HETEROCYCLIC COMPOUNDS USEFUL IN THE TREATMENT OF DISEASE

COMPOSES HETEROCYCLIQUES UTILES DANS LE TRAITEMENT DE MALADIES

English Abstract

Heterocyclic compounds are described that are lysophosphatidic acid receptor
ligands that are useful in the treatment of lysophosphatidic acid receptor-
dependent
diseases and conditions, including but not limited to diseases involving
fibrosis, such as
fibrosis of the heart, kidney, liver and lung,and scleroderma; inflammatory
diseases
such as diabetic nephropathy and nonalcoholic steatohepatitis (NASH); ocular
diseases
such as diseases involving retinal degeneration; nerve diseases such as
pruritus and
pain.

Claims

CLAIMS
WHAT IS CLAIMED IS:
1 . A compound having the structure of Formula X
<IMG>
or a pharmaceutically acceptable salt or prodrug thereof,
wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=O)NH2, -C(=O)NHRB,
C(=O)NHSO2RB or -C(=O)NHCH2CH2SO3H or a carboxylic acid isostere;
RB is optionally substituted C1-C4 alkyl or has the structure of one of
<IMG> , and <IMG> ;
L1 is optionally substituted C1-C6 alkylene; C1-C6 fluoroalkylene; or
optionally
substituted C1-C6 heteroalkylene, or L1, when present is -CH2-, <IMG> , or
disubstituted dimethylmethane;
A1 is N or C;
Ring A has the structure of one of:
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<IMG> , and <IMG> ;
RC is -CN, -F, -Cl, -Br, -l, -OC1-C4 alkyl, C3-C6 cycloalkyl, or C1-C4
fluoroalkyl;
RD is -N(RF)-C(=O)XCH(RG)-CY, wherein X is O and CY is phenyl substituted
with one RH:
<IMG>
RE, RF and RG independently are -H or C1-C4 alkyl or C3-C6 cycloalkyl or RE
and
RF independently are -H or C1-C4 alkyl or C1-C6 cycloalkyl and one RG is -C1-
C4 alkyl
and is taken together with the RH pheny moiety of the Ring A RD substituent
and the
carbon atom to which RG and said phenyl moiety is attached to define a
substituted or
unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and
the other
RG, if present, is as defined for RE;
each RH is independently -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S(=O)RJ,
-S(=O)2RJ, -N(RJ)S(=O)2RJ, -S(=O)2N(RL)2, -C(=O)RJ, -OC(=O)RJ, -CO2RJ, -
OCO2RJ, -N(RL)2, -C(=O)N(RL)2, -OC(=O)N(RL)2, -NRJC(=O)N(RL)2, -NRJC(=O)RJ, -
NRJC(=O)ORJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4
alkoxy,and C1-
C4 heteroalkyl;
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RJ is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted
C1-C6
heteroalkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted
C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted
or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted
or unsubstituted C3-C6 cycloalkyl), -C1-C4 alkylene-(substituted or
unsubstituted
heterocycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted aryl), or C1-
C4 alkylene-
(substituted or unsubstituted heteroaryl),
RL independently are -H, substituted or unsubstituted C1-C6 alkyl, substituted
or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl,
substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -C1-C4 alkylene-(substituted or unsubstituted C3-C6 cycloalkyl), -
C1-C4
alkylene-(substituted or unsubstituted heterocycloalkyl), -C1-C4
alkylene(substituted or
unsubstituted aryl), or -C1-C4 alkylene-(substituted or unsubstituted
heteroaryl),
or when RH is -S(=O)2N(RL)2, -N(RL)2, -C(=O)N(RL)2,-OC(=O)N(RL)2 or -
N(RJ)C(=O)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL groups
independently are C1-C6 alkyl which are taken together with the N atom to
which they
are attached to define a substituted or unsubstituted heterocycle.
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2. The compound according to
claim 1 , wherein:
RA is -CO2H;
L1 is <IMG> ;
in the ring <IMG> , RH is -F;
in the ring <IMG> , A1 is C and RH is -H;
Ring A has the structure of <IMG> ;
RC is -F;
RF is -H;
RG is -CH3; and
in the CY ring <IMG> , RH is -Cl.
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3. The compound according to claim 1, wherein:
RA is -CO2H, tetrazolyl <IMG> , -C(=O)NH2, or -C(=O)NHSO2RB;
L1 is -CH2-, <IMG> , or disubstituted dimethylmethane;
in the ring <IMG> , RH is -H, a halogen, or -CH3;
in the ring <IMG> , A1 is C or N and RH is -H;
Ring A has the structure of <IMG> ;
RC is -F, -Cl, -CN, or -CF3;
RF is -H;
RG is -CH3 in an R configuration; and
in the CY ring <IMG> , RH is -H or a halogen.
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- 236 -
4. The compound according to
claim 3 , wherein:
RA is -CO2H;
L1 is <IMG> ;
in the ring <IMG> , RH is -H;
in the ring <IMG> , A1 is N and RH is -H,
RC is -F, and
in the CY ring <IMG> , RH is -Cl.
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. The compound according to claim 3 , wherein:
R A is ¨CO2H;
is <IMG> ;
in the ring <IMG> , R H is ¨H;
in the ring <IMG> , A1 is N and R H is ¨H;
R c is ¨Cl; and
in the CY ring <IMG> , R H is ¨Cl.
6. The compound according to claim 3 , wherein
in the ring <IMG> , A1 is C and R H is ¨H.
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7 . The compound according to claim 6 , wherein:
R A is -CO2H, and
L1 is <IMG>
8 The compound according to claim 7 , wherein:
in the ring <IMG> R H is ¨H.
9 . The compound according to claim 8 , wherein:
R c is ¨F; and
in the CY ring <IMG> R H is ¨Cl.
10. The compound according to claim 8 , wherein
R c is ¨F; and
in the CY ring <IMG> R H is ¨H.
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11 . The compound according to claim 8 , wherein
R C is ¨CF3; and
in the CY ring <IMG> R H is ¨H.
12 . The compound according to claim 8 , wherein:
R C is ¨CI, and
in the ring <IMG> R H is ¨H.
13. The compound of claim 8 , wherein:
R C is ¨CN; and
in the ring <IMG> R H is ¨H.
141. The compound of claim 8., wherein:
R C is ¨CN; and
in the ring <IMG> R H is ¨Cl.
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15 . The compound according to claim 7 , wherein:
in the ring <IMG> R H is ¨F.
16 . The compound according to claim 15, wherein:
R C is ¨F; and
in the CY ring <IMG> R H is ¨Cl.
17. The compound according to claim 15, wherein:
R C is ¨F; and
in the CY ring <IMG> R H is ¨H.
18. The compound according to claim 15, wherein:
R C is ¨CF3, and
in the CY ring <IMG> R H is ¨H.
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19 . The compound according to claim 15, wherein:
R C is ¨CI, and
in the CY ring <IMG> R H is ¨H.
20,. The compound according to claim 7 , wherein:
in the ring <IMG> R H is ¨Cl.
21. The compound according to claim 20, wherein:
R C is ¨F; and
in the CY ring <IMG> R H is ¨Cl.
22 . The compound according to claim 20, wherein:
R C is ¨F; and
in the CY ring <IMG> R H is ¨H.
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23 . The compound according to claim 20, wherein:
R C is ¨Cl; and
in the CY ring <IMG> R H is ¨H.
241. The compound according to claim 7 , wherein:
in the ring <IMG> R H is ¨CH3.
25. The compound according to claim 24, wherein:
R C is ¨F; and
in the CY ring <IMG> R H is ¨Cl.
26. The compound according to claim 24, wherein:
R C is ¨F; and
in the CY ring <IMG> R H is ¨H.
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27 . The compound according to claim 24, wherein:
R C is ¨CI; and
in the CY ring <IMG> R H is ¨H.
28 . The compound according to claim 6 , wherein:
R A is -C(=O)NH2;
L1 is <IMG>
in the ring <IMG> R H is ¨H;
R C is ¨F; and
in the CY ring <IMG> R H is ¨Cl.
29 . The compound according to claim 6 , wherein:
R A is -C(=O)NHSO2R B, where R B is ¨CH3; and
L1 is <IMG>
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30. The compound according to claim 29, wherein:
in the ring <IMG> R H is ¨F.
31. The compound according to claim 30, wherein:
R c is ¨F; and
in the CY .ng <IMG> R H
n is ¨Cl.
32 The compound according to claim 30, wherein:
R c is ¨F, and
in the CY ring <IMG> R H is ¨H.
33 . The compound according to claim 30, wherein:
R c is ¨Cl; and
in the CY ring <lMG> R H is ¨Cl.
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34 . The compound according to claim 29, wherein:
in the ring <IMG> R H is ¨H.
35 . The compound according to claim 34 , wherein:
R c is ¨CI; and
in the CY ring <IMG> R H is ¨H.
36 . The compound according to claim 34, wherein:
R c is ¨F, and
in the CY ring <IMG> R H is ¨Cl.
37. The compound according to claim 6 wherein:
R A is tetrazolyl <IMG>
L1 is <IMG> and
in the ring <IMG> R H is ¨H.
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38. The compound according to claim 37, wherein:
R c is ¨F; and
in the CY ring <IMG> R H is ¨Cl.
39. The compound according to claim 37, wherein:
R c is ¨Cl; and
in the CY ring <IMG> R H is ¨H.
40. The compound according to claim 37, wherein:
R c is ¨Cl; and
in the CY ring <IMG> R H is ¨Cl.
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41. The compound according to claim 3 , wherein:
R A is ¨CO2H;
L1 is dimethylmethane <IMG>
in the ring <IMG> R H is ¨H;
in the ring <IMG> A1 is C and R H is ¨H;
and R c is ¨CN.
42 . The compound according to claim 41, wherein:
in the CY ring <IMG> R H is ¨Cl.
43. The compound according to claim 41, wherein:
in the CY ring <IMG> R H is ¨H.
44 . The compound according to claim 1 , wherein R G is in an R or
S
configuration.
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45 . A pharmaceutical composition comprising:
the compound according to claim 1 ; and
a pharmaceutically acceptable excipient.
46 . A method for treating a lysophosphatidic acid-dependent disease
or condition in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of the
compound
according to claim 1.
47. The method according to claim 46, whrein the lysophosphatidic
acid-dependent disease or condition is diabetic nephropathy or nonalcoholic
steatohepatitis (NASH).
- 250 -

Description

HETEROCYCLIC COMPOUNDS USEFUL IN THE TREATMENT OF DISEASE
CROSS REFERENCE TO RELATED APPLICATIONS
[01] This application is a continuation of United States Patent Application
No. 14/776,954,
filed on September 15, 2015, which is a a 371 National Phase of
PCT/US2014/030712, filed on
March 17, 2014, which claims the benefit of U.S. Provisional Patent
Application Serial No.
61/801,426, filed March 15, 2013, U.S. Provisional Patent Application Serial
No. 61/801,231,
filed March 15, 2013, and U.S. Provisional Patent Application Serial No.
61/827,409, filed May
24, 2013, the entire contents of all of which are hereby incorporated by
reference herein.
STATEMENT OF GOVERNMENT INTEREST
[02] This invention was made with government support under Grants DK092005 and
CA174019 awarded by the National Institutes of Health. The US government has
certain rights
in the invention.
FIELD OF THE INVENTION
[03] The present invention relates to compounds having pharmacological
activity, to
processes for preparation of such compounds, to pharmaceutical compositions
comprising
them, and to their use in therapy and prophylaxis of disease in a subject in
need thereof, in
particular for human and veterinarian treatments of pain, pruritus, cancer,
inflammation and
fibrotic diseases.
BACKGROUND OF THE INVENTION
[04] Lysophospholipids affect fundamental cellular functions that include
proliferation,
differentiation, survival, migration, adhesion, invasion, and morphogensis.
Abnormal functions
influence many biological processes leading to disease that include, but are
not limited to
fibrotic disease, inflammation, cancer and peripheral nerve injury.
Lysophosphatidic acid (LPA)
- 1 -
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is a lysophospholipid that has been shown to act through specific G protein-
coupled receptors
(GPCRs) in an autocrine and paracrine fashion. Antagonists of the LPA
receptors find use in
the treatment of diseases, disorders or conditions in which LPA plays a role.
[05] Agents that interact with the lysophosphatidic acid receptors [LPARs] to
reduce signal
transduction through those receptors (i.e., by competitive or noncompetitive
inhibition or acting
as inverse agonists) reduce manifestations of the diseases described herein.
Diseases and
conditions whose etiology, progression or persistence is effected by in whole
or in part by
signaling through the lysophosphatidic acid receptor subtype 1 (LPA1R) are
considered LPA-
dependent. New agents having therapeutic utility for treating those LPA-
dependent and other
conditions and diseases described herein are needed.
SUMMARY OF THE INVENTION
[06] Disclosed herein are compounds that inhibit the physiological activity of
lysophosphatidic
acid (LPA), and therefore, are useful as agents for the treatment or
prevention of diseases in
which inhibition of the physiological activity of LPA is useful.
[07] In one aspect, those compounds are useful for the treatment of fibrosis
of organs (e.g.,
liver, kidney, lung, heart and the like), liver diseases (e.g., acute
hepatatis, chronic hepatitis,
liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure,
nonalcoholic
steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and
the like), cell
proliferative disease such as cancers (including but not limited to solid
tumor, solid tumor
metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma,
leukemia, chronic
lymphocytic leukemia (CLL), invasive metastasis of cancer cell, and the like),
inflammatory
diseases (including but not limited to psoriasis, nephropathy, pneumonia and
the like),
gastrointestinal tract disease (including but not limited to (irritable bowel
syndrome (IBS),
inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the
like), renal disease,
urinary tract-associated disease (including but not limited to benign
prostatic hyperplasia or
- 2 -
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symptoms associated with neuropathic bladder disease, spinal cord tumor,
hernia of
intervertebral disk, spinal canal stenosis, symptoms derived from diabetes,
lower urinary tract
disease (including but not limited to obstruction of lower urinary tract, and
the like), inflammatory
disease of lower urinary tract, (including but not limited to dysuria,
frequent urination, and the
like), pancreas disease, abnormal angiogenesis-associated disease (including
but not limited to
arterial obstruction and the like), scleroderma, brain-associated disease
(including but not
limited to cerebral infarction, cerebral hemorrhage, and the like), nervous
system diseases
(including but not limited to neuropathic pain, peripheral neuropathy,
pruritus and the like),
ocular disease (including but not limited to age-related macular degeneration
(AMD), diabetic
retinopathy, proliferative vitreo-retinopathy (PVR), cicatricial pemphigoid,
glaucoma filtration
surgery scarring, and the like).
[08] The compounds of the invention include compounds of Formula I that have
the structure:
A B L2 A
L¨R Formula I
[09] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
-C(=0)NHSO2RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[010] L1 is absent or optionally substituted C1-C6 alkylene, optionally
substituted C3-C6
cycloalkylene, optionally substituted C1-C6 fluoroalkylene, optionally
substituted C1-C6
heteroalkylene, or -UV-Z-, wherein -UV- is defined by -OW-, -WO-, -N(R)W-, -
WN(Fe)-, -
N(R)C(=O)-, -SW-, -S(=O)W-, or -C(=0)N(RJ)-, wherein W is optionally
substituted C1-C3
alkylene or optionally substituted C3-C6 cycloalkylene or W is -C(RL)2-, Z is
optionally substituted
C1-06 alkylene, optionally substituted C3-06 cycloalkylene or C1-
C6fluoroalkylene or Z is -C(RL)2-
; and n is 0, 1, 0r2;
- 3 -
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[011] L2 is absent, or optionally substituted C1-C6 alkylene, optionally
substituted C3-C6
cycloalkylene, C1-C6 fluoroalkylene, optionally substituted C1-C6
heteroalkylene, -0-, -S-, -
S(=0)-, -S(=0)2-, -N(RB)-, -C(=0)-, or -C(=0)N(RB)-;
[012] wherein RB is -H or -optionally substituted C1-C4 alkyl, or has the
structure of one of:
0y1Z;( )r0
[013] o ;
[014] Ring A is a 5 or 6 membered heteroarene having the structure of one
of:
RE
N, I ) RN %--N RD \---RD
c RD Rc)==kRD RC RD
Rc
0 N=c ¨(
RD RD Rc RD RD
Rc RD
Rc
RE
0
0 N c r:
Rc/
' T.s.:("H N \ I
/ = R RD Rc µ1
)=RD N RD Re RD
RD
7
[015] wherein the dashed line indicates the point of attachment of Ring A
to Ring 6;
[016] wherein one of Rc and RD is -H, -CN, -F, -Br, -I, -0C1-C4 alkyl,
C1-C4 alkyl, C3-C6
cycloalkyl, or C1-C4fluoroalkyl,
[017] and the other Rc or RD is -N(RE)C(=0)XCH(RG)-CY, -N(RE)C(=0)XC(RG)2-CY,
-N(RE)C(=0)X-CY, -C(=0)-N(RE)-CH(RG)X-CY, or -C(=0)-N(RE)-C(RG)2X-CY, wherein
X is
absent, -0-, -NH- or -CH2-;
[018] RE is -H, C1-C4 alkyl or C1-C4fluoroalkyl;
[019] RE is -H or C1-C4 alkyl;
[020] RG is independently selected RE, or one RG is C1-C4 alkylne and is
taken together with
CY and the the carbon atom to which RG and CY is attached to define a
substituted or
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unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and
the other RG, if
present, is as defined for RE;
[021] CY is optionally substituted C1-C6 alkyl, optionally substituted C3-
C10 cycloalkyl,
optionally substituted 02-C10 heterocycloalkyl, optionally substituted aryl,
or optionally
substituted heteroaryl, wherein if CY is substituted then CY is substituted
with 1, 2, or 3
independently selected RH,
[022] wherein each RH is independently -H, halogen, -CN, -NO2, -OH, -OR, -
SR,
-S(=0)R, -S(=0)2RJ, -N (RJ)S(=0)2RJ, -S(=0)2N(R1)2, -C(=0)R, OC(=0)RJ, -
C(=0)0RJ,
-0C=0)0RJ, -N(RI-)2, -C(=0)N(RI-)2, -0C(=0)N(RI-)2, -N(RJ)C(=0)N(RI-)2, -
N(RJ)C(=0)RJ,
-N(RJ)C(=0)0RJ, C1-04 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4
alkoxy, or C1-C4
heteroalkyl;
[023] wherein each RJ is independently optionally substituted C1-C6 alkyl,
optionally
substituted C1-C6 heteroalkyl, optionally substituted C1-C6 fluoroalkyl,
optionally substituted C3-
C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted
aryl, optionally
substituted heteroaryl, -C1-C4 alkylene-(optionally substituted 03-C6
cycloalkyl), -01-04 alkylene-
(optionally substituted heterocycloalkyl), -C1-C4 alkylene-(optionally
substituted aryl), or -Ci-C4
alkylene-(optionally substituted heteroaryl), and
[024] wherein RI- is independently -H, optionally substituted 01-06 alkyl,
optionally
substituted C1-C6 heteroalkyl, optionally substituted C1-C6 fluoroalkyl,
optionally substituted C3-
C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted
aryl, optionally
substituted heteroaryl, -01-C4 alkylene-(optionally substituted C3-C6
cycloalkyl), -Ci-C4 alkylene-(
optionally substituted heterocycloalkyl), -C1-C4 alkylene-(optionally
substituted aryl), or -Ci-04
alkylene-(optionally substituted heteroaryl),
[025] or when RH is -S(=0)2N(RI-)2, -N(RI)2, -C(=0)N(RI-)2, -0C(=0)N(RI-)2
or
- 5 -
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-N(W)C(=0)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL groups
independently
are C1-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[026] or when W is -C(RL)2, or Z is -C(RL)2- each RL is independently -H or
C1-C6 alkyl, or
the RL groups independently are C1-06 alkyl which are taken together with the
carbon atom to
which they are attached to define a carbocycle;
[027] Ring B is a optionally substituted C3-C10 cycloalkylene, optionally
substituted C2-C10
heterocycloalkylene, optionally substituted arylene, or optionally substituted
heteroarylene,
wherein if ring B is substituted then ring B is substituted with 1,2, or 3
independently selected
RH, wherein RH is as previously defined; and
[028] Ring C is absent or optionally substituted C3-C10 cycloalkylene,
optionally substituted
C2-C10 heterocycloalkylene, optionally substituted arylene, or optionally
substituted
heteroarylene, where if ring C is substituted then ring C is substituted with
1, 2, or 3
independently selected RH, wherein RH is as previously defined;
[020] wherein when Ring B is substituted or unsubstituted arylene, Ring C
is absent, L2 is
absent, Cis -UV-Z-, wherein -UV- is -N(RJ)-C(=0)-, wherein RE is -H, RD is
-N(RE)-C(=0)XCH(RG)-CY, wherein X is -0-, RG is -CH3 and RE is -H, and RD is -
H, -CH3 or -
CF3,
[030] or when Ring B is optionally substituted arylene and Ring C is
substituted or
unsubstituted arylene or is substituted or unsubstituted C3-C10 cycloalkylene,
or Ring B is
substituted or unsubstituted C3-C10 cycloalkylene and Ring C is substituted or
unsubstituted
arylene, L2 is absent, Lis C1-C6 alkylene,
[031] and RD is -H or -CH3 and RA is -CO2H or -0O2R6
,
[032] then Ring A has the structure of one of:
- 6 -
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RE
I
N-....! ,,N--N.; = N"Xr RE¨Ni N I
Rc R
D R D Rc
c )--''--NRID "----RD
R
N =
:,'
s---N ' R -,r .1.-- (N<
ni,,- RE-----ir
N...____L.
RD 04 N=(
RD Fzc\ RD RD71 RD
RC RD
0 RE
E N. s=
R--...,Nr- QYNI,N-i- c.:I.Z.:-.' IN11-'-X r r
, /
, , , N R, ..'s'N RD Rc''' .....'N-----
NRD
N RD/ mc
RD
RD RD
t-----
[033] RD rc
,
[034] and when Ring B is C2-C10 heterocycloalkylene, Ring C is substituted
or unsubstituted
arylene, L2 is absent, L' is C1-C6 alkylene, Rc is -CH3 and RA is -CO2H or
-CO2RB, then Ring A has the structure of one of:
N, ,.. E IN......,_>; ,,N....N:.!
p, , R¨N N I
y....
s..
Rc ...;N
R RD We-NW"
Rc
N '
µ RcN ' e,,,,..õ- Rõ..e_r
;''
N / ' N .......Aµ
10-- N=( RD / -
RD RD
Re RD RD
RE
0 i
0 N , rcrIN N.
E
RNA -:-N( \ j( I
N p.c., \ D R N RD RD N RD
RC/ rx =
[035] R RD RD RD R
[036] Other compounds of the invention have the structures indicated by the
numbered
embodiment and claims herein.
DETAILED DESCRIPTION OF THE INVENTION
[037] Definitions
[0381 As used herein and unless otherwise stated or implied by context, terms
that are used
herein have the meanings defined below. Unless otherwise contraindicated or
implied, e.g., by
including mutually exclusive elements or options, in these definitions and
throughout this
- 7 -
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specification, the terms "a" and "an" mean one or more and the term "or" means
and/or where
permitted by context. Thus, as used in the specification and the appended
claims, the singular
forms "a," "an" and "the" include plural referents unless the context clearly
dictates otherwise.
[039] At various locations in the present disclosure, e.g., in any disclosed
embodiments or
in the claims, reference is made to compounds, compositions, or methods that
"comprise"
one or more specified components, elements or steps. Invention embodiments
also
specifically include those compounds, compositions, compositions or methods
that are or that
consist of or that consist essentially of those specified components, elements
or steps. The
terms "comprising", "consist of" and "consist essentially of" have their
normally accepted
meanings under U.S. patent law unless otherwise specifically stated. The term
"comprised
of" is used interchangeably with the term "comprising" and are stated as
equivalent terms.
For example, disclosed compositions, devices, articles of manufacture or
methods that
"comprise" a component or step are open and they include or read on those
compositions or
methods plus an additional component(s) or step(s). Similarly, disclosed
compositions,
devices, articles of manufacture or methods that "consist of" a component or
step are closed
and they would not include or read on those compositions or methods having
appreciable
amounts of an additional component(s) or an additional step(s). Furthermore,
use of the term
"including" as well as other forms, such as "include", "includes," and
"included," is not limiting.
The section headings used herein are for organizational purposes only and are
not to be
construed as limiting the subject matter described. Unless otherwise
indicated, conventional
methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant
DNA techniques and pharmacology are employed.
[040] "Bond" or "single bond" as used herein means a chemical bond between two
atoms, or
two moieties when the atoms joined by the bond are considered to be part of
larger
substructure. As explicitly stated or implied by context, when a group
described herein is a
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bond, the referenced group is absent thereby allowing a bond to be formed
between the
remaining identified groups.
[041] "Membered ring" as used herein means any cyclic structure. The term
"membered" is
meant to denote the number of skeletal atoms that constitute the ring. Thus,
by way of example
and not limitation, those membered rings include cyclohexyl, pyridinyl,
pyranyl and thiopyranyl,
which are 6-membered rings and cyclopentyl, pyrrolyl, furanyl, and thienyl,
which are 5-
membered rings.
[042] "Moiety" as used herein means a specific segment, fragment or
functional group of a
molecule or compound. Chemical moieties are sometimes indicated as chemical
entities that
are embedded in or appended (i.e., a substituent or variable group) to a
molecule or compound.
[043] "Alkyl" as used herein is a collection of carbon atoms that are
covalently linked
together in normal, secondary, tertiary or cyclic arrangements, i.e., in a
linear, branched,
cyclic arrangement or some combination thereof. An alkyl substituent to a
structure is that
chain of carbon atoms that is covalently attached to the structure through a
sp3 carbon of the
substituent. The alkyl substituents, as used herein, contains one or more
saturated moieties
or groups and may additionally contain unsaturated alkyl moieties or groups,
i.e., the
substituent may comprise one, two, three or more independently selected double
bonds or
triple bonds of a combination thereof, typically one double or one triple bond
if such
unsaturated alkyl moieties or groups are present.
[044] Unsaturated alkyl moieties or groups include moieties or groups as
described below
for alkenyl, alkynyl, cycloalkyl, and aryl moieties. Saturated alkyl moieties
contain saturated
carbon atoms (sp3) and no aromatic, sp2 or sp carbon atoms. The number of
carbon atoms
in an alkyl moiety or group can vary and typically is 1 to about 50, e.g.,
about 1-30 or about 1-
20, unless otherwise specified, e.g., C1.8 alkyl or C1-C8 alkyl means an alkyl
moiety
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containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and Cl_s alkyl or C1-C6 means
an alkyl moiety
containing 1, 2, 3, 4, 5 or 6 carbon atoms.
[045] When an alkyl substituent, moiety or group is specified, species may
include methyl,
ethyl, 1-propyl (n-propyl), 2-propyl (/so-propyl, -CH(CH3)2), 1-butyl (n-
butyl), 2-methyl-1-propyl
(iso-butyl, -CH2CH(CH3)2), 2-butyl (sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-
propyl (t-butyl, -
C(CH3)3), amyl, isoamyl, sec-amyl and other linear, cyclic and branch chain
alkyl moieties.
Unless otherwise specified, alkyl groups can contain species and groups
described below for
cycloalkyl, alkenyl, alkynyl groups, aryl groups, arylalkyl groups, alkylaryl
groups and the like.
[046] Cycloalkyl as used here is a monocyclic, bicyclic or tricyclic ring
system composed of
only carbon atoms. The term "cycloalkyl" encompasses a monocyclic or
polycyclic aliphatic,
non-aromatic radical, wherein each of the atoms forming the ring (i.e.
skeletal atoms) is a
carbon atom. The number of carbon atoms in an cycloalkyl substituent, moiety
or group can
vary and typically is 3 to about 50, e.g., about 1-30 or about 1-20, unless
otherwise specified,
e.g., C3.8 alkyl or C3-C8 alkyl means an cycloalkyl substituent, moiety or
group containing 3, 4,
5, 6, 7 or 8 carbon atoms and C3.6 alkyl or C3-C6 means an cycloalkyl
substituent, moiety or
group containing 3, 4, 5 or 6 carbon atoms. Cycloalkyl substituents, moieties
or groups will
typically have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or
20 carbon atoms and
may contain exo or endo-cyclic double bonds or endo-cyclic triple bonds or a
combination of
both wherein the endo-cyclic double or triple bonds, or the combination of
both, do not form a
cyclic conjugated system of 4n + 2 electrons; wherein the bicyclic ring system
may share one
(i.e., Spiro ring system) or two carbon atoms and the tricyclic ring system
may share a total of 2,
3 or 4 carbon atoms, typically 2 or 3.
[047] Unless otherwise specified, cycloalkyl substituents, moieties or
groups can contain
moieties and groups described for alkenyl, alkynyl, aryl, arylalkyl, alkylaryl
and the like and
can contain one or more other cycloalkyl moieties. Thus, cycloalkyls may be
saturated, or
partially unsaturated. Cycloalkyls may be fused with an aromatic ring, and the
points of
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attachment to the aromatic ring are at a carbon or carbons of the cycloalkyl
substituent,
moiety or group that is not an aromatic ring carbon atom. Cycloalkyl groups
include groups
having from 3 to 10 ring atoms. Cycloalkyl substituents, moieties or groups
include
cyclopropyl, cyclopentyl, cyclohexyl, adamantly or other cyclic all carbon
containing moieties.
Cycloalkyls further include cyclobutyl, cyclopentenyl, cyclohexenyl,
cycloheptyl and
cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted. Depending
on the
substituent structure, a cycloalkyl substituent can be a monoradical or a
diradical (i.e., an
cycloalkylene, such as, but not limited to, cyclopropan-1,1-diyl, cyclobutan-
1,1-diyl,
cyclopentan-1,1-diyl, cyclohexan-1,1-diyl, cyclohexan-1,4-diyl, cycloheptan-
1,1-diyl, and the
like). When cycloalkyl is used as a Markush group (i.e., a substituent) the
cycloalkyl is
attached to a Markush formula with which it is associated through a carbon
involved in a
cyclic carbon ring system carbon of the cycloalkyl group that is not an
aromatic carbon.
[048]
"Alkylamine" as used herein means an -N(alkyl),Hy group, moiety or substituent
where
x and y are independently selected from the group x=1, y=1 and x=2, y=0.
Alkylamine includes
those -N(alkyl)Fl groups wherein x=2 and y=0 and the alkyl groups taken
together with the
nitrogen atom to which they are attached form a cyclic ring system.
"Heteroalkylene" as used herein means an alkylene (i.e. alkanediy1) group,
moiety or substituent
in which one or more skeletal atoms of the alkyl are selected from an atom
other than carbon,
e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
Heteroalkylene includes Cr
C6 heteroalkylene or Crat heteroalkylene. Exemplary heteroalkylenes include,
but are not
limited to, -OCH2-, -OCH(CH3)-, -0C(CH3)2-, -OCH2CH2-, -CH20-, -CH(CH3)0-,
C(CH3)20-,
-CH2CH20-, -CH2OCH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -SCH2-, -SCH(CH3)-, -
SC(CH3)2-,
-SCH2CH2-, -CH2S-, -CH(CH3)S-, -C(CH3)2S-, -CH2CH2S-, -CH2SCH2-,-CH2SCH2CH2-,
-CH2CH2SCH2-, -S(=0)2CH2-, -S(=0)2CH(CH3)-, -S(=0)2C(CH3)2-, -S(=0)2CH2CH2-,
-CH2S(=0)2-, -CH(CH3)S(=0)2-, -C(CH3)2S(=0)2-, -CH2CH2S(=0)2-, -CH2S(=0)20H2-,
-CH2S(=0)2CH2CH2-, CH2CH2S(=0)2CH2-, -NHCH2-, -NHCH(CH3)-, -NHC(CH3)2-,
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-NHCH2CH2-, -CH2NH-, -CH(CH3)NH-, -C(CH3)2NH-, -CH2CH2NH-, -CH2NHCH2-,
-CH2NHCH2CH2-, -CH2CH2NHCH2-, and the like.
[049] "Carboxylic acid bioisostere" as used herein means a functional
group, moiety or
substituent that exhibits similar physical, biological and/or chemical
properties as a carboxylic
acid moiety. By way of example and not limitation, carboxylic acid
bioisosteres include,
N,\ N-Ck N-S
\i)t, ,OH µ,I)LN N-
,CN \s) /0 µ,ii.'
H H
\çX
OH
0
N F,C\/0F,
OH )c0H
OH OH 0 =
[050] "Alkenyl" as used herein means a substituent, moiety or group that
comprises one
or more double bond moities (e.g., -CH=CH-) or 1, 2, 3, 4, 5 or 6 or more,
typically 1, 2 or 3
such moieties and can include an aryl moiety or group such as benzene, and
additionally
comprises linked normal, secondary, tertiary or cyclic carbon atoms, i.e.,
linear, branched,
cyclic or any combination thereof unless the alkenyl moiety is a vinyl moiety
(e.g., -CH=CH2).
An alkenyl moiety, group or substituent with multiple double bonds may have
the double
bonds arranged contiguously (i.e. a 1,3 butadienyl moiety) or non-contiguously
with one or
more intervening saturated carbon atoms or a combination thereof, provided
that a cyclic,
contiguous arrangement of double bonds do not form a cyclically conjugated
system of 4n +
2 electrons (i.e., aromatic). The number of carbon atoms in an alkenyl group
or moiety can
vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless
otherwise specified,
e.g., C2.8 alkenyl or C2-8 alkenyl means an alkenyl moiety containing 2, 3, 4,
5, 6, 7 or 8
carbon atoms and C2_6 alkenyl or C2-6 alkenyl means an alkenyl moiety
containing 2, 3, 4, 5
or 6 carbon atoms. Alkenyl moieties or groups will typically have 2, 3, 4, 5,
6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
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[051] When an alkenyl moiety, group or substituent is specified, species
include, by way
of example and not limitation, any of the alkyl or cycloalkyl, groups moieties
or substituents
described herein that has one or more double bonds, methylene (=CH2),
methylmethylene
(=CH-CH3), ethylmethylene (=CH-CH2-CH3), =CH-CH2-CH2-CH3, vinyl (-CH=CH2),
ally!, 1-
methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl,
cyclopentenyl, 1-methyl-
cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl and other linear, cyclic and
branched
chained all carbon containing moieties containing at least one double bond.
When alkenyl is
used as a Markush group (i.e., a substituent) the alkenyl is attached to a
Markush formula
with which it is associated through an unsaturated carbon of a double bond of
the alkenyl
moiety or group unless specified otherwise.
[052] "Alkynyl" as used herein means a substituent, moiety or group that
comprises one
or more triple bond moieties (i.e., -CC-), e.g., 1, 2, 3, 4, 5, 6 or more,
typically 1 or 2 triple
bonds, optionally comprising 1, 2, 3, 4, 5, 6 or more double bonds, with the
remaining bonds
(if present) being single bonds and comprising linked normal, secondary,
tertiary or cyclic
carbon atoms, i.e., linear, branched, cyclic or any combination thereof,
unless the alkynyl
moiety is ethynyl. The number of carbon atoms in an alkenyl moiety or group
can vary and
typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise
specified, e.g., C2-8
alkynyl or C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or
8 carbon atoms.
Alkynyl groups will typically have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19 or
20 carbon atoms.
[053] When an alkynyl moiety or group is specified, species include, by way
of example
and not limitation, any of the alkyl moieties, groups or substituents
described herein that has
one or more double bonds, ethynyl, propynyl, butynyl, iso-butynyl, 3-methyl-2-
butynyl, 1-
pentynyl, cyclopentynyl, 1-methyl-cyclopentynyl, 1-hexynyl, 3-hexynyl,
cyclohexynyl and
other linear, cyclic and branched chained all carbon containing moieties
containing at least
one triple bond. When an alkynyl is used as a Markush group (i.e., a
substituent) the alkynyl
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is attached to a Markush formula with which it is associated through one of
the unsaturated
carbons of the alkynyl functional group.
[054] "Aromatic" as used herein refers to a planar ring having a
delocalized pi-electron
system containing 4n+2 pi electrons, where n is a positive integer. Aromatic
rings can be formed
from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics are
optionally
substituted. The term "aromatic" includes both carboxcylic aryl ("aryl", e.g.,
phenyl) and
heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g.,
pyridine). The term includes
monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms)
groups.
[055] "Aryl" as used here means an aromatic ring system or a fused ring system
with no ring
heteroatoms comprising 1, 2, 3 or 4 to 6 rings, typically 1 to 3 rings,
wherein the rings are
composed of only carbon atoms; and refers to a cyclically conjugated system of
4n + 2
electrons (Huckel rule), typically 6, 10 0114 electrons some of which may
additionally participate
in exocyclic conjugation (cross-conjugated (e.g., quinone). Aryl substituents,
moieties or groups
are typically formed by five, six, seven, eight, nine, or more than nine,
carbon atoms. Aryl
substituents, moieties or groups are optionally substituted. Exemplary aryls
include C6-C10 aryls
such as phenyl and naphthalenyl and phenanthryl. Depending on the structure,
an aryl group
can be a monoradical or a diradical (i.e., an arylene group). Exemplary
arylenes include, but are
not limited to, phenyl-1,2-ene, phenyl-1,3-ene, and phenyl-1,4-ene. When aryl
is used as a
Markush group (i.e., a substituent) the aryl is attached to a Markush formula
with which it is
associated through an aromatic carbon of the aryl group.
[056] "Arylalkyl" as used herein means a substituent, moiety or group where
an aryl
moiety is bonded to an alkyl moiety, i.e., -alkyl-aryl, where alkyl and aryl
groups are as
described above, e.g., -CH2-C6H5 or -CH2CH(CH3)-C6H5. When arylalkyl is used
as a
Markush group (i.e., a substituent) the alkyl moiety of the arylalkyl is
attached to a Markush
formula with which it is associated through a sp3 carbon of the alkyl moiety.
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[057] "Alkylaryl" as used herein means a substituent, moiety or group where
an alkyl
moiety is bonded to an aryl moiety, i.e., -aryl-alkyl, where aryl and alkyl
groups are as
described above, e.g., -C6H4-CH3 or -C6I-14-CH2CH(CH3). When alkylaryl is used
as a
Markush group (i.e., a substituent) the aryl moiety of the alkylaryl is
attached to a Markush
formula with which it is associated through a sp2 carbon of the aryl moiety.
[058] "Substituted alkyl", "substituted cycloalkyl", "substituted alkenyl",
"substituted
alkynyl", substituted alkylaryl", "substituted arylalkyl", "substituted
heterocycle", "substituted
aryl" and the like as used herein mean an alkyl, alkenyl, alkynyl, alkylaryl,
arylalkyl
heterocycle, aryl or other group or moiety as defined or disclosed herein that
has a
substituent(s) that replaces a hydrogen atom(s) or a substituent(s) that
interrupts a carbon
atom chain. Alkenyl and alkynyl groups that comprise a substituent(s) are
optionally
substituted at a carbon that is one or more methylene moieties removed from
the double
bond.
[059] "Optionally substituted alkyl", "optionally substituted alkenyl",
"optionally substituted
alkynyl", "optionally substituted alkylaryl", "optionally substituted
arylalkyl", "optionally
substituted heterocycle", "optionally substituted aryl", "optionally
substituted heteroaryl",
"optionally substituted alkylheteroaryl", "optionally substituted
heteroarylalkyl" and the like as
used herein mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle,
aryl, heteroaryl,
alkylheteroaryl, heteroarylalkyl, or other substituent, moiety or group as
defined or disclosed
herein that has a substituent(s) that optionally replaces a hydrogen atom(s)
or a
substituent(s) that interrupts a carbon atom chain. Such substituents are as
described herein.
For a phenyl moiety, the arrangement of any two substituents present on the
aromatic ring
can be ortho (o), meta (m), or para (p). An optionally substituted fluoroalkyl
is an alkyl or
cycloalkyl moiety, typically a linear alkyl, wherein one or more hydrogen
atoms is replaced by
fluorine and at least one other atom other than carbon and fluorine.
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An optionally substituted or substituted substituent, moiety or group includes
those having one
or more additional group(s) that replace its hydrogen atom(s) individually and
independently
selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
alkoxy, aryloxy,
alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,
cyano, halo, nitro,
haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono- and di-
substituted amino groups,
and the protected derivatives thereof. By way of example and not limitation an
optional
substituent(s) may be halide, -CN, -NO2, or LsRs, wherein each Ls is
independently selected
from a bond, -0-, -C(=0)-, -C(=0)0-, -S-, -S(=0)-, -S(=0)2-, -NH-, -NHC(=0)-, -
C(=0)NH-,
S(=0)2NH-, -NHS(=0)2, -0C(=0)NH-, -NHC(=0)0-, or -(C1-C6 alkylene)-; and each
Rs is
selected from -H, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl, or heterocycloalkyl.
The protecting groups that may form the protective derivatives of the above
substituents may be
found in sources such as Greene and Wuts, above. Optional substituents include
those selected
from the group consisting of halogen, -CN, -NH2, -OH, -N(CH3)2, alkyl,
fluoroalkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio,
arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone, and arylsulfone, those selected from the group
consisting of halogen,
-CN, -NH2, -OH, NH(0H3), -N(CH3)2, -CO2H, -0O2alkyl, -C(=0)NH2, -C(=0)NHalkyl,
-
C(=0)N(alky1)2, -S(=0)2NH2, -S(=0)2NH(alkyl), -S(=0)2N(alky1)2, alkyl,
cycloalkyl, fluoroalkyl,
heteroalkyl, alkoxy, fluoroalkoxy, -S-alkyl and-S(=0)2a1ky1 or those selected
from the group
consisting of halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -
CF3, -OCH3, and -
OCF3. Typically, an optionally substituted, substituent, moiety or group is
substituted with one or
two of the preceding groups, or more typically with one of the preceding
groups. An optional
substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or
unsaturated carbon
atoms, excluding aromatic carbon atoms) further includes oxo (=0).
[060] "Heterocycle" or "heterocyclic" as used herein means a cycloalkyl or
aromatic ring
system wherein one or more, typically 1, 2 or 3, but not all of the carbon
atoms comprising
the ring system are replaced by a heteroatom which is an atom other than
carbon, including,
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N, 0, S, Se, B, Si, P, typically N, 0 or S wherein two or more heteroatoms may
be adjacent
to each other or separated by one or more carbon atoms, typically 1-17 carbon
atoms, 1-7
atoms or 1-3 atoms. Heterocycles includes heteroaromatic rings (also known as
heteroaryls)
and heterocycloalkyl rings (also known as heteroalicyclic groups) containing
one to four
heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected
from 0, S and N,
wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and
with the
proviso that the any ring does not contain two adjacent 0 or S atoms.
[061 Non-
aromatic heterocyclic, substituents, moieties or groups (also known as
heterocycloalkyls) have at least 3 atoms in their ring system, and aromatic
heterocyclic
groups have at least 5 atoms in their ring system and include benzo-fused ring
systems.
Heterocyclics with 3, 4, 5, 6 and 10 atoms include aziridinyl azetidinyl,
thiazolyl, pyridyl and
quinolinyl, respectively. Nonaromatic heterocyclic substituents, moieties or
groups are
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothienyl, oxazolidinonyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidinyl, morpholinyl,
thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl,
thietanyl,
homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-
tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-
pyranyl, dioxanyl, 1,3-
dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,
dihydrothienyl, dihydrofuranyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-
azabicyclo[3.1.0)hexanyl,
3azabicyclo[4.1.0)heptanyl, 3H-indoly1 and quinolizinyl. Aromatic heterocyclic
includes, by
way of example and not limitation, pyridinyl, imidazolyl, pyrimidinyl,
pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,
indazolyl, indolizinyl,
phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl,
oxadiazolyl, thiadiazolyl,
furazanyl, benzofurazanyl, benzo-thiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl,
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quinoxalinyl, naphthyridinyl, and furopyridinyl. Non-aromatic heterocycles may
be substituted
with one or two oxo (=0) moieties, and includes pyrrolidin-2-one.
[062] When heterocycle is used as a Markush group (i.e., a substituent) the
heterocycle is
attached to a Markush formula with which it is associated through a carbon or
a heteroatom
of the heterocycle, where such an attachment does not result in an unstable or
disallowed
formal oxidation state of that carbon or heteroatom. A heterocycle that is C-
linked is bonded
to a molecule through a carbon atom include moieties such as -(CH2)n-
heterocycle where n is
1, 2 or 3 or -C<heterocycle where C< represents a carbon atom in a heterocycle
ring. A
heterocycle that is N-linked is a nitrogen containing heterocycle that is
bonded a heterocycle
ring nitrogen sometimes described as -N<heterocycle where N< represents a
nitrogen atom
in a heterocycle ring. Thus, nitrogen-containing heterocycles may be C-linked
or N-linked and
include pyrrole substituents, which may be pyrrol-1-y1 (N-linked) or pyrrol-3-
y1 (C-linked),
imidazole substituents, which may be imidazol-1-y1 or imidazol-3-y1 (both N-
linked) or
imidazol-2-yl, imidazol-4-y1 or imidazol-5-y1 (all C-linked).
[063] "Heteroaryl" as used herein means an aryl ring system wherein one or
more,
typically 1, 2 or 3, but not all of the carbon atoms comprising the aryl ring
system are
replaced by a heteroatom which is an atom other than carbon, including, N, 0,
S, Se, B, Si,
P, typically, oxygen (-0-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a
protecting group or
C1_6 optionally substituted alkyl, wherein the heteroatom participates in the
conjugated system
either through pi-bonding with an adjacent atom in the ring system or through
a lone pair of
electrons on the heteroatom and may be optionally substituted on one or more
carbons or
heteroatoms, or a combination of both, in a manner which retains the
cyclically conjugated
system.
[064] Heterocycles and heteroaryls, include, by way of example and not
limitation,
heterocycles and heteroaryls described in Paquette, Leo A.; "Principles of
Modern
Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly
Chapters 1, 3, 4, 6,
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7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs"
(John Wiley
& Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and
28; and J. Am.
Chem. Soc. 1960, 82:5545-5473 particularly 5566-5573). Examples of heteroaryls
include by
way of example and not limitation pyridyl, thiazolyl, pyrimidinyl, furanyl,
thienyl, pyrrolyl,
pyrazolyl, purinyl, imidazolyl, benzofuranyl, indolyl, isoindoyl, quinolinyl,
isoquinolinyl,
benzimidazolyl, pyridazinyl, pyrazinyl, benzothiopyran, benzotriazine,
isoxazolyl,
pyrazolopyrimidinyl, quinoxalinyl, thiadiazolyl, triazolyl and the like.
Heterocycles that are not
heteroaryls include, by way of example and not limitation,
tetrahydrothiophenyl,
tetrahydrofuranyl, indolenyl, piperidinyl, pyrrolidinyl, 2-pyrrolidonyl,
tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 2H-
pyrrolyl, 3H-indolyl,
4H-quinolizinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, piperazinyl,
quinuclidinyl,
morpholinyl, oxazolidinyl and the like.
[065] Other heteroaryls include, by way of example and not limitation, the
following
moieties:
H H
N rON,s Nµ 4101 0
I II .1µ1 N
N w
= N N Na) (N_IN
\ 1\1\\
N N N N _____
N S 0 N,N, c,0)
/ I
r r N
[066] Monocyclic heteroaryls include, by way of example and not limitation,
pyridinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl,
thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl,
oxadiazolyl, thiadiazolyl, and
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furazanyl. Heteroaryls include those substituents, moieties or groups
containing 0-3 N atoms,
1-3 N atoms or 0-3 N atoms, 0-1 0 atoms and 0-1 S atoms. A heteroaryl may be
monocyclic
or bicyclic. The ring system of a heteroaryls ring typically contains 1-9
carbons (i.e., C1-C9
heteroaryl). Monocyclic heteroaryls include C1-05 heteroaryls. Monocyclic
heteroaryls include
those having 5-membered or 6-membered ring systems. Bicyclic heteroaryls
include C6-Cg
heteroaryls. Depending on the structure, a heteroaryl group can be a
nnonoradical or a
diradical (i.e., a heteroarylene group).
[067] "Heterocycloalkyl" or "heteroalicyclic" as used herein means a
cycloalkyl group, moiety
or substituent wherein at least on carbon of the cycloalkyl chain is replaces
with a heteroatom
selected from the group consisting of nitrogen, oxygen and sulfur. The
heterocycloalkyl may be
fused with an aryl or heteroaryl. Heterocycloalkyls, also referred to as non-
aromatic
heterocycles, include by way of example and not limitation:
0 0 0 0 0 0
cs 0,,s,2 A N
0 0 o 0 N
i NN
_______________________________________ N-N 0 0
I 1 j NO
N.) )
[068] Heterocycloalkyl includes, by way of example and not limitation,
oxazolidinonyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl.
Heteroalicyclics further
includes all ring forms of carbohydrates, including but not limited to
monosaccharides,
disaccharides and oligosaccharides. Typically, a heterocycloalkyl is a C2-C10
heterocycloalkyl
and includes 04-C10 heterocycloalkyl. A heterocycloalkyl may contain 0-2 N
atoms, 0-2 0 atoms
or 0-1 S atoms.
- 20 -
CA 3046894 2019-06-18

[069] "Heteroarylalkyl" as used herein means a substituent, moiety or group
where a
heteroaryl moiety is bonded to an alkyl moiety, i.e., -alkyl-heteroaryl, where
alkyl and
heteroaryl groups are as described above. When heteroarylalkyl is used as a
Markush group
(i.e., a substituent) the alkyl moiety of the heteroarylalkyl is attached to a
Markush formula
with which it is associated through a sp3 carbon of the alkyl moiety.
[070] "Alkylheteroaryl" as used herein means a substituent, moiety or group
where a
heteroaryl moiety is bonded to an alkyl moiety, i.e., -heteroaryl-alkyl, where
heteroaryl and
alkyl groups are as described above. When heteroarylalkyl is used as a Markush
group (i.e.,
a substituent) the heteroaryl moiety of the heteroarylalkyl is attached to a
Markush formula
with which it is associated through a sp2 carbon or heteroatom of the alkyl
moiety.
[071] "Halogen" or "halo" as used herein means fluorine, chlorine, bromine
or iodine.
[072] "Haloalkyl" as used herein means an alkyl substituent moiety or group
in which one or
more of its hydrogen atoms are replaced by one or more independently selected
halide atoms.
Haloalkyl includes C1-C4 haloalkyl. Example but non-limiting C1-C4 haloalkyls
are -CH2CI,
CH2Br, -CH21, -CHBrCI, -CHCI-CH2CI and ¨CHCI-CH21.
[073] "Haloalkylene" as used herein means an alkylene substituent, moiety
or group in which
one or more hydrogen atoms are replaced by one or more halide atoms.
Haloalkylene includes
C1-C6haloalkylenes or C1-C4 haloalkylenes.
[074] "Fluoroalkyl" as used herein means an alkyl in which one or more
hydrogen atoms are
replaced by a fluorine atom. Fluoroalkyl includes C1-C6 and C1-C4
fluoroalkyls. Example but
non-limiting fluoroalkyls include -CH3F, -CH2F2 and -CF3 and perfluroalkyls.
[075] "Fluoroalkylene" as used herein means an alkylene in which one or
more hydrogen
atoms are replaced by a fluorine atom. Fluoroalkylene includes C1-06
fluoroalkylenes or C1-C4
fluoroalkylenes.
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[076] The term "heteroalkyl" refers to an alkyl group in which one or more
skeletal atoms of
the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen,
sulfur,
phosphorus or combinations thereof. In one aspect, a heteroalkyl is a C1-C6
heteroalkyl.
[077] "Protecting group" as used here means a moiety that prevents or
reduces the ability
of the atom or functional group to which it is linked from participating in
unwanted reactions.
Non-limiting examples are for -ORPR, wherein RPR is a protecting group for the
oxygen atom
found in a hydroxyl, while for -C(0)-OR, RPR may be a carboxylic acid
protecting group; for
-SRPR, RPR may be a protecting group for sulfur in thiols and for -NHRPR or -
N(RPR)2-, at least
one of RPR is a nitrogen atom protecting group for primary or secondary
amines. Hydroxyl,
amine, ketones and other reactive groups may require protection against
reactions taking
place elsewhere in the molecule. The protecting groups for oxygen, sulfur or
nitrogen atoms
are usually used to prevent unwanted reactions with electrophilic compounds,
such as
acylating agents. Typical protecting groups for atoms or functional groups are
given in
Greene (1999), "Protective groups in organic synthesis, 3' ed.", Wiley
Interscience.
[078] "Estee' as used herein means a substituent, moiety or group that
contains a
-C(0)-0- structure (i.e., ester functional group) wherein the carbon atom of
the structure is
not directly connected to another heteroatom and is directly connected to -H
or another
carbon atom. Typically, esters comprise or consist of an organic moiety
containing 1-50
carbon atoms, 1-20 carbon atoms or 1-8 carbon atoms and 0 to 10 independently
selected
heteroatoms (e.g., 0, S, N, P, Si), typically 0-2 where the organic moiety is
bonded through
the -C(0)-0- structure and include ester moieties such as organic moiety-C(0)-
0-. The
organic moiety usually comprises one or more of any of the organic groups
described herein,
e.g., C1_20 alkyl moieties, C2-20 alkenyl moieties, C2-20 alkynyl moieties,
aryl moieties, C3-8
heterocycles or substituted derivatives of any of these, e.g., comprising 1,
2, 3, 4 or more
substituents, where each substituent is independently chosen. Exemplary, non-
limiting
substitutions for hydrogen or carbon atoms in these organic groups are as
described above
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for substituted alkyl and other substituted moieties and are independently
chosen. The
substitutions listed above are typically substituents that one can use to
replace one or more
carbon atoms, e.g., -0- or -C(0)-, or one or more hydrogen atom, e.g.,
halogen, -NH2 or -OH.
Exemplary esters include by way of example and not limitation, one or more
independently
selected acetate, propionate, isopropionate, isobutyrate, butyrate, valerate,
isovalerate,
caproate, isocaproate, hexanoate, heptanoate, octanoate, phenylacetate esters
or benzoate
esters. When ester is used as a Markush group (i.e., a substituent) the single
bonded oxygen
of the ester functional group is attached to a Markush formula with which it
is associated.
[079] "Acetal", "thioacetal", "ketal", "thioketal" and the like as used
herein means a moiety,
group or substituent comprising or consisting of a carbon to which is bonded
two of the same
or different heteroatoms wherein the heteroatoms are independently selected S
and 0. For
acetal the carbon has two bonded oxygen atoms, a hydrogen atom and an organic
moiety.
For ketal, the carbon has two bonded oxygen atoms and two independently
selected organic
moieties where the organic moiety is as described herein alkyl or optionally
substituted alkyl
group. For thioacetals and thioketals one or both of the oxygen atoms in
acetal or ketal,
respectively, is replaced by sulfur. The oxygen or sulfur atoms in ketals and
thioketals are
sometimes linked by an optionally substituted alkyl moiety. Typically, the
alkyl moiety is an
optionally substituted C1-8 alkyl or branched alkyl structure such as -C(CI-
13)2-, -CH(CH3)-, -
CH2-, -CH2-CH2-, -C[(02-C4 alkyl) 1
/2,0, 2, 3- or ¨[CH(C2-C4 alkyl)]1, Some of these moieties
can serve as protecting groups for an aldehyde or ketone include, by way of
example and not
limitation, acetals for aldehydes and ketals for ketones and contain -0-CH2-
CH2-CH2-0- or -
0-CH2-CH2-0- moieties that form a Spiro ring with the carbonyl carbon, and can
be removed
by chemical synthesis methods or by metabolism in cells or biological fluids.
[080] "Ether" as used herein means an organic moiety, group or substituent
that comprises
or consists of 1, 2, 3, 4 or more -0- moieties, usually 1 or 2, wherein no two
-0- moieties are
immediately adjacent (i.e., directly attached) to each other. Typically,
ethers comprise an
- 23 -
CA 3046894 2019-06-18

organic moiety containing 1-50 carbon atoms, 1-20 carbon atoms or 1-8 carbon
atoms and 0 to
independently selected heteroatoms (e.g., 0, S, N, P, Si), typically 0-2. An
ether moiety,
group or substituent includes organic moiety-0- wherein the organic moiety is
as described
herein for alkyl or optionally substituted alkyl group. When ether is used as
a Markush group
(i.e., a substituent) the oxygen of the ether functional group is attached to
a Markush formula
with which it is associated. When ether is a used as substituent in a Markush
group it is
sometimes designated as an "alkoxy" group. Alkoxy includes C1-C4 ether
substituents such as,
by way of example and not limitation, methoxy, ethoxy, propoxy, iso-propoxy
and butoxy. Ether
further includes those substituents, moieties or groups that contain one
(excluding ketal) or
more -OCH2CH20-, moieties in sequence (i.e., polyethylene or PEG moieties).
[081] "Carbonate" as used here means a substituent, moiety or group that
contains a -0-
C(=0)-0- structure (i.e., carbonate functional group). Typically, carbonate
groups as used
here comprise or consist of an organic moiety containing 1-50 carbon atoms, 1-
20 carbon
atoms or 1-8 carbon atoms and 0 to 10 independently selected heteroatoms
(e.g., 0, S, N,
P, Si), typically 0-2, bonded through the -0-C(=0)-0- structure, e.g., organic
moiety-0-
C(=0)-0-. When carbonate is used as a Markush group (i.e., a substituent) one
of the singly
bonded oxygen atoms of the carbonate functional group is attached to a Markush
formula
with which it is associated.
[082] "Carbamate" or "urethane" as used here means a substituent, moiety or
group that
contains a -0-C(=0)N(RPR)-, -0-C(=0)N(RPR)2, -0-C(=0)NH(optionally substituted
alkyl) or -
0-C(=0)N(optionally substituted alky1)2- structure (i.e., carbamate functional
group) where
RPR and optionally substituted alkyl are independently selected and RPR are
independently -H,
a protecting group or an organic moiety as described for ester, alkyl or
optionally substituted
alkyl. Typically, carbamate groups as used here comprise or consist of an
organic moiety
containing about 1-50 carbon atoms, 1-20 carbon atoms or 1-8 carbon atoms and
0 to 10
independently selected heteroatoms (e.g., 0, S, N, P, Si), typically 0-2,
bonded through the -
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0-C(=0)-NRPR- structure, e.g., organic moiety-0-C(=0)-NRPR- or -0-C(=0)-NR-
organic
moiety. When carbamate is used as a Markush group (i.e., a substituent) the
singly bonded
oxygen (0-linked) or nitrogen (N-linked) of the carbamate functional group is
attached to a
Markush formula with which it is associated. The linkage of the carbamate
substituent is
either explicitly stated (N- or 0-linked) or implicit in the context to which
this substituent is
referred.
[083] For
any substituent group or moiety described by a given range of carbon atoms,
the
designated range means that any individual number of carbon atoms is
described. Thus,
reference to, e.g., "C1-C4 optionally substituted alkyl", "C2-6 alkenyl
optionally substituted
alkenyl", "C3-C8 optionally substituted heterocycle" specifically means that a
1, 2, 3 or 4 carbon
optionally substituted alkyl moiety as defined herein is present, or a 2, 3,
4, 5 or 6 carbon
alkenyl, or a 3, 4, 5, 6, 7 or 8 carbon moiety comprising a heterocycle or
optionally substituted
alkenyl moiety as defined herein is present. All such designations are
expressly intended to
disclose all of the individual carbon atom groups and thus ''C1-C4 optionally
substituted alkyl"
includes, e.g., 3 carbon alkyl, 4 carbon substituted alkyl and 4 carbon alkyl,
including all
positional isomers and the like are disclosed and can be expressly referred to
or named. For
esters, carbonates and carbamates defined by a given range of carbon atoms,
the designated
range includes the carbonyl carbon of the respective functional group. Thus a
Cl ester refers to
a formate ester and a C2 ester refers to an acetate ester. The organic
substitutents, moieties
and groups described herein, and for other any other moieties described
herein, usually will
exclude unstable moieties except where such unstable moieties are transient
species that one
can use to make a compound with sufficient chemical stability for the one or
more of the uses
described herein. Substituents, moieties or groups by operation of the
definitions herein that
results in those having a pentavalent carbon are specifically excluded.
[084] "LPA-dependent", "LPA-mediated" or like terms as used herein means a
disease or
condition whose etiology, progression or persistence is effected by in whole
or in part by
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signaling through one or more lysophosphatidic acid receptor subtypes,
including by way of
example and not limitation lysophosphatidic acid receptor subtypes 1-6
(LPARs). LPA-
dependent or LPA-mediated diseases and conditions include but not limited to
fibrosis of organs
(e.g., liver, kidney, lung, heart and the like), liver diseases (e.g., acute
hepatatis, chronic
hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative
failure, nonalcoholic
steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and
the like), cell
proliferative disease (e.g., cancers, including but not limited to solid
tumor, solid tumor
metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma,
leukemia, chronic
lymphocytic leukemia (CLL), invasive metastasis of cancer cell, and the like),
inflammatory
disease (e.g., psoriasis, nephropathy, pneumonia and the like),
gastrointestinal tract disease
(e.g., irritable bowel syndrome (IBS), inflammatory bowel disease (IBD),
abnormal pancreatic
secretion, and the like), renal disease, urinary tract-associated disease
(e.g., 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 (e.g., obstruction of lower urinary tract, and the
like), inflammatory disease
of lower urinary tract (e.g., dysuria, frequent urination, and the like),
pancreas disease,
abnormal angiogenesis-associated disease (e.g., arterial obstruction and the
like), scleroderma,
brain-associated disease (e.g., cerebral infarction, cerebral hemorrhage, and
the like), nervous
system diseases (e.g., neuropathic pain, peripheral neuropathy, pruritus and
the like), ocular
disease (e.g., age-related macular degeneration (AMD), diabetic retinopathy,
proliferative vitreo-
retinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery
scarring, and the like).
[085]
"LPA1R selective agents", LPA1R selective compounds" and like terms as used
herein
means agents or compounds that interact with the lysophosphatidic acid subtype
1 receptor in
preference to the lysophosphatidic acid receptor 2-6. Typically, that
preference is manifested by
10-fold stronger binding affinity of the agent to LPA1R in comparison to other
known LPARs as
measured by experimentally determined KD values.
- 26 -
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[086] "Pharmaceutically acceptable formulation" as used herein means a
composition
comprising an active pharmaceutical ingredient, such as a compound having the
formula of 1-V1
in addition to one or more pharmaceutically acceptable excipients or refers to
a composition
prepared from an active pharmaceutical ingredient and one or more
pharmaceutically
acceptable excipients, wherein the composition is suitable for administration
to a subject, such
as a human or an animal, in need thereof. For a pharmaceutically acceptable
formulation to be
suitable for administration to a human the formulation must have biological
activity for treating or
preventing a disease or condition disclosed herein or an expectation must
exist that the
formulation would have a desired activity towards an "intent to treat" disease
or condition.
Typically, the "intent to treat" disease or condition is a lysophosphatidic
acid receptor-mediated
condition or disease. More typically the disease or condition to be treated or
prevented is a
lysophosphatidic acid lysophosphatidic acid type 1 receptor-mediated disease
or condition. A
pharmaceutically acceptable formulation that is suitable for administration to
an animal does not
necessarily require a biological activity for treating or preventing a disease
or condition, and
may be administered to the animal in order to evaluate a potential
pharmacological or biological
activity of a Formula 1-XII compound. Those formulations must therefore be
suitable for treating
or preventing a disease or condition disclosed herein in an animal in need
thereof or is suitable
for evaluating a pharmacological or biological activity of a Formula 1-X11
compound.
Compositions that are suitable only for use in vitro assays or which contain a
vehicle,
component or excipient in an amount not permitted in a drug product are
specifically excluded
from the definition of a pharmaceutically acceptable formulation.
[087] The pharmaceutically acceptable formulation may be comprised of, or be
prepared
from, one, two or more Formula 1-XII compounds, typically one or two, and one
or more '
pharmaceutically acceptable excipients. More typically, the formulations will
consist essentially
of or consist of a single Formula 1-XII compound and one or more
pharmaceutically acceptable
excipients. Other formulations may be comprised of, consist essentially of, or
consist of one,
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two or more Formula 1-XII compounds and one two or more compounds in current
use for
treating lysophosphatidic acid lysophosphatidic acid type 1 receptor-mediated
disease or
condition disclosed herein and one or more pharmaceutically acceptable
excipients. Typically
those formulations will consist essentially of or consist of a single Formula
1-XII compound, a
single compound in current use for treating a lysophosphatidic acid
lysophosphatidic acid type 1
receptor-mediated disease or condition and one or more pharmaceutically
acceptable
excipients.
[088] "Solid formulation" as used herein refers to a pharmaceutically
acceptable formulation
comprising at least one Formula 1-XII compound and one or more
pharmaceutically acceptable
excipients in solid form(s) wherein the formulation is in a unit dosage form
suitable for
administration of a solid. The dosage units include tablets, capsules,
caplets, gelcaps,
suspensions and other dosage units typically associated with parenteral or
enteral (oral)
administration of a solid.
[089] "Liquid formulation" as used herein refers to a pharmaceutically
acceptable formulation
wherein at least one Formula 1-X11 compound has been admixed or contacted with
one or more
pharmaceutically acceptable excipients, wherein at least one of the excipients
is in liquid form in
proportions required for a liquid formulation, i.e., such that a majority of
the mass amount of the
Formula 1-X11 compound(s) is dissolved into the non-solid excipient. Dosage
units containing a
liquid formulation include syrups, gels, ointments and other dosage units
typically associated
with parenteral or enteral administration of a pharmaceutical formulation to a
subject in need
thereof in liquid form.
[090] "Prevent, "preventing" and like terms as used herein takes on its
normal and
customary meaning in the medical arts and therefore does not require that each
instance to
which the term refers be avoided with certainty.
[091] Numbered embodiments
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CA 3046894 2019-06-18

