1.14 (m, 3H), 0.55 (br s, 1H), 0.53-0.45
(m, 3H) hLPA1 IC.sub.50 = 47 nM
[0976] The following analogs were synthesized according to the
methods described for the preparation of Example 1 except that the
intermediate 4 was used (instead of Example 1F).
##STR00332##
[0977] Intermediate 3 was prepared from 2,5-dibromo-pyrazine using
the same synthetic sequence as described for the preparation of
Example 1.
TABLE-US-00003 Example Structure & Name Analytical &
Biology Data Method 212 ##STR00333## LCMS, [M + H]+ = 447.1 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (s, 1H), 8.34 (s, 1H),
5.53 (br d, J = 15.0 Hz, 2H), 5.36 (br s, 1H), 4.12 (s, 3H), 3.16
(br s, 1H), 3.06 (br s, 1H), 2.74 (br d, J = 11.6 Hz, 3H), 2.66 (br
t, J = 10.1 Hz, 1H), 2.07 (br d, J = 13.1 Hz, 1H), 1.87-1.79 (m,
3H), 1.66 (br t, J = 13.0 Hz, 2H), 1.60-1.48 (m, 2H), 1.41 (br s,
1H), 1.22 (br s, 2H), 1.06-0.99 (m, 1H), 0.86 (br s, 1H), 0.68 (br
s, 2H) hLPA1 IC.sub.50 = 40 nM Example 1 (1S,3S)-3-((5-(5-
(((butyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)pyrazin-2- yl)oxy)cyclohexane-1- carboxylic acid 213
##STR00334## LCMS, [M + H]+ = 445.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.80-8.73 (m, 1H), 8.37- 8.30 (m, 1H), 5.54
(br d, J = 13.1 Hz, 2H), 5.40-5.31 (m, 1H), 4.12 (s, 3H), 3.12-3.02
(m, 1H), 3.02-2.92 (m, 1H), 2.83 (br s, 3H), 2.70-2.60 (m, 1H),
2.12-2.01 (m, 1H), 1.86-1.79 (m, 3H), 1.71-1.61 (m, 2H), 1.59-1.48
(m, 2H), 0.98-0.85 (m, 1H), 0.85-0.70 (m, 1H), 0.49-0.36 (m, 1H),
0.36-0.23 (m, 1H), 0.23-0.09 (m, 1H), 0.09--0.07 (m, 1H) hLPA1
IC.sub.50 = 1070 nM Example 1 (1S,3S)-3-((5-(5-
((((cyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)-1-
methyl-1H-1,2,3-triazol-4- yl)pyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid 214 ##STR00335## LCMS, [M + H]+ =
459.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H),
8.33 (br s, 1H), 5.51 (br d, J = 16.5 Hz, 2H), 5.34 (br s, 1H),
4.12 (br s, 3H), 3.56 (br s, 1H), 3.18 (br d, J = 10.4 Hz, 1H),
3.08 (br d, J = 5.5 Hz, 1H), 2.71 (br d, J = 9.5 Hz, 3H), 2.64 (br
s, 1H), 2.34-2.19 (m, 1H), 2.08-2.02 (m, 1H), 1.90 (br s, 1H),
1.86-1.78 (m, 3H), 1.75 (br s, 1H), 1.71 (br s, 1H), 1.64 (br d, J
= 13.4 Hz, 3H), 1.59- 1.46 (m, 3H), 1.40 (br s, 1H) hLPA1 IC.sub.50
= 68 nM Example 1 (1S,3S)-3-((5-(5- ((((cyclobutylmethyl)(methyl)
carbamoyl)oxy)methyl)-1- methyl-1H-1,2,3-triazol-4-
yl)pyrazin-2-yl)oxy) cyclohexane-1-carboxylic acid 215 ##STR00336##
LCMS, [M + H]+ = 459.3 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.76 (s, 1H), 8.34 (s, 1H), 5.54 (s, 2H), 5.35 (br s, 1H),
4.47-4.22 (m, 1H), 4.11 (s, 3H), 3.53-3.31 (m, 1H), 2.63 (br s,
4H), 2.10-2.03 (m, 1H), 1.87-1.76 (m, 3H), 1.73-1.60 (m, 3H), 1.57
(br s, 3H), 1.51 (br d, J = 12.2 Hz, 2H), 1.43 (br s, 4H) hLPA1
IC.sub.50 = 84 nM Example 1 (1S,3S)-3-((5-(5-
(((cyclopentyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)pyrazin-2- yl)oxy)cyclohexane-1- carboxylic
acid
EXAMPLE 216
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)--
1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00337##
[0978] 216A. Methyl
3-bromo-6-(3-hydroxyprop-1-yn-1-yl)pyrazine-2-carboxylate
##STR00338##
[0980] A mixture of methyl 3,6-dibromopyrazine-2-carboxylate (16.5
g, 55.8 mmol), propargyl alcohol (3.33 mL, 55.8 mmol), and TEA
(46.6 mL, 335 mmol) in MeCN (100 mL) was degassed with N.sub.2 and
then CuI (0.531 g, 2.79 mmol) and
bis(triphenylphosphine)Palladium(II) chloride (1.96 g, 2.79 mmol)
were successively added. The reaction mixture was degassed with
N.sub.2 for 3 cycles & stirred at rt for 18 h, then was
filtered through a pad of Celite. The filtrate was concentrated in
vacuo. The crude oil was chromatographed (120 g SiO.sub.2 eluted
with EtOAc/hexane using a continuous gradient from 0% to 80% over
25 min) to give the title product (5.40 g, 19.9 mmol, 35.7% yield)
as a brownish oil.
[0981] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.53 (s, 1H), 4.56
(d, J=6.3 Hz, 2H), 4.04 (s, 3H), 2.09-2.00 (m, 1H)
216B. Methyl
3-bromo-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazine-2-ca-
rboxylate
##STR00339##
[0983] To a solution of Example 216A (2.7 g, 9.96 mmol) in
1,4-dioxane (100 mL) were successively added added
TMSCH.sub.2N.sub.3 (1.48 mL, 9.96 mmol),
chloro(pentamethylcyclopenta-dienyl)bis(triphenylphosphine)Rutheni-
um(II) (0.397 g, 0.498 mmol), and CuI (0.095 g, 0.498 mmol). The
mixture was degassed with N.sub.2 for 3 cycles. The resulting
homogenous mixture was then heated at 50.degree. C. (oil bath) for
16 h, then was cooled to rt and concentrated in vacuo. The residue
was dissolved in THF (40 mL) and cooled to 0.degree. C.; TBAF (19.9
mL of a 1 M solution in THF, 19.9 mmol) was added at 0.degree. C.
The reaction mixture was allowed to warm to rt and stirred at rt
for 60 min, after which sat. aq. NaHCO.sub.3 aqueous solution (20
mL) was added. The mixture was stirred for 1 h and filtered. The
filtrate was concentrated in vacuo. The crude brown oily product
was chromatographed (SiO.sub.2; 80 g; elution with
EtOAc/Hexane--continuous gradient from 0% to 80% over 25 min) to
give title product (1.5 g, 4.57 mmol, 45.9% yield) as a light
brownish solid.
[0984] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.42 (s, 1H),
4.90-4.85 (m, 3H), 4.15 (s, 3H), 4.07 (s, 3H)
216C. Methyl
3-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-tr-
iazol-4-yl)pyrazine-2-carboxylate
##STR00340##
[0986] p-TsOH.H.sub.2O (0.087 g, 0.457 mmol) was added to a
solution of Example 216B (3.0 g, 9.14 mmol) and
3,4-dihydro-2H-pyran (2.502 mL, 27.4 mmol) in DCM (10 mL) at
0.degree. C. The reaction mixture was stirred overnight at rt and
neutralized with satd aq. NaHCO.sub.3 to pH 7 at 0.degree. C. The
mixture was partitioned between CH.sub.2Cl.sub.2 (10 mL) and water
(10 mL), and the aqueous layer was extracted with DCM (3.times.10
mL). The combined organic extracts were dried (MgSO.sub.4),
filtered, and concentrated in vacuo. The crude oil was
chromatographed (40 g SiO.sub.2; elution with
EtOAc/Hexane--continuous gradient from 0% to 50% over 25 min) to
give the title compound (3.50 g, 8.49 mmol, 93% yield) as light
brownish oil.
[0987] [M-THP+H]=328.1/330.1; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.31 (s, 1H), 5.28-5.09 (m, 2H), 4.75-4.71 (m, 1H), 4.19
(s, 3H), 4.03 (s, 3H), 3.82-3.75 (m, 1H), 3.53-3.45 (m, 1H),
1.85-1.44 (m, 6H)
216D.
3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2-
,3-triazol-4-yl)pyrazine-2-carboxylic acid
##STR00341##
[0989] A solution of LiOH.H.sub.2O (0.484 g, 11.53 mmol) in water
(6 mL) was added dropwise to a stirred solution of Example 216C
(1.0 g, 2.43 mmol) in THF (6 mL) at 0.degree. C. The reaction
mixture was allowed to warm to rt and stirred at rt for 60 min,
then was quenched carefully with 1N aq. HCl to pH .about.5 at
0.degree. C. and extracted with DCM (20.times.5 mL). The combined
organic extracts were washed with brine and dried over
Na.sub.2SO.sub.4. Volatiles were removed in vacuo to afford the
title compound (0.80 g, 2.01 mmol, 83% yield) as a light yellowish
solid.
[0990] [M-THP+H]=313.9/315.9; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 9.46 (s, 1H), 5.42 (d, J=13.5 Hz, 1H), 4.90 (d, J=13.8 Hz,
1H), 4.24 (s, 3H), 3.87 (td, J=10.9, 2.6 Hz, 1H), 3.73 (d, J=11.3
Hz, 1H), 1.93-1.50 (m, 7H)
217E.
3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2-
,3-triazol-4-yl)pyrazine-2-carbonyl chloride
##STR00342##
[0992] A mixture of Example 217D (228 mg, 0.573 mmol) and
1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.114 mL, 0.859 mmol) in
DCM (2 mL) was stirred at rt for 1 h. The reaction mixture was
concentrated in vacuo to give the title compound (239 mg, 0.574
mmol, 100% yield) as yellowish oil which was used in the next
reaction without further purification.
218F.
(3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,-
2,3-triazol-4-yl)pyrazin-2-yl)methanol
##STR00343##
[0994] A solution of Example 218E (3.14 g, 7.54 mmol) in THF (20
mL) was added dropwise to a suspension of NaBH.sub.4 (0.656 g,
17.33 mmol) in EtOH (20 mL) at -78.degree. C. The reaction was
stirred at -78.degree. C. for 1 h. Aq. HCl (9.80 mL of a 1.0 N
solution, 9.80 mmol) was added cautiously to the reaction to make
it weakly acidic at -78.degree. C. The mixture was then basified
with sat'd aq. NaHCO.sub.3 to pH.about.8 and extracted with EtOAc
(4.times.20 mL). The combined organic extracts were dried
(MgSO.sub.4) and concentrated in vacuo. The crude oily product was
chromatographed (40 g SiO.sub.2; elution with EtOAc/Hexane
(continuous gradient from 0% to 80% over 25 min) to give the title
compound (2.50 g, 6.51 mmol, 86% yield) as a light yellowish
solid.
[0995] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.13 (s, 1H), 5.47
(d, J=13.2 Hz, 1H), 4.98 (d, J=13.2 Hz, 1H), 4.89-4.85 (m, 2H),
4.76 (t, J=2.9 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.19 (s, 3H),
3.93-3.81 (m, 1H), 3.62 (dt, J=10.9, 3.9 Hz, 1H), 1.86-1.47 (m,
6H)
218G.
2-Bromo-3-(chloromethyl)-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)pyrazine
##STR00344##
[0997] To a solution of Example 218F (190 mg, 0.494 mmol) in
CHCl.sub.3 (3 mL) was added methanesulfonyl chloride (0.057 mL,
0.74 mmol), iPr.sub.2NEt (0.259 mL, 1.48 mmol) and DMAP (6.0 mg,
0.049 mmol) at 0.degree. C. After the addition was complete, the
reaction mixture was stirred at rt for 30 min. after which LiCl
(105 mg, 2.472 mmol) and DMF (3 mL) were successively added. The
mixture was stirred at rt for 1 h and then concentrated in vacuo.
The residue was partitioned between water and EtOAc (10 mL each).
The organic phase was washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. The crude oily product was chromatographed
(12 g SiO.sub.2; elution with EtOAc/Hexane (continuous gradient
from 0% to 50% over 10 min) to give the title compound (175 mg,
0.435 mmol, 88% yield) as a white solid.
[0998] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.14 (s, 1H),
5.33-5.19 (m, 2H), 4.84 (s, 2H), 4.75 (t, J=3.4 Hz, 1H), 4.19 (s,
3H), 3.88-3.75 (m, 1H), 3.59-3.47 (m, 1H), 1.87-1.46 (m, 6H)
218H.
2-Bromo-3-methyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methy-
l)-1H-1,2,3-triazol-4-yl)pyrazine
##STR00345##
[1000] To a 0.degree. C. solution of NaBH.sub.4 (286 mg, 7.55 mmol)
in EtOH (20 mL) was added dropwise a solution of Example 218G (760
mg, 1.89 mmol) in THF (20 mL). After the addition was complete, the
reaction was stirred at rt for 6 h. LCMS indicated the reaction was
still not complete, so additional NaBH.sub.4 (286 mg, 7.55 mmol)
was added and the reaction mixture was stirred for 3 days, then
cautiously quenched with water at 0.degree. C. The mixture was
extracted with EtOAc (3.times.5 mL). The combined organic extracts
were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated
in vacuo. The crude oily product was chromatographed (24 g
SiO.sub.2; elution with EtOAc/Hexane (continuous gradient from 0%
to 50% over 10 min) to give the title compound (600 mg, 1.63 mmol,
86% yield) as a white solid.
[1001] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.04 (s, 1H),
5.29-5.20 (m, 2H), 4.75 (t, J=3.4 Hz, 1H), 4.20 (s, 3H), 3.86 (ddd,
J=11.3, 8.3, 3.0 Hz, 1H), 3.59-3.50 (m, 1H), 2.72 (s, 3H),
1.85-1.49 (m, 6H)
218I.
3-Methyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,-
2,3-triazol-4-yl)pyrazin-2-ol
##STR00346##
[1003] A mixture of Example 218H (600 mg, 1.63 mmol) KOH (1.00 mL
of a 7 M aq. solution, 7.0 mmol) in water (5 mL) and dioxane (5 mL)
was degassed under N.sub.2 and then tBuXphos (83 mg, 0.196 mmol)
and Pd.sub.2(dba).sub.3 (44.8 mg, 0.049 mmol) were added. The
reaction mixture was degassed under N.sub.2 again and then stirred
at 80.degree. C. overnight. The reaction was cooled to rt, then was
acidified to pH 5 with 1N aq. HCl at 0.degree. C. and partitioned
between water and EtOAc. The organic phase was separated, dried
(MgSO.sub.4), and concentrated in vacuo. The crude oily product was
chromatographed (12 g SiO.sub.2; elution with EtOAc/Hexane
(continuous gradient from 0% to 100% over 7 min) to give the title
compound (340 mg, 1.11 mmol, 68.3% yield) as a light yellowish
solid.
[1004] [M-THP+H]=222.2; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.04 (s, 1H), 5.24-5.15 (m, 2H), 4.88-4.72 (m, 1H), 4.16 (s, 3H),
3.90 (ddd, J=11.2, 8.2, 3.2 Hz, 1H), 3.72-3.52 (m, 1H), 2.55 (s,
3H), 1.90-1.44 (m, 7H)
218J. Isopropyl
(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl-
)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate
##STR00347##
[1006] To a mixture of Example 218I (340 mg, 1.11 mmol)),
((1S,3R)-isopropyl 3-hydroxycyclo-hexane carboxylate (373 mg, 2.00
mmol) in THF (5 mL) were successively added n-Bu.sub.3P (0.556 mL,
2.227 mmol) and (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone)
(562 mg, 2.23 mmol). The reaction mixture was then stirred at
80.degree. C. for 18 h, then was cooled to rt and concentrated in
vacuo. The crude oily product was chromatographed (24 g SiO.sub.2;
elution with EtOAc/Hexane (continuous gradient from 0% to 50% over
10 min) to give the title compound (527 mg, 1.11 mmol, 100% yield)
as a clear oil.
[1007] [M+H].sup.+=474.2
218K. Isopropyl
(1S,3S)-3-((5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methyl-
pyrazin-2-yl)oxy)cyclohexane-1-carboxylate
##STR00348##
[1009] A mixture of Example 218J (527 mg, 1.11 mmol) and pyridinium
p-toluenesulfonate (28 mg, 0.11 mmol) in MeOH (10 mL) was stirred
at rt for 3 days and then concentrated in vacuo. The crude oily
product was chromatographed (24 g SiO.sub.2; elution with
EtOAc/Hexane (continuous gradient from 0% to 100% over 10 min) to
give the title compound (277 mg, 0.711 mmol, 63.9% yield) as a
clear oil.
[1010] [M+H].sup.+=390.2; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.89 (s, 1H), 5.54 (br s, 1H), 5.04 (dt, J=12.4, 6.3 Hz, 1H), 4.83
(s, 2H), 4.16-4.10 (m, 3H), 2.74 (tt, J=11.1, 3.9 Hz, 1H), 2.56 (s,
3H), 2.23 (br d, J=14.0 Hz, 1H), 2.01 (br dd, J=8.8, 4.1 Hz, 2H),
1.89 (ddd, J=13.9, 11.4, 2.8 Hz, 1H), 1.82-1.47 (m, 5H), 1.26 (dd,
J=6.3, 2.8 Hz, 6H)
218L. Isopropyl
(1S,3S)-3-((3-methyl-5-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl-
)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate
##STR00349##
[1012] A solution of 4-nitrophenyl chloroformate (172 mg, 0.854
mmol) in DCM (1 mL) was added dropwise to a solution of Example
218K (277 mg, 0.711 mmol) and pyridine (0.288 mL, 3.56 mmol) in DCM
(5 mL) over 1 h at 0.degree. C. The reaction was then stirred at rt
for 18 h, then was concentrated in vacuo. The crude oily product
was chromatographed (12 g SiO.sub.2; elution with EtOAc/Hexane
(continuous gradient from 0% to 50% over 10 min) to give the title
compound (366 mg, 0.66 mmol, 93% yield) as a light yellowish
oil.
[1013] [M+H].sup.+=555.2; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.79 (s, 1H), 8.33-8.28 (m, 2H), 7.44-7.37 (m, 2H), 6.02-5.94 (m,
2H), 5.52 (br s, 1H), 5.03 (dt, J=12.6, 6.2 Hz, 1H), 4.23 (s, 3H),
2.74 (tt, J=11.1, 3.9 Hz, 1H), 2.52 (s, 3H), 2.22 (br d, J=14.0 Hz,
1H), 2.03-1.96 (m, 2H), 1.93-1.83 (m, 1H), 1.81-1.52 (m, 4H),
1.30-1.22 (m, 6H)
EXAMPLE 218
[1014] To a solution of Example 218L (8 mg, 0.014 mmol) in DCM (1
mL) was added N-methyl propan-1-amine (1.8 .mu.L; 0.017 mmol) and
DIPEA (7.6 .mu.L, 0.043 mmol). The reaction mixture was stirred at
rt for 2 h, then was concentrated in vacuo. The crude oil was (4 g
SiO.sub.2; elution with EtOAc/Hexane (continuous gradient from 0%
to 30% over 10 min) to give the corresponding carbamate-isopropyl
ester Example as a clear oil. This ester intermediate was stirred
with 1N aq. NaOH (0.2 mL) in THF (1 mL) and MeOH (0.2 mL) at rt for
18 h and then acidified to pH=.about.2 with TFA. The reaction
mixture was purified by preparative HPLC (Sunfire C18 30.times.100
mm-regenerated column; detection at 220 nm; flow rate=40 mL/min;
continuous gradient from 20% B to 100% B over 10 min+2 min hold
time at 100% B, where A=90:10:0.1 H.sub.2O:MeCN:TFA and B=90:10:0.1
MeCN:H.sub.2O:TFA) to give Example 218 (5 mg, 11.0 .mu.mol, 76%
yield) as a clear oil.
