NZ792410A - Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator - Google Patents
Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulatorInfo
- Publication number
- NZ792410A NZ792410A NZ792410A NZ79241017A NZ792410A NZ 792410 A NZ792410 A NZ 792410A NZ 792410 A NZ792410 A NZ 792410A NZ 79241017 A NZ79241017 A NZ 79241017A NZ 792410 A NZ792410 A NZ 792410A
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- chosen
- mmol
- groups
- pharmaceutically acceptable
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- 230000000051 modifying Effects 0.000 title 2
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 title 1
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 12
- 150000003839 salts Chemical class 0.000 claims abstract 9
- 239000011780 sodium chloride Substances 0.000 claims abstract 9
- 125000000217 alkyl group Chemical group 0.000 claims 25
- 229910052736 halogen Inorganic materials 0.000 claims 15
- 150000002367 halogens Chemical class 0.000 claims 15
- 125000001424 substituent group Chemical group 0.000 claims 6
- 125000003545 alkoxy group Chemical group 0.000 claims 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000004434 sulfur atoms Chemical group 0.000 claims 1
- 201000003883 cystic fibrosis Diseases 0.000 abstract 1
- 239000002207 metabolite Substances 0.000 abstract 1
Abstract
Compounds of Formula (I), pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed. same are also disclosed.
Description
nds of Formula (I), pharmaceutically acceptable salts thereof, deuterated derivatives
of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical
compositions comprising the same, methods of treating cystic fibrosis using the same, and
methods for making the same are also disclosed.
NZ 792410
Modulator of Cystic Fibrosis Transmembrane Conductance Regulator, Pharmaceutical
Compositions, Methods of Treatment, and Process for Making the Modulator
This application is a divisional application of New Zealand patent application 752486, which
is the national phase entry in New Zealand of PCT international application
(published as
content of each of which are incorporated herein by reference.
Disclosed herein is a modulator of Cystic Fibrosis Transmembrane tance
Regulator (CFTR), pharmaceutical compositions ning the modulator, s of
treatment of cystic fibrosis, and a process for making the modulator.
Cystic is (CF) is a recessive c disease that affects approximately
70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no
cure.
In patients with CF, ons in CFTR endogenously expressed in respiratory
epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid
transport. The ing decrease in anion transport contributes to enhanced mucus
accumulation in the lung and accompanying microbial infections that ultimately cause death
in CF patients. In addition to respiratory disease, CF patients lly suffer from
gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death.
In addition, the majority of males with cystic fibrosis are infertile, and ity is reduced
among females with cystic fibrosis.
Sequence analysis of the CFTR gene has revealed a variety of disease causing
mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell
:870; and Kerem, B-S. et al. (1989) Science 73-1080; Kerem, B-S et al. (1990)
Proc. Natl. Acad. Sci. USA 7-8451). To date, greater than 2000 mutations in the CF
gene have been identified; currently, the CFTR2 database contains information on only 322
of these identified mutations, with sufficient evidence to define 281 mutations as disease
g. The most prevalent disease-causing mutation is a on of phenylalanine at
position 508 of the CFTR amino acid sequence, and is commonly referred to as the F508del
mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is
associated with severe disease.
The deletion of residue 508 in CFTR prevents the nascent protein from folding
correctly. This results in the inability of the mutant protein to exit the endoplasmic lum
(ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for
anion transport present in the membrane is far less than
observed in cells sing wild-type CFTR, i.e., CFTR having no mutations. In
addition to impaired trafficking, the mutation results in defective channel gating.
Together, the reduced number of channels in the membrane and the defective gating
lead to d anion and fluid transport across epitheha. (Quinton, P. M. (1990),
FASEB J. 4: 2709-2727). The channels that are defective because of the F508del
mutation are still functional, albeit less onal than wild-type CFTR channels.
ans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell.
Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in
CFTR that result in defective trafficking, synthesis, and/or channel gating could be upor
down-regulated to alter anion secretion and modify disease progression and/or
severity.