[092] The following embodiments exemplify the invention and are not meant
to limit the
invention in any manner. In certain embodiments, the compounds presented
herein possess
one or more stereocenters and each center independently exists in either the R
or S
configuration. The compounds presented herein include all diastereomeric,
enantiomeric, and
epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are
obtained, if
desired, by methods such as, stereoselective synthesis and/or the separation
of stereoisomers
by chiral chromatographic columns. The methods and formulations described
herein include the
use of pharmaceutically acceptable salts of compounds having the structure of
Formulas (I-VI),
as well as active metabolites of these compounds having the same type of
activity. In some
situations, compounds may exist as tautomers. All tautomers are included
within the scope of
the compounds presented herein. In specific embodiments, the compounds
described herein
will exist as salts, including pharmaceutically acceptable salts. The salt
forms include inorganic
addition salts such as F Cr, Br, 1- and sulfate salts and organic addition
salts such as mesylate,
besylate, tosylate, citrate, succinate, fumarate and malonate. In other
embodiments, the
compounds described herein exist as quaternary ammonium salts.
[093] 1. A compound of Formula I having the structure
L2 L-1RA
Formula I
or a pharmaceutically acceptable salt or prodrug thereof,
[094] wherein RA is -CO2H, -0O2R8, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHR8, -
C(=0)NHSO2R8 or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[095] L1 is absent or substituted or unsubstituted C1-C6 alkylene,
substituted or unsubstituted
C1-C6 fluoroalkylene, substituted or unsubstituted C3-08 cycloalkylene,
substituted or
unsubstituted C1-C6 heteroalkylene, or -UV-Z-, wherein -UV-is defined by -OW-,
-WO-, -N(RJ)W-
, -WN(RJ)-, -N(R)C(=O)-, -SW-, -S(=O)W-, or -C(=0)N(RJ)-, wherein W is
substituted or
- 29 -
CA 3046894 2019-06-18

unsubstituted 01-03 alkylene, or W is -C(RI)2; Z is substituted or
unsubstituted 01-06 alkylene,
substituted or unsubstituted 03-08 cycloalkylene, or C1-C6 fluoroalkylene or Z
is -C(RL)2-; and n
is 0, 1, or 2;
[096] L2 is absent, or substituted or unsubstituted 01-06 alkylene,
substituted or
unsubstituted 03-C8 cycloalkylene, 01-06 fluoroalkylene, substituted or
unsubstituted C3-08
cycloalkylene, substituted or unsubstituted 01-C6 heteroalkylene, -0-, -S-, -
SO-, -SO2-, -
C(=0)-, or -C(=0)N(RJ)-;
[097] wherein RB is substituted or unsubstituted 01-04 alkyl, or has the
structure of one of:
ll
[098] o ;
[099] Ring A is a 5 or 6 membered heteroarene having the structure of one
of:
RE
NI\
,D
Rc Rc RD Rc
Rc
N
RD
Rc N N
re
N =
0 /RD Rc ¨(RD
RD Rc/N¨\RD
RN
RE
0 ,N
rNy
Rc RD Re"--N-RD
Rc õD
RC/ RD 7.----CRD RC r%
[0100] wherein the dashed line indicates the point of attachment of Ring A to
Ring B;
= [0101] wherein one of Rc and RD is -H, -ON, -F, -01, -Br, -I, -001-04
alkyl, 01-04 alkyl, 03-06
cycloalkyl, or 01-04 fluoroalkyl,
[0102] and the other Rc or RD is -NRFC(=0)XCH(RG)-CY, -N(RF)C(=0)XC(RG)2-CY,
or -
NRFC(=0)X-CY, -C(=0)-N(RF)-CH(RG)X-CY, or -C(=0)-N(RF)-C(RG)2X-CY,
[0103] wherein X is absent, -0-, -NH- or -CH2-;
- 30 -
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[0104] RE is -H, -C1-C4 alkyl or -C1-C4 fluoroalkyl,
[0105] fe is -H or C1-C4 alkyl, and
[0106] RG is independently selected RE or one RG is C1-C4 alkyl and is taken
together with CY
and the the carbon atom to which RG and CY is attached to define a substituted
or unsubstituted
carbocycle or substituted or unsubstituted heterocycle and the other RG, if
present, is as defined
for RE;
[0107] wherein CY is substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted C3-
C10 cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl,
substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted
then CY is
substituted with 1, 2, or 3 independently selected Rh',
[0108] RH is independently -H, halogen, -CN, -NO2, -OH, -OR', -SR, -S(=0)RJ,
-S(=0)2RJ, -N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)RJ, OC(=0)RJ, -CO2RJ, -0CO2RJ,
-N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2, N(RJ)C(=0)N(RL)2, -N(RJ)C(=0)RJ,
-N(RJ)C(=0)ORJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4
alkoxy, or Ci-C4
heteroalkyl,
[0109] wherein each RJ is independently substituted or unsubstituted C1-C6
alkyl, substituted
or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl, substituted or
unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted C3-06 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
C1-C4 alkylene-(substituted or unsubstituted aryl), and -C1-C4 alkylene-
(substituted or
unsubstituted heteroaryl), and
[0110] wherein each RL is independently -H, 01-C6 alkyl, C1-C6 heteroalkyl, Ci-
C6 fluoroalkyl,
substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted
heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
C1-C4 alkylene-
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(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C4 alkylene-(substituted
or unsubstituted
heterocycloalkyl),
alkylene(substituted or unsubstituted aryl), or -C1-C4 alkylene-
(substituted or unsubstituted heteroaryl), or
[0111] when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2 or
-N(RJ)C(=0)N(RL)2, each RL is independently -H or 01-C6 alkyl, or the RL
groups independently
are C1-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0112] or when W or Z is -C(RL)2 - each RL is independently -H, C1-06 alkyl,
or the RL groups
independently are 01-C6 alkyl which are taken together with the carbon atom to
which they are
attached to define a carbocycle;
[0113] Ring B is substituted or unsubstituted C3-C10 cycloalkylene,
substituted or
unsubstituted C2-C10 heterocycloalkylene, substituted or unsubstituted
arylene, or substituted or
unsubstituted heteroarylene, where if ring B is substituted then ring B is
substituted with 1,2, or
3 independently selected RH, wherein RH is as previously defined; and
[0114] Ring C is absent or substituted or unsubstituted C3-C10 cycloalkylene,
substituted or
unsubstituted C2-C10 heterocycloalkylene, substituted or unsubstituted
arylene, or substituted or
unsubstituted heteroarylene, wherein if ring C is substituted then ring C is
substituted with 1, 2,
or 3 independently selected RH, wherein RH is as previously defined,
[0115] wherein when Ring B is substituted or unsubstituted arylene, Ring C is
absent, L2 is
absent, Lis -UV-Z, wherein -UV- is -N(R)C(=O)-, wherein Rr is -H, RD is
-N(RF)C(=0)XCH(RG)-CY, wherein X is -0-, RG is -CH3 and RF is -H, and Re is -
H, -CH3 or -CF3,
[0116] or when Ring B is substituted or unsubstituted arylene and Ring C is
substituted or
unsubstituted arylene or is substituted or unsubstituted C3-C10 cycloalkylene,
or Ring B is
substituted or unsubstituted C3-C10 cycloalkylene and Ring C is substituted or
unsubstituted
arylene, L2 is absent, Cis C1-C6 alkylene,
- 32 -
CA 3046894 2019-06-18

[0117] and RD is -H or -CH3 and RA is -002H or -CO2RB,
[0118] then Ring A has the structure of one of:
RE
I
,N '= / s ,IV, ,,N....N;;=!
IN =
N)jr- RE¨N N
\ -As.
RC)---\ RD Re RD
RC RD N RD
N =
';," c N = / -I--
'..-1µ1.:,- rNµ
p,,- Rr
N..._____L
RD 04 Nr---(
RD RC RD RC)%1 RD
RC RD
RE
0 i
E 0 N : c.r..-N ' N-:;-..--NX
R--....1-1(:- TR\11- N \ / c_L I X I
NJ ,c R N RD Rc Ro
r.sc/ , rc D
Rc RD
[0119] ' R" R
,
[0120] and when Ring B is C2-010 heterocycloalkylene, Ring C is substituted or
unsubstituted
arylene, L2 is absent, Cis 01-06 alkylene, Rc is -CH3 and RA is -002H or
-CO2RB,
[0121] then Ring A has the structure of one of:
E ,NX ,,N-...Ns>(
N
RC' R=D R¨RNCRD \Nf'---(RD
N '
µ RC,.(,N rN, RE....
hi.:_k_ .N..õ
;., ..;... /..r-
6 N
RD -4RD Rc)N1---RD
RC RD
RE
0 I
E 0.,,, NN, : rczN_r_. rµI''.
IR---õN . N
I \ / , j( X..µõ 1
l-----'5' R N RD Rc N RD
N c)-----( -
R , R RD RC RD
[0122] - R- .
[0123] In some embodiments RD is -H, -ON, -F, -Cl, -Br, -I, -001-04 alkyl, 01-
04 alkyl, 03-06
cycloalkyl, or 01-04 fluoroalkyl and RD is -N(RF)-0(=0)X0H(RG)-0Y, -N(RF)-
-0(=0)X0(RG)2-0Y or -N(RF)-0(=0)X-CY, wherein RF and each IR independently
are -H or 01-
04 alkyl.
- 33 -
CA 3046894 2019-06-18

[0124] In some embodiments RA is -002H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2,
-C(=0)NHRB, C(=0)NHSO2RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere.
[0125] In preferred embodiments RA is -CO2H, -CO2RB, -CN, or -C(=0)NHSO2RB,
wherein RB
is substituted or unsubstituted C1-C4 alkyl or has the structure of one of:
oYo
[0126] o
[0127] In some embodiments Ll is absent or substituted or unsubstituted 01-C6
alkylene, C-
06 fluoroalkylene, fluoroalkylene, or substituted or unsubstituted C1-06
heteroalkylene.
[0128] In some preferred embodiments 12 is absent or substituted or
unsubstituted 01-06
alkylene or -UV-Z-, wherein -UV- is defined by -OW-, -WO-, -N(R)W-, -WN(RJ)-,
-N(R)C(=O)-, -SW-, -S(=0),W-, or -C(=0)N(RJ)-, wherein W is substituted or
unsubstituted
03 alkylene, Z is substituted or unsubstituted C1-06 alkylene or C1-C6
fluoroalkylene; and n is
0,1, or 2.
[0129] In particularly preferred embodiments L1 is -CH2-,
X?rs
[0130] , dimethylmethane (i.e., -C(CH3)2-), or -UV-Z- wherein -UV-is defined
by -WO-,
or -C(=0)N(RJ)-, wherein W is substituted or unsubstituted 01-03 alkylene; and
Z is
substituted or unsubstituted Cl-C6 alkylene.
[0131] In some embodiments L2 is absent, or substituted or unsubstituted C1-C6
alkylene, 01-
06 fluoroalkylene, substituted or unsubstituted C1-C6 heteroalkylene, -0-, -S-
, -S(=0)-, S(=0)2-,
or -C(=0)-.
[0132] In some preferred embodiments L2 is absent, -0-, -S-, -S(=0)-, S(=0)2-,
-N(RJ)-, or -
C(=0)-.
[0133] In some embodiments Ring A is a 5 or 6 membered heteroarene having one
of the
structures of:
- 34 -
CA 3046894 2019-06-18

RIE
ci -RD RcR
N, D IR R ,N ,
N I
N47- RE¨N N
RD N RD
Rc
N =
sie" N
= 2;--
1µ1.____L N=
RD R ( RD Rcp RD RE RC)I RD
Rc RD
RE
0
0 N
R N \
R N RD RD
D
c RD
[0134] ,c, RR R
[0135] In some embodiments, Formula I compounds have RD defined as -H, -CN, -
F,
-CI, -Br, -I, -001-04 alkyl, 01-04 alkyl, 03-06cycloalkyl, or 01-04
fluoroalkyl.
[0136] In more preferred embodiments, Formula I compounds have RD defined as -
H,
-F, -CN, -CH3, or -CF3.
[0137] In some embodiments, Formula I compounds have RD defined as
XCH(RG)-CY, -N(RF)C(=0)XC(R3)2-CY, or -N(RF)C(=0)X-CY, wherein X is absent, -0-
,
-NH- or -CH2-, wherein RF is -H or C1-04 alkyl and X, CY and RG are as
previously defined.
[0138] In more preferred embodiments, Formula I compounds have RD defined as
-N(RF)0(=0)0CH(RG)-CY, -N(RF)C(=0)NHC(RG)-CY, or -N(RF)C(=0)CH2-CY, wherein RF
is -H
or C1-04 alkyl and X, CY and RG are as previously defined.
[0139] In some embodiments, Formula I compounds have RE defined as -H or 01-C4
alkyl, 01-
06 cycloalkyl or 01-C4 fluoroalkyl.
[0140] In more preferred embodiments, Formula I compounds have RE defined as -
H, -CH3,
cyclopropyl or -CF3.
[0141] In some embodiments, Formula I compounds have RF defined as H, C1-04
alkyl or C3-
C6 cycloalkyl.
[0142] In more preferred embodiments, Formula I compounds have RF defined as -
H.
- 35 -
CA 3046894 2019-06-18

[0143] In some embodiments of Formula I compounds one RG is -C1-C4 alkyl and
is taken
together with CY and the the carbon atom to which RD and CY is attached to
define a
substituted or unsubstituted carbocycle or a substituted or unsubstituted
heterocycle and the
other RG, if present is -H.
[0144] In other embodiments of Formula I compounds RG is independently -H or
C1-C4 alkyl.
[0145] In some embodiments of Formula I compounds Ring B is substituted or
unsubstituted
C3-C10 cycloalkylene, substituted or unsubstituted C2-C10 heterocycloalkylene,
a substituted or
unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein
if ring B is
substituted then ring B is substituted with 1, 2, or 3 independently selected
RH.
[0146] In some embodiments of Formula I compounds Ring C is substituted or
unsubstituted
C3-C10 cycloalkylene, substituted or unsubstituted C2-C10 heterocycloalkylene,
a substituted or
unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein
if ring C is
substituted then ring C is substituted with 1, 2, or 3 independently selected
RH.
[0147] In some embodiments of Formula I compounds CY is substituted or
unsubstituted C1"
C6 alkyl, substituted or unsubstituted C3-C cycloalkyl, substituted or
unsubstituted C2-C10
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl,
wherein if CY is substituted then CY is substituted with 1, 2, or 3
idependently selected RH.
[0148] In some preferred embodiments Ring A has the structure of one of:
RE
hit ' pi
[0149] R = N4'..-\ RE N/
N
\ I
RD
õD \r-NRD N"--NRD
RC RC RD RC
RC
=
[0150] Particularly preferred Formula I compounds have Ring B and Ring C each
independently defined as 1,4-substituted aryl or heteroaryl, RA is -CO2H, RD
is -F or
-CN, RD is -NRFC(=0)0CH(RG)-CY, RE is -CH3, and RF, RG, and CY are as
previously defined.
- 36 -
CA 3046894 2019-06-18

[0151] Other particularly preferred Formula I compounds have Ring B defined as
1,4-
substituted aryl or heteroaryl, 12 is -UV-Z- wherein -UV-is defined by -WO-, -
WN(R)-, or
-C(=0)N(R)-, wherein W is CH2, Z is substituted or unsubstituted 01-C6
alkylene, RA is
-CO2H, RD is -N(RF)C(=0)0CH(RG)-CY, RE is -CH3, and RG, RF, RG, and CY are as
previously
defined.
[0152] 2. The compound of embodiment 1 wherein Ring A has the structureof one
of:
RE
_ /1µ1 ,
N, I N, R h¨ N N I
N,D
[0153] RC Rc RD RC) RE)
Rc
=
[0154] 3. The compound of embodiment 1 or 2 wherein RD is -H, -ON, -F, -CH3,
or
-CF3.
[0155] 4. The compound of embodiment 1, 2 or 3 wherein RD is -F or -CN.
[0156] 5. The compound of embodiment 1, 2, 3 or 4 wherein L2, is absent.
[0157] 6 The compound of embodiment 1, 2, 3, 4 or 5 wherein 1_1, when present,
is a
geminally substituted alkyl, cycloalkyl or heterocycloalkyl group, or is UV-Z-
,
[0158] wherein -UV-is defined by -OW-, -WO-, -N(R)W-, -WN(Fe)-, -N(W)C(=0)-, -
SW-, -
S(=0),-,W-, or -C(=0)N(R)-, wherein W is substituted or unsubstituted 01-03
alkylene or W is -
C(RL)2, wherein RL independenly are -H or 01-04 alkyl or the two RL are
independenly 01-04
alkyl taken together with the carbon to which RL is attached to define a
carbocycle, Z is
substituted or unsubstituted 01-C6 alkylene or C1-06 fluoroalkylene; and n is
0, 1, or 2.
[0159] 7. The compound of embodiments 6 wherein L1, when present, is -CH2-,
Or
dimethylmethane, or -UV-Z- wherein -UV- is defined by -WO-, -WN(RJ)-, or -
C(=0)N(RJ)-,
wherein W is -CH2-, Z is substituted or unsubstituted 01-C6 alkylene.
[0160] 8. The compound of any one of embodiments 1-7 wherein RF is -H.
- 37 -
CA 3046894 2019-06-18

[0161] 9. The compound of any one of embodiments 1-8 wherein RG is -CH3.
[0162] 10. The compound of any one of embodiments 1-9 wherein CY is
substituted or
unsubstituted substituted phenyl.
[0163] 11. The compound of any one of embodiments 1-10 wherein RH is -H,
halogen, -CN, -
NO2, -OH,-OR, -SR, -S(=0)RJ, -S(=0)2RJ, -N(RL)2, 01-04 alkyl, 01-04
fluoroalkyl, 01-04
fluoroalkoxy, 01-04 alkoxy, and 01-04 heteroalkyl.
[0164] 12. The compound of any one of embodiments 1-11 wherein RH are
independently
selected from -H, halogen or substituted or unsubstituted 01-04 alkyl or
substituted 01-04
alkoxy.
[0165] 13. The compound of any one of embodiments 1-12 wherein RH is
independently -H, -
Cl, -F, -CH3, -CF3, -OCH3 or -00F3.
[0166] 14. A compound of Formula II having the structure:
A 1 A
L¨ R Formula II
[0167] or a pharmaceutically acceptable salt or prodrug thereof
[0168] wherein RA is -002H, -CO2RB, -CN, tetrazolyl, -0(=0)NH2, -0(=0)NHR6
,
C(=0)NHSO2R8 or -0(=0)NHCH2CH2S03H or a carboxylic acid isostere,
[0169] RB is optionally substituted 01-C4 alkyl or has the structure of one
of:
[0170] o ;
[0171] L1 is absent or optionally substituted C1-C6 alkylene; optionally
substituted C1-06
fluoroalkylene, or optionally substituted 01-06 heteroalkylene or -UV-Z-,
wherein -UV-is defined
by -OW-, -WO-, -N(R)W-, -WN(RJ)-, -N(R)O(0)-, -SW-, -S(=0)W-, or
-C(=0)N(RJ)-, wherein W is optionally substituted 01-03 alkylene or W is -
0(RL)2-, Z is optionally
substituted C1-C6 alkylene or C1-06 fluoroalkylene or Z is -C(RL)2-; and n is
0, 1, or 2;
- 38 -
CA 3046894 2019-06-18

[0172] Ring A is a 5 or 6 membered heteroarene having the structure of one of:
RE
Rc R RcR
N, D Rci RD
N\re' '-----s=
\ RE_N/
Nc_r
RD NRD
Rc
R
RD 0 D
Rc
RD C RD
Rc R D
RE
0
N
R (DT:2(N
N c
RD R RD RD N RD R N RD
r. D
[0173]
[0174] wherein RD is -H, -ON, -F, -Cl, -Br, -I, -001-04 alkyl, 01-04 alkyl, C3-
C6cycloalkyl, or C1-
04 fluoroalkyl;
[0175] RD is -N(RF)C(=0)XCH (RG)-CY, -N(RF)C(=0)XC(RG)2-CY, or -N(RF)C(=0)X-
CY; where
X is absent, -0-, -NH- or -CH2-;
[0176] RE is -H or 01-04 alkyl, 01-06 cycloalkyl or 01-04fluoroalkyl;
[0177] RF is -H, 01-04 alkyl or 01-06 cycloalkyl;
[0178] RG is independently selected RE, or one of RG is 01-04 alkyl and is
taken together with
CY and the the carbon atom to which RG and CY are attached to define a
substituted or
unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the
other RG, if
present, is as defined for RE;
[0179] Ring B is optionally substituted C3-C1,3 cycloalkylene, optionally
substituted C2-C10
heterocycloalkylene, optionally substituted arylene, or optionally substituted
heteroarylene,
where if ring B is substituted then ring B is substituted with 1, 2, or 3
independntly selected RH;
[0180] Ring C is absent or optionally substituted 03-010 cycloalkylene,
optionally substituted
02-010 heterocycloalkylene, optionally substituted arylene, or optionally
substituted
- 39 -
CA 3046894 2019-06-18

heteroarylene, wherein if ring C is substituted then ring C is substituted
with 1, 2, or 3
independently selected RH;
[0181] CY is optionally substituted 01-06 alkyl, optionally substituted C3-C10
cycloalkyl,
optionally substituted 02-010 heterocycloalkyl, optionally substituted aryl,
or optionally
substituted heteroaryl, wherein if CY is substituted then CY is substituted
with 1, 2, or 3
independently selected RH, or
[0182] wherein each RH is independently selected -H, halogen, -CN, -NO2, -OH, -
OR, -SR, -
S(=0)RJ, -S(=0)2RJ, - N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)R, -0C(=0)RJ,
-C(=0)ORJ, -0C(=0)0RJ, -N(R1-)2, -C(=0)N(R1-)2, -0C(=0)N (R1)2, -N(RJ)C(=0)N
(RL)2, -
N(RJ)C(=0)RJ, -N(RJ)C(=0)ORJ, 01-04 alkyl, C1-C4 fluoroalkyl, 01-04
fluoroalkoxy, 01-04 alkoxy,
or 01-04 heteroalkyl, and
[0183] wherein RJ is optionally substituted 01-06 alkyl, optionally
substituted 01-06
heteroalkyl, optionally substituted 01-06 fluoroalkyl, optionally substituted
C3-06 cycloalkyl,
optionally substituted heterocycloalkyl, optionally substituted aryl,
optionally substituted
heteroaryl, -01-04 alkylene-(optionally substituted 03-06 cycloalkyl), -01-04
alkylene-(optionally
substituted heterocycloalkyl), -01-04 alkylene-(substituted or unsubstituted
aryl), or -01-04
alkylene-(optionally substituted heteroaryl), and
[0184] each RL is independently -H, optionally substituted C1-06 alkyl,
optionally substituted
01-C6 heteroalkyl, optionally substituted C1-06 fluoroalkyl, optionally
substituted 03-06 cycloalkyl,
optionally substituted heterocycloalkyl, optionally substituted aryl,
optionally substituted
heteroaryl, -01-04 alkylene-(optionally substituted 03-C6 cycloalkyl), -01-04
alkylene-(optionally
substituted heterocycloalkyl), -01-04 alkylene-(optionally substituted aryl),
or -01-04 alkylene-
(optionally substituted heteroaryl), or
[0185] when RH is -S(=0)2N(R1)2, N(RI)2, -C(=0)N(RI-)2, -0C(=0)N(RI-)2 or
- 40 -
CA 3046894 2019-06-18

-N(R)C(=0)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL groups
independently
are 01-06 alkyl which are taken together with the N atom to which they are
attached to define an
optionally substituted heterocycle,
[0186] or when W or Z is -C(RL)2, each RL is independently -H or C1-C6 alkyl,
or the RL
groups independently are 01-C6 alkyl which are taken together with the carbon
atom to which
they are attached to define a carbocycle;
[0187] wherein when Ring B is substituted or unsubstituted arylene, Ring C is
absent, L1 is -
UV-Z, wherein -UV- is -N(R)C(=O)-, wherein RJ is -H, RD is -N(RE)C(=0)XCH(RG)-
CY, wherein
X is -0-, RG is -CH3 and RE is -H, and RD is -H, -CH3 or -CF3, or when Ring B
is substituted or
unsubstituted arylene and Ring C is substituted or unsubstituted arylene or is
substituted or
unsubstituted cycloalkylene, or Ring B is substituted or unsubstituted C3-
C10
cycloalkylene and Ring C is substituted or unsubstituted arylene and L1 is C1-
C6 alkylene,
[0188] and Rc is -H or -CH3 and RA is -CO2H or -0O2RB,
[0189] then Ring A has the structure of one of:
RE
N, ,N
N\
D ci D
RC R R R
Rc
N
s Pc N
/7'N =:r D rNµ
R
RD RC RD RC RD
RE
0
N1¨ N
RD---j-N I RD R"D
k '
c/N Rc
RD
[0190] R R R RcD
[0191] and when Ring B is 02-010 heterocycloalkylene, Ring C is substituted or
unsubstituted
arylene, L1 is C1-06 alkylene, RD is -CH3 and RA is -CO2H or -0O2R6
,
[0192] then Ring A has the structure of one of:
- 41 -
CA 3046894 2019-06-18

NI\ I
Re)---NRD NNRD
RC RD
c m ,
' N
N\
NRD o
RD N=c
,,D R
RD
RC RD
N
0 N N%;N:)<
14-N \ I
N
rk
Rc RD R N RD Re N RD
[0193] RD RD
[0194] In preferred embodiments Ring A has the structure of one of:
E
OXE,NX //1\1,,N*
N, I
R¨N 1\1µ
RC
I = RC RD RC RD
RC/ RD N RD
[0195] R
[0196] Particularly preferred Formula II compounds have Ring B and Ring C
defined each as
1,4-substituted aryl or heteroaryl, RA is CO2H, and RD is -N(RF)C(=0)0CH(RG)-
CY.
[0197] Particularly preferred Formula II compounds have Ring B defined as 1,4-
substituted
aryl or heteroaryl, L1 is -UV-Z-, wherein -UV-is defined by -WO-, -WN(RJ)-, or
-C(0)N(R)-,
wherein W is -CH2-, Z is substituted or unsubstituted 01-C6 alkylene, RA is -
CO2H, RD is -
N(RF)C(=0)0CH(RG)-CY.
[0198] 15. A compound of Formula III having the structure:
AI=
A2
co 410 Formula Ill
A3
[0199] or a pharmaceutically acceptable salt or prodrug thereof,
[0200] wherein RA is -002H, -CO2RB, -ON, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
C(=0)NHSO2R8 or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
- 42 -
CA 3046894 2019-06-18

[0201] RB is substituted or unsubstituted 01-C4 alkyl or has the structure of
one of
[0202] o ;
[0203] L1 is absent or is substituted or unsubstituted 01-C6 alkylene, C1-06
fluoroalkylene; or
substituted or unsubstituted 01-06 heteroalkylene or -UV-Z- wherein -UV-is
defined by -OW-, -
WO-, -N(RJ)W-, -WN(RJ)-, -N(R)C(=O)-, -SW-, -S(=O)W-, or
-C(=0)N(RJ)-, wherein W is substituted or unsubstituted C1-C3 alkylene or W is
-C(R1-)2-, Z is
substituted or unsubstituted C1-06 alkylene or C1-06 fluoroalkylene; and n is
0,1, or 2;
[0204] Ring A is a 5-6 membered heteroarenes having one the structure of one
of:
RE
' N, ,N '
,/(µLN%!
N s\ I R R¨N N
Nr\i-RD
Rc RD RC/ \ RD C RD Rc
RCRD N¨(
RC/ RD
Rc RD
RE
0
RN --õ rNi NIT rN..µ,õ
, ' 1- N I
/
c/N RC N D c c RD R N RD Rc".--IN'N RD
R RD R R
[0205] wherein Re is -H, -ON, -F, -Cl, -Br, -I, -001-04 alkyl, C1-04 alkyl, 03-
06 cycloalkyl, or C1-
C4 fluoroalkyl;
[0206] RD is -N(RF)C(=0)XCH(RG)-CY, -N(RF)C(=0)XC(R3)2-CY, or -N(RF)C(=0)X-CY.
wherein Xis absent, -0-, -NH- or -CH2-;
[0207] RE is -H or 01-04 alkyl, 01-06 cycloalkyl or 01-04 fluoroalkyl;
[0208] RF -H, 01-0.4 alkyl or C1-06 cycloalkyl;
[0209] RG is independently selected RE, or one RG is -C1-04 alkyl and is taken
together with
CY and the the carbon atom to which RG and CY is attached to define a
substituted or
- 43 -
CA 3046894 2019-06-18

unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the
other RG, if
present, is as defined for RE;,
[0210] Al, A2 and A3 are independently =NH-, -N=, =CH- or -CH=;,
[0211] Ring C is absent or substituted or unsubstituted C3-C10 cycloalkylene,
substituted or
unsubstituted 02-C10 heterocycloalkylene, substituted or unsubstituted
arylene, or substituted or
unsubstituted heteroarylene, wherein if ring C is substituted then ring C is
substituted with 1, 2,
or 3 independently selected RH;
[0212] CY is substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted C3-C10
cycloalkyl, substituted or unsubstituted 02-010 heterocycloalkyl, substituted
or unsubstituted aryl,
or substituted or unsubstituted heteroaryl, wherein if CY is substituted then
CY is substituted
with 1,2, or 3 RH;
[0213] wherein each RH is independently -H, halogen, -CN, -NO2, -OH, -OR, -
SR', -S(=0)RJ,
-S(=0)2RJ, -N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)RJ, -0C(=0)RJ, -C(=0)ORJ, -
0C(=0)0RJ, -
N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2, N(RJ)C(=0)N(RL)2, -N(RJ)C(=0)RJ, -
NRJC(=0)ORJ, C1-C4
alkyl, C1-04 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, or C1-04
heteroalkyl;
[0214] each RJ is independently substituted or unsubstituted C1-C6 alkyl,
substituted or
unsubstituted C1-06 heteroalkyl, substituted or unsubstituted C1-06
fluoroalkyl, substituted or
unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted C3-C6 cycloalkyl), -C1-04 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
01-C4 alkylene-(substituted or unsubstituted aryl), or C1-C4 alkylene-
(substituted or
unsubstituted heteroaryl);
[0215] each RL is independently -H, substituted or unsubstituted C1-C6 alkyl,
substituted or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl, substituted or
unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl,
substituted or
- 44 -
CA 3046894 2019-06-18

unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted cycloalkyl), -C1-04 alkylene-(substituted or unsubstituted
heterocycloalkyl), -C1-C4
alkylene(substituted or unsubstituted aryl), or
-C1-C4 alkylene-(substituted or unsubstituted heteroaryl), or
[0216] when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2 or
N(RJ)C(=0)N(RL)2,
each RL is independently -H or C1-C6 alkyl, or the RL groups independently are
C1-C6 alkyl which
are taken together with the N atom to which they are attached to define a
substituted or
unsubstituted heterocycle, or
[0217] when W or Z is -C(RL)2, each RI- is independently -H or C1-C6 alkyl, or
the RL groups
independently are C1-C6 alkyl which are taken together with the carbon atom to
which they are
attached to define a carbocycle;
[0218] wherein when A', A2 and A3 are =CH- or -CH=, Ring C is absent, Ll is -
UV-Z, wherein -
UV- is -N(R)C(=O)-, wherein IR is -H, RD is -N(RF)C(=0)XCH(RG)-CY, wherein X
is -0-, RG is -
CH3 and RF is -H, and RD is -H, -CH3 or -CF3,
[0219] or when Ring C is substituted or unsubstituted arylene or substituted
or unsubstituted
C3-C10 cycloalkylene
[0220] and RD is -H or -CH3 and RA is -CO2H or -0O2RB ,
[0221] then Ring A has the structure of one of:
- 45 -
CA 3046894 2019-06-18

RE
I
E ,Nz...,s, ,,N--.N.;
R ¨N N 1
RC RD RC RD
RC).---RD NN RD
/ Ns>:, Rc ......,N ..5:7;,:, ,,,.....7,
NN...1r.
RE_.......c7,N,isr:,c,.
N\ \N="-(µ
D 0
RC (RD Re/NI CRD
RCr NR
RD RD
RE
o i
f)=-1qt N.' 1 .
R --,IsA.:_. .......(Ni- N \ / c..,4'--)( ,..,C 1
N
RC RD R N RD Fic N RD
DC/ RD RD RD
[0222] - ,
[0223] and when Ring C is substituted or unsubstituted arylene, L1 is C1-C6
alkylene, RD is -
CH3 and RA is -CO2H or -CO2R13,
[0224] then Ring A has the structure of one of:
N, 2....., E 71:)( ,,N1-..N*
pi . R ¨N isk I
\r-s\RD N'\RD
RD RD
R RC
42.s.sN';õ( Rcs.......? N:,:.- RE_......c.7,Nx..
RD 01Z-1- \N-=(
RD RD RC / '
/1µ1 RD
RC
RE
0
RE-, : cl:t "
RC ,
ri N / ' = N'l- i '
\ c,.--'= ' I
DC/N RD RD RC R-
, R N RD Rc RD
[0225] .
[0226] In preferred embodiments Ring A has the structure of one of:
RE
I
'r ,N \ N1-.,),( p rµ1
, ,.!
r- õ N
N , 1
/
D Ni'µRD
RD RD RD RD __ RD RE_N
RCi -R
[0227] RC .
[0228] Particularly preferred Formula III compounds have Ring C is defined as
1,4-substituted
phenyl or pyridyl, RA is -CO2H, and RD is -N(RF)C(=0)OCH(RG)-CY; L1 is
- 46 -
CA 3046894 2019-06-18

-UV-Z- wherein -UV- is defined by -WO-, -WN(RJ)-, or -C(=0)N(RJ)-, wherein W
is
-CH2-, Z is substituted or unsubstituted C1-C6 alkylene, RA is -CO2H, and RD
is
-N(RF)C(=0)0CH(RG)-CY.
[0229] 16. A compound of Formula IV having the structure:
RHAi
coLiRA Formula IV
[0230] or a pharmaceutically acceptable salt or prodrug thereof,
[0231] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
-C(=0)NHSO2RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0232] Fe is optionally substituted -C1-C4 alkyl or has the structure of one
of:
' 0 '
y,
[0233] o ;
[0234] L1 is -UV-Z-, wherein -UV-is defined by -OW-, -WO-, -N(R)W-, -WN(RJ)-,
-N(R)C(=O)-, -SW-, -S(=0),W-, or -C(=0)N(RJ)-, wherein W is substituted or
unsubstituted C1-
C3 alkylene or W is -C(RL)2-, Z is substituted or unsubstituted C1-C6 alkylene
or substituted or
unsubstituted Cl-C6 fluoroalkylene or Z is -C(RI-)2-; and n is 0, 1, or 2;
[0235] Al is independently =N- or =CH-;
[0236] Ring A is a 5 or 6 membered heteroarene having one of the structures
of:
- 47 -
CA 3046894 2019-06-18

RE
I
0 \ N ,,:.-..
Ni;_r 2 Ni r, . RE¨N\ D
N1µ....z...,....L D
\
RD RC RD Rc RD ,r 17Z N R
Rc R-
-'ssiµls;.( IRc*N \ -::-- eN RE.......r
Nv__ a
0 r- N D
RD Rc RD Rc RD
Rcf R
RD
RE
0 i
RE N , N = /-;Nr
' 0' \
1 / .
_.
R N RD RD
N c
ci R RD Rc RD
R RD
,
[0237] wherein RD is -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, C1-C4 alkyl, C3-
C6 cycloalkyl, or C1-
C4 fluoroalkyl;
[0238] RD is -N(RE)C(=0)XCH(RG)-CY, -N(RE)C(=0)XC(RG)2-CY, or -N(RE)C(=0)X-CY,
wherein X is absent, -0-, -NH- or -CH2-;
[0239] RE is -H or C1-C4 alkyl, C3-C6 cycloalkyl or C1-C4 fluoroalkyl;
[0240] RE is -H, C1-04 alkyl or C3-C6 cycloalkyl;
[0241] RG is independently selected RE, or one RG is -C1-C4 alkyl and is taken
together with
CY and the carbon atom to which RG and CY is attached to define a substituted
or unsubstituted
carbocycle or a substituted or unsubstituted heterocycle, and the other RG, if
present, is as
defined for RE;
[0242] CY is 01-C6 alkyl, a substituted or unsubstituted C3-Clo cycloalkyl, a
substituted or
unsubstituted C2-010 heterocycloalkyl, a substituted or unsubstituted aryl, or
a substituted or
unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted
with 1, 2, or 3 RH;
[0243] wherein each RH is independently -H, halogen, -ON, -NO2, -OH, -OR, -
SR',
-S(=0)RJ, -S(=0)2RJ, -N(RJ)S(=0)2RJ, -S(=0)2N(RI)2, -C(=0)R, -0C(=0)RJ, -
C(=0)GRJ,
-0C(=0)0RJ, -N(R1-)2, -C(=0)N(RI-)2, -0C(=0)N(RL)2, N(RJ)C(=0)N(RI-)2, -
N(RJ)C(=0)RJ,
- 48 -
CA 3046894 2019-06-18

-N(RJ)C(=0)ORJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4
alkoxy, or Cl-C4
heteroalkyl;
[0244] wherein RJ is independently substituted or unsubstituted C1-C6 alkyl,
substituted or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-06
fluoroalkyl, substituted or
unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted C3-C6 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
C1-C4 alkylene-(substituted or unsubstituted aryl), or C1-C4 alkylene-
(substituted or
unsubstituted heteroaryl); and
[0245] each RL is independently -H, substituted or unsubstituted 01-C6 alkyl,
substituted or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -01-C4 alkylene-
(substituted or
unsubstituted C3-C6 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
C1-C4 alkylene-(substituted or unsubstituted aryl), or
-C1-C4 alkylene-(substituted or unsubstituted heteroaryl),
[0246] or when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2 or
-N(R)C(=0)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL groups
independently
are C1-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0247] or when W or Z is -C(RL)2, each RL is independently -H or C1-C6 alkyl,
or the RL
groups independently are 01-C6 alkyl which are taken together with the carbon
atom to which
they are attached to define a carbocycle,
[0248] or when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(R1)2, -0C(=0)N(RL)2 or
- 49 -
CA 3046894 2019-06-18

-N(RJ)C(=0)N(RL)2, each RL is independently is -H or C1-C6 alkyl, or the RL
groups
independently are C1-06 alkyl which are taken together with the N atom to
which they are
attached to define a substituted or unsubstituted heterocycle,
[0249] or when W is -C(RL)2-, each RL is independently -H, C1-C6 alkyl, or the
RL groups
independently are C1-C6 alkyl which are taken together with the carbon atom to
which they are
attached to define a carbocycle;
[0250] wherein A1 is =CH-, L1 is -UV-Z, wherein -UV- is -N(R)C(=O)-, wherein
RJ is -H, RD is
-N(RF)-C(=0)XCH(RG)-CY, wherein X is -0-, RG is -CH3 and RF is -H, and Re is -
H, -CH3 or -
CF3,
[0251] and Re is -H or -CH3 and RA is -CO2H or CO2RB ,
[0252] then Ring A has the structure of one of:
RIE
Repi .
N, D R RD,,
) 1._._ E iNX e--N*
N \ /
c;_. R N RD N RD
R
Rc
N .
RD / -1-
RD
,N, RE-__ r-
N).--- 0 rc Re RD
Rc/N¨\RD
Re RD
RE
0 i
R..--I"" r- N \ / R c,,,,-.'Xf.
N / Rc 4D N RD RND
Ref R 13 RD R. r,
[0253] ,
[0254] In preferred embodiments Ring A has the structure of one of:
RE
i
,o,..,-( N, ::,.... N, 5Nr\
/ µ N* RE_ N N
)
N \ I
'-----NRD \-NRD Rc RD RC'
RD
Rc
[0255] Rc
[0256] Particularly preferred Formula IV compounds have L1 defined as -UV-Z-,
wherein
- 50 -
CA 3046894 2019-06-18

-UV -is defined by -WO-, -WN(RJ)-, or -C(=0)N(RJ)-, wherein W is -CH2-, Z is
substituted or
unsubstituted 01-06 alkylene, RA is -CO2H, and RD is -N(RF)C(=0)0CH(RG)-CY.
[0257] 17. A compound of Formula V having the structure:
RH
Al
\ / Li¨RA Formula V
RC
RD
[0258] or a pharmaceutically acceptable salt or prodrug thereof,
[0259] wherein RA is -CO2H, -CO2R8, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHR8,
C(=0)NHSO2R8 or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere,
[0260] wherein R8 is optionally substituted C1-04 alkyl or has the structure
of one of
[0261] o .
[0262] L1 is -UV-Z-, wherein -UV-is defined by -OW-, -WO-, -N(R)W-, -WN(RJ)-, -
N(R)C(=O)-
-SW-, -S(=0),-,W-, or -C(=0)N(RJ)-, wherein W is substituted or unsubstituted
C1-03 alkylene or
W is -C(RI-)2-, Z is substituted or unsubstituted C1-C6 alkylene or
substituted or unsubstituted C1-
06 fluoroalkylene or Z is -C(R1)2-; and n is 0, 1, or 2;
[0263] Al is =N- or =CH-;
[0264] Ring A is a 5 membered heteroarene having the structure of one of:
RE
RN
Nisfk o --"YNRD
Rc RD Rc RD RC RD Rc R
FX E
0
E N ,
o ,P4 n
RLA
RD Rc RD R- R- Rc/ RD Rc RD
[0265] RD
-51 -
CA 3046894 2019-06-18

[0266] wherein RD is -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, C1-C4 alkyl, C3-
C6cycloalkyl, or Cr
C4 fluoroalkyl;
[0267] RD is -N(RE)C(=0)XCH(RG)-CY, -N(RE)C(=0)XC(RG)2-CY, or -N(RE)C(=0)X-CY;
wherein X is absent, -0-, -NH- or -CH2-;
[0268] RE is -H or C1-C4 alkyl, C3-06 cycloalkyl or C1-C4 fluoroalkyl;
[0269] RE is -H, C1-04 alkyl or -C3-C6 cycloalkyl;
[0270] RG is independently selected RE, or one RG is -C1-C4 alkyl and is taken
together with
CY and the carbon atom to which RG and CY is attached to define a substituted
or unsubstituted
carbocycle or a substituted or unsubstituted heterocycle, and the other RG, if
present, is as
defined for RE;
[0271] CY is substituted or unsubstituted 01-C6 alkyl, substituted or
unsubstituted C3-C10
cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted
or unsubstituted aryl,
or a substituted or unsubstituted heteroaryl, wherein if CY is substituted
then CY is substituted
with 1, 2, or 3 independently selected RH;
[0272] RH is independently -H, halogen, -CN, -NO2, -OH,-OR, -SR, -S(=0)RJ, -
S(=0)2RJ, -N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)RJ, -0C(=0)RJ, -C(=0)0RJ, -
0C(=0)0RJ,
-C(=0)N(RL)2, -0C(=0)N(RI-)2, NRJC(=0)N(R1-)2, -NRJC(=0)RJ,
-NRJC(=0)ORJ, C1-C4 alkyl, C1-C4 fluoroalkyl, 01-C4 fluoroalkoxy, C1-C4
alkoxy,and Ci-C4
heteroalkyl;
[0273] wherein each IR is independently substituted or unsubstituted 01-C6
alkyl, substituted
or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl, substituted or
unsubstituted C3-06 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -01-04 alkylene-
(substituted or
unsubstituted 03-C6 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
- 52 -
CA 3046894 2019-06-18

C1-C4 alkylene-(substituted or unsubstituted aryl), or 01-C4 alkylene-
(substituted or
unsubstituted heteroaryl);
[0274] wherein each RL is independently -H, substituted or unsubstituted C1-C6
alkyl,
substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted
C1-C6 fluoroalkyl,
substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted
heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
C1-C4 alkylene-
(substituted or unsubstituted C3-C6 cycloalkyl), -01-C4 alkylene-(substituted
or unsubstituted
heterocycloalkyl), -C1-C4 alkylene(substituted or unsubstituted aryl), or -Ci-
C4 alkylene-
(substituted or unsubstituted heteroaryl),
[0275] or when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2
or -N(RJ)C(=0)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL
groups
independently are C1-C6 alkyl which are taken together with the N atom to
which they are
attached to define a substituted or unsubstituted heterocycle,
[0276] or when W or Z is -C(RL)2, each RL is independently -H or C1-C6 alkyl,
or the RL
groups independently are Cl-C6 alkyl which are taken together with the carbon
atom to which
they are attached to define a carbocycle.
[0277] wherein when A1 is =CH-, L1 is -UV-Z, wherein -UV- is -N(R)C(0)-, and
Rc is -
H, -CH3 or -C F3, then Ring A has the structure of one of:
RIE
RCR
N, D RC
Ne/ N
N,µ RN RD
RD N"¨====RD RD
RC
0 RE
RD Rc RD RLf7 RN
RC/ RD RC/N
Rc
[0278] R RDD
[0279] Particularly preferred Formula V compounds have L1 defined as UV-Z-
wherein
- 53 -
CA 3046894 2019-06-18

-UV-is defined by -WO-, -WN(RJ)-, or -C(=0)N(RJ)-, wherein W is -CH2-, Z is
substituted or
unsubstituted C1-C6 alkylene, RA is -CO2H, and RD is -N(RF)C(=0)0CH(RG)-CY.
[0280] 18. A compound of Formula VI having the structure:
RH
A'
= L1¨R' Formula VI
RC
N,
0/ RF
RG 0
414 RH
[0281] or a pharmaceutically acceptable salt or prodrug thereof,
[0282] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
-C(=0)NHS02RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere, wherein
[0283] RB is optionally substituted C1-a4 alkyl or has the structure of one
of:
[0284] o ;
[0285] Ll is UV-Z- wherein -UV-is defined by -OW-, -WO-, -N(R)W-, -WN(RJ)-,
-N(R)C(=O)-, -SW-, -S(=0),W-, or -C(=0)N(RJ)-, wherein W is substituted or
unsubstituted C1"
C3 alkylene or W is -C(R1)2-, Z is substituted or unsubstituted C1-06 alkylene
or substituted or
unsubstituted C1-C6fluoroalkylene or Z is -C(RL)2-; and n is 0, 1, or 2;
[0286] Al is independently =N- or =CH-;
[0287] Ring A is a 5 membered heteroarene having one of the structures of:
- 54 -
CA 3046894 2019-06-18

RIE
N, ,N
Ni I s -r = R N NI\ D
Rc
DD RDRD Rc ER Re RD Re RD
Rc
0
DE O/µ
'
RD
DDC/ D T..
RCR RD
RD
[0288] wherein RD is defined as -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, C1-
C4 alkyl, C3-C6
cycloalkyl, or C1-C4 fluoroalkyl;
[0289] wherein RD is the -N(RF)C(=0)CH(RG)-CY substituent of Formula VI
wherein CY is
phenyl substituted with one RH;
[0290] RG is independently selected RE, or one RG is -C1-C4 alkyl and is taken
together with
CY and the carbon atom to which RG and CY is attached to define a substituted
or unsubstituted
carbocycle or a substituted or unsubstituted heterocycle, and the other RG, if
present, is as
defined for RE;
[0291] RF is -H, -01-C4 alkyl or -C3-06 cycloalkyl;
[0292] RH is independently selected from -H, halogen, -CN, -NO2, -OH, -OR, -
SR, -S(=0)RJ,
-S(=0)2RJ, -N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)R, OC(=0)RJ, -CO2RJ,
-0C(=0)0RJ, -N(R1-)2, -C(=0)N(RL)2, -0C(=0)N(RI-)2, N(RJ)C(=0)N(R1)2,
-N(RJ)C(=0)RJ, -N(RJ)C(=0)0Rj, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4
fluoroalkoxy, Cl-C4
alkoxy,and C1-C4 heteroalkyl;
[0293] wherein IR is substituted or unsubstituted C1-06 alkyl, substituted or
unsubstituted
Ci-
C6 heteroalkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted C3-C6
cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, a
substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted C3-C6
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
C1-C4 alkylene-
(substituted or unsubstituted aryl), or C1-C4 alkylene-(substituted or
unsubstituted heteroaryl);
- 55 -
CA 3046894 2019-06-18

[0294] wherein each RL is independently -H, substituted or unsubstituted C1-C6
alkyl,
substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted
C1-C6 fluoroalkyl,
substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted
heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
C1-C4 alkylene-
(substituted or unsubstituted cycloalkyl), -C1-C4 alkylene-(substituted or
unsubstituted
heterocycloalkyl), -C1-C4 alkylene(substituted or unsubstituted aryl), or -C1-
C4 alkylene-
(substituted or unsubstituted heteroaryl),
[0295] or when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RI-)2 or
N(RJ)C(=0)N(RI-)2, each RL is independently -H or C1-C6 alkyl, or the RL
groups independently
are C1-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0296] or when W or Z is -C(RL)2, each RL is independently -H or C1-C6 alkyl,
or the RI-
groups independently are C1-C6 alkyl which are taken together with the carbon
atom to which
they are attached to define a carbocycle.
[0297] In preferred embodiments Ring A has the structure of one of:
RE
(-2))( z/N,N:;ar 1,N,N.%(
Nr\ I
N RD
R
r` RD RC) RE
¨N
RD
[0298] ry Rc
[0299] Particularly preferred Formula VI compounds have L1 as -UV-Z- wherein -
UV- is
-C(=0)NH-, -CH20- or -CH2NH-, Z is substituted -CH-, and RA is -CO2H.
[0300] 19. A compound of Formula VII having the structure of:
- 56 -
CA 3046894 2019-06-18

RH R\
Al N¨z
110 "RA
Rc 0
N, F
R Formula VII
RG
4114RH
[0301] or a pharmaceutically acceptable salt or prodrug thereof,
[0302] wherein RA is -CO2H, -CO2RE, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHRE,
-C(=0)NHSO2RE or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0303] RE is optionally substituted C1-C4 alkyl or has the structure of one
of:
=====7;rN.,,,
[0304]
[0305] A' is independently =N- or =CH-;
[0306] Ring A has the structure of one of:
RE
,0 N Rc R ,..N.2 RC). N. RN'
I
)==( D N D
RRD
[0307] R-
Rc
[0308] RC is -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, C1-C4 alkyl, C3-05
cycloalkyl, or C1-C4
fluoroalkyl;
[0309] wherein RD is the -N(RF)C(=0)CH(RG)-CY substituent of Formula VII
wherein CY is
phenyl substituted with one RH;
[0310] RE, RF and RG independently are -H or 01-C4 alkyl;
[0311] Z is -C(RL)2-;
- 57 -
CA 3046894 2019-06-18