[1015] [M+H].sup.+=447.3; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.72 (s, 1H), 5.69 (br d, J=7.4 Hz, 2H), 5.53 (br s, 1H), 4.18 (s,
3H), 3.26 (br t, J=7.2 Hz, 1H), 3.13 (br t, J=7.2 Hz, 1H),
2.97-2.79 (m, 4H), 2.52 (s, 3H), 2.32 (br d, J=14.0 Hz, 1H),
2.16-1.99 (m, 2H), 1.93-1.37 (m, 7H), 0.98-0.71 (m, 3H). hLPA
IC.sub.50=194 nM
TABLE-US-00004 Example Structure & Name Analytical &
Biology Data Method 219 ##STR00350## LCMS, [M + H].sup.+ = 461.4;
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.69 (s, 1H), 5.68 (br.
s., 2H), 5.53 (br. s., 1H), 4.19 (s, 3H), 3.36-3.10 (m, 2H),
2.97-2.79 (m, 4H), 2.53 (s, 3H), 2.32 (d, J = 14.0 Hz, 1H),
2.14-1.97 (m, 2H), 1.94-1.12 (m, 9H), 1.02- 0.74 (m, 3H) hLPA1
IC.sub.50 = 21 nM Example 218 (1S,3S)-3-((5-(5-(((butyl
(methyl)carbamoyl)oxy)methyl)-1- methyl-1H-1,2,3-triazol-4-yl)-3-
methylpyrazin-2-yl)oxy) cyclohexane-1-carboxylic acid 220
##STR00351## LCMS, [M + H].sup.+ = 458.9. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.57 (s, 1H), 5.54 (d, J = 19.1 Hz, 2H),
5.38 (s, 1H), 4.10 (s, 3H), 3.05 (br s, 1H), 2.93 (br s, 1H),
2.85-2.76 (m, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 2.41-2.12 (m, 8H).
0.40 (br s, 1H), 0.24 (br s, 1H), 0.16 (br s, 1H), -0.04 (br s,
1H). hLPA1 IC.sub.50 = 149 nM Example 218
(1S,3S)-3-((5-(5-((((cyclopropyl- methyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methyl-pyrazin-2-
yl)oxy)cyclohexane-1-carboxylic acid 221 ##STR00352## LCMS, [M +
H].sup.+ = 473.2. .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.66
(s, 1H), 5.64 (br s, 2H), 5.51 (s, 1H), 4.17 (s, 3H), 3.31 (d, J =
7.5 Hz, 1H), 3.17 (d, J = 7.3 Hz, 1H), 2.91-2.77 (m, 4H), 2.61-2.35
(m, 1H), 2.50 (s, 3H), 2.29 (d, J = 14.1 Hz, 1H), 2.10-1.50 (m,
13H). hLPA1 IC.sub.50 = 23 nM Example 218 (1S,3S)-3-((5-(5-
((((cyclobutylmethyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-3-methylpyrazin-
2-yl)oxy)cyclohexane-1-carboxylic acid 222 ##STR00353## LCMS; [M +
H].sup.+ = 475.4; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.58
(br s, 1H), 5.54 (br d, J = 13.0 Hz, 2H), 5.38 (br s, 1H), 4.12 (br
s, 3H), 3.18 (br d, J = 9.2 Hz, 1H), 3.03 (br s, 1H), 2.80- 2.58
(m, 4H), 2.44 (br s, 3H), 2.09 (br d, J = 13.6 Hz, 1H), 1.94-1.03
(m, 10H), 0.92-0.55 (m, 6H) hLPA1 IC.sub.50 = 19 nM Example 218
(1S,3S)-3-((5-(5-(((isopentyl (methyl)carbamoyl)oxy)methyl)-1-
methyl-1H-1,2,3-triazol-4-yl)-3- methylpyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid 223 ##STR00354## LCMS; [M + H].sup.+
= 475.4; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.58 (s, 1H),
5.54 (br d, J = 15.9 Hz, 2H), 5.37 (br s, 1H), 4.11 (br s, 2H),
3.22-2.99 (m, 2H), 2.80-2.67 (m, 3H), 2.62- 2.53 (m, 4H), 2.44 (s,
2H), 2.13-1.96 (m, 1H), 1.90- 0.59 (m, 15H) hLPA1 IC.sub.50 = 56 nM
Example 218 (1S,3S)-3-((3-methyl-5-(1-methyl-
5-(((methyl(pentyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-
yl)pyrazin-2-yl)oxy)cyclohexane-1- carboxylic acid 224 ##STR00355##
LCMS; [M + H].sup.+ = 461.2; .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 8.72 (s, 1H), 5.69 (br d, J = 14.3 Hz, 2H), 5.53 (br s,
1H), 4.18 (s, 3H), 3.12 (br d, J = 7.4 Hz, 1H), 3.03- 2.77 (m, 6H),
2.53 (s, 3H), 2.32 (br d, J = 14.0 Hz, 1H), 2.18-1.53 (m, 7H),
0.99- 0.74 (m, 6H) hLPA1 IC.sub.50 = 121 nM Example 218
(1S,3S)-3-((5-(5- (((isobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-3-methylpyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid 225 ##STR00356## LCMS; [M + H].sup.+
= 473.4; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.57 (s, 1H),
5.54 (br d, J = 14.4 Hz, 2H), 5.38 (br s, 1H), 4.11 (br s, 3H),
3.29-3.07 (m, 2H), 2.82-2.70 (m, 3H), 2.57 (br d, J = 11.3 Hz, 1H),
2.43 (s, 3H), 2.16-1.97 (m, 1H), 1.93-1.01 (m, 9H), 0.70- 0.12 (m,
3H), 0.06--0.40 (m, 2H) hLPA1 IC.sub.50 = 70 nM Example 218
(1S,3S)-3-((5-(5-((((2- cyclopropylethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methylpyrazin-2-yl)
oxy)cyclohexane-1-carboxylic acid 226 ##STR00357## LCMS; [M +
H].sup.+ = 473.5; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.56
(s, 1H), 5.53 (s, 2H), 5.38 (br s, 1H), 4.10 (s, 3H), 3.64 (br s,
1H), 2.62 (br s, 4H), 2.44 (s, 3H), 2.19-2.02 (m, 1H), 1.95- 1.24
(m, 15H) hLPA1 IC.sub.50 = 49 nM Example 218 (1S,3S)-3-((5-(5-
(((cyclopentyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-3-methylpyrazin-2- yl)oxy)cyclohexane-1-carboxylic
acid 227 ##STR00358## LCMS; [M + H].sup.+ = 487.5; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.58 (s, 1H), 5.61-5.48 (m, 2H), 5.40
(br s, 1H), 4.12 (br s, 3H), 3.20- 2.91 (m, 2H), 2.84-2.69 (m, 3H),
2.64 (br s, 1H), 2.48-2.42 (m, 3H), 2.10 (br d, J = 13.1 Hz, 1H),
1.96- 1.07 (m, 15H), 0.89 (br s, 1H) hLPA1 IC.sub.50 = 18 nM
Example 218 (1S,3S)-3-((5-(5- ((((cyclopentylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-3-methylpyrazin-
2-yl)oxy)cyclohexane-1-carboxylic acid 228 ##STR00359## LCMS; [M +
H].sup.+ = 495.3; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.56
(br s, 1H), 7.38-7.04 (m, 4H), 6.96 (br s, 1H), 5.68-5.47 (m, 2H),
5.37 (br s, 1H), 4.47-4.21 (m, 2H), 4.19-3.97 (m, 3H), 2.83-2.66
(m, 3H), 2.62 (br t, J = 11.0 Hz, 1H), 2.46-2.32 (m, 3H), 2.13-
2.04 (m, 1H), 1.95-1.40 (m, 7H) hLPA1 IC.sub.50 = 60 nM
(1S,3S)-3-((5-(5- (((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-3-methylpyrazin-2-yl)oxy)
cyclohexane-1-carboxylic acid 229 ##STR00360## LCMS; [M + H].sup.+
= 459.0; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.58-8.57 (m,
1H), 5.54 (br s, 2H), 5.39 (br s, 1H), 4.10 (s, 4H), 2.82- 2.57 (m,
4H), 2.47-2.39 (m, 3H), 2.18-1.31 (m, 14H) hLPA1 IC.sub.50 = 76 nM
(1S,3S)-3-((5-(5- (((cyclobutyl(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methylpyrazin-2-yl)
oxy)cyclohexane-1-carboxylic acid 230 ##STR00361## LCMS; [M +
H].sup.+ = 465.4; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.58
(s, 1H), 5.56 (br s, 2H), 5.39 (br s, 1H), 4.54-4.17 (m, 2H), 4.11
(s, 3H), 3.39-3.14 (m, 2H), 2.89-2.69 (m, 3H), 2.64 (br t, J = 10.8
Hz, 1H), 2.45 (s, 3H), 2.10 (br d, J = 13.7 Hz, 1H), 1.94-1.41 (m,
9H) hLPA1 IC.sub.50 = 390 nM (1S,3S)-3-((5-(5-((((3-
fluoropropyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-3-methylpyrazin-2-yl) oxy)cyclohexane-1-carboxylic
acid 231 ##STR00362## LCMS; [M + H].sup.+ = 475.2; .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta. 8.71 (s, 1H), 5.68 (br d, J = 12.1 Hz,
2H), 5.54 (br s, 1H), 4.23-4.16 (m, 3H), 3.14 (s, 1H), 3.04-2.96
(m, 3H), 2.93-2.81 (m, 2H), 2.53 (s, 3H), 2.32 (br d, J = 14.0 Hz,
1H), 2.16-1.97 (m, 2H), 1.94-1.84 (m, 1H), 1.83- 1.55 (m, 4H),
1.04-0.72 (m, 9H) hLPA1 IC.sub.50 = 88 nM
(1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(neopentyl)carbamoyl)
oxy)methyl)-1H-1,2,3-triazol-4- yl)pyrazin-2-yl)oxy)cyclohexane-1-
carboxylic acid 232 ##STR00363## LCMS; [M + H].sup.+ = 479.2;
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.67 (s, 1H), 5.80- 5.57
(m, 2H), 5.54 (br s, 1H), 4.26-4.16 (m, 3H), 3.57-3.27 (m, 2H),
3.10- 2.77 (m, 4H), 2.59-2.46 (m, 3H), 2.32 (br d, J = 13.8 Hz,
1H), 2.13-1.97 (m, 2H), 1.95-1.53 (m, 5H), 1.42-1.13 (m, 6H);
.sup.19F NMR (471 MHz, CDCl.sub.3): .delta. -139.12 (s, 1 F) hLPA1
IC.sub.50 = 191 nM (1S,3S)-3-((5-(5-((((2-fluoro-2-
methylpropyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-3-methylpyrazin-2-yl) oxy)cyclohexane-1-carboxylic
acid 233 ##STR00364## LCMS; [M + H].sup.+ = 491.2; .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.70 (s, 1H), 5.69 (br d, J = 5.1 Hz,
2H), 5.51 (br s, 1H), 4.16 (s, 3H), 3.72- 3.34 (m, 2H), 3.04-2.75
(m, 4H), 2.49 (br d, J = 4.6 Hz, 3H), 2.33-1.49 (m, 14H); .sup.19F
NMR (377 MHz, CDCl.sub.3): .delta. -130.34 (br s, 1 F) hLPA1
IC.sub.50 = 122 nM (1S,3S)-3-((5-(5-(((((1-fluoro-
cyclobutyl)methyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-3-methylpyrazin-
2-yl)oxy)cyclohexane-1-carboxylic acid 234 ##STR00365## LCMS; [M +
H].sup.+ = 505.2; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.64
(s, 1H), 5.71- 5.61 (m, 2H), 5.52 (br s, 1H), 4.19 (s, 3H), 3.68-
3.37 (m, 2H), 3.07-2.91 (m, 3H), 2.84 (tt, J = 11.2, 3.7 Hz, 1H),
2.51 (d, J = 3.5 Hz, 3H), 2.29 (br d, J = 13.9 Hz, 1H), 2.12-1.96
(m, 2H), 1.94-1.35 (m, 13H); .sup.19F NMR (377 MHz, CDCl.sub.3):
.delta. -139.45 to -147.94 (m, 1 F) hLPA1 IC.sub.50 = 72 nM
(1S,3S)-3-((5-(5-(((((1- fluorocyclopentyl)methyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-3-
methylpyrazin-2- yl)oxy)cyclohexane-1-carboxylic acid 235
##STR00366## LCMS; [M + H].sup.+ = 473.0; .sup.1H NMR (500 MHz,
CDCl.sub.3): .delta. 8.72 (s, 1H), 5.82- 5.56 (m, 2H), 5.53 (br s,
1H), 4.17 (s, 3H), 3.29- 2.80 (m, 6H), 2.52 (s, 3H), 2.31 (br d, J
= 14.0 Hz, 1H), 2.14-1.97 (m, 2H), 1.91- 1.54 (m, 5H), 1.10-0.90
(m, 3H), 0.75-0.11 (m, 4H) hLPA1 IC.sub.50 = 70 nM
(1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(((1R,2R)-2-
methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-
yl)pyrazin-2-yl)oxy)cyclohexane-1- carboxylic acid 236 ##STR00367##
LCMS; [M + H].sup.+ = 473.0; .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 8.72 (s, 5H), 5.69 (br d, J = 6.9 Hz, 2H), 5.52 (br s, 1H),
4.17 (s, 3H), 3.28- 2.80 (m, 6H), 2.58-2.46 (m, 3H), 2.31 (br d, J
= 13.8 Hz, 1H), 2.12-1.97 (m, 2H), 1.93-1.54 (m, 5H), 1.10-0.89 (m,
3H), 0.74- 0.11 (m, 4H) hLPA1 IC.sub.50 = 46 nM
(1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(((1S,2S)-2-methyl-
cyclopropyl)methyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-
yl)pyrazin-2-yl)oxy)cyclohexane-1- carboxylic acid
EXAMPLE 237
(1S,3S)-3-((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-met-
hyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-
-1-carboxylic acid
##STR00368##
[1016] 237A. Isopropyl
(1S,3S)-3-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-car-
boxylate
##STR00369##
[1018] To a N.sub.2-flushed, 50 mL round bottom flask was added
(E)-diazene-1,2-diylbis (piperidin-1-ylmethanone) (2.11 g, 8.35
mmol), toluene (15 mL) and n-Bu.sub.3P (2.1 mL, 8.35 mmol); the
dark orange solution became a light yellow solution after the
addition of n-Bu.sub.3P. The solution was stirred at rt for 30 min,
then 5-bromo-3-(trifluoromethyl)pyridin-2-ol (1.01 g, 4.17 mmol)
and (1S,3R)-isopropyl 3-hydroxycyclohexanecarboxylate (1.40 g, 7.51
mmol) were successively added. The reaction mixture was heated to
80.degree. C. for 16 h, then was cooled to rt. EtOAc (10 mL) and
water (5 mL) were added, and the mixture was stirred for 10 min and
the organic layer was separated. The aqueous layer was
back-extracted with EtOAc (2.times.10 mL). The combined organic
extracts were washed with brine (10 mL), dried (MgSO.sub.4), and
concentrated in vacuo to give the crude product. This crude
material was chromatographed (SiO.sub.2, 120 g; elution with
EtOAc/hexanes (continuous gradient from 0 to 100%) to afford the
title compound (1.7 g, 4.14 mmol, 99% yield) as a colorless
oil.
[1019] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.32 (d, J=2.4
Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 5.52 (br s, 1H), 5.06-4.94 (m,
1H), 2.69 (tt, J=11.6, 3.9 Hz, 1H), 2.23-2.17 (m, 1H), 2.03-1.93
(m, 2H), 1.82-1.43 (m, 5H), 1.22 (d, J=6.3 Hz, 6H). LCMS,
[M+H].sup.+=410.
237B. Isopropyl
(1S,3S)-3-((5-(3-hydroxyprop-1-yn-1-yl)-3-(trifluoromethyl)pyridin-2-yl)o-
xy)cyclohexane-1-carboxylate
##STR00370##
[1021] To a 100 mL round bottom flask containing Example 237A (1.7
g, 4.1 mmol) and prop-2-yn-1-ol (0.70 g, 12.4 mmol) in MeCN (21 ml)
was added Et.sub.3N (2.89 mL, 20.7 mmol). The solution was quickly
degassed (evacuation under vacuum, then refill with N.sub.2
(3.times.)). Trans-dichlorobis (triphenylphosphine) palladium (II)
chloride (0.29 g, 0.41 mmol) and CuI (0.039 g, 0.21 mmol) were
added. The solution degassed (evacuation under vacuum, then refill
with N.sub.2 (3.times.)). The reaction was heated to reflux at
80.degree. C. for 24 h, then was cooled to rt. The reaction mixture
was filtered through a Celite.RTM. plug, which was washed with
EtOAc (2.times.10 mL). The combined filtrates were concentrated in
vacuo and the residue was chromatographed (40 g SiO.sub.2;
continuous gradient from 0% to 100% EtOAc in Hexanes for 20 min) to
give the title compound as a white solid (1.13 g, 2.93 mmol, 71%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.35 (d, J=2.4
Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 5.58 (br s, 1H), 5.06-4.97 (m,
1H), 4.50 (d, J=6.2 Hz, 2H), 2.70 (tt, J=11.6, 3.9 Hz, 1H),
2.24-2.17 (m, 1H), 2.03-1.93 (m, 2H), 1.82-1.43 (m, 5H), 1.22 (d,
J=6.3 Hz, 6H). LCMS, [M+H].sup.+=386.2.
237C. Isopropyl
(1S,3S)-3-((5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifl-
uoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate
##STR00371##
[1023] To a solution of Example 237B (1.13 g, 2.9 mmol) in
1,4-dioxane (20 mL) was added TMSCH.sub.2N.sub.3 (0.68 g, 5.3
mmol),
chloro(pentamethylcyclopentadienyl)bis(triphenyl-phosphine)Ruthenium(II)
(0.12 g, 0.15 mmol), and CuI (0.028 g, 0.15 mmol). The mixture was
quickly evacuated and backfilled with N.sub.2 (this sequence was
repeated three times). The resulting homogenous mixture was then
heated in a 50.degree. C. oil bath for 16 h (when the external and
internal temp. are between 49 to 50.degree. C.), then was cooled to
rt and concentrated on a rotary evaporator to dryness (the waste
trap content was collected, labeled as azide-containing hazardous
waste and disposed accordingly). The residue was dissolved in THF
(20 mL). TBAF (5.86 mL of a 1 M solution in THF, 5.86 mmol) was
added and the mixture was stirred at rt for 60 min. The reaction
was quenched with sat'd aq. NaHCO.sub.3 (20 mL) and extracted with
EtOAc (4.times.20 mL). The combined organic extracts were washed
with brine (20 mL), dried (MgSO.sub.4) and concentrated in vacuo.