CFTR is a cAMP/ATP-mediated anion channel that is sed in a variety
of cell types, including absorptive and secretory lia cells, where it tes anion
flux across the membrane, as well as the activity of other ion channels and proteins. In
epithelial cells, normal functioning of CFTR is critical for the nance of
electrolyte transport throughout the body, including respiratory and digestive tissue.
CFTR is composed of approximately 1480 amino acids that encode a protein which is
made up of a tandem repeat of transmembrane domains, each containing six
transmembrane helices and a nucleotide binding domain The two transmembrane
domains are linked by a large, polar, regulator}' (R)-domain with multiple
phosphory lation sites that regulate channel activity and cellular trafficking.
Chloride ort takes place by the coordinated activity of ENaC and CFTR
present on the apical membrane and the Na+-K+-ATPase pump and CT channels
expressed on the basolateral surface of the cell. Secondary' active ort of chloride
from the luminal side leads to the accumulation of intracellular chloride, which can then
ely leave the cell via Cl" channels, resulting in a vectorial transport. Arrangement
of Na+/2C17K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+
channels on the basolateral surface and CFTR on the luminal side coordinate the
secretion of chloride via CFTR on the luminal side. e water is probably never
actively transported itself, its flow across epithelia depends on tiny transepithelial
osmotic gradients ted by the bulk flow of sodium and chloride.
Accordingly, there is a need for novel treatments of CFTR ed diseases.
SUBSTITUTE SHEET (RULE 26)
sed herein are novel compounds, including compounds of Formulae I-
IV and pharmaceutically acceptable salts thereof. For example, compounds of Formula
I can be depicted as:
9 o x
...A., N
S,R’r L-ArV
or a pharmaceutically acceptable salt thereof,
wherein:
- one of Y1 and Y2 is N and the other is CH;
- X is chosen from 0, NH, and N(Ci-C4 alkyl) groups;
- R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups,
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens,
wherein each R is ndently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R2 is ndently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is ndently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently a halogen;
- k is 0 or 1;
- ris 0 or 1;
- mis 0,1, 2, or 3;
- n is 0 or 1;
- p is 0, 1, 2, 3, 4, or 5; and
- qis 0, 1, 2, 3, 4, 5, 6, 7, or 8.
SUBSTITUTE SHEET (RULE 26)
Also disclosed herein are pharmaceutical compositions comprising at least
one of the novel compounds disclosed herein and/or at least one pharmaceutically
acceptable salt thereof, which compositions may further include at least one additional
active pharmaceutical ingredient and/or at least one carrier. Also disclosed are methods
of treating the CFTR-mediated disease cystic fibrosis comprising stering at least
one of the novel compounds disclosed herein and/or at least one pharmaceutically
acceptable salt thereof, optionally as part of a pharmaceutical composition comprising at
least one additional component, to a subject in need thereof.
Also disclosed are methods of treating the CFTR-mediated disease cystic
fibrosis sing administering at least one of the novel compounds disclosed herein
and/or at least one pharmaceutically acceptable salt thereof, -(2.2-
difluorobenzo[d][l,3]dioxolyl)-N-(l-(2,3-dihydroxypropyl)fluoro(l-hydroxy-
ylpropanyl)-lH-mdolyl)cyclopropanecarboxamide (Compound II), andN-
[2,4-bis(l,l-dimethylethyl)hydroxyphenyl]-l,4-dihydrooxoquinoline
carboxamide (Compound III), optionally as part of at least one pharmaceutical
ition comprising at least one additional component, to a t in need thereof.
Brief Description of the Drawings
shows the structures of non-limiting examples of novel compounds
disclosed herein.
is a X-ray Powder ctogram (“XRPD”) of a spray dried
dispersion (SDD) of 50% Compound 1 in HPMCAS-HG.
is a spectrum showing a modulated differential scanning calorimetry
(MDSC) spectrum of a spray dried dispersion (SDD) of 50% Compound 1 in
HPMCAS-HG.
is a entative list of CFTR genetic mutations.
is an XRPD of a sample of the sodium salt of nd 1 prepared
as reported in the e of the sodium salt of Compound 1.