[0312] RH is independently -H, halogen, -CN, -NO2, -OH,-OR, -SR, -S(=0)RJ, -
S(0)2R, -
N(RJ)S(=0)2Rj, -S(=0)2N(RL)2, -C(=0)RJ, -0C(=0)RJ, -CO2RJ, -0CO2RJ, -N(RL)2, -
C(=O)N (RL)2,
-0C(=0)N(RL)2, NRJC(=0)N(RL)2, -NRJC(=0)RJ, -NRJC(=0)0RJ, C1-C4 alkyl, C1-C4
fluoroalkyl,
01-04fluoroalkoxy, 01-04 alkoxy,and 01-04 heteroalkyl;
[0313] RJ is substituted or unsubstituted C1-06 alkyl, substituted or
unsubstituted 01-C6
heteroalkyl, 01-06 fluoroalkyl, substituted or unsubstituted 03-C6 cycloalkyl,
substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted
heteroaryl, -C1-C4 alkylene-(substituted or unsubstituted 03-06 cycloalkyl), -
C1-C4 alkylene-
(substituted or unsubstituted heterocycloalkyl), -01-04 alkylene-(substituted
or unsubstituted
aryl), or 01-04 alkylene-(substituted or unsubstituted heteroaryl);
[0314] RI- is -H, substituted or unsubstituted C1-06 alkyl, substituted or
unsubstituted C1-C6
heteroalkyl, substituted or unsubstituted 01-06 fluoroalkyl, substituted or
unsubstituted C3-06
cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-04 alkylene-(substituted or
unsubstituted 03-C6
cycloalkyl), -01-04 alkylene-(substituted or unsubstituted heterocycloalkyl), -
01-04
alkylene(substituted or unsubstituted aryl), or
-01-04 alkylene-(substituted or unsubstituted heteroaryl),
[0315] or when RH is -S(=0)2N(RI)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2 or
-N(RJ)C(=0)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL
groups independently
are C1-06 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0316] or each RL in Z is independently -H or 01-06 alkyl, or the RL groups
independently are
C1-06 alkyl which are taken together with the carbon atom to which they are
attached to define a
carbocycle.
- 58 -
CA 3046894 2019-06-18

[0317] In some embodiments, Formula VII compounds have RF defined as -H, C1-C4
alkyl or
01-C6 cycloalkyl and each RH Fe and RI- are as previously defined;
[0318] In particularly preferred Formula VII compounds RA is -CO2H.
[0319] 20. A compound of Formula VIII having the structure:
R- Rk
A1 \N¨z
1111 V11 \RA
Rc
N, F
R Formula VIII
RG
H
[0320] or a pharmaceutically acceptable salt or prodrug thereof,
[0321] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
-C(=0)NHS02RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0322] RI' is optionally substituted C1-C4 alkyl or has the structure of one
of:
)0y\
[0323] 0 0 0 0
[0324] A1 is =N- or =CH-;
[0325] Ring A has the structure of one of:
RE
E
N I
N\
RD N RD
c R Rc RD RC) RD R ¨N
[0326] R Rc
[0327] Rc -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, C1-C4 alkyl, C3-C6
cycloalkyl, or Ci-04
fluoroalkyl;
- 59 -
CA 3046894 2019-06-18

[0328] wherein RD is the -N(RE)C(=0)CH(RG)-CY substituent of Formula VII
wherein CY is
phenyl substituted with one RH;
[0329] RE and RE independently are -H or 01-C4 alkyl or C3-C6 cycloalkyl;
[0330] RG is -H or C1-C4 alkyl or is C1-C4 alkyl that is taken together with
the the RH pheny
moiety of the Ring A RD substituent and the carbon atom to which RG and said
phenyl moiety is
attached to define a carbocycle;
[0331] W is -C(RL)2-;
[0332] Z is -C(RL)2-;
[0333] RH is -H, halogen, -CN, -NO2, -OH,-OR, -SR", -S(=0)RJ, -S(=0)2RJ, -
N(R)S(0)2R, -
S(=0)2N(RI-)2, -C(=0)RJ, -0C(=0)RJ, -CO2RJ, -0CO2RJ, -
C(=0)N(RL)2, -0C(=0)N(RL)2,
NRJC(=0)N(RL)2, -NRJC(=0)RJ, -NRJC(=0)ORJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-
C4
fluoroalkoxy, C1-04 alkoxy,and C1-C4 heteroalkyl;
[0334] RJ is substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted C1-C6
heteroalkyl, is substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted C3-C6
cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-04 alkylene-(substituted or
unsubstituted C3-C6
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
Ci-C4 alkylene-
(substituted or unsubstituted aryl), or C1-C4 alkylene-(substituted or
unsubstituted heteroaryl);
[0335] RI- independently are -H, substituted or unsubstituted C1-06 alkyl,
substituted or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl, substituted or
unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted C3-06 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
C1-C4 alkylene(substituted or unsubstituted aryl), or -C1-C4 alkylene-
(substituted or
unsubstituted heteroaryl),
- 60 -
CA 3046894 2019-06-18

[0336] or when RH is -S(=0)2N(RL)2, -N(RL)2, -0(=0)N(RL)2, -0C(=0)N(RL)2 or -
N(RJ)C(=0)N(RL)2, each RL is independently -H or 01-06 alkyl, or the RL groups
independently
are C1-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0337] or each RL is in W or Z independently -H or C1-C6 alkyl, or the RL
groups independently
are 01-C6 alkyl which are taken together with the carbon atom to which they
are attached to
define a carbocycle.
[0338] In some embodiments, Formula VIII compounds have RF defined as -H, C1-
04 alkyl or
C3-06 cycloalkyl.
[0339] In particularly preferred Formula VIII compounds RA is -002H and RJ is -
H.
[0340] 21. A compound of Formula IX having the structure:
R
RH A
A1 0¨z/
W
R-
N, F
R Formula IX
RG 0
ORH
[0341] or a pharmaceutically acceptable salt or prodrug thereof,
[0342] wherein RA is -002H, -CO2RB, -CN, tetrazolyl, -0(=0)NH2, -0(=0)NHRB,
0(=-0)NHSO2R8 or -0(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0343] RB is optionally substituted 01-04 alkyl or has the structure of one
of:
[0344] 0 0 0 0
- 61 -
CA 3046894 2019-06-18

[0345] Ring has the structure of one of:
RE
R ¨N N
Rc
Rc R Rc RD RD N RD
[0346] Rc
[0347] Rc - H, -CN, -F, -CI, -Br, -I, -0C1-C4 alkyl, C1-C4 alkyl, C3-C6
cycloalkyl, or C1-C4
fluoroalkyl;
[0348] wherein RD is the -N(RE)C(=0)CH(RG)-CY substituent in Formula IX
wherein CY is
phenyl substituted with one RH;
[0349] RE, RE and RG independently are -H, C1-C4 alkyl or C1-C6 cycloalkyl or
RE and RE
independenly are -H, C1-C4 alkyl or C1-C6 cycloalkyl and RG is C1-C4 alkyl
that is taken together
with the the RH pheny moiety of the Ring A RD substituent and the carbon atom
to which RG and
said phenyl moiety is attached to define a carbocycle;
[0350] RH is independently -H, halogen, -CN, -NO2, -OH,-OR, -SR', -S(=0)RJ, -
S(=0)2RJ, -
N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)RJ, -0C(=0)RJ, -CO2RJ, -0CO2RJ, -N(RL)2, -
C(=0)N(RL)2,
-0C(=0)N(RI-)2, NRJC(=0)N(RL)2, -NRJC(=0)RJ, -NRJC(=0)ORJ, 01-C4 alkyl, C1-04
fluoroalkyl,
C1-C4 fluoroalkoxy, C1-C4 alkoxy,and C1-C4 heteroalkyl;
[0351] RJ is substituted or unsubstituted C1-06 alkyl, substituted or
unsubstituted C1-C6
heteroalkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted C3-C6
cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted C3-06
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
C1-C4 alkylene-
(substituted or unsubstituted aryl), or C1-C4 alkylene-(substituted or
unsubstituted heteroaryl);
[0352] W is -C(RL)2-;
[0353] Z is -C(RL)2-;
- 62 -
CA 3046894 2019-06-18

[0354] RL independently are -H, substituted or unsubstituted C1-C6 alkyl,
substituted or
unsubstituted C1-06 heteroalkyl, substituted or unsubstituted C1-06
fluoroalkyl, substituted or
unsubstituted 03-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-04 alkylene-
(substituted or
unsubstituted C3-06 cycloalkyl), -01-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
C1-04 alkylene(substituted or unsubstituted aryl), or -01-04 alkylene-
(substituted or
unsubstituted heteroaryl),
[0355] or each RL in W or Z independently are 01-06 alkyl which are taken
together with the
carbon atom to which they are attached to define a carbocycle.
[0356] In preferred Formula IX compounds RA is -CO2H.
[0357] 22. A compound of Formula X having the structure:
RH RH
Al 4
A L
, 1R Formula X
[0358] or a pharmaceutically acceptable salt or prodrug thereof,
[0359] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
C(=0)NHSO2RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0360] RB is optionally substituted 01-04 alkyl or has the structure of one
of:
oYo yo ).(N
[0361] 0 0 0 0
[0362] L1 is absent or optionally substituted C1-06 alkylene; C1-06
fluoroalkylene; or optionally
substituted 01-06 heteroalkylen or L1, when present is -
Cn2-, , or disubstituted
dimethylmethane.
- 63 -
CA 3046894 2019-06-18

[0363] A' is =N- or =CH-;
[0364] Ring A has the structure of one of::
RE
= N
N;lir E
D
Rc\ ¨N k
R N¨NR
R0 RD Re RD
R Is
\
Re N =
N =
ciN
NI\ a D "NN<
NRD Rc RD ,E N RD
Rcr
RD
RE
0
RcN N'T
0 N R
N \
\ '
R N RD RXRD
pc/N R D Rc RD
[0365] - R-
[0366] Rc is -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, C1-C4 alkyl, C3-C6
cycloalkyl, or C1-C4
fluoroalkyl;
[0367] RD is -NRFC(=0)XCH(RG)-CY, -NRFC(=0)XC(RG)2-CY, or -NRFC(=0)X-CY; where
X is
absent, -0-, -NH- or -C H2-;
[0368] RE, RF and RG independently are -H or C1-C4 alkyl or C3-C6 cycloalkyl
or RE and RF
independently are -H, C1-C4 alkyl or C1-C6 cycloalkyl and one RG is C1-04
alkyl and is taken
together with CY and the carbon atom to which RG and CY are attached to define
a substituted
or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and
the other RG, if
present, is as defined for RE;
[0369] RH is -H, halogen, -CN, -NO2, -OH,-OR, -SR, -S(=O)W, -S(=0)2RJ, -
N(RJ)S(=0)2RJ, -
S(=0)2N(RL)2, -C(=0)RJ, -0C(=0)RJ, -0O217, -0CO2RJ, -N(RL)2, -C(=0)N(RL)2, -
0C(=0)N(RL)2,
NRJC(=0)N(RL)2, -NRJC(=0)W, -NRJC(=0)0RJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-
C4
fluoroalkoxy, C1-C4 alkoxy,and C1-C4 heteroalkyl;
[0370] RJ is substituted or unsubstituted Ci-C6 alkyl, substituted or
unsubstituted 01-C6
heteroalkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted C3-C6
- 64 -
CA 3046894 2019-06-18

cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted C3-C6
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
C1-C4 alkylene-
(substituted or unsubstituted aryl), or Gra, alkylene-(substituted or
unsubstituted heteroaryl);
[0371] RL independently are -H, substituted or unsubstituted C1-C6 alkyl,
substituted or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted Cl-C6
fluoroalkyl, substituted or
unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted C3-C6 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl),
alkylene(substituted or unsubstituted aryl), or -C-C4 alkylene-(substituted or
unsubstituted heteroaryl),
[0372] or when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2 or -
N(RJ)C(=0)N(RL)2, each RL is independently -H or C1-C6 alkyl, or the RL groups
independently
are Cl-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle;
[0373] CY is substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted C3-C10
cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted
or unsubstituted aryl,
or substituted or unsubstituted heteroaryl, wherein if CY is substituted then
CY is substituted
with 1,2, or 3 RH,
[0374] wherein when L1 is not absent and Re is -H or -CH3 and RA is -CO2H or -
CO2RB , then
Ring A has the structure of one of:
- 65 -
CA 3046894 2019-06-18

RE
I .
piX ,,NI-N>,
NI\
RD rsi"--RD
-Y----:-C D
Rc R R- RD Rc
DE N ,
sY c N . / ==--
..--N ' RN ,-- (rµl ' p1( r\-----q1/4:-.
N k _1( N=( r. R0
71 0
RD RD RC
RD RD
R-
Rc
RE
0 1 N , N_I:K
E clr Naes'
R -.... N / ' c I X I
C,N
1:-- \
R N RD Rc ...s.'N RD
N RcT-------- I
RC RD
RD
[0375] R RD ,
[0376] In preferred embodiments Ring A has the structure of one of:
RE
I .
zN,N..1:- r,s,lz:1,r- Nõ. ', ,,N,..N.Y,
N, I \ / RE--N1 N __IN
D
RC
R Re RD Re RD
RC N RD
RD \ --
[0377] R
[0378] 23. A compound of Formula XI having the structure:
RH RH
1_A1 7q \ /\ / L 4-
1¨R A Formula XI
. At _________________
RCA
RD
,
[0379] or a pharmaceutically acceptable salt or prodrug thereof,
[0380] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHR6
,
C(=0)NHSO2R6 or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0381] RB is optionally substituted C1-C4 alkyl or has the structure of one
of:
H
)r N
[0382] 0 0 0 0
- 66 -
CA 3046894 2019-06-18

[0383] L1 is absent or optionally substituted C1-C6 alkylene; Cl-C6
fluoroalkylene; or optionally
X
substituted C1-C6 heteroalkylene or Ll, when present is -
CH2-, , or disubstituted
dimethylmethane.
[0384] A1 is =N- or =CH-;
[0385] Ring A has the structure of one of:
RE
_
N I N I
RD RC RD RC RD RC
NNRD
[0386] Rc
[0387] Rc is -H, -CN, -F, -Cl, -Br, -I, -0C1-C4 alkyl, 01-C4 alkyl, 03-C6
cycloalkyl, or C1-C4
fluoroalkyl;
[0388] RD is -N(RF)C(=0)XCH(RG)-CY, -N(RF)C(=0)XC(RG)2-CY, or -N(RF)C(=0)X-CY;
where
X is absent, -0-, -NH- or -CH2-;
[0389] RE, RF and RG independently are -H or C1-04 alkyl or C3-06 cycloalkyl
or RE and RF
independently are -H or C1-04 alkyl or C1-C6 cycloalkyl and one RG is C1-C4
alkyl and is taken
together with CY and carbon atom to which RG and CY are attached to define a
substituted or
unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and
the other RG, if
present, is as defined for RE;
[0390] RH is -H, halogen, -CN, -NO2, -
SRJ, -S(=0)RJ, -S(=0)2RJ, -N(R)S(0)2R, -
S(=0)2N(R1-)2, -C(=0)RJ, -0C(=0)RJ, -CO2RJ, -0CO2RJ, -N(RL)2, -C(=0)N(RI-)2, -
0C(=0)N(R1)2,
NRJC(=0)N(RI-)2, -NRJC(=0)RJ, -NRJC(=0)ORJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-
C4
fluoroalkoxy, C1-C4 alkoxy,and C1-C4 heteroalkyl;
[0391] RJ is substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted 01-C6
heteroalkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted C3-C6
cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
- 67 -
CA 3046894 2019-06-18

substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted C3-C6
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
C1-C4 alkylene-
(substituted or unsubstituted aryl), or C1-04 alkylene-(substituted or
unsubstituted heteroaryl);
[0392] RI- independently are -H, substituted or unsubstituted C1-06 alkyl,
substituted or
unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C8
fluoroalkyl, substituted or
unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene-
(substituted or
unsubstituted C3-C6 cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
C1-C4 alkylene(substituted or unsubstituted aryl), or -C1-C4 alkylene-
(substituted or
unsubstituted heteroaryl),
[0393] or when RH is -S(=0)2N(RL)2, -N(RI-)2, -C(=0)N(RI-)2, -0C(=0)N(RL)2 or -

N(RJ)C(=0)N(RL)2, each RI- is independently -H or C1-06 alkyl, or the RL
groups independently
are C1-C6 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0394] CY is C1-06 alkyl, a substituted or unsubstituted C3-010 cycloalkyl, a
substituted or
unsubstituted C2-Clo heterocycloalkyl, a substituted or unsubstituted aryl, or
a substituted or
unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted
with 1, 2, or 3 RH,
[0395] wherein when L1 is not absent and RD is -H or -CH3 and RA is -CO2H or -
0O2R6 , then
Ring A has the structure of one of:
RE
gl
N\c' RE¨N,
N
Rc RD RC RD RC
RD NLRD
[0396]
[0397] In particularly preferred Formula XI compounds RA is -CO2H, and RD is
-NRFC(=0)0CH(RG)-CY.
[0398] 24. A compound of Formula XII having the structure:
- 68 -
CA 3046894 2019-06-18

RH RH
A LI-RA Formula XII
RC
N,
0/ RF
Rc 0
411PRH
[0399] or a pharmaceutically acceptable salt or prodrug thereof,
[0400] wherein RA is -002H, -CO2RB, -ON, tetrazolyl, -C(=0)NH2, -C(=0)NHRB,
C(=0)NHSO2RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
[0401] RB is optionally substituted Ci-C4 alkyl or has the structure of one
of:
H
Oyc) )yN
[0402] 0 0 0
[0403] L1 is absent or optionally substituted C1-C6 alkylene; C1-06
fluoroalkylene; or optionally
substituted 01-C6 heteroalkylene, or Ll, when present is -CF12-, ,
or disubstituted
dimethylmethane.
[0404] A1 is =N- or =CH-;
[0405] Ring A has the structure of one of:
RE
m,N E,NX
N \ I R¨N N
D
c Fµ. RC RD RC RD
Rc
[0406] R
[0407] RC is - H, -CN, -F, -Cl, -Br,- I, -001-04 alkyl, C1-04 alkyl, 03-C6
cycloalkyl, or 01-04
fluoroalkyl;
- 69 -
CA 3046894 2019-06-18

[0408] wherein RD is the -N(RF)C(=0)CH(RG)-CY substituent in Formula XII
wherein CY is
phenyl substituted with one RH;
[0409] RE, RF and RG independently are -H or C1-04 alkyl or 03-C6 cycloalkyl
or RE and RF
independently are -H or 01-04 alkyl or Cl-C6 cycloalkyl and one RG is -C1-C4
alkyl and is taken
together with the RH pheny moiety of the Ring A RD substituent and the carbon
atom to which
RG and said phenyl moiety is attached to define a substituted or unsubstituted
carbocycle or a
substituted or unsubstituted heterocycle, and the other RG, if present, is as
defined for RE;
[0410] RH is -H, halogen, -ON, -NO2, -OH,-OR, -SR, -S(=0)RJ, -S(=0)2RJ, -
N(RJ)S(=0)2RJ, -
S(=0)2N(RL)2, -C(=0)RJ, -0C(=0)RJ, -CO2RJ, -00O2R-1, -N(RL)2, -C(=0)N(RL)2, -
0C(=0)N(RL)2,
NRJC(=0)N(RL)2, -NRJC(=0)RJ, -NRJC(=0)ORJ, 01-C4 alkyl, C1-C4 fluoroalkyl, C1-
C4
fluoroalkoxy, Ci-C4 alkoxy,and C1-C4 heteroalkyl;
[0411] RJ is substituted or unsubstituted 01-C6 alkyl, substituted or
unsubstituted 01-C6
heteroalkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or
unsubstituted C3-C6
cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted 03-C6
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
C C4 alkylene-
(substituted or unsubstituted aryl), or C1-C4 alkylene-(substituted or
unsubstituted heteroaryl);
[0412] RL independently are -H, substituted or unsubstituted Cl-C6 alkyl,
substituted or
unsubstituted Cl-C6 heteroalkyl, substituted or unsubstituted C1-C6
fluoroalkyl, substituted or
unsubstituted 03-C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -01-C4 alkylene-
(substituted or
unsubstituted C3-06 cycloalkyl), -C1-04 alkylene-(substituted or unsubstituted
heterocycloalkyl), -
01-C4 alkylene(substituted or unsubstituted aryl), or -01-C4 alkylene-
(substituted or
unsubstituted heteroaryl),
- 70 -
CA 3046894 2019-06-18

[0413] or when RH is -S(=0)2N(RL)2, -N(RL)2, -C(=0)N(RL)2, -0C(=0)N(RL)2 or -
N(RJ)C(=0)N(RL)2, each RL is independently -H or 01-06 alkyl, or the RL groups
independently
are 01-06 alkyl which are taken together with the N atom to which they are
attached to define a
substituted or unsubstituted heterocycle,
[0414] wherein when L1 is not absent and Rc is -H or -CH3 and RA is -CO2H or -
CO2R8 then
Ring A has the structure of one
RE
,N
N\\
N
[0415] /N; RE¨N
N D
RD
RD RD
Re Rci
Rc
[0416] In particularly preferred Formula XII compounds RA is -CO2H.
[0417] 25. A composition comprising, essentially consisting of or consisting
of one or more
compounds of Formula I-XII and one or more excipients.
[0418] In preferred embodiments the composition comprises, consists
essentially of, or
consists of one compound of Formula I-XII and one or more excipients.
[0419] In other preferred embodiments the composition is a pharmaceutically
acceptable
formulation comprising, consisting essentially of, or consisting of one
compound of Formula I-XII
and one or more pharmaceutically acceptable excipients.
[0420] 26. A compound of Formula I-XII or a pharmaceutically acceptable salt
or prodrug
thereof wherein the binding affinity of the compound to lysophosphatidic acid
receptor-1
(LPA1R) is between about 10 pM and 1 pM or less
[0421] 27. The compound of embodiment 19 wherein the compound is a selective
lysophosphatidic acid receptor-1 (LPA1R) compound.
- 71 -
CA 3046894 2019-06-18

[0422] 28. A compound of Formula 1-XII or a pharmaceutically acceptable salt,
or prodrug
thereof wherein the compound is a selective lysophosphatidic acid receptor-1
(LPA1R)
compound.
[0423] 29. The compound of embodiment 20, 21 or 22 wherein the compound is a
selective
lysophosphatidic acid receptor-1 (LPA1R) compound wherein the binding affinity
(i.e., KD) of the
LPA1R compound is between about 1 pM and 1 pM or less. In preferred
embodiments the KD is
100 nM or less, more preferably 10 nM or less.
[0424] 30. A compound of Table 1.
[0425] 31. The compound of embodiment 30 wherein the compound is 1-(4-{441-(2-
Chloro-
pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-
cyclopropane-carboxylic
acid, 2-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-
indan-2-carboxylic acid, 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxy-
carbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino) phenyl acetic acid, 2-(R)- (4-{4-[(R,S)-1-(2-
Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino) phenyl propanoic
acid, 2(R)4[4-[3-
methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoyliamino]-3-
phenyl-propanoic
acid,
2(S)-[[4-[3-methy1-4-((R)-phenylethoxycarbonyl-amino)isoxazol-5-
yl]benzoyl]amino]-3-
phenyl-propanoic acid, (R)-2-{443-Methy1-44(S)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-y1]-
benzoylamino}-3-phenyl-propionic acid, (S)-
2-{443-Methy1-4-((S)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzoylamino}-3-phenyl-propionic acid, (R)-
2-(4-{4-[(R)-1-
(2-Chloro-pheny1)-ethoxycarbonylam ino]-3-methyl-isoxazol-5-y1}-benzoylamino)-
3-phenyl-
propionic acid , (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-5-
y1}-benzoylamino)-3-(4-fluoro-pheny1)-propionic acid , (R)-3-(4-Chloro-pheny1)-
2-(4-{4-[(R)-1-(2-
chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-
propionic acid ,
(R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzoylamino)-3-(3,4-difluoro-pheny1)-propionic acid , (R)-3-(2-Chloro-pheny1)-
2-(4-{4-[(R)-1-(2-
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CA 3046894 2019-06-18

chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-
propionic acid ,
(R)-3-(4-Bromo-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-propionic
acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(2-fluoro-pheny1)-
propionic acid,
(R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzoylamino)-3-p-tolyl-propionic acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(4-
trifluoromethyl-pheny1)-
propionic acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-5-
y1}-benzoylamino)-3-(4-cyano-pheny1)-propionic
acid, (R)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-cyclopropyl-
propionic acid,
32. The compound of embodiment 30 wherein the compound is (R)-2-[[4-[2,5-
dimethy1-4-((R)-1-
phenylethoxycarbonylamino)pyrazol-3-yl]benzoyliamino]-3-phenyl-propanoic acid,
(R)-24[442, 5-
dim ethy1-4-((R)-1- phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-3-(4-
fluorophenyl)propanoic acid, (R)- 3-
(4-bromopheny1)-24[442,5-dimethyl-44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyljamino]propanoic acid,
(R)- 3-(4-
chloropheny1)-24[442,5-dimethy1-44(R)-1-phenylethoxycarbonyl-amino)pyrazol-3-
yl]benzoyl]amino]propanoic acid or (R)- 3-(3,4-difluoropheny1)-24[442,5-
dimethy1-44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-ylibenzoyl]amino]propanoic acid.
[0426] 33. The compound of embodiment 30 wherein the compound is 2-[4-[4-[2,5-
dimethyl-
4-(1-phenylethoxycarbonylamino)pyrazol-3-yl]phenyliphenyl]acetic, 2-
[4-[4-[4-[1-(2-chloro-
phenyl)ethoxycarbonylamino]-2,5-dimethyl-pyrazol-3-yl]phenyliphenyliacetic
acid, 24444-[441-
(2-fluorophenypethoxycarbonylamino]-2,5-dimethyl-pyrazol-3-yl]pheny1]-phenyl]
acetic acid, 2-
[4-[4-[4-[1-(2 ,6-difluorophenypethoxycarbonylami no]-2, 5-dimethyl- pyrazol-3-
y11-
phenyl] phenyl]acetic acid, 244-[44441-(2-methoxyphenypethoxycarbonyl-amino]-
2,5-di-methyl-
pyrazol-3-yl]phenyliphenyliacetic acid, 1-
[4-[4-[2,5-dimethy1-4-(1-phenylethoxy-
carbonylamino)pyrazol-3-yl]phenyliphenylicyclopropanecarboxylic acid, 1-[4-[6-
[2,5-di-methy1-4-
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CA 3046894 2019-06-18

(1-phenylethoxycarbonylamino)pyrazol-3-y1]-3-pyridyl]phenyl]cyclo-propane
carboxylic acid, 1-
[4-[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-2,5-dimethyl-pyrazol-3-
yl]phenyl]phenyl]cyclopropanecarboxylic acid, 1-[4444441-(2-fluoropheny1)-
ethoxycarbonyl-
amino]-2,5-dimethyl-pyrazol-3-yl]phenyl]phenyl]cyclopropanecarboxylic acid,
144444441-(2,6-
difluorophenypethoxycarbonylamino]-2,5-dimethyl-pyrazol-3-
yl]phenyl]phenyl]cyclo-
propanecarboxylic acid, 144444441-(2-methoxyphenypethoxy-carbonylamino]-2,5-
dimethyl-
pyrazol-3-yl]phenyl]phenyl]cyclopropanecarbmlic acid, 2-[44442,5-dimethy1-4-(1-
phenyl-
ethoxycarbonylamino)pyrazol-3-yl]phenyl]phenyl]-2-methyl-propanoic acid,
24444444142-
chlorophenypethoxycarbonylam ino]-2, 5-dim ethyl-pyrazol-3-yl]phenyl] pheny1]-
2-methyl-
propanoic acid, 2-[4-[4-[4-[1-(2-fluorophenyl)ethoxycarbonyl-amino]-2,5-
dimethyl-pyrazol-3-
yl]phenyl]pheny1]-2-methyl-propanoic acid, 214444441-(2,6-
difluorophenyl)ethoxycarbonyl-
amino]-2,5-dimethyl-pyrazol-3-yl]phenyl]pheny1]-2-methyl-propanoic acid or 2-
[4-[4-[4-[1-(2-
methoxyphenyl)ethoxycarbonylamino]-2, 5-dim ethyl-pyrazol-3-yl]pheny1]-phenyl]-
2-methyl-
propanoic acid.
[0427] 34. The compound of embodiment 30 wherein the compound is (R)-24[4-[1,5-
dimethy1-
4-((R)-1-phenylethoxycarbonylamino)pyrazol-3-yl]benzoyllamino]-3-phenyl-
propanoic acid, (R)-
2-[[4-[1, 5-dim ethy1-44(R)-1-phenylethoxycarbonylam i no)pyrazol-3-
yl]benzoyl]amino]-3-(4-
fluorophenyl)propanoic acid, (R)- 3-
(4-bromopheny1)-2-[[441,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid,
((R)- 3-(4-
chloropheny1)-2-[[4-[1,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-amino) pyrazol-
3-
yl]benzoyl]amino]propanoic acid or (R)- 3-(3,4-difluoropheny1)-24[441,5-
dimethy1-4-((R)-1-
phenylethoxycarbonyl-ami no)pyrazol-3-yl] benzoyl]ami no] propanoic acid.
[0428] 35. The compound of embodiment 30 wherein the compound is (R)- 2-(4-{5-
[(R)-1-(2-
Chloro-pheny1)-ethoxycarbonylam ino]-4-methyl-pyrazol-1-y1}-benzoylamino)-3-
phenyl-propionic
acid.
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CA 3046894 2019-06-18

[0429] 36. The compound of embodiment 30 wherein the compound is (R)-2-{4-[3-
Methy1-4-
((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yli-benzylamino}-3-phenyl-
propionic acid, (R)-3-
(2-Fluoro-pheny1)-2-{443-methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-
A-
benzylamino}-propionic acid, (R)-2-{443-Methy1-44(R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-
5-y1]-benzylamino}-3-(4-trifluoromethyl-pheny1)-propionic acid, (R)-3-
Cyclopropy1-2-{443-methy1-
4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1Fbenzylamino}-propionic
acid, (R)-3-(2-
Chloro-pheny1)-2-{4-[3-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-
A-
benzylamino}-propionic acid, (R)-
3-(4-Chloro-pheny1)-2-{4-[3-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzylaminol-propionic acid, (R)- 2-(4-{4-
[(R)-1-(2-Chloro-
pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-phenyl-
propionic acid,
(R)- 2-
(4-{4-[(R)_1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzylamino)-3-(2-fluoro-pheny1)-propionic acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-(4-trifluoromethyl-
pheny1)-
propionic acid, (R)- 3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-
3-methyl-isoxazol-5-y1}-benzylamino)-propionic acid or (R)-2-(4-{4-[(R)-1-(2-
Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-cyclopropyl-
propionic acid.
[0430] 37. The compound of embodiment 30 wherein the compound is 2-{443-Methy1-
4-((R)-
1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-benzyloxy}-3-phenyl-propionic
acid, 2-{443-
Methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-benzyloxy}-3-phenyl-
propionic acid,
(RS)-3-Cyclopropy1-2-{413-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-yli-
benzyloxy}-propionic acid or
(RS)-3-Cyclopropy1-2-{4-[3-methy1-44(R)-1-phenyl-
ethoxycarbonylaminoyisoxazol-5-yli-benzyloxy}-propionic acid.
[0431] 38. The compound of embodiment 30 wherein the compound is 24444454142-
chlorophenypethoxycarbonylamino]-4-cyano-pyrazol-1-yl]phenyl]phenyliacetic
acid, (R)-1-[4-[4-
[1, 5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-yl]phenyliphenyl]cyclo-
propane
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CA 3046894 2019-06-18

carboxylic acid, (R)-
1444442, 5-d im ethy1-4-(1- phenyl ethoxycarbo nylam i no) pyrazol-3-
yliphenyl]phenylicyclopropane carboxylic acid, (R)-1-(4'-{541-(2-Chloro-
pheny1)-ethoxycarbonyl-
amino]-4-fluoro-pyrazol-1-y1}-3-fluoro-bipheny1-4-y1)-cyclopropanecarboxylic
acid, (R)-1-(4'-{5-[1-
(2-Chloro-pheny1)-ethoxycarbonylam ino]-4-fluoro-pyrazol-1-y1}-2-fluoro-
bipheny1-4-y1)-cyclo-
propanecarboxylic acid, (R)-1-(2-Chloro-4'-{541-(2-chloro-pheny1)-
ethoxycarbonylamino]-4-
fluoro-pyrazol-1-y1}-bipheny1-4-y1)-cyclopropanecarboxylic
acid, .. (R)-1-(4'-{541-(2-Chloro-
pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-methyl-biphenyl-4-y1)-
cyclopropanecarboxylic acid, (R)-1-(4'-{511-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-
pyrazol-1-y1}-biphenyl-4-y1)-cyclopropanecarboxylic acid, (R)-
1-{4'-[5-(1-Phenyl-
ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-y1]-bipheny1-4-y1}-
cyclopropanecarboxylic acid,
(R)-1-{2- Fluoro-4'-[5-(1- ph enyl- ethoxycarbonylam ino)-4-trifluoromethyl-
pyrazol-1-y1]- bipheny1-4-
y1}-cyclopropanecarboxylic acid or (R)-1-(4-{545-(1-Phenyl-
ethoxycarbonylamino)-pyrazol-1-yli-
pyridin-2-y1}-pheny1)-cyclopropanecarboxylic acid.
[0432] 39. The compound of embodiment 30 wherein the compound is 2-[[443-
methy1-4-(1-
phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]-3-phenyl-propanoic
acid, 3-
cyclopropy1-24[443-methy1-4-(1-phenylethoxycarbonylam ino)isoxazol-5-
ylibenzoyliam ino]-
propanoic acid, 24[443-methy1-4-(1- ph enylethoxycarbonylam ino)isoxazol-5-
yllbenzoy1Fam ino]-
3- phenoxy- propanoic acid,
24[443-methy1-4-(1-phenylethoxycarbonylamino)-isoxazol-5-
ylibenzoyliamino]-4-phenyl-butanoic acid, 24[44441-(2-chlorophenypethoxy-
carbonylamino]-3-
methyl-isoxazol-5-ylibenzoyliamino]-3-phenyl-propanoic acid, 2-
[[4-[4-[1-(2-
chlorophenyl)ethoxycarbonylam ino]-3-methyl-isoxazol-5-yl]benzoyl]am ino]-3-
cyclopropyl-
propanoic acid, 24[444-[1-(2-chlorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-y11-
benzoyl]amino]-4-phenyl-butanoic acid, 24[4-[441-(2-
chlorophenypethoxycarbonylamino]-3-
methyl-isoxazol-5-yl]benzoyl]amino]-3-phenoxy-propanoic acid, 2-[[4-[4-[1-(2-
fluoropheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-yl]benzoyl]amino]-4-phenyl-butanoic
acid, 24[444-[1-
(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-yllbenzoyl]amino]-3-
phenoxy-
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CA 3046894 2019-06-18

propanoic acid, 3-
cyclopropy1-24[44441-(2-fluorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-yl]benzoyllamino]propanoic acid, 24[44441-(2-fluorophenypethoxy-
carbonylamino]-
3-methyl-isoxazol-5-yl]benzoyflamino]-3-phenyl-propanoic acid, 3-(4-
methoxypheny1)-2-[[443-
methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoy1]-amino]propanoic
acid, 3-(4-
fluoropheny1)-24[443-methy1-4-(1 -phenylethoxycarbonylam ino)-isoxazol-5-
yl]benzoyflamino]propanoic acid, 3-
(2,6-difluoropheny1)-2-[[4-[3-methy1-4-(1-
phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]propanoic acid, 3-(3-
cyano-pheny1)-2-
[[4-[3-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]-
propanoic acid, 3-
(2-chloropheny1)-24[4-[3-methy1-4-(1-phenylethoxycarbonylamino)-isoxazol-5-
yl]benzoyl]amino]propanoic acid, 3-
(4-chloropheny1)-2-[[4-[3-methy1-4-(1-
phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]propanoic acid, 2-[[4-[3-
methy1-4-(1-
phenylethoxycarbonylam ino)isoxazol-5-yl]benzoyl]am ino]-3-[4-(trifl
uoromethyl)pheny1]-
propanoic acid, 3-(4-hydroxypheny1)-2-[[443-methy1-4-(1-
phenylethoxycarbonylamino)-isoxazol-
5-yl]benzoyl]amino]propanoic acid, 3-
(3,4-difluoropheny1)-2-[[4-[3-methy1-4-(1-
phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]propanoic acid, 3-(4-
bromo-pheny1)-2-
[[4-[3-methy1-4-(1-phenylethoxycarbonylam ino)isoxazol-5-yl]benzoyl]amino]-
propanoic acid, 2-
[[4-[3-methy1-4-(1-phenyl ethoxycarbonylam ino)isoxazol-5-yl]benzoyl]-amino]-
344-
(trifluoromethoxy)phenyl]propanoic acid, 2-[[44441-(2-chlorophenypethoxy-
carbonylamino]-3-
methyl-isoxazol-5-yl]benzoyl]amino]-3-(4-methoxyphenyl)propanoic
acid, 24[41441-(2-
chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-yl]benzoynamino]-3-(4-
fluorophenyl)propanoic acid,
24[444-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-
isoxazol-5-yl]benzoyflamino]-3-(2,6-difluorophenyl)propanoic
acid, 24[444-[1-(2-chloro-
phenypethoxycarbonylamino]-3-methyl-isoxazol-5-yl]benzoyl]amino]-3-(3-
cyanopheny1)-
propanoic acid, 3-(2-chloropheny1)-2-[[44441-(2-
chlorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-yl]benzoyllamino]propanoic acid, 3-
(4-chloropheny1)-2-[[4-[4-[1-(2-
chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyl]amino]propanoic acid, 2-[[4-
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CA 3046894 2019-06-18

[441-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-ylibenzoyl]amino]-
344-
(trifluoromethyl)phenyl]propanoic
acid, .. 21[444-0 -(2-chlorophenyl)ethoxycarbonylamino]-3-
methyl-isoxazol-5-ylibenzoyl]amino]-3-(4-hydroxyphenyl)propanoic acid, 3-(4-
bromo-pheny1)-2-
[[44441-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-yl]benzoyli-
amino]propanoic
acid, 24[41441-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
yllbenzoyl]amino]-3-
(3,4-difluorophenyl)propanoic acid, 24[44441-(2-chloropheny1)-
ethonicarbonylamino]-3-methyl-
isoxazol-5-yl]benzoyliamino]-344-(trifluoromethoxy)-phenyl]propanoic
acid, 2-[[4-[4-[1-(2-
fluorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-yl]benzoyl]amino]-3-(4-
methoxyphenyl)propanoic acid, 3-
(4-fluorophenyI)-2-[[4-[4-[1-(2-
fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyl]amino]propanoic acid, 3-
(2, 6-d ifluoropheny1)-24[44441 -(2-fluorop henypethoxycarbonylam ino]-3-
methyl- isoxazol-5-
yl]benzoyflamino]propanoic acid, 3-
(3-cyanopheny1)-2-[[4-[4-[1-(2-fluorophenyl)ethoxy-
carbonylamino]-3-methyl-isoxazol-5-ylibenzoyl]amino]propanoic acid, 3-(2-
chloropheny1)-24[4-
[44142-flu oroph enyl) ethoxycarbonylam ino]-3-methyl- isoxazol-5-
yl]benzoyliam inoj-propanoic
acid, 3-(4-chloropheny1)-24[44441-(2-fluorophenyl)ethoxycarbonylam ino]-3-m
ethyl- isoxazol-5-
yl] benzoyl]a m in o]propanoi c acid, 24[44441-(2-fluorophenypethoxy-
carbonylamino]-3-methyl-
isoxazol-5-yl]benzoyliamino]-344-(trifluoromethyl)pheny1]-propanoic
acid, 24[4444142-
fluorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-ylibenzoyliamino]-3-(4-
hydroxyphenyl)propanoic acid, 3-
(3,4-difluorophenyI)-2-[[4-[4-[1-(2-
fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyliamino]propanoic acid, 3-(4-
bromopheny1)-24[44441-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyl]amino]propanoic acid, 24[44441-(2-fluorophenypethoxycarbonylamino]-
3-methyl-
isoxazol-5-ylibenzoyl]amino]-344-(trifluoromethoxy)phenyl]propanoic
acid, ( )-(4-{4-[ 1-(2-
Chloro-pheny1)-ethoxycarbonyl-amino]-3-methyl-isoxazol-5-y1}-
benzoylaminoyacetic acid, ( )-2-
(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-2-
methyl-propionic acid, ( )-2-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-
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CA 3046894 2019-06-18

5-yI}-benzoylamino)-propionic acid, ( )-2-(4-{441-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-y1}-benzoylamino)-3-hydroxy-propionic
acid, ( )-1-(4-{4-[1-(2-Chloro-
phenyl)ethoxycarbonyl-amino]-3-methyl-isoxazol-5-y1}-benzoy1)-pyrrolidine-2-
carboxylic acid or
( )-2-(4-{441-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-
propionic acid.
[0433] 40. The compound of embodiment 30 wherein the compound is 2-{p43-Fluoro-
4-(1-
phenylethoxycarbonylamino)-5-isoxazolypenzoylamino}-3-phenylpropionic acid, 2-
(p-{4-[1-(0-
Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}benzoylamino)-3-phenyl-
propionic
acid, 3-
Cyclopropy1-2-{p-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
benzoylamino}propionic acid, 2-(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-
fluoro-5-
isoxazolyl}benzoylamino)-3-cyclopropylpropionic acid, 2-[({p-[3-Fluoro-4-(1-
phenylethoxy-
carbonylamino)-5-isoxazolyl]phenyl}methyl)arnino]-3-phenylpropionic
acid, 2-{[(p-{4-[1-(o-
Chlorophenypethoxycarbonylam i no]-3-fluoro-5-isoxazolyl}phenyl)methyl]amino}-
3-
phenyl propionic acid, 3-
Cyclopropy1-24({p43-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methypamino]propionic acid, 2-{[(p-{441-(o-
Chlorophenypethoxycarbonyl-
amino]-3-fluoro-5-isoxazolyl}phenyl)methyl]amino}-3-cyclopropylpropionic acid,
2-({p-[3-Fluoro-
4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]phenyl}methoxy)-3-phenylpropionic
acid, 2-[(p-
{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazolyl}pheny1)-
methoxy]-3-
phenylpropionic acid, 3-
Cyclopropy1-2-({p43-fluoro-4-(1-phenylethoxycarbonyl-amino)-5-
isoxazolyl]phenyl}methoxy)propionic acid or 2-[(p-{441-(o-Chlorophenypethoxy-
carbonylamino]-
3-fluoro-5-isoxazolyl}phenyl)methoxy]-3-cyclopropylpropionic acid.
[0434] 41. The compound of embodiment 30 wherein the compound is 2-Benzy1-3-
{543-
fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}propionic
acid, 2-Benzy1-3-
(5-{441-(o-chlorophenypethoxycarbonylaminol-3-fluoro-5-isoxazoly1}-2-pyridyl-
amino)propionic
acid, 2-
(Cyclopropylmethyl)-3-{543-fluoro-4-(1-phenylethoxycarbonyl-amino)-5-
isoxazoly1]-2-
pyridylamino}propionic acid, 3-(5-{441-(o-Chlorophenyl)ethoxy-carbonylamino]-3-
fluoro-5-
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CA 3046894 2019-06-18

isoxazoly11-2-pyridylamino)-2-(cyclopropylmethyl)propionic acid, 2-Benzy1-3-
{543-fluoro-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-propionic acid, 2-
Benzy1-3-(5-{4-[1-(o-
chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridyloxy)propionic acid 2-Benzy1-
3-(5-{441-(o-chlorophenypethoxycarbonyl-amino]-3-fluoro-5-isoxazoly1}-2-
pyridyloxy)propionic
acid, 2-
(Cyclopropylmethyl)-3-{543-fluoro-4-(1-phenylethoxycarbonyl-amino)-5-
isoxazoly1]-2-
pyridyloxy}propionic acid, 3-
(5-{441-(o-Chlorophenypethoxy-carbonylamino]-3-fluoro-5-
isoxazoly1}-2-pyridyloxy)-2-(cyclo-propylmethyl)propionic
acid, 2-{543-Fluoro-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}-3-phenyl-propionic
acid, 2454441-
(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-pyridylami no)-3-
phenylpropionic
acid, 3-
Cyclopropy1-2-{543-fluoro-4-(1-phenylethoxy-carbonylamino)-5-isoxazoly1]-2-
pyridylamino}propionic acid, 2-(5-{441-(o-Chloropheny1)-ethoxycarbonylamino]-3-
fluoro-5-
isoxazoly1}-2-pyridylamino)-3-cyclopropyl-propionic
acid, 2-{543-Fluoro-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-phenyl-propionic
acid, 2-(5-{441-(o-
Chlorophenypethoxycarbonylamino]-3-fluoro-5-iso-xazoly1}-2-pyridyloxy)-3-
phenylpropionic acid,
3-Cyclopropy1-2-{543-fluoro-4-(1-phenyl-ethoxy-carbonylam ino)-5-isoxazoly1]-2-
pyridyloxy}propionic acid, 2-
(5-{411-(o-Chloro-pheny1)-ethoxycarbonylamino]-3-fluoro-5-
isoxazoly1}-2-pyridyloxy)-3-cyclopropylpropionic
acid, 2-{p-[3-fluoro-4-(1-
phenylethoxycarbonylamino)-5-isoxazolypenzoylamino}-3-phenylpropionic acid, 2-
(p-{441-(o-
chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazolyl}benzoyl-amino)-3-
phenylpropionic
acid, 3-
cyclopropy1-2-{p-[3-fluoro-4-(1-phenylethoxycarbonyl-am ino)-5-
isoxazolyl]benzoylaminolpropionic acid, 2-(p-{441-(o-chlorophenyl)ethoxy-
carbonylamino]-3-
fluoro-5-isoxazolyl}benzoylamino)-3-cyclopropylpropionic
acid, 24({p-[3-fluoro-4-(1-
phenylethoxycarbonylamino)-5-isoxazolyl]phenyl}methyl)amino]-3-phenyl-
propionic acid, 2-{[(p-
{4-[1 -(o-chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-
phenyl)methyl]amino}-3-
phenylpropionic acid, 3-
cyclopropy1-2[({p43-fluoro-4-(1-phenyl-ethoxycarbonylam ino)-5-
isoxazolyl]phenyl}methyl)amino]propionic acid, 2-
{[(p-{441-(o-
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CA 3046894 2019-06-18

chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-isoxazolyllphenyl)methyl]amino}-3-
cyclo-
propylpropionic acid, 2-
({p-[3-fluoro-4- (1 -phenylethoxycarbonylam ino)-5-isoxazoly1]-
phenyl}methoxy)-3-phenyl propionic acid, 2-[(p-{441-(o-
chlorophenypethoxycarbonyl-amino]-3-
fluoro-5-isoxazolyl}phenyl)methoxy]-3-phenylpropionic acid, 3-cyclopropy1-2-
({p43-fluoro-4-(1-
phenylethoxycarbonylamino)-5-isoxazolyl]phenyl}methoxy)propionic
acid, 2-[(p-{4-[1-(o-
chlorophenyl)ethoxycarbonylam ino]-3-fluoro-5-isoxazolyl}phenyl)methoxy]-3-
cyclopropylpropionic acid, 2-
benzy1-3-{5-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-pyridylamino}propionic
acid, 2-benzy1-3-(5-{441-(o-chlorophenypethoxy-
carbonylamino]-3-fluoro-5-isoxazoly1}-2-pyridylamino)propionic acid, 2-
(cyclopropyl-methyl)-3-
{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}-
propionic acid, 3-(5-
{441-(o-chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-pyridyl-
amino)-2-
(cyclopropylmethyl)propionic acid, 2-benzy1-3-{543-fluoro-4-(1-phenylethoxy-
carbonylamino)-5-
isoxazoly1]-2-pyridyloxy}propionic acid, 2-
benzy1-3-(5-{4-[1-(o-chloro-
phenyl)ethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-pyridyloxy)propionic
acid, 2-(cyclo-
propylmethyl)-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyloxy}-
propionic acid, 3-
(5-{441-(o-chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridyloxy)-2-(cyclopropylmethyl)propionic acid, 2-{543-fluoro-4-(1-
phenylethoxycarbonyl-
amino)-5-isoxazoly1]-2-pyridylamino}-3-phenylpropionic
acid, 2-(5-{441-(o-chloropheny1)-
ethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-pyridylamino)-3-phenylpropionic
acid, 3-
cyclopropy1-2-{543-fluoro-4-(1-phenylethoxycarbonylam ino)-5-isoxazoly1]-2-
pyridylam ino}-
propionic acid, 2-
(5-{441-(o-chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridylamino)-3-cyclopropylpropionic acid, 2-{543-fluoro-4-(1-
phenylethoxycarbonylamino)-5-
isoxazoly1]-2-pyridyloxy}-3-phenylpropionic
acid, 2-(5-{4-[1-(o-chlorophenyl)ethoxy-
carbonylamino]-3-fluoro-5-isoxazoly1}-2-pyridyloxy)-3-phenyl-propionic acid, 3-
cyclopropy1-2-{5-
[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-iso-xazoly1]-2-
pyridyloxy}propionic acid or 2-(5-{4-
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[1-(o-chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-isoxazolyI}-2-pyridyloxy)-3-
cyclopropylpropionic acid.
[0435] 42. The compound of embodiment 30 wherein the compound is 2-{p43-Cyano-
4-(1-
phenylethoxycarbonylam ino)-5-isoxazolyl]benzoylam ino}-3- phenylpropionic
acid, 2-(p-{411 -(0-
Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazolyl}benzoylamino)-3-phenyl-
propionic
acid, 2-
{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolypenzoyl-amino}-3-
cyclopropylpropionic acid, 2-
(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}benzoylamino)-3-cyclopropylpropionic
acid, 24({p43-Cyano-4-(1-
phenylethoxycarbonylamino)-5-isoxazolyliphenyl}methypamino]-3-phenylpropionic
acid, 2-{[(p-
{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methylFamino)-3-
phenylpropionic acid, 2-
[({p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-iso-
xazolyl]phenyl}methyDamino]-3-cyclopropylpropionic
acid, 2-{[(p-{441-(o-Chloropheny1)-
ethoxycarbonylamino]-3-cyano-5-isoxazoly1}phenyOmethyl]amino}-3-
cyclopropylpropionic acid,
2-({p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]phenyl}methoxy)-3-
phenylpropionic acid, 2-
[(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-iso-
xazolyl}phenyl)methoxy]-3-phenylpropionic acid, 2-({p43-Cyano-4-(1-
phenylethoxycarbonyl-
amino)-5-isoxazolyliphenyl}methoxy)-3-cyclopropylpropionic acid or 2-[(p-{441-
(o-Chloro-
phenypethoxycarbonylamino]-3-cyano-5-isoxazolyl}phenyOmethoxy]-3-
cyclopropylpropionic
acid.
[0436] 43. A compound of embodiment 30 wherein the compound is 2-Benzy1-3-{543-
cyano-
4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}propionic acid, 2-
Benzy1-3-(5-{4-
[1-(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-isoxazolyI}-2-pyridylamino)-
propionic acid,
3-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyl-amino}-2-
(cyclopropylmethyl)propionic acid, 3-(5-{441-(o-Chlorophenypethoxycarbonyl-
amino]-3-cyano-5-
isoxazoly1}-2-pyridylamino)-2-(cyclopropylmethyl)propionic acid, 2-Benzy1-3-
{543-cyano-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}propionic acid, 2-Benzy1-
3-(5-{441-(0-
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CA 3046894 2019-06-18

chlorophenyl)ethoxycarbonylamino]-3-cyano-5-isoxazolyI}-2-pyridyloxy)propionic
acid, 34543-
Cyano-4-(1-phenylethoxycarbonylam ino)-5- isoxazolyI]-2-pyridyloxy}-2-
(cyclopropylmethyppropionic acid, 3-(5-{441-(o-Chlorophenypethoxycarbonyl-
amino]-3-cyano-5-
isoxazoly1}-2-pyridyloxy)-2-(cyclopropylmethyl)propionic
acid, 2-{5-[3-Cyano-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly11-2-pyridylarnino}-3-phenylpropionic
acid, 2-(5-{4-[1-(o-
Chlorophenypethoxycarbonylam ino]-3-cyano-5-isoxazoly1}-2-pyridyl-amino)-3-
phenylpropionic
acid, 2-
{543-Cyano-4-(1-phenylethoxycarbonylarnino)-5-iso-xazoly11-2-pyridylarnino}-3-
cyclopropylpropionic acid, 2-
(5-{441-(o-Chlorophenypethoxy-carbonylamino]-3-cyano-5-
isoxazoly11-2-pyridylamino)-3-cyclopropylpropionic
acid, .. 2-{543-Cyano-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-phenylpropionic acid,
2-(5-{441-(0-
Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-pyridyloxy)-3-
phenylpropionic acid,
2-{543-Cyano-4-(1-phenylethoxycarbonylann ino)-5-isoxazolyI]-2-pyridyloxy}-3-
cyclopropylpropionic acid, 2-
(5-{441-(o-Chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-pyridyloxy)-3-cyclopropylpropionic
acid, 2-{p-[3-cyano-4-(1-phenyl-
ethoxycarbonylamino)-5-isoxazolyl]benzoylamino}-3-phenylpropionic
acid, 2-(p-{4-[1-(o-
chlorophenyl)ethoxycarbonylam ino]-3-cyano-5-isoxazolyl}benzoylamino)-3-
phenylpropionic
acid, 2-
{p43-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolylibenzoylamino}-3-cyclo-
propylpropionic acid, 2-
(p-{441-(o-chlorophenypethoxycarbonylamino]-3-cyano-5-iso-
xazolyl}benzoylamino)-3-cyclopropylpropionic
acid, 2-[({p-p-cyano-4-(1-phenylethoxy-
carbonylamino)-5-isoxazolynphenyl}methyl)amino]-3-phenylpropionic acid, 2-{[(p-
{441-(o-
chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazolyl}phenyl)methyl]amino}-3-
phenyl-
propionic acid, 2-
[({p43-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]phenyll-
methyl)amino]-3-cyclopropylpropionic acid, 2-{[(p-{441-(o-
chlorophenypethoxycarbonyl-amino]-
3-cyano-5-isoxazolyl}phenyl)methyliamino}-3-cyclopropylpropionic acid, 2-({p43-
cyano-4-(1-
phenylethoxycarbonylamino)-5-isoxazolyliphenyl}methoxy)-3-phenylpropionic
acid, 2-[(p-{441-
(o-chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazolyllphenyl)-methoxy]-3-
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CA 3046894 2019-06-18

phenylpropionic acid, 2-
({p[3-cyano-4-(1-phenylethoxycarbonylam ino)-5-
isoxazolyl]phenyl}methoxy)-3-cyclopropylpropionic acid, 2-[(p-{411-(o-
chlorophenypethoxy-
carbonylamino]-3-cyano-5-isoxazolyl}phenyOmethoxy]-3-cyclopropylpropionic
acid, 2-benzy1-3-
{543-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}-
propionic acid, 2-
benzy1-3-(5-{4-0-(o-chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridylamino)propionic acid, 3-{5-[3-cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridylam ino}-2-(cyclopropylmethyl)propionic acid, 3-
(5-{4-[1-(o-chloro-
phenyl)ethoxycarbonylamino]-3-cyano-5-isoxazoly11-2-pyridylamino)-2-
(cyclopropylmethyl)-
propionic acid, 2-
benzy1-3-{5-[3-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyloxy}propionic acid, 2-benzy1-3-(5-{441-(o-
chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-pyridyloxy)propionic acid, 3-{5-[3-cyano-4-(1-
phenylethoxycarbonyl-amino)-5-
isoxazoly1]-2-pyridyloxy}-2-(cyclopropylmethyl)propionic
acid, 3-(5-{4-[1-(o-chloro-
phenypethoxycarbonylamino]-3-cyano-5-isoxazoly11-2-pyridyloxy)-2-
(cyclopropylmethyl)-
propionic acid, 2-{543-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyl-amino}-3-
phenylpropionic acid, 2-(5-{441-(o-chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-
pyridylamino)-3-phenylpropionic acid, 2-{543-cyano-4-(1-phenylethoxy-
carbonylamino)-5-
isoxazoly1]-2-pyridylamino}-3-cyclopropylpropionic acid, 2-
(5-{4-[1-(o-
chlorophenyl) ethoxycarbonylam i no]-3-cyano-5-isoxazoly1}-2-pyridylam ino)-3-
cyclopropyl-
propionic acid, 2-{543-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyloxy}-3-
phenylpropionic acid, 2-(5-{441-(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
iso-xazoly1}-2-
pyridyloxy)-3-phenylpropionic
acid, 2-{5-[3-cyano-4-(1-phenylethoxycarbonyl-amino)-5-
isoxazoly1]-2-pyridyloxy}-3-cyclopropylpropionic acid or
2-(5-{4-[1-(o-chloropheny1)-
ethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-pyridyloxy)-3-
cyclopropylpropionic acid.
[0437] 44. A compound of embodiment 30 wherein the compound is 2-Benzy1-3-{543-
methy1-
4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}propionic acid, 2-
Benzy1-3-(5-{4-
[1-(o-chlorophenyl)ethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-pyridylamino)-
propionic acid,
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CA 3046894 2019-06-18