The crude was chromatographed (continuous gradient from 0% to 70%
EtOAc/hexanes over 27 min, then gradient from 70 to 100% in 8 min;
80 g Gold ISCO SiO.sub.2 column) and then preparative HPLC under
the following conditions: Column: Phenomenex Luna 5u C18 100A
30.times.250 mm; Mobile Phase A: 10:90 MeCN:H.sub.2O with 0.1% TFA;
Mobile Phase B: 90:10 MeCN:H.sub.2O with 0.1% TFA; Gradient: 0-100%
B over 20 min, then a 5-min hold at 100% B; Flow: 30 mL/min.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to afford the title compound (0.50 g,
1.13 mmol, 38.5% yield) (the later eluting fraction). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.55 (d, J=2.5 Hz, 1H), 8.25 (d,
J=2.5 Hz, 1H), 5.62 (br s, 1H), 5.06-4.99 (m, 1H), 4.86 (s, 2H),
4.18 (s, 3H), 2.73 (tt, J=11.5, 3.8 Hz, 1H), 2.28-2.22 (m, 1H),
2.05-1.98 (m, 2H), 1.85-1.45 (m, 5H), 1.22 (d, J=6.2 Hz, 6H). The
regiochemistry of this desired product was determined by 1D-NoE NMR
experiments. LCMS, [M+H].sup.+=443.2.
237D. Isopropyl
(1S,3S)-3-((5-(1-methyl-5-4((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-
-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxyla-
te
##STR00372##
[1025] To a solution of Example 237C (116 mg, 0.26 mmol) and
4-nitrophenyl chloroformate (106 mg, 0.52 mmol) in DCM (3 mL) was
added pyridine (0.085 mL, 1.05 mmol) at rt. A white solid was
formed. The reaction mixture was stirred at rt for 16 h, after
which the solid was filtered off and washed with DCM. The combined
filtrate and washes were evaporated in vacuo. The crude product was
chromatographed (12 g SiO.sub.2, elution with continuous gradient
from 0 to 100% EtOAc in DCM) to give the title compound (114 mg,
0.19 mmol, 71.6% yield) as a white solid. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.65 (d, J=2.2 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H),
8.31 (d, J=9.1 Hz, 2H), 7.40 (d, J=9.1 Hz, 2H), 5.64 (br s, 1H),
5.45 (s, 2H), 5.06-4.99 (m, 1H), 4.25 (s, 3H), 2.74 (t, J=11.7 Hz,
1H), 2.29-2.22 (m, 1H), 2.05-1.98 (m, 2H), 1.86-1.45 (m, 5H), 1.22
(d, J=6.2 Hz, 6H). LCMS, [M+H].sup.+=608.3.
EXAMPLE 237
##STR00373##
[1027] To a solution of Example 237D (5.4 mg, 8.9 .mu.mol) and
1-cyclopropyl-N-methylmethanamine (2.0 .mu.L, 0.018 mmol) in THF
(0.4 mL) was added N-ethyl-N-isopropyl-propan-2-amine (5 .mu.L,
0.027 mmol). The mixture was stirred at rt for 1 h, after which a
solution of LiOH.H.sub.2O (3.7 mg, 0.088 mmol) in water (0.4 mL)
and MeOH (0.2 mL) was added. The reaction mixture was stirred at rt
for 48 h, then was acidified to pH=4 with 1N aq. HCl and extracted
with EtOAc (3.times.5 mL). The combined organic extracts were dried
(MgSO.sub.4) and concentrated in vacuo. The crude product was
purified via preparative LC/MS with the following conditions:
Column: XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile
Phase A: 5:95 MeCN:H.sub.2O with 10 mM NH.sub.4OAc; Mobile Phase B:
95:5 MeCN:H.sub.2O with 10 mM NH.sub.4OAc; Continuous gradient:
20-60% B over 20 min, then a 4-min hold at 100% B; Flow: 20 mL/min.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to afford the title compound (2.4 mg,
51% yield).
[1028] The following compounds were prepared by the general
synthetic scheme for Example 237.
TABLE-US-00005 Analytical & Biology Example Structure &
Name Data Method 237 ##STR00374## LCMS, [M + H].sup.+ = 512.0.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.32 (s,
1H), 5.55 (br s, 1H), 5.33 (s, 2H), 4.12 (s, 3H), 2.71 (s, 3H),
2.66-2.58 (m, 1H), 2.54 (s, 2H), 2.41-2.12 (m, 9H). 0.41 (br s,
1H), 0.25 (br s, 1H), 0.18 (br s, 1H), -0.01 (br s, 1H). hLPA1
IC.sub.50 = 2400 nM Example 237 (1S,3S)-3-((5-(5-
((((cyclopropylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-
(trifluoromethyl)pyridin-2- yl)oxy)cyclohexane-1-carboxylic acid
238 ##STR00375## LCMS, [M + H].sup.+ = 526.0. .sup.1 NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.56 (s, 1H), 8.12 (s, 1H), 5.32 (br s, 1H),
5.15 (s, 1H), 5.11 (s, 1H), 3.91 (s, 3H), 3.0-2.85 m, 3H), 2.50 (s,
3H), 1.88-1.13 (m, 15H). hLPA1 IC.sub.50 = 174 nM (1S,3S)-3-((5-(5-
(((cyclopentyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)-3-(trifluoromethyl)pyridin-2- yl)oxy)cyclohexane-1-carboxylic
acid 239 ##STR00376## LCMS, [M + H].sup.+ = 512.5. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.34 (s, 1H), 5.55 (br s,
1H), 5.33 (s, 2H), 4.12 (s, 3H), 2.71 (s, 3H), 2.54 (s, 2H),
2.12-1.36 (m, 14H). hLPA1 IC.sub.50 = 440 nM (1S,3S)-3-((5-(5-
((((cyclobutylmethyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-
(trifluoromethyl)pyridin-2- yl)oxy)cyclohexane-1-carboxylic acid
240 ##STR00377## LCMS, [M + H].sup.+ = 526.0. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.79 (s, 1H), 8.36 (s, 1H), 5.57 (br s, 1H),
5.37 (br s, 2H), 4.14 (s, 3H), 2.64 (s, 3H), 2.59-2.52 (m, 2H),
2.15-1.32 (m, 16H). hLPA1 IC.sub.50 = 1207 nM (1S,3S)-3-((5-(5-
(((cyclobutyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-
yl)-3-(trifluoromethyl)pyridin-2- yl)oxy)cyclohexane-1-carboxylic
acid
EXAMPLE 241
(1S,3S)-3-((6-(5-(2-(((Cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-1-met-
hyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxyl-
ic acid
##STR00378##
[1029] 241A. Methyl
(1S,3S)-3-((6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-
-yl)oxy)cyclohexane-1-carboxylate
##STR00379##
[1031] To a stirred solution of methyl
(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-
pyridin-3-yl)oxy)cyclohexane-1-carboxylate (3.28 g, 9.10 mmol) in
CH.sub.2Cl.sub.2 (45.5 ml) were added NaHCO.sub.3 (3.82 g, 45.5
mmol) and Dess-Martin periodinane (4.63 g, 10.9 mmol) and the
reaction mixture was stirred at rt for 1 h. The white solid was
filtered off through Celite.RTM. and rinsed with EtOAc. The
combined filtrates were washed with sat. aq. NaHCO.sub.3, water,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product was chromatographed (120 g Redisep.RTM.
SiO.sub.2 column; isocratic 60% EtOAc in Hex) to afford the title
compound as a clear, colorless oil (3.10 g, 95%). LC-MS,
[M+H].sup.+=359.1. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 10.96
(s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 4.77-4.72
(m, 1H), 4.36 (s, 3H), 3.70 (s, 3H), 2.87-2.80 (m, 1H), 2.51 (s,
3H), 2.20-2.08 (m, 1H), 2.02-1.91 (m, 3H), 1.80-1.59 (m, 4H).
241B Methyl
(1S,3S)-3-((2-methyl-6-(1-methyl-5-vinyl-1H-1,2,3-triazol-4-yl)pyridin-3--
yl)oxy)cyclohexane-1-carboxylate
##STR00380##
[1033] To a cooled (0.degree. C.) suspension of
methyltriphenylphosphonium bromide (3.77 g, 10.55 mmol) in THF
(70.3 mL) was added KOtBu (0.947 g, 8.44 mmol), and the reaction
mixture was stirred at 0.degree. C. for 30 min. To this reaction
mixture was added a solution of Example 241A (2.52 g, 7.03 mmol) in
THF (10 mL). The reaction was stirred at 0.degree. C. for 30 min,
then was allowed to warm to rt. After 1 h at rt, the reaction was
quenched with sat. aq. NH.sub.4Cl, then was diluted with EtOAc. The
aqueous layer was extracted with EtOAc (2.times.25 mL). The
combined organic extracts were washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The crude product
was chromatographed (220 g Redisep.RTM. SiO.sub.2 column;
continuous gradient from 0-60% EtOAc in Hex) to afford the title
compound as a white gum (2.2 g, 88%). LC-MS, [M+H].sup.+=357.0.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.91 (d, J=8.5 Hz, 1H),
7.42 (dd, J=18.3, 12.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 5.93-5.88
(m, 1H), 5.70-5.66 (m, 1H), 4.71 (br s, 1H), 4.15 (s, 3H), 3.70 (s,
3H), 2.84 (tt, J=10.5, 3.9 Hz, 1H), 2.53 (s, 3H), 2.16 (br d,
J=13.8 Hz, 1H), 2.02-1.87 (m, 3H), 1.87-1.71 (m, 1H), 1.71-1.54 (m,
3H).
241C Methyl
(1S,3S)-3-((6-(5-(2-hydroxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methy-
lpyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00381##
[1035] To a cooled (0.degree. C.) solution of Example 241B (1.45 g,
4.07 mmol) in THF (13.6 ml) was added dropwise 9-BBN (17.9 mL of a
0.5M solution in THF; 8.95 mmol). The ice bath was then removed and
the reaction was warmed to 65.degree. C. After 4 h at 65.degree.
C., the reaction mixture was cooled to 0.degree. C. and a solution
of sodium perborate tetrahydrate (2.50 g, 16.3 mmol) in water (10
mL) was added. The reaction was then warmed to rt and stirred at rt
for 18 h; water was then added. The aqueous layer was extracted
with EtOAc (2.times.20 mL). The combined organic extracts were
washed with brine, dried (MgSO.sub.4) and concentrated in vacuo.
The crude product was chromatographed (120 g Redisep.RTM. SiO.sub.2
column; continuous gradient from 0-100% EtOAc in Hex) to afford the
title compound as a colorless oil (0.37 g, 24%). LC-MS,
[M+H].sup.+=375.1. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92
(d, J=8.6 Hz, 1H), 7.30-7.25 (m, 1H), 6.71-6.42 (m, 1H), 4.74-4.68
(m, 1H), 4.06-3.98 (m, 5H), 3.70 (s, 3H), 3.26 (td, J=5.6, 1.4 Hz,
2H), 2.83 (tt, J=10.3, 3.9 Hz, 1H), 2.51 (s, 3H), 2.14 (dt, J=13.9,
4.3 Hz, 1H), 2.02-1.87 (m, 3H), 1.82-1.56 (m, 4H).
241D. Methyl
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(2-(((4-nitrophenoxy)carbonyl)oxy)ethy-
l)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00382##
[1037] To a solution of Example 241C (370 mg, 0.988 mmol) and
4-nitrophenyl chloroformate (299 mg, 1.48 mmol) in THF (9.9 mL) was
added pyridine (0.24 mL, 2.96 mmol). The reaction mixture was
stirred at rt for 3 h, then was concentrated in vacuo. The crude
product was chromatographed (120 g Redisep.RTM. SiO.sub.2 column;
continuous gradient from 0-100% EtOAc in Hex) to afford the title
compound as a white solid (387 mg, 72.6%). LC-MS,
[M+H].sup.+=540.1. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.30
(d, J=9.4 Hz, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.34 (d, J=9.4 Hz, 2H),
7.24 (d, J=8.5 Hz, 1H), 4.75-4.69 (m, 3H), 4.14 (s, 3H), 3.72 (s,
3H), 3.66 (t, J=6.3 Hz, 2H), 2.89-2.83 (m, 1H), 2.50 (s, 3H), 2.17
(br d, J=14.0 Hz, 1H), 2.04-1.89 (m, 3H), 1.87-1.72 (m, 1H),
1.70-1.59 (m, 3H).
EXAMPLE 241
[1038] To a solution of Example 241D (11 mg, 0.020 mmol) and
iPr.sub.2NEt (7.1 .mu.l, 0.041 mmol) in THF (1 mL) was added
1-cyclobutyl-N-methylmethanamine (2.0 mg, 0.020 mmol). The reaction
was stirred at rt for 1 h. Water (0.5 mL) was added, followed by
aq. LiOH.H.sub.2O (0.05 mL of a 2N solution, 0.10 mmol). The
reaction was stirred at rt for 18 h, then was acidified with 1N aq.
HCl to pH .about.4 and extracted with EtOAc (3.times.5 mL). The
combined organic extracts were washed with brine, dried
(MgSO.sub.4) and concentrated in vacuo. The crude material was
purified by preparative HPLC (Column: XBridge C18, 19.times.200 mm,
5-.mu.m particles; Mobile Phase A: 5:95 MeCN:water with 10 mM
NH.sub.4OAc; Mobile Phase B: 95:5 MeCN:water with 10 mM
NH.sub.4OAc; continuous gradient: 15-55% B over 25 min, then a
4-min hold at 100% B; Flow: 20 mL/min). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford the title compound (5.7 mg, 58.7%). LC-MS,
[M+H].sup.+=486.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84
(br s, 1H), 7.48 (br d, J=8.5 Hz, 1H), 4.76 (br s, 1H), 4.30 (br s,
2H), 4.02 (s, 3H), 3.53 (br s, 2H), 3.21-3.11 (m, 1H), 3.03-2.93
(m, 1H), 2.71 (br s, 3H), 2.63-2.56 (m, 1H), 2.42 (s, 3H),
2.33-2.24 (m, 1H), 2.02-1.37 (m, 14H). hLPA1 IC.sub.50=41 nM.
[1039] The following examples were prepared according to the
synthetic scheme described for Example 241.
TABLE-US-00006 Analytical & Biology Example Structure &
Name Data Method 242 ##STR00383## LC-MS, [M + H].sup.+ = 460.2
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83 (d, J = 8.5 Hz,
1H), 7.47 (d, J = 8.5 Hz, 1H), 4.78 (br s, 1H), 4.30 (br s, 2H),
4.03 (s, 3H), 3.56-3.46 (m, 2H), 3.11-2.85 (m, 2H), 2.76-2.61 (m,
4H), 2.43 (s, 3H), 2.06-1.99 (m, 1H), 1.92-1.74 (m, 3H), 1.69-1.20
(m, 6H), 0.86- 0.57 (m, 3H). hLPA1 IC.sub.50 = 319 nM Example 241
(1S,3S)-3-((2-Methyl-6-(1-methyl-5-
(2-((methyl(propyl)carbamoyl)oxy)-
ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid, TFA salt 243 ##STR00384##
LC-MS, [M + H].sup.+ = 486.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.83 (d, J = 8.5 Hz, 1H), 7.46 (br d, J = 8.7 Hz, 1H), 4.73
(br s, 1H), 4.32 (br t, J = 6.1 Hz, 2H), 4.23- 4.11 (m, 1H), 4.01
(s, 3H), 3.53 (br t, J = 6.0 Hz, 2H), 2.60-2.55 (m, 4H), 2.42 (s,
3H), 1.99-1.22 (m, 16H). hLPA1 IC.sub.50 = 72 nM. Example 241
(1S,3S)-3-((6-(5-(2-((Cyclopentyl- (methyl)carbamoyl)oxy)ethyl)-1-
methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 244
##STR00385## LC-MS, [M + H].sup.+ = 508.0 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.82 (br d, J = 8.2 Hz, 1H), 7.48 (br d, J =
4.9 Hz, 1H), 7.36- 7.24 (m, 3H), 7.15 (br d, J = 5.2 Hz, 1H), 7.04
(br s, 1H), 4.74 (br s, 1H), 4.43- 4.30 (m, 3H), 4.17 (br s, 1H),
4.05-3.92 (m, 3H), 3.56-3.49 (m, 2H), 2.71 (s, 3H), 2.60-2.54 (m,
1H), 2.44-2.36 (m, 3H), 1.98-1.48 (m, 8H). hLPA1 IC.sub.50 = 54 nM.
Example 241 (1S,3S)-3-((6-(5-(2-((Benzyl)methyl)-
carbamoyl)oxy)ethyl)-1-methyl-1H-
1,2,3-triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 245 ##STR00386## LC-MS, [M +
H].sup.+ = 474.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.83
(br d, J = 8.5 Hz, 1H), 7.46 (br d, J = 8.6 Hz, 1H), 4.75 (br s,
1H), 4.31 (br s, 2H), 4.02 (s, 3H), 3.56- 3.47 (m, 2H), 2.93-2.55
(m, 7H), 2.43 (s, 3H), 2.04-1.48 (m, 8H), 0.71 (br d, J = 10.8 Hz,
6H). hLPA1 IC.sub.50 = 69 nM. Example 241
(1S,3S)-3-((6-(5-(2-((Isobutyl- (methyl)carbamoyl)oxy)ethyl)-1-
methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 246
##STR00387## LC-MS, [M + H].sup.+ = 458.3 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.84 (br s, 1H), 7.45 (br d, J = 8.6 Hz, 1H),
4.75 (br s, 1H), 4.31 (t, J = 6.1 Hz, 2H), 4.03 (s, 3H), 3.51 (br
t, J = 6.0 Hz, 2H), 3.21- 2.62 (m, 5H), 2.42 (br s, 3H), 2.08-1.95
(m, 1H), 1.91-1.74 (m, 3H), 1.72- 1.50 (m, 8H). hLPA1 IC.sub.50 =
210 nM. Example 241 (1S,3S)-3-((2-Methyl-6-(1-methyl-5-
(2-((pyrrolidine-1-carbonyl)oxy)-
ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid, TFA salt 247 ##STR00388##
LC-MS, [M + H].sup.+ = 472.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.83 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 4.75
(br s, 1H), 4.31 (br t, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.52 (br t,
J = 5.7 Hz, 2H), 3.24- 3.15 (m, 1H), 2.68- 2.56 (m, 4H), 2.43 (s,
3H), 2.08-1.38 (m, 14H). hLPA1 IC.sub.50 = 41 nM. Example 241
(1S,3S)-3-((6-(5-(2- ((Cyclobutyl)methyl)carbamoyl)oxy)
ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
2-methylpyridin-3-yl)oxy)cyclo- hexane-1-carboxylic acid, TFA salt
248 ##STR00389## LC-MS, [M + H].sup.+ = 472.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.49 (br s, 1H), 7.01 (br s, 1H), 4.75 (br s,
1H), 4.29 (br s, 2H), 4.02 (s, 3H), 3.54- 3.24 (m, 2H), 3.00-2.94
(m, 2H), 2.71-2.63 (m, 2H), 2.35 (br s, 3H), 2.09- 1.45 (m, 14H).
hLPA1 IC.sub.50 = 144 nM. Example 241
(1S,3S)-3-((6-(5-(2-(((Cyclobutyl- methyl)carbamoyl)oxy)ethyl)-1-
methyl-1H-1,2,3-triazol-4-yl)-2-
methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid, TFA salt
EXAMPLE 249
(1S,3S)-3-((6-(5-(3-((Benzyl(methyl)carbamoyl)oxy)propyl)-1-methyl-1H-1,2,-
3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00390##
[1040] 249A (2-(Benzyloxy)ethyl)triphenylphosphonium bromide
##STR00391##
[1042] Benzyl 2-bromoethyl ether (0.78 mL, 4.96 mmol) was added to
a solution of Ph.sub.3P (1 g, 3.81 mmol) in toluene (7.63 mL) and
the reaction was stirred at 105.degree. C. for 18 h, then was
cooled to rt. Diethyl ether (50 mL) was added, and the mixture was
stirred for 15 min at rt; the precipitated product was collected by
filtration, rinsed with ether and air-dried to afford the title
product (1.46 g, 80%) as a white solid. LC-MS, [M].sup.+=397.1.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.87-7.73 (m, 9H), 7.63
(td, J=7.8, 3.3 Hz, 6H), 7.27-7.19 (m, 3H), 6.92 (d, J=6.6 Hz, 2H),
4.36 (dt, J=11.7, 5.7 Hz, 2H), 4.27 (s, 2H), 4.11-4.01 (m, 2H).