Definitions
As used herein, the term “alkyl” refers to a saturated, branched or
unbranched aliphatic hydrocarbon containing carbon atoms (such as, for example, 1, 2,
SUBSTITUTE SHEET (RULE 26)
3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13,14, 15,16,17,18,19, or 20 carbon atoms). Alkyl
groups may be substituted or unsubstituted.
The term “alkoxy” as used herein refers to an alky l or cycloalkyl covalently
bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.
As used herein, “cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or
clic non-aromatic hydrocarbon groups having 3 to 12 s (such as, for
example 3-10 carbons). “Cycloalkyf’ groups encompass monocyclic, bicyclic, tricyclic,
bridged, fused, and spiro rings, including mono spiro and dispiro rings. Non-limiting
examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
adamantyl, norbomyl, and o[2.0.2.1]heptane. Cycloalkyl groups may be
substituted or unsubstituted.
“Substituted,” whether preceded by the term “optionally” or not, tes
that at least one hydrogen of the “substituted” group is replaced by a substituent. Unless
otherwise indicated, an “optionally substituted” group may have a suitable substituent at
each substitutable position of the group, and when more than one position in any given
structure may be substituted with more than one tuent chosen from a ied
group, the substituent may be either the same or different at each position.
As used herein, “deuterated derivative(s)” means the same chemical structure,
but with one or more en atoms replaced by a deuterium atom.
As used herein, “CFTR” means cystic fibrosis transmembrane conductance
regulator.
As used herein, “mutations” can refer to mutations in the CFTR gene or the
CFTR protein. A “CFTR gene on” refers to a on in the CFTR gene, and a
“CFTR protein mutation” refers to a mutation in the CFTR protein. A genetic defect or
mutation, or a change in the nucleotides in a gene in general results in a mutation in the
CFTR protein translated from that gene, or a frame shift(s).
The term “F508del” refers to a mutant CFTR protein which is lacking the
amino acid phenylalanine at on 508.
As used herein, a patient who is “homozygous” for a particular gene mutation
has the same mutation on each allele.
SUBSTITUTE SHEET (RULE 26)
As used , a patient who is ‘‘heterozygous” for a particular gene
mutation has this mutation on one allele, and a different mutation on the other .
As used herein, the term “modulator” refers to a nd that increases the
activity of a biological compound such as a protein. For example, a CFTR modulator is
a compound that increases the activity of CFTR. The increase in activity resulting from
a CFTR modulator includes but is not d to compounds that correct, potentiate,
stabilize and/or amplify CFTR.
As used herein, the term “CFTR corrector” refers to a compound that
facilitates the processing and trafficking of CFTR to se the amount of CFTR at the
cell surface. Compounds of Formulae (I), (It), (III), (IV), and (V), and Compound II,
and their pharmaceutically acceptable salts thereof disclosed herein are CFTR
correctors.
As used herein, the term “CFTR potentiator” refers to a compound that
ses the channel activity of CFTR protein located at the cell surface, resulting in
ed ion transport. Compound III disclosed herein is a CFTR potentiator.
As used herein, the term “active pharmaceutical ingredient” (“API”) refers to
a biologically active compound.
As used herein, the term “pharmaceutically acceptable salt” refers to a salt
form of a compound of this disclosure wherein the salt is nontoxic. Pharmaceutically
acceptable salts of the compounds of this disclosure include those derived from suitable
inorganic and organic acids and bases. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable
salts in detail in J. ceutical Sciences, 1977, 66, 1-19.
As used herein, the term “amorphous” refers to a solid material having no long
range order in the position of its les. Amorphous solids are generally
supercooled liquids in which the les are arranged in a random manner so that
there is no well-defined arrangement, e.g., molecular packing, and no long range order.