2-(Cyclopropylmethyl)-3-{543-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridylannino}propionic acid, 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-
methyl-5-
isoxazoly1}-2-pyridylamino)-2-(cyclopropylmethyl)propionic acid, 2-Benzy1-3-
{543-methy1-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}propionic acid, 2-Benzy1-
3-(5-{441-(0-
chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-pyridyl-
oxy)propionic acid, 2-
(Cyclopropylmethyl)-3-{543-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly11-2-
pyridyloxy}propionic acid, 3-
(5-{441-(o-Chlorophenyl)ethoxycarbonylamino]-3-methyl-5-
isoxazoly1}-2-pyridyloxy)-2-(cyclopropylmethyl)propionic
acid, 2-{5-[3-Methy1-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}-3-phenylpropionic
acid, 2-(5-{4-0-(o-
Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-pyridylamino)-3-
phenylpropionic
acid, 2-(5-{4- [1-(o- Chl o rophenypethoxycarbonylam i no]-3- methyl- 5-
isoxazoly1}-2- pyridyl am ino)- 3-
cyclopropylpropionic acid, 2-{543-Methy1-4-(1-phenylethoxy-carbonylamino)-5-
isoxazoly1]-2-
pyridyloxy}-3-phenylpropionic acid, 2-(5-{441-(o-Chloro-
phenypethoxycarbonylamino]-3-methy1-
5-isoxazoly1}-2-pyridyloxy)-3-phenylpropionic
acid, 3-Cyclopropy1-2-{5-[3-methy1-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyl-oxy}propionic
acid, 2-(5-{4-[1-(o-
Chlorophenyl)ethoxycarbonylam ino]-3-m ethyl-5-isoxazoly1}-2-pyridyloxy)-3-
cyclopropylpropionic
acid, 2-
benzy1-3-{5-[3-m ethy1-4-(1-p he nyl-ethoxycarbonylam ino)-5-isoxazoly1]-2-
pyridylamino}propionic acid, 2-benzy1-3-(5-{4-[1-(o-
chlorophenypethoxycarbonylamino]-3-
methyl-5-isoxazoly1}-2-pyridylamino)propionic acid, 2-(cyclopropylmethyl)-3-{5-
[3-methy1-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylaminolpropionic
acid, 3- (5-{4- [1 -(o-
chlorophenyl)ethoxycarbonylam i no]-3-m ethy1-5-i soxazoly1}-2-pyridyl am i
no)-2-
(cycl op ropylmethyl)propionic acid, 2-benzy1-3-{543-methy1-4-(1-
phenylethoxycarbonylamino)-5-
isoxazoly1]-2-pyridyloxy}propionic acid, 2-
benzy1-3-(5-{4-[1-(o-
chlorophenyl)ethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridyloxy)propionic acid, 2-
(cyclopropylmethyl)-3-{543-m ethy1-4-(1- phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridyloxy}propionic acid, 3-
(5-{441-(o-chlorophenyl) ethoxycarbonyla m n 0]-3- m ethy1-5-
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CA 3046894 2019-06-18

isoxazoly1}-2-pyridyloxy)-2-(cyclopropylmethyl)propionic
acid, 2-{543-methy1-4-(1-phenyl-
ethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}-3-phenylpropionic
acid, .. 2-(5-{411-(0-
chlorophenypethoxycarbonylamino]-3-methyl-5-isoxazoly1}-2-pyridylamino)-3-
phenyl-propionic
acid, 3-
cydopropy1-2-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}propionic acid, 2-(5-{4-[1-(o-chlorophenyl)ethoxycarbonylamino]-3-
methy1-5-
isoxazoly1}-2-pyridylamino)-3-cyclopropylpropionic acid, 2-{543-methy1-4-(1-
phenylethoxy-
carbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-phenylpropionic
acid, 2-(5-{4-[1-(o-chloro-
phenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-pyridyloxy)-3-
phenylpropionic acid, 3-
cyclopropy1-2-{543-methy1-4-(1-phenylethoxycarbonylam ino)-5- isoxazoly1]-2-
pyridyloxy}-
propionic acid, 2-(5-{441-(o-chlorophenypethoxycarbonylamino]-3-methy1-5-
isoxazoly1}-2-
pyridyloxy)-3-cyclopropylpropionic acid, 3-{p43-methy1-4-(1-
phenylethoxycarbonylamino)-5-
isoxazolylibenzoylamino}-4-phenylbutyric
acid, .. 4-cyclopropy1-3-{p43-methyl-4-(1-phenyl-
ethoxycarbonylamino)-5-isoxazolypenzoylamino}butyric acid, 34({p43-methyl-4-(1-
phenyl-
ethoxycarbonylamino)-5-isoxazolyliphenyl}methypamino]-4-phenylbutyric acid, 4-
cyclo-propy1-3-
[({p43-methyl-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]phenyl}methyl)-
amino]butyric acid,
3-({p[3-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]phenylymethoxy)-4-
phenylbutyric
acid, 4-
cyclopropy1-3-({p-[3-methy1-4-(1-phenylethoxycarbonyl-amino)-5-
isoxazolyl]phenyl}methoxy)butyric acid, 3-{543-methy1-4-(1-
phenylethoxycarbonyl-amino)-5-
isoxazoly1]-2-pyridylamino}-4-phenylbutyric
acid, 4- cyclopropyl- 3-{5-[3- methyl-4- (1-
phenylethoxycarbonylam ino)-5-isoxazoly1]-2-pyridylam ino}butyric
acid, .. 3-{5-[3-methy1-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-4-phenylbutyric acid, 4-
cyclo-propy1-3-
{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}butyric
acid.
[0438] 45. A compound of embodiment 30 wherein the compound is 2-[[4-[1,5-
dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-yl]benzoyliamino]-3-(4-
methoxyphenyl)propanoic acid, 2-
[[4-[1, 5-dimethy1-4-(1- phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-
3-(4-
fluorophenyl)propanoic acid, 3-
(2,6-difluoropheny1)-2-[[4-[1, 5-dimethy1-4- (1- phenylethoxy-
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CA 3046894 2019-06-18

carbonylam ino)pyrazol-3-yl]benzoyl]amino]propanoic
acid, 3-(3-cyanopheny1)-2-[[441 , 5-
dim ethy1-4- (1- phenylethoxycarbonylamino) pyrazol-3-yl]benzoyl]am
nolpropanoic acid, 3- (2-
chloropheny1)-2-[[4-[1 ,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoy1]-
am ino]propanoic acid, 3-
(4-chloropheny1)-24[441 , 5-di methy1-4-(1 -phenylethoxycarbonyl-
amino)pyrazol-3-yl]benzoyl]amino]propanoic
acid, 2-[[4-[1,5-dimethy1-4-(1-phenylethoxy-
carbonylamino)pyrazol-3-yl]benzoyl]amino]-3-[4-
(trifluoromethyl)phenyl]propanoic acid, 2-[[4-
[1 ,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-3-(4-
hydroxyphenyl)propanoic acid, 3-(3,4-difluoropheny1)-24[441,5-dimethy1-4-(1-
phenylethoxy-
carbonylamino)pyrazol-3-yl]benzoyllamino]propanoic
acid, 3-(4-brom opheny1)-2-[[4- [1 , 5-
dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]am ino]propanoic
acid, 24[4-[1,5-
dim ethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-344-
(trifluoro-
methoxy)phenyl]propanoic acid, 2-[[4-[4-[1-(2-
chlorophenyl)ethoxycarbonylamino]-1,5-dimethyl-
pyrazol-3-yl]benzoyl]amino]-3-(4-methoxyphenyl)propanoic
acid, 2-[[4-[4-[1-(2-
chlorophenyl)ethoxycarbonylamino]-1 , 5-di methyl-pyrazol-3-yl]benzoyllam i
no]-3- (4-fluoro-
phenyl)propanoic acid, 2-[[4-[4-[1 -(2-chlorophenyl)ethoxycarbonylamino]- 1, 5-
dimethyl-pyrazol-3-
yl]benzoyl]amino]-3-(2,6-difluorophenyl)propanoic
acid, 2-[[4-[4-[1-(2-chloro-
phenyl) ethoxycarbonylami no]-1 ,5-dimethyl-pyrazol-3-yl]benzoyl]amino]-3-(3-
cyanopheny1)-
propanoic acid, 3-
(2-chloropheny1)-24[44441-(2-chlorophenypethoxycarbonylamino]-1 , 5-
dimethyl-pyrazol-3-yl]benzoyllam ino]propanoic
acid, 3-(4-chloropheny1)-2-[[4-[4-[1-(2-
chlorophenyl)ethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyllamino]propanoic acid, 2-
[[4-[4-[1- (2-chlorophenyl)ethoxycarbonylam ino]-1 ,5-dimethyl-pyrazol-3-
yl]benzoy1]-am ino]-3-[4-
(trifluoromethyl)phenyl]propanoic acid, 2-[[4-[4-[1-(2-chlorophenyl)ethoxy-
carbonylamino]-1,5-
dimethyl-pyrazol-3-yl]benzoyl]amino]-3-(4-hydroxyphenyl)propanoic
acid, 2-[[4-[4-[1-(2-
chlorophenyl)ethoxycarbonylamino]-1, 5-di methyl-pyrazol-3-Abenzoyll-ami no]-3-
(3,4-
difluorophenyl) propanoic acid, 3-
(4-bromopheny1)-2-[[4-[4-[1-(2-chloro-
phenyl)ethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-yl]benzoyl]amino]propanoic
acid, 2-[[4-[4-
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[1-(2-chlorophenypethoxycarbonylamino]- 1, 5-dimethyl-pyrazol-3-yl]benzoyl]am
ino]-3- [4-
(trifluoromethoxy)phenyl]propanoic acid, 2-[[44411-(2-
fluorophenypethoxycarbonyl-amino]-1,5-
dimethyl-pyrazol-3-yl]benzoyl]amino]-3-(4-methoxyphenyl)propanoic acid, 3-(4-
fluorophenyI)-2-
[[4-[4-[1-(2-fluorophenyl)ethoxycarbonylamino]-1 ,5-dimethyl-pyrazol-3-
yl]benzoyliamino]propanoic acid, 3-(2,6-difluoropheny1)-2-[[44441-(2-
fluorophenyl)ethoxy-
carbonylam ino]-1,5-dimethyl-pyrazol-3-ylibenzoyl]amino]propanoic acid, 3-(3-
cyanopheny1)-2-
[[44441-(2-fluorophenyl)ethoxycarbonylamino]-1 ,5-dimethyl-pyrazol-3-
ylibenzoyliamino]-
propanoic acid, 3-
(2-chloropheny1)-24[4[4[1-(2-fluorophenypethoxycarbonylam ino]- 1 , 5-
dimethyl-pyrazol-3-yl]benzoyliam ino]propanoic
acid, 3-(4-chloropheny1)-24[44441-(2-
fluorophenypethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
ylibenzoyl]amino]propanoic acid, 2-
[[44441-(2-fluorophenypethoxycarbonylamino]-1 ,5-dimethyl-pyrazol-3-
ylibenzoyl]am ino]-344-
(trifluoromethyl)phenyl]propanoic acid, 2-[[444-0 -(241
uorophenypethoxycarbonyl-am inol- 1, 5-
dimethyl-pyrazol-3-yl]benzoynamino]-3-(4-hydroxyphenyl)propanoic acid, 3-(3,4-
difluoropheny1)-
2-[[44441-(2-fluorophenyl)ethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyl]amino]propanoic acid, 3-
(4-bromopheny1)-24[44441-(2-fluorophenypethoxy-
carbonylamino]-1 ,5-dimethyl-pyrazol-3-yl]benzoyliamino]propanoic
acid, 24[4444142-
fluorophenypethoxycarbonylamino]-1 ,5-dimethyl-pyrazol-3-yl]benzoyl]amino]-344-
(trifluoromethoxy)phenyl]propanoic
acid, 2-{p-[1-methy1-5-methy1-4-(1-phenylethoxy-
carbonylam i no)- 1 h-pyrazol-3-yl]benzoylamino}-3-phenylpropionic acid, 3-
cyclopropy1-2-{p-[1-
methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1h-pyrazol-3-ylibenzoylamino}-
propionic
acid, 2-
(p-{441-(o-chlorophenyl)ethoxycarbonylami no]-1-methy1-5-methyl- 1 h-pyrazol-3-
yl}benzoylamino)-3-phenylpropionic acid, 2-(p-{441-(o-chlorophenypethoxy-
carbonylamino]-1-
methy1-5-methy1-1h-pyrazol-3-yl}benzoylamino)-3-cyclopropylpropionic acid,
24({p41-methyl-5-
methyl-4-(1-phenylethoxycarbonylamino)-1 h-pyrazol-3-ylipheny1}-methypamino]-3-
phenylpropionic acid, 3-
cyclopropy1-24({p41-methyl-5-methyl-4-(1-phenyl-
ethoxycarbonylam ino)- 1 h-pyrazol-3-yl]phenyllmethyDamino]propionic
acid, 2-{[(p-{441-(o-
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CA 3046894 2019-06-18

chlorophenyl)ethoxycarbonylam ino]-1-methy1-5-methy1-1h-pyrazol- 3-yl}phenyl)m
ethyl]-am ino}- 3-
phenylpropionic acid, 2-{[(p-{441-(o-chlorophenypethoxycarbonylamino]-1-methyl-
5-methyl-1h-
pyrazol-3-yl}phenyl)methyl]aminol-3-cyclopropylpropionic acid, 2-({p-[1-methy1-
5-methy1-4-(1-
phenylethoxycarbonylamino)-1h-pyrazol-3-yl]phenyl}methoxy)-3-phenyl-propionic
acid, 3-
cyclopropy1-2-({p41-methyl-5-methyl-4-(1-phenylethoxycarbonylam ino)-1h-
pyrazol-3-
yl]phenyl}methoxy)propionic acid, 2-[(p-{441-(o-chlorophenypethoxycarbonyl-
amino]-1-methyl-
5-methyl-1h-pyrazol-3-yl}phenyOmethoxy]-3-phenylpropionic
acid, 2-[(p-{4-[1-(o-
chlorophenyl) ethoxycarbonylam ino]-1-methy1-5-methy1-1h-pyrazol-3-y1}pheny1)-
methoxy]-3-
cyclopropylpropionic acid, 3-
{p-[1-methy1-5-methy1-4-(1-phenylethoxycarbonyl-amino)-1h-
pyrazol-3-yl]benzoylamino}-4-phenylbutyric acid, 4-cyclopropy1-3-{p41-methy1-5-
methyl-4-(1-
phenylethoxycarbonylamino)-1h-pyrazol-3-yl]benzoylaminolbutyric acid, 3-[({p-
[1-methy1-5-
methy1-4-(1-phenylethoxycarbonylamino)-1h-pyrazol-3-yl]phenyl}rnethypamino]-4-
phenylbutyric
acid, 4-
cyclopropy1-34({p-[1-methyl-5-methyl-4-(1-phenylethoxycarbonyl-amino)-1h-
pyrazol-3-
yl]phenyl}methypamino]butyric acid, 3-({p41-methy1-5-methy1-4-(1-
phenylethoxycarbonylamino)-
1h-pyrazol-3-yllphenyl}methoxy)-4-phenylbutyric acid or 4-cyclopropy1-3-({p41-
methy1-5-methyl-
4-(1-phenylethoxycarbonylamino)-1h-pyrazol-3-yl]phenyllmethoxy)butyric acid.
[0439] 46. A compound of embodiment 30 wherein the compound is 244-[444-cyano-
5-(1-
phenylethoxycarbonylamino)pyrazol-1-yliphenyliphenyl]acetic acid, 14444-[4-
cyano-5-(1-
phenylethoxycarbonylamino)pyrazol-1-yl]phenyl]phenylicyclopropanecarboxylic
acid, 1-14-[4-[5-
[1-(2-chlorophenypethoxycarbonylamino]-4-cyano-pyrazol-1-
yliphenyl]phenylicyclo-
propanecarboxylic acid, 2-
[4-[4-[4-cyano-5-(1-phenylethoxycarbonylamino)pyrazol-1-y1]-
phenyl]pheny1]-2-methyl-propanoic acid, 244444541-(2-
chlorophenypethoxycarbonyl-amino]-4-
cyano-pyrazol-1-yl]phenyl]pheny1]-2-methyl-propanoic
acid, 1-{4'44-Fluoro-5-(1-
phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-4-
biphenylyllcyclopropanecarboxylic acid, 1-(4'-
{541-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-4-
biphenyly1)-
cyclopropanecarboxylic acid, 1-{3-Fluoro-4'-[4-fluoro-5-(1-
phenylethoxycarbonylamino)-1H-
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CA 3046894 2019-06-18

pyrazol- 1 -y1]-4- bi phenylyl}cyclopropanecarboxyl ic
acid, 144'4541- (o-C hloro ph enyl) ethoxy-
carbonylam ino]-4-fluoro-1 H-pyrazol-1-y1}-3-fluoro-4-
biphenylyl)cyclopropanecarboxylic acid, 1 -
{2-F1 u oro-4'-[4-fl uoro-5- (1- phenylethoxycarbonyla m ino)- 1 H- pyrazol-1 -
y1]-4- bi phenyl yI}-
cyclopropaneca rboxyl ic acid, 1 -(4'-{5- [1 -(o-Chlo rophenyl) eth
oxycarbonyla m n *441 uoro- 1 H-
pyrazo 1- 1 -y1}-241 uoro-4-bi p he nyly1) cyclopropanecarboxyl ic
acid, 1 -(2- Chlo ro-4'-{541- (o-
chlorophenyl) ethoxycarbo nylam ino]-4-fluoro-1 H-pyrazo 1- 1 -y1}-4-
biphenylyl)cyclo propane-
carboxylic acid, 1 -
(4-{p-[4- F 1 uoro-5- (1 -phenylethoxyca rbonylam ino)-1 H-pyrazol-1-y1]-
phenyl}toly1) cyclopropanecarboxylic acid, 1-[4-(p-{5-0-(o-
Chlorophenypethoxycarbonyl-aminol-
441 uoro- 1 H-pyrazol-1-yl}phenyl)tolyl]cyclopropanecarboxyl ic
acid, 1-(p-{5-[5-(1-
Phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid, 1-
[p- (5-{5-[1-(o-Ch lorop henyl)ethoxycarbonylam no]- 1 H-pyrazol-1-y1}-2-
pyridy1)-
phenylicyclopropanecarboxyl ic acid, 1 - (p-{5-[4-M ethy1-5-(1- phenyl
ethoxycarbonylam i no)- 1 H -
pyrazo I- 1-yI]- 2- pyri dyl}phenyl)cyclopropaneca rboxylic
acid, 1-[p-(5-{5-[1-(o-Chloro-
phenyl)ethoxycarbonylamino]-4-methyl-1 H-pyrazol-1 -y1}-2- pyridyl)
phenyl]cyclop ro pa ne-
carboxyl ic acid, 1 -
(2- Fl uoro-4-{5-[5-(1 -phenylethoxyca rbonylami no)- 1 H-pyrazol- 1 -y1]-2-
pyridyl}phenypcyclopropanecarboxylic acid, 144-(5-{541-(o-
Chlorophenypethoxycarbonyl-
amino]-1H-pyrazol-1-y11-2-pyridy1)-2-fluorophenylicyclopropanecarboxylic acid,
1-(3-Fluoro-4-{5-
[5-(1-phenylethoxycarbonylamino)-1 H-pyrazol- 1-y1]-2- pyridyl}phenyl) cycl
opropane-carboxyl ic
acid, 1 -
[4-(5-{5-[1 -(o-Chlorophenyl)ethoxycarbonylam ino]-1 H -pyrazol- 1 -yI}-2-
pyri dyI)-3-
uorophenyl]cyclopropanecarboxyl ic acid, 1-(p-{5-[4-Methy1-5-(1-phenylethoxy-
carbonylamino)-
1 H - pyrazol-1 -y1]-2- pyri dyl}p henyl)cyclopropaneca rboxyl i c
acid, 1 -(p-{5-[4-M ethy1-5- (1 -
phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridyl}phenyl)cyclopropane-
carboxylic acid, 1-
[p- (5-{541- (o-Chlorop henyl)ethoxycarbo nylam no]-4- m ethyl- 1 H-pyrazol- 1
-y1}-2-
pyridyl)phenylicyclopro pa necarboxylic
acid, 1 -(2-F1 uoro-4-{5-[4- m ethy1-5- (1 -phenyl-
ethoxyca rbonylam i no)- 1 H- pyrazol- 1-y1]- 2- pyridyl} ph enyl)
cyclopropaneca rboxyl ic acid, 1 44- (5-{5-
[1- (o-Chlorophenyl)ethoxycarbonylami no]-4- methyl-1 H-pyrazo 1-1 -y1}-2-pyri
dy1)-2-
- 90 -
CA 3046894 2019-06-18

fluorophenyl]cyclopropanecarboxylic
acid, 1-(3-Fluoro-4-{544-methy1-5-(1-phenylethoxy-
carbonylamino)-1H-pyrazol- 1-y1]-2-pyridyllphenyl)cyclopropanecarboxylic acid,
1-[4-(5-{5-[1-(o-
Chlorophenyl)ethoxycarbonylam ino]-4-methy1-1H-pyrazol-1-y1}-2-pyridy1)-341
uoro-
phenyl]cyclopropanecarboxylic acid, 1-(p-{5-[4-Fluoro-5-(1-
phenylethoxycarbonylamino)-1H-
pyrazol-1-y1]-2-pyridyl}phenyl)cyclopropanecarboxylic
acid, 1-[p-(5-{5-[1-(o-Chloro-
phenypethoxycarbonylami no]-4-fluoro-1H-pyrazol-1-y1}-2-
pyridyl)phenylicyclopropane-
carboxyl ic acid, 1-(2-Fluoro-4-{5-[4-fluoro-5-(1-phenylethoxycarbonylamino)-
1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid, 144-
(5-{541-(o-Chlorophenypethoxy-
carbonylamino]-4-fluoro-1H-pyrazol-1-y1}-2-pyridy1)-2-
fluorophenylicyclopropanecarboxylic acid,
1-(3-Fluoro-4-{5-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y11-2-
pyridyl}phenyl)cyclopropanecarboxylic acid, 144-(5-{541-(o-
Chlorophenypethoxycarbonyl-
am ino]-4-fluoro-1H-pyrazol-1-y11-2-pyridy1)-3-
fluorophenyl]cyclopropanecarboxylic acid, 1-(p-{5-
[4-Cyano-5-(1-phenylethoxycarbonylam ino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclo-
propanecarboxylic acid, 14p-(5-{541-(o-Chlorophenyl)ethoxycarbonylamino]-4-
cyano-1H-
pyrazol-1-y1}-2-pyridyl)phenylicyclopropanecarboxylic
acid, 1-(4-{544-Cyano-5-(1-phenyl-
ethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-2-
fluorophenyl)cyclopropanecarboxylic acid,
1-[4-(5-{5-[-(o-Chlorophenypethoxycarbonylamino]-4-cyano-1H-pyrazol-1-y1}-2-
pyridy1)-2-
fluorophenylicyclopropanecarboxylic acid, 1-(4-{544-Cyano-5-(1-phenylethoxy-
carbonylam ino)-
1H-pyrazol-1-y1]-2-pyridy1}-3-fluorophenyl)cyclopropane-carboxylic acid or 144-
(5-{5-[1-(o-
Chlorophenypethoxycarbonylamino]-4-cyano-1H-pyrazol-1-y1}-2-pyridy1)-3-
fluorophenylicyclopropanecarboxylic acid.
[0440] 47. A compound of embodiment 30 wherein the compound is 3-pheny1-2-[[4-
[5-(1-
phenylethoxycarbonylamino)oxazol-4-yl]benzoyl]amino]propanoic acid, 3-
cyclopropy1-2-[[4-[5-
(1-phenylethoxycarbonylamino)oxazol-4-yl]benzoyl]amino]propanoic acid, 4-
pheny1-24[445-(1-
phenylethoxycarbonylamino)oxazol-4-yl]benzoyl]amino]butanoic acid, 3-phenoxy-2-
[[445-(1-
phenylethoxycarbonylamino)oxazol-4-yl]benzoyllamino]propanoic acid, 3-Pheny1-2-
[({p-[5-(1-
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CA 3046894 2019-06-18

phenylethoxycarbonylamino)-1,3-oxazol-4-yl]phenyl}methyl)-amino]propionic
acid, 3-
Cyclopropy1-2-[({p-[5-(1-phenylethoxycarbonylam ino)- 1, 3-oxazol-4-yl]pheny1}-
methyl)amino]propion ic acid, 3-Pheny1-2-({p45-(1-phenylethoxycarbonyl-amino)-
1,3-oxazol-4-
yl]phenyl}methoxy)propionic
acid, 4-Pheny1-3-({p45-(1-phenylethoxy-carbonylamino)-1,3-
oxazol-4-yl]phenyl}methoxy)butyric acid or 4-Cyclopropy1-3-({p-[5-(1-
phenylethoxycarbonyl-
amino)- 1, 3-oxazol-4-yl]phenyl}methoxy)butyric acid.
[0441] 48. A compound of embodiment 30 wherein the compound is 2-[[441-methyl-
5-(1-
phenylethoxycarbonylamino)imidazol-4-yl]benzoyl]amino]-3-phenyl-propanoic
acid, 3-
cyclopropy1-24[441 -methy1-5-(1-phenylethoxycarbonylam ino)im idazol-4-
ylibenzoy1)-
am ino]propanoic acid,
24[441-methy1-541-phenylethoxycarbonylamino)imidazol-4-
yl]benzoyliamino]-4-phenyl-butanoic
acid, 24[4-0-methyl-5-(1-phenylethoxycarbonyl-
amino)imidazol-4-ylibenzoyl]amino]-3-phenoxy-propanoic
acid, 2-[({p-[1-Methy1-5-(1-
phenylethoxycarbonylamino)-1H-imidazol-4-yl]phenyl}methypamino]-3-
phenylpropionic acid, 3-
Cyclopropy1-2-[({p-[1-methy1-5-(1-phenylethoxycarbonylam ino)-1H-imidazol-4-
yl]phenyl}methyl)amino]propionic acid, 2-({p41-Methy1-5-(1-
phenylethoxycarbonylamino)-1H-
imidazol-4-yl]phenyl}methoxy)-3-phenylpropionic acid, 3-Cyclopropy1-2-({p-[1-
methy1-5-(1-
phenylethoxycarbonylamino)-1H-imidazol-4-yl]phenyl}methoxy)propionic acid, 3-
[({p-[1-Methy1-
5-(1-phenylethoxycarbonylamino)-1H-imidazol-4-yl]phenyl}methypamino]-4-
phenylbutyric acid,
4-Cyclopropy1-3- [({p-[1- methy1-5-(1-phenylethoxycarbonylamino)- 1H- imidazol-
4-
yl]phenyl}methyl)amino]butyric acid, 3-({p-[1-Methy1-5-(1-phenylethoxycarbonyl-
amino)-1H-
imidazol-4-yl]phenyl}methoxy)-4-phenylbutyric acid or 4-Cyclopropy1-3-({p-[1-
methy1-5-(1-
phenylethoxycarbonylamino)-1H-imidazol-4-yl]phenyl}methoxy)butyric acid.
[0442] 49. A compound of embodiment 30 wherein the compound is 2-[[4-[1,2-
dimethy1-3-
oxo-5-(1-phenylethoxycarbonylamino)pyrazol-4-yl]benzoyl]amino]-3-phenyl-
propanoic acid, 3-
cyclopropy1-24[4-[1,2-dimethyl-3-oxo-5-(1-phenylethoxycarbonylam ino)pyrazol-4-
yl] benzoyliami no]propanoic
acid, 24[441,2-di methy1-3-oxo-5-(1-phenylethoxycarbonyl-
- 92 -
CA 3046894 2019-06-18

am i no)pyrazol-4-yl]benzoyl]am ino]-4-phenyl-butanoic
acid, 24[441,2- dim ethy1-3-oxo-5-(1-
phenylethoxycarbonylamino)pyrazol-4-yl]benzoyl]arnino]-3-phenoxy-propanoic
acid, 2-[({p-[1,2-
D i methy1-3-oxo-5-(1- phenylethoxyca rbonylam no)- 1, 2- di hyd ropyrazo 1-4-
y1]- p he ny1}-
methyl)a mi no]-3-p henyl propi on ic
acid, 3-Cyclopropy1-2- [({p- [1, 2- di methy1-3- oxo- 5- (1-
phenylethoxycarbonylamino)-1,2-dihydropyrazol-4-
yl]phenyl}methypamino]propionic acid, 2-({p-
[1,2- Dim ethy1-3-oxo-5-(1- phenylethoxycarbonylam i no)- 1,2- di hydropyrazol-
4-y1]-
phenyl}m ethoxy)-3- phenyl pro pioni c
acid, 3-Cyclopropy1-2-({p41,2-dimethyl-3-oxo-5-(1-
phenylethoxycarbonylamino)-1,2-dihydropyrazol-4-yl]phenyl}methoxy)propionic
acid, 3-[({p-[1,2-
Di m ethy1-3-oxo-5-(1-phenyl ethoxycarbonylam no)-1,2-di hyd ropyrazol-4-y1]-
pheny1}-
m ethyl) am i no]-4-phenyl butyric
acid, 4-Cycl opropy1-34({p41,2-d m ethy1-3-oxo-5- (1-phenyl-
ethoxycarbonylamino)-1,2-dihydropyrazol-4-yl]phenyl}methypamino]butyric acid,
3-({p-[1,2-
Di methy1-3-oxo-5-(1-phenylethoxycarbonyl am i no)-1,2-dihyd ropyrazo 1-4-y1]-
p he ny1}- m ethoxy)-4-
phenyl butyric acid or 4-
Cyclopropy1-3-({p-[1,2-dimethy1-3-oxo-5-(1-phenylethoxy-
carbonylamino)-1,2-dihydropyrazol-4-yl]phenyl}methoxy)butyric acid.
[0443] 50. A compound of embodiment 30 wherein the compound is 3-pheny1-2-[[4-
[5-(1-
phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyliamino]propanoic acid, 3-
cyclopropy1-24[4-[5-
(1-phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]amino]propanoic acid, 4-
pheny1-2-[[4-[5-
(1-phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]amino]butanoic acid, 3-
phenoxy-24[4-[5-
(1-phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]aminoi-propanoic acid, 3-
Pheny1-2-[({p-[5-
(1- p he nylethoxyca rbonyla mi no)-4- pyri m idinyl]phenylymethyl)-am no]pro
pi on ic acid, 3-
Cyclopropy1-2-[({p-[5-(1-phenylethoxycarbonylam ino)-4- pyrim idiny1]-
phenyl}methyl)amino]propionic acid, 3-Pheny1-2-({p45-(1-phenylethoxy-
carbonylamino)-4-
pyrimidinyl]phenyl}methoxy)propionic acid, 3-Cyclopropy1-2-({p45-(1-
phenylethoxycarbonyl-
amino)-4-pyrimidinyl]phenyl}methoxy)propionic
acid, 4-Pheny1-34({p45-(1-phenylethoxy-
carbonyl am ino)-4-pyrim id i nyl]phenyllm ethyl) am ino]butyric
acid, .. 4-Cyclopropy1-3-[({p-[5-(1-
phenylethoxycarbonylam i no)-4- pyrim idi nyl]phenyl}methypam noi- butyric
acid, 4-Phenyl-3-({p-[5-
- 93 -
CA 3046894 2019-06-18

(1-phenylethoxycarbonylamino)-4-pyrimidinyl]phenylymethoxy)butyric acid, 4-
Cyclopropy1-3-({p-
[5-(1-phenylethoxycarbonylannino)-4-pyrimidinyl]phenyl}methoxy)butyric acid,
24[446-methy1-5-
(1-phenylethoxycarbonyl-amino)pyrimidin-4-yl]benzoyl]amino]-3-phenyl-propanoic
acid, 3-
cyclopropy1-24[446-methy1-5- (1-phe nyl ethoxycarbonylam no)- pyri m idi n-4-
ylibenzoyl]amino]propanoic acid, 24[4-[6-methy1-5-(1-phenylethoxycarbonyl-
amino)pyrimidin-4-
yl]benzoyl]amino]-4-phenyl-butanoic acid or
24[446-m ethyl-5- (1- phenyl-
ethoxycarbonylamino)pyrimidin-4-yl]benzoy1]-amino]-3-phenoxy-propanoic acid.
[0444] 51. A compound of embodiment 30 wherein the compound is 3-pheny1-2-[[4-
[4-(1-
phenylethoxycarbonylam i no)pyri midi n-5-yl]benzoyl] am ino]propanoic acid, 3-
cycl opropy1-24[444-
(1-phenylethoxycarbonyla m i no) pyri m id i n-511] be nzoyl]ami no]propanoi c
acid, 4-pheny1-24[444-
(1-phenylethoxycarbonylamino)pyrimidin-5-yl]benzoyl]amino]butanoic acid or 3-
phenoxy-2-[[4-
[4-(1-phenylethoxycarbonylamino)pyrimidin-5-yl]benzoyliamino]-propanoic acid,
[0445] 52. A compound of embodiment 30 wherein the compound is 3-pheny1-2-[[4-
[3-(1-
phenylethoxycarbonylamino)pyrazin-2-yl]benzoyliamino]propanoic acid, 3-cyclo
propy1-24[443-
( 1-phenylethoxycarbonyla m i no) pyrazi n-2-yl] be nzoyl]am no]propanoi c
acid, 4-pheny1-2-[[4-[3-(1-
phenylethoxycarbonylamino)pyrazin-2-yl]benzoyl]amino]butanoic acid or 3-
phenoxy-24[443-(1-
phenylethoxycarbonyl am i no) pyrazi n-2-yl]benzoyl] am i no] propa no ic
acid.
[0446] 53. A compound of embodiment 30 wherein the compound is 1-{p-[3-Methy1-
4-(1-
phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-piperidinecarboxylic acid,
(1-{p43-Methy1-4-
(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-piperidypacetic acid, 1-
(1-{p43-Methy1-4-
(1-phenylethoxycarbonylamino)-5-isoxazolylipheny1}-4-piperidyl)cyclo-
propanecarboxylic acid,
[1-(1-{p43-Methyl-4-(1-phenylethoxyca rbonyl am ino)-5-isoxazoly1]- pheny1}-4-
pi peri dyl)cycl opropyl]acetic acid, 1-{543-Methy1-4-(1-phenylethoxycarbonyl-
amino)-5-isoxazoly1]-
2-pyridy1}-4-piperidinecarboxylic
acid, ( 1-{543-M ethy1-44 1- phenyl-ethoxycarbonylam ino)-5-
isoxazoly1]-2-pyridy1}-4-piperidyl)acetic acid, 1-
(1-{543-Methy1-4-(1-
phenylethoxycarbonyl am i no)-5-isoxazoly1]-2- pyridy1}-4- pi peri
dyl)cyclopropanecarboxyl ic acid, [1-
- 94 -
CA 3046894 2019-06-18

(1-{543-Methy1-4-(1- phenylethoxycarbonylamino)-5-isoxazoly11-2-pyridy11-4-
piperidyl)cyclopropyl]acetic
acid, 1-{p43-Fluoro-4-(1- phenylethoxyca rbonylam ino)-5-
isoxazolyl]pheny1}-4-piperidinecarboxylic
acid, (1-{p43- F luoro-4-(1 -phenyl ethoxycarbonyl-
am ino)-5-isoxazo lyl]pheny1}-4- pi peridypaceti c
acid, 1 -(1-{ p-[3- Fl uo ro-4-(1- p henylethoxy-
carbonyl am i no)- 5- isoxazo lyl] phenyI}-4-piperidyl)cyclopropanecarboxylic
acid, [1-(1-{p43-Fluoro-
4-(1-phenylethoxycarbonylamino)-5-isoxazolyllpheny1}-4-
piperidyl)cyclopropyl]acetic acid, 1-{5-
[3- Fluoro-4-(1- phenyl ethoxycarbonylam ino)-5- isoxazoly1]-2- pyridyI}- 4-
pi peridi ne- carboxyl ic acid,
(1-{543-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-4-
piperidyl)acetic acid,
1- (1-{5-[3- F luoro-4-(1- phenylethoxycarbonylam i n o)-5-isoxazolyI]-2-
pyridyI}-4-
pi peridyl)cycl opropanecarboxyl ic acid, [1-(1-{543-Fluoro-4-(1-phenylethoxy-
carbonylamino)-5-
isoxazolyI]-2-pyridy1}-4-piperidyl)cyclopropyl]acetic
acid, 1 -{p-[3-Cyano-4-(1 -
phenylethoxycarbonylam ino)-5-isoxazolyl]pheny1}-4-pi peridinecarboxylic acid,
(1-{p13-Cyan o-4-
(1-phe nylethoxyca rbonylam no)-5- i soxazol yl]phenyI}-4-pi peridyl) acetic
acid, 1-(1-{p-p-Cyano-4-
(1-phenylethoxycarbonylamino)-5-isoxazolylipheny11-4-piperidypcyclo-
propanecarboxylic acid,
[1-(1-{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-pheny1}-4-
piperidyl)cyclopropyl]acetic acid, 1-{543-Cyano-4-(1-phenylethoxycarbonyl-
amino)-5-isoxazoly1]-
2-pyridy1}-4-piperidinecarboxylic
acid, (1 -{543-Cyano-4-(1- phenyl-ethoxycarbonylam ino)-5-
isoxazoly1]-2-pyridy1}-4-piperidyl)acetic acid, 1-(1-{543-Cyano-4-(1-
phenylethoxycarbonylamino)-
5-isoxazolyI]-2-pyridy1}-4-piperidyl)cyclopropanecarboxylic
acid, [1-(1-{5-[3-Cyano-4-(1-
phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-4-
piperidyl)cyclopropyl]acetic acid, 1-{p-[5-
(1- Phenylethoxycarbonylam i no)-1 H- pyrazol-1-yl]pheny11-4- pi perid
necarboxyl ic acid, (1 -{p-[5-(1-
Phenylethoxycarbonylamino)-1 H-pyrazol-1 -yl] ph e nyI}-4- pi peridyl) acetic
acid, 1-(1-{p-[5- (1-
P henylethoxyca rbonyla m no)-1 H-pyrazol-1 -yl] phenyl}-4-piperidyl)
cyclopropanecarboxylic acid,
[1- (1-{p-[5-(1-Phenylethoxycarbo nyl-a m ino)-1 H-pyrazol-1-yl]pheny1}-4-
piperidyl)cyclopropyl]acetic acid, 1-{5-[5-(1-Phenylethoxy-carbonylamino)-1H-
pyrazol-1-y1]-2-
pyridyI}-4- pi peridi neca rboxyl i c acid, (1-{5-[5-(1- Phenyl-
ethoxycarbonylamino)-1 H-pyrazol-1-y1]-2-
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CA 3046894 2019-06-18

pyridyI}-4-piperidyl)acetic acid, 1-(1-{545-(1-Phenylethoxycarbonylamino)-1H-
pyrazol-1-y1]-2-
pyridyI}-4-piperidyl)cyclopropanecarboxylic acid, [1-(1-{5-[5-(1-
Phenylethoxycarbonylamino)-1H-
pyrazol-1-y1]-2-pyridy1}-4-piperidy1)-cyclopropyl]acetic
acid, 1-{p-[4-Methy1-5-(1-
phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-piperidinecarboxylic
acid, (1 -{p-[4-
Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidyl)acetic acid, 1-(1-
{p-[4-Methy1-5-(1-phenylethoxy-carbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidyl)cyclopropanecarboxylic acid, [1-(1-{p-[4-Methy1-5-(1-
phenylethoxycarbonylamino)-1H-
pyrazol-1-Apheny1}-4-piperidyl)cyclopropyHacetic acid, 1-
{5-[4-Methy1-5-(1-
phenylethoxycarbonylamino)-1 H-pyrazol-1-y1]-2-pyridy1}-4-piperidinecarboxylic
acid, (1-{5- [4-
Methy1-5-(1 -p henylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-4-
piperidyl)acetic acid, 1-
(1-{5-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy11-4-
piperidyl)cyclopropanecarboxylic acid, [1-(1-{5-[4-Methy1-5-(1-
phenylethoxycarbonylamino)-1H-
pyrazol-1-y1]-2-pyridy1}-4-piperidyl)cyclopropyllacetic
acid, 1-{p-[4-Fluoro-5-(1-
phenylethoxycarbonylamino)-1 H-pyrazol-1-yl]pheny1}-4-piperidine-carboxylic
acid, .. (1-{p-[4-
Fluoro-5-(1 -phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny11-4-
piperidypacetic acid, 1-(1-
{p-[4- Fluoro-5-(1-phenylethoxycarbonylamino)-1 H-pyrazol-1-yl]pheny1}-4-
piperidypcyclopropanecarboxylic acid, [1-(1-{p44-Fluoro-5-(1-phenylethoxy-
carbonylamino)-1H-
pyrazol-1-ylipheny1}-4-piperidyl)cyclopropyliacetic
acid, 1-{5-[4-Fluoro-5-(1-
phenylethoxycarbonylamino)-1 H-pyrazol-1-y1]-2-pyridy1}-4-piperidinecarboxylic
acid, (1-{5- [4-
Fluoro-5-(1 -phenylethoxycarbonylamino)-1 H-pyrazol- 1-y1]-2-pyridy1}-4-
piperidyl)acetic acid, 141-
{544- Fluoro-5-(1- phenylethmcarbonyla mino)-1 H-pyrazol-1-y1]-2-pyridy11-4-
piperidyl)cyclopropanecarboxylic acid, [1-(1-{544-Fluoro-5-(1-
phenylethoxycarbonylamino)-1H-
pyrazol-1-y1]-2-pyridy1}-4-piperidyl)cyclopropyllacetic
acid, 1-{p-[4-Cyano-5-(1-phenyl-
ethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-piperidinecarboxylic acid, (1-
{p44-Cyano-5-(1-
phenylethoxycarbonylamino)-1H-pyrazol-1-ylipheny11-4-piperidyl)acetic acid, 1-
(1-{p44-Cyano-
541 -phenylethoxycarbonylam ino)-1 H-pyrazol-1-yl]pheny1}-4-
piperidyl)cyclopropane-carboxyl ic
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CA 3046894 2019-06-18

acid, [1-
(1-{p-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-phenyl}-4-
piperidyl)cyclopropyl]acetic acid, 1-{544-Cyano-5-(1-phenylethoxycarbonyl-
amino)-1H-pyrazol-
1-y1]-2-pyridy1}-4-piperidinecarboxylic acid, (1-{5-[4-Cyano-5-(1-phenyl-
ethoxycarbonylamino)-
1H-pyrazol-1-y1]-2-pyridy1}-4-piperidypacetic acid, 1-
(1-{544-Cyano-5-(1-
phenylethoxycarbonylami no)- 1H- pyrazol-1-y11-2-pyridy1}-4- pi
peridyl)cyclopropane-carboxylic
acid or [1-
(1-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-4-
piperidyl)cyclopropyl]acetic acid.
[0447] 54. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of Table 1 and one or more pharmaceutically
acceptable excipients.
[0448] 55. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 31 and one or more pharmaceutically
acceptable
excipients.
[0449] 56. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 32 and one or more pharmaceutically
acceptable
excipients.
[0450] 57. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 33 and one or more pharmaceutically
acceptable
excipients.
[0451] 58. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 34 and one or more pharmaceutically
acceptable
excipients.
[0452] 59. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 35 and one or more pharmaceutically
acceptable
excipients.
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[0453] 60. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 36 and one or more pharmaceutically
acceptable
excipients.
[0454] 61. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 37 and one or more pharmaceutically
acceptable
excipients.
[0455] 62. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 38 and one or more pharmaceutically
acceptable
excipients.
[0456] 63. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 39 and one or more pharmaceutically
acceptable
excipients.
[0457] 64. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 40 and one or more pharmaceutically
acceptable
excipients.
[0458] 65. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 41 and one or more pharmaceutically
acceptable
excipients.
[0459] 66. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 42 and one or more pharmaceutically
acceptable
excipients.
[0460] 67. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 43 and one or more pharmaceutically
acceptable
excipients.
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[0461] 68. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 44 and one or more pharmaceutically
acceptable
excipients.
[0462] 69. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 45 and one or more pharmaceutically
acceptable
excipients.
[0463] 70. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 46 and one or more pharmaceutically
acceptable
excipients.
[0464] 71. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 47 and one or more pharmaceutically
acceptable
excipients.
[0465] 72. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 48 and one or more pharmaceutically
acceptable
excipients.
[0466] 73. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 49 and one or more pharmaceutically
acceptable
excipients.
[0467] 74. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 50 and one or more pharmaceutically
acceptable
excipients.
[0468] 75. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 51 and one or more pharmaceutically
acceptable
excipients.
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[0469] 76. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 52 and one or more pharmaceutically
acceptable
excipients.
[0470] 77. A pharmaceutically acceptable formulation comprising, consisting
essentially of, or
consisting of a compound of embodiment 53 and one or more pharmaceutically
acceptable
excipients.
[0471] 78. A method comprising administering an effective amount of a Formula
[-XII
compound to a subject having a LPA-dependent or LPA-mediated disease or
condition.
[0472] 79. The method of embodiment 78 wherein the LPA-dependent or LPA-
mediated
disease or condition is a disease with fibrosis of the organs.
[0473] 80. The method of embodiment 79 wherein the fibrosis is of the liver,
kidney, lung,
heart, eye and the like.
[0474] 81. The method of embodiment 78 wherein the LPA-dependent or LPA-
mediated
disease or condition is chronic pain
[0475] 82. The method of embodiment 78 wherein the LPA-dependent or LPA-
mediated
disease or condition is pruritus.
[0476] 83. The method of embodiment 78 wherein the LPA-mediated disease is a
proliferative
disease including 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, including ovarian, breast and
triple negative breast
cancer and the like,
[0477] 84. The method of embodiment 78 wherein the LPA-mediated disease is an
inflammatory disease including psoriasis, nephropathy, pneumonia and the like,
[0478] 85. The method of embodiment 78 wherein the LPA-mediated disease is a
gastrointestinal disease such as inflammatory bowel disease,
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CA 3046894 2019-06-18

[0479] 86. The method of embodiment 78 wherein the LPA-mediated disease is an
ocular
disease including age-related macular degeneration (AMD), diabetic
retinopathy, proliferative
vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery
scarring, uveitis and
the like,
[0480] 87. The method of embodiment 78 wherein the LPA-mediated disease is a
liver
disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver
cirrhosis, cholestatic
pruritus, portal hypertension, regenerative failure, nonalcoholic
steatohepatitis (NASH), liver
hypofunction, hepatic blood flow disorder, and the like,
[0481] 88. The method of embodiment 78 wherein the LPA-mediated disease is a
renal
disease including chronic kidney disease, end stage renal disease, uremic
pruritus, nephropathy
including diabetic nephropathy and the like,
[0482] 89. The method of embodiment 78 wherein the LPA-mediated disease is a
skin
disease including scleroderma, skin scarring, atopic dermatitis, psoriasis and
the like,
[0483] 90. The method of any one of embodiments 78-89 wherein the subject is a
human.
[0484] 91. The method of any one of embodiments 78-90 wherein the compound is
selected
from Table 1.
[0485] 92. The method of any one of embodiments 78-90 wherein the compound is
1-(4-{4-[1-
(2-Chloro- phenyl)-ethoxycarbonylam ino]-3-methyl-isoxazol-5-y1}-benzoylamino)-
cyclo-
propanecarboxylic acid, 2-(4-{4-[1-(2-Chloro-phenyl)-ethoxycarbonyl-amino]-3-
methyl-iso-xazol-
5-yll-benzoylamino)-indan-2-carboxylic acid, 2-
(S)- (4-{4-[(R,S)-1-(2-Chloro-phenyl)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino) phenyl acetic acid,
2-(R)- (4-{4-
[(R,S)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-iso-xazol-5-y1}-
benzoylamino) phenyl
propanoic acid,
2(R)-([4-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)isoxazol-5-
ylibenzoyl]amino]-3-phenyl-propanoic acid, 2(S)-[[443-methyl-44(R)-
phenylethoxycarbonyl-
amino)isoxazol-5-ylibenzoyl]amino]-3-phenyl-propanoic acid, (R)-2-{443-Methyl-
4-((S)-1-phenyl-
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ethoxycarbonylam ino)- isoxazo 1-5-y1]- benzoy lam in o}-3-p henyl- propion ic
acid, (S)-2-{4-[3- Methyl-
4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1Fbenzoylamino}-3-phenyl-
propionic acid,
(R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzoylamino)-3-phenyl-propionic acid ,
(R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylam ino]-3-methyl-isoxazol-5-y1}-benzoylam ino)-3-(4-fluoro-
pheny1)-propionic acid,
(R)-3-(4-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}- benzoyl am i no)- propionic
acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(3,4-difluoro-
pheny1)-propionic
acid , (R)-3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino)-propionic acid , (R)-3-(4-Bromo-pheny1)-2-(4-{4-
[(R)-1-(2-chloro-
pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic
acid, (R)-2-(4-
{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-3-(2-
fluoro-pheny1)-propionic acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-y1}-benzoylamino)-3-p-tolyl-propionic
acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-
pheny1)-ethoxycarbonylam ino]-3- methyl- isoxazol-5-y1}- benzoyl am ino)- 3-
(4-trifluorom ethyl-
pheny1)-pro picnic acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino)-3-(4-cyano-pheny1)-propionic acid, (R)-2-(4-{4-
[(R)-1-(2-chloro-
pheny1)-ethoxycarbonylam ino]-3- methyl- isoxazol-5-y1}- benzoyl amino)-3-
cyclo propyl- propi on ic
acid , (R)- 24[442, 5-d imethy1-44(R)- 1- phenylethoxycarbonylam ino)pyrazol-
3- yl]benzoyl]am ino]-
3- phenyl- propanoic acid, (R)-24[4-[2,5-dimethy1-44(R)-1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-(4-fluorophenyl)propanoic acid, (R)- 3-(4-bromopheny1)-2-
[[4-[2,5-dimethy1-
4-((R)-1-phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]arnino]propanoic
acid, (R)- 3-(4-
chloropheny1)-2-[[4-[2,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-amino)pyrazol-
3-
yl]benzoyl]amino]propanoic acid, (R)- 3-(3,4-difluoropheny1)-24[442,5-dimethyl-
44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid, (R)-
24[441,5-dimethy1-
4-((R)-1-phenylethoxycarbonylamino)pyrazol-3-yl]benzoyllamino]-3-phenyl-
propanoic acid, (R)-
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CA 3046894 2019-06-18

24[441, 5-di methy1-4-((R)-1-phenylethoxycarbonylam i no)pyrazol-3-
yl]benzoyl]ami no]-3-(4-
fluorophenyl)propanoic acid, (R)- 3-
(4-bromopheny1)-2-[[441,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyliamino]propanoic acid,
((R)- 3-(4-
chloropheny1)-24[441,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-amino)pyrazol-3-
yl]benzoyliamino]propanoic acid, (R)- 3-(3,4-difluoropheny1)-2-[[441,5-
dimethyl-44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-ylibenzoyliamino]propanoic acid, (R)- 2-
(4-{5-[(R)-1-(2-
Chloro-pheny1)-ethoxycarbonylamino]-4-methyl-pyrazol-1-y1}-benzoylamino)-3-
phenyl-propionic
acid, (R)-
2-{4-[3-Methyl-4- ((R)- 1-phenyl- ethoxycarbonylam ino)- isoxazol-5-y1]-
benzylam i no}-3-
phenyl-propionic acid, (R)-
3-(2-Fluoro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzylamino}-propionic acid, (R)-2-{443-
Methy1-4-((R)-1-
phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-benzylamino}-3-(4-trifluoromethyl-
pheny1)-propionic
acid, (R)-
3-Cyclopropy1-2-{4-[3-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-
y11-
benzylamino}-propionic acid, (R)-
3-(2-Chloro-pheny1)-2-{4-[3-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y11-benzylamino}-propionic acid, (R)-3-(4-
Chloro-pheny1)-2-{4-
[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yli-benzylamino}-
propionic acid,
(R)- 2-
(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzylamino)-3-phenyl-propionic acid, (R)- 2-
(4{4-[(R)_1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-(2-fluoro-pheny1)-
propionic acid,
(R)- 2-
(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yll-
benzylamino)-3-(4-trifluoromethyl-pheny1)-propionic acid, (R)- 3-(2-Chloro-
pheny1)-2-(4-{4-[(R)-1-
(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yll-benzylamino)-
propionic acid,
(R)-2-(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzylamino)-3-cyclopropyl-propionic acid, 2-
{443-Methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzyloxy}-3-phenyl-propionic acid, 2-{4-
[3-Methy1-4-((R)-
1-phenyl-ethoxycarbonylamino)-isoxazol-5-yli-benzyloxy}-3-phenyl-propionic
acid, (RS)-3-
Cyclopropy1-2-{443-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y11-
benzyloxy}-
- 103 -
CA 3046894 2019-06-18

propionic acid, (RS)-3-Cyclopropy1-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-
isoxazol-5-yli-benzyloxy}-propionic acid, 244-[445-[1-(2-
chlorophenyl)ethoxycarbonylamino]-4-
cyano-pyrazol-1-yl]phenyliphenyl]acetic acid, (R)-
1-[4-[4-[1,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-yliphenyliphenyl-cyclopropane carboxylic
acid, (R)-1-[4-
[4-[2, 5-d imethy1-4-(1-phenylethoxycarbonylam ino)-pyrazol-3-
yl]phenyl]phenyl]cyclopropane
carboxylic acid, (R)-1-(4'-{5-[1-(2-Chloro-pheny1)-ethoxycarbonyl-am ino]-4-
fluoro-pyrazol-1-y1}-3-
fluoro-bipheny1-4-y1)-cyclopropanecarboxylic
acid, (R)-1-(4'-{5-[1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-fluoro-bipheny1-4-y1)-cyclo-
propanecarboxylic
acid, (R)-
1-(2-Chloro-4'-{541-(2-chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-
y1}-
bipheny1-4-y1)-cyclopropanecarboxylic acid, (R)-
1-(4'-{5-[1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-methyl-bipheny1-4-y1)-
cyclopropanecarboxylic
acid, (R)-1-(4'-{541 -(2-Chloro-pheny1)-ethoxy-carbonylamino]-4-fluoro-pyrazol-
1-y1}-biphenyl-4-
y1)-cyclopropanecarboxylic acid, (R)- 1-{4'45-(1-Phenyl-ethoxycarbonylamino)-4-
trifluoromethyl-
pyrazol-1-y1]-bipheny1-4-y1}-cyclo-propanecarboxylic
acid, (R)-1-{2-Fluoro-4'-[5-(1-phenyl-
ethoxycarbonylamino)-4-trifluoro-methyl-pyrazol-1-y1]-bipheny1-4-y1}-
cyclopropanecarboxylic
acid, (R)-
1-(4-{545-(1-Phenyl-ethonicarbonylamino)-pyrazol-1-yli-pyridin-2-y1}-pheny1)-
cyclopropanecarboxylic acid,
[0486] 93. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 31.
[0487] 94. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 32.
[0488] 95. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 33.
[0489] 96. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 34.
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CA 3046894 2019-06-18

[0490] 97. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 35.
[0491] 98. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 36.
[0492] 99. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 37.
[0493] 100. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 38.
[0494] 101. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 39.
[0495] 102. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 40.
[0496] 103. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 41.
[0497] 104. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 42.
[0498] 105. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 43.
[0499] 106. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 44.
[0500] 107. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 45.
[0501] 108. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 46.
- 105 -
CA 3046894 2019-06-18