249B. Methyl
(1S,3S)-3-((6-(5-(3-(benzyloxy)prop-1-en-1-yl)-1-methyl-1H-1,2,3-triazol--
4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00392##
[1044] In a sealed tube was placed Example 249A (0.116 g, 0.243
mmol), Example 241A (0.058 g, 0.162 mmol), K.sub.2CO.sub.3 (0.067
g, 0.485 mmol), and THF (1.6 mL). The reaction was stirred at
115.degree. C. for 2 h, then was cooled to rt. The mixture was
diluted with EtOAc, washed with brine, dried (MgSO.sub.4), and
concentrated in vacuo. The crude product was chromatographed (12 g
Redisep.RTM. SiO.sub.2 column, eluting with 0-100% EtOAc in Hex) to
afford the title compound as a yellow solid (35 mg, 45%) as a
mixture of cisltrans isomers.
249C Methyl
(1S,3S)-3-((6-(5-(3-(benzyloxy)propyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2--
methyl pyridine-3-yl)oxy)cyclohexane-1-carboxylate
##STR00393##
[1046] To a solution of Example 249B (35 mg, 0.073 mmol) in MeOH
(20 mL) under Ar was added 20% Pd(OH).sub.2 on carbon (10.31 mg,
0.015 mmol) and ammonium formate (93 mg, 1.47 mmol). The reaction
mixture was stirred in a sealed tube at 65.degree. C. for 18 h,
then was cooled to rt. The reaction was filtered through a pad of
Celite.RTM., rinsed with MeOH, and the filtrate was concentrated in
vacuo. The crude material was purified by preparative HPLC using
the following conditions: Column: Sunfire Prep C18 OBD Sum
30.times.100 mm; Mobile Phase A: 10:90 MeCN:water with 0.1% TFA;
Mobile Phase B: 90:10 MeCN:water with 0.1% TFA; Gradient: 20-100% B
over 12 min; Flow: 40 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford the title compound (40 mg, 92%) as a yellow solid. LC-MS,
[M+H].sup.+=479.3.
249D. Methyl
(1S,3S)-3-((6-(5-(3-hydroxypropyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-meth-
yl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00394##
[1048] To a solution of Example 249C (40 mg, 0.067 mmol) in EtOH (2
mL) and AcOH (1 mL) was added 10% Pd/C (7.2 mg, 6.8 .mu.mol), and
H.sub.2 gas was bubbled through the reaction mixture for a few
minutes; the reaction was then stirred under H.sub.2-balloon for 72
h. The reaction mixture was filtered through a pad of Celite.RTM.,
rinsed with MeOH, and the combined filtrate/rinses were
concentrated in vacuo. The crude material was purified by
preparative HPLC using the following conditions: Column: Sunfire
Prep C18 OBD 5u 30.times.100 mm; Mobile Phase A: 10:90 MeCN:water
with 0.1% TFA; Mobile Phase B: 90:10 MeCN:water with 0.1% TFA;
Gradient: 20-100% B over 12 min; Flow: 40 mL/min. Fractions
containing the desired product were combined and dried via
centrifugal evaporation to afford the title compound 246D (23 mg,
68%) as a colorless solid. LC-MS, [M+H].sup.+=389.2. .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 8.10-7.98 (m, 2H), 5.02-4.96 (m, 1H),
4.15 (s, 3H), 3.71 (s, 3H), 3.62 (br t, J=5.6 Hz, 2H), 3.18 (br t,
J=7.2 Hz, 2H), 2.91-2.83 (m, 1H), 2.71 (s, 3H), 2.20-2.10 (m, 1H),
2.07-1.90 (m, 5H), 1.85-1.65 (m, 4H).
249E Methyl
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(3-(((4-nitrophenoxy)carbonyl)oxy)prop-
yl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
##STR00395##
[1050] To a solution of Example 249D (21 mg, 0.042 mmol) and
4-nitrophenyl chloroformate (12.6 mg, 0.063 mmol) in THF (1 mL) was
added pyridine (10 .mu.l, 0.13 mmol). The reaction was stirred at
rt for 18 h, then was concentrated in vacuo. The crude product was
chromatographed (4 g Redisep.RTM. SiO.sub.2 column, eluting with
0-100% EtOAc in Hex) to afford the title compound (10 mg, 43%) as a
white solid. LC-MS, [M+H].sup.+=554.2.
EXAMPLE 249
[1051] To a solution of Example 249E (10 mg, 0.018 mmol) and DIEA
(6.31 .mu.l, 0.036 mmol) in THF (1 mL) was added
N-methyl-1-phenylmethanamine (2.2 mg, 0.018 mmol). After 1 h, water
(0.5 mL) was added, followed by aq. LiOH (0.070 mL of a 2M
solution, 0.139 mmol). The reaction mixture was stirred at rt for
18 h, after which the pH was adjusted with 1N aq. HCl to .about.4
and the mixture was extracted with EtOAc (3.times.). The combined
organic extracts were washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. The crude material was purified by
preparative HPLC using the following conditions: Column: Sunfire
Prep C18 OBD 5u 30.times.100 mm; Mobile Phase A: 10:90 MeCN:water
with 0.1% TFA; Mobile Phase B: 90:10 MeCN:water with 0.1% TFA;
Gradient: 20-100% B over 12 min; Flow: 40 mL/min. Fractions
containing the desired product were combined and dried via
centrifugal evaporation, then re-purified by preparative HPLC using
the following conditions: Column: Sunfire Prep C18 OBD 5u
30.times.100 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA;
Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Gradient: 20-100% B
over 12 min; Flow: 40 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford the title compound (2.1 mg, 18%) as a white solid. LC-MS,
[M+H].sup.+=522.3. .sup.1H NMR (400 MHz, 60.degree. C., CD.sub.3OD)
.delta. 7.65 (br d, J=8.4 Hz, 1H), 7.32 (br d, J=8.8 Hz, 1H),
7.23-7.05 (m, 5H), 4.69-4.61 (m, 1H), 4.30 (s, 2H), 4.09 (t, J=5.6
Hz, 2H), 3.90 (br s, 3H), 3.16-3.08 (m, 2H), 2.75-2.63 (m, 4H),
2.39 (s, 3H), 2.04-1.89 (m, 3H), 1.89-1.75 (m, 3H), 1.72-1.49 (m,
4H). hLPA1 IC.sub.50=122 nM.
Synthesis of Amine Intermediate for the Preparation of Example
250
Intermediate 5. N-methyl-2-propoxyethan-1-amine
##STR00396##
[1052] Intermediate 5A.
N-benzyl-N-methyl-2-propoxyethan-1-amine
##STR00397##
[1054] To a solution of 2-(benzyl(methyl)amino)ethan-1-ol (1 mL,
6.15 mmol) in dry DMF (5 mL) was added 60% NaH in mineral oil
(0.369 g, 9.23 mmol) at 0.degree. C. After 1 h, 1-chloropropane
(0.813 mL, 9.23 mmol) was added. The reaction mixture was stirred
overnight at rt, then was quenched with ice water and extracted
with EtOAc. The organic phase was washed with water and brine,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude oily
product was chromatographed (24 g SiO.sub.2; elution with
EtOAc/Hexane (continuous gradient from 0% to 100% over 10 min)) to
give the free amine as an oil. This oil was treated with 2.0 M HCl
in ether to give N-benzyl-N-methyl-2-propoxyethan-1-amine HCl salt
(1.2 g, 4.92 mmol, 80% yield) as a clear oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.67-7.61 (m, 2H), 7.47-7.43 (m, 3H), 4.34-4.20
(m, 2H), 4.04-3.93 (m, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.34-3.27 (m,
1H), 3.14-3.06 (m, 1H), 2.74 (d, J=5.1 Hz, 3H), 1.65-1.59 (m, 2H),
0.93 (t, J=7.4 Hz, 3H)
Intermediate 5
[1055] A mixture of Intermediate 5A (1.2 g, 4.92 mmol) and 20%
Pd(OH)2-C (0.346 g, 2.461 mmol) in EtOH (5 mL) was stirred at
60.degree. C. under 1 atmosphere H.sub.2 for 2 h, then was filtered
and concentrated in vacuo to provide the title intermediate as the
HCl salt (0.72 g, 4.69 mmol, 95% yield) as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 9.41 (br s, 2H), 3.81 (t, J=4.8
Hz, 2H), 3.44 (t, J=6.6 Hz, 2H), 3.24-3.11 (m, 2H), 2.77 (br t,
J=5.0 Hz, 3H), 1.60 (sxt, J=7.1 Hz, 2H), 0.90 (t, J=7.4 Hz,
3H).
Synthesis of Amine Intermediate 6 for Examples 254 & 255
Intermediate 6. 2-fluoro-N-methylbutan-1-amine
##STR00398##
[1056] Intermediate 6A. 1-(benzyl(methyl)amino)butan-2-ol
##STR00399##
[1058] A solution of N-methyl-1-phenylmethanamine (6.09 mL, 46.4
mmol) and 1,2-epoxybutane (1.0 mL, 11.6 mmol) in EtOH (50 mL) was
stirred under reflux for 8 h, then was cooled to rt and
concentrated in vacuo. The crude residue was chromatographed (80 g
SiO.sub.2; elution with MeOH/DCM (continuous gradient from 0% to
10% over 20 min) to give the title compound (500 mg, 2.59 mmol,
22.3% yield) as a clear oil. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.35-7.24 (m, 5H), 3.72-3.41 (m, 4H), 2.42-2.32 (m, 2H),
2.23 (s, 3H), 1.50-1.36 (m, 2H), 0.97 (t, J=7.6 Hz, 3H);
[M+H].sup.+=194.3
Intermediate 6B. N-benzyl-2-fluoro-N-methylbutan-1-amine
##STR00400##
[1060] DAST (0.697 mL in THF, 5.28 mmol) was added to a solution of
Intermediate 6A (0.51 g, 2.64 mmol) in DCM (3 mL) at -78.degree. C.
and the reaction was stirred for 5 h at -78.degree. C. and for 18 h
at rt. Volatiles were concentrated in vacuo and the residue was
carefully quenched with water (2 mL). The aqueous solution
containing product was purified by prepHPLC (Sunfire C18
30.times.100 mm-regenerated column; detection at 220 nm; flow
rate=40 mL/min; continuous gradient from 0% B to 100% B over 10
min+2 min hold time at 100% B, where A=90:10:0.1 H.sub.2O:MeCN:TFA
and B=90:10:0.1 MeCN:H.sub.2O:TFA) and appropriate fractions were
concentrated to obtain an oil. The residue was treated with 2.0 M
HCl in ether (3.61 mL, 7.22 mmol) to give the HCl salt of the title
compound (0.22 g, 1.127 mmol, 42.7% yield) as a clear oil. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.54 (s, 5H), 5.12-4.91 (m, 1H),
4.68-4.22 (m, 2H), 3.56-3.41 (m, 2H), 3.01-2.83 (m, 3H), 1.84-1.60
(m, 2H), 1.06 (q, J=7.7 Hz, 3H); .sup.19F NMR (471 MHz,
METHANOL-d.sub.4) .delta. -186.78 (s), -188.25(s);
[M+H].sup.+=196.3
Intermediate 6
[1061] A mixture of Intermediate 6B (0.22 g, 0.95 mmol) and 20%
Pd(OH)2-C (0.067 g, 0.475 mmol) in EtOH (5 mL) was stirred at
60.degree. C. under 1 atmosphere of H.sub.2 for 2 h. The mixture
was filtered and concentrated in vacuo to provide the title
compound as the HCl salt (0.099 g, 9.41 mmol, 99% yield) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.06-9.40 (m,
2H), 5.34-4.94 (m, 1H), 3.38-3.02 (m, 2H), 2.81 (br s, 3H), 1.75
(br d, J=1.5 Hz, 2H), 1.04 (br t, J=6.2 Hz, 3H); .sup.19F NMR (377
MHz, CDCl.sub.3) .delta.: -185.22 (br s, F).
Intermediate 7. 4-fluoro-N-methylpentan-1-amine (for the synthesis
of Example 256)
##STR00401##
[1062] 7A. N-benzyl-4-hydroxy-N-methylpentanamide
##STR00402##
[1064] N-methyl-1-phenylmethanamine (5.78 mL, 44.9 mmol) was added
to a mixture of 5-methyl dihydrofuran-2(3H)-one (1.426 mL, 14.98
mmol) and toluene (20 mL), and NaOMe solution (sodium (1.033 g,
44.9 mmol) added to MeOH (15 mL)) was added dropwise at 20 to
30.degree. C., followed by stirring for 18 h at rt. The reaction
was quenched by addition of ice water (20 mL) and HOAc (3.43 mL, 60
mmol) was added dropwise. The aqueous layer was extracted with
EtOAc (2.times.20 mL). The combined organic extracts were washed
with water and concentrated in vacuo. The crude oily product was
chromatographed (40 g SiO.sub.2; elution with EtOAc/Hexane
(continuous gradient from 0% to 100% over 10 min)) to give the
title compound (1.5 g, 6.78 mmol, 45.2% yield) as a clear oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.13 (m, 5H),
4.63-4.53 (m, 2H), 3.85 (dddd, J=14.0, 8.0, 6.2, 4.2 Hz, 1H), 3.02
(dd, 4.5 Hz, 1H), 2.98-2.91 (m, 3H), 2.66-2.45 (m, 2H), 1.97-1.70
(m, 2H), 1.21 (dd, J=17.6, 6.4 Hz, 3H)); [M+H].sup.+=222.2.
7B. 5-(benzyl(methyl)amino)pentan-2-ol
##STR00403##
[1066] Intermediate 7A (1.5 g, 6.78 mmol) was added to a suspension
of LAH (4.07 mL of a 2.0 M solution in THF; 8.13 mmol) in THF (50
mL). The mixture was heated at reflux for 18 h, then was cooled to
0.degree. C. Brine (.about.1 mL) was carefully added until no more
gas was generated. The solids were filtered off, and the filtrate
was concentrated in vacuo. The crude residue was chromatographed
(12 g SiO.sub.2; elution with MeOH/DCM (continuous gradient from 0%
to 10% over 20 min) to give the title compound (1.35 g, 6.51 mmol,
96% yield) as a clear oil. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.40-7.25 (m, 5H), 3.84-3.73 (m, 1H), 3.56 (q, J=12.7 Hz,
2H), 2.59-2.51 (m, 1H), 2.49-2.39 (m, 1H), 2.18 (s, 3H), 1.82-1.67
(m, 3H), 1.50-1.40 (m, 1H), 1.22 (d, J=6.3 Hz, 3H);
[M+H].sup.+=208.3.
7C. N-benzyl-4-fluoro-N-methylpentan-1-amine
##STR00404##
[1068] DAST (1.03 mL in THF, 7.81 mmol) was added to a solution of
Intermediate 7B (0.81 g, 3.91 mmol) in DCM (3 mL) at -78.degree. C.
and the reaction was stirred for 5 h at -78.degree. C. and for 18 h
at rt. The reaction was concentrated in vacuo and carefully
quenched with water (2 mL). The aqueous solution was purified by
preparative HPLC (Sunfire C18 30.times.100 mm-regenerated column;
detection at 220 nm; flow rate=40 mL/min; continuous gradient from
0% B to 100% B over 10 min+2 min hold time at 100% B, where
A=90:10:0.1 H.sub.2O:MeCN:TFA and B=90:10:0.1 MeCN:H.sub.2O:TFA)
and appropriate fractions were concentrated to give an oil. The
residue was treated with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to
give the title compound as the HCl salt (0.12 g, 0.488 mmol, 12.50%
yield) as a clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
12.21 (br s, 1H), 7.62 (br s, 2H), 7.50-7.41 (m, 3H), 4.80-4.55 (m,
1H), 4.32-4.15 (m, 2H), 3.23-2.83 (m, 2H), 2.81-2.64 (m, 3H),
2.21-1.94 (m, 2H), 1.78-1.55 (m, 2H), 1.40-1.27 (m, 3H); .sup.19F
NMR (377 MHz, CDCl.sub.3) .delta. -173.65 (d, J=38.9 Hz, F);
[M+H].sup.+=210.2
Intermediate 7
[1069] A mixture of Intermediate 7C (0.12 g, 0.488 mmol) and 20%
Pd(OH)2-C (0.034 g, 0.24 mmol) in EtOH (5 mL) was stirred at
60.degree. C. under 1 atmosphere H.sub.2 for 2 h. The reaction was
filtered and concentrated in vacuo to provide the title compound as
the HCl salt (0.05 g, 0.321 mmol, 65.8% yield) as a white solid.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.51 (br s, 2H),
4.83-4.62 (m, 1H), 3.01 (br s, 2H), 2.70 (br s, 3H), 2.13-1.94 (m,
2H), 1.81-1.65 (m, 2H), 1.41-1.29 (m, 3H); .sup.19F NMR (471 MHz;
CDCl.sub.3) .delta. -173.53 (s, 1F).