[0502] 109. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 47.
[0503] 110. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 48.
[0504] 111. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 49.
[0505] 112. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 50.
[0506] 113. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 51.
[0507] 114. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 52.
[0508] 115. The method of any one of embodiments 78-90 wherein the compound is
selected
from embodiment 53.
[0509] 116. A composition comprising, consisting essentially of or consisting
of one or more
compounds of Formula (1-XII) and one or more agents currently used to treat a
LPA -dependent
or LPA -mediated disease or a disease or condition described herein.
[0510] 117. A pharmaceutically acceptable formulation comprising, consisting
essentially of or
consisting of one or more compounds of Formula (1-X11), one or more agents
currently used to
treat a LPA -dependent or LPA -mediated disease and one or more
pharmaceutically
acceptable excipients.
[0511] 118. A method comprising administering in combination with or co-
administrating a
compound of Formula (I-X11) to a subject with a LPA-dependent or LPA-mediated
disease or
condition and a currently used agent to treat a LPA -dependent or LPA -
mediated disease
- 106 -
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[0512] The one or more additional therapeutically active agents other than
compounds of
Formula (I-X11) are selected from: corticosteroids, immunosuppressants,
analgesics, anti-cancer
agents, anti-inflammatories, chemokine receptor antagonists, bronchodilators,
leukotriene
receptor antagonists, leukotriene formation inhibitors, platelet activating
factor receptor
antagonists, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors,
phospholipase A2
inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin
inhibitors, decon-gestants,
mast cell stabilizers, antihistamines, mucolytics, anticholinergics,
antitussives, expectorants,
and 13-2 agonists.
[0513] In preferred embodiments the currently used agent(s) are selected from
those
described in the Merck Index known to affect lysophosphatidic acid receptor
signaling. In other
preferred embodiments the Formula (I-X11) compound is selected from Table 1.
[0514] In other embodiments, therapies which combine a compound of Formula (I-
X11), with
currently used agents that act on differing signalling pathways to the LPA
synthesis or signalling
pathway so as to provide complementary clinical outcomes, are encompassed
herein for
treating LPA-dependent or LPA-mediated diseases or conditions.
[0515] Examples of additional therapeutic agents include, but are not limited
to, any of the
following: gossypol, genasense, polyphenol E, Chlorofusin, all trans-retinoic
acid (ATRA),
bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-
aza-2'-
deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide,
gemcitabine, imatinib,
geldanamycin, 17-N-Allylamino-17 -Demethoxygeldanamycin (17 -AAG),
flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD 184352, TaxolTM
(paclitaxel), and analogs ofTaxolTm, such as TaxotereTm, U0126, PD98059,
PD184352,
PD0325901, ARRY-142886, SB239063, SP600 125, BAY 43-9006, wortmannin, or
LY294002,
Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin;
aclarubicin; acodazole
hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate;
- 107 -
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amino glutethimide; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine;
azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene
hydrochloride; bisnafide
dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin;
calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride;
carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol
mesylate;
cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;
decitabine;
dexormaplatin; deazaguanine; deazaguanine mesylate; diaziquone; doxorubicin;
doxorubicin
hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin;
edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;
epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine;
estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
fadrozole
hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil;
flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride;
hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II
(including
recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b;
interferon alfa-n1;
interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin;
irinotecan hydrochloride;
lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium;
lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine;
methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;
mitocarcin;
mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane;
mitoxantrone hydrochloride;
mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran;
pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone
hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;
prednimustine;
procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine;
rogletimide; safingol; safingol hydrochloride; semustine; simtrazene;
sparfosate sodium;
- 108 -
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sparsomycin; Spiro germanium hydrochloride; spiromustine; spiroplatin;
streptonigrin;
streptozotocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride;
temoporfm; teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate;
trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil
mustard; uredepa;
vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate;
vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine
tartrate; vinrosidine
sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride,
mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.),
ethylenimine,
hexamethlymelamine, thiotepa, busulfan), carmustine, lomusitne, semustine,
streptozocin,
ortriazenes, dacarbazine, methotrexate, fluorouracil, floxouridine,
Cytarabine, mercaptopurine,
thioguanine, pentostatin, hydroxyprogesterone
caproate, megestrol acetate,
medroxyprogesterone acetate, estrogens, diethlystilbestrol, ethinyl estradiol,
tamoxifen),
testosterone propionate, fluoxymesterone, flutamide, leuprolide, cisplatin,
carboblatin,
mitoxantrone), procarbazine, mitotane, amino glutethimide, Erbulozole,
Dolastatin 10, Mivobulin
isethionate, Vincristine, NSC-639829, Discodermolide, ABT -751, Altorhyrtin A
and Altorhyrtin
C), Spongistatins 1-9, Cemadotin hydrochloride, Epothilone A, Epothilone B,
Epothilone C,
Epothilone D, Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone AN-
oxide, 16-aza-
epothilone B, 21aminoepothilone B, 21-hydroxyepothilone D, 26-
fluoroepothilone, Auristatin PE,
Soblidotin, Cryptophycin 52, Vitilevuamide, Tubulysin A, Canadensol,
Centaureidin, Oncocidin
Al Fijianolide B, Laulimalide, Narcosine, Nascapine, Hemiasterlin, Vanadocene
acetylacetonate,
lndanocine Eleutherobins (such as Desmethyleleutherobin,
Desacetyleleutherobin,
lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin,
Halichondrin B,
Diazonamide A, Taccalonolide A, Diozostatin, (-)-Phenylahistin, Myoseverin B,
Resverastatin
phosphate sodium, Aprepitant, cannabis, marinol, dronabinol, erythropoetin-a,
Filgrastim,
rituximab, natalizumab, cyclophosphamide, penicillamine, cyclosporine,
nitrosoureas, cisplatin,
- 109 -
CA 3046894 2019-06-18

carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine,
pyrimidine analogues,
protein synthesis inhibitors, dactinomycin, anthracyclines, mitomycin C,
bleomycin, mithramycin,
Atgame Thymoglobuline , OKT30, basiliximab, daclizumab, cyclosporin,
tacrolimus, sirolimus,
Interferons, opioids, infliximab, etanercept, adalimumab, golimumab,
leflunomide, sulfasalazine,
hydroxychloroquinine, minocycline, rapamicin, mycophenolic acid, mycophenolate
mofetil,
FTY720, Cyclosporin A (CsA) or tacrolimus (FK506), aspirin, salicylic acid,
gentisic acid, choline
magnesium salicylate, choline salicylate, choline magnesium salicylate,
choline salicylate,
magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen,
fenoprofen calcium,
flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac
tromethamine, naproxen,
oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin,
meclofenamate,
meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, valdecoxib,
parecoxib,
etoricoxib, lumiracoxib, betamethasone, prednisone, alclometasone,
aldosterone, amcinonide,
beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,
clobetasone,
clocortolone, cloprednol, cortisone, cortivazol, deflazacort,
deoxycorticosterone, desonide,
desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone,
difluprednate,
fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide,
fluocinolone acetonide,
fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone,
fluprednidene, fluticasone,
formocortal , halcinonide, halornetasone, hydrocortisone/cortisol,
hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone,
meprednisone,
methylprednisolone, methylprednisolone aceponate, mometasone furoate,
paramethasone,
prednicarbate, prednisone/prednisolone, rimexolone, tixocortol, triamcinolone,
ulobetasol,
pioglitazone, clofibrate, fenofibrate gemfibrozil, folic acid, isbogrel,
ozagrel, ridogrel, dazoxiben,
lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin,
and rosuvastatin,
edaravone, vitamin C, TROLOXTm, citicoline and minicycline, (2R)-2-
propyloctanoic acid,
propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol,
esmolol and acebutolol,
memantine, traxoprodil, tirofiban lamifiban, argatroban, enalapril,
cyclandelate, losartan,
- 110 -
CA 3046894 2019-06-18

valsartan, candesartan, irbesartan, telmisartan, olmesartan mepyramine
(pyrilamine),
antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine,
dimenhydrinate,
pheniramine, chlorphenamine (chlorpheniramine), dexchlorpheniramine,
brompheniramine,
triprolidine, cetirizine, cyclizine, chlorcyclizine, hydroxyzine, meclizine,
loratadine, desloratidine,
promethazine, alimemazine (trimeprazine), cyproheptadine, azatadine,
ketotifen, acrivastine,
astemizole, cetirizine, mizolastine, terfenadine, azelastine, epinastine,
levocabastine,
olopatadine, levocetirizine, fexofenadine, rupatadine, bepotastine),
mucolytics, anticholinergics,
antitussives, analgesics, expectorants, albuterol, ephedrine, epinephrine,
fomoterol,
metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone,
flunisolide, fluticasone
propionate, triamcinolone acetonide, ipratropium bromide, pseudoephedrine,
theophylline,
montelukast, pranlukast, tomelukast, zafirlukast, ambrisentan, bosentan,
enrasentan,
sitaxsentan, tezosentan, iloprost, treprostinil, pirfenidone, epinephrine,
isoproterenol,
orciprenaline, xanthines, zileuton.
[0516] 119. The method of embodiments 116-118 wherein the subject is a human.
[0517] 120. The method of embodiments 116-119 wherein the Formula 1-XII
compound(s) are
selected from Table 1.
[0518] 121. The method of embodiments 116-119 wherein the Formula I-XI I
compound(s) are
selected from the group consisting of 1-(4-{441-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-y1}-benzoylamino)-cyclo-propanecarboxylic acid, 2-(4-{4-[1-
(2-Chloro-phenyI)-
ethoxycarbonylam ino]-3-methyl-isoxazol- 5-yI}-benzoylam i no)- indan-2-
carboxyl ic acid, 2-(S)- (4-
{4-[(R, S)-1-(2-Chloro-pheny1)-ethoxycarbonylam no]-3-methyl- isoxazol-5-y1}-
benzoylam ino)
phenyl acetic acid, 2-(R)- (4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino) phenyl propanoic
acid, 2(R)4[443-methy1-4-((R)-1-
phenylethoxycarbonylamino)isoxazol-5-yllbenzoyl]amino]-3-phenyl-propanoic
acid, 2(S)4[4-[3-
methy1-4-((R)-phenylethoxycarbonyl-amino)isoxazol-5-yl]benzoyl]amino]-3-phenyl-
propanoic
acid, (R)-2-{443-Methy1-44(S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-
benzoylamino}-3-
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CA 3046894 2019-06-18

phenyl-propionic acid, (S)-2-{443-Methy1-44(S)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-y1]-
benzoylamino}-3-phenyl-propionic acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-phenyl-propionic
acid , (R)-2-(4-
{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-3-(4-
fluoro-phenyt)-propionic acid , (R)-3-(4-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-
chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic acid ,
(R)-2-(4-{4-[(R)-1-
(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-
(3,4-difluoro-
pheny1)-propionic acid , (R)-
3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic acid ,
(R)-3-(4-Bromo-
pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-propionic acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-y1}-benzoylam ino)-3-(2-fluoro-pheny1)-propionic acid, (R)-2-
(4-{4-[(R)-1-(2-
Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yll-benzoylamino)-3-p-
tolyl-propionic
acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-3-(4-trifluoromethyl-pheny1)-propionic acid, (R)-2-(4-{4-[(R)-1-
(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(4-cyano-pheny1)-
propionic acid,
(R)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzoylamino)-3-cyclopropyl-propionic acid (R)-
2-[[4-[2, 5-dim ethy1-4-((R)-1 -
phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-3-phenyl-propanoic acid,
(R)-2- [[4-[2,
acid, (R)- 3-(4-bromopheny1)-2-R4-[2, 5-
di methy1-4-((R)- 1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid,
(R)- 3-(4-
chloropheny1)-24[4-[2,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-amino)pyrazol-3-
yl]benzoyliamino]propanoic acid, (R)- 3-(3,4-difluoropheny1)-2-[[442,5-
dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-ylibenzoyliamino]propanoic acid, (R)-
2-[[4-[1,5-
dimethy1-44(R)-1-phenylethoxycarbonylamino)pyrazol-3-yl]benzoyliamino]-3-
phenyl-propanoic
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CA 3046894 2019-06-18

acid, (R)-24[441 ,5-dimethy1-4-((R)-1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]-3-
(4-fluorophenyl)propanoic acid,
(R)- 3-(4-bromopheny1)-2-[[441,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-ylibenzoyl]amino]propanoic acid,
(R)- 3-(4-
chloropheny1)-24[441,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-amino)pyrazol-3-
ylibenzoyliamino]propanoic acid, (R)- 3-(3,4-difluoropheny1)-2-[[4-[1,5-
dimethyl-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-ylibenzoyliamino]propanoic acid, (R)- 2-
(4-{5-[(R)-1-(2-
Chloro-pheny1)-ethoxycarbonylamino]-4-methyl-pyrazol-1-y1}-benzoylamino)-3-
phenyl-propionic
acid,
(R)-2-{443-Methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-
benzylamino}-3-
phenyl-propionic acid,
(R)-3-(2-Fluoro-pheny1)-2-{4-[3-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzylaminol-propionic acid, (R)-2-{4-[3-
Methy1-4-((R)-1-
phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-benzylamino}-3-(4-trifluoromethyl-
pheny1)-propionic
acid,
(R)-3-Cyclopropy1-2-{443-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-y11-
benzylaminoypropionic acid,
(R)-3-(2-Chloro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzylamino}-propionic acid, (R)-3-(4-
Chloro-pheny1)-2-{4-
[3-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yli-benzylam ino}-
propionic acid,
(R)- 2-
(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-0-
benzylamino)-3-phenyl-propionic acid, (R)- 2-
(4-{4-[(R)_1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-(2-fluoro-pheny1)-
propionic acid,
(R)- 2-
(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzylamino)-3-(4-trifluoromethyl-pheny1)-propionic acid, (R)- 3-(2-Chloro-
pheny1)-2-(4-{4-[(R)-1-
(2-chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-
propionic acid,
(R)-2-(4-{4-[(R)- 1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzylamino)-3-cyclopropyl-propionic acid, 2-
{4-[3-Methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzyloxy}-3-phenyl-propionic acid, 2-{4-
[3-Methyl-4- ((
acid,
(RS)-3-
Cyclopropy1-2-{443-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yll-
benzyloxyl-
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CA 3046894 2019-06-18

propionic acid, (RS)-3-Cyclopropy1-2-{443-methyl-4-((R)-1-phenyl-
ethoxycarbonylamino)-
isoxazol-5-yli-benzyloxy}-propionic acid, 24444-[541-(2-chlorophenypethoxy-
carbonylamino]-4-
cyano-pyrazol-1-yl]phenyl]phenyl]acetic acid,
(R)-1-[4-[4-[1,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-yl]phenyliphenylicyclo-propane carboxylic
acid, (R)-1-[4-
[4-[2, 5-d imethy1-4-(1-phenylethoxycarbonylam ino) pyrazol-3-
yl]phenyl]pheny1]-cyclopropane
carboxylic acid, (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonyl-amino]-4-
fluoro-pyrazol-1-y1}-3-
fluoro-bipheny1-4-y1)-cyclopropanecarboxylic
acid, (R)-1-(4'-{5-[1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-fluoro-biphenyl-4-y1)-cyclo-
propanecarbmlic
acid,
(R)-1-(2-Chloro-4'-{5-[1-(2-chloro-pheny1)-ethoxycarbonylam ino]-4-fluoro-
pyrazol-1-y1}-
bipheny1-4-y1)-cyclopropanecarboxylic acid,
(R)-1-(4'-{5-[1-(2-Chloro-phenyI)-
ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-methyl-bipheny1-4-y1)-
cyclopropane-carboxylic
acid,
(R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-
biphenyl-4-
y1)-cyclopropanecarboxylic acid, (R)- 1-{4'45-(1-Phenykethoxycarbonyl-amino)-4-
trifluoromethyl-
pyrazol-1-y1]-bipheny1-4-y1}-cyclopropanecarboxylic
acid, (R)-1-{2-Fluoro-4'-[5-(1-phenyl-
ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]-bipheny1-4-y1}-
cyclopropanecarbmlic acid,
(R)-1-(4-{545-(1-Phenyl-ethoxycarbonylamino)-pyrazol-1-y11-pyridin-2-y1}-
pheny1)-
cyclopropanecarboxylic acid,
[0519] 122. The method of embodiments 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 31.
[0520] 123. The method of embodiments 116-119 wherein the Formula 1-XI I
compound(s) are
selected from embodiment 32.
[0521] 124. The method of embodiments 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 33.
[0522] 125. The method of embodiment 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 34.
- 114 -
CA 3046894 2019-06-18

[0523] 126. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 35.
[0524] 127. The method of embodiment 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 36.
[0525] 128. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 37.
[0526] 129. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 38.
[0527] 130. The method of embodiment 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 39.
[0528] 131. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 40.
[0529] 132. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 41.
[0530] 133. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 42.
[0531] 134. The method of embodiment 116-119 wherein the Formula 1-XII
compound(s) are
selected from embodiment 43.
[0532] 135. The method of embodiment 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 44.
[0533] 136. The method of embodiment 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 45.
[0534] 137. The method of embodiment 116-119 wherein the Formula 1-X11
compound(s) are
selected from embodiment 46.
- 115 -
CA 3046894 2019-06-18

[0535] 138. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 47.
[0536] 139. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 48.
[0537] 140. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 49.
[0538] 141. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 50.
[0539] 142. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 51.
[0540] 143. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 52.
[0541] 144. The method of embodiment 116-119 wherein the Formula I-XII
compound(s) are
selected from embodiment 53.
[0542] 145. The composition of embodiment 116 where the currently used agent
is a mast
cell stabilizing agent
[0543] 146. The composition of embodiment 116 where the currently used agent
is a platelet
activating factor receptor antagonist,
[0544] 147. The composition of embodiment 145 where the mast cell stabilizing
agent is
cromoglicate, nedocromil, azelastine, bepotastine, epinastine, ketotifen,
olopatadine and
rupatadine.
[0545] 148. The composition of embodiment 146 where the platelet activating
factor receptor
antagonist is rupatadine, SM-12502, CV-3988 and WEB 2170.
[0546] 1A. A compound wherein the compound has the structure of Formula I
- 116 -
CA 3046894 2019-06-18

C _____________
[0547](A)1 A Formula I
L2 L¨R
[0548] or a pharmaceutically acceptable salt or prodrug thereof,
[0549] wherein RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C(=0)NH2, -C(=0)NHIRB,
-C(=0)NHSO2RB or -C(=0)NHCH2CH2S03H or a carboxylic acid isostere;
wherein RB is -H or -C1-C4 alkyl, or has the structure of one of:
oYo yo
[0550] o ;
[0551] L1 is absent or substituted or unsubstituted C1-C6 alkylene,
substituted or unsubstituted
C3-C6 cycloalkylene, C1-C6 fluoroalkylene, substituted or unsubstituted C1-C6
heteroalkylene, or
-UV-Z-, wherein -UV- is defined by -OW-, -WO-, -N(R)W-,
-WN(RJ)-, -N(R)C(=O)-, -SW-, -S(=0)õW- or -C(=0)N(RJ)-, wherein W is
substituted or
unsubstituted 01-C3 alkylene or substituted or unsubstituted C3-C6
cycloalkylene or W is -C(RL)2-
, and wherein Z is substituted or unsubstituted C1-C6 alkylene, substituted or
unsubstituted C3-
C6 cycloalkylene, or C1-C6 fluoroalkylene or Z is -C(R1-)2-; wherein n is 0,
1, or 2;
[0552] L2 is absent, or substituted or unsubstituted C1-C6 alkylene,
substituted or
unsubstituted C3-C6 cycloalkylene, C1-C6 fluoroalkylene, substituted or
unsubstituted C1-C6
heteroalkylene, -0-, -S-, -S(=0)-, -S(=0)2-, -C(=0)-, or -C(=0)N(RJ)-;
[0553] Ring A is a 5-6 membered heteroarene selected from one of:
- 117 -
CA 3046894 2019-06-18

RE
I
,,
,N \ ,N-......) N,N*
NX .1_\1:_r
r- RE_ N
N 1
D
R Rc R( D Re RD
R-, Rc
1µ1* Rc,rN.,-' eNt=i- ,-NN.;:_. RE........e.
NI\ a
õrD )¨(
RD Rc __ RD N
i
Rc RD
R- RD
RE
0
., / N, '.,
RN ,' C'TNR\I j_ 1----1\1\
. N¶ c- I X I
N c D R N RD Rc RD
c/ R
RD Rc R
[0554] R RD ,
[0555] wherein the dashed line indicates the point of attachment of Ring A to
Ring B; wherein
one of RD and RD is -H, -ON, -F, -Cl, -Br, -I, -0C1-04 alkyl, -01-C4 alkyl, -
03-C6 cycloalkyl, or -C1-
C4 fluoroalkyl, and the other RD or RD is -N(RF)-C(=0)XCH(RG)-CY, -N(RF)-
C(=0)XC(RG)2-CY, -
N(RF)-C(=0)X-CY, -C(=0)-N(RF)-CH(RG)X-CY, -C(=0)-N(RF)-C(RG)2X-CY, or -C(=0)X-
N(RF)-X-
CY, wherein X is absent, -0-, -NH- or -CH2-;
[0556] RE is -H, -C1-C4 alkyl or -01-C4 fluoroalkyl; RF is -H or C1-04 alkyl;
RG is independently
selected RE, or one RG is -C1-04 alkyl and is taken together with the carbon
atom to which RG is
attached and the carbon or heteroatom to which CY is attached to define a
substituted or
unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and
the other RG, if
present, is as defined for RE;
[0557] CY is substituted or unsubstituted 01-06 alkyl, substituted or
unsubstituted 03-C10
cycloalkyl, substituted or unsubstituted C2-010 heterocycloalkyl, substituted
or unsubstituted aryl,
or substituted or unsubstituted heteroaryl, wherein if CY is substituted then
CY is substituted
with 1, 2, or 3 independently selected RH;
[0558] wherein each RH is independently selected from -H, halogen, -ON, -NO2, -
OH,
-OR, -SR, -S(=0)RJ, -S(=0)2RJ, -N(RJ)S(=0)2RJ, -S(=0)2N(RL)2, -C(=0)RJ,
OC(=0)RJ, -CO2RJ,
-0CO2RJ, -N(RL)2, -C(=0)N(RI-)2, -0C(=0)N(RL)2, -N(RJ)C(=0)N(RL)2, -
N(RJ)C(=0)RJ, -
- 118 -
CA 3046894 2019-06-18

N(RJ)C(=0)0RJ, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-04 fluoroalkoxy, C1-C4
alkoxy, and Ci-as
heteroalkyl, wherein each R.-I is independently substituted or unsubstituted
C1-C6 alkyl,
substituted or unsubstituted 01-C6 heteroalkyl, Cl-C6 fluoroalkyl, substituted
or unsubstituted C3-
C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted C3-C6
cycloalkyl), -C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -
Ci-C4 alkylene-
(substituted or unsubstituted aryl), or -C1-04 alkylene-(substituted or
unsubstituted heteroaryl);
[0559] wherein each RL is independently -H, substituted or unsubstituted Cl-C6
alkyl,
substituted or unsubstituted C1-C6 heteroalkyl, C1-C6 fluoroalkyl, substituted
or unsubstituted C3-
C6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl,
substituted or unsubstituted heteroaryl, -C1-C4 alkylene-(substituted or
unsubstituted cycloalkyl),
-C1-C4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C1-C4
alkylene(substituted or
unsubstituted aryl), or -C1-04 alkylene-(substituted or unsubstituted
heteroaryl), or when RH is -
S(0)2N(RL)2, -N(RL)2, -C(0)N(RL)2, -0C(0)N(RL)2 or -N(RF)C(=0)N(RL)2, each RL
is
independently -H or C1-06 alkyl, or the RL groups independently are C1-C6
alkyl which are taken
together with the N atom to which they are attached to define a substituted or
unsubstituted
heterocycle, or when W is -C(RL)2- or Z is -C(RL)2, each RL is independently -
H, C1-C6 alkyl, or
the RL groups independently are Ci-C6 alkyl which are taken together with the
carbon atom to
which they are attached to define a carbocycle;
[0560] Ring B is substituted or unsubstituted C3-C10 cycloalkylene,
substituted or
unsubstituted 02-C10 heterocycloalkylene, substituted or unsubstituted
arylene, or substituted or
unsubstituted heteroarylene, where if ring B is substituted then ring B is
substituted with 1, 2, or
3 independently selected RH, wherein RH is as previously defined;
[0561] Ring C is absent or substituted or unsubstituted C3-C10 cycloalkylene,
substituted or
unsubstituted C2-C10 heterocycloalkylene, substituted or unsubstituted
arylene, or substituted or
- 1 1 9 -
CA 3046894 2019-06-18

unsubstituted heteroarylene, where if ring C is substituted then ring C is
substituted with 1, 2, or
3 independently selected RH, wherein RH is as previously defined,
[0562] wherein when Ring B is substituted or unsubstituted arylene, Ring C is
absent, L2 is
absent, L1 is -UV-Z-, wherein -UV- is -N(R)C(=O)-, wherein RJ is -H, RD is -
N(RF)-
C(=0)XCH(RG)-CY, wherein X is -0-, RG is -CH3 and RF is -H, and Rc is -H, -CH3
or -CF3,
[0563] or when Ring B is substituted or unsubstituted arylene and Ring C is
substituted or
unsubstituted arylene or is substituted or unsubstituted C3-C10 cycloalkylene,
or Ring B is
substituted or unsubstituted C3-C cycloalkylene and Ring C is substituted or
unsubstituted
arylene, L2 is absent, L1 is 01-C6 alkylene,
[0564] and Rc is -H or -CH3 and RA is -CO2H or CO2RD
[0565] then Ring A has the structure of one of::
RE
N I
Rc, Rc N RD RD
Rc
= RcrN\j.--
RD Rc
RD RcIN
RD
RN c
RD
RC
RE
0
0 N Nj'N
1 /
RC ,,D Rc ss'N RD RND
Rc/ RD RD Rc
[0566]
[0567] and when Ring B is C2-C10 heterocycloalkylene, Ring C is substituted or
unsubstituted
arylene, L2 is absent, L1 is C1-C6 alkylene, Rc is -CH3 and RA is -CO2H or
CO2RD, then Ring A
has the structure of one of:
- 120 -
CA 3046894 2019-06-18

N, ., E ,N //N.-Ns)!
I ' R ¨N N 1
\N----- RD
Rd RD Rd
.----N '
s;,/... RN c' , zõs.. ,:lr
r
N \ a D
r RD Rd/N RD
Rd RD
RE
0 I
RE , Tw.:,__ Nr\-1;X- c)
NV-----'1, eir
N , ' I
1 / ' ,, ---
TC--
D
.F4, C/ N R- R N RD RN RD
[0568] ¨ RD R Rd RD
=
[0569] 2A. The compound of embodiment 1A wherein Rc is -H, -ON, -F, -Cl, -Br, -
I, -001-C4
alkyl, -C1-C4 alkyl, -C3-06cycloalkyl, or -C1-04 fluoroalkyl and RD is -N(RF)-
C(=0)XCH(RG)-CY, -
N(RF)-C(=0)XC(RG)2-CY, -N(RF)-C(=0)X-CY, wherein RF and each RD independently
are -H or
C1-C4 alkyl.
[0570] 3A. The compound of embodiment 2A wherein Ring A is selected from one
of:
RE
Is
RN N
/Nõ-z......õ/ //N--Ns)!
i
--..-*;"----N D D RD \N------Ro
Rd R Rd R RC
¨E
rµl* RN' eN-'-
1\/.._::_____L
N=( P;'''' K ----(N---r
D RD RC RD i
R D Rd RD
Rc R
RE
0 I
REN ,, O NI` : r.--;\1.-- Nr<RD R ey
, / µ
T\J-:- N \ /'-µ c) A
RD Rc RD C/ N RD
/IN
N Rc R N
c/
[0571] R RD = ,
[0572] wherein RD is -N(RF)-C(=0)XCH(RD)-CY, and Rc is -H, -CH3 or -CF3,
[0573] Ring B is substituted or unsubstituted arylene or substituted or
unsubstituted
heteroarylene, Ring C is absent; L2 is absent; L1 is -UV-Z-, wherein -UV- is -
OW-, -WO-, -
N(R)W-, -WN(RJ)-, -N(R)C(=O)-, -SW-, -S(=0)W-, or -C(=0)N(RJ)-, wherein W is
substituted
- 121 -
CA 3046894 2019-06-18

or unsubstituted C1-03 alkylene; and n is 0, 1, or 2; or Ring B and Ring C
independently are
substituted or unsubstituted arylene or substituted or unsubstituted arylene
L2 is absent, Cis C1-
C6 alkylene.
[0574] 4A. The compound of embodiment 2A wherein Ring A has the structure of
one of:
N.,
RE¨N
RD N RD
RC RD Rc
NI
N=( N I
RD R RD
RC RD
RE
0
NçN I c I
N Rc N RD RND
RN
[0575]
Rc/ RD - RD Rc RD
[0576] wherein Ring B is substituted or unsubstituted arylene and Ring C is
substituted or
unsubstituted arylene or is substituted or unsubstituted C3-C10 cycloalkylene,
or Ring B is
substituted or unsubstituted C3-C10 cycloalkylene and Ring C is substituted or
unsubstituted
arylene, L2 is absent and Lis C1-C6 alkylene.
[0577] 5A. The compound of embodiment 2A wherein L2 is absent and L1 is C1-C6
alkylene,
or substituted or unsubstituted C3-C6 cycloalkylene, substituted or
unsubstituted C1-C6
heteroalkylene or L2 and Ring C are absent and L1 is -UV-Z-, wherein -UV- is
defined by -OW-, -
WO-, -N(R)W-, -WN(RJ)-, -N(R)C(=O)-, -SW-, -S(=O)W-, or -C(=0)N(RJ)-, wherein
W is
substituted or unsubstituted C1-C3 alkylene; and n is 0, 1, or 2.
[0578] 6A. The compound of embodiment 5A wherein L1 is -UV-Z- wherein -UV- is
defined by
-OW-, -WO-, -N(R)W-, -WN(R)- or -C(=0)N(RJ)-, wherein W is substituted or
unsubstituted C1-
C3 alkylene.
- 122 -
CA 3046894 2019-06-18

[0579] 7A. The compound of embodiment 5A wherein L1 is -UV-Z-, wherein -UV- is
defined by
-WO-, -WN(RJ)- or -C(=0)N(RJ)-, wherein W is substituted or unsubstituted C1-
C3 alkylene, and
L2 is absent.
[0580] 8A. The compound of embodiment 7A wherein Z is substituted or
unsubstituted 01-C6
alkylene.
[0581] 9A. The compound of embodiment 7A wherein Z is substituted or
unsubstituted C1-06
alkylene and RA is -CO2H or -CO2RB.
[0582] 10A. The compound of embodiment 7A, wherein L1 is -UV-Z-, wherein -UV-
is defined
by -C(=0)N(RJ)-, wherein RJ is -H or -CH3.
[0583] 11A. The compound of embodiment 7A wherein L1 is UV-Z-, wherein -UV-,
is defined
by -WO-.
[0584] 12A. The compound of embodiment 7A wherein L1 is UV-Z-, wherein -UV-,
is defined
by - WN(RJ)-, wherein RJ is -H or -CH3.
[0585] 13A. The compound of embodiment 2A wherein L1 is absent or a
substituted or
unsubstituted substituted C1-C4 alkylene or a substituted or unsubstituted C3
cycloalkylene (i.e.,
cyclopropyl-di-yl).
X(s
[0586] 14A. The compound of embodiment 2 wherein L1 is -CH2-, or
-C(CH3)2-=
[0587] 15A. The compound of embodiment 2 wherein Ring A has the structure of
one of:
RE
z/N,N.;;;.- E ,
\
N \ I
D R ¨N RD Ns RD
c R FzcRI) RC) RD
[0588] R Rc
- 123 -
CA 3046894 2019-06-18

[0589] wherein RD is -H, -CN, -CH3, or -CF3, RD is -N(RE)C(=0)XCH(RG)-CY, -
N(RE)C(=0)XC(RG)2-CY, or -N(RE)C(=0)X-CY and I: is -UV-Z- wherein -UV- is
defined by -WO
-WN(R-1)- or -C(=0)N(R)-.
[0590] 16A. The compound of embodiment 15A wherein RD is -H, -CH3 or -CF3 and
RD is -
N(RE)C(=0)XCH(RG)-CY.
[0591] 17A. The compound of embodiment 15A wherein RD is -N(RE)C(=0)XCH(RG)-
CY,
wherein -X- is -N(RE)- or -0-; and wherein RG and each RE, independently
selected, are -H or -
CH3.
[0592] 18A. The compound of embodiment 17A wherein RG is -CH3, in the R or S
configuration, and CY is substituted or unsubstituted phenyl or substituted or
unsubstituted
heteroaryl.
[0593] 19A. The compound of embodiment 17A wherein RD is -N(RE)C(=0)0CH(RG)-
CY,
wherein CY is unsubstituted or substituted phenyl, wherein substituted phenyl
is phenyl that is
substituted with one or two of independently selected R.
[0594] 20A. The compound of embodiment 17A, wherein RD is -N(RE)C(=0)0CH(CH3)-
CY,
wherein RE is -H, and wherein CY is unsubstituted phenyl.
[0595] 21A. The compound of embodiment 17A, wherein RD is -N(RE)-C(=0)0CH(CH3)-
CY,
wherein RE is -H, and wherein CY is substituted phenyl, wherein substituted
phenyl is phenyl
that is substituted with one or two of independently selected RJ, wherein RJ
are halogens.
[0596] 22A. The compound of embodiment 21A, wherein RD is -NH-C(0)OOH(CH3)-CY
wherein CY is substituted phenyl, wherein substituted phenyl is phenyl that is
substituted with
one RH, wherein RJ is -F, -Cl or -Br.
[0597] 23A. The compound of embodiment 21A, wherein RD is -NH-C(=0)0CH(CH3)-
CY,
wherein CY is substituted phenyl, wherein substituted phenyl is phenyl that is
substituted with
one RH, wherein RJ is -Cl.
- 124 -
CA 3046894 2019-06-18

[0598] 24A. The compound of embodiment 19A, wherein RD is -NH-C(=0)0CH(CH3)-CY
CH3 0
/*L
40 0 N '
[H, Halogen]
having the structure of
[0599] 25A. The compound of claim 19A wherein RD is -NH-C(=0)0CH(CH3)-CY
wherein the
methyl group in RD is in the R configuration.
[0600] 26A. The compound of any one of embodiments 5-25 wherein Ring A has the
structure
N I
RD
of: Rc , wherein L2 is absent and Ring B is substituted or unsubstituted
arylene, or
substituted or unsubstituted heteroarylene,
[0601] provided that when Ring C is not absent and L1 is C1-C6 alkylene, or
Ring C is absent
and L1 is -UV-Z, wherein -UV- is -N(R)C(=0)-, and RD has the structure of -
N(RF)-
C(=0)XCH(RG)-CY, -N(RF)-C(=0)XC(RG)2-CY or -N(RF)-C(=0)X-CY,and RA is -CO2H,
then Rc
is other than -H, -CH3 and -CF3.
[0602] 27A. The compound of embodiment 26A wherein Rc is -H, -CH3 or -CF3, and
RD is -
NH-C(=0)0CH(RG)-CY, wherein RG is -H or -CH3, in the R or S configuration, and
-CY is
substituted or unsubstituted phenyl.
[0603] 28A. The compound of embodiment 26A wherein L2 and Ring C are absent,
Ring B is
substituted or unsubstituted arylene, or substituted or unsubstituted
heteroarylene, and L1 is -
UV-Z-, wherein -UV-, is defined by -WO-, -WN(RJ)- or -C(0)N(R)-.
[0604] 29A. The compound of embodiment 26A wherein L2 and Ring C are absent,
Ring B is
substituted or unsubstituted arylene, or substituted or unsubstituted
heteroarylene, and L1 is -
UV-Z-, wherein -UV-, is defined by -WN(RJ)- or -C(=0)N(RJ)-, wherein RJ is -H
or -CH3.
- 125 -
CA 3046894 2019-06-18

[0605] 30A. The compound of embodiment 29A wherein L1 is -UV-Z-, wherein -UV-
is defined
by -C(=0)NH-, and wherein Z is substituted or unsubstituted C1-C6 alkylene.
[0606] 31A. The compound of embodiment 29A wherein L1 is -UV-Z-, wherein -UV-
is defined
by -WO-, wherein W is substituted or unsubstituted 01-C3 alkylene, and wherein
Z is substituted
or unsubstituted C1-C6 alkylene.
[0607] 32A. The compound of embodiment 29A wherein L1 is -UV-Z-, wherein -UV-
is defined
by -W-NH-, wherein W is substituted or unsubstituted Ci-C3 alkylene, and
wherein Z is
substituted or unsubstituted C1-06 alkylene.
[0608] 33A. The compound of embodiment 26A wherein L1 is -UV-Z-, wherein -UV-
is defined
by -WO-, -WN(R-1)- or -C(=0)N(RJ), wherein RJ is -H or -CH3, and wherein Z is
substituted or
unsubstituted C1-C6 alkylene, wherein the alkylene is -CH(CH2-cyclopropyI)-, -
CH(CH2-aryl) or -
CH(CH2-heteroaryl), wherein the aryl or heteroaryl is substituted or
unsubstituted.
[0609] 34A. The compound of embodiment 33A wherein L1 is -UV-Z-, wherein -UV-
is defined
by -C(=0)NH-, -WO- or -W-NH-, wherein -W- is -CH2-.
[0610] 35A. The compound of embodiment 33A wherein RA is -CO2H or -CO2R8.
[0611] 36A. The compound of embodiment 33A wherein L1 is -UV-Z-, wherein -UV-
is defined
by -CH20-, -CH2-NH- or -C(=0)NH-, wherein Z is substituted or unsubstituted C1-
C6 alkylene,
wherein the alkylene is -CH(CH2-cyclopropyl)-, -CH(CH2-aryl) or -CH(CH2-
heteroaryl), wherein
the aryl or heteroaryl is unsubstituted or substituted with 1, 2, or 3
independently selected
substituted or unsubstituted C1-C4 alkyl or halogen.
[0612] 37A. The compound of embodiment 36A wherein said substituted or
unsubstituted C1"
C4 alkyl or halogen substituent or substituents of the aryl or heteroaryl of -
CH(CH2-aryl) or -
CH(CH2-heteroaryl) are selected from the group consisting of -CH3, -CF3, -F, -
Cl or -Br.
[0613] 38A. The compound of embodiment 33A, wherein L1 is -UV-Z- and wherein
RA is -
CO2H to which Z is attached to define -Ll-RA (i.e., -UV-Z-RA), wherein -UV- is
defined by -
- 126 -
CA 3046894 2019-06-18

C(=0)NH-, -WO- or -W-NH-, wherein -W- is -CH2-, and Z is -CH(CH2-aryl),
wherein the aryl is
substituted or unsubstituted, having the structure of one of
C C
H2 H2
0 OH [H, CI] 0 OH [H, F, Cl, CH3, CF3]
H
[H, F]
0
[0614] 0 OH [H, F, CI, Br, CH3,
CF3]
[0615] 39A. The compound of embodiment 36A wherein the -CH(CH2-aryl)
substituent of Z in
the -L1-R' is in the R configuration.
[0616] 40A. The compound of embodiment 33A wherein L1 is -UV-Z- and wherein RA
is -
002H to which Z is attached to define -L1-R' (i.e., -UV-Z-RA), wherein -UV- is
defined by -
C(=0)NH-, -WO- or -W-NH-, wherein -W- is -CH2 -, and Z is -CH(CH2-cyclopropyI)-
, having the
structure of
CA)"14v0x xv
H2
H2
00H 0
001-1 0 OH
[0617] 41A. The compound of embodiment 1A, 2A, 3A, or 4A, wherein the compound
has the
structure of Formula III
A6A2
LL-RA Formula III
[0618] A3 ,
wherein Al, A2 and A3 are
independently -N=, =N-, =CH- or -CH=.
- 127 -
CA 3046894 2019-06-18

[0619] 42A. The compound of embodiment 41A wherein Ring A wherein Ring A has
the
RE
",1µ11, ,NN(1,(µ ,)=1
N I N\ R_NE N
ppID D
c - R RC RD RC
N N RD
structure of one of: R , wherein
when L1 is C1-C6 alkylene, RD is -N(RF)-C(=0)XCH(RG)-CY, -N(RF)-C(=0)XC(RG)2-
CY, wherein
RF is -H, RG is -H or -CH3; RA is -CO2H or CO2RB, and Re is -H or -CH3, then
Ring A has the
N,_ e
R¨N N
N RD
structure of one of: -
[0620] 43A. The compound of embodiment 41A, wherein Ring A wherein Ring A has
the
RE
N, ,N
N\ RE¨N N N,Npp,D YNRD Nr.---
.S\ RD
C RC RD R- RD Rc
structure of one of: R
[0621] wherein Ring C is a substituted or unsubstituted arylene or
heteroarylene, L1 is 01-C6
alkylene, RA is -CO2H or CO2RB, RD is -N(RF)-C(=0)XCH(RG)-CY, -N(RF)-
C(=0)XC(RG)2-CY,
wherein RF is -H, RG is -CH3 and CY is substituted phenyl and Rc is - is -CN, -
F, -CI, -Br, -I, -
0C1-C4 alkyl, -C2-C4 alkyl, -C3-C6cycloalkyl, or -C2-C4 fluoroalkyl.
[0622] 44A. The compound of embodiment 41A, wherein Ring A has the structure
of one of:
RE
RD
N
N I
RN NJ\ I
RC RD Rc RD RD
c
[0623] R R
c , wherein Ring C is a
substituted or unsubstituted arylene or heteroarylene, L1 is C1-C6 alkylene,
RA is -CO2H or -
002R6, RD is -N(RF)-C(=0)XCH(RG)-CY, -N(RF)-C(=0)XC(RG)2-CY, wherein X is -0-,
RF is -CH3,
- 128 -
CA 3046894 2019-06-18

RG is -H or -CH3 and CY is substituted phenyl and RG is - is -H, -CN, -F, -Cl,
-Br, -I, -0C1-C4
alkyl, -C1-C4 alkyl, -C3-C6cycloalkyl, or -C1-C4 fluoroalkyl.
[0624] 45A. The compound of embodiment 1A, 2A or 5A wherein the compound has
the
RH
A1
A \ Ll¨RA Formula IV
structure of Formula IV ,
wherein Ring A has the
RE
E
" N
RY---NRD N¨NRD
R Rc RD Rc) R¨N
RD
structure of one of: Rc ,
wherein Al
is =N- or =C-; RD is -NRFC(=0)0CH(RG)-CY; L1 is -UV-Z-, wherein -UV- is
defined by -
C(=0)N(1:)-, wherein RJ is -H or -CH3; RF and RG independently are -H or -CH3;
and RA is -
CO2H or -CO2RB.
[0625] 46A. The compound of embodiment 2A wherein the compound has the
structure of
Formula VII
RH
111
o F
R
RG 0 Formula VI
[0626] RH
, wherein Ring A is a 5 membered
heteroarene having one of the structures of:
RE
,N
c
D R N"¨NRD
R c RD Rc RD
Rc ,
wherein RD is the -
- 129 -
CA 3046894 2019-06-18

N(RF)C(=0)CH(RG)-CY substituent of Formula VI wherein CY is phenyl substituted
with one RH,
and Rc is -H, -CH3, CF3 or -F; RA is -CO2H or -CO2RB; and RF and RG
independently are -H or -
CH3; and RH independently are -H, halogen, -CH3 or -CF3.
[0627] 47A. The compound of embodiment 2A wherein the compound has the
structure of
Formula VII
RH R\
Al N¨z
c \ A
0
N, F
0/ R Formula VII
RG
ORH .,
wherein A1 is =CH- or =N-;Ring A is a 5
membered heteroarene having the structure of one of:
RE
E N
N I
c 1:t Rc RD R __________ Nc) RDRD N¨NRD
)
Rc , wherein RD is the
-N(RF)C(0)CH(RG)CY substituent of Formula VII wherein CY is phenyl substituted
with one
RH; and RG is -H, -CH3, CF3 or -F; RA is -CO2H or -CO2RB; RE and RF
independently are -H or
C1-C4 alkyl; RG is -H or -CH3; RH independently are -H, halogen, -CH3 or -CF3;
and Z is C(RI)2,
wherein one RL is -H and the other RI- is -H or C1-04 alkyl.
- 130 -
CA 3046894 2019-06-18

[0628] 48A The compound of embodiment 2A wherein the compound has the
structure of
RH 1 R
110 A N¨z
\
W R=
RC
0./N"--RF Formula VIII
RG 0
Formula VIII RH
,wherein A' is =CH- or =N-;
wherein Ring A is a 5 membered heteroarene having the structure of one of
RE
I,
NiN, I 5=4_ RE
¨N
\N:5-j\RD
Rc RD RC) RD
Rc Rc ,
wherein RD is the -
N(RF)C(=0)CH(RG)-CY substituent of Formula VII wherein CY is phenyl
substituted with one RH;
RA is -CO2H or -0O2R8; W is -C(RL)2- or _________________________________ ;
RE and RF independently are -H or C1-C4
alkyl; RG is -H or -CH3; RH independently are -H, halogen, -CH3 or -CF3; and Z
is -C(RL)2,
wherein one RL is -H and the other RL is -H or C1-C4 alkyl.
- 131 -
CA 3046894 2019-06-18

[0629] 49A. The compound of embodiment 2A wherein the compound has the
structure of
RE1A1 RA
0-Z
W
RC
0./Ns-RE Formula IX
RG 0
Formula IX 4111 RH ,
wherein A1 is =CH- or =N-;
wherein Ring A is a 5 membered heteroarene having the structure of one of
RIE
RN
NI-JN
c R Rc R RC R
c
[0630] R R
[0631] wherein RD is the -N(RE)C(=0)CH(RG)-CY substituent of Formula VII
wherein CY is
phenyl substituted with one RH; RA is -CO2H or -CO2RE;
[0632] wherein W is -C(R1)2- or _________________________________________ ;
RE and RE independently are -H or C1-C4 alkyl; RG
is -H or -CH3; RH independently are -H, halogen, -CH3 or -C F3, and Z is -
C(RL)2, wherein one RL
is -H and the other RL is -H or C1-a4 alkyl.
- 132 -
CA 3046894 2019-06-18

[0633] 50A. The compound of embodiment 2A wherein the compound has the
structure of
RH RH
A'
Formula XII
RC
0/ RF
RG 0
1.1 RH
Formula XII
,wherein A1 is =CH-
or =N-; wherein Ring A is a 5 membered heteroarene having the structure of one
of
RE
,N
rµ1,\ I N, r RE¨N N
D
R RC RD RC RD
Re Re ,
wherein RD is the -
N(RF)C(=0)CH(RG)-CY substituent of Formula VII wherein CY is phenyl
substituted with one RH;
)Xs
RA is -CO2H or -CO2RB; wherein W is -C(R1)2- or _________________________ ;
RE and RF independently are -H or
C1-C4 alkyl; RG is -H or -CH3; RH independently are -H, halogen, -CH3 or -CF3;
and Z is -C(RL)2,
wherein one RL is -H and the other RL is -H or C1-C4 alkyl.
[0634] 51A The compound of embodiment 2A wherein the compound is selected from
Table
1.
[0635] 52A. The compound of embodiment 51A wherein the compound is 1-(4-{4-[1-
(2-
Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yll-benzoylamino)-
cyclopropanecarboxylic acid, 2-(4-{441-(2-Chloro-phenyl)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzoylamino)-indan-2-carboxylic acid, 2-(S)-(4-{4-[(R,S)-1-(2-
Chloro-phenyl)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino) phenyl acetic acid,
2-(R)-(4-{4-
[(R,S)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino) phenyl
- 133 -
CA 3046894 2019-06-18

propanoic acid,
2(R)-[[4-[3-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]-3-phenyl-propanoic acid,
2(S)4[4-[3-methy1-4-((R)-1-
phenylethoxycarbonylamino)isoxazol-5-yl]benzoyliamino]-3-phenyl-propanoic
acid, (R)-24[4-
[2, 5-dim ethy1-4-((R)-1-phenylethoxycarbonyla mino) pyrazol-3-
yl]benzoyl]amino]-3-phenyl-
propanoic acid, (R)-
2-[[4-[1 , 5-di methy1-4-((R)-1-phenylethoxycarbonyla mi no) pyrazol-3-
yl]benzoyljamino]-3-phenyl-propanoic acid, (R)-
24[442,5-dimethy1-44(R)-1-
phenylethoxycarbonylamino)pyrazol-3-yl]benzoyliamino]-3-(4-
fluorophenyl)propanoic acid, (R)-
2-[[4-[1, 5-di m ethy1-44(R)-1-phenylethoxycarbonyl amino) pyrazol-3-
ylibenzoyl]am ino]-3-(4-
fluorophenyl)propanoic acid, (R)- 3-
(4-bromopheny1)-2-[[442,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid,
(R)- 3-(4-
bromopheny1)-2-[[4-[1,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-amino)pyrazol-3-
ylibenzoyliamino]propanoic acid, (R)-
3-(4-chloropheny1)-24[442,5-dirnethyl-44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-ylibenzoyl]amino]propanoic acid,
(R)- 3-(4-
chloropheny1)-24[441 ,5-dim ethy1-4-((R)-1- phenylethoxycarbonyl-ami no)
pyrazol-3-
yl]benzoyliamino]propanoic acid, (R)- 3-(3,4-difluoropheny1)-2-[[442,5-
dimethy1-44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyliamino]propanoic acid,
(R)- 3-(3,4-
difluoropheny1)-2-[[4-[1 , 5-dim ethyl-4-((R)- 1-phenylethoxycarbonyl-a mi no)
pyrazol-3-
ylibenzoyliamino]propanoic acid, (R)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-yll-benzoylamino)-3-cyclopropyl-propionic acid, (R)-2-{443-
Methy1-4-((S)-1-
phenyl-ethoxycarbonylamino)-isoxazol-5-yli-benzoylaminol-3-phenyl-propionic
acid, (S)-2-{443-
Methy1-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yli-benzoylamino}-3-
phenyl-propionic
acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-3-phenyl-propionic acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(4-fluoro-pheny1)-
propionic acid,
(R)-3-(4-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-yll-benzoylamino)-propionic
acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
- 134 -
CA 3046894 2019-06-18

ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(3,4-difluoro-
pheny1)-propionic
acid, (R)-
3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylarnino]-3-
methyl-
isoxazol-5-ylybenzoylarnino)-propionic acid, (R)-3-(4-Bromo-pheny1)-2-(4-{4-
[(R)-1-(2-chloro-
pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic
acid, (R)-3-(4-
Bromo-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-propionic acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-y1}-benzoylamino)-3-(2-fluoro-pheny1)-propionic acid, (R)-
2-(4-{4-[(R)-1-(2-
Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-ylybenzoylamino)-3-p-
tolyl-propionic
acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-3-(4-trifluoromethyl-pheny1)-propionic acid, (R)-2-(4-{4-[(R)-1-
(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-3-(4-cyano-pheny1)-
propionic acid,
(R)- 2-
(4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-methyl-pyrazol-1-y1}-
benzoylamino)-3-phenyl-propionic acid, (R)-
2-{443-Methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzylamino}-3-phenyl-propionic acid, (R)-
3-(2- Fluoro-
pheny1)-2-{443-methy1-4-(( -phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-
benzylamino}-
propionic acid, (R)-
2-{4-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylam ino)-isoxazol-5-y1]-
benzylamino}-3-(4-trifluoromethyl-pheny1)-propionic acid, (R)-3-Cyclopropy1-2-
{4-(3-methyl-4-
((R)-1-phenyl-ethoxycarbonylam ino)-isoxazol-5-y1]-benzylamino}-propionic
acid, (R)-3- (2-
Chloro-pheny1)-2-{443-methy1-4- ((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-
y1]-
benzylamino}-propionic acid, (R)-
3-(4-Chloro-pheny1)-2-{4-[3-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzylaminol-propionic acid, (R)- 2-(4-{4-
[(R)-1-(2-Chloro-
pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-phenyl-
propionic acid,
(R)- 2-
(4-{4-[(R)_1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzylamino)-3-(2-fluoro-pheny1)-propionic acid, (R)-
2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-(4-trifluoromethyl-
pheny1)-
propionic acid, (R)- 3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-
- 135 -
CA 3046894 2019-06-18

3-methyl-isoxazol-5-y1}-benzylamino)-propionic
acid, (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-3-cyclopropyl-
propionic acid, 2-{4-
[3-Methy1-44(R)-1-phenyl-ethoxycarbonylam inoyisoxazol-5-y1}-benzyloxy}-3-
phenyl-propionic
acid,
(RS)-3-Cyclopropy1-2-{443-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-y1]-
benzyloxy}-propionic acid,
(RS)-3-Cyclopropy1-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzyloxy}-propionic acid, 2-
[4-[4-[5-[1-(2-
chlorophenyl)ethoxycarbonylamino]-4-cyano-pyrazol-1-yliphenyl]phenyliacetic
acid, (R)-1-(444-
[1, 5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenylicyclopropane
carboxylic acid, (R)-
144-[442,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yliphenyliphenyl]cyclopropane carboxylic
acid, (R)-1-(4'-{541-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-3-fluoro-bipheny1-4-y1)-
cyclopropanecarboxylic acid,
(R)-1-(4-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-
fluoro-bipheny1-
4-y1)-cyclopropanecarboxylic acid, (R)-
1-(2-Chloro-4'-{5-[1-(2-chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-bipheny1-4-y1)-
cyclopropanecarboxylic acid, (R)-1-
(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-y1}-2-
methyl-bipheny1-4-y1)-
cyclopropanecarboxylic acid, (R)-1-(4'-{541-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-
pyrazol-1-y1}-bipheny1-4-y1)-cyclopropanecarboxylic acid, (R)-
144'4541-Phenyl-
ethoxycarbonylam ino)-4-trifl uoromethyl-pyrazol-1-y1]-bipheny1-4-y1}-
cyclopropanecarboxylic acid,
(R)-1-{2-Fluoro-4.45-(1-phenyl-ethoxycarbonylam ino)-4-trifluoromethyl-pyrazol-
1-y1]- biphenyl-4-
ylycyclopropanecarboxylic acid, (R)-1-(4-{545-(1-Phenykethoxycarbonylamino)-
pyrazol-1-y1}-
pyridin-2-y1}-pheny1)-cyclopropanecarboxylic acid.
[0636] 53A. A compound of any one of embodiments 1A-52A for preparation of
mendicant for
treating a LPA-dependent disease or condition.
[0637] The compounds of Table 1 are exemplary of the invention but not
limiting, wherein
compounds 57-458 are prepared according to the appropriately modified
procedures of the
examples for preparation of compounds 1-458.
- 136 -
CA 3046894 2019-06-18

[0638] TABLE 1
Cpd Name
1 1-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-cyclopropanecarboxylic acid
2 2-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yll-
benzoylamino)-indan-2-carboxylic acid
3 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino) phenyl acetic acid
4 2-(R)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino) phenyl propanoic acid
2(R)-[[4-[3-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoynamino]-3-
phenyl-propanoic acid
6 2(S)-[[4-[3-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyliamino]-3-
phenyl-propanoic acid
7 (R)-24[442,5-dimethy1-4-((R)-1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-
3-phenyl-propanoic acid
8 (R)-24[441,5-dimethy1-44(R)-1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-
3-phenyl-propanoic acid
9 (R)-2-[[4-[2,5-dimethy1-4-((R)-1-phenylethoxycarbonylamino)pyrazol-3-
ylibenzoyliamino]-
3-(4-fluorophenyl)propanoic acid
(R)-24[441,5-dimethy1-44(R)-1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-
3-(4-fluorophenyl)propanoic acid
11 (R)- 3-(4-bromopheny1)-24[442,5-dimethy1-44(R)-1-phenylethoxycarbonyl-
amino)Pyrazol-
3-ylibenzoyl]amino]propanoic acid
12 (R)- 3-(4-bromopheny1)-24[441,5-dimethy1-44(R)-1-phenylethoxycarbonyl-
amino)pyrazol-
- 137 -
CA 3046894 2019-06-18

3-yllbenzoyl]amino]propanoic acid
13 (R)- 3-(4-chloropheny1)-2-[[4-[2,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-
3-yl]benzoyl]amino]propanoic acid
14 (R)- 3-(4-chloropheny1)-2-[[441,5-dimethy1-4-((R)-1-phenylethoxycarbonyl-
amino)pyrazol-
3-yl]benzoyl]amino]propanoic acid
15 (R)- 3-(3,4-difluoropheny1)-24[442,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-
amino)pyrazol-3-yl]benzoyl]amino]propanoic acid
16 (R)- 3-(3,4-difluoropheny1)-24[441,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-
amino)pyrazol-3-yl]benzoyl]amino]propanoic acid
17 (R)-2-(4-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-cyclopropyl-propionic acid
18 (R)-2-{443-Methy1-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-
benzoylamino}-3-
phenyl-propionic acid
19 (S)-2-{443-Methy1-44(S)-1-phenyl-ethoxycarbonylaminoyisoxazol-5-y1]-
benzoylamino}-3-
phenyl-propionic acid
20 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-
5-y1}-
benzoylamino)-3-phenyl-propionic acid
21 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-(4-fluoro-pheny1)-propionic acid
22 (R)-3-(4-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino)-propionic acid
23 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-(3,4-difluoro-pheny1)-propionic acid
24 (R)-3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino)-propionic acid
- 138 -
CA 3046894 2019-06-18

25 (R)-3-(4-Bromo-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino)-propionic acid
26 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-(2-fluoro-phenyl)-propionic acid
27 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-p-tolyl-propionic acid
28 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-(4-trifluoromethyl-phenyl)-propionic acid
29 (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-3-(4-cyano-pheny1)-propionic acid
30 (R)- 2-(4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-methyl-
pyrazol-1-y1}-
benzoylamino)-3-phenyl-propionic acid
31 (R)-2-{443-Methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-
benzylamino}-3-
phenyl-propionic acid
32 (R)-3-(2-Fluoro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-
y1]-benzylamino}-propionic acid
33 (R)-2-{4-[3-Methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-
benzylamino}-3-
(4-trifluoromethyl-pheny1)-propionic acid
34 (R)-3-Cyclopropy1-2-{443-methy1-44(R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-yli-
benzylamino}-propionic acid
35 (R)-3-(2-Chloro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-
y1]-benzylamino}-propionic acid
36 (R)-3-(4-Chloro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-
A-benzylarnino}-propionic acid
37 (R)- 2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1)-
- 139 -
CA 3046894 2019-06-18

benzylamino)-3-phenyl-propionic acid
38 (R)- 2-(4-{4-[(R)_1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzylamino)-3-(2-fluoro-phenyl)-propionic acid
39 (R)- 2-(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzylamino)-344-trifluoromethyl-phenyl)-propionic acid
40 (R)- 3-(2-Chloro-phenyl)-2-(4-{4-[(R)-1-(2-chloro-phenyl)-
ethoxycarbonylamino1-3-methyl-
isoxazol-5-y1}-benzylamino)-propionic acid
41 (R)-2-(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-yll-
benzylamino)-3-cyclopropyl-propionic acid
42 2-{443-Methyl-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yll-benzyloxy}-
3-phenyl-
propionic acid
43 2-{443-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yli-
benzyloxy}-3-phenyl-
propionic acid
44 (RS)-3-Cyclopropy1-2-{4-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-y1]-
benzyloxy}-propionic acid
45 (RS)-3-(4-Chloro-phenyl)-2-{443-methyl-44(R)-1-phenyl-ethoxycarbonyloxy)-
isoxazol-5-
y1]-benzyloxy}-propionic acid
46 244444541-(2-chlorophenypethoxycarbonylamino]-4-cyano-pyrazol-1-
yliphenyl]phenyliacetic acid
47 (R)-144-[411,5-dimethyl-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yliphenyliphenyl]cyclopropane carboxylic acid
48 (R)-1-[4-[4-[2,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenyl]cyclopropane carboxylic acid
49 (R)-1-(4'-{541-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-
y1}-3-fluoro-
biphenyl-4-y1)-cyclopropanecarboxylic acid
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CA 3046894 2019-06-18