TABLE-US-00007 Example Structure & Name Analytical &
Biology Data Method 250 ##STR00405## LCMS; [M + H].sup.+ = 490.3;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.85 (br s, 1H), 7.47
(d, J = 8.6 Hz, 1H), 5.66 (br s, 2H), 4.77 (br s, 1H), 4.10 (s,
3H), 2.83 (br s, 3H), 2.71-2.61 (m, 1H), 2.43 (s, 3H), 2.08- 1.98
(m, 1H), 1.91-1.76 (m, 3H), 1.72-1.34 (m, 6H), 0.79 (br s, 3H), 6
protons are in water suppression area LPA1 IC.sub.50 = 314 nM
Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(2-
propoxyethyl)carbamoyl)oxy)methyl)-
1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic
acid 251 ##STR00406## LCMS; [M + H].sup.+ = 458.1; .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.64 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 8.8
Hz, 1H), 7.89-7.79 (m, 1H), 5.54 (s, 2H), 4.84 (br s, 1H), 4.23 (br
s, 3H), 3.23- 3.15 (m, 1H), 3.14-2.98 (m, 1H), 2.94 (br s, 4H),
2.19-2.01 (m, 2H), 1.98- 1.75 (m, 5H), 1.73-1.61 (m, 1H), 1.03 (br
s, 3H), 0.70-0.51 (m, 2H), 0.42- 0.22 (m, 2H) LPA1 IC.sub.50 = 27
nM Example 3 (1S,3S)-3-((6-(1-methyl-5- (((methyl(((1R,2R)-2-
methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 252 ##STR00407##
LCMS; [M + H].sup.+ = 458.1; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.64 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.82
(br d, J = 8.0 Hz, 1H), 5.54 (s, 2H), 4.84 (br s, 1H), 4.23 (br s,
3H), 3.24- 3.14 (m, 1H), 3.14-2.97 (m, 1H), 2.93 (br s, 4H),
2.19-2.00 (m, 2H), 1.98- 1.61 (m, 6H), 1.02 (br s, 3H), 0.69-0.50
(m, 2H), 0.42-0.20 (m, 2H) LPA1 IC.sub.50 = 29 nM Example 3
(1S,3S)-3-((6-(1-methyl-5- (((methyl(((1S,2S)-2-
methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 253 ##STR00408##
LCMS; [M + H].sup.+ = 478.1; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.84 (br d, J = 8.5 Hz, 1H), 7.47 (br d, J = 8.6 Hz, 1H),
5.67 (br s, 4H), 4.77 (br s, 2H), 4.10 (s, 4H), 2.86 (br s, 2H),
2.65 (br t, J = 10.1 Hz, 1H), 2.42 (s, 3H), 2.08-1.99 (m, 1H),
1.91-1.75 (m, 3H), 1.73-1.44 (m, 4H), 1.37-0.97 (m, 6H) 3 protons
are in water suppression area LPA1 IC.sub.50 = 134 nM Example 1
(1S,3S)-3-((6-(5-((((2-fluoro-2- methylpropyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy) cyclohexane-1-carboxylic acid 254 ##STR00409## LCMS; [M +
H].sup.+ = 479.1; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.59
(s, 1H), 5.71-5.48 (m, 2H), 5.39 (br s, 1H), 4.73-4.21 (m, 1H),
4.11 (s, 3H), 3.57- 3.19 (m, 2H), 2.90-2.74 (m, 3H), 2.64 (br t, J
= 11.1 Hz, 1H), 2.45 (s, 3H), 2.19- 2.04 (m, 1H), 1.96-1.72 (m,
3H), 1.70-1.24 (m, 6H), 0.97-0.60 (m, 3H); .sup.19F NMR (471 MHz,
DMSO-d.sub.6) .delta. -73.42 (br s, TFA), -185.33 (br d, J = 97.1
Hz, F) LPA1 IC.sub.50 = 132 nM (1S,3S)-3-((5-(5-((((2-
fluorobutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-3-methylpyrazin-2-
yl)oxy)cyclohexane-1-carboxylic acid; mixture of diastereomers 255
##STR00410## LCMS; [M + H].sup.+ = 478.2; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85 (br s, 1H), 7.47 (br d, J = 8.2 Hz, 1H),
5.76-5.51 (m, 2H), 4.77 (br s, 1H), 4.69-4.20 (m, 1H), 4.09 (s,
3H), 3.60- 3.20 (m, 2H), 2.94-2.73 (m, 3H), 2.62 (br s, 1H), 2.40
(br s, 3H), 2.07-1.19 (m, 10H), 0.98-0.55 (m, 3H); .sup.19F NMR
(471 MHz, DMSO-d.sub.6) .delta. -73.54 (s, TFA), -185.49 (s) LPA1
IC.sub.50 = 57 nM Example 1 (1S,3S)-3-((6-(5-((((2-
fluorobutyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid; mixture of diastereomers 256
##STR00411## LCMS; [M + H].sup.+ = 492.3; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.83 (br d, J = 8.5 Hz, 1H), 7.45 (br d, J =
8.5 Hz, 1H), 5.62 (br d, J = 13.7 Hz, 2H), 4.85-4.29 (m, 2H), 4.08
(s, 3H), 3.25- 3.03 (m, 2H), 2.83-2.68 (m, 3H), 2.62 (br t, J =
10.2 Hz, 1H), 2.40 (s, 3H), 1.99 (br d, J = 13.7 Hz, 1H), 1.90-
0.97 (m, 11H), 0.84 (br t, J = 7.2 Hz, 3H); .sup.19F NMR (471 MHz,
DMSO-d.sub.6) .delta. -73.75 (s, TFA), -170.59 (br d, J = 65.9 Hz,
F) LPA1 IC.sub.50 = 17 nM Example 1 (1S,3S)-3-((6-(5-((((4-
fluoropentyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid
EXAMPLE 257
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)-
methyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclo-
hexane-1-carboxylic acid
##STR00412##
[1070] 257A. (E)-N-benzylbut-2-enamide
##STR00413##
[1072] EDC (36.7 g, 192 mmol) was added portionwise to a solution
of crotonic acid (15.0 g, 174 mmol), benzyl amine (21.0 mL, 192
mmol) and DIPEA (33.5 mL, 192 mmol) in DCM (300 mL). The reaction
mixture was stirred overnight and then poured onto 10% aq.
KHSO.sub.4 (250 mL) and extracted with EtOAc (100 mL). The organic
layer was washed once again with 10% aq. KHSO.sub.4 followed by
brine (150 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo
to give the title compound as a white solid (25 g, 143 mmol, 82%
yield). [M+H].sup.+=176.2; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.40-7.20 (m, 5H), 6.98-6.82 (m, 1H), 5.84 (br dd, J=15.1,
1.7 Hz, 2H), 4.52 (d, J=5.8 Hz, 2H), 1.87 (dd, J=6.9, 1.7 Hz,
3H)
257B. N-benzyl-2-methylcyclopropanecarboxamide
##STR00414##
[1074] In an Erlenmeyer flask containing Et.sub.2O (50 mL) and aq.
40% KOH (5 mL) was added N-methyl-N'-nitro-N-nitrosoguanidine (504
mg, 3.42 mmol) portionwise (with vigorous stirring) over 15 min at
0.degree. C. Upon complete addition, stirring was stopped and the
aqueous layer was separated. The ether layer was dried with KOH
pellets and allowed to stand for 5 min, then decanted into a third
flask with KOH pellets and then poured onto a THF solution (2 mL)
containing Example 257A (300 mg, 1.712 mmol). Pd(OAc).sub.2 (3.84
mg, 0.017 mmol) was subsequently added and the reaction allowed to
warm to rt and stirred for 1 h at rt. The reaction was concentrated
in vacuo, and the crude oil was chromatographed (12 g SiO.sub.2;
elution with EtOAc/Hexane (continuous gradient from 0% to 50% over
20 min) to give the title compound (310 mg, 1.61 mmol, 94% yield)
as a white solid. [M+H].sup.+=190.2; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.37-7.26 (m, 5H), 5.82 (br s, 1H), 4.44 (dd,
J=5.6, 2.3 Hz, 2H), 1.46-1.32 (m, 1H), 1.22-1.15 (m, 1H), 1.12-1.03
(m, 4H), 0.57 (ddd, J=7.9, 6.2, 3.7 Hz, 1H)
257C (1R,2R)--N-benzyl-2-methylcyclopropane-1-carboxamide and 257D
(1S,2S)--N-benzyl-2-methylcyclopropane-1-carboxamide
##STR00415##
[1076] Example 257B (2.0 g, 10.6 mmol) was separated by chiral
preparative HPLC (Instrument: Berger MG II (CTR-L409-PSFCl),
Column: Chiralpak ID, 21.times.250 mm, 5 micron, Mobile Phase: 15%
IPA/85% CO2, Flow Conditions: 45 mL/min, 150 Bar, 40.degree. C.,
Detector Wavelength: 220 nm, Injection Details: 0.25 mL of an
.about.200 mg/mL in IPA) to give Example 257C (0.9 g, 4.76 mmol,
45.0% yield, 99.0% ee) and Example 257D (0.9 g, 4.76 mmol, 45.0%
yield, 99.0% ee) as white solids. The absolute stereochemistry of
these two isomers was previously determined in the literature
reference Bioorg. Med. Chem. Lett. 2007, 17, 1788.
257E. N-benzyl-1-((1R,2R)-2-methylcyclopropyl)methanamine
##STR00416##
[1078] To a solution of Example 257C (0.90 g, 4.76 mmol) in THF (50
mL) was added BH3.THF (23.8 mL of a 1M solution in THF, 23.8 mmol)
dropwise. Upon completion of the addition (10 min), the mixture was
heated at reflux for 5 h, then cooled to rt and quenched via
successive addition of MeOH (2 mL) and 1N aq. HCl dropwise (10 mL).
The resulting solution was stirred at 50.degree. C. for 1 h and
then partitioned between water and Et.sub.2O (50 mL each). The
aqueous layer was neutralized with 7N aq. KOH and extracted with
DCM (3.times.10 mL). The organic layers were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The oily product was
diluted with EtOAc and treated with HCl gas. The resulting solids
were filtered, washed with hexane and dried to give the title
compound (HCl salt; 0.9 g, 4.25 mmol, 89% yield) as a white
solid.
[1079] [M+H].sup.+=176.2; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.56-7.43 (m, 5H), 4.21 (s, 2H), 3.02-2.90 (m, 2H), 1.12 (d, J=5.5
Hz, 3H), 0.93-0.73 (m, 2H), 0.59 (dt, 5.0 Hz, 1H), 0.50 (dt, J=7.8,
5.3 Hz, 1H)
257F.
N-benzyl-N-methyl-1-((1R,2R)-2-methylcyclopropyl)methanamine
##STR00417##
[1081] A solution of Example 257E (0.90 g, 5.13 mmol), 36% aq.
formaldehyde solution (1.97 mL, 25.7 mmol), and HOAc (3 mL, 52.4
mmol) in MeOH (10 mL) was stirred at rt for 5 min. NaBH(OAc).sub.3
(2.177 g, 10.27 mmol) was then added. The reaction mixture was
stirred at rt for 20 min and then concentrated in vacuo and the
residue was partitioned between DCM (20 mL) and 1N NaOH (50 mL).
The organic layer was dried (MgSO.sub.4) and concentrated in vacuo.
The residue was treated with 2.0 M HCl in ether (3 mL, 6.0 mmol) to
give the title compound (HCl salt; 0.97 g, 4.30 mmol, 84% yield) as
a white solid. [M+H].sup.+=176.2; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.55-7.51 (m, 5H), 4.49 (dd, J=13.0, 7.3 Hz, 1H), 4.24 (br
d, J=13.2 Hz, 1H), 3.22-3.14 (m, 1H), 3.02 (dt, J=13.3, 7.8 Hz,
1H), 2.85 (d, J=5.9 Hz, 3H), 1.15 (d, J=5.7 Hz, 3H), 0.94-0.79 (m,
2H), 0.66-0.53 (m, 2H)
257G. N-methyl-1-((1R,2R)-2-methylcyclopropyl)methanamine
##STR00418##
[1083] A mixture of Example 257F HCl salt (0.97 g, 4.30 mmol) and
20% Pd(OH).sub.2--C (0.1 g, 0.712 mmol) in EtOH (40 mL) was stirred
at 60.degree. C. under 1 atmosphere of H.sub.2 for 2 h. The
reaction was filtered and concentrated in vacuo to provide the
title compound (HCl salt, 0.54 g, 3.98 mmol, 93% yield) as a white
solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 2.91 (d, J=7.3 Hz,
2H), 2.71 (s, 3H), 1.12 (d, J=5.9 Hz, 3H), 0.92-0.75 (m, 2H), 0.59
(dt, J=8.4, 4.9 Hz, 1H), 0.48 (dt, J=8.0, 5.1 Hz, 1H)
EXAMPLE 257
[1084] To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1
mL) was added Example 257G HCl salt (7.4 mg, 0.054 mmol) and DIPEA
(0.028 mL, 0.163 mmol). The reaction mixture was stirred at rt for
2 h and then concentrated in vacuo. The residue was stirred with
1.0 M aq. NaOH (0.54 mL, 0.54 mmol) in THF (1 mL)/MeOH (0.2 mL) at
rt for 18 h, then concentrated in vacuo and purified by preparative
HPLC (Xbridge C18 5u OBD 19.times.100 mm column; detection at 220
nm; flow rate=20 mL/min; continuous gradient from 15% B to 100% B
over 10 min+2 min hold time at 100% B, where A=90:10:0.1
H.sub.2O:MeCN:TFA and B=90:10:0.1 MeCN:H.sub.2O:TFA) to give the
title compound (TFA salt; 26 mg, 0.044 mmol, 81% yield) as a
yellowish oil.
[1085] [M+H].sup.+=472.1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.05 (d, J=8.8 Hz, 1H), 7.66 (br t, J=9.9 Hz, 1H), 5.67-5.53 (m,
2H), 4.80 (br s, 1H), 4.18 (s, 3H), 3.28-2.91 (m, 5H), 2.86 (br s,
1H), 2.66 (s, 3H), 2.15-1.56 (m, 8H), 1.01 (br dd, J=12.1, 5.1 Hz,
3H), 0.72-0.46 (m, 2H), 0.43-0.13 (m, 2H); .sup.19F NMR (377 MHz,
CDCl.sub.3) .delta. -75.88 (s, TFA). hLPA1 IC.sub.50=18 nM
EXAMPLE 258
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclopropyl)-
methyl)
carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclo-
hexane-1-carboxylic acid
##STR00419##
[1086] 258A.
N-methyl-1-((1S,2S)-2-methylcyclopropyl)methanamine
##STR00420##
[1088] The same synthetic sequence to prepare Example 257G (from
Example 257C) was used to prepare Example 258A from Example 257D
(HCl salt; 0.53 g, 3.91 mmol, 91% yield) as a white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 2.91 (d, J=7.3 Hz, 2H), 2.75-2.70
(m, 3H), 1.12 (d, J=5.7 Hz, 3H), 0.95-0.76 (m, 2H), 0.59 (dt,
J=8.5, 4.9 Hz, 1H), 0.48 (dt, J=8.2, 5.1 Hz, 1H)
EXAMPLE 258
[1089] To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1
mL) added Example 258A HCl salt (7.35 mg, 0.054 mmol) and DIPEA
(0.028 mL, 0.163 mmol). The reaction mixture was stirred at rt for
2 h, then was concentrated in vacuo. The residue was stirred with
1.0 M aq. NaOH (0.542 mL, 0.542 mmol) in THF (1 mL)/MeOH (0.2 mL)
at rt for 18 h and then purified by preparative HPLC (Xbridge C18
5u OBD 19.times.100 mm column; detection at 220 nm; flow rate=20
mL/min; continuous gradient from 30% B to 100% B over 10 min+2 min
hold time at 100% B, where A=90:10:0.1 H.sub.2O:MeCN:TFA and
B=90:10:0.1 MeCN:H.sub.2O:TFA) to give the title compound (TFA
salt, 27 mg, 0.046 mmol, 84% yield) as a yellowish oil.
[M+H].sup.+=472.1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04
(d, J=8.8 Hz, 1H), 7.63 (br t, J=9.6 Hz, 1H), 5.72-5.51 (m, 2H),
4.79 (br d, J=3.1 Hz, 1H), 4.18 (s, 3H), 3.29-2.80 (m, 6H), 2.65
(s, 3H), 2.11-1.98 (m, 2H), 1.97-1.56 (m, 6H), 1.01 (br dd, J=13.4,
5.1 Hz, 3H), 0.69-0.16 (m, 4H). hLPA1 IC.sub.50=19 nM
EXAMPLE 259
(1S,3S)-3-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-
-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00421##
[1090] 259A. N-benzyl-2,2-difluoro-N-methylpropan-1-amine
##STR00422##
[1092] To a solution of 1-(benzyl(methyl)amino)propan-2-one (1.28
g, 7.22 mmol) and DAST (2.86 mL, 21.66 mmol) in DCM (12 ml) was
added CsF (0.329 g, 2.166 mmol) portionwise, followed by a few
drops of TFA at rt. The reaction mixture was stirred for 18 h at
rt, then was quenched with satd aq. NaHCO.sub.3. The aqueous layer
was extracted with DCM (50 mL.times.3). The combined organic
extracts were washed with water, brine, dried (MgSO.sub.4) and
concentrated in vacuo. The crude oily product was chromatographed
(12 g SiO.sub.2; elution with EtOAc/Hexane (continuous gradient
from 0% to 50% over 10 min) and then further purified by
preparative HPLC to give a clear oil. This material was treated
with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the title
compound (HCl salt, 334 mg, 1.417 mmol, 19.6% yield) as a white
solid.
[1093] [M+H].sup.+=482.3; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.68 (dt, J=3.8, 2.8 Hz, 2H), 7.55-7.38 (m, 3H), 4.56-4.18 (m, 2H),
3.65-3.15 (m, 2H), 2.94 (s, 3H), 1.80 (t, J=19.3 Hz, 3H); .sup.19F
NMR (377 MHz, CDCl.sub.3) .delta. -87.77 to -91.55 (m, F)
259B. 2,2-difluoro-N-methylpropan-1-amine
##STR00423##
[1095] A mixture of Example 259A (HCl salt; 0.33 g, 1.40 mmol) and
20% Pd(OH).sub.2--C (0.10 g, 0.712 mmol) in EtOH (40 mL) was
stirred at 60.degree. C. under 1 atmosphere H.sub.2 for 2 h.
Filtration and concentration in vacuo provided
2,2-difluoro-N-methylpropan-1-amine (HCl salt, 200 mg, 1.37 mmol,
98% yield) as a white solid.
[1096] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 3.63 (t, J=14.9
Hz, 2H), 2.81 (s, 3H), 1.79 (t, J=19.1 Hz, 3H); .sup.19F NMR (471
MHz, CD.sub.3OD) .delta. -98.01 (s)
EXAMPLE 259
[1097] To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1
mL) added Example 259B (HCl salt; 15.78 mg, 0.108 mmol) and DIPEA
(0.047 mL, 0.271 mmol). The reaction mixture was stirred at
50.degree. C. for 18 h and then concentrated in vacuo. The residue
was stirred with 1.0 M aq. NaOH (0.271 mL, 0.271 mmol) in THF (1
mL)/MeOH (0.2 mL) at rt for 18 h and then purified by preparative
LC/MS (Column: XBridge C18, 19.times.200 mm, 5-.mu.m particles;
Mobile Phase A: 5:95 MeCN:H.sub.2O with 10-mM NH.sub.4OAc; Mobile
Phase B: 95:5 MeCN:H.sub.2O with 10-mM NH.sub.4OAc; Gradient:
15-55% B over 20 min, then a 4-min hold at 100% B; Flow: 20 mL/min)
to give the title compound (TFA salt; 9.3 mg, 0.015 mmol, 27.4%
yield) as a yellowish oil. [M+H].sup.+=482.3; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.85 (br d, J=7.9 Hz, 1H), 7.49 (br d, J=8.5
Hz, 1H), 5.70 (br d, J=18.3 Hz, 2H), 4.79 (br s, 1H), 4.11 (br s,
3H), 3.76-3.52 (m, 1H), 2.95-2.78 (m, 3H), 2.64 (br t, J=10.4 Hz,
1H), 2.42 (s, 3H), 2.03 (br d, J=13.7 Hz, 1H), 1.92-1.74 (m, 3H),
1.69-1.34 (m, 8H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta.