50 (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-
y11-2-fluoro-
biphenyl-4-y1)-cyclopropanecarboxylic acid
51 (R)-1-(2-Chloro-4'-{5-[ 1-(2-chloro-pheny1)-ethoxycarbonylamino]-4-
fluoro-pyrazol-1-y1}-
biphenyl-4-y1)-cyclopropanecarboxylic acid
52 (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-
A-2-methyl-
biphenyl-4-y1)-cyclopropanecarboxylic acid
53 (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-
y1}-biphenyl-4-
y1)-cyclopropanecarboxylic acid
54 (R)- 1-{4'-[5-(1-Phenyl-ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-
y1]-biphenyl-4-
y1}-cyclopropanecarboxylic acid
55 (R)-1-{2-Fluoro-4'45-(1-phenykethoxycarbonylamino)-4-trifluoromethyl-
pyrazol-1-y1]-
biphenyl-4-y1}-cyclopropanecarboxylic acid
56 (R)-1-(4-{545-(1-Phenyl-ethoxycarbonylamino)-pyrazol-1-y1]-pyridin-2-y1}-
pheny1)-
cyclopropanecarboxylic acid
57 24[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-Abenzoyliamino]-3-
phenyl-
propanoic acid
58 3-cyclopropy1-24[4-[3-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]propanoic acid
59 24[4-[3-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]-
3-phenoxy-
propanoic acid
60 24[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoyliamino]-4-
phenyl-
butanoic acid
61 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyliamino]-
3-phenyl-propanoic acid
62 24[44441-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoylJamino]-
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CA 3046894 2019-06-18

3-cyclopropyl-propanoic acid
63 24[44441-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyliamino]-
4-phenyl-butanoic acid
64 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyliamino]-
3-phenoxy-propanoic acid
65 24[44441-(2-fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyl]amino]-
4-phenyl-butanoic acid
66 21[44441-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyl]amino]-
3-phenoxy-propanoic acid
67 3-cyclopropy1-2-[[44441-(2-fluorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-
yl]benzoyl]amino]propanoic acid
68 24[44441-(2-fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyl]amino]-
3-phenyl-propanoic acid
69 3-(4-methoxypheny1)-2-[[4-[3-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-
5-
yl]benzoyl]amino]propanoic acid
70 3-(4-fluoropheny1)-21[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]propanoic acid
71 3-(2,6-difluoropheny1)-2-[[4-[3-methy1-4-(1-
phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyliamino]propanoic acid
72 3-(3-cyanopheny1)-2-[[4-[3-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]propanoic acid
73 3-(2-chloropheny1)-24[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-
ylibenzoyflamino]propanoic acid
74 3-(4-chloropheny1)-2-[[4-[3-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-
5-
yl]benzoyl]amino]propanoic acid
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CA 3046894 2019-06-18

75 24[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoyl]amino]-
344-
(trifluoromethyl)phenyl]propanoic acid
76 3-(4-hydrowheny1)-2-[[443-methyl-4-(1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyliamino]propanoic acid
77 3-(3,4-difluoropheny1)-2-[[4-[3-methyl-4-(1-phenylethoxycarbonylam
ino)isoxazol-5-
yl]benzoyl]amino]propanoic acid
78 3-(4-bromopheny1)-24[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyliamino]propanoic acid
79 24[443-methy1-4-(1-phenylethoxycarbonylamino)isoxazol-5-ylibenzoyliamino]-
344-
(trifluoromethoxy)phenyljpropanoic acid
80 2-[[44441-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyl]amino]-
3-(4-methoxyphenyl)propanoic acid
81 24[44441-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyl]amino]-
3-(4-fluorophenyl)propanoic acid
82 24[44441 -(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyliamino]-
3-(2,6-difluorophenyl)propanoic acid
83 24[44441 -(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyliamino]-
3-(3-cyanophenyl)propanoic acid
84 3-(2-chloropheny1)-24[444-(1-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-
isoxazol-5-
yl]benzoyl]amino]propanoic acid
85 3-(4-chloropheny1)-24[44441-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-
isoxazol-5-
yl]benzoyl]amino]propanoic acid
86 2-[[444-[1-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyliamino]-
344-(trifluoromethyl)phenyl]propanoic acid
87 24[444-[ 1 -(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyl]amino]-
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CA 3046894 2019-06-18

3-(4-hydroxyphenyl)propanoic acid
88 3-(4-bromopheny1)-24[44441-(2-chlorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-
ylibenzoyl]amino]propanoic acid
89 24[44441-(2-chlorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylpenzoyliamino]-
3-(3,4-difluorophenyl)propanoic acid
90 2-[[44441-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyliamino]-
344-(trifluoromethoxy)phenyl]propanoic acid
91 24[44441-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyliamino]-
3-(4-methoxyphenyl)propanoic acid
92 3-(4-fluoropheny1)-24[44441-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-
isoxazol-5-
ylpenzoyl]amino]propanoic acid
93 3-(2,6-difluoropheny1)-2-[[44441-(2-fluorophenypethoxycarbonylamino]-3-
methyl-
isoxazol-5-ylpenzoyl]amino]propanoic acid
94 3-(3-cyanopheny1)-24[44441 -(2-fluorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-
ylibenzoyl]amino]propanoic acid
95 3-(2-chloropheny1)-24[444-[ 1 -(2-fluorophenyl)ethoxycarbonylarnino]-3-
methyl-isoxazol-5-
ylpenzoyl]amino]propanoic acid
96 3-(4-chloropheny1)-24[44441-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-
isoxazol-5-
ylpenzoyl]amino]propanoic acid
97 24[44441 -(2-fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylpenzoyl]amino]-
344-(trifluoromethyl)phenylipropanoic acid
98 24[44441 -(2-fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
yl]benzoyllamino]-
3-(4-hydroxyphenyl)propanoic acid
99 3-(3,4-difluoropheny1)-24[44441 -(2-fluorophenyl)ethoxycarbonylamino1-3-
methyl-
isoxazol-5-yl]benzoyl]annino]propanoic acid
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CA 3046894 2019-06-18

100 3-(4-bromopheny1)-24[44441-(2-fluorophenypethoxycarbonylamino]-3-methyl-
isoxazol-5-
yl]benzoyljamino]propanoic acid
101 2-[[44441-(2-fluorophenypethoxycarbonylamino]-3-methyl-isoxazol-5-
ylibenzoyliamino]-
344-(trifluoromethoxy)phenyl]propanoic acid
102 24[441,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]-3-(4-
methoxyphenyl)propanoic acid
103 24[441,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
ylibenzoyliamino]-3-(4-
fluorophenyppropanoic acid
104 3-(2,6-difluoropheny1)-2-[[4-[1,5-dimethyl-4-(1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]propanoic acid
105 3-(3-cyanopheny1)-24[441,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-
3-
ylibenzoyl]amino]propanoic acid
106 3-(2-chloropheny1)-2-[[4-[1,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]propanoic acid
107 3-(4-chloropheny1)-2-[[4-[1,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]propanoic acid
108 24[441,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-[4-
(trifluoromethyl)phenyl]propanoic acid
109 24[441,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-(4-
hydroxyphenyl)propanoic acid
110 3-(3,4-difluoropheny1)-2-[[4-[1,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]propanoic acid
111 3-(4-bromopheny1)-24[441,5-dimethyl-4-(1-phenylethoxycarbonylamino)pyrazol-
3-
yl]benzoyliamino]propanoic acid
112 24[441,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyliamino]-344-
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CA 3046894 2019-06-18

(trifluoromethoxy)phenyl]propanoic acid
113 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-1, 5-di methyl-pyrazol-
3-
yl]benzoyl]amino]-3-(4-methoxyphenyl)propanoic acid
114 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylam ino]-1,5-dimethyl-pyrazol-
3-
yl]benzoyl]amino]-3-(4-fluorophenyl)propanoic acid
115 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-1, 5-dimethyl- pyrazol-
3-
yl]benzoyl]amino]-3-(2,6-difluorophenyl)propanoic acid
116 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylam ino]-1,5-dimethyl-pyrazol-
3-
yl]benzoyl]amino]-3-(3-cyanophenyl)propanoic acid
117 3-(2-chlorophenyI)-2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-1,
5-di methyl-
pyrazol-3-yl]benzoyl]amino]propanoic acid
118 3-(4-chlorophenyI)-2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylami no]-
1, 5-dimethyl-
pyrazol-3-yl]benzoyl]amino]propanoic acid
119 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylam ino]-1,5-dimethyl-pyrazol-
3-
yl]benzoyl]amino]-344-(trifluoromethyl)phenyl]propanoic acid
120 2-[[444-[1 -(2-chlorophenypethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyllamino]-3-(4-hydroxyphenyl)propanoic acid
121 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-1, 5-dimethyl- pyrazol-
3-
yl]benzoyl]amino]-3-(3,4-difluorophenyl)propanoic acid
122 3-(4-bromophenyI)-2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-1,5-
dimethyl-
pyrazol-3-yl]benzoyl]amino]propanoic acid
123 2-[[4-[4-[1-(2-chlorophenyl)ethoxycarbonylam ino]-1,5-dimethyl-pyrazol-
3-
yl]benzoyl]amino]-344-(trifluoromethoxy)phenyl]propanoic acid
124 2-[[4-[4-[1-(2-fluorophenyl)ethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyl]amino]-3-(4-methoxyphenyl)propanoic acid
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CA 3046894 2019-06-18

125 3-(4-fluoropheny1)-24[44441-(2-fluorophenypethoxycarbonylamino]-1,5-
dimethyl-pyrazol-
3-ylibenzoyliamino]propanoic acid
126 3-(2,6-difluoropheny1)-2-[[44441-(2-fluorophenyl)ethoxycarbonylamino]-1,5-
dimethyl-
pyrazol-3-yl]benzoyl]amino]propanoic acid
127 3-(3-cyanopheny1)-24[4-[441-(2-fluorophenypethoxycarbonylamino]-1,5-
dimethyl-pyrazol-
3-yl]benzoyl]amino]propanoic acid
128 3-(2-chloropheny1)-24[444-0-(2-fluorophenyl)ethoxycarbonylamino]-1,5-
dimethyl-pyrazol-
3-ylibenzoyliamino]propanoic acid
129 3-(4-chloropheny1)-24[44441-(2-fluorophenypethoxycarbonylamino]-1,5-
dimethyl-pyrazol-
3-yl]benzoyl]amino]propanoic acid
130 24[44441-(2-fluorophenypethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyl]amino]-344-(trifluoromethyl)phenyl]propanoic acid
131 24[44441-(2-fluorophenypethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyliamino]-3-(4-hydroxyphenyl)propanoic acid
132 3-(3,4-difluoropheny1)-2-[[44441-(2-fluorophenyl)ethoxycarbonylamino]-1,5-
dimethyl-
pyrazol-3-yl]benzoyliamino]propanoic acid
133 3-(4-bromopheny1)-24[44441-(2-fluorophenypethoxycarbonylamino]-1,5-
dimethyl-
pyrazol-3-yl]benzoyliamino]propanoic acid
134 2-[[4-[4-[1-(2-fluorophenyl)ethoxycarbonylamino]-1,5-dimethyl-pyrazol-3-
yl]benzoyl]amino]-344-(trifluoromethoxy)phenyl]propanoic acid
135 2-{p-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]benzoylamino}-
3-
phenylpropionic acid
136 2-(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}benzoylamino)-3-
phenylpropionic acid
137 3-Cyclopropy1-2-{p43-fluoro-4-(1-phenylethoxycarbonylamino)-5-
- 147 -
CA 3046894 2019-06-18

isoxazolypenzoylamino}propionic acid
138 2-(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}benzoylamino)-3-
cyclopropylpropionic acid
139 24({p43-Fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyllmethyDamino]-3-
phenylpropionic acid
140 2-([(p-{4-[1-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}phenyl)methyl]amino}-3-phenylpropionic acid
141 3-Cyclopropy1-2-[({p-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methyDaminolpropionic acid
142 2-{[(p-{411-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazoly1}phenyl)methyliamino}-3-cyclopropylpropionic acid
143 2-({p43-Fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyliphenyl}methoxy)-3-
phenylpropionic acid
144 2-[(p-{4-[1-(o-ChlorophenyDethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}phenyl)methoxy]-
3-phenylpropionic acid
145 3-Cyclopropy1-2-({p-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methoxy)propionic acid
146 2-[(p-{4-[1-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}phenyDrnethoxy]-
3-cyclopropylpropionic acid
147 2-{p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolypenzoylamino}-3-
phenylpropionic acid
148 2-(p-{4-[l-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}benzoylamino)-3-
phenylpropionic acid
149 2-(p13-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolypenzoylamino}-3-
cyclopropylpropionic acid
- 148 -
CA 3046894 2019-06-18

150 2-(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}benzoylamino)-3-
cyclopropylpropionic acid
151 2-[({p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methyl)amino]-3-
phenylpropionic acid
152 2-{[(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methyl]amino}-3-phenylpropionic acid
153 2-[({p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyliphenyl}methypamino]-3-
cyclopropylpropionic acid
154 2-{[(p-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methyl]amino}-3-cyclopropylpropionic acid
155 2-({p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyliphenyl}methoxy)-
3-
phenylpropionic acid
156 2-[(p-{4-[1-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methoxy]-
3-phenylpropionic acid
157 2-({p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methoxy)-3-
cyclopropylpropionic acid
158 2-[(p-{4-[1-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methoxy]-
3-cyclopropylpropionic acid
159 2-Benzy1-3-{5-[3-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylaminolpropionic acid
160 2-Benzy1-3-(5-{441-(o-chlorophenypethoxycarbonylamino]-3-methy1-5-
isoxazoly1}-2-
pyridylamino)propionic acid
161 2-(Cyclopropylmethyl)-3-{543-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridylamino}propionic acid
162 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridylamino)-
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CA 3046894 2019-06-18

2-(cyclopropylmethyl)propionic acid
163 2-Benzy1-3-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyloxy}propionic acid
164 2-Benzy1-3-(5-{441-(o-chlorophenyl)ethoxycarbonylamino1-3-methy1-5-
isoxazoly1}-2-
pyridyloxy)propionic acid
165 2-(Cyclopropylmethyl)-3-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly11-2-
pyridyloxy}propionic acid
166 3-(5-{4-[1-(o-Chloropheny)ethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridyloxy)-2-
(cyclopropylmethyl)propionic acid
167 2-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
Pyridylamino}-3-
phenylpropionic acid
168 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridylamino)-
3-phenylpropionic acid
169 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridylamino)-
3-cyclopropylpropionic acid
170 2-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-
3-
phenylpropionic acid
171 2-(5-{441-(o-Chlorophenypethoxycarbonylamino}-3-methy1-5-isoxazoly1}-2-
pyridyloxy)-3-
phenylpropionic acid
172 3-Cyclopropy1-2-{5-[3-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
pyridyloxy}propionic acid
173 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridyloxy)-3-
cyclopropylpropionic acid
174 2-Benzy1-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}propionic acid
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CA 3046894 2019-06-18

175 2-Benzy1-3-(5-{441-(o-chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazoly1}-2-
pyridylamino)propionic acid
176 2-(Cyclopropylmethyl)-3-{5-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridylaminolpropionic acid
177 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-
pyridylamino)-
2-(cyclopropylmethyl)propionic acid
178 2-Benzy1-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyloxy}propionic acid
179 2-Benzy1-3-(5-{441-(o-chlorophenypethoxycarbonylamino]-3-fluoro-5-
isoxazoly1}-2-
pyridyloxy)propionic acid
180 2-(Cyclopropylmethyl)-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridyloxy}propionic acid
181 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-
pyridyloxy)-2-
(cyclopropylmethyl)propionic acid
182 2-{5-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-
pyridylamino}-3-
phenylpropionic acid
183 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridylamino)-
3-phenylpropionic acid
184 3-Cyclopropy1-2-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
pyridylamino}propionic acid
185 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridylamino)-
3-cyclopropylpropionic acid
186 2-{543-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-
3-
phenylpropionic acid
187 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-
pyridyloxy)-3-
- 151 -
CA 3046894 2019-06-18

phenylpropionic acid
188 3-Cyclopropy1-2-{5-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-
2-
pyridyloxy}propionic acid
189 2-(5-{4-[1-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-
pyridyloxy)-3-
cyclopropylpropionic acid
190 2-Benzy1-3-{5-[3-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-
pyridylamino}propionic acid
191 2-Benzy1-3-(5-{4-0-(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-
pyridylamino)propionic acid
192 3-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-2-
(cyclopropylmethyppropionic acid
193 3-(5-{4-[1-(o-ChlorophenyDethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridylamino)-
2-(cyclopropylmethyl)propionic acid
194 2-Benzy1-3-{5-[3-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-
pyridyloxy}propionic acid
195 2-Benzy1-3-(5-{4-[1-(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-
pyridyloxy)propionic acid
196 3-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-2-
(cyclopropylmethyl)propionic acid
197 3-(5-{411-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridyloxy)-2-
(cyclopropylmethyl)propionic acid
198 2-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-3-
phenylpropionic acid
199 2-(5-{4-[1-(o-Chlorophenyl)ethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridylamino)-
3-phenylpropionic acid
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CA 3046894 2019-06-18

200 2-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-3-
cyclopropylpropionic acid
201 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly11-2-
pyridylamino)-
3-cyclopropylpropionic acid
202 2-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-
phenylpropionic acid
203 2-(5-{4-[1-(o-ChlorophenyDethoxycarbonylamino]-3-cyano-5-isoxazoly11-2-
pyridyloxy)-3-
phenylpropionic acid
204 2-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-
cyclopropylpropionic acid
205 2-(5-{4-[1-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridyloxy)-3-
cyclopropylpropionic acid
206 2-{p-p-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolypenzoylamino}-3-
phenylpropionic acid
207 2-(p-{441-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}benzoylamino)-3-
phenylpropionic acid
208 3-Cyclopropy1-2-{p-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]benzoylaminolpropionic acid
209 2-(p-{4-[1-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazolyilbenzoylamino)-3-
cyclopropylpropionic acid
210 2-[({p43-Fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyliphenyllmethyDamino]-3-
phenylpropionic acid
211 2-{[(p-{4-[1-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}phenyl)methyl]amino}-3-phenylpropionic acid
212 3-Cyclopropy1-24({p43-fluoro-4-(1-phenylethoxycarbonylamino)-5-
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CA 3046894 2019-06-18

isoxazolyl]phenyl}methyl)amino]propionic acid
213 2-{[(p-{441-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}phenyl)methyljamino}-3-cyclopropylpropionic acid
214 2-({p43-Fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methoxy)-3-
phenylpropionic acid
215 2-[(p-{4-0-(o-Chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazolyl}phenyl)methoxy]-
3-phenylpropionic acid
216 3-Cyclopropy1-2-({p43-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methoxy)propionic acid
217 2-[(p-{4-[1-(o-Chlorophenyl)ethoxycarbonylarnino]-3-fluoro-5-
isoxazolyl}phenyl)rnethoxy]-
3-cyclopropylpropionic acid
218 2-{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]benzoylamino}-3-
phenylpropionic acid
219 2-(p-{441-(o-Chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazolyl}benzoylamino)-3-
phenylpropionic acid
220 2-{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolylibenzoylamino}-3-
cyclopropylpropionic acid
221 2-(p-{4-[1-(o-Chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazolyl}benzoylamino)-3-
cyclopropylpropionic acid
222 24({p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methyl)amino]-3-
phenylpropionic acid
223 2-{[(p-{441-(o-Chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methyljamino}-3-phenylpropionic acid
224 24({p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methyl)amino]-3-
cyclopropylpropionic acid
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CA 3046894 2019-06-18

225 2-{Rp-{4-[1-(o-ChlorophenyDethoxycarbonylamino]-3-cyano-5-
isoxazolyl}phenyl)methyllamino}-3-cyclopropylpropionic acid
226 2-({p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methoxy)-3-
phenylpropionic acid
227 2-Rp-{4-[1-(o-Chlorophenypethoxycarbonylarnino]-3-cyano-5-
isoxazoly1}phenyl)methoxy]-
3-phenylpropionic acid
228 2-({p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methoxy)-3-
cyclopropylpropionic acid
229 2-Rp-{4-[1-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-
isoxazoly1}phenyl)methoxy]-
3-cyclopropylpropionic acid
230 2-Benzy1-3-{543-methyl-4-(1-phenylethoxycarbonylamino)-5-isoxazoly11-2-
pyridylaminolpropionic acid
231 2-Benzy1-3-(5-{411-(o-chlorophenyi)ethoxycarbonylamino]-3-methyl-5-
isoxazoly1}-2-
pyridylamino)propionic acid
232 2-(Cyclopropylmethyl)-3-{513-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridylamino}propionic acid
233 3-(5-{4-[1-(o-Chlorophenyl)ethoxycarbonylamino]-3-methyl-5-isoxazoly1}-2-
pyridylamino)-
2-(cyclopropylmethyDpropionic acid
234 2-Benzy1-3-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridyloxylpropionic acid
235 2-Benzy1-3-(5-{4-[1-(o-chlorophenypethoxycarbonylarnino]-3-methyl-5-
isoxazoly1}-2-
pyridyloxy)propionic acid
236 2-(Cyclopropylmethyl)-3-{543-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridyloxy}propionic acid
237 3-(5-{4-[1-(o-ChlorophenyDethoxycarbonylamino]-3-methyl-5-isoxazoly1}-2-
pyridyloxy)-2-
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(cyclopropylmethyl)propionic acid
238 2-{5-[3-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-3-
phenylpropionic acid
239 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridylamino)-
3-phenylpropionic acid
240 3-Cyclopropy1-2-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly11-
2-
pyridylamino}propionic acid
241 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridylamino)-
3-cyclopropylpropionic acid
242 2-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-
3-
phenylpropionic acid
243 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridyloxy)-3-
phenylpropionic acid
244 3-Cyclopropy1-2-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
pyridyloxy}propionic acid
245 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-methy1-5-isoxazoly1}-2-
pyridyloxy)-3-
cyclopropylpropionic acid
246 2-Benzy1-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylaminolpropionic acid
247 2-Benzy1-3-(5-{4-[1-(o-chlorophenyl)ethoxycarbonylamino]-3-fluoro-5-
isoxazoly1}-2-
pyridylamino)propionic acid
248 2-(Cyclopropylmethyl)-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridylaminolpropionic acid
249 3-(5-{441-(o-Chloropheny)ethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridylamino)-
2-(cyclopropylmethyl)propionic acid
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250 2-Benzy1-3-{5-[3-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-
pyridyloxy}propionic acid
251 2-Benzy1-3-(5-{441-(o-chlorophenypethoxycarbonylamino]-3-fluoro-5-
isoxazoly1}-2-
pyridyloxy)propionic acid
252 2-(Cyclopropylmethyl)-3-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-
isoxazoly1]-2-
pyridyloxy}propionic acid
253 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-
pyridyloxy)-2-
(cyclopropylmethyl)propionic acid
254 2-{543-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-3-
phenylpropionic acid
255 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridylamino)-
3-phenylpropionic acid
256 3-Cyclopropy1-2-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
pyridylaminolpropionic acid
257 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridylamino)-
3-cyclopropylpropionic acid
258 2-{543-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-
3-
phenylpropionic acid
259 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly11-2-
pyridyloxy)-3-
phenylpropionic acid
260 3-Cyclopropy1-2-{543-fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
pyridyloxylpropionic acid
261 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-fluoro-5-isoxazoly1}-2-
pyridyloxy)-3-
cyclopropylpropionic acid
262 2-Benzy1-3-{543-cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
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CA 3046894 2019-06-18

pyridylaminolpropionic acid
263 2-Benzy1-3-(5-{441-(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-
pyridylamino)propionic acid
264 3-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-2-
(cyclopropylmethyl)propionic acid
265 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridylamino)-
2-(cyclopropylmethyl)propionic acid
266 2-Benzy1-3-{5-[3-cyano-4-(1-phenylethwrycarbonylamino)-5-isoxazoly1]-2-
pyridyloxy}propionic acid
267 2-Benzy1-3-(5-{4-[1-(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-
isoxazoly1}-2-
pyridyloxy)propionic acid
268 3-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-2-
(cyclopropylmethyl)propionic acid
269 3-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridyloxy)-2-
(cyclopropylmethyl)propionic acid
270 2-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridylamino}-
3-
phenylpropionic acid
271 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridylamino)-
3-phenylpropionic acid
272 2-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-3-
cyclopropylpropionic acid
273 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridylamino)-
3-cyclopropylpropionic acid
274 2-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-
phenylpropionic acid
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CA 3046894 2019-06-18

275 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly11-2-
pyridyloxy)-3-
phenylpropionic acid
276 2-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-3-
cyclopropylpropionic acid
277 2-(5-{441-(o-Chlorophenypethoxycarbonylamino]-3-cyano-5-isoxazoly1}-2-
pyridyloxy)-3-
cyclopropylpropionic acid
278 3-{p43-Methyl-4-(1-phenylethoxycarbonylamino)-5-isoxazolylibenzoylamino}-4-
phenylbutyric acid
279 4-Cyclopropy1-3-{p-[3-methy1-4-(1-phenylethoxycarbonylamino)-5-
isoxazolypenzoylamino}butyric acid
280 34({p43-Methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methypamino]-4-
phenylbutyric acid
281 4-Cyclopropy1-34({p43-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyliphenyl}methyl)amino]butyric acid
282 3-({p43-Methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyliphenyl}methoxy)-4-
phenylbutyric acid
283 4-Cyclopropy1-3-({p43-methyl-4-(1-phenylethoxycarbonylamino)-5-
isoxazolyliphenyllmethoxy)butyric acid
284 3-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridylamino}-4-
phenylbutyric acid
285 4-Cyclopropy1-3-{5-[3-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
pyridylamino}butyric acid
286 3-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridyloxy}-
4-
phenylbutyric acid
287 4-Cyclopropy1-3-{543-methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-
2-
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pyridyloxy}butyric acid
288 244-[4-[4-cyano-5-(1-phenylethoxycarbonylamino)pyrazol-1-
yl]phenyl]phenyliacetic acid
289 1-[4-[4-[4-cyano-5-(1-phenylethoxycarbonylamino)pyrazol-1-
yl]phenyl]phenyl]cyclopropanecarboxylic acid
290 144444541-(2-chlorophenypethoxycarbonylamino]-4-cyano-pyrazol-1-
yl]phenyl]phenyl]cyclopropanecarboxylic acid
291 24444-[4-cyano-5-(1-phenylethoxycarbonylamino)pyrazol-1-yl]phenyl]phenyl]-
2-methyl-
propanoic acid
292 244444541-(2-chlorophenypethoxycarbonylamino]-4-cyano-pyrazol-1-
yl]phenyliphenyl]-
2-methyl-propanoic acid
293 1-{4'-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-4-
biphenyly1}cyclopropanecarboxylic acid
294 1-(4'-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-
4-
biphenylyl)cyclopropanecarboxylic acid
295 1-{3-Fluoro-4'-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-
4-
biphenylyl}cyclopropanecarboxylic acid
296 1-(4'-{5-[1-(o-Chlorophenypethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-
3-fluoro-4-
biphenylyl)cyclopropanecarboxylic acid
297 1-{2-Fluoro-4'-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-
4-
biphenylyl}cyclopropanecarboxylic acid
298 1-(4'-{5-[1-(o-Chlorophenypethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-
2-fluoro-4-
biphenylyl)cyclopropanecarboxylic acid
299 1-{2-Chloro-4'-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-
4-
biphenylyl}cyclopropanecarboxylic acid
300 1-(2-Chloro-4'-{511-(o-chlorophenypethoxycarbonylamino]-4-fluoro-1H-
pyrazol-1-y1}-4-
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CA 3046894 2019-06-18

biphenylypcyclopropanecarboxylic acid
301 1-(4-{p44-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-
yl]phenyl}tolyl)cyclopropanecarboxylic acid
302 1-[4-(p-{5-[1-(o-Chlorophenypethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-
yl}phenyl)tolylicyclopropanecarboxylic acid
303 1-(p-{5-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
304 14p-(5-{541-(o-Chloropheny)ethoxycarbonylamino]-1H-pyrazol-1-y1}-2-
pyridyl)phenyl]cyclopropanecarboxylic acid
305 1-(p-{5-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
306 1-[p-(5-{541-(o-Chlorophenypethoxycarbonylamino]-4-methy1-1H-pyrazol-1-y1}-
2-
pyridyl)phenylicyclopropanecarboxylic acid
307 1-(2-Fluoro-4-{545-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
308 144-(5-{541-(o-Chlorophenypethoxycarbonylamino]-1H-pyrazol-1-y1}-2-
pyridy1)-2-
fluorophenyl]cyclopropanecarboxylic acid
309 1-(3-Fluoro-4-{5-[5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
310 1-[4-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-1H-pyrazol-1-y1}-2-
pyridy1)-3-
fluorophenyl]cyclopropanecarboxylic acid
311 14p-(5-{541-(o-Chlorophenyl)ethoxycarbonylamino]-4-methy1-1H-pyrazol-1-y1}-
2-
pyridyl)phenylicyclopropanecarboxylic acid
312 1-(2-Fluoro-4-{5-[4-methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-
y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
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CA 3046894 2019-06-18

313 1-[4-(5-{5-[1-(o-Chlorophenypethoxycarbonylamino]-4-methy1-1H-pyrazol-1-
y1}-2-pyridy1)-
2-fluorophenylicyclopropanecarboxylic acid
314 1-(3-Fluoro-4-{5[4-methy1-5-(1-phenylethoxycarbonylam ino)-1H-pyrazol-1-
y1]-2-
pyridyllphenyl)cyclopropanecarboxylic acid
315 144-(5-{541-(o-Chlorophenypethoxycarbonylamino]-4-methyl-1H-pyrazol-1-y1}-
2-pyridy1)-
3-fluorophenylicyclopropanecarboxylic acid
316 1-(p-{5-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
317 14p-(5-{541-(o-Chlorophenypethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-
2-
pyridyl)phenyl]cyclopropanecarboxylic acid
318 1-(2-Fluoro-4-{5-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-
y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
319 144-(5-{541-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-
2-pyridy1)-
2-fluorophenylicyclopropanecarboxylic acid
320 1-(3-Fluoro-4-{5-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-
y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
321 144-(5-{541-(o-Chloropheny)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-y1}-
2-pyridy1)-
3-fluorophenylicyclopropanecarboxylic acid
322 1-(p-{5-[4-Cyano-5-(1-phenylethoxycarbonylam i no)-1H-pyrazol- 1-y1]-2-
pyridyl}phenyl)cyclopropanecarboxylic acid
323 1-[p-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-cyano-1H-pyrazol-1-
y1}-2-
pyridyl)phenylicyclopropanecarboxylic acid
324 1-(4-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-2-
fluorophenyl)cyclopropanecarboxylic acid
325 1-[4-(5-{5-[1-(o-Chlorophenypethoxycarbonylamino]-4-cyano-1H-pyrazol-1-y1}-
2-pyridy1)-
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CA 3046894 2019-06-18

2-fluorophenyl]cyclopropanecarboxylic acid
326 1-(4-1544-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-3-
fluorophenyl)cyclopropanecarboxylic acid
327 144-(5-{541-(o-Chlorophenypethoxycarbonylamino]-4-cyano-1H-pyrazol-1-y1}-2-
pyridy1)-
3-fluorophenylicyclopropanecarboxylic acid
328 2-{p-[1-Methy1-5-methy1-4-(1-phenylethoxycarbonylamino)-1H-pyrazol-3-
yl]benzoylamino}-3-phenylpropionic acid
329 3-Cyclopropy1-2-{p-[1-methy1-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-
pyrazol-3-
yl]benzoylamino}propionic acid
330 2-(p-{441-(o-Chlorophenypethoxycarbonylamino]-1-methy1-5-methyl-1H-pyrazol-
3-
yl}benzoylamino)-3-phenylpropionic acid
331 2-(p-{4-[1-(o-Chlorophenypethoxycarbonylamino]-1-methy1-5-methy1-1H-
pyrazol-3-
yl}benzoylamino)-3-cyclopropylpropionic acid
332 24({p-[1-Methy1-5-methy1-4-(1-phenylethoxycarbonylamino)-1H-pyrazol-3-
yl]phenyl}methyl)amino]-3-phenylpropionic acid
333 3-Cyclopropy1-2-[({p-[1-methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-
pyrazol-3-
yl]phenyllmethypamino]propionic acid
334 2-{[(p-{441-(o-Chloropheny)ethoxycarbonylamino]-1-methy1-5-methy1-1H-
pyrazol-3-
yl}phenypmethyl]amino}-3-phenylpropionic acid
335 2-{[(p-{4-[1-(o-Chlorophenypethoxycarbonylamino]-1-methy1-5-methyl-1H-
pyrazol-3-
yl}phenyl)methyl]amino}-3-cyclopropylpropionic acid
336 2-({p-[1-Methy1-5-methy1-4-(1-phenylethoxycarbonylamino)-1H-pyrazol-3-
Aphenyllmethoxy)-3-phenylpropionic acid
337 3-Cyclopropy1-2-({p41-methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-
pyrazol-3-
yl]phenyl}methoxy)propionic acid
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CA 3046894 2019-06-18

338 2-[(p-{441-(o-Chlorophenypethoxycarbonylamino]-1-methyl-5-methyl-1H-
pyrazol-3-
yl}phenyl)methoxy]-3-phenylpropionic acid
339 2-[(p-{4-[1-(o-Chlorophenypethoxycarbonylamino]-1-methy1-5-methyl-1H-
pyrazol-3-
yl}phenyl)methoxy]-3-cyclopropylpropionic acid
340 3-{p41-Methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-pyrazol-3-
yl]benzoylamino}-4-phenylbutyric acid
341 4-Cyclopropy1-3-{p-[1-methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-
pyrazol-3-
yl]benzoylamino}butyric acid
342 34({p41-Methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-pyrazol-3-
yliphenyl}methypamino]-4-phenylbutyric acid
343 4-Cyclopropy1-3-[({p41-methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-
pyrazol-3-
yl]phenyllmethyl)amino]butyric acid
344 3-({p-[1-Methyl-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-pyrazol-3-
yl]phenyllmethoxy)-4-phenylbutyric acid
345 4-Cyclopropy1-3-({p41-methy1-5-methyl-4-(1-phenylethoxycarbonylamino)-1H-
pyrazol-3-
yl]phenyl}methoxy)butyric acid
346 3-pheny1-24[445-(1-phenylethoxycarbonylamino)oxazol-4-
yl]benzoyl]amino]propanoic
acid
347 3-cyclopropy1-24[445-(1-phenylethoxycarbonylamino)oxazol-4-
yl]benzoyl]amino]propanoic acid
348 4-pheny1-2-[[445-(1-phenylethoxycarbonylamino)oxazol-4-
yl]benzoyliamino]butanoic acid
349 3-phenoxy-24[4[5-(1-phenylethoxycarbonylamino)oxazol-4-
yl]benzoyl]amino]propanoic
acid
350 3-Pheny1-24({p45-(1-phenylethoxycarbonylamino)-1,3-oxazol-4-
yl]phenyl}methyl)amino]propionic acid
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351 3-Cyclopropy1-21({p45-(1-phenylethoxycarbonylamino)-1,3-oxazol-4-
yl]phenyllmethyl)amino]propionic acid
352 3-Pheny1-2-({p45-(1-phenylethoxycarbonylamino)-1,3-oxazol-4-
yl]phenyl}methoxy)propionic acid
353 4-Pheny1-3-({p45-(1-phenylethoxycarbonylamino)-1,3-oxazol-4-
yliphenyl}methoxy)butyric
acid
354 4-Cyclopropy1-3-({p45-(1-phenylethoxycarbonylamino)-1,3-oxazol-4-
yliphenyl}methoxy)butyric acid
355 24[441-methy1-5-(1-phenylethoxycarbonylamino)imidazol-4-yl]benzoyl]amino]-
3-phenyl-
propanoic acid
356 3-cyclopropy1-2-[[4-[1-methy1-5-(1-phenylethoxycarbonylamino)imidazol-4-
yl]benzoyl]amino]propanoic acid
357 24[441-methy1-5-(1-phenylethoxycarbonylamino)imidazol-4-yl]benzoyllamino]-
4-phenyl-
butanoic acid
358 24[441-methy1-5-(1-phenylethoxycarbonylamino)imidazol-4-yl]benzoyl]amino]-
3-phenoxy-
propanoic acid
359 24({p41-Methyl-5-(1-phenylethoxycarbonylamino)-1H-imidazol-4-
yl]phenyllmethyl)amino]-3-phenylpropionic acid
360 3-Cyclopropy1-2-[({p-[1-methy1-5-(1-phenylethoxycarbonylamino)-1H-imidazol-
4-
yl]phenyl}methypamino]propionic acid
361 2-({p-[1-Methyl-5-(1-phenylethoxycarbonylamino)-1H-imidazol-4-
yl]phenyl}methoxy)-3-
phenylpropionic acid
362 3-Cyclopropy1-2-({p-[1-methy1-5-(1-phenylethoxycarbonylamino)-1H-imidazol-
4-
yl]phenyl}methoxy)propionic acid
363 3-[({p-[1-Methy1-5-(1-phenylethoxycarbonylamino)-1H-imidazol-4-
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yl]phenyllmethyDamino]-4-phenylbutyric acid
364 4-Cyclopropy1-34({p-[1-methyl-5-(1-phenylethoxycarbonylamino)-1H-imidazol-
4-
Aphenyl}methyl)amino]butyric acid
365 3-({p41-Methyl-5-(1-phenylethoxycarbonylamino)-1H-imidazol-4-
yl]phenyl}methoxy)-4-
phenylbutyric acid
366 4-Cyclopropy1-3-({p-[1-methy1-5-(1-phenylethoxycarbonylamino)-1H-imidazol-
4-
yl]phenyl}methoxy)butyric acid
367 24[441,2-dimethy1-3-oxo-5-(1-phenylethoxycarbonylamino)pyrazol-4-
yl]benzoyl]amino]-3-
phenyl-propanoic acid
368 3-cyclopropy1-2-[[4-[1,2-dimethy1-3-oxo-5-(1-
phenylethoxycarbonylamino)pyrazol-4-
yl]benzoyl]amino]propanoic acid
369 24[441,2-dimethy1-3-oxo-5-(1-phenylethoxycarbonylamino)pyrazol-4-
yl]benzoyllamino]-4-
phenyl-butanoic acid
370 2-[[441,2-dimethy1-3-oxo-5-(1-phenylethcmcarbonylamino)pyrazol-4-
ylibenzoyl]amino]-3-
phenoxy-propanoic acid
371 24({p41,2-Dimethyl-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-
yliphenyl}methypaminol-3-phenylpropionic acid
372 3-Cyclopropy1-2-[({p-[1,2-dimethyl-3-oxo-5-(1-phenylethoxycarbonylamino)-
1,2-
dihydropyrazol-4-yl]phenyl}methyl)amino]propionic acid
373 2-({p-[1,2-Dimethy1-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-
yl]phenyllmethoxy)-3-phenylpropionic acid
374 3-Cyclopropy1-2-({p41,2-dimethyl-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-yl]phenyl}methoxy)propionic acid
375 3-[({p-[1,2-Dimethy1-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-
yl]phenyl}methyl)amino]-4-phenylbutyric acid
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376 4-Cyclopropy1-34({p41,2-dimethyl-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-yl]phenyl}methyDamino]butyric acid
377 3-({p-[1,2-Dimethy1-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-
yl]phenyllmethoxy)-4-phenylbutyric acid
378 4-Cyclopropy1-3-({p41,2-dimethyl-3-oxo-5-(1-phenylethoxycarbonylamino)-1,2-
dihydropyrazol-4-yliphenyl}methoxy)butyric acid
379 3-pheny1-24[445-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyl]amino]propanoic
acid
380 3-cyclopropy1-2-[[4-[5-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyl]amino]propanoic acid
381 4-pheny1-24[445-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyliamino]butanoic
acid
382 3-phenoxy-2-[[4-[5-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyllamino]propanoic acid
383 3-Pheny1-2-[({p45-(1-phenylethoxycarbonylamino)-4-
pyrimidinyliphenyl}methyl)amino]propionic acid
384 3-Cyclopropy1-2-[({p45-(1-phenylethoxycarbonylamino)-4-
pyrimidinyl]phenyl}methyl)amino]propionic acid
385 3-Pheny1-2-({p-[5-(1-phenylethoxycarbonylamino)-4-
pyrimidinyl]phenyl}methoxy)propionic
acid
386 3-Cyclopropy1-2-({p45-(1-phenylethoxycarbonylamino)-4-
pyrimidinyl]phenyl}methoxy)propionic acid
387 4-Pheny1-3-[({p45-(1-phenylethoxycarbonylamino)-4-
pyrimidinyliphenyl}methyl)amino]butyric acid
388 4-Cyclopropy1-3-[({p-[5-(1-phenylethoxycarbonylamino)-4-
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pyrimidinyliphenyl}methypamino]butyric acid
389 4-Pheny1-3-({p45-(1-phenylethoxycarbonylamino)-4-
pyrimidinyliphenyl}methoxy)butyric
acid
390 4-Cyclopropy1-3-({p45-(1-phenylethoxycarbonylamino)-4-
pyrimidinyl]phenyl}methoxy)butyric acid
' 391 24[446-methy1-5-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyl]amino]-3-phenyl-
propanoic acid
392 3-cyclopropy1-2-[[4-[6-methy1-5-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyliamino]propanoic acid
393 24[446-methy1-5-(1-phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]amino]-
4-phenyl-
butanoic acid
' 394 2-[[446-methy1-5-(1-phenylethoxycarbonylamino)pyrimidin-4-
yl]benzoyl]amino]-3-
phenoxy-propanoic acid
395 3-pheny1-24[444-(1-phenylethoxycarbonylamino)pyrimidin-5-
yl]benzoyl]aminojpropanoic
acid
396 3-cyclopropy1-2-[[4-[4-(1-phenylethoxycarbonylamino)pyrimidin-5-
yl]benzoyliamino]propanoic acid
397 4-phenyl-24[4[4-(1-phenylethoxycarbonylamino)pyrimidin-5-
ylibenzoyliaminolbutanoic
acid
398 3-phenoxy-2-[[444-(1-phenylethoxycarbonylamino)pyrimidin-5-
yl]benzoyl]amino]propanoic acid
399 3-phenyl-24[4[3-(1-phenylethoxycarbonylamino)pyrazin-2-
ylibenzoyl]amino]propanoic
acid
400 3-cyclopropy1-2-[[443-(1-phenylethoxycarbonylamino)pyrazin-2-
ylibenzoyl]amino]propanoic acid
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'
CA 3046894 2019-06-18

401 4-phenyl-24[4[3-(1-phenylethoxycarbonylamino)pyrazin-2-
yl]benzoyliamino]butanoic
acid
402 3-phenoxy-24[4[3-(1-phenylethoxycarbonylamino)pyrazin-2-
ylibenzoyl]amino]propanoic
acid
403 1-{p43-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidinecarboxylic acid
404 (1-{p-[3-Methy1-4-(1-phenylethoxycarbonylarnino)-5-isoxazolyl]pheny1}-4-
piperidypacetic
acid
405 1-(1-{p43-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidyl)cyclopropanecarboxylic acid
406 [1-(1-{p-[3-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidyl)cyclopropyliacetic acid
,
407 1-{5-[3-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-pyridy1}-4-
piperidinecarboxylic acid
408 (1-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-4-
piperidypacetic acid
409 1-(1-{5-[3-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-pyridyll-
4-
piperidyl)cyclopropanecarboxylic acid
410 [1-(1-{543-Methy1-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-
4-
piperidyl)cyclopropyl]acetic acid
411 1-{p-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidinecarboxylic acid
412 (1-{p-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidyl)acetic
acid
413 1-(1-{p-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
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piperidyl)cyclopropanecarboxylic acid
414 [1-(1-{p-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyllpheny1}-4-
piperidyl)cyclopropyl]acetic acid
415 1-{543-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy11-4-
piperidinecarboxylic acid
416 (1-{5-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-pyridy1}-4-
piperidyl)acetic acid
417 1-(1-{5-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-
4-
piperidyl)cyclopropanecarboxylic acid
418 [1-(1-{5-[3-Fluoro-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-
pyridy1}-4-
piperidyl)cyclopropyllacetic acid
419 1-{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny11-4-
piperidinecarboxylic acid
420 (1-{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidypacetic
acid
421 1-(1-{p-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny11-4-
piperidyl)cyclopropanecarboxylic acid
422 [1-(1-{p43-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyl]pheny1}-4-
piperidyl)cyclopropyl]acetic acid
423 1-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-pyridy1}-4-
piperidinecarboxylic acid
424 (1-{513-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-4-
piperidypacetic acid
425 1-(1-{5-[3-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazolyI]-2-pyridy1}-
4-
piperidyl)cyclopropanecarboxylic acid
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426 [1-(1-{543-Cyano-4-(1-phenylethoxycarbonylamino)-5-isoxazoly1]-2-pyridy1}-
4-
piperidyl)cyclopropyliacetic acid
427 1-{p-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidinecarboxylic
acid
428 (1-{p-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidypacetic acid
429 1-(1-{p-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidyl)cyclopropanecarboxylic acid
430 [1-(1-{p-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidyl)cyclopropyliacetic acid
431 1-{545-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-y11-2-pyridy1}-4-
piperidinecarboxylic
acid
432 (1-{5-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-0]-2-pyridy1}-4-
piperidypacetic acid
433 1-(1-{5-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-4-
piperidyl)cyclopropanecarboxylic acid
434 [1-(1-{5-[5-(1-Phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-4-
piperidyl)cyclopropyliacetic acid
435 1-{p-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidinecarboxylic acid
436 (1-{p-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidyl)acetic acid
437 1-(1-{p-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-
4-
piperidyl)cyclopropanecarboxylic acid
438 [1-(1-{p-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]phenyl}-
4-
piperidypcyclopropyl]acetic acid
439 1-{5-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-
4-
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piperidinecarboxylic acid
440 (1-{544-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy11-
4-
piperidyl)acetic acid
441 1-(1-{5-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-4-
piperidyl)cyclopropanecarboxylic acid
442 [1-(1-{5-[4-Methy1-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-4-
piperidyl)cyclopropyliacetic acid
443 1-{p-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidinecarboxylic acid
444 (1-{p44-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-ylipheny1}-4-
piperidyl)acetic acid
445 1-(1-{p-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-
4-
piperidyl)cyclopropanecarboxylic acid
446 [1-(1-{p44-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-ylipheny1}-
4-
piperidyl)cyclopropyl]acetic acid
447 1-{544-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y11-2-pyridy1}-
4-
piperidinecarboxylic acid
448 (1-{544-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-
4-
piperidypacetic acid
449 1-(1-{5-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-4-
piperidyl)cyclopropanecarboxylic acid
450 [1-(1-{5-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy11-4-
piperidyl)cyclopropyl]acetic acid
451 1-{p-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidinecarboxylic acid
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452 (1-{p-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny11-4-
piperidyl)acetic acid
453 1-(1-{p-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-4-
piperidyl)cyclopropanecarboxylic acid
454 [1-(1-{p-(4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]pheny1}-
4-
piperidyl)cyclopropyllacetic acid
455 1-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy11-
4-
piperidinecarboxylic acid
456 (1-{544-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-pyridy1}-
4-
piperidyl)acetic acid
457 1-(1-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-4-
piperidypcyclopropanecarboxylic acid
458 [1-(1-{544-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-y1]-2-
pyridy1}-4-
piperidyl)cyclopropyl]acetic acid
EXAMPLES
[0639] HPLC Methods
[0640] HPLC traces for examples synthesized were recorded using a HPLC
consisting of
Agilent HPLC pumps, degasser and UV detector, equipped with an Agilent 1100
series auto-
sampler. A MS detector (APCI) PE Sciex API 150 EX was incorporated for
purposes of
recording mass spectral data. HPLC/mass traces were obtained using one of
three
chromatographic methods:
[0641] Method 1: Column Zorbax C18, size 4.6 mm X 7.5 cm; Solvent A: 0.05 %
TFA in
water, Solvent B: 0.05 % TFA in acetonitrile; Flow rate ¨ 0.7 mUmin; Gradient:
5 % B to 100 %
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CA 3046894 2019-06-18

B in 9 min, hold at 100 % B for 4 min and 100 % B to 5 % B in 0.5 min; UV
detector ¨ channel 1
= 220 nm, channel 2 = 254 nm.
[0642] Method 2: Column Zorbax C18, size 4.6 mm X 7.5 cm;
Solvent A: 0.05 % TFA in water, Solvent B: 0.05 % TFA in acetonitrile;
Flow rate ¨0.7 mL/min; Gradient: 5 % B to 100 % B in 5 min, hold at 100 % B
for 2 min and 100
% B to 5 % B in 0.5 min; UV detector ¨ channel 1 = 220 nm, channel 2 = 254 nm.
[0643] Method 3: Column SunFireTM (Waters) C18, size 2.1 mm X 50 mm;
Solvent A: 0.05 % TFA in water, Solvent B: 0.05 % TFA in acetonitrile;
Flow rate ¨0.8 mL/min; Gradient: 10 % B to 90 % B in 2.4 min, hold at 90 % B
for 1.25 min and
90 % B to 10 % B in 0.25 min, hold at 101% B for 1.5 min.; UV detector ¨
channel 1 = 220 nm,
channel 2 = 254 nm.
[0644] Example 1: 1-(4-{441-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-
y1}-benzoylamino)-cyclopropanecarboxylic acid
[0645] Step 1: 2-(4-carboxymethyl-benzoyI)-3-oxo-butyric acid t-butyl ester
t-Butyl acetoacetate (15.1mL, 89.0 mmol) was added to a suspension of
magnesium chloride
(8.48g, 89.0 mmol) in dichloromethane (88mL) that had been cooled to 0 C. To
the mixture was
added pyridine (13.8mL, 171mmol) and stirring continued for an additional 15
minutes. 4-
(Chlorocarbonyl)benzoic acid methyl ester (17.0g, 85.6 mmol) in
dichloromethane (88mL) was
then added dropwise to the reaction. This mixture was stirred at 0 C for
90minutes and then at
room temperature for 90 minutes. At this time the mixture was treated with
0.2M hydrochloric
acid solution (10mL). The organic layer was diluted with dichloromethane
(70mL), washed with
0,2M hydrochloric acid solution (30mL), separated, dried over anhydrous
Na2SO4, filtered and
concentrated in vacuo. A yellow oil was obtained that was used directly in the
next step (17.1g,
68%).
Method 2, Rt 5.4 min. MS (ESI) m/z 321.2 [M +
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CA 3046894 2019-06-18