-73.67 (s, TFA), -93.07 (br d, J=64.2 Hz). hLPA1 IC.sub.50=134
nM
EXAMPLE 260
(1S,3S)-3-((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl--
1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00424##
[1098] 260A. 4-(benzyl(methyl)amino)butan-2-one
##STR00425##
[1100] A mixture of N-methyl-1-phenylmethanamine (2.57 mL, 20
mmol), paraformaldehyde (0.901 g, 30.0 mmol) and conc. HCl (1.67
mL, 20.0 mmol) in iPrOH (2 mL) and acetone (50 mL) was stirred
under reflux overnight and then concentrated in vacuo. The residue
was diluted with water, basified to pH 14 with 1 N aq. NaOH
solution (33.4 mL, 33.4 mmol) and extracted with ether. The organic
phase was dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give the title compound (4.0 g, 20.9 mmol, 94% yield), which was
used directly in the next reaction. [M+H].sup.+=192.2; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.34-7.22 (m, 5H), 3.49 (s, 2H),
2.74-2.67 (m, 2H), 2.66-2.58 (m, 2H), 2.19 (s, 3H), 2.14 (s,
3H)
260B. 4-(benzyl(methyl)amino)butan-2-ol
##STR00426##
[1102] NaBH.sub.4 (2.37 g, 62.7 mmol) was added to a solution of
Example 260A (4.0 g, 20.9 mmol) in MeOH (90 mL) at 0.degree. C.
under N.sub.2. The reaction mixture was stirred for 1 h at
0.degree. C.; water was then added at 0.degree. C. and the mixture
was concentrated in vacuo. The residue was dissolved in EtOAc,
washed with water, dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The residue was chromatographed (SiO.sub.2; elution with
isocratic 10% EtOH/CHCl.sub.3) to give the title compound (3.5 g,
18.11 mmol, 87% yield) as a light yellowish oil. [M+H].sup.+=194.2;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35-7.27 (m, 5H),
3.99-3.86 (m, 1H), 3.72-3.31 (m, 2H), 2.76 (td, J=12.0, 3.3 Hz,
1H), 2.59-2.48 (m, 1H), 2.22 (s, 3H), 1.72-1.61 (m, 1H), 1.54-1.45
(m, 1H), 1.15 (d, J=6.2 Hz, 3H)
260C. N-benzyl-3-fluoro-N-methylbutan-1-amine
##STR00427##
[1104] DAST (1.367 mL, 10.35 mmol) was added to a solution of
Example 260B (1.0 g, 5.17 mmol) in DCM (5 mL) at -78.degree. C. and
the reaction was stirred for 5 h at -78.degree. C. and 18 h at rt,
after which it was quenched with sat. aq. NaHCO.sub.3 (50 mL). The
aqueous layer was extracted with DCM (20 mL.times.3), and the
combined organic extracts were dried (MgSO.sub.4) and concentrated
in vacuo. The crude oil was purified by preparative HPLC (Sunfire
C18 30.times.100 mm-regenerated column; detection at 220 nm; flow
rate=40 mL/min; continuous gradient from 0% B to 100% B over 10
min+2 min hold time at 100% B, where A=90:10:0.1 H.sub.2O:MeCN:TFA
and B=90:10:0.1 MeCN:H.sub.2O:TFA) and appropriate fractions were
concentrated in vacuo to give an oil. This product was treated with
2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the title compound
(HCl salt; 0.15 g, 0.647 mmol, 12.5% yield) as a white solid.
[M+H].sup.+=196.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.69-7.54 (m, 2H), 7.50-7.34 (m, 3H), 4.97-4.57 (m, 1H), 4.39-3.96
(m, 2H), 3.38-3.21 (m, 1H), 3.08-2.88 (m, 1H), 2.77-2.64 (m, 3H),
2.57-1.96 (m, 2H), 1.54-1.29 (m, 3H); .sup.19F NMR (377 MHz,
CDCl.sub.3) .delta. -176.04 (s), -176.11 (s)
260D
##STR00428##
[1106] A mixture of Example 260C (HCl salt; 0.15 g, 0.647 mmol) and
20% Pd(OH).sub.2--C (0.045 g, 0.324 mmol) in EtOH (5 mL) was
stirred at 60.degree. C. under 1 atmosphere H.sub.2 for 2 h.
Filtration and concentration in vacuo provided the title compound
(HCl salt; 0.075 g, 0.530 mmol, 82% yield) as a white solid.
[1107] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.01-4.71 (m, 1H),
3.13 (br s, 2H), 2.72 (br s, 3H), 2.33-2.06 (m, 2H), 1.53-1.25 (m,
3H); .sup.19F NMR (377 MHz, CDCl.sub.3) .delta. -175.47 (s, 1F)
EXAMPLE 260
[1108] To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1
mL) was added Example 260D (HCl salt; 15.4 mg, 0.11 mmol) and DIPEA
(0.047 mL, 0.271 mmol). The reaction mixture was stirred at rt for
1 h, then was concentrated in vacuo. The residue was stirred with
1.0 M aq. NaOH (0.271 mL, 0.271 mmol) in THF (1 mL)/MeOH (0.2 mL)
at rt for 18 h and then was purified by preparative HPLC (Sunfire
C18 30.times.100 mm-regenerated column; detection at 220 nm; flow
rate=40 mL/min; continuous gradient from 30% B to 100% B over 10
min+2 min hold time at 100% B, where A=90:10:0.1 H.sub.2O:MeCN:TFA
and B=90:10:0.1 MeCN:H.sub.2O:TFA) to give the title compound (TFA
salt; 24 mg, 0.040 mmol, 73.4% yield) as a yellowish oil.
[1109] [M+H].sup.+=478.1; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.18 (br d, J=8.5 Hz, 1H), 8.00 (br d, J=8.0 Hz, 1H), 5.57-5.42 (m,
2H), 4.90 (br s, 1H), 4.78-4.51 (m, 1H), 4.23 (s, 3H), 3.55-3.41
(m, 2H), 3.04-2.93 (m, 3H), 2.91-2.82 (m, 1H), 2.82-2.75 (m, 4H),
2.23-2.06 (m, 1H), 2.06-1.95 (m, 1H), 1.95-1.77 (m, 6H), 1.69 (br
s, 1H), 1.42-1.31 (m, 3H); .sup.19F NMR (471 MHz, CDCl.sub.3)
.delta. -76.03 (br s, TFA), -176.02 (dd, J=135.2, 9.3 Hz, F). hLPA1
IC.sub.50=50 nM.
TABLE-US-00008 Example Structure & Name Analytical &
Biology Data Method 261 ##STR00429## LCMS; [M + H].sup.+ = 464.0;
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.18-8.05 (m, 1H), 7.82-
7.68 (m, 1H), 5.73-5.46 (m, 2H), 4.96-4.69 (m, 2H), 4.22 (br d, J =
12.9 Hz, 3H), 3.03 (br d, J = 7.2 Hz, 3H), 2.96- 2.84 (m, 1H),
2.78-2.63 (m, 3H), 2.21-1.53 (m, 9H), 1.41- 1.22 (m, 4H); .sup.19F
NMR (471 MHz, CDCl.sub.3) .delta. -75.91 (br s, TFA), -175.36 to
-181.71 (m, 1 F) LPA1 IC.sub.50 = 145 nM Example 1
(1S,3S)-3-((6-(5-((((2- fluoropropyl)(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 262 ##STR00430## LCMS; [M +
H].sup.+ = 472.2; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.16
(d, J = 8.8 Hz, 1H), 7.94 (br d, J = 9.0 Hz, 1H), 5.57- 5.40 (m,
2H), 4.87 (br s, 1H), 4.21 (d, J = 6.4 Hz, 3H), 3.27- 3.06 (m, 2H),
3.04-2.94 (m, 3H), 2.86 (br d, J = 3.5 Hz, 1H), 2.76 (d, J = 4.6
Hz, 3H), 2.20-1.56 (m, 8H), 1.09- 1.01 (m, 3H), 0.73-0.23 (m, 4H)
LPA1 IC.sub.50 = 29 nM (1S,3S)-3-((2-methyl-6-(1-
methyl-5-(((methyl((2-methyl- cyclopropyl)methyl)carbamoyl)
oxy)methyl)-1H-1,2,3-triazol-4-yl) pyridin-3-yl)oxy)cyclohexane-1-
carboxylic acid; mixture of diastereomers 263 ##STR00431## LCMS; [M
+ H].sup.+ = 474.3; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.83 (br d, J = 8.5 Hz, 1H), 7.46 (br d, J = 8.9 Hz, 1H), 5.64 (br
s, 2H), 4.77 (br s, 1H), 4.09 (s, 3H), 3.18-2.95 (m, 2H), 2.90-2.72
(m, 3H), 2.63 (br d, J = 10.4 Hz, 1H), 2.40 (s, 3H), 2.05-1.40 (m,
8H), 0.97-0.66 (m, 3H), 0.43- 0.07 (m, 4H) LPA1 IC.sub.50 = 76 nM
(1S,3S)-3-((2-methyl-6-(1-methyl- 5-(((methyl((1-methylcyclo-
propyl)methyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)
pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 264 ##STR00432##
LCMS; [M + H].sup.+ = 474.4; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.84 (br s, 1H), 7.48 (br s, 1H), 5.63 (br d, J = 17.1 Hz,
2H), 4.79 (br s, 1H), 4.11 (s, 3H), 3.57 (br dd, J = 12.1, 6.0 Hz,
2H), 3.26 (dd, J = 10.4, 5.8 Hz, 1H), 3.20-3.11 (m, 1H), 3.06 (br
s, 1H), 2.93 (br s, 1H), 2.90-2.76 (m, 3H), 2.63 (br s, 1H),
2.09-1.43 (m, 8H), 0.92-0.64 (m, 9H) LPA1 IC.sub.50 = 76 nM
(1S,3S)-3-((2-methyl-6-(1- methyl-5-(((methyl(neopentyl)
carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid
EXAMPLE 265
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)pyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid
##STR00433##
[1110] 265A.
3,6-dibromo-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine
##STR00434##
[1112] A solution of ethyl 3,6-dibromopicolinate (3.0 g, 9.71 mmol)
in THF (50 mL) was stirred at 0.degree. C., then LiBH.sub.4 (7.28
mL of a 2M solution in THF, 14.57 mmol) was added portionwise over
5-10 min. Vigorous gas evolution ensued. The reaction mixture was
stirred at rt overnight, then was quenched with 1N aq. HCl slowly,
adjusting the pH to .about.7. The mixture was partitioned between
EtOAc and water (50 mL each) and extracted with EtOAc (3.times.).
The combined organic extracts were dried (MgSO.sub.4) and
concentrated in vacuo. The residue was chromatographed (24 g
SiO.sub.2) to provide 3,6-dibromopyridin-2-yl)methanol (1.89 g,
7.08 mmol, 72.9% yield).
[1113] To a solution of (3,6-dibromopyridin-2-yl)methanol (2.46 g,
9.22 mmol) in CH.sub.2Cl.sub.2 (12 mL) was added
3,4-dihydro-2H-pyran (2.52 mL, 27.6 mmol) and pyridinium
p-toluenesulfonate (0.116 g, 0.461 mmol). The reaction was stirred
overnight at rt, then quenched with water and extracted with DCM,
washed with water, brine, dried (MgSO.sub.4) and concentrated in
vacuo. The residue was chromatographed (24 g SiO.sub.2, continuous
gradient from 0-100% EtOAc/hexanes over 20 min) to give the title
compound (3.4 g, 9.40 mmol, 100% yield). 1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.72 (d, J=8.53 Hz, 1H), 7.32 (d, J=8.25 Hz,
1H), 4.94 (d, J=11.83 Hz, 1H), 4.88 (t, J=3.30 Hz, 1H), 4.69 (d,
J=11.83 Hz, 1H), 3.94-4.09 (m, 1H), 3.49-3.70 (m, 1H), 1.49-2.00
(m, 8H)
265B.
3-(5-Bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)pro-
p-2-yn-1-ol
##STR00435##
[1115] To a solution of Example 265A (3.4 g, 9.69 mmol) and
prop-2-yn-1-ol (0.677 mL, 11.62 mmol) in MeCN (30 mL) was added
Et.sub.3N (6.00 mL). The solution was degassed with N.sub.2 for 5
mins, after which Pd(Ph.sub.3).sub.2Cl.sub.2 (0.340 g, 0.484 mmol)
and CuI (0.092 g, 0.484 mmol) were added. The reaction mixture was
degassed with N.sub.2 for 5 min, then was stirred at rt for 16 h
under N.sub.2. LCMS indicated at this time indicated that the
reaction was complete. The reaction mixture was filtered through a
pad of Celite and washed with EtOAc (4.times.30 mL). The filtrate
was concentrated in vacuo and the residue was chromatographed (80 g
SiO.sub.2, elution by continuous gradient from 0% to 100% EtOAc/Hex
over 80 min at 35 mL/min) to give the title compound (2.90 g, 8.89
mmol, 92% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.86
(d, J=8.25 Hz, 1H), 7.26 (d, J=8.25 Hz, 1H), 4.98 (d, J=11.55 Hz,
1H), 4.88 (t, J=3.30 Hz, 1H), 4.69 (d, J=11.55 Hz, 1H), 4.53 (d,
J=6.05 Hz, 2H), 3.99 (dt, J=2.75, 10.45 Hz, 1H), 3.53-3.65 (m, 1H),
1.47-1.95 (m, 6H)
265C.
(4-(5-Bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-
-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol
##STR00436##
[1117] To a solution of Example 265B (2.9 g, 8.89 mmol) in dioxane
(40 mL) was added CuI (0.068 g, 0.356 mmol),
chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)Ruthenium(II)
(0.283 g, 0.356 mmol). The resulting suspension was degassed with
N.sub.2 for 3 min, after which trimethylsilylmethyl azide (1.404 g,
9.78 mmol) was added. The mixture was degassed with N.sub.2 for
another 5 min, then was heated in an oil bath at 50.degree. C. for
20 h under N.sub.2, then was cooled to rt. The mixture was filtered
through Celite; the filtrate was concentrated in vacuo, and
chromatographed (120 g SiO.sub.2; elution with continuous gradient
from 0 to 60% EtOAc/Hex over 65 min at 120 mL/min) to give the
title compound (2.30 g, 5.05 mmol, 56.8% yield). .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.10 (d, J=8.25 Hz, 1H), 7.97 (d, J=8.53
Hz, 1H), 6.41 (t, J=7.57 Hz, 1H), 5.05 (d, J=14.30 Hz, 1H), 4.86
(t, J=3.30 Hz, 1H), 4.80 (dd, J=1.38, 7.43 Hz, 2H), 4.76 (d,
J=14.03 Hz, 1H), 3.86-3.97 (m, 1H), 3.83 (s, 2H), 3.53-3.64 (m,
1H), 1.51-2.02 (m, 8H), 0.18-0.27 (m, 9H)
265D.
(4-(5-Bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-
-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate
##STR00437##
[1119] TBAF (5.56 mL of a 1M solution in THF, 5.56 mmol) was added
dropwise to a solution of Example 265C (2.3 g, 5.05 mmol) in THF
(15 mL) and the reaction mixture was stirred at rt overnight, then
was quenched with satd aq. NaHCO.sub.3 (50 mL) and stirred for 20
min at rt. The mixture was extracted with EtOAc (2.times.100 mL);
the combined organic extracts were dried with Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude product was
chromatographed (40 g SiO.sub.2; continuous gradient from 0% to
100% EtOAc over 30 min, at 20 mL/min) to give
(4-(5-bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-meth-
yl-1H-1,2,3-triazol-5-yl)methanol (1.69 g, 4.41 mmol, 87% yield).
To a solution of this material (0.41 g, 1.07 mmol) and pyridine
(0.433 mL, 5.35 mmol) in DCM (5 mL) was added 4-nitrophenyl
chloroformate (0.431 g, 2.140 mmol) in DCM (2 mL). The reaction
mixture was stirred at rt overnight, then
(cyclobutylmethyl)methylamine (0.318 g, 3.21 mmol) was added,
followed by Et.sub.3N (1.49 mL, 10.7 mmol). The reaction was
stirred at rt for 3 h, then was partitioned between DCM and sat'd
aq. NaHCO.sub.3. The organic layer was washed with brine and
concentrated in vacuo. The residue was chromatographed (40 g
SiO.sub.2; continuous gradient from 0% to 100% EtOAc over 30 min,
at 20 ml/min) to give the title compound (0.52 g, 0.921 mmol, 86%
yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.05 (d, J=8.3
Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 5.83 (br d, J=16.0 Hz, 2H), 5.01
(d, J=11.8 Hz, 1H), 4.93 (t, J=3.2 Hz, 1H), 4.77 (d, J=12.1 Hz,
1H), 4.10-4.24 (m, 3H), 3.90-4.07 (m, 1H), 3.53-3.70 (m, 1H),
3.10-3.42 (m, 2H), 2.70-2.98 (m, 3H), 1.46-2.05 (m, 13H)
265E.
(4-(5-hydroxy-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-
-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate
##STR00438##
[1121] To a degassed solution of Example 265D (510 mg, 1.00 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (509
mg, 2.01 mmol) and KOAc (295 mg, 3.01 mmol) in THF (4013 .mu.l) was
added PdCl.sub.2(dppf) (36.7 mg, 0.050 mmol). The vial was purged
with N.sub.2, sealed and stirred at 80.degree. C. overnight, then
was cooled to rt. The mixture was diluted with EtOAc and filtered;
the filtrate was concentrated in vacuo, re-dissolved in THF (5 mL)
and this crude pinacol boronate product was used in the next step
without further purification. To the solution of this crude pinacol
boronate product in THF (5 mL) was added aq. NaOH (2.01 mL of a 1 M
solution, 2.01 mmol), followed by aq. H.sub.2O.sub.2 (0.830 mL,
10.03 mmol). The reaction mixture was stirred at rt for 2 h, after
which satd. aq. Na.sub.2S.sub.2O.sub.3 (1 mL) was added; the
mixture was stirred at rt for 10 min, then was extracted with EtOAc
(3.times.10 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
chromatographed (24 g SiO.sub.2; continuous gradient from 0 to 100%
EtOAc/Hex over 20 min at 20 mL/min) to give the title compound (379
mg, 0.851 mmol, 85% yield). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.22 (br s, 1H), 8.07 (d, J=8.53 Hz, 1H), 7.30 (d, J=8.53
Hz, 1H), 5.73 (br d, J=9.08 Hz, 2H), 5.14 (d, J=12.93 Hz, 1H), 4.92
(d, J=12.65 Hz, 1H), 4.77-4.86 (m, 1H), 4.15 (br d, J=5.23 Hz, 3H),
3.96-4.06 (m, 1H), 3.60-3.73 (m, 1H), 3.34 (br d, J=7.43 Hz, 1H),
3.18 (br d, J=6.88 Hz, 1H), 2.74-2.99 (m, 3H), 1.60-1.98 (m,
13H)
265E. Isopropyl
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-met-
hyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)pyridin-3-yl)oxy)cyclohexane-1-
-carboxylate
##STR00439##
[1123] To a solution of Example 265D (275 mg, 0.617 mmol), Example
1F (610 mg, 1.54 mmol) in t-AmOH (5 mL) was added Cs.sub.2CO.sub.3
(603 mg, 1.85 mmol); the reaction was stirred at 65.degree. C. for
24 h. Then more Example 1F (244 mg, 0.617 mmol) and
Cs.sub.2CO.sub.3 (241 mg, 0.741 mmol) were added to the reaction,
which was heated at 65.degree. C. for another 24 h, then cooled to
rt. Water (5 mL) was added and the mixture was stirred at rt for 10
min, then was extracted with EtOAc (3.times.10 mL). The combined
organic extracts were dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The residue was chromatographed (24 g SiO.sub.2, continuous
gradient from 0 to 100% EtOAc/Hex over 18 min at 15 mL/min) to give
(1S,3S)-isopropyl 3-((6-(5-((((cyclobutylmethyl)
(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(((tetrah-
ydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)cyclohexanecarboxylate
(290 mg, 0.402 mmol, 65.1% yield).