[0646] Step 2: 5-(4-Methoxycarbonyl-phenyl)-3-methyl-isoxazole-4-carboxylic
acid tert-butyl
ester
[0647] 5-(4-methylcarboxy-phenyl)-3-methyl-isoxazol-4-yl-carboxylic acid t-
butyl ester
A mixture of 2-(4-carboxymethyl-benzoyI)-3-oxo-butyric acid t-butyl ester
[example 1, step 1]
(7.45g, 23.2 mmol), hydroxylamine hydrochloride (5.17g, 74.4 mmol), ethanol
(46.5mL) and
water (32.2mL) was heated at 60-62 C for 2 hours. At this point the reaction
was allowed to cool
and the resulting mixture was partitioned between ethyl acetate and water. The
organic layer
was dried over anhydrous MgSO4, filtered and concentrated in vacuo. A crude
product was
obtained that was purified by silica gel chromatography initially with
hexane/ethyl acetate 9/1 as
eluting solvent to afford 5-(4-Methoxycarbonyl-phenyl)-3-methyl-isoxazole-4-
carboxylic acid tert-
butyl ester (4.69g, 64%)
Method 2, Rt 6.14 min. MS (ESI) m/z 318.2 [M + W].
[0648] Step 3: 5-(4-Methoxycarbonyl-phenyl)-3-methyl-isoxazole-4-carboxylic
acid5-(4-
Methoxycarbonyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid tert- butyl ester
[Example 1, step
2] (6.35g mg, 20 mmol) was dissolved in dichloromethane (100 mL) and to this
was added
trifluoroacetic acid (50mL). The mixture was stirred for 2 hours at room
temperature when the
volatiles were removed. The product (5.2g, 99 %) was used as is in Step 4.
Method 2, Rt 4.08 min. MS (ESI) m/z 262 [M + W];
[0649] Step 4: 1-(4-{441-(2-Chloro-phenyl)-ethoxycarbonylam i no]-3-methyl-
benzoic acid methyl ester
[0650] 5-(4-methylcarboxy-phenyl)-3-methyl-isoxazol-4-yl-carboxylic acid
[Example 1, step 3] (3.91g, 15.0 mmol) was suspended in toluene (120 mL) and
to this was
added diisopropylethylamine (3.13mL, 18.0mmol). To the resulting solution was
added
diphenylphosphoryl azide (3.56mL, 16.5mmol) and this mixture was heated to 90
C. After 15
minutes, 1-(2-chlorophenyI)-ethanol (2.98mL, 22.5mm01) was added slowly and
heating
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maintained for 4 hours. The reaction was allowed to cool overnight. This
mixture was diluted
with toluene, transferred to a separatory funnel, extracted with water. The
organic layer was
dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield a
crude product
(8.34g). The crude was purified by silica gel chromatography eluting with a
gradient from 30% to
40% ethyl acetate in hexanes to afford purified product (3.59g, 58%) as three
fractions. Method
2, Rt 5.70 min. MS (ESI) m/z 415.4 [M +
[0651] Step 5: 1-(4-{441-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoic acid
[0652] 1-(4-{441-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-benzoic
acid methyl ester [Example 1, step 4] (1.5g, 3.62 mmol) was dissolved in
THF/water (1/1: 20mL)
and treated with LiOH (5.1mL of a 1M aqueous solution). The resulting mixture
was stirred at
room temperature for 3 hours. The reaction was acidified to pH2, transferred
to a separatory
funnel, diluted with water and extracted with dichloromethane. The organic
layer was dried over
anhydrous MgSO4, filtered and concentrated in vacuo to afford the product
(0.8g, 55%). Method
2, Rt 4.77 min. MS (ESI) m/z 401.3 [M + H+].
[0653] Step 6: 1-Aminocyclopropanecarboxylic acid methyl ester
1-Aminocyclopropanecarboxylic acid (202mg, 2mm01) in methanol (4mL) was cooled
to -10 C
and to this was added dropwise thionyl chloride (581pL, 8mmo1). The mixture
was allowed to
warm and was then refluxed for 2 hours. Solvents were evaporated and the
residue redissolved
in boiling alcohol. To the cooled solution was added diethyl ether to the
point of turbidity when
the mixture was refridgerated for 2 days. The resulting precipitates afford
the product (223mg,
67%) that was used in Step 7.
[0654] Step 7: 1-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-cyclopropanecarboxylic acid methyl ester
- 176 -
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[0655] To 1-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-benzoic
acid [Example 1, step 5] (49.8mg, 0.12 mmol) was added 1-hydroxybenzotriazole
(18mg,
0.13mmol), N-(3-dimethylaminopropyI)-ethylcarbodiimide (EDCI: 25mg, 0.13
mmol),
dichloromethane (2 mL), diisopropylethylamine (52pL, 0.30 mmol), and 1-
Aminocyclo-
propanecarboxylic acid methyl ester [example 1, step 6](20 mg, 0.13 mmol) and
this mixture
was stirred overnight. At this point the mixture was diluted with ethyl
acetate (20 mL) and
washed with saturated sodium bicarbonate solution (10 mL), citric acid
solution (5 mL) and
water. The organic layer was dried over anhydrous MgSO4, filtered and
concentrated in vacuo
to yield a crude product (101mg). The residue was purified by preparative TLC,
eluting with a
40% mixture of ethyl acetate in hexane v/v. Following extraction of the
purified band, the
product was obtained (55 mg, 92%). Method 2, Rt 4.76 min. MS (ESI) m/z 498.4
[M +
[0656] Step 8: 1-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-cyclopropanecarboxylic acid
1-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-
cyclopropanecarboxylic acid methyl ester [example 1, step 7](55mg, 0.11mmol)
was dissolved
in a 1:1 mixture of THF/water and treated with lithium hydroxide (8mg,
0.33mm01). The resulting
mixture was stirred at room temperature for 2 days. At this point the pH was
adjusted to 2 with
hydrochloric acid and the mixture was extracted with ethyl acetate (3x20mL).
The organic layer
was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield a
crude product
(190mg). The residue was purified by preparative TLC, eluting with a 45%
mixture of acetone in
dichloromethane v/v. Following extraction of the purified band, the product
was obtained (22
mg, 41%).
Method 2, Rt 4.30 min. MS (ESI) m/z 484.6 [M + H4].
[0657] Example 2: 2-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-
y1}-benzoylamino)-indan-2-carboxylic acid
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[0658] Step 1: 2-Amino-2-indancarboxylic acid methyl ester
2-Amino-2-indancarboxylic acid methyl ester was prepared according to a
similar procedure as
described for example 1, step 6 from 2-Amino-2-indancarboxylic acid
hydrochloride (214mg,
Immo!) that was used directly. Yield 155mg (68%)
[0659] Step 2: 2-(4-{4-[1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylaminoyindan-2-carboxylic acid methyl ester
[0660] 2-(4-{4-[ 1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-
y1}-
benzoylaminoyindan-2-carboxylic acid methyl ester was prepared according to a
similar
procedure as described for example 1, step 7 from 1-(4-{441-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoic acid [Example 1, step 5]
(49.8mg, 0.12
mmol) and 2-amino-2-indancarboxylic acid methyl ester [example 2, step 1].
Yield 55 mg,
(81%). Method 2, Rt 5.49 min. MS (ESI) m/z 574.6 [M +1-1].
[0661] Step 3: 2444441 -(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-indan-2-carboxylic acid
2-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-
benzoylamino)-
indan-2-carboxylic acid was prepared according to a similar procedure as
described for example
1, step 8 from 2-(4-{441-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino)-indan-2-carboxylic acid methyl ester [example 2, step 7](55mg,
0.11mmol).Yield
6 mg, (11%). Method 2, Rt 5.00 min. MS (ESI) m/z 560.3[M +
[0662] Example 3 : 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzoylamino) phenyl acetic acid
[0663] Step 1: L-phenylglycine methyl ester was prepared according to a
similar procedure as
described for example 1, step 6 from L-phenylglycine (756mg, 5mmo1) that was
used directly.
Yield 480mg (58%).
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[0664] Step 2: 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino) phenyl acetic acid methyl ester
[0665] 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino) phenyl acetic acid methyl ester was prepared according to a
similar procedure
as described for example 1, step 7 from 1-(4-{4-[1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-y1}-benzoic acid [Example 1, step 5]( (58.1mg, 0.14 mmol)
and L-
phenylglycine methyl ester [Example 3, step 1] which was used without
purification. Yield 60mg
(76%) Method 2, Rt 5.41 min. MS (ESI) m/z 548.6 [M + H+].
[0666] Step 3: 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino) phenyl acetic acid
[0667] 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino) phenyl acetic acid was prepared according to a similar procedure
as described
for example 1, step 8 from 2-(S)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-
methyl-isoxazol-5-ylybenzoylamino) phenyl acetic acid methyl ester [example 3,
step 2](60mg,
0.11 mmol).Yield 4 mg (11%). Method 2, Rt 4.90 min. MS (ESI) m/z 534.4 [M +
H4].
[0668] Example 4 : 2-(R)- (4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}- benzoylam i no) phenyl propanoic acid
[0669] Step 1: D-phenylalanine methyl ester
[0670] D-phenylalanine methyl ester was prepared according to a similar
procedure as
described for example 1, step 6 from D-phenylalanine (1.12g, 7mm01). Yield
650mg (53%).
[0671] Step 2: 2-(R)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoylamino) phenyl propanoic acid methyl ester
[0672] 2-(R)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino) phenyl propanoic acid methyl ester was prepared according to a
similar
procedure as described for example 1, step 7 from 1-(4-{441-(2-Chloro-pheny1)-
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ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoic acid [Example 1, step 51
(58.1mg, 0.14
mmol) and D-phenylalanine methyl ester [example 4, step 11 to yield the
product (40mg, 49%)
which was used directly. Method 2, Rt 5.6 min. MS (ESI) m/z 562.2 [M + 1-1+].
[0673] Step 3: 2-
(R)-(4-{4-[(R, S)-1-(2-Chloro-pheny1)-ethoxycarbonylam ino]-3-methyl-
isoxazol-5-y1}- benzoylam i no) phenyl propanoic acid
[0674] 2-(R)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzoylamino) phenyl propanoic acid was prepared according to a similar
procedure as
described for example 1, step 8 from 2-(R)-(4-{4-[(R,S)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino) phenyl propanoic
acid methyl
ester [example 4, step 2](40mg, 0.07mm01). Yield 8mg (21%).Method 2, Rt 4.94
min. MS (ESI)
m/z 548.5 [M + 1-1].
[0675] Example 5 - 2 (R)4[443-methy1-4-((R)-1-phenylethoxycarbonylam
ino)isoxazol-5-
yl]benzoyl]amino]-3-phenyl-propanoic acid
[0676] Step 1: 2(R)-[[443-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoic
acid methyl ester
[0677] 2(R)-[[4-[3-methyl-4-((R)-1-phenylethoxycarbonylam ino)isoxazol-5-
yllbenzoic acid
methyl ester was prepared according to a similar procedure as described for
example 1, step 4
from 5-(4-Methoxycarbonyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid
[Example 1, step 3]
(1.55g, 5.9 mmol) and 1-(R)-(+)-phenyl-ethanol. Yield 1.18g (52%).
[0678] Step 2: 2(R)4[443-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoic
acid
[0679] 2(R)4[443-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoic acid
was prepared according to a similar procedure as described for example 1, step
5 from 2(R)-([4-
[3-methy1-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-yl]benzoic acid methyl
ester
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[Example 5, step 1] (1.5g, 3.62 mmol). Yield 1.04g, (91%). Method 3, Rt 2.72
min. MS (ESI) m/z
367.3 [M +
[0680] Step 3:
2(R)-[[4-[3-methyl-4-((R)-1-phenylethoxycarbonylam ino)isoxazol-5-
yl]benzoyl]amino]-3-phenyl-propanoic acid methyl ester
[0681] 2(R)-[[4-[3-methyl-4-((R)-1-phenylethoxycarbonylam ino)isoxazol-5-
yl]benzoyl]ami no]-
3-phenyl-propanoic acid methyl ester was prepared according to a similar
procedure as
described for example 1, step 7 from
2(R)-[[4-[3-methyl-4-((R)-1-
phenylethoxycarbonylamino)isoxazol-5-yl]benzoic acid [Example 5, step 2]
(64,7mg, 0.18 mmol)
and D-phenylalanine methyl ester [example 4, step 1]. Yield 100 mg, 92%).
Method 3, Rt 3.04 min. MS (ESI) m/z 528.3 [M +
[0682] Step 4:
2(R)-[[4-[3-methyl-4-((R)-1-phenylethoxycarbonylam i no)isoxazol-5-
yl]benzoyl]amino]-3-phenyl-propanoic acid (sodium salt)
[0683] 2(R)1[443-methyl-44(R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]-
3-phenyl-propanoic acid was prepared according to a similar procedure as
described for
example 1, step 8 from 2(R)4[4-[3-methyl-44(R)-1-
phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]-3-phenyl-propanoic acid methyl ester [example 5, step
3](100mg, 0.19mmol).
The crude material (21mg) was dissolved in methanol and treated with 1N sodium
hydroxide
(40pL) before drying to afford the product as its sodium salt (22 mg, 22%).
Method 3, Rt 3.04
min. MS (ESI) m/z 514.3 [M + Hi].
[0684] Example 6:
2(S)4[443-methyl-4-((R)-1-phenylethoxycarbonylamino)isoxazol-5-
yl]benzoyl]amino]-3-phenyl-propanoic acid
[0685] The title compound was prepared according to an analagous procedure to
that
described for example 5 from 5-(4-Methoxycarbonyl-phenyl)-3-methyl-isoxazole-4-
carboxylic
acid [Example 1, step 3] (64.7mg, 0.18mmol) and L-phenylalanine methyl ester
to afford the
product as its sodium salt (18mg, 18 /0).Method 3 Rt 3.05 min. MS (ESI) m/z
514.3 [M +
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[0686] Example 7: (R)-24[442,5-dimethy1-44(R)-1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-phenyl-propanoic acid
[0687] Step 1: 5-(4-Methoxycarbonyl-pheny1)-1,3-dimethy1-1H-pyrazole-4-
carboxylic acid tert-
butyl ester and 3-(4-Methoxycarbonyl-phenyl)-1,5-dimethy1-1H-pyrazole-4-
carboxylic acid tert-
butyl ester:
[0688] 4-(2-tert-Butoxycarbony1-3-oxo-butyry1)-benzoic acid methyl ester
[Example 1, Step 1]
(crude 76.0 g, 208.8 mmol on 100% purity basis) was dissolved in ethanol (2.2
L). Methyl
hydrazine (9.72 g, 210.9 mmol) was added to the above solution dropwise under
stirring at room
temperature. The reaction mixture was stirred another 3 hrs at RT after
finishing the addition.
The completion of reaction was confirmed by LC/MS. The solvent was removed
under vacuum.
The residue was dissolved in Et0Ac (700 mL) and washed with water (2 X 500
mL). The
organics were dried over Na2SO4, filtered and evaporated. Mixture of products
obtained as an
oil, which was used in the next step without further purification. Crude yield
72.6 g. Method 3, Rt
3.12 min. MS (ESI) nilz 331.0 [M + H+].
[0689] Step 2: 5-(4-Methoxycarbonyl-phenyl)-1,3-dimethy1-1H-pyrazole-4-
carboxylic acid and
3-(4-Methoxycarbonyl-pheny1)-1,5-dimethy1-1H-pyrazole-4-carboxylic acid:
[0690] A mixture of 5-(4-Methoxycarbonyl-phenyl)-1,3-dimethy1-1H-pyrazole-4-
carboxylic acid
tert- butyl ester and 3-(4- Methoxycarbonyl- phenyl)- 1, 5-dimethyl- 1H-
pyrazole-4-carboxylic acid
tert-butyl ester [Example 7, Step 11(5.00 g., 15.13 mmol) was dissolved into
CH2Cl2 (120.0 mL)
and trifluoroacetic acid (40.0 mL) was added and the reaction mixture was
stirred for 3 h at
room temperature. The volatiles were removed under vacuum. The residue was
dissolved into
ethyl acetate (50.0 mL). It was then extracted with saturated aq. Na2CO3
solution (40 mL).
Separated aqueous layer was washed with ethyl acetate (2x20 mL). Then it was
treated with 1
M HCI to pH 2. Then it was extracted with ethyl acetate (2x35 mL), dried
(Na2SO4), filtered and
concentrated to yield white solid mixture of acids (3.0 g., 72%). TLC on
silica plate (15%
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acetone in DCM): two fluorescent spots of two isomers Rf: 0.2 and Rf: 0.125.
Method 3, Rt 2.94
min. MS (ESI) m/z 275.0 [M + F1];
[0691] Step 3: 442,5-Dimethy1-44(R)-1-phenyl-ethoxycarbonylamino)-2H-pyrazol-3-
y1]-
benzoic acid methyl ester and 441,5-Dimethy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-1H-
pyrazol-3-y1]-benzoic acid methyl ester:
[0692] The mixture of acid isomers [Example 7, Step 21(6.0 g., 21.88 mmol),
was suspended
in anhydrous toluene (180.0 mL), under nitrogen and stirring. Then
diisopropylethyl amine (3.39
g., 26.24 mmol) was added. A clear solution was generated to which diphenyl
phosphoryl azide
7.22 g, 26.24 mmol) was added. The reaction mixture was heated to 950 C. Then
(R)-(+)-1-
phenylethyl alcohol (4.008 g, 32.8 mmol) was added dropwise at 95 C over a
period of 40
minutes. Then the reaction mixture was heated for an additional 5 hr at 95 C,
followed by
stirring at room temperature overnight. Next day it was diluted with Et0Ac
(300 mL), washed
with sat. aq. Na2CO3 solution (200.0 mL) and water (2x500 mL), dried (Na2SO4),
filtered and
concentrated to yield crude oily carbamate (12.5 g). The crude was purified by
column
chromatography (SiO2), initial elution with DCM (250 mL) and then gradient
elution
Acetone:DCM (2% acetone in DCM to 10% acetone in DCM). Two pure isomers were
obtained.
Fast moving isomer (1.667 g, 19.4%) and slow moving isomer (2.132 g, 24.77%)
were obtained
[> 95% by HPLC purity]. A fraction containing a mixture of isomers (0.812 g,
9.4%) was
obtained. A) Slow moving spot: Method 3, Rt 2.78 min. MS (ESI) m/z 394.2 [M +
HI tentatively
assigned as (R)- 441,5-Dimethy1-4-(1-phenyl-ethoxycarbonylamino)-1H-pyrazol-3-
A-benzoic
acid methyl ester.B) Fast moving spot: Method 3, Rt 2.80 min. MS (ESI) m/z
394.4 [M + Hi;
tentatively assigned as (R)- 442,5-Dimethy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-2H-pyrazol-
3-y1]-benzoic acid methyl ester.
[0693] Step 4: 442,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-2H-pyrazol-
3-y1]-
benzoic acid:
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[0694] 442,5-Dimethy1-44(R)-1-phenyl-ethoxycarbonylamino)-2H-pyrazol-3-y1]-
benzoic acid
methyl ester [Example 7, Step 3B] (240 mg, 0.61 mmol) was dissolved in
THE/water (2/1 v/v,
2.25 mL) and treated with LiOH (1.2 mL of a 1M aqueous solution, 2 eq.). The
resulting mixture
was stirred at room temperature overnight. The reaction was acidified to pH2,
diluted with water
and extracted with Et0Ac (2 X 40 mL). The organic layer was dried over
anhydrous MgSO4,
filtered and concentrated in vacuo to afford the product (180 mg, 78%). Method
3, Rt 2.81 min.
MS (ESI) miz 380.2 [M + H4].
[0695] Step 5: (R)- 2-{442,5-Dimethy1-44(R)-1-phenyl-ethoxycarbonylamino)-2H-
pyrazol-3-
y1Fbenzoylamino}-3-phenyl-propionic acid methyl ester:
To 442,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-2H-pyrazol-3-
y1Fbenzoic acid
[Example 7, step 4] (100 mg, 0.26 mmol) was added 1-hydroxybenzotriazole (43
mg, 0.32
mmol), EDCI (67 mg, 0.34 mmol), dimethylformamide (2 mL),
diisopropylethylamine (184 pL,
1.06 mmol), and D-phenylalanine methyl ester [Example 4, Step 1] (86 mg, 0.39
mmol) and this
mixture was stirred overnight. At this point the mixture was diluted with
ethyl acetate (20 mL)
and washed with 1N sodium hydroxide solution (10nnL), and water. The organic
layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo to yield the crude
product (193 mg),
which was purified by silica gel chromatography, eluting with an ethyl
acetate/dichloromethane
gradient to provide the title compound (95 mg, 68%). > 95% by HPLC purity.
Method 3, Rt 2.91
min. MS (ESI) miz 541.3 [M + H4].
[0696] Step 6: (R)-
24[4-[2, 5-dim ethy1-4-((R)-1-phenylethoxycarbonylam ino)pyrazol-3-
yl]benzoyl]amino]-3-phenyl-propanoic acid:
[0697] (R)- 2-
{442,5-Dimethy1-44(R)-1-phenyl-ethoxycarbonylamino)-2H-pyrazol-3-y1]-
benzoylamino}-3-phenyl-propionic acid methyl ester [Example 7, step 5] (95 mg,
0.176 mmol)
was dissolved in a 2:1 mixture of THE/water (2.25 mL) and treated with 1M
lithium hydroxide
solution (2 mL). The resulting mixture was stirred at room temperature
overnight. The pH of the
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aqueous layer was adjusted to 2 with hydrochloric acid and the mixture was
extracted with ethyl
acetate (3x20mL). The organic layer was dried over anhydrous MgSO4, filtered
and
concentrated in vacuo to yield the crude product (112 mg). The crude material
was purified by
silica-gel chromatography, eluting with a dichloromethane/acetone gradient.
(90 mg, 97%).
Method 3, Rt 2.90 min. MS (ESI) m/z 527.5 [M +
[0698] Example 8: (R)-24[4-[1,5-dimethyl-44(R)-1-
phenylethoxycarbonylamino)pyrazol-3-
yllbenzoyl]amino]-3-phenyl-propanoic acid
[0699] Step 1: 4-
[1,5-Di methy1-4-((R)-1- phenyl-ethoxycarbonylam ino)- 1H-pyrazol-3-y1]-
benzoic acid:
[0700] 4-[1,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-1H-pyrazol-3-y1]-
benzoic acid
methyl ester [Example 7, Step 3A] (240 mg, 0.61 mmol) was dissolved in
THF/water (2/1 v/v,
2.25 mL) and treated with LiOH (1.2 mL of a 1M aqueous solution, 2 eq.). The
resulting mixture
was stirred at room temperature overnight. The reaction was acidified to pH2,
transferred to a
separatory funnel, diluted with water and extracted with Et0Ac (2 X 40 mL).
The organic layer
was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford
the product (205
mg, 89%). Purity is 97% by HPLC. Method 3, Rt 2.43 min. MS (ESI) m/z 380.2 [M
+ 1-141.
[0701] Step 2: (R)- 2-{441,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-1H-
pyrazol-3-
y1]-benzoylamino}-3-phenyl-propionic acid methyl ester:
[0702] 4-[1,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-1H-pyrazol-3-y1]-
benzoic acid
[Example 8, Step 1] (100 mg, 0.26 mmol) was added 1-hydroxybenzotriazole (43
mg, 0.32
mmol), EDCI (67 mg, 0.34 mmol), dimethylformamide (2 mL),
diisopropylethylamine (184 pL,
1.06 mmol), and D-phenylalanine methyl ester [Example 4, Step 1] (86 mg, 0.39
mmol) and this
mixture was stirred overnight. At this point the mixture was diluted with
ethyl acetate (20 mL)
and washed with 1N sodium hydroxide solution (10mL), and water. The organic
layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo to yield the crude
product (150 mg)
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CA 3046894 2019-06-18

which was purified by silica gel chromatography, eluting with a ethyl
acetate/dichloromethane
gradient to provide the product (75 mg, 53%). Purity > 97% by HPLC. Method 3,
Rt 3.05 min.
MS (ESI) m/z 541.2 [M + W].
[0703] Step 3: (R)-
2-[[4-[1,5-dimethy1-44(R)-1-phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-phenyl-propanoic acid:
[0704] (R)- 2-
{441,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-1H-pyrazol-3-y1]-
benzoylamino}-3-phenyl-propionic acid methyl ester [Example 8, step 2] (75 mg,
0.139 mmol)
was dissolved in a 2:1 mixture of THF/water (1.5 mL) and treated with 1M
lithium hydroxide
solution (0.28 mL). The resulting mixture was stirred at room temperature
overnight. The pH of
the aqueous layer was adjusted to 2 with hydrochloric acid and the mixture was
extracted with
ethyl acetate (3x20mL). The organic layer was dried over anhydrous MgSO4,
filtered and
concentrated in vacuo to yield the product [>95% HPLC purity] (60 mg, 82%).
Method 3, Rt 2.69
min. MS (ESI) m/z 527.5 [M + W].
[0705] Example 9: (R)-24[442,5-dimethy1-44(R)-1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-(4-fluorophenyl)propanoic acid
[0706] Step 1: (R)-2-Amino-3-(4-fluoro-phenyl)-propionic acid methyl ester
hydrochloride:
[0707] (R)-2-Amino-3-(4-fluoro-phenyl)-propionic acid methyl ester
hydrochloride was
prepared according to a similar procedure as described for example 1, step 6
from D-4-
Fluorophenyl alanine (1 g, 5.46 mmol). Yield 900 mg, (71 %). Method 3, Rt 0.54
min. MS (ESI)
m/z 198.3 [M + H+].
[0708] Step 2: (R)- 2-{442,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-2H-
pyrazol-3-
y1]-benzoylamino}-3-(4-fluoro-pheny1)-propionic acid methyl ester:
[0709] (R)- 2-
{442,5-Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-2H-pyrazol-3-y1]-
benzoylamino}-3-(4-fluoro-pheny1)-propionic acid methyl ester was prepared
according to a
similar procedure as described for example 7, step 5 from (R)- 4-[2,5-Dimethy1-
4-(1-phenyl-
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ethoxycarbonylamino)-2H-pyrazol-3-y1]-benzoic acid [Example 7, Step 4] (50 mg,
0.132 mmol)
and (R)-2-Amino-3-(4-fluoro-phenyl)-propionic acid methyl ester hydrochloride
[Example 9, Step
1]. Yield 59 mg (80%).
[0710] Step 3: (R)-
24[442, 5-di methy1-4-((R)-1-phenylethoxycarbonylamino)pyrazol-3-
yl] benzoyl]ami no]-3-(441 uorophenyl) propanoic acid:
[0711] (R)-2-[[4-[2, 5-d imethy1-4-(( R)-1-phenylethoxycarbonylamino) pyrazol-
3-
yl]benzoyl]amino]-3-(4-fluorophenyl)propanoic acid was prepared according to a
similar
procedure as described for example 7, step 6 from (R)- 2-{4-[2,5-Dimethy1-4-
((R)-1-phenyl-
ethoxycarbonylamino)-2H-pyrazol-3-y1Fbenzoylamino}-3-(4-fluoro-phenyl)-
propionic acid methyl
ester [Example 9, Step 2] (59 mg, 0.11 mmol) to afford the product 55 mg
(87%). Method 3, Rt
2.73 min. MS (ESI) m/z 545.4 [M + H+].
[0712] Example 10: (R)-24[4-[1,5-dimethy1-4-((R)-1-
phenylethoxycarbonylamino)pyrazol-3-
yl]benzoyl]amino]-3-(4-fluorophenyl)propanoic acid The title compound was
prepared according
to an analogous procedure to that described for example 8 from 441,5-Dimethy1-
4-((R)-1-
phenyl-ethoxycarbonylamino)-1H-pyrazol-3-yll-benzoic acid [Example 8, Step 1]
(50 mg, 0.132
mmol) and (R)-2-Amino-3-(4-fluoro-phenyl)-propionic acid methyl ester
hydrochloride [Example
9, Step 1]. Yield 55 mg, (87%). Method 3, Rt 2.69 min. MS (ESI) m/z 545.4 [M +
[0713] Example 11: (R)- 3-
(4-bromopheny1)-24[442, 5-d imethy1-44(R)- 1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid
[0714] Step 1: (R)-2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester
hydrochloride:
[0715] The title compound was prepared using a similar procedure as described
for example
1, step 6 from D-4-bromophenyl alanine (1 g, 4.1 mmol). Yield 550 mg (46 %).
Method 3, Rt
1.70 min. MS (ESI) m/z 258.1 [M +
[0716] Step 2: (R)- 3-
(4-bromopheny1)-2-[[442 , 5-dim ethy1-44(R)-1-
phenylethoxycarbonylamino)-pyrazol-3-yl]benzoyl]amino]propanoic acid
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[0717] The title compound was prepared according to an analogous procedure to
that
described for example 9 (steps 2 & 3) from 442,5-Dimethy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-2H-pyrazol-3-y11-benzoic acid [Example 7, Step 4] and (R)-
2-Amino-3-(4-
bromo-pheny1)-propionic acid methyl ester hydrochloride [Example 11, Step 1].
Yield 30 mg
(65%). Method 3, Rt 3.03 min. MS (ESI) m/z 607.4 [M + 1-1].
[0718] Example 12: (R)- 3-
(4-bromopheny1)-2-[[4-[1, 5-di methy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid The title
compound
was prepared according to an analogous procedure to that described for example
8 from 4-[1,5-
Dimethy1-4-((R)-1-phenyl-ethoxycarbonylamino)-1H-pyrazol-3-y1]-benzoic acid
[Example 8, Step
1] (50 mg, 0.132 mmol) and 3-(4-bromo-phenyl)-propionic acid methyl ester
hydrochloride
[Example 11, Step 1]. Yield 60 mg, (80%). Method 3, Rt 3.02 min. MS (ESI) m/z
619.2 [M +
[0719] Example 13: (R)- 3-
(4-chloropheny1)-24[4-[2,5-dimethy1-44(R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyllamino]propanoic acid
[0720] Step 1: (R)- 2-Amino-3-(4-chloro-phenyl)-propionic acid methyl ester
hydrochloride:
[0721] (R)- 2-Amino-3-(4-chloro-phenyl)-propionic acid methyl ester
hydrochloride was
prepared using a similar procedure as described for example 1, step 6 from D-4-
chlorophenyl
alanine (1 g, 5 mmol). Yield 940 mg (75 %). Method 3, Rt 0.03 min. MS (ESI)
m/z 214.0 [M +
H+].
[0722] Step 2: (R, R)- 3-
(4-chloropheny1)-24[4-[2,5-dimethy1-4-(1-
phenylethoxycarbonylamino)-pyrazol-3-yl]benzoyl]amino]propanoic acid
[0723] The title compound was prepared according to an analogous procedure to
that
described for example 9 (steps 2 & 3) from (R)- 4-[2,5-Dimethy1-4-(1-phenyl-
ethoxycarbonylamino)-2H-pyrazol-3-y1]-benzoic acid [Example 7, Step 4] and (R)-
2-Amino-3-(4-
chloro-pheny1)-propionic acid methyl ester hydrochloride [Example 13, Step 1].
Yield 40 mg
(55%). Method 3, Rt 2.80 min. MS (ESI) m/z 561.3 [M + H+].
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[0724] Example 14: (R)- 3-
(4-chloropheny1)-2-[[441,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid
[0725] The title compound was prepared according to an analogous procedure to
that
described for example 8 from 441,5-Dimethy1-44(R)-1-phenyl-
ethoxycarbonylamino)-1H-
pyrazol-3-y1]-benzoic acid [Example 8, Step 1] and (R)- 2-Amino-3-(4-chloro-
phenyl)-propionic
acid methyl ester hydrochloride [Example 8, Step 1]. Yield 40 mg (54%)Method
3, Rt 3.00 min.
MS (ESI) m/z 561.3 [M + H+].
[0726] Example 15: (R)- 3-
(3,4-difluoropheny1)-24[442,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid
[0727] Step 1: (R)- 2-Amino-3-(3,4-difluoro-phenyl)-propionic acid methyl
ester hydrochloride:
[0728] (R)- 2-Amino-3-(3,4-difluoro-phenyl)-propionic acid methyl ester
hydrochloride was
prepared using a similar procedure as described for example 1, step 6 from D-
3,4-
difluorophenyl alanine (1 g, 4.97 mmol). Yield 1.04 g, 83 %). Method 3, Rt
0.16 min. MS (ESI)
m/z 216.0 [M + H];
[0729] Step 2: (R)- 3-
(3,4-difluoropheny1)-2-[[4-[2,5-dimethy1-4-((R)-1-
phenylethoxycarbonylamino)-pyrazol-3-yl]benzoyl]amino]propanoic acid:
[0730] The title compound was prepared according to an analogous procedure to
that
described for example 9 (steps 2 & 3) from (R)- 4-[2,5-Dimethy1-4-(1-phenyl-
ethoxycarbonylamino)-2H-pyrazol-3-y1]-benzoic acid [Example 7, Step 4] (50 mg,
0.132 mmol)
and (R)- 2-Amino-3-(3,4-difluoro-phenyl)-propionic acid methyl ester
hydrochloride [Example 15,
Step 1]. Yield 30 mg (61%). Method 3, Rt 2.96 min. MS (ESI) m/z 563.4 [M +
[0731] Example 16: (R)- 3-
(3,4-difluoropheny1)-2-[[441,5-dimethy1-4-((R)-1-
phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid
[0732] The title compound was prepared according to an analogous procedure to
that
described for example 8 from 4-[1,5-Dimethy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-1H-
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pyrazol-3-y1]-benzoic acid [Example 8, Step 1] (50 mg, 0.132 mmol) and (R)- 2-
Amino-3-(3,4-
difluoro-pheny1)-propionic acid methyl ester hydrochloride [Example 15, Step
1]. Yield 20 mg
(56%). Method 3, Rt 2.71 min. MS (ESI) m/z 563.3 [M + H+].
[0733] Example 17: (R)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-cyclopropyl-propionic acid
[0734] Step 1: (R)-2-Amino-3-cyclopropylpropionic acid methyl ester
hydrochloride:
[0735] (R)- 2-Amino-3-cyclopropylpropionic acid methyl ester hydrochloride was
prepared
using a similar procedure as described for example 1, step 6 from (R)- 2-Amino-
3-
cyclopropylpropionic acid and used directly. Yield 350mg (100%).
[0736] Step 2: 4-{4414(R)-2-Chloro-phenylyethoxycarbonylami no]-3-m ethyl-
isoxazol-5-y1}-
benzoic acid methyl ester
[0737] Prepared in analogous fashion as in Example 5 Step 1 using 5-(4-
methoxycarbonyl-
pheny1)-3-methyl-isoxazole-4-carboxylic acid [Example 1, step 3] (3.47 g,
13.28 mmol) and (R)-
1-(2-chloropheny1)-ethanol. Yield = 1.81 g (4.36 mmol, 25 %). HPLC (254 nm):
Method 3 Rt
3.31 min. MS (ESI) m/z 415.5 [M + H+].
[0738] Step 3: 4-{441 -((R-2-Chloro-phenyl)-ethoxycarbonylam i no]-3-methyl-
isoxazol-5-y1}-
benzoic acid
[0739] Prepared in analogous fashion as in Example 5, Step 2 using 4-{441-((R)-
2-chloro-
pheny1)-ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoic acid methyl ester
[Example 17,
step 2](1.81 g, 4.46 mmol). Yield = 1.70 g (4.25 mmol, 95 %). HPLC (254 nm):
Method 3 Rt
3.01 min. MS (ESI) m/z 401.2 [M +
[0740] Step 4: (R)-2-(4-{441-((R)-2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-
5-y1}-benzoylamino)-3-cyclopropyl-propionic acid
[0741] The title compound was prepared according to an analogous procedure to
that
described for example 5 from 4-{441-((R)-2-chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
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isoxazol-5-y1}-benzoic acid [Example 17, step 3] (50mg, 0.13 mmol) and (R)- 2-
Amino-3-
cyclopropylpropionic acid methyl ester hydrochloride [Example 17, step 1].
Yield 22mg (34%).
Method 3, Rt 3.27min. MS (ESI) m/z 512.5 [M + H+].
[0742] Example 18: (R)-2-{443-Methy1-4-((S)-1-phenyl-ethoxycarbonylam ino)-
isoxazol-5-y1]-
benzoylamino}-3-phenyl-propionic acid Step 1:
443-Methy1-44(S)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzoic acid
[0743] 443-Methy1-44(S)-1-phenyl-ethoxycarbonylaminoyisoxazol-5-y1]-benzoic
acid was
prepared in analogous fashion to example 17 [steps & 3] from 5-(4-
methoxycarbonyl-pheny1)-3-
methyl-isoxazole-4-carboxylic acid [Example 1, step 3] (1 g, 3.3 mmol) and (S)-
1-(2-
chloropheny1)-ethanol. Yield = 800 mg (2.19 mmol, 60 /0). HPLC (254 nm):
Method 3 Rt 2.67
min. MS (ESI) m/z 367.4 [M + F14].
[0744] Step 2: (S,
R)-2-{443-Methy1-4-(1-phenyl-ethoxycarbonylam ino)-isoxazol-5-y1]-
benzoylamino}-3-phenyl-propionic acid
[0745] The title compound was prepared according to an analogous procedure to
that
described for example 5 from (S)-443-Methy1-4-(1-phenyl-ethoxycarbonylam ino)-
isoxazol-5-y1]-
benzoic acid [Example 18, step 2] (61 mg, 0.12 mmol) and D-phenylalanine
methyl ester
hydrochloride. Yield = 30 mg (0.06 mmol, 49 %). HPLC (254 nm): Method 3 Rt
3.05 min. MS
(ESI) m/z 514.5 [M + H+].
[0746] Example 19: (S)-2-{443-Methy1-4-((S)-1-phenyl-ethoxycarbonylam ino)-
isoxazol-5-y1]-
benzoylamino}-3-phenyl-propionic acid
[0747] The title compound was prepared according to an analogous procedure to
that
described for example 18 from 443-Methy1-44(S)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-y1]-
benzoic acid [Example 18, step 2] (61 mg, 0.12 mmol) and L-phenylalanine
methyl ester
hydrochloride. Yield = 22 mg (0.04 mmol, 36 %). HPLC (254 nm): Method 3 Rt
2.87 min. MS
(ESI) m/z 514.5 [M + H+].
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[0748] Example 20: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-phenyl-propionic acid
[0749] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4414(R)-2-Chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-
phenylalanine
methyl ester. Yield = 65 mg (0.12 mmol, 77 %). HPLC (254 nm): Method 3 Rt 2.93
min. MS
(ESI) m/z 566.3 [M + Hi].
[0750] Example 21: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-(4-fluoro-pheny1)-propionic acid
[0751] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4414(R)-2-Chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-4-
fluorophenylalanine methyl ester. Yield = 65 mg (0.12 mmol, 77 %). HPLC (254
nm): Method 3
Rt 2.93 min. MS (ESI) m/z 566.3 [M + H+].
[0752] Example 22 (R)-
3-(4-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic acid
[0753] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{441-((R)-2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and 0-4-
chlorophenylalanine methyl ester. Yield = 64 mg (0.11 mmol, 74%). HPLC (254
nm): Method 3
Rt 3.11 min. MS (ESI) m/z 583.4 [M + H+].
[0754] Example 23: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-(3,4-difluoro-pheny1)-propionic acid
[0755] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4414(R)-2-Chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
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isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and 0-3,4-
difluorophenylalanine methyl ester hydrochloride. Yield = 41 mg (0.07 mmol, 47
%). HPLC (254
nm): Method 3 Rt 2.96 min. MS (ESI) m/z 584.1 [M + He].
[0756] Example 24: (R)-3-(2-Chloro-pheny1)-2-(4-{4-[(R)-1-(2-
chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic acid
[0757] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{441-((R)-2-Chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-2-
chlorophenylalanine methyl ester hydrochloride. Yield = 41 mg (0.07 mmol, 47
%). HPLC (254
nm): Method 3 Rt 3.06 min. MS (ESI) m/z 584.2 [M + He].
[0758] Example 25: (R)-3-(4-Bromo-pheny1)-2-(4-{4-[(R)-1-(2-
chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzoylamino)-propionic acid
[0759] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4-[(R)-1-(2-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-4-
bromophenylalanine methyl ester hydrochloride. Yield = 65 mg (0.10 mmol, 35
%). HPLC (254
nm): Method 3 Rt 3.28 min. MS (ESI) nilz 626.3, 628.4 [M + He].
[0760] Example 26: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-(2-fluoro-pheny1)-propionic acid
[0761] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4-[(R)- 1-(2-chloro-phenyl)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-2-
fluorophenylalanine methyl ester hydrochloride. Yield = 70 mg (0.12 mmol, 52
%). HPLC (254
nm): Method 3 Rt 3.12 min. MS (ESI) m/z 566.5, 567.8 [M + He].
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[0762] Example 27: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-p-tolyl-propionic acid
[0763] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4-[(R)- 1-(4-chloro-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and 0-4-
methylphenylalanine methyl ester hydrochloride. Yield = 37 mg (0.07 mmol, 43
%). HPLC (254
nm): Method 3 Rt 3.13 min. MS (ESI) m/z 562.3 [M + H+].
[0764] Example 28: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-(4-trifluoromethyl-pheny1)-propionic acid
[0765] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4-[(R)-1-(4-bromo-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-4-
trifluoromethylphenylalanine methyl ester hydrochloride. Yield = 40 mg (0.06
mmol, 44 %).
HPLC (254 nm): Method 3 Rt 3.00 min. MS (ESI) m/z 616.2 [M + 1-1].
[0766] Example 29: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzoylamino)-3-(4-cyano-pheny1)-propionic acid
[0767] The title compound was prepared according to an analogous procedure to
that
described for example 17 from 4-{4-[(R)-1-(4-bromo-pheny1)-
ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-benzoic acid [Example 17, step 3] (60 mg, 0.15 mmol) and D-4-
cyanophenylalanine methyl ester hydrochloride. Yield = 17 mg (0.03 mmol, 20
/0). HPLC (254
nm): Method 3 Rt 2.93 min. MS (ESI) m/z 573.2 [M + H+].
[0768] Example 30: (R)- 2-(4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-
4-methyl-
pyrazol-1-y1}-benzoylamino)-3-phenyl-propionic acid Step 1: 2-(4-Cyano-pheny1)-
4-methy1-2H-
pyrazole-3-carboxylic acid ethyl ester
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[0769] A solution of trichloroacetyl chloride (12.92 mL, 115.8 mmol) in
dichloromethane (30
mL) was cooled to -10 C under a nitrogen atmosphere. A solution of ethyl
propenyl ether (12.82
mL, 115.8 mmol) and pyridine (9.36 mL, 115.8 mmol) was added dropwise at a
rate to maintain
the internal temperature at -10 C. After addition was complete, the reaction
was warmed to
room temperature and stirred for 24 hours. The mixture was filtered and the
solids were washed
with dichloromethane (50 mL). The filtrates were evaporated to dryness under
vacuum to yield
an oil (31.71 g). This material was dissolved in ethanol (400 mL) and treated
with 4-
cyanophenylhydrazine hydrochloride (24.81 g, 139 mmol). The resulting mixture
was refluxed
for 3 hours and then cooled to room temperature. The volatiles were evaporated
in vacuo, the
residue was dissolved in Et0Ac (1 L) and washed with 1 N aqueous HCI solution
(2 X 300 mL).
The organic layer was separated, washed with water, dried over anhydrous
Na2SO4, filtered and
concentrated in vacuo to obtain a yellow solid (27.8 g). This was triturated
with Et0Ac (130 mL)
and the remaining solids removed by filtration (do not contain product). The
filtrates were
concentrated to 50 mL volume and the precipitated solids were filtered (do not
contain product).
The filtrates were concentrated and purified by silica gel chromatography,
eluting with a 100/0 to
88/12 hexanes/acetone gradient. Collected fractions containing a mixture of
the two isomeric
products, which were concentrated to dryness and triturated with methanol to
yield the ,desired
isomer [2-(4-cyano-phenyl)-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester]
as a yellow solid
(3.77g, 14.8 mmol, 13%). HPLC (254 nm): Method 3 Rt 2.93 min. MS (ES!) m/z
256.3 [M + 1-11
1H NMR (500 MHz, CDCI3) 6 7.73 (d, J = 8.5 Hz, 2 H); 7.58 (s, 1 H); 7.52 (d, J
= 8.5 Hz, 2 H);
4.27 (q, J= 7.1 Hz, 2 H); 2.35 (s, 3 H); 1.26 (t, J= 7.1 Hz, 3 H).
[0770] Step 2: 2-(4-Cyano-phenyl)-4-methyl-2H-pyrazole-3-carboxylic acid
[0771] A stirred solution of 2-(4-Cyano-phenyl)-4-methyl-2H-pyrazole-3-
carboxylic acid ethyl
ester [Example 30, step 11(500 mg, 1.96 mmol) in THF (10 mL) was treated with
LiOH 1 N
aqueous solution (10 mL) and the resulting mixture was stirred at room
temperature for 6 hours,
after which time analysis by HPLC/MS indicates approximately 60% conversion to
product. The
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reaction mixture was diluted with ethyl acetate (100 mL) and washed with 1 N
aqueous NaOH
solution (100 mL). The organic layer contained unreacted starting material.
The aqueous layer
was acidified to pH 1 with 1 N HCI aqueous solution and the resulting
suspension was extracted
with ethyl acetate (100 mL). The organic layer was separated, dried over
anhydrous MgSO4,
filtered and concentrated in vacuo to afford the pure product as a white solid
(289 mg, 1.27
mmol, 65 c/o). HPLC (254 nm): Method 3 Rt 2.56 min. MS (ESI) m/z 228.3 [M +
[0772] Step 3: [2-(4-Cyano-phenyl)-4-methy1-2H-pyrazol-3-y1]-carbamic acid (R)-
1-(2-chloro-
pheny1)-ethyl ester
[0773] 2-(4-Cyano-phenyl)-4-methyl-2H-pyrazole-3-carboxylic acid [Example 30,
step 2] (218
mg, 0.96 mmol) was suspended in toluene (10 mL) and treated with
diisopropylethylamine (200
pL, 1.16 mmol),. The resulting solution was treated with diphenylphosphoryl
azide (230 pL, 1.06
mmol) and heated to 65 C. (R)- 1-(2-chloro-phenyl)-ethanol (227 mg, 1.44
mmol) was added to
the reaction mixture and the temperature was increased to 105 C for 30
minutes, during which
time vigorous gas evolution was observed. The reaction was brought to 65 C
and stirred at that
temperature for 4 hours. The reaction was deemed complete by HPLC/MS. After
cooling, the
volatiles were removed in vacuo and the crude residue was purified by silica
gel
chromatography, eluting with a hexanes/ethyl acetate gradient. Product was
isolated as a white
solid (120 mg, 0.31 mmol, 33 AD). HPLC (254 nm): Method 3 Rt 3.84 min. MS
(ESI) m/z 381.2
[M + H+].
[0774] Step 4: 4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-methyl-
pyrazol-1-yll-
benzoic acid
[0775] A solution containing (R)42-(4-Cyano-pheny1)-4-methyl-2H-pyrazol-3-y1]-
carbamic acid
1-(2-chloro-phenyl)-ethyl ester (120 mg, 0.32 mmol) and THF (1.5 mL) was
treated with a 1 N
aqueous LiOH solution (1.5 mL) and the resulting mixture was stirred at room
temperature for
36 hours, followed by heating to 45 C for 24 hours. The reaction mixture was
diluted with ethyl
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acetate (50 mL) and washed with 1 N aqueous NaOH solution (50 mL). The aqueous
layer was
acidified to pH 1 with 1 N HCI aqueous solution and the resulting suspension
was extracted with
ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous
MgSO4, filtered
and concentrated in vacuo to afford the pure product as a white solid. Yield =
62 mg (0.16
mmol, 49 %). HPLC (254 nm): Method 3 Rt 3.14 min. MS (ESI) m/z 399.2 [M + Hi].
[0776] Step 3: (R)-2-(4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-
methyl-pyrazol-1-
yI}-benzoylamino)-3-phenyl-propionic acid methyl ester
[0777] 4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-methyl-pyrazol-1-
y1}-benzoic
acid (62 mg, 0.16 mmol), was
dissolved in DMF (1.4 mL) and treated with di-
isopropylethylamine (112 pL, 0.62 mmol) under nitrogen. EDCI (40 mg, 0.20
mmol) and HOBt
(26 mg, 0.19 mmol) was added and the resulting mixture was stirred for 30
minutes. D-
Phenylalanine methyl ester hydrochloride (50 mg, 0.23 mmol) was added and the
resulting
mixture stirred at room temperature overnight. The reaction was diluted with
Et0Ac (50 mL) and
transferred to a separatory funnel. The organics were washed with 1 N HCI
aqueous solution
and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
crude residue
was purified by preparative TLC plate (1000 pm), eluting with a 7:3 v/v
hexanes/ethyl acetate
mixture. The product was obtained as a white solid. Yield = 35 mg (0.06 mmol,
39 %). HPLC
(254 nm): Method 3 Rt 3.28 min. MS (ESI) m/z 561.3, 563.3 [M + Hi].
[0778] Step 4: (R)- 2-(4-{5-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-
methyl-pyrazol-
1-ylybenzoylamino)-3-phenyl-propionic acid
[0779] A solution containing (R)-2-(4-{5-[(R)-1-(2-Chloro-pheny1)-
ethoxycarbonylamino]-4-
methyl-pyrazol-1-y1}-benzoylamino)-3-phenyl-propionic acid methyl ester (35
mg, 0.06 mmol),
and THF (1 mL) was treated with a 1 N aqueous LiOH solution (125 pL) and the
resulting
mixture was stirred at room temperature for 18 hours. The reaction mixture was
diluted with
ethyl acetate (50 mL) and acidified to pH 1 with 1 N HCI aqueous solution. The
organic layer
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was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo
to afford the
pure product as a white solid. Yield = 20 mg (0.04 mmol, 61 %). HPLC (254 nm):
Method 3 Rt
3.19 min. MS (ESI) m/z 547.6, 550.6 [M + H+].
[0780] Example 31: (R)-2-{4-[3-Methyl-44(R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-yli-
benzylamino}-3-phenyl-propionic acid
[0781] Step 1: 5-(4-Chloromethyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid
tert-butyl ester
[0782] A stirred suspension of MgCl2 (2.97 g, 31.2 mmol) in dichloromethane
(30 mL) under
nitrogen was treated dropwise with tert-butyl acetoacetate (5.17 mL, 31.2
mmol) and the
resulting mixture was cooled to 0 C. The mixture was stirred at that
temperature for 15 minutes
and then treated with dropwise addition of pyridine (4.85 mL, 60.0 mmol).
After 15 minutes, a
solution of 4-(chloromethyl)benzoyl chloride (5.67 g, 30.0 mmol) in
dichloromethane (30 mL)
was added dropwise. The resulting mixture was maintained at 0 C for 1 hour
and then at room
temperature for an additional hour. The reaction was quenched with careful
addition of water
(100 mL) and the mixture was transferred to a separatory funnel. The organic
layer was washed
with a 1 N HCI aqueous solution (2 X 100 mL) then dried over anhydrous MgSO4,
filtered and
concentrated in vacuo. The crude residue was dissolved in ethanol (60 mL) and
treated with a
solution of NH2OH.HCI (6.67 g, 96.0 mmol) in water (13 mL). This mixture was
heated to 60 C
for 2 hours and at room temperature overnight. A thick white precipitate
formed which was
filtered, rinsed with ethanol and air-dried. The mother liquor was
concentrated and cooled to 0
C to yield a second crop of solid which was filtered and air-dried. Combined
yield = 5.82 g (19.0
mmol, 63 %). HPLC (254 nm): Method 3 Rt 3.49 min. MS (ESI) m/z 308.4 [M + H+].
[0783] Step 2: 5-(4-Chloromethyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid
[0784] 5-(4-Chloromethyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid tert-
butyl ester (4.61 g,
15.0 mmol) was dissolved in dichloromethane (7.5 mL) and treated with
trifluoroacetic acid (7.5
mL). The resulting mixture was stirred at room temperature for 18 hours, after
which time the
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reaction was deemed complete by HPLC/MS. The volatiles were removed in vacuo
to yield the
crude product as a white solid (3.8 g, 15.0 mmol, quant.), which was used as
is in the next step.
[0785] Step 3: [5-(4-Chloromethyl-phenyl)-3-methyl-isoxazol-4-yl]-carbamic
acid (R)-1-
phenyl-ethyl ester
[0786] 5-(4-Chloromethyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid (3.0 g,
12.0 mmol)
was suspended in toluene (120 mL) and treated with triethylamine (2.02 mL,
14.4 mmol). The
resulting solution was treated with diphenylphosphoryl azide (2.85 mL, 13.2
mmol) and heated
to 65 C. (R)-1-(phenyl)-ethanol (1.9 g, 15.6 mmol) was added to the reaction
mixture and the
temperature was increased to 105 C for 30 minutes, during which time vigorous
gas evolution
was observed. The reaction was brought to 65 C and stirred at that
temperature for 4 hours.
The reaction was deemed complete by HPLC/MS. After cooling, the volatiles were
removed in
vacuo and the crude residue was purified by silica gel chromatography, eluting
with a
hexanes/ethyl acetate gradient. Product isolated as a white solid (3.16 g,
8.52 mmol, 71 %).
HPLC (254 nm): Method 3 Rt 3.02 min. MS (ESI) m/z 371.2 [M + H+].
[0787] Step 4: (R)- 2-{443-Methyl-4-((R-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-y1]-
benzylamino}-3-phenyl-propionic acid methyl ester
[0788] A solution containing [5-(4-Chloromethyl-phenyl)-3-methyl-isoxazol-4-
y1]-carbamic acid
(R)-1-phenyl-ethyl ester (74 mg, 0.2 mmol), DMF (2 mL) and triethylamine (224
pL, 1.6 mmol)
was treated with D-phenylalanine methyl ester hydrochloride (173 mg, 0.80
mmol) and heated
to 80 C for 3 hours. The reaction was deemed complete by HPLC/MS. The
reaction was
cooled, partitioned between Et0Ac and water and transferred to a separatory
funnel. The
organic layer was washed with water and brine, dried over anhydrous MgSO4,
filtered and
concentrated in vacuo. The crude yellow oily residue was purified by silica
gel chromatography
eluting with a hexanes/Et0Ac gradient. The product was obtained as a colorless
film (77 mg,
0.15 mmol, 75 To). HPLC (254 nm): Method 3 Rt 2.67 min. MS (ESI) m/z 514.4 [M
+ HIT
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[0789] Step 5: (R)-2-{443-Methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-y1]-
benzylam ino}-3-phenyl-propionic acid
[0790] A solution containing (R)- 2-{443-Methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-
isoxazol-5-y1]-benzylamino}-3-phenyl-propionic acid methyl ester (77 mg, 0.15
mmol) and THF
(1.5 mL) was treated with a 1 N aqueous LiOH solution (1.5 mL) and the
resulting mixture was
stirred at room temperature for 18 hours. The reaction mixture was diluted
with ethyl acetate (50
mL) and acidified to pH - 5 with 1 N HCI aqueous solution. The organic layer
was separated,
dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was triturated
with diethyl ether to afford the pure product as a white solid (9 mg, 0.018
mmol, 12 %). HPLC
(254 nm): Method 3 Rt 2.74 min. MS (ESI) m/z 500.5 [M +
[0791] Example 32: (R)-
3-(2-Fluoro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzylamino}-propionic acid
[0792] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
chloromethyl-pheny1)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl
ester [Example
31, step 3](100 mg, 0.27 mmol), and D-2-fluorophenyl-alanine methyl ester
hydrochloride. Yield
= 10 mg (0.02 mmol, 7 %). HPLC (254 nm): Method 3 Rt 2.64 min. MS (ESI) m/z
518.4 [M +
[0793] Example 33: (R)-2-{443-Methy1-44(R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-y11-
benzylannino}-3-(4-trifluoromethyl-pheny1)-propionic acid
[0794] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
chloromethyl-pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-phenyl-ethyl
ester [Example
31, step 3](100 mg, 0.27 mmol), and D-4-trifluoromethylphenyl-alanine methyl
ester
hydrochloride. Yield = 18 mg (0.03 mmol, 11%). HPLC (254 nm): Method 3 Rt 3.10
min. MS
(ESI) m/z 568.5 [M + Hi].
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[0795] Example 34: (R)-3-Cyclopropy1-2-{443-methyl-4-((R)-1-phenyl-
ethoxycarbonylamino)-
isoxazol-5-y1]-benzylamino}-propionic acid The title compound was prepared in
analogous
fashion as in Example 31 using [5-(4-chloromethyl-phenyl)-3-methyl-isoxazol-4-
y1]-carbamic
acid (R)-1-phenyl-ethyl ester [Example 31, step 3](100 mg, 0.27 mmol), and (R)-
2-Amino-3-
cyclopropylpropionic acid methyl ester hydrochloride [Example 17, step 1].
Yield = 13 mg (0.03
mmol, 35 %). HPLC (254 nm): Method 3 Rt 2.82 min. MS (ESI) m/z 464.5 [M +1-
11].
[0796] Example 35: (R)-3-(2-Chloro-pheny1)-2-{4-[3-methy1-4-((R)-
1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzylaminol-propionic acid
[0797] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
chloromethyl-pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-phenyl-ethyl
ester [Example
31, step 3](100 mg, 0.27 mmol), and D-2-chlorophenyl-alanine methyl ester
hydrochloride. Yield
= 38 mg (0.07 mmol, 27 %). HPLC (254 nm): Method 3 Rt 3.05 min. MS (ESI) m/z
534.2 [M +
H+].
[0798] Example 36: (R)-3-(4-Chloro-pheny1)-2-{443-methy1-4-((R)-1-
phenyl-
ethoxycarbonylamino)-isoxazol-5-yli-benzylamino}-propionic acid
[0799] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
chloromethyl-pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-phenyl-ethyl
ester [Example
31, step 3}(100 mg, 0.27 mmol), and D-4-chlorophenyl-alanine methyl ester
hydrochloride. Yield
= 8 mg (0.01 mmol, 5 0/0). HPLC (254 nm): Method 3 Rt 3.13 min. MS (ESI) m/z
534.4 [M + Hi].
[0800] Example 37: (R)- 2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzylamino)-3-phenyl-propionic acid
[0801] Step 1: [5-(4-Chloromethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic
acid (R)-1-(2-
chloro-pheny1)-ethyl ester
[0802] [5-(4-Chloromethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-
(2-chloro-
pheny1)-ethyl ester was prepared in analogous fashion as in Example 31, steps
1-3 from 5-(4-
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chloromethyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid [Example 31, step
21(1.95 g, 7.75
mmol) and (R)-1-(2-chlorophenyI)-ethanol (1.82 g, 11.62 mmol). Yield = 1.33 g
(3.28 mmol, 42
/0). HPLC (254 nm): Method 3 Rt 3.31 min. MS (ESI) m/z 405.3 [M +
[0803] Step 2: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-
5-yI}-benzylamino)-3-phenyl-propionic acid methyl ester
[0804] (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-methyl-
isoxazol-5-y1}-
benzylamino)-3-phenyl-propionic acid methyl ester was prepared in analogous
fashion as in
Example 31, steps 4 from [5-(4-Chloromethyl.phenyl)-3-methyl-isoxazol-4-y1]-
carbamic acid (R)-
1-(2-chloro-pheny1)-ethyl ester [Example 37, step 11(101 mg, 0.25 mmol) and D-
phenylalanine
methyl ester hydrochloride. Yield = 45 mg (0.08 mmol, 33 To). HPLC (254 nm):
Method 3 Rt
2.90 min. MS (ESI) m/z 548.5 [M + H+].
[0805] Step 3: (R)- 2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-
5-y1}-benzylamino)-3-phenyl-propionic acid
[0806] Prepared in analogous fashion as in Example J, Step 5 using the
following reagents
and amounts: (R)-2-(4-{4-[(R)-1-(2-Chloro-pheny1)-ethoxycarbonylamino]-3-
methyl-isoxazol-5-
y1}-benzylamino)-3-phenyl-propionic acid methyl ester [Example 37, step 2] (45
mg, 0.08 mmol).
Yield = 6 mg (0.01 mmol, 14 %). HPLC (254 nm): Method 3 Rt 2.69 min. MS (ESI)
m/z 534.3 [M
+ H+].
[0807] Example 38: (R)- 2-(4-{4-[(R)_1-(2-Chloro-pheny1)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzylamino)-3-(2-fluoro-pheny1)-propionic acid
[0808] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
Chloromethyl-pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-(2-chloro-
phenyI)-ethyl ester
[Example 37, step 11(101 mg, 0.25 mmol), and D-2-fluorophenyl-alanine methyl
ester
hydrochloride. Yield = 30 mg (0.05 mmol, 22 To). HPLC (254 nm): Method 3 Rt
2.57 min. MS
(ESI) m/z 552.3 [M + H+].
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[0809] Example 39: (R)- 2-(4-(4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-
3-methyl-
isoxazol-5-y1}-benzylamino)-3-(4-trifluoromethyl-phenyl)-propionic acid
[0810] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
Chloromethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-(2-chloro-
phenyl)-ethyl ester
[Example 37, step 1](101 mg, 0.25 mmol), and D-4-trifluoromethylphenyl-alanine
methyl ester
hydrochloride. Yield = 38 mg (0.06 mmol, 25 %). HPLC (254 nm): Method 3 Rt
3.06 min. MS
(ESI) m/z 602.6 [M + H+].
[0811] Example 40: (R)- 3-
(2-Chloro-phenyl)-2-(4-{4-[(R)-1-(2-chloro-phenyl)-
ethoxycarbonylamino]-3-methyl-isoxazol-5-y1}-benzylamino)-propionic acid
[0812] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
Chloromethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-(2-chloro-
phenyI)-ethyl ester
[Example 37, step 1](101 mg, 0.25 mmol), and D-2-chlorophenyl-alanine methyl
ester
hydrochloride. Yield = 8 mg (0.01 mmol, 5 To). HPLC (254 nm): Method 3 Rt 2.78
min. MS (ESI)
m/z 569.3 [M +
[0813] Example 41: (R)-2-(4-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-
methyl-
isoxazol-5-y1}-benzylamino)-3-cyclopropyl-propionic acid
[0814] The title compound was prepared in analogous fashion as in Example 31
using [5-(4-
Chloromethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-(2-chloro-
phenyI)-ethyl ester
[Example 37, step 1](101 mg, 0.25 mmol), and (R)-2-Amino-3-
cyclopropylpropionic acid methyl
ester hydrochloride [Example 17, step 1]. Yield = 8 mg (0.01 mmol, 3 %). HPLC
(254 nm):
Method 3 Rt 2.80 min. MS (ESI) m/z 498.4 [M +
[0815] Example 42: 2-{443-Methyl-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-y1]-
benzyloxy}-3-phenyl-propionic acid
[0816] Step 1: {p43-Methyl-4-((R)-1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methyl
acetate
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[0817] [5-(4-Chloromethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-
phenyl-ethyl
ester [Example 31, step 3] (1g, 2.8mm01e) was mixed with potassium acetate
(2g, 14mmol) and
sodium iodide (0.5g, 2.8mm01e) and to this was added N,N-dimethylacetamide
(20mL). The
mixture was sonicated and then heated to 80 C for 1.5hrs. The mixture was
cooled to room
temperature and partitioned between saturated sodium chloride solution and
ethyl acetate. The
organic layer was further washed with water 4 times and then saturated sodium
chloride
solution before drying over magnesium sulfate. The filtered solution was
evaporated to give a
solid that was used directly. Yield = 0.94 g (2.4 mmol, 87 %). HPLC (254 nm):
Method 3 Rt 2.89
min. MS (ESI) m/z 395.3 [M + 1-11.
[0818] Step 2: [5-(4-Hydroxymethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic
acid (R)-1-
phenyl-ethyl ester
[0819] {p43-Methy1-4-((R)-1-phenylethoxycarbonylamino)-5-
isoxazolyl]phenyl}methyl acetate
[Example 42, step 1](0.94g, 2.4mm01e) was dissolved in THF (20mL) and methanol
(20mL) and
to this was added potassium carbonate (981mg, 7.1mmole). The resulting mixture
was allowed
to stir for 1.5 hours at room temperature when LC/MS indicated formation of a
single product
[HPLC (254 nm): Method 3 Rt 2.93 min. MS (ESI) m/z 353.2 [M + H+]. Solvents
were
evaporated and the residue was partitioned between saturated sodium chloride
solution and
ethyl acetate. The organic phase was dried over magnesium sulfate, filtered
and evaporated to
give a residue that was chromatographed in a gradient of 0-50% ethyl acetate
in hexanes to
afford the product. Yield 0.63g (1.79mmole, 74%).
[0820] Step 3: Methyl-2-diazo-phenylpropanoate
[0821] D-phenylalanine methyl ester hydrochloride (2g, 9.3mm01e) was
partitioned between
saturated sodium bicarbonate solution and ethyl acetate. The organic phase was
dried over
magnesium sulfate, filtered and evaporated to give a residue that was used
directly. D-
phenylalanine methyl ester (836mg, 4.7mm01e) was dissolved in chloroform
(20mL) and acetic
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CA 3046894 2019-06-18