[1124] A mixture of this THP ether (330 mg, 0.468 mmol) and PPTS
(23.5 mg, 0.094 mmol) in MeOH (4 mL) was heated at 60.degree. C.
overnight, then was cooled to rt. Volatiles were removed in vacuo
and the residue was partitioned between DCM and satd aq.
NaHCO.sub.3. The organic extract was dried (Na.sub.2SO.sub.4) was
concentrated in vacuo. The crude product was chromatographed (24 g
SiO.sub.2; continuous gradient from 0 to 100% EtOAc/Hex over 20 min
at 20 mL/min and then at 100% EtOAc for 10 min) to give the title
compound (274 mg, 0.491 mmol, 100% yield). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.13 (br dd, J=3.71, 8.12 Hz, 1H), 7.32 (d,
J=8.53 Hz, 1H), 5.70 (s, 2H), 4.99-5.14 (m, 1H), 4.78-4.90 (m, 1H),
4.75 (br s, 1H), 4.24 (s, 3H), 3.20-3.34 (m, 2H), 2.82-2.96 (m,
3H), 2.67-2.79 (m, 1H), 2.33-2.63 (m, 1H), 1.46-2.15 (m, 16H),
1.07-1.32 (m, 6H)
EXAMPLE 265
[1125] To a solution of 265E (17 mg, 0.032 mmol) in THF (0.5 mL)
was added 4 drops of MeOH at rt, after which LiOH.H.sub.2O (0.080
mL, 0.321 mmol) was added. The reaction mixture was stirred at rt
overnight, then was purified by preparative HPLC ((PHENOMENEX.RTM.,
Axia 5.mu., C18 30.times.100 mm column; detection at 220 nm; flow
rate=40 mL/min; continuous gradient from 0% B to 100% B over 10
min+2 min hold time at 100% B, where A=90:10:0.1 H.sub.2O:MeOH:TFA
and B=90:10:0.1 MeOH:H.sub.2O:TFA)) to give the title compound (15
mg, 0.024 mmol, 75% yield). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.19 (br d, J=8.25 Hz, 1H), 7.65 (br d, J=8.53 Hz, 1H),
5.51-5.66 (m, 2H), 4.90-5.12 (m, 2H), 4.84 (br s, 1H), 4.24 (s,
3H), 3.29 (br dd, J=7.15, 16.78 Hz, 2H), 2.88 (br s, 4H), 2.38-2.68
(m, 1H), 1.49-2.22 (m, 15H). LCMS, [M+H].sup.+=488.3. hLPA1
IC.sub.50=68 nM
EXAMPLE 266
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(fluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-c-
arboxylic acid
##STR00440##
[1127] To a solution of Example 265E (50 mg, 0.094 mmol) in DCM (1
mL) at 0.degree. C., was added bis(2-methoxyethyl)aminosulfur
trifluoride (0.061 mL, 0.283 mmol) dropwise under N.sub.2. The
reaction mixture was gradually warmed to rt and stirred at rt for 2
h, then was slowly quenched by addition of satd aq. NaHCO.sub.3
followed by DCM. The organic layer was dried using a stream of
N.sub.2 and the crude product (1S,3S)-isopropyl
3-((6-(5-((((cyclobutylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(fluoromethyl)pyr-
idin-3-yl)oxy) cyclohexanecarboxylate) was used in the next step
without further purification. To a solution of the crude isopropyl
ester (50 mg, 0.094 mmol) in THF (0.5 mL) was added 4 drops of MeOH
at rt, followed by aq. LiOH (0.235 mL, 0.941 mmol). The reaction
mixture was stirred at rt overnight, then was filtered. The crude
product was purified by preparative HPLC (PHENOMENEX.RTM., Axia
5.mu. C18 30.times.100 mm column; detection at 220 nm; flow rate=40
mL/min; continuous gradient from 0% B to 100% B over 10 min+2 min
hold time at 100% B, where A=90:10:0.1 H.sub.2O:MeOH:TFA and
B=90:10:0.1 MeOH:H20:TFA to give the title compound (25 mg, 0.039
mmol, 41.8% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.19
(br d, J=8.53 Hz, 1H), 7.62-7.71 (m, 1H), 5.49-5.77 (m, 4H), 4.84
(br s, 1H), 4.22 (br d, J=4.40 Hz, 3H), 3.16-3.44 (m, 2H),
2.80-2.98 (m, 4H), 1.26-2.68 (m, 16H). LCMS, [M+H]+=490.3. hLPA1
IC.sub.50=27 nM.
EXAMPLE 267
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-
-carboxylic acid
##STR00441##
[1129] To a mixture of Example 265E (80 mg, 0.151 mmol) and 75 mg
of Celite in DCM (1.5 mL) was added pyridinium dichromate (73.9 mg,
0.196 mmol). The reaction mixture was stirred at rt for 90 min,
after which more pyridinium dichromate (73.9 mg; 0.196 mmol) was
added, and the reaction was stirred overnight at rt. EtOAc was
added and the mixture was filtered through Celite. The filtrate was
concentrated in vacuo, and the crude product was chromatographed (4
g SiO.sub.2, continuous gradient from 0 to 100% EtOAc/Hex over 12
min at 8 mL/min) to give (1S,3S)-isopropyl
3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-formylpyridin-3-yl)oxy)cyclohex-
anecarboxylate (15 mg, 0.028 mmol, 18% yield). To a RT solution of
the above aldehyde (15 mg, 0.028 mmol) in DCM (0.3 mL) was added
bis(2-methoxyethyl)aminosulfur trifluoride (0.032 mL, 0.148 mmol)
in one portion. The mixture was stirred at rt for 2 h; volatiles
were removed via an N.sub.2 stream, and the crude difluoromethyl
product (1S,3S)-isopropyl3-((6-(5-((((cyclobutylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)p-
yridin-3-yl)oxy) cyclohexanecarboxylate was directly in the next
step without further purification. To a solution of this isopropyl
ester (13 mg, 0.024 mmol) in THF (0.5 mL) was added aq. LiOH (0.118
mL, 0.473 mmol) and 4 drops of MeOH. The reaction mixture was
stirred at rt for 2 days, filtered and the crude product was
purified by preparative HPLC, (PHENOMENEX.RTM., Axia 5.mu. C18
30.times.100 mm column; detection at 220 nm; flow rate=40 mL/min;
continuous gradient from 0% B to 100% B over 10 min+2 min hold time
at 100% B, where A=90:10:0.1 H.sub.2O:MeOH:TFA and B=90:10:0.1
MeOH:H.sub.2O:TFA) to give the title compound (2 mg, 3.19 .mu.mol,
13.5% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.28 (d,
J=8.80 Hz, 1H), 7.37-7.65 (m, 1H), 6.62-7.05 (m, 1H), 5.71 (br s,
2H), 4.80 (br d, J=2.64 Hz, 1H), 4.17 (br d, J=7.92 Hz, 3H),
3.09-3.45 (m, 2H), 2.72-3.02 (m, 4H), 1.36-2.65 (m, 15H). LCMS,
[M+H].sup.+=508.2. hLPA IC.sub.50=30 nM
Alternatively, the title compound can also be synthesized as
follows.
267A. (3,6-Dibromopyridin-2-yl)methanol
##STR00442##
[1131] To a 0.degree. C. solution of ethyl 3,6-dibromopicolinate
(5.0 g, 16.2 mmol) in THF (30 mL) was added LiBH.sub.4 in THF
(12.14 mL of a 2 M solution, 24.28 mmol) portionwise over 10 min.
Vigorous gas evolution ensued. After 1 h at rt, the reaction
mixture was slowly quenched with satd aq., stirred for 10 min, then
was extracted with EtOAc. The pH of the aqueous phase was adjusted
to 7-8 by addition of 1N aq. HCl, then was extracted again with
EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo. The crude material was chromatographed
(40 g SiO.sub.2; EtOAc/Hexane; continuous gradient from 0% to 100%
EtOAc over 30 min, at 20 mL/min) to give the title compound (3.0 g,
11.24 mmol, 69.4% yield), 1H NMR (500 MHz, CDCl.sub.3) .delta. 7.72
(d, J=7.98 Hz, 1H), 7.35 (d, J=7.98 Hz, 1H), 4.77 (d, J=4.95 Hz,
2H), 3.78 (t, J=5.09 Hz, 1H)
267B. 3,6-Dibromo-2-(difluoromethyl)pyridine
##STR00443##
[1133] Anhydrous DMSO (4.04 mL, 56.9 mmol) was added dropwise to a
solution of (COCl).sub.2 (2.277 mL, 26.0 mmol) in DCM (25 mL) at
-78.degree. C. After stirring at -78.degree. C. for 15 min, a
solution of Example 267A (2.17 g, 8.13 mmol) in DCM (25 mL) was
added dropwise. After stirring for 15 min at -78.degree. C., TEA
(10.2 mL, 73.2 mmol) was added dropwise. The reaction was allowed
to warm to rt over 1 h (the reaction mixture became cloudy); more
DCM (50 mL) was added and the mixture was stirred for 2 h at rt.
The reaction was quenched with brine (20 mL) and extracted with DCM
(2.times.50 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The crude oil was
chromatographed (80 g SiO.sub.2; elution with EtOAc/Hexane
(continuous gradient from 0% to 60% over 20 min) to give
3,6-dibromopicolinaldehyde (1.92 g, 7.25 mmol, 89% yield) as a
light yellowish oil. To a solution of the 3,6-dibromopicolin
-aldehyde (1.5 g, 5.66 mmol) in DCM (6 mL) at rt was added
bis(2-methoxyethyl)aminosulfur trifluoride (1.46 mL, 6.79 mmol) in
one portion. The mixture was stirred at rt for 1 h, then was
carefully quenched with sat'd aq. NaHCO.sub.3, adjusted to pH=7-8
and extracted with DCM (2.times.). The combined organic extracts
were concentrated in vacuo. The residue was chromatographed
(EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 20
min, at 15 mL/min) to give the title compound (1.48 g, 5.16 mmol,
91% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.83 (d,
J=8.53 Hz, 1H), 7.51 (d, J=8.53 Hz, 1H), 6.65-7.00 (m, 1H)
[1134] Example 267B can then be used as the starting material for
the synthesis of Example 267. The synthetic sequence is analogous
to that used for the synthesis of Example 1 (i.e. regioselective
Sonogashira coupling of the less hindered bromide of Example 267B
with propargyl alcohol, followed by Ru-mediated [3+2] cycloaddition
with trimethylsilyl azide to form the 1,2,3-triazole, etc.).
[1135] Example 267: 1H NMR (400 MHz, CDCl.sub.3) .delta. 8.28 (d,
J=8.80 Hz, 1H), 7.37-7.65 (m, 1H), 6.62-7.05 (m, 1H), 5.71 (br s,
2H), 4.80 (br d, J=2.64 Hz, 1H), 4.17 (br d, J=7.92 Hz, 3H),
3.09-3.45 (m, 2H), 2.72-3.02 (m, 4H), 1.36-2.65 (m, 15H). LCMS,
[M+H]+=508.2 hLPA1 IC.sub.50=30 nM
EXAMPLE 268
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1--
carboxylic acid
##STR00444##
[1136] 268A. 3,6-Dibromo-2-(methoxymethyl)pyridine
##STR00445##
[1138] A solution of (3,6-dibromopyridin-2-yl)methanol (1.67 g,
6.26 mmol) in anhydrous THF (29 mL) was slowly added to a stirring
suspension of NaH (0.30 g, 7.51 mmol) in anhydrous THF (5 ml) at
0-5.degree. C. under N.sub.2. After gas evolution stopped, MeI
(0.587 mL, 9.38 mmol) was added slowly dropwise and the reaction
was warmed to rt over 1 h. Brine (10 mL) was added slowly to the
reaction, which was then extracted with EtOAc (2.times.50 mL). The
combined organic extracts were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The crude material was chromatographed (24 g
SiO.sub.2; EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc
over 30 min, at 10 mL/min) to give the title compound (1.70 g, 6.05
mmol, 97% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.72
(d, J=8.25 Hz, 1H), 7.34 (d, J=8.25 Hz, 1H), 4.66 (s, 2H), 3.52 (s,
3H).
[1139] Example 268B was then used for the synthesis of Example 268.
The synthetic sequence is analogous to that used for the synthesis
of Example 1 (i.e. regioselective Sonogashira coupling of the less
hindered bromide of Example 268B with propargyl alcohol, followed
by Ru-mediated [3+2] cycloaddition with trimethylsilyl azide to
form the 1,2,3-triazole, etc.).
[1140] Example 268: .sup.1H NMR (500 MHz, DMSO-d6) .delta. 7.95 (br
d, J=8.24 Hz, 1H), 7.60 (br d, J=8.85 Hz, 1H), 5.63 (br d, J=12.82
Hz, 2H), 4.81 (br s, 1H), 4.53 (br s, 2H), 4.10 (br s, 3H),
3.03-3.27 (m, 2H), 2.68-2.82 (m, 3H), 2.59 (br d, J=10.38 Hz, 1H),
2.56 (s, 3H), 1.32-2.36 (m, 16H); LCMS, [M+H]+=502.3; hLPA1
IC.sub.50=103 nM
EXAMPLE 269
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane--
1-carboxylic acid
##STR00446##
[1142] Example 269 was synthesized using commercially available
3,6-dibromo-2-(trifluoromethyl) pyridine, using the same synthetic
sequence as for the preparation of Example 1.
[1143] Example 269: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.39
(br d, J=8.80 Hz, 1H), 7.54 (d, J=9.08 Hz, 1H), 5.71 (br s, 1H),
4.86 (br s, 1H), 4.21 (br d, J=13.76 Hz, 3H), 3.12-3.40 (m, 2H),
2.89-2.99 (m, 1H), 2.74-2.89 (m, 3H), 2.35-2.66 (m, 1H), 2.17-2.37
(m, 1H), 1.42-2.29 (m, 14H)
[1144] LCMS, [M+H]+=526.2; hLPA.sub.1 IC.sub.50=10 nM.
EXAMPLE 270
(1S,3S)-3-((2-cyano-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1-
H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00447##
[1145] 270A. 3,6-Dibromopicolinonitrile
##STR00448##
[1147] To a suspension of 3,6-dibromopicolinic acid (0.5 g, 1.780
mmol), NH.sub.4Cl (0.381 g, 7.12 mmol) and Et.sub.3N (1.985 ml,
14.24 mmol) in THF (7.12 mL) was added 1-propanephosphonic
anhydride (4.24 mL, 7.12 mmol) dropwise at 0.degree. C. The
reaction was slowly warmed to rt, then was heated to 80.degree. C.
for 48 h, then was cooled to rt. The mixture was partitioned
between water and EtOAc (10 mL each) and extracted with EA
(2.times.10 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
chromatographed (40 g SiO.sub.2; EtOAc/Hexane; continuous gradient
from 0% to 100% EtOAc over 30 min, at 20 mL/min) to give the title
compound (0.32 g, 1.22 mmol, 68.6% yield) as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 7.88 (d, J=8.53 Hz, 1H), 7.60 (d,
J=8.53 Hz, 1H).
[1148] Example 270 was synthesized using Example 270A, using the
same synthetic sequence as for the preparation of Example 1 (except
that N-methyl, N-propylamine was used to generate the carbamate of
Example 270 rather than the N-methyl, N-cyclobutylmethylamine that
was used in Example 1).
[1149] Example 270: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.30 (d, J=9.16 Hz, 1H), 7.98 (d, J=9.16 Hz, 1H), 5.54 (br d,
J=19.53 Hz, 2H), 5.01 (br s, 1H), 4.14 (s, 3H), 3.00-3.25 (m, 2H),
2.77 (br d, J=9.16 Hz, 3H), 2.63 (br t, J=10.22 Hz, 1H), 1.15-2.21
(m, 10H), 0.58-0.96 (m, 3H)
[1150] LCMS, [M+H].sup.+=457.1; hLPA1 IC.sub.50=11 nM
EXAMPLE 271
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-meth-
yl-1H-1,2,3-triazol-4-yl)-2-(2-hydroxypropan-2-yl)pyridin-3-yl)oxy)cyclohe-
xane-1-carboxylic acid
##STR00449##
[1151] 271A. Ethyl
3-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-tr-
iazol-4-yl)picolinate
##STR00450##
[1153] This compound was synthesized from commercially available
ethyl 3,6-dibromopicolinate, using the same synthetic sequence as
for Example 265. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.20 (d,
J=8.53 Hz, 1H), 8.05 (d, J=8.53 Hz, 1H), 5.26-5.40 (m, 2H), 4.76
(t, J=3.44 Hz, 1H), 4.50 (q, J=7.15 Hz, 2H), 4.19 (s, 3H), 3.83
(ddd, J=3.03, 8.05, 11.21 Hz, 1H), 3.46-3.62 (m, 1H), 1.51-1.88 (m,
6H), 1.48 (t, J=7.15 Hz, 3H)
271B. Ethyl
3-hydroxy-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3--
triazol-4-yl)picolinate
##STR00451##
[1155] To a degassed solution of Example 271A (433 mg, 1.02 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (517
mg, 2.036 mmol) and KOAc (300 mg, 3.05 mmol) in THF (4.07 mL) was
added PdCl.sub.2(dppf) (37.2 mg, 0.051 mmol). The vial was purged
with N.sub.2, sealed and stirred at 80.degree. C. overnight, then
was cooled to rt. The mixture was filtered and the filtrate (crude
pinacol boronate) was used directly in the next step without
further purification
[1156] To a solution of the above crude boronate product (397 mg,
1.018 mmol) in EtOAc (7 mL) and THF (2 mL) was added H.sub.2O.sub.2
(0.946 mL, 10.2 mmol). The reaction was stirred at rt for 3 h, then
was extracted with EtOAc. To the aqueous phase was added satd aq.
Na.sub.2S.sub.2O.sub.3 (3 mL) and 2 drops of 1N aq. NaOH; the
mixture was stirred for 5 min and extracted again with EtOAc
(2.times.5 mL). The combined organic extracts were concentrated in
vacuo. The residue was chromatographed (40 g SiO.sub.2;
EtOAc/Hexane--continuous gradient from 0% to 100% EtOAc over 30
min, at 20 mL/min) to give the title compound (328 mg, 88% yield).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 10.74 (s, 1H), 8.35 (d,
J=8.80 Hz, 1H), 7.46 (d, J=8.80 Hz, 1H), 5.22-5.57 (m, 2H), 4.81
(t, J=3.58 Hz, 1H), 4.52 (dq, J=2.06, 7.11 Hz, 2H), 4.19 (s, 3H),
3.93 (br s, 1H), 3.84 (ddd, J=2.61, 8.32, 11.07 Hz, 1H), 3.43-3.60
(m, 1H), 1.48-2.06 (m, 9H)
271C.
2-(2-hydroxypropan-2-yl)-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)o-
xy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol
##STR00452##
[1158] To a solution of Example 271B (0.3g, 0.828 mmol) in THF (7
mL) was added dropwise CH.sub.3MgBr (1.95 mL of a 3.5 M solution in
THF, 6.62 mmol) at 0.degree. C. The resulted mixture was allowed to
warm to rt and stirred at rt for 3 h. Satd aq. NH.sub.4Cl was then
carefully added to quench the reaction, which was extracted with
EtOAc. The aqueous layer was carefully adjusted to pH 6 by using 1
N aq. HCl, then extracted again with EtOAc (2.times.). The combined
organic extracts were dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The crude product was chromatographed (24 g SiO.sub.2;
EtOAc/Hexane--continuous gradient from 0% to 100% EtOAc over 30
min, at 10 mL/min) to give the title compound (110 mg, 0.316 mmol,
38.1% yield).
EXAMPLE 271
[1159] Example 271C was converted to Example 271 by a similar
sequence used to convert Example 1C to Example 1.
[1160] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 7.96 (d, J=8.54 Hz,
1H), 7.59 (br d, J=8.54 Hz, 1H), 5.49 (s, 2H), 4.85 (br s, 1H),
4.13 (br s, 2H), 3.79 (br d, J=16.78 Hz, 1H), 3.07-3.26 (m, 2H),
2.88 (s, 1H), 2.68-2.75 (m, 2H), 2.55 (s, 3H), 1.19-2.16 (m, 20H).
LCMS, [M+H].sup.+=516.3.
[1161] hLPA.sub.1 IC.sub.50=225 nM
EXAMPLE 272
(1S,3S)-3-((2-Methoxy-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-
-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic
acid
##STR00453##
[1163] Example 272 was synthesized from
3,6-dibromo-2-(methoxy)pyridine using the same synthetic sequence
as for the preparation of Example 1 from 3,6-dibromopyridine. LCMS,
[M+H].sub.+=462.1; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.81
(d, J=8.0 Hz, 1H), 7.33-7.30 (m, 1H), 5.79 (br s, 2H), 4.72-4.67
(m, 1H), 4.18 (s, 3H), 4.04 (s, 3H), 3.25 (br t, J=7.3 Hz, 1H),
3.18-3.07 (m, 1H), 3.06-2.95 (m, 1H), 2.92 (s, 1.5H), 2.83 (s,
1.5H), 2.16-2.07 (m, 2H), 2.05-1.83 (m, 4H), 1.79-1.68 (m, 2H),
1.68-1.52 (m, 2H), 1.50-1.33 (m, 1H), 0.95-0.85 (m, 1.5H), 0.76 (br
t, J=7.2 Hz, 1.5H)
[1164] hLPA.sub.1 IC.sub.50=4 nM
[1165] The following examples were synthesized according to the
procedures described above.
TABLE-US-00009 Example Structure & Name Analytical &
Biology Data Method 273 ##STR00454## LCMS, [M + H]+ = 512.4 1H NMR
(500 MHz, DMSO- d.sub.6) .delta. 8.33 (br d, J = 8.85 Hz, 1H),
7.87-8.11 (m, 1H), 5.62 (br d, J = 17.09 Hz, 2H), 5.06 (br s, 1H),
4.18 (s, 2H), 2.69- 3.38 (m, 6H), 2.11 (br d, J = 13.43 Hz, 1H),
1.78-2.02 (m, 3H), 1.44-1.76 (m, 3H), 1.14-1.35 (m, 1H), 1.05 (d, J
= 6.10 Hz, 1H), 0.71-0.97 (m, 1H), 0.47 (br s, 1H), 0.30 (br s,
2H), 0.13-0.26 (m, 1H) hLPA1 IC.sub.50 = 7 nM. Example 269
(1S,3S)-3-((6-(5- ((((cyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-
(trifluoromethyl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid
274 ##STR00455## 1H NMR (500 MHz, DMSO- d6) .delta. 8.27 (br d, J =
8.54 Hz, 1H), 7.95 (br d, J = 8.85 Hz, 1H), 5.57 (br d, J = 13.43
Hz, 2H), 5.01 (br s, 1H), 4.13 (s, 2H), 2.97-3.21 (m, 2H), 2.93 (q,
J = 7.22 Hz, 2H), 2.65-2.79 (m, 3H), 1.21-2.13 (m, 8H), 1.17 (t, J
= 7.17 Hz, 3H), 0.50- 0.85 (m, 2H) LCMS, [M + H]+ = 499.9 hLPA1
IC.sub.50 = 28 nM. Example 269 (1S,3S)-3-((6-(1-methyl-5-
(((methyl(propyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)-2-
(trifluoromethyl)pyridin-3-yl) oxy)cyclohexane-1-carboxylic acid
275 ##STR00456## 1H NMR (500 MHz, DMSO- d6) .delta. 8.27 (br d, J =
8.85 Hz, 1H), 7.94 (br d, J = 8.85 Hz, 1H), 5.55 (br d, J = 12.82
Hz, 2H), 5.00 (br s, 1H), 4.13 (br s, 3H), 2.99-3.23 (m, 2H), 2.92
(q, J = 7.32 Hz, 1H), 2.74 (br s, 1H), 2.70 (br s, 2H), 1.33-2.13
(m, 10H), 1.08-1.27 (m, 3H), 0.91-1.00 (m, 1H), 0.85 (br s, 1H),
0.61 (br s, 2H) LCMS, [M + H]+ = 514.1 hLPA1 IC.sub.50 = 5.6 nM.
Example 269 (1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-(trifluoromethyl)pyridin- 3-yl)oxy)cyclohexane-1-
carboxylic acid 276 ##STR00457## 1H NMR (500 MHz, DMSO- d6) .delta.
8.27 (d, J = 8.84 Hz, 1H), 7.96 (d, J = 9.00 Hz, 1H), 5.56 (br s,
2H), 5.01 (br s, 1H), 4.13 (s, 3H), 3.65 (m, 1H), 2.54-2.70 (m,
4H), 1.73-2.14 (m, 4H), 1.25-1.71 (m, 12H) LCMS, [M + H]+ = 526.5
hLPA1 IC.sub.50 = 15 nM. Example 269 (1S,3S)-3-((6-(5-
(((cyclopentyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-(trifluoro- methyl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid 277 ##STR00458## 1H NMR (500 MHz,
DMSO- d6) .delta. 8.16 (br d, J = 8.24 Hz, 1H), 7.82 (br d, J =
8.85 Hz, 1H), 7.01-7.34 (m, 1H), 5.62 (br d, J = 13.12 Hz, 2H),
4.94 (br s, 1H), 4.13 (s, 3H), 2.95- 3.22 (m, 2H), 2.75 (br d, J =
16.78 Hz, 3H), 2.66 (br t, J = 10.68 Hz, 1H), 2.06 (br d, J = 13.43
Hz, 1H), 1.39-1.95 (m, 8H), 1.18-1.34 (m, 2H), 0.52-0.88 (m, 3H)
LCMS, [M + H]+ = 482.2 hLPA1 IC.sub.50 = 35 nM Example 267
(1S,3S)-3-((2-(difluoromethyl)-6- (1-methyl-5-
(((methyl(propyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-
yl)pyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 278 ##STR00459##
1H NMR (500 MHz, DMSO- d6) .delta. 8.16 (d, J = 8.85 Hz, 1H), 7.82
(br d, J = 8.85 Hz, 1H), 6.87-7.22 (m, 1H), 5.62 (br d, J = 10.99
Hz, 2H), 4.93 (br s, 1H), 4.13 (br s, 3H), 2.96- 3.29 (m, 2H),
2.61-2.87 (m, 4H), 0.52-2.18 (m, 15H) LCMS, [M + H].sup.+ = 496.2
hLPA1 IC.sub.50 = 22 nM Example 267 (1S,3S)-3-((6-(5-
(((butyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-(difluoromethyl)pyridin- 3-yl)oxy)cyclohexane-1- carboxylic
acid 279 ##STR00460## 1H NMR (500 MHz, DMSO- d6) .delta. 8.16 (d, J
= 8.75 Hz, 1H), 7.80 (d, J = 8.92 Hz, 1H), 6.84- 7.23 (m, 1H), 5.63
(s, 2H), 4.92 (br s, 1H), 4.13 (s, 3H), 2.83 (s, 2H), 2.61-2.74 (m,
1H), 2.55 (s, 3H), 2.01-2.17 (m, 1H), 1.40-1.95 (m, 7H), 1.25 (s,
1H), -0.16-0.98 (m, 5H) LCMS, [M + H]+ = 494.2 hLPA1 IC.sub.50 = 21
nM Example 267 (1S,3S)-3-((6-(5- ((((cyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-
(difluoromethyl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 280
##STR00461## 1H NMR (500 MHz, DMSO- d6) .delta. 8.16 (d, J = 8.75
Hz, 1H), 7.80 (d, J = 8.92 Hz, 1H), 6.89- 7.22 (m, 1H), 5.62 (s,
2H), 4.92 (br s, 1H), 2.74 (s, 3H), 2.60-2.72 (m, 1H), 2.55 (s,
3H), 1.79 (d, J = 123.19 Hz, 15H) LCMS, [M + H]+ = 494.2 hLPA1
IC.sub.50 = 22 nM Example 267 (1S,3S)-3-((6-(5-
(((cyclobutyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2-(difluoromethyl) pyridin-3-yl)oxy)cyclohexane-1-
carboxylic acid 281 ##STR00462## 1H NMR (500 MHz, DMSO- d6) .delta.
8.16 (d, J = 8.85 Hz, 1H), 7.82 (br d, J = 8.85 Hz, 1H), 6.88-7.19
(m, 1H), 5.62 (br d, J = 10.99 Hz, 2H), 4.93 (br s, 1H), 4.02-4.24
(m, 3H), 2.97- 3.34 (m, 2H), 2.60-2.85 (m, 4H), -0.24-2.48 (m, 16H)
LCMS, [M + H]+ = 508.2 hLPA1 IC.sub.50 = 35 nM Example 267
(1S,3S)-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-(difluoromethyl)
pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 282 ##STR00463## 1H
NMR (500 MHz, DMSO- d6) .delta. 8.16 (br d, J = 8.75 Hz, 1H), 7.80
(br d, J = 8.84 Hz, 1H), 6.85-7.47 (m, 6H), 5.69 (br s, 2H), 4.91
(br s, 1H), 4.37 (br s, 2H), 4.07 (br d, J = 14.22 Hz, 3H),
2.61-2.89 (m, 4H), 1.42-2.16 (m, 8H) LCMS, [M + H]+ = 530.9 hLPA1
IC.sub.50 = 19 nM Example 267 (1S,3S)-3-((6-(5-
(((benzyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-
triazol-4-yl)-2- (difluoromethyl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 283 ##STR00464## 1H NMR (500
MHz, DMSO- d6) .delta. 7.97 (br d, J = 7.02 Hz, 1H), 7.61 (br d, J
= 8.54 Hz, 1H), 5.66 (br d, J = 8.54 Hz, 2H), 4.84 (br s, 2H), 4.54
(br d, J = 2.75 Hz, 2H), 4.11 (s, 3H), 3.34 (s, 1H), 2.97-3.22 (m,
2H), 2.71-2.86 (m, 3H), 2.62-2.70 (m, 1H), 1.23-2.13 (m, 10H), 1.01
(d, J = 6.41 Hz, 1H), 0.56-0.87 (m, 3H) LCMS, [M + H]+ = 476.2
hLPA1 IC.sub.50 = 475 nM Example 268 (1S,3S)-3-((2-(methoxymethyl)-
6-(1-methyl-5-(((methyl(propyl) carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 284
##STR00465## 1H NMR (500 MHz, DMSO- d6) .delta. 7.98 (br d, J =
8.85 Hz, 1H), 7.61 (br d, J = 8.85 Hz, 1H), 5.66 (br d, J = 8.85
Hz, 2H), 4.84 (br s, 1H), 4.54 (d, J = 2.44 Hz, 2H), 4.11 (s, 3H),
3.00-3.28 (m, 2H), 2.61-2.85 (m, 4H), 0.57-2.16 (m, 18H) LCMS, [M +
H]+ = 490.3 hLPA1 IC.sub.50 = 48 nM Example 268
(1S,3S)-3-((6-(5-(((butyl(methyl) carbamoyl)oxy)methyl)-1-
methyl-1H-1,2,3-triazol-4-yl)-2- (methoxymethyl)pyridin-3-yl)
oxy)cyclohexane-1-carboxylic acid 285 ##STR00466## 1H NMR (500 MHz,
DMSO- d6) .delta. 7.98 (br d, J = 8.54 Hz, 1H), 7.60 (br d, J =
8.54 Hz, 1H), 5.66 (br d, J = 12.82 Hz, 2H), 4.82 (br s, 1H), 4.42-
4.65 (m, 2H), 4.12 (s, 3H), 2.92-3.22 (m, 2H), 2.61-2.89 (m, 4H),
0.64-2.16 (m, 14H), -0.11-0.53 (m, 4H) LCMS, [M + H]+ = 488.3 hLPA1
IC.sub.50 = 1008 nM Example 268 (1S,3S)-3-((6-(5-((((cyclopropyl-
methyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-(methoxymethyl)pyridin- 3-yl)oxy)cyclohexane-1- carboxylic
acid 286 ##STR00467## 1H NMR (500 MHz, DMSO- d6) .delta. 7.96 (br
d, J = 8.54 Hz, 1H), 7.60 (br d, J = 8.85 Hz, 1H), 5.63 (s, 2H),
4.82 (br s, 1H), 4.52 (br s, 2H), 4.09 (s, 3H), 3.32 (s, 3H),
2.59-2.81 (m, 4H), 1.26-2.24 (m, 15H) LCMS, [M + H]+ = 488.3 hLPA1
IC.sub.50 = 92 nM Example 268 (1S,3S)-3-((6-(5-(((cyclobutyl
(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)-
2-(methoxymethyl) pyridin-3-yl) oxy)cyclohexane-1-carboxylic acid
287 ##STR00468## 1H NMR (500 MHz, DMSO- d6) .delta. 7.98 (d, J =
8.54 Hz, 1H), 7.61 (d, J = 8.85 Hz, 1H), 5.66 (s, 2H), 4.84 (br s,
1H), 4.54 (d, J = 2.75 Hz, 2H), 4.11 (s, 3H), 3.91 (s, 1H),
2.73-2.92 (m, 1H), 2.65 (br s, 3H), 2.56 (s, 1H), 1.24-2.12 (m,
17H) LCMS, [M + H]+ = 502.3 hLPA1 IC.sub.50 = 118 nM Example 268
(1S,3S)-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-(methoxymethyl)
pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 288 ##STR00469## 1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.12 (br d, J = 8.53 Hz, 1H),
7.95 (br s, 1H), 5.39-5.59 (m, 2H), 4.87 (br s, 1H), 4.20 (br s,
3H), 3.23 (br s, 2H), 2.84 (br s, 1H), 2.68-2.79 (m, 3H), 1.46-2.19
(m, 10H), 0.88 (br s, 3H) LCMS, [M + H]+ = 449.1 hLPA1 IC.sub.50 =
29 nM Example 93 (1S,3S)-3-((2-methyl-6-(1-
methyl-5-((((methyl-d3)(propyl) carbamoyl)oxy)methyl)-1H-1,2,3-
triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 289
##STR00470## 1H NMR (500 MHz, DMSO- d6) .delta. 8.29 (d, J = 8.85
Hz, 1H), 7.98 (br d, J = 9.16 Hz, 1H), 5.45-5.65 (m, 2H), 4.99 (br
s, 1H), 4.12 (s, 3H), 2.91-3.14 (m, 2H), 2.83 (br s, 3H), 2.56-
2.69 (m, 1H), 1.41-2.04 (m, 8H), 0.71-1.03 (m, 1H), -0.08- 0.50 (m,
4H) LCMS, [M + H]+ = 469.1 hLPA1 IC.sub.50 = 40 nM Example 270
(1S,3S)-3-((2-cyano-6-(5- ((((cyclopropylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 290 ##STR00471## .sup.1H NMR
(500 MHz, DMSO- d.sub.6) .delta. 8.30 (br s, 1H), 7.92 (br d, J =
9.77 Hz, 1H), 6.91-7.38 (m, 5H), 5.47-5.72 (m, 2H), 5.00 (br s,
1H), 4.25-4.50 (m, 3H), 3.94-4.20 (m, 2H), 2.60-2.88 (m, 4H),
1.37-2.18 (m, 8H) LCMS, [M + H]+ = 505.3 hLPA1 IC.sub.50 = 2 nM
Example 270 (1S,3S)-3-((6-(5- (((benzyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-cyanopyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 291 ##STR00472## 1H NMR (500
MHz, DMSO- d6) .delta. 8.30 (br d, J = 8.85 Hz, 1H), 7.98 (d, J =
9.16 Hz, 1H), 5.40-5.65 (m, 2H), 5.00 (br s, 1H), 4.13 (br s, 3H),
2.99- 3.29 (m, 2H), 2.70-2.83 (m, 3H), 2.62 (br t, J = 9.92 Hz,
1H), 0.59-2.17 (m, 15H) LCMS, [M + H]+ = 471.3 hLPA1 IC.sub.50 = 15
nM Example 270 (1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)
methyl)-1-methyl-1H-1,2,3-triazol-
4-yl)-2-cyanopyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 292
##STR00473## 1H NMR (500 MHz, DMSO- d6) .delta. 8.24-8.45 (m, 1H),
8.30 (br d, J = 8.67 Hz, 1H), 7.97 (br d, J = 9.09 Hz, 1H), 5.43-
5.68 (m, 2H), 5.01 (br s, 1H), 4.05-4.22 (m, 3H), 3.56 (br s, 1H),
3.05-3.30 (m, 2H), 2.66- 2.83 (m, 3H), 1.09-2.37 (m, 15H) LCMS, [M
+ H]+ = 483.2 hLPA1 IC.sub.50 = 20 nM Example 270
(1S,3S)-3-((2-cyano-6-(5- ((((cyclobutylmethyl)(methyl)
carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 293 ##STR00474## 1H NMR (500
MHz, DMSO- d6) .delta. 8.30 (d, J = 9.16 Hz, 1H), 7.97 (br d, J =
9.16 Hz, 1H), 5.52 (br s, 2H), 5.00 (br s, 1H), 4.12 (s, 3H),
3.40-3.67 (m, 1H), 2.74 (br s, 3H), 2.57- 2.66 (m, 1H), 1.29-2.22
(m, 14H) LCMS, [M + H]+ = 469.3 hLPA1 IC.sub.50 = 23 nM Example 270
(1S,3S)-3-((2-cyano-6-(5- (((cyclobutyl(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-
yl)oxy)cyclohexane-1-carboxylic acid 294 ##STR00475## 1H NMR (500
MHz, DMSO- d6) .delta. 8.29 (d, J = 8.85 Hz, 1H), 7.97 (br d, J =
9.16 Hz, 1H), 5.52 (br s, 2H), 5.00 (br s, 1H), 4.12 (s, 3H),
3.50-3.69 (m, 1H), 2.65 (br s, 3H), 2.60 (br s, 1H), 1.22-2.11 (m,
16H) LCMS, [M + H]+ = 483.3 hLPA1 IC.sub.50 = 15 nM Example 270
(1S,3S)-3-((2-cyano-6-(5- (((cyclopentyl(methyl)carbamoyl)
oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)
cyclohexane-1-carboxylic acid
* * * * *