acid (0.055mL, 0.94mm01e) was added. The solution was warmed to reflux with
the slow drop
wise addition of isoamyl nitrite (0.76mL, 5.6mmole) which was complete prior
to solvent boiling.
The mixture was refluxed for a further 30 minutes to afford a yellow solution
that was cooled to
0 C. The organic solution was washed with 1N sulfuric acid (25mL), water
(20mL), saturated
sodium bicarbonate solution (25mL), water (25mL) and 1N sulfuric acid (25mL).
The organic
phase was dried over magnesium sulfate, filtered and evaporated to give a
residue that was
chromatographed in a gradient of 0-5% ethyl acetate in hexanes to afford the
product. Yield
0.65g (3.4 mmole, 72%).
[0822] Step 4: 2-{443-Methyl-44(R)-1-phenyl-ethoxycarbonylamino)-
isoxazol-5-y1]-
benzyloxy}-3-phenyl-propionic acid methyl ester
[0823] [5-(4-Hydroxymethyl-phenyl)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-
phenyl-ethyl
ester [Example 42, step 2] (100mg, 0.28mmo1e) and Methyl-2-diazo-
phenylpropanoate
[Example 42, step 3] (61mg, 0.39mm01e) were suspended in benzene (3mL) in a
screw cap vial.
To this was added diRhodium tetraacetate (1mg, 0.002mm01e). After 10 minutes
at room
temperature the vial was heated to 90 C for 1 hour. The mixture was cooled to
room
temperature and the mixture chromatographed in a gradient of 0-20% ethyl
acetate in hexanes
to afford the product. Yield = 52 mg (0.1 mmol, 36%). HPLC (254 nm): Method 3
Rt 3.56 min.
MS (ESI) m/z 515.5 [M + 1-1].
[0824] Step 5: 2-{443-Methyl-44(R)- 1-phenyl-ethoxycarbonylamino)-
isoxazol- 5-yI]-
benzyloxy}-3-phenyl-propionic acid
[0825] 2-{413-Methyl-44(R)-1-phenyl-ethoxycarbonylaminoyisoxazol-5-y1]-
benzyloxy}-3-
phenyl-propionic acid methyl ester (52mg, 0.10mmole) was dissolved in 2/1 v/v
THF/water (4.5
mL) and the mixture stirred for 24 hours. The reaction mixture was diluted
with ethyl acetate (50
mL) and washed with saturated sodium bicarbonate solution. The aqueous layer
was acidified
to pH ¨ 3 with 6 N HCI and extracted with ethyl acetate. The organic layer was
separated, dried
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CA 3046894 2019-06-18

over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was co-
evaporated with
diethyl ether to afford the pure product as a white solid (22 mg, 0.043 mmol,
44 %). HPLC (254
nm): Method 3 Rt 3.03 min. MS (ES1) m/z 501.5 [M +
[0826] Example 43: 2-{4-[3-Methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-
5-y1]-
benzyloxy}-3-phenyl-propionic acid
[0827] Example 43 was prepared in analogous fashion to example 42 from [5-(4-
Hydroxymethyl-pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-phenyl-ethyl
ester [Example
42, step 2] (100mg, 0.28mmo1e) dissolved in 15% THF in benzene (1.15mL) using
Methy1-2-
diazo-phenylpropanoate that was synthesized from L-phenylalanine methyl ester
hydrochloride
(2g, 9.3mm01e). Yield 20mg (0.04mm01e, 14%). HPLC (254 nm): Method 3 Rt 2.96
min. MS
(ESI) m/z 501.6 [M + H+].
[0828] Example 44:
(RS)-3-Cyclopropy1-2-{4-[3-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-isoxazol-5-y1]-benzyloxy}-propionic acid
[0829] Step 1: D,L-2-amino-cyclopropylpropanoic acid methyl ester
[0830] Prepared in analogous fashion to Example 1, step 6 from D,L-2-amino-
cyclopropylpropanoic acid (500mg, 3.87mm01e). The crude residue was
partitioned between
saturated sodium bicarbonate solution and ethyl acetate. The organic phase was
dried over
magnesium sulfate, filtered and evaporated to give a residue that was used
directly. Yield
295mg (2.06mm01e, 53%)
[0831] Step 2: R,S Methyl-2-diazo-cyclopropylpropanoate
[0832] Prepared in analogous fashion to Example 42, step 3 from D,L-2-amino-
cyclopropylpropanoic acid methyl ester (295mg, 2.06mm01e) and used directly.
Yield 200mg
(1.29mmo1e, 62%)
[0833] Step 3: (RS)-3-Cyclopropy1-2-{4-[3-methy1-4-((R)-1-phenyl-
ethoxycarbonylamino)-
isoxazol-5-y1]-benzyloxy}-propionic acid methyl ester
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[0834] Prepared in analogous fashion to Example 42, step 4 from [5-(4-
Hydroxymethyl-
pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-phenyl-ethyl ester
[Example 42, step 2]
(90mg, 0.25mm01e) dissolved in 15% THF in benzene (1 mL) and R,S Methy1-2-
diazo-
cyclopropylpropanoate [Example 44, step 2] (118mg, 0.75mm01e]. Yield 50mg
(0.1mmole,
40%). HPLC (254 nm): Method 3 Rt 2.99 min. MS (ESI) m/z 479.1 [M + H+].
[0835] Step 4: : (RS)-3-Cyclopropy1-2-{443-methy1-44(R)-1-phenyl-
ethoxycarbonylamino)-
isoxazol-5-y1]-benzyloxy}-propionic acid
[0836] Prepared in analogous fashion to Example 42, step 5 from (RS)-3-
Cyclopropy1-2-{443-
methy1-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-benzyloxyl-
propionic acid methyl
ester [Example 44, step 3] (50mg, 0.1mmole). Yield 21mg (0.1mmole, 40%). HPLC
(254 nm):
Method 3 Rt 3.06 min. MS (ESI) m/z 465 [M +
[0837] Example 45:
(RS)-3-(4-Chloro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonyloxy)-isoxazol-5-y1]-benzyloxy}-propionic acid
[0838] Step 1: D,L-2-Amino-3(4-chlorophenyl)propanoic acid methyl ester
[0839] Prepared in analogous fashion to Example 1, step 6 from D,L-2-Amino-3(4-
chlorophenyl)propanoic acid (600mg, 3mmole). The crude residue was partitioned
between
saturated sodium bicarbonate solution and ethyl acetate. The organic phase was
dried over
magnesium sulfate, filtered and evaporated to give a residue that was used
directly. Yield
698mg (3.3mm01e, 100%)
[0840] Step 2: R,S Methyl-2-diazo-3(4-chlorophenyl)propanoate
[0841] Prepared in analogous fashion to Example 42, step 3 from D,L-2-Amino-
3(4-
chlorophenyl)propanoic acid methyl ester [Example 45, step 1](698mg, 3.3mm01e)
and used
directly. Yield 275mg (1.33mm01e, 40%)
[0842] Step 3: (RS)-3-(4-Chloro-pheny1)-2-{443-methy1-4-((R)-1-phenyl-
ethoxycarbonyloxy)-
isoxazol-5-y1]-benzyloxy}-propionic acid methyl ester
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[0843] Prepared in analogous fashion to Example 42, step 4 from [5-(4-
Hydroxymethyl-
pheny1)-3-methyl-isoxazol-4-y1]-carbamic acid (R)-1-phenyl-ethyl ester
[Example 42, step 2]
(90mg, 0.25mm01e) dissolved in 15% THF in benzene (1 mL) and R,S Methy1-2-
diazo-3(4-
chlorophenyl)propanoate [Example 45, step 2] (200mg, 0.89 mmole). Yield 55mg
(0.1mmole,
40%). HPLC (254 nm): Method 3 Rt 3.49 min. MS (ESI) m/z 549.6 [M +
[0844] Step 4: (RS)-3-(4-Chloro-pheny1)-2-{4-[3-methyl-4-((R)-1-phenyl-
ethoxycarbonyloxy)-
isoxazol-5-y1]-benzyloxy}-propionic acid
[0845] Prepared in analogous fashion to Example 42, step 5 from (RS)-3-
Cyclopropy1-2-{443-
methy1-44(R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-y1]-benzyloxy}-propionic
acid methyl
ester [Example 44, step 3] (55mg, 0.1mmole). Yield 20mg (0.04mm01e, 37%). HPLC
(254 nm):
Method 3 Rt 3.26 min. MS (ESI) m/z 535 [M +
[0846] Example 46: 2-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-
pyrazol-1-
yl]phenyl]phenyl]acetic acid
[0847] Step 1 - 5-amino-1-(4-bromophenyl)pyrazole-4-carbonitrile
[0848] (4-bronnophenyl)hydrazine hydrochloride (2.24 g, 10 mmol) was suspended
in ethanol
(20 mL) and treated with triethylamine (1.53 mL, 11 mmol). The resulting
solution was then
treated with malononitrile (1.22 g, 10 mmol) added portionwise. After a small
exotherm was
observed, the reaction was heated to reflux for 1 hour. The reaction was
cooled to room
temperature; the solids were collected by vacuum filtration and rinsed with
cold ethanol. The
solids were air-dried. Yield = 0.93 g, 3.5 mmol (35 %). HPLC (254 nm): Method
2, Rt 5.82 min.
MS (ESI) m/z 265 [M +1-1+]; 263 [M + HI 184 [(M ¨ Br) +1-1].
[0849] Step 2 - 1-(2-chlorophenyl)ethyl N42-(4-bromopheny1)-4-cyano-pyrazol-3-
ylicarbamate
[0850] A solution of 5-amino-1-(4-bromophenyl)pyrazole-4-carbonitrile [Example
46, step 1]
(26 mg, 0.1 mmol) in CH2Cl2 (1 mL) was treated with triethylamine (28 pL, 0.2
mmol), followed
by phosgene (100 pL of a 20 % viv solution in toluene, 0.2 mmol est.). The
resulting solution
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was stirred at room temperature for 30 minutes. ( )-1-(2-chlorophenyl)ethanol
(23 mg, 0.15
mmol) was added and the resulting mixture stirred at room temperature
overnight. The reaction
was concentrated in vacuo to remove volatiles, and the residue was purified by
chromatography
on silica-gel, eluting with a 4:1 mixture of hexanes/ethyl acetate v/v. The
product was obtained
as a colorless film. Yield = 27 mg (0.06 mmol, 61 %). HPLC (254 nm): Method 1,
Rt 6.31 min.
MS (ESI) miz 447 [M + W]; 445 [M + W]. 1H NMR (500 MHz, CDCI3) 6 7.90 (s, 1
H); 7.57 (d, J
= 8.8 Hz, 2 H); 7.37¨ 7.35 (m, 1 H); 7.32 (d, J = 8.8 Hz, 2 H); 7.27 (m, 3 H);
6.70 (br, 1 H); 6.14
(q, J= 6.5 Hz, 1 H); 1.54 (d, J= 6.5 Hz, 3 H).
[0851] Step 3 - ethyl 2-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-
cyano-pyrazol-1-
yl]phenyl]phenyl]acetate
[0852] In a pressure vessel, 1-(2-chlorophenyl)ethyl N42-(4-bromopheny1)-4-
cyano-pyrazol-3-
yl]carbamate [Example 46, step 2] (80 mg, 0.18 mmol) was dissolved in a 2:1
v/v mixture of
toluene and ethanol (2 mL) and treated with Na2CO3 (0.6 mL of a 2N aqueous
solution) and [4-
(2-ethoxy-2-oxo-ethyl)phenyl]boronic acid (75 mg, 0.36 mmol). The resulting
mixture was
degassed under Ar for 15 minutes, then treated with Pd[Ph3P14 (8 mg, 0.007
mmol). The vessel
was capped and immersed in an oil bath at 80 C, with vigorous magnetic
stirring. Reaction was
deemed complete after 14 hours. Reaction cooled to room temperature and
partitioned between
ethyl acetate and water. The organic layer was washed with water and brine.
The combined
aqueous layers were back-extracted with ethyl acetate. The combined organic
layers were dried
over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was
purified by
chromatography on silica-gel, eluting with a 4:1 mixture of hexanes/ethyl
acetate v/v. The
product was obtained as a white solid. Yield = 82 mg (0.16 mmol, 89 %). HPLC
(254 nm):
Method 1, Rt 6.94 min. MS (ESI) m/z 529.3 [M + W]; 485.1 [(M ¨ Et0) + W].
[0853] Step 4 : 2-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-
pyrazol-1-
yl]phenyl]phenyl]acetic acid
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[0854] Ethyl 2-
[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-pyrazol-1-
yl]phenyl]phenyllacetate [Example 46, step 3] (45 mg, 0.085 mmol) was
dissolved in THE (1
mL) and treated with LiOH (1 mL of a 1M aqueous solution). The resulting
mixture was stirred at
room temperature for 2 hours. The reaction was transferred to a separatory
funnel, diluted with
water and extracted with ethyl acetate. The organic layer was discarded and
the aqueous layer
was brought to pH 2 with a 0.1 N HCI solution. The product was extracted with
ethyl acetate.
The organic layer was dried over anhydrous MgS0.4, filtered and concentrated
in vacua to yield
a white solid as the pure product. Yield = 42 mg (0.085 mmol, quantitative).
HPLC (254 nm):
Method 1, Rt 6.99 min. MS (ESI) m/z 501.3 [M + HI 457.2 [(M ¨ CO2H) + NMR
(500
MHz, DMSO-d6) 6 12.39 (br, 1 H); 10.42 (br, 1 H); 8.31 (s, 1 H); 7.82 (d, J=
8.6 Hz, 2 H); 7.67
(d, J = 8.3 Hz, 2 H); 7.56 (d, J = 8.6 Hz, 2 H); 7.43 (d, J = 7.7 Hz, 1 H);
7.39 (d, J = 8.3 Hz, 2 H);
7.33¨ 7.29 (m, 3 H); 5.94 (q, J= 6.5 Hz, 1 H); 3.64 (s, 2 H); 1.44 (br, 3 H).
[0855] Example 47: (R)-144-[441,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenyl]cyclopropane carboxylic acid
[0856] Step 1: 2-(4-Bromo-benzoyI)-3-oxo-butyric acid ethyl ester
[0857] Ethyl acetoacetate (1.97mL, 15.6 mmole) was added to a suspension of
magnesium
chloride (1.49g, 15.6 mmole) in dichloromethane (15mL) that had been cooled to
0 C. To the
mixture was added pyridine (2.43mL, 30mm01e) and stirring continued for an
additional 15
minutes. 4-Bromobenzoyl chloride (3.29g, 15mmole) in dichloromethane (15mL)
was then
added to the reaction. This mixture was stirred at 0 C for 15minutes and then
at room
temperature for 1 hour. At this time the mixture was treated with 6N
hydrochloric acid solution
(20mL). The organic layer was separated, dried over anhydrous MgSO4, filtered
and
concentrated in vacua to give a colorless oil that was used directly in the
next step.
[0858] Step 2: 3-(4-Bromo-phenyl)-1,5-dimethy1-1H-pyrazole-4-carboxylic acid
ethyl ester and
5-(4-Bromopheny1)-1,3-dimethy1-1H-pyrazole-4-carboxylic acid ethyl ester
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[0859] 2-(4-Bromo-benzoyI)-3-oxo-butyric acid ethyl ester [example 47, step 1]
(4.7g,
15mmole), methylhydrazine (0.79mL,15.1 mmole), p-toluenesulfonic acid (0.15g)
were mixed
with ethanol (150mL) and this mixture was heated to 78 C for 2 hours. At this
point the reaction
was allowed to cool and the resulting mixture was partitioned between ethyl
acetate and water.
The organic layer was dried over anhydrous MgSO4, filtered and concentrated in
vacuo. A crude
product was obtained that was purified by silica gel chromatography initially
with hexane/ethyl
acetate 95/5 as eluting solvent and then with hexane/ethyl acetate 88/12 to
afford 3-(4-Bromo-
pheny1)-1,5-dimethy1-1H-pyrazole-4-carboxylic acid ethyl ester (600mg, 12%)
and 5-(4-Bromo-
pheny1)-1,3-dimethy1-1H-pyrazole-4-carboxylic acid ethyl ester (190mg, 4%).
[0860] Step 3: 3-(4-Bromopheny1)-1,5-dimethy1-1H-pyrazole-4-carboxylic acid
[0861] A mixture of 3-(4-Bromopheny1)-1,5-dimethy1-1H-pyrazole-4-carboxylic
acid ethyl ester
[example 47, step 2] (600mg, 1.85 mmole), 1N sodium hydroxide solution
(18.5mL) and dioxane
(18.5mL) was stirred at 100 C for 3 hours. Upon cooling the mixture was
acidified to pH 3-4 with
3N hydrochloric acid solution and this was extracted with ethyl acetate. The
organic layer was
dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the
product as a solid
(422mg, 77%).
[0862] Step 4: (R)-1-(phenyl)ethyl N42-
(4-bromopheny1)- 1,5-dimethy1-1H-pyrazol-3-
ylicarbam ate
[0863] A suspension of 3-(4-Bromopheny1)-1,5-dimethy1-1H-pyrazole-4-carboxylic
acid
[example 47, step 3] (50 mg, 0.17 mmol) in toluene (1mL) and triethylamine
(17mg, 0.17
mmole) was treated with diphenylphosphoryl azide (44pL, 0.20 mmole) and the
mixture stirred
at 45 C for 3 hours and then 95 C with the evolution of a gas. After 30
minutes (R)-(+)-1-
phenylethanol (25 mg, 0.20 mmole) was added. Heating was continued for a
further 1 hour
before the mixture was allowed to cool. The reaction was concentrated in vacuo
and the residue
dissolved in ethyl acetate and the solution washed with 0.1M potassium
carbonate solution and
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then brine. The organic layer was dried over anhydrous MgSO4, filtered and
concentrated in
vacuo to afford the product (64mg, 91%) that was used directly in the next
step. HPLC (254
nm): Method 3 Rt 3.10 min. MS (ESI) m/z 416.2, 414.4 [M + H+].
[0864] Step 5: 2-
[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropane
carboxylic acid methyl ester.
[0865] Methyl 1-(4-bromophenyl)cyclopropanecarboxylate (1g, 3.92 mmole),
potassium
acetate (461mg, 4.7 mmole), and bis(pinacolato)diboron (1.19g, 4.70 mmole)
were mixed in
dioxane (10mL) and degassed for 10minutes under a stream of argon. [1,1'-
bis(diphenylphosphino)ferrocene]palladium(II) dichloride (32mg) was added and
the mixture
was heated at 95 C for 2 hours. At this point the mixture was allowed to cool
and the mixture
was partitioned between ethyl acetate and water. The organic layer was dried
over anhydrous
MgSO4, filtered and concentrated in vacuo. A crude product was obtained that
was purified by
silica gel chromatography with hexane/ethyl acetate 95/5 as eluting solvent to
afford the product
as a white solid (1.02g, 86%).
[0866] Step 6:
(R)-1444441,5-dimethyl-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenyl]cyclopropanecarboxylic acid methyl ester
[0867] In a pressure vessel, (R)-1-(phenyl)ethyl N42-(4-bromopheny1)-1,5-
dimethyl-1H-
pyrazol-3-yl]carbamate [example 47, step 4) (64 mg, 0.16 mmol) was dissolved
in a 2:1 v/v
mixture of toluene and ethanol (2 mL) and treated with Na2CO3 (0.5 mL of a 2N
aqueous
solution) and 244-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl]cyclopropane carboxylic
acid methyl ester [Example 47, step 5] (52 mg, 0.17 mmol). The resulting
mixture was degassed
under argon for 15 minutes, and then treated with tetrakis (triphenyl-
phosphine)palladium(0) (1
mg, 0.006 mmol). The vessel was capped and immersed in an oil bath at 80 C,
with vigorous
magnetic stirring overnight. This reaction was cooled to room temperature and
partitioned
between ethyl acetate and water. The organic layer was washed with water and
brine. The
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combined aqueous layers were back-extracted with ethyl acetate. The combined
organic layers
were dried over anhydrous MgSO4, filtered and concentrated in vacuo. This
material was
purified by preparative TLC eluting with hexane/ethyl acetate 1/1 v/v to give
the product as a
yellow film (10 mg, 13%).
[0868] Step 7: (R)-
1444442,5-dimethyl-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenyl]cyclopropanecarboxylic acid
[0869] (R)-1-[4-[4-[1,5-dimethy1-4-(1-phenylethoxycarbonylami no) pyrazol-3-
yl]phenyl]phenyl]cyclopropanecarboxylic acid methyl ester [example 47, step 6]
(10mg, 0.02
mmole) was dissolved in THE (1 mL) and treated with LiOH (1 mL of a 2M aqueous
solution).
The resulting mixture was stirred overnight and then refluxed for 5 hours. The
reaction was
cooled and transferred to a separatory funnel, diluted with water and
extracted with ethyl
acetate. The organic layer was discarded and the aqueous layer was brought to
pH 1 with a 0.1
N HCI solution when the product was extracted with ethyl acetate. This organic
layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo. A residue was
obtained which was
triturated with dimethoxyethane. The solids were filtered and the filtrate
evaporated to dryness
to yield a residue that was purified by preparative TLC, eluting with ethyl
acetate/hexane 2/1 v/v.
The product was obtained as a white solid (3 mg, 28 %). HPLC (254 nm): Method
3 Rt 3.12
min. MS (ESI) nilz 496.6 [M +
[0870] Example 48: (R)-1444442,5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenyl]cyclopropane carboxylic acid
[0871] Step 1: 5-(4-Bromo-phenyl)-1,3-dimethy1-1H-pyrazole-4-carboxylic acid
[0872] A mixture of 5-(4-Bromo-phenyl)-1,3-dimethy1-1H-pyrazole-4-carboxylic
acid ethyl
ester [example 47, step 2] (190mg, 0.59 mmole), 1N sodium hydroxide solution
(5.9mL) and
dioxane (5.9mL) was stirred at 100 C for 1 hour. Upon cooling the mixture was
acidified to pH 3-
4 with 3N hydrochloric acid solution and this was extracted with ethyl
acetate. The organic layer
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was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield
the product as a
solid (170mg, 98%).
[0873] Step 2: (R)-1 -(phenyl)ethyl N15-(4-Bromo-phenyl)-1,3-dimethy1-1H-
pyrazole-4-yll-
carbamate
[0874] 5-(4-Bromo-phenyl)-1,3-dimethy1-1H-pyrazole-4-carboxylic acid [example
48, step 1]
(50 mg, 0.17 mmol) was used to prepare (R)-1-(phenyl)ethyl N45-(4-Bromo-
phenyl)-1,3-
dimethy1-1H-pyrazole-4-ylicarbamate according to the procedure described for
example 47, step
4 to afford the product (64mg, 91%) that was used in the next step. HPLC (254
nm): Method 3
Rt 3.03 min. MS (ESI) m/z 416.5 [M +
[0875] Step 3: (R)-1-[444- [2, 5-dimethy1-4-(1-
phenylethoxycarbonylamino)pyrazol-3-yl]phenyl]-
phenyncyclopropane carboxylic acid methyl ester
[0876] In a pressure vessel, (R)-1-(phenyl)ethyl N-[5-(4-Bromo-pheny1)-1,3-
dimethy1-1H-
pyrazole-4-yl]carbamate [example 48, step 2) (64 mg, 0.16 mmol) was used to
prepare the
product as an oil (32 mg, 41%) using a similar procedure to that described for
example 47, step
6
[0877] Step 4: (R)-
144-[442,5-dimethy1-4-(1-phenylethoxycarbonylamino)pyrazol-3-
yllphenyl]phenyl]cyclopropane carboxylic acid
[0878] (R)-1-[4-[4-[2, 5-dimethy1-4- (1-phenylethoxycarbonylamino)pyrazol-3-
yl]phenyl]phenyl]cyclopropane carboxylic acid methyl ester [example 48, step
3] (32mg, 0.06
mmole) was dissolved in THF (3 mL) and treated with LiOH (3 mL of a 2M aqueous
solution).
The resulting mixture was stirred overnight and then refluxed for 5 hours. The
reaction was
cooled and transferred to a separatory funnel, diluted with water and
extracted with ethyl
acetate. The organic layer was discarded and the aqueous layer was brought to
pH 1 with a 0.1
N HCI solution when the product was extracted with ethyl acetate. This organic
layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo. A residue was
obtained which was
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triturated with dimethoxyethane. The solids were filtered and the filtrate
evaporated to dryness
to yield a residue that was purified by preparative TLC, eluting with ethyl
acetate/hexane 2/1 v/v.
The product was obtained as a white solid (10 mg, 32 %). HPLC (254 nm): Method
3 Rt 2.92
min. MS (ESI) m/z 496.6 [M + F1].
[0879] Example 49: (R)-1-(4'-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-
fluoro-pyrazol-
1-y11-3-fluoro-biphenyl-4-y1)-cyclopropanecarboxylic acid
[0880] Step 1: Ethyl (E)-4-(dimethylamino)-2-oxo-but-3-enoate
[0881] Ethyl pyruvate (5 g, 43.1 mmol) was dissolved in 0H2Cl2 (86 mL) and
treated with
dimethylformamide dimethylacetal (5.73 mL, 43.1 mmol). The reaction was
stirred at room
temperature for 2 hours and concentrated in vacuo. The crude was used as is in
the next step.
Yield = 7.4 g.
[0882] Step 2: ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate
[0883] 4-Bromophenyl hydrazine hydrochloride (2.0 g, 8.95 mmol) was dissolved
in Me0H
(18 mL) and treated with crude ethyl (E)-4-(dimethylamino)-2-oxo-but-3-enoate
[example 3, step
11(1.54 g, 9.0 mmol). The resulting mixture was stirred at room temperature
for 6 hours. The
volatiles were removed in vacuo and the residue was purified by chromatography
on silica-gel,
eluting with a 95:5 mixture of hexanes/ethyl acetate v/v, increasing the
polarity to 9:1 over time.
Two isomeric products were isolated: ethyl 2-(4-bromophenyl)pyrazole-3-
carboxylate as an
orange solid (0.82 g, 2.78 mmol, 31 %) and ethyl 1-(4-bromophenyl)pyrazole-3-
carboxylate as a
red solid (0.44 g, 1.49 mmol, 17 %).
[0884] Ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate: HPLC (254 nm): Method 2
Rt 5.22
min. MS (ESI) m/z 297 [M + H+]; 294.8 [M + HI 252 [(M - Et0) + H+]; 250 [(M -
Et0) + HIT 1H
NMR (500 MHz, CD0I3) 6 7.69 (d, J= 1.9 Hz, 1 H); 7.58 (d, J= 8.7 Hz, 2 H);
7.32 (d, J- 8.7 Hz,
2 H); 7.03 (d, J= 1.9 Hz, 1 H); 4.26 (q, J= 7.1 Hz, 2 H); 1.28 (t, J = 7.1 Hz,
3 H).
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[0885] Ethyl 1-(4-bromophenyl)pyrazole-3-carboxylate: 1H NMR (500 MHz, CDCI3)
6 7.91 (d,
J = 2.4 Hz, 1 H); 7.65 (d, J = 7.2 Hz, 2 H); 7.60 (d, J = 7.2 Hz, 2 H); 7.00
(d, J = 2.4 Hz, 1 H);
4.44 (q, J= 7.0 Hz, 2 H); 1.43 (t, J= 7.0 Hz, 3 H).
[0886] Step 3: 2-(4-Bromo-phenyI)-4-fluoro-2H-pyrazole-3-carboxylic acid ethyl
ester
[0887] Ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate (1.08 g, 3.68 mmol) was
dissolved in
acetonitrile (12 mL) and the resulting mixture was treated with glacial acetic
acid (4.6 mL). To
this solution, 1-chloromethy1-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)
(Selectfluor , 3.91 g, 11.04 mmol) was added in one portion and the resulting
mixture was
heated to 105 C for 18 hours. The mixture was cooled to room temperature and
the volatiles
were removed in vacuo. The crude residue was loaded directly onto a silica-gel
column and
purified by elution with 95:5 mixture of hexanes/ethyl acetate v/v, increasing
the polarity to 9:1
over time. The product was isolated as a white solid (410 mg, 1.31 mmol, 36 %)
and starting
material was recovered (272 mg, 0.93 mmol, 25 %). For 2-(4-Bromo-phenyI)-4-
fluoro-2H-
pyrazole-3-carboxylic acid ethyl ester: HPLC (254 nm): Method 3 Rt 2.97 min.
MS (ESI) m/z
313.1 [M + H+]. 1H NMR (500 MHz, CD0I3) 67.60 (s, 1 H); 7.58 (d, J= 9 Hz, 2
H); 7.29 (d, J= 9
Hz, 2 H); 4.30 (q, J= 7.1 Hz, 2 H); 1.28 (t, J= 7.1 Hz, 3 H).
[0888] Step 4: 2-(4-Bromo-phenyl)-4-fluoro-2H-pyrazole-3-carboxylic acid
[0889] A stirred solution of 2-(4-bromo-pheny1)-4-fluoro-2H-pyrazole-3-
carboxylic acid ethyl
ester (410 mg, 1.31 mmol) in THF (13 mL) was treated with LiOH 1 N aqueous
solution (13 mL)
and the resulting mixture was stirred at room temperature overnight. The
reaction was deemed
complete by thin layer chromatography and H PLC/MS. The reaction mixture was
partitioned
between ethyl acetate and 1 N aqueous HCI solution (100 mL v/v) and
transferred to a
separatory funnel. The organic layer was separated and the aqueous layer was
back-extracted
with ethyl acetate (30 mL). The combined organic layers were dried over
anhydrous MgSO4,
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filtered and concentrated in vacuo to afford the pure product as a white solid
(347 mg, 1.22
mmol, 93%). HPLC (254 nm): Method 3 Rt 2.82 min. MS (ESI) m/z 285.1 [M + h1+].
[0890] Step 5: (R)42-(4-Bromo-pheny1)-4-fluoro-2H-pyrazol-3-y1Fcarbamic acid 1-
(2-chloro-
pheny1)-ethyl ester
[0891] 2-(4-Bromo-pheny1)-4-fluoro-2H-pyrazole-3-carboxylic acid (347 mg, 1.22
mmol) was
suspended in toluene (12 mL) and treated with triethylamine (205 pL, 1.46
mmol). The resulting
solution was treated with diphenylphosphoryl azide (316 pL, 1.46 mmol) and
heated to 65 C.
(R)- 1-(2-Chloro-phenyl)-ethanol (230 mg, 1.46 mmol) was added to the reaction
mixture and
the temperature was increased to 105 C for 30 minutes, during which time
vigorous gas
evolution was observed. The reaction was brought to 65 C and stirred at that
temperature for 4
hours. The reaction was deemed complete by HPLC/MS. After cooling, the
volatiles were
removed in vacuo and the crude residue was purified by silica gel
chromatography, eluting with
a hexanes/ethyl acetate gradient. Product isolated as a white solid (452 mg,
1.03 mmol, 85 %).
HPLC (254 nm): Method 3 Rt 3.16 min. MS (ESI) m/z 440.1 [M +
[0892] Step 6: (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-fluoro-
pyrazol-1-y1}-
3-fluoro-biphenyl-4-y1)-cyclopropanecarboxylic acid
[0893] A stirred suspension of (R)42-(4-Bromo-pheny1)-4-fluoro-2H-pyrazol-3-
yli-carbamic
acid 1-(2-chloro-phenyl)-ethyl ester (88 mg, 0.2 mmol), 2:1 v/v
toluene/ethanol (2 mL), 2 M
aqueous solution of Na2CO3 (670 pL) and 1-(4-borono-2-
fluorophenyl)cyclopropane-1-carboxylic
acid (45 mg, 0.2 mmol) was degassed under nitrogen for 10 minutes and treated
with Pd[Ph3Ph
(12 mg, 0.01 mmol). The resulting mixture was immersed in an oil bath with
stirring at 90 C for
12 hours. The reaction was cooled, transferred to a separatory funnel and
diluted with ethyl
acetate (50 mL). The mixture was carefully treated with 1 N aqueous HCI
solution (20 mL). The
organic layer was separated, washed with brine, dried over anhydrous MgSO4,
filtered and
concentrated in vacuo. The crude residue was purified by preparative TLC plate
(1000 pm),
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eluting with a 1:1 v/v hexanes/ethyl acetate mixture. The product was obtained
as a tan solid.
Yield = 35 mg (35 %). HPLC (254 nm): Method 3, Rt 3.11 min. MS (ESI) m/z 538.3
[M +
[0894] Example 50: (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-
fluoro-pyrazol-
1-y11-2-fluoro-bipheny1-4-y1)-cyclopropanecarboxylic acid
[0895] The title compound was prepared in analogous fashion as in Example 49
using (R)-[2-
(4-Bromo-pheny1)-4-fluoro-2H-pyrazol-3-y1]-carbamic acid 1-(2-chloro-phenyl)-
ethyl ester
(Example 49, Step 5 (88 mg, 0.2 mmol), and 1 44-(dihydroxyborany1)-3-
fluoropheny1]-
cyclopropane-1-carboxylic acid. Yield 40 mg (37 %) as a light yellow solid.
HPLC (254 nm):
Method 3, Rt 3.14 min. MS (ESI) m/z 538.3 [M +
[0896] Example 51: (R)-1-(2-Chloro-4'-{541-(2-chloro-pheny1)-
ethoxycarbonylamino]-4-fluoro-
pyrazol-1-y1}-biphenyl-4-y1)-cyclopropanecarboxylic acid
[0897] The title compound was prepared in analogous fashion as in Example 49
using (R)42-
(4-Bromo-pheny1)-4-fluoro-2H-pyrazol-3-y1]-carbamic acid 1-(2-chloro-
phenyl)ethyl ester
(Example 49, Step 5 (88 mg, 0.2 mmol), and 143-chloro-4-
(dihydroxyboranyl)phenylj-
cyclopropane-1-carboxylic acid. Yield 24 mg (22 %) as a light yellow solid.
HPLC (254 nm):
Method 3, Rt 3.40 min. MS (ESI) m/z 554.4 [M +
[0898] Example 52: (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-
fluoro-pyrazol-
1-y11-2-methyl-bipheny1-4-y1)-cyclopropanecarboxylic acid
[0899] The title compound was prepared in analogous fashion as in Example 49
using (R)-[2-
(4-Bromo-pheny1)-4-fluoro-2H-pyrazol-3-yl]-carbamic acid 1-(2-chloro-phenyl)-
ethyl ester
(Example 49, Step 5 (88 mg, 0.2 mmol), and 144-(dihydroxyborany1)-3-
methylphenyl]cyclo-
propane-1-carboxylic acid. Yield 36 mg (34 %) as a light yellow solid. HPLC
(254 nm): Method
3, Rt 3.19 min. MS (ESI) m/z 534.3 [M +
[0900] Example 53: (R)-1-(4'-{541-(2-Chloro-pheny1)-ethoxycarbonylamino]-4-
fluoro-pyrazol-
1-yll-bipheny1-4-y1)-cyclopropanecarboxylic acid
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[0901] The title compound was prepared in analogous fashion as in Example 49
using (R)-[2-
(4-Bromo-pheny1)-4-fluoro-2H-pyrazol-3-y1]-carbamic acid 1-(2-chloro-phenyl)-
ethyl ester
(Example 49, Step 5 (88 mg, 0.2 mmol), and 4-(1-
carboxycyclopropyl)phenylboronic acid,
pinacol ester. Yield 9 mg (9 %) as a white solid. HPLC (254 nm): Method 3, Rt
3.20 min. MS
(ESI) m/z 520.0 [M + H+].
[0902] Example 54: (R)- 1-{4'45-(1-Phenyl-ethoxycarbonylamino)-4-
trifluoromethyl-pyrazol-1-
y1Fbiphenyl-4-y1}-cyclopropanecarboxylic acid
[0903] Step 1: 2-(4-Bromo-phenyI)-4-iodo-2H-pyrazole-3-carboxylic acid ethyl
ester
10904] Ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate (Example 49, Step 2, 294
mg, 1.0
mmol) was dissolved in methanol (3 mL) and treated dropwise with iodine
monochloride (115
pL, 2.3 mmol). The resulting mixture was heated to 50 C for 3 hours. Another
aliquot of iodine
monochloride (120 pL) was added and heating continued for additional 3 hours.
The reaction
was deemed complete by HPLC/MS. After cooling to room temperature, the
reaction mixture
was diluted with ethyl acetate (30 mL) and transferred to a separatory funnel.
The organic layer
was washed successively with 1 N Na2S203 aqueous (30 mL) and brine (30 mL).
The organic
layer was separated, washed with brine, dried over anhydrous MgSO4, filtered
and concentrated
in vacuo. The product [2-(4-bromo-phenyl)-4-iodo-2H-pyrazole-3-carboxylic acid
ethyl ester]
was obtained as a pale yellow solid (420 mg, quant.) and used as is in the
next step. HPLC (254
nm): Method 3, Rt 3.33 min. MS (ESI) mk 421.0, 423.0 [M
[0905] Step 2: 2-(4-Bromo-phenyl)-4-trifluoromethy1-2H-pyrazole-3-carboxylic
acid ethyl ester
[0906] 2-(4-Bromo-phenyl)-4-iodo-2H-pyrazole-3-carboxylic acid ethyl ester
(420 mg, 1.0
mmol) was dissolved in DMF (4 mL) and the resulting solution was degassed with
nitrogen for
minutes. (1,10-Phenanthroline) (trifluoromethyl) copper (1)
(TrifluoromethylatorTm, 520 mg,
1.5 mmol) was added in one portion under an inert atmosphere and the resulting
mixture was
stirred at 50 C for 18 hours. The reaction was cooled to room temperature and
filtered through
- 219 -
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a pad of Celite and rinsed thoroughly with ethyl acetate. The filtrates were
washed with 1 N HCI
aqueous, brine, dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The crude
product 2-(4-bromo-pheny1)-4-trifluoromethy1-2H-pyrazole-3-carboxylic acid
ethyl ester was
used as is in the next step (291 mg, 0.80 mmol, 80 %). HPLC (254 nm): Method
3, Rt 3.23 min.
MS (ESI) m/z 365.2 [M + H+].
[0907] Step 3: 2-(4-Bromo-pheny1)-4-trifluoromethy1-2H-pyrazole-3-carboxylic
acid
[0908] 2-(4-Bromo-pheny1)-4-trifluoromethy1-2H-pyrazole-3-carboxylic acid
ethyl ester (291
mg, 0.80 mmol) in THF (8 mL) was treated with LiOH 1 N aqueous solution (8 mL)
and the
resulting mixture was stirred at room temperature for 3 hours. The reaction
was deemed
complete by thin layer chromatography and HPLC/MS. The reaction mixture was
partitioned
between ethyl acetate and 1 N aqueous HCl solution (100 mL v/v) and
transferred to a
separatory funnel. The organic layer was separated and the aqueous layer was
back-extracted
with ethyl acetate (30 mL). The combined organic layers were dried over
anhydrous MgSO4,
filtered and concentrated in vacuo to afford the pure product as a white solid
(268 mg, 0.80
mmol, quant.). HPLC (254 nm): Method 3 Rt 2.97 min. MS (ESI) m/z 335.2 [M +
[0909] Step 4: (R)- [2-(4-Bromo-phenyl)-4-trifluoromethy1-2H-pyrazol-3-y1]-
carbamic acid 1-
phenyl-ethyl ester
[0910] 2-(4-Bromo-pheny1)-4-trifluoromethy1-2H-pyrazole-3-carboxylic acid (268
mg, 0.80
mmol) was suspended in toluene (8 mL) and treated with triethylamine (135 pL,
0.97 mmol).
The resulting solution was treated with diphenylphosphoryl azide (209 pL, 0.97
mmol) and
heated to 65 C. (R)-1-(phenyl)-ethanol (118 mg, 0.97 mmol) was added to the
reaction mixture
and the temperature was increased to 105 C for 30 minutes, during which time
vigorous gas
evolution was observed. The reaction was brought to 65 C and stirred at that
temperature for 4
hours. The reaction was deemed complete by HPLC/MS. After cooling, the
volatiles were
removed in vacuo and the crude residue was purified by silica gel
chromatography, eluting with
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a hexanes/ethyl acetate gradient. Product isolated as a white solid (195 mg,
0.43 mmol, 54 %).
HPLC (254 nm): Method 3 Rt 3.23 min. MS (ESI) m/z 454.0, 456.1 [M + H+].
[0911] Step 5: (R)- 1-{4'45-(1-Phenyl-ethoxycarbonylamino)-4-trifluoromethyl-
pyrazol-1-y1J-
biphenyl-4-y1}-cyclopropanecarboxylic acid
[0912] A stirred suspension of (R)- [2-(4-Bromo-phenyl)-4-trifluoromethyl-2H-
pyrazol-3-yl]-
carbamic acid 1-phenyl-ethyl ester (98 mg, 0.22 mmol), 2:1 v/v toluene/ethanol
(2.2 mL), 2 M
aqueous solution of Na2CO3 (720 pL) and 4-(1-carboxycyclopropyl)phenylboronic
acid, pinacol
ester (124 mg, 0.43 mmol) was degassed under nitrogen for 10 minutes and
treated with
Pd[Ph3P]4 (12 mg, 0.01 mmol). The resulting mixture was immersed in an oil
bath with stirring at
95 C for 3 hours. The reaction was cooled, transferred to a separatory funnel
and diluted with
ethyl acetate (50 mL). The mixture was carefully treated with 1 N aqueous HCI
solution (20 mL).
The organic layer was separated, washed with brine, dried over anhydrous
MgSO4, filtered and
concentrated in vacuo. The crude residue was purified by preparative TLC plate
(1000 pm),
eluting with a 1:1 v/v hexanes/ethyl acetate mixture. The product was obtained
as a tan solid.
Yield = 6.8 mg (6 %). HPLC (254 nm): Method 3, Rt 3.21 min. MS (ESI) m/z 536.3
[M
[0913] Example 55: (R)-142-Fluoro-4'-[5-(1-phenyl-ethoxycarbonylamino)-4-
trifluoromethyl-
pyrazol-1-y11-biphenyl-4-y1}-cyclopropanecarboxylic acid
[0914] The title compound was prepared in analogous fashion as in Example 54
using(R)- [2-
(4-Bromo-phenyl)-4-trifluoromethyl-2H-pyrazol-3-yl]-carbamic acid 1-phenyl-
ethyl ester
(Example 54, Step 4 (98 mg, 0.22 mmol) and 1-[4-(dihydroxyboranyI)-3-
fluorophenyl]cyclopropane-1-carboxylic acid. Yield 7 mg (6 %) as a white
solid. HPLC (254 nm):
Method 3, Rt 3.11 min. MS (ESI) m/z 554.4 [M + 1-1+]
[0915] Example 56: (R)-1-(4-{5-[5-(1-Phenyl-ethoxycarbonylamino)-pyrazol-1-y1]-
pyridin-2-y1}-
phenyl)-cyclopropanecarboxylic acid
[0916] Step 1: 2-(6-Chloro-pyridin-3-yI)-2H-pyrazole-3-carboxylic acid ethyl
ester
- 221 -
CA 3046894 2019-06-18

[0917] 2-(6-Chloro-pyridin-3-yI)-2H-pyrazole-3-carboxylic acid ethyl ester was
prepared in
analogous fashion as in Example 49, Step 2 using (6-chloro-pyridin-3-yI)-
hydrazine
hydrochloride (9.89 g, 48.68 mmol; prepared according to W02005/92856A1) and
ethyl (E)-4-
(dimethylamino)-2-oxo-but-3-enoate (7.82 g, 45.68 mmol, Example 49, Step 1).
Yield = 1.35 g
(5.38 mmol, 12 %). HPLC (254 nm): Method 3 Rt 2.87 min. MS (ESI) m/z 252.2 [M
+ W]. 1H
NMR (500 MHz, CDC13)15 8.50 (d, J = 3.0 Hz, 1 H); 7.77 (dd, J1= 3.0 Hz, J2 =
8.5 Hz, 1 H); 7.74
(d, J = 2.0 Hz, 1 H); 7.43 (d, J = 8.5 Hz, 1 H); 7.08 (d, J = 2.0 Hz, 1 H);
4.28 (q, J = 7.5 Hz, 2 H);
1.30 (t, J= 7.5 Hz, 3 H).
[0918] Step 2: 2-(6-Chloro-pyridin-3-yI)-2H-pyrazole-3-carboxylic acid
hydrochloride salt
[0919] A stirred solution of 2-(6-Chloro-pyridin-3-yI)-2H-pyrazole-3-
carboxylic acid ethyl ester
[Example 56, step 1] (1.35 g, 5.4 mmol) in THF/water 8:2 v/v (35 mL) was
treated with LiOH 1 N
aqueous solution (6.5 mL) and the resulting mixture was stirred at room
temperature for 3
hours. The reaction was deemed complete by thin layer chromatography and
HPLC/MS. The
reaction mixture was diluted with water (100 mL) and washed with
dichloromethane (60 mL).
The aqueous layer was acidified with 1 N aqueous HCI solution to pH 2
resulting in a white
suspension. The solids were filtered, rinsed with water and air-dried to
afford the title compound
as a white solid. Yield = 0.90 g (3.46 mmol, 64 /0). HPLC (254 nm): Method 3
Rt 2.65 min. MS
(ESI) m/z 224.3 [M + W].
[0920] Step 3: (R)42-(6-Chloro-pyridin-3-y1)-2H-pyrazol-3-y1]-carbamic acid 1-
phenyl-ethyl
ester
[0921] 2-(6-Chloro-pyridin-3-yI)-2H-pyrazole-3-carboxylic acid hydrochloride
salt [Example 56,
step 2]( 0.90 g, 4.03 mmol) was suspended in toluene (27 mL) and treated with
di-
isoproprylethylamine (1.28 mL, 8.86 mmol). The resulting solution was treated
with
diphenylphosphoryl azide (855 pL, 4.83 mmol) and heated to 65 C. (R)- 1-
(phenyl)-ethanol
(600 pL, 6.03 mmol) was added to the reaction mixture and the temperature was
increased to
- 222 -
CA 3046894 2019-06-18

105 C for 30 minutes, during which time vigorous gas evolution was observed.
The reaction
was brought to 65 C and stirred at that temperature for 4 hours. The reaction
was deemed
complete by HPLC/MS. After cooling, volatiles were removed in vacuo and the
crude residue
purified by silica gel chromatography, eluting with a hexanes/ ethyl acetate
gradient. Product
isolated as a white solid. Yield = 0.60 g (1.75 mmol, 44 %). HPLC (254 nm):
Method 3 Rt 3.05
min. MS (ESI) m/z 343.2 [M + Hi].
[0922] Step 4: (R)-1-(4-{544-Methy1-5-(1-phenyl-ethoxycarbonylamino)-pyrazol-1-
y11-pyridin-
2-y1}-pheny1)-cyclopropanecarboxylic acid methyl ester
[0923] A stirred suspension of (R)-[2-(6-Chloro-pyridin-3-y1)-2H-pyrazol-3-y1]-
carbamic acid 1-
phenyl-ethyl ester [Example 56, step 3] (240 mg, 0.70 mmol) in 2:1 v/v
toluene/ethanol (7 mL), 2
M aqueous solution of Na2CO3 (1.5 mL) and 144-(4,4,5,5-
tetramethy141,3,2]dioxaborolan-2-y1)-
pheny1]-cyclopropanecarboxylic acid methyl ester (260 mg, 0.84 mmol) was
degassed under
nitrogen for 10 minutes and treated with Pd[Ph3P]4 (42 mg, 0.036 mmol). The
resulting mixture
was immersed in an oil bath with stirring at 90 C for 15 hours. The reaction
was cooled,
transferred to a separatory funnel and diluted with ethyl acetate (50 mL). The
mixture was
carefully treated with 1 N aqueous HC1 solution (20 mL). The organic layer was
separated,
washed with brine, dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The crude
residue was purified by silica gel chromatography, eluting with a 0-30%
hexanes/ethyl acetate
gradient of increasing polarity. The product was obtained as a tan solid.
Yield = 136 mg (0.28
mmol, 40 /0). HPLC (254 nm): Method 3 Rt 2.93 min. MS (ESI) m/z 483.4 [M +
Hi].
[0924] Step 6: (R)-1-(4-{5-[5-(1-Phenyl-ethoxycarbonylamino)-pyrazol-1-y1]-
pyridin-2-y1}-
pheny1)-cyclopropanecarboxylic acid
[0925] A solution of (R)-1-(4-{544-Methy1-5-(1-phenyl-ethoxycarbonylamino)-
pyrazol-1-y1]-
pyridin-2-y1}-pheny1)-cyclopropanecarboxylic acid methyl ester (136 mg, 0.28
mmol) in a 2:1 v/v
mixture of THF/water (3 mL) was treated with a 1 N LiOH aqueous solution (420
pL) and stirred
- 223 -
CA 3046894 2019-06-18

at ambient temperature for 16 hours. The reaction was brought to pH 1 by
addition of a 1 N HCI
aqueous solution. The mixture was extracted with Et0Ac and washed with water.
The organic
layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The
product was
obtained as an off white solid Prepared in analogous fashion as in Example Ml,
Step 6 using
the following reagents and amounts: (R)-1-(4-{545-(1-phenyl-
ethoxycarbonylamino)-pyrazol-1-
ylypyridin-2-yll-phenyl)-cyclopropanecarboxylic acid methyl ester (136 mg,
0.28 mmol),
THE/water 2:1 v/v (3 mL), 1 N aqueous LiOH solution (420 pL). Yield = 15 mg
(0.032 mmol, 11
%). HPLC (254 nm): Method 3 Rt 2.93 min. MS (ESI) miz 483.3 [M +
[0926] Compounds 57-458 of Table 1 and derivatives thereof are prepared from
the
according to procedures outlined for compounds 1-56. The heterocyclic amines
or esters
required to assemble the corresponding carbamates were prepared based on
methods
described in citations 1-24.
[0927] Certain isoxazole substitutions are prepared following construction of
the appropriate
aryl isoxazole (3, Scheme 1). Direct flurorination or bromination and
cyanation provides
arylbromide (4) or acid (5) after palladium catalyzed carbonylation.
[0928] Scheme 1
o o o 0 Br
DMF, DMA NH2OH
,
I
- Br Br 0
2 ¨0 3
--A CO2H
Selectfluor
,0 Co, pdC12(dpPO
or Br2/HOAc
followed by Zn(CN)2, R
\
Br
______________________________________________ =-= N \
0 F. F, Br, CN
Pd[PPh314 ¨0 ¨ A= Ch, N
0
[0929] 4 5
- 224 -
CA 3046894 2019-06-18

[0930] Acid (5, scheme 2) may be directly coupled with amines to afford amide
intermediates
(6) which may be converted to the carbamate products (7) following acid
hydrolysis, Curtius
rearrangement and deprotection with acid.
[0931] Scheme 2
0 0
A
R \ / N¨z. \Re õo / N----z=RA
\ / HBTU, DIEA N
/ 1) LOH / \
0 R 0
¨0 F121,1*.zThG )\ ¨0 2) DPPA R NH
RG 04
6 0
. 0 oli RG
R
F= F, Br, CN . RH
A= CH, N 3) TFA
7
[0932]
[0933] The acid (5) may be reduced to alcohol (8) and/or converted to its
chloride (9) as in
scheme 3. Alcohols may be converted to their ether analogs (10) by rhodium
catalyzed insertion
into diazo intermediates 2N+-z-RB, or the amines (11) may be generated from
chlorides (IX)
[0934] Scheme 3
CO2H --A
BH3.THF SOCl2
5 8 9
F= F, Br, CN i) H2NA'.R6 , isoamyl nitrite
A= CH, N HN--zR8
4" 2
2) Nr.z...-le , Rh20Ac4
. I
--A .--A
N ,
\ /
) /
R 0 R 0
¨0 ¨0
[0935] 10 11
- 225 -
CA 3046894 2019-06-18

[0936] Alternatively the bromides (4) may be directly coupled to alcohols or
amines (UV-Z-RB)
whereby U is -OH or ¨NH2 by thermal or metal catalyzed halide displacement as
in scheme 4.
All key intermediates (10-12) may be further modified to produce final
products as described in
scheme 1 using acid hydrolysis, Curtius rearrangement followed by acid
deprotection
Scheme 4
, \
N
0 0
--O --O
[0937] 4 12
[0938] Example 57. Receptor Binding Assays
[0939] Binding affinity of compounds of Formula I-XII were determined based on
their ability
to displace tritiated lysophosphatidic acid ([31-1]-LPA) from CHO cells
expressing LPA1R in a
protocol similar to that described in reference 17. In a 96 well format, CHO
cells expressing
human LPA1R [Cerep] were treated with [31-1]-LPA (2nM). Test compounds were
added in
increasing concentration to each well and incubated at room temperature for 90
minutes. At this
time the plates were washed and the wells counted for radioactivity. Results
were compared to
a control in which cells were treated with [31-1]-LPA in the presence of 10pM
unlabeled LPA. The
specific ligand binding to the receptors was defined as the difference between
the total binding
and the nonspecific binding determined in the presence of an excess of
unlabelled ligand. The
results were expressed as a percent of control specific binding ((measured
specific
binding/control specific binding) x 100) and as a percent inhibition of
control specific binding
(100-((measured specific binding/control specific binding) x 100)) obtained in
the presence of
the test compounds. The IC50 value (concentration causing a half-maximal
inhibition of control
specific binding) and Hill coefficient (nH) were determined by non-linear
regression analysis of
the competition curve generated with mean replicate values using Hill equation
curve fitting (Y =
- 226 -
CA 3046894 2019-06-18

D + [(A ¨ D)/(1 + (C/C50)nH)], where Y = specific binding, D = minimum
specific binding, A =
maximum specific binding, C = compound concentration, C50 = IC50, and nH =
slope factor).
This analysis was performed using a software developed at Cerep (Hill
software) and validated
by comparison with data generated by the commercial software SigmaPlot 4.0
for Windows
(C) 1997 by SPSS Inc.). The inhibition constant (Ki) was calculated using the
Cheng Prusoff
equation (Ki = IC50/(1+(LJKD)), where L = concentration of radioligand in the
assay, and KD =
affinity of the radioligand for the receptor). A scatchard plot was used to
determine the Kd.
[0940] Example 58. Calcium Flux Assay
[0941] Inhibition of LPA-stimulated Ca2+ flux was used to assess compound
potency using
FLIPR technology in a 96 well plate format. The assay buffer used was a
modified Hanks
Balanced Salt Solution (HBSS) where HBSS was supplemented to contain 20mM
HEPES and
2.5mM Probenecid at pH7.4 (Millipore, GPCR Profiler). LPA1R expressing cells
(Millipore)
were plated and prepared 24 hours prior to assay of test articles. Ca2+ ion
flux was assessed
from fluorescence of a Fluo-based No Wash Ca24 dye. Antagonist data are
generated from
plates with LPA concentrations sufficient to generate 80% efficacy [EC80].
Percentage inhibition
was calculated from a reduction of efficacy according to concentration of
compounds of Formula
I-VI. For dose responses the inhibition data was used to calculate compound
IC50.
[0942] The agonist assay was conducted on a FLIPRTETRA instrument where the
test
compound(s), vehicle controls, and reference agonist were added to the assay
plate after a
fluorescence baseline was established. The agonist assay was a total of 180
seconds and was
used to assess each compound's ability to activate each GPCR assayed. Upon
completion of
the agonist assay, the assay plate was removed from the FLIPRTETRA and
incubated at 25 C for
seven (7) minutes. After the incubation period, the assay plate was placed
back in the
FL' pRTETRA and the antagonist assay was initiated.
- 227 -
CA 3046894 2019-06-18

[0943] Antagonist Assay: Using ECK, potency values determined during the
agonist assay,
all pre-incubated sample compound wells were challenged with E080
concentration of reference
agonist after establishment of a fluorescence baseline. The antagonist assay
was conducted
using the same assay plate that was used for the
agonist assay. The antagonist assay was conducted on a FLIPRTETRA instrument
where
9 vehicle controls and EC80 concentration of reference agonist were added to
appropriate wells.
The antagonist assay was a total of 180 seconds and was used to assess each
compound's
ability to inhibit each GPCR assayed.
[0944] Data Processing: All assay plate data were subjected to appropriate
baseline
corrections. After baseline corrections were applied, maximum fluorescence
values were
exported and data processed to calculate percentage activation (relative to
Emax reference
agonist and vehicle control values), percentage inhibition (relative to EC80
and vehicle control
values), and additional statistical values (i.e. Z', percentage variation
between replicate data
values) to assess the quality of each plate. Where assay plate data were
rejected, additional
experiments were conducted. All dose response curves were generated using
GraphPad Prism.
The curves were fit by utilizing "Sigmoidal Dose Response (Variable Slope)"
equation where the
bottom parameter was fixed to "0." Where appropriate, the top parameter was
fixed to "100" to
better predict potency values when a full curve was not generated by the
concentrations
assayed.
[0945] Antagonist activity data for representative compounds prepared
according to the
synthetic methods disclosed herein are presented in Table 2.
[0946] Table 2. In vitro biological data for representative compounds of
Formula I-XII Unless
otherwise noted, compounds that were tested had an IC50 of less than 50 pM in
the LPA1R Ca2+
flux functional assay.
Example LPA1 R Example LPA1 R Example LPA1 R
- 228 -
CA 3046894 2019-06-18

Number Antagonist Number Antagonist Number Antagonist
Activity Activity Activity
1 C 20 A 37 A
2 C 21 A 38 A
3 D 22 A 39 A
4 B 23 A 40 A
A 24 A 41 A
6 D 25 A 42 A
7 D 26 A 43 B
8 D 27 A 44 A
9 D 28 A 45 A
D 29 C 46 C
11 D 30 D 47 B
12 D 30 C 48 C
13 D 31 A 49 A
14 D 31 A 50 A
D 32 A 51 A
16 D 33 A 52 A
17 A 34 A 53 A
18 D 35 A 54 B
19 D 36 A 55 B
56 A
- 229 -
CA 3046894 2019-06-18

[0947] Unless otherwise noted, compounds that were tested had an I050 of less
than 50 pM in
the LPA1R Ca2+ flux functional assay. A = less than 0.3 pM; B = greater than
0.3 pM and
less than 1 pM; C = greater than 1 pM and less than 50 pM; D = greater than 50
pM
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[2] 2) Maiti, Swarupananda; Sridharan, Vellaisamy; Menendez, J. Carlos;
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Combinatorial Chemistry, 2010, vol. 12, # 5 p. 713 ¨ 722
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US2009/36450 Al, 2009
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Heterocyclic
Chemistry, 1985, vol. 22, p. 1621 ¨ 1630
[5] 5) Dehmel, Florian; Abarbri, Mohamed; Knoche!, Paul; Synlett, 2000,
# 3 p. 345 ¨
346
[6] 6) Abarbri, Mohamed; Thibonnet, Jerome; Berillon, Kaurent; Dahmel,
Florian;
Rottlaender, Mario; Knochel, Paul; Journal of Organic Chemistry, 2000, vol.
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[7] 7) Gagnon et al.; Canadian Journal of Chemistry, 1953, vol. 31, p.
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[8] 8) Malki, Fatiha; Touati, Abdelkader; Rahal, Said; Moulay, Saad;
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