Amorphous solids are generally isotropic, i.e. t similar properties in all directions
and do not have definite melting points. For e, an amorphous material is a solid
material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction
(XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several
SUBSTITUTE SHEET (RULE 26)
broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of
an amorphous solid. See, US 2004/0006237 for a comparison of XRPDs of an
amorphous material and crystalline material.
As used herein, the term "substantially amorphous" refers to a solid material
having little or no long range order in the position of its molecules. For example,
substantially amorphous materials have less than 15% crystallinity (e g., less than 10%
crystallinity or less than 5% crystallinity). It is also noted that the term 'substantially
amorphous' includes the descriptor, hous', which refers to als having no
(0%) crystallinity.
As used herein, the term "dispersion" refers to a disperse system in which one
substance, the dispersed phase, is distributed, in discrete units, throughout a second
nce (the continuous phase or vehicle). The size of the sed phase can vary
considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in
size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a
solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical
ations, a solid dispersion can e a crystalline drug (dispersed phase) in an
amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed
phase) in an amorphous polymer (continuous phase). In some embodiments, a solid
dispersion includes the polymer tuting the dispersed phase, and the drug constitute
the continuous phase. Or, a solid dispersion includes the drug constituting the dispersed
phase, and the polymer constituting the continuous phase.
The terms “patient"’ and “subject” are used interchangeably and refer to an
animal including humans.
The terms "effective dose" and "effective amount" are used interchangeably
herein and refer to that amount of a compound that produces the desired effect for which
it is administered (e.g., improvement in CF or a symptom of CF, or lessening the
severity of CF or a symptom of CF). The exact amount of an effective dose will depend
on the purpose of the ent, and will be ainable by one skilled in the art using
known techniques (see, e.g., Lloyd (1999) The Art, e and Technolog}' of
Pharmaceutical Compounding).
SUBSTITUTE SHEET (RULE 26)
As used herein, the terms "treatment," "treating," and the like generally mean
the improvement of CF or its symptoms or lessening the ty of CF or its symptoms
in a subject. “Treatment,” as used herein, includes, but is not limited to, the following:
increased growth of the subject, increased weight gain, reduction of mucus in the lungs,
improved pancreatic and/or liver function, reduction of chest infections, and/or
reductions in coughing or shortness of breath. ements in or lessening the
severity of any of these symptoms can be readily assessed according to standard
methods and techniques known in the art.
As used herein, the term “in combination with,” when referring to two or
more compounds, , or additional active pharmaceutical ingredients, means the
administration of two or more compounds, agents, or active pharmaceutical ingredients
to the patient prior to, concurrent with, or subsequent to each other.
The terms “about” and “approximately”, when used in connection with doses,
amounts, or weight percent of ients of a composition or a dosage form, include
the value of a ied dose, amount, or weight percent or a range of the dose, amount,
or weight percent that is recognized by one of ordinary skill in the art to provide a
pharmacological effect equivalent to that obtained from the specified dose, amount, or
weight percent.
Each of Compounds of Formulae (I), (II), (III), (IV), and (V), and
nds II, III, IV, and ceutically able salts thereof described, and
their deuterated derivatives herein independently can be administered once daily, twice
daily, or three times daily. In some embodiments, at least one compound chosen from
Compounds of Formulae (I), (II), (III), (IV), and (V), and pharmaceutically acceptable
salts thereof, and their deuterated derivatives is administered once daily. In some
embodiments, at least one compound chosen from Compounds of Formulae (I), (II),
(III), (IV), and (V), and pharmaceutically acceptable salts thereof, and their deuterated
derivatives are stered twice daily. In some embodiments, at least one compound
chosen from Compound II and pharmaceutically acceptable salts thereof is stered
once daily. In some embodiments, at least one compound chosen from nd II
and pharmaceutically acceptable salts thereof is stered twice daily. In some
ments, at least one compound chosen from Compound III and pharmaceutically
acceptable salts thereof is administered once daily. In some embodiments, at least one
SUBSTITUTE SHEET (RULE 26)
compound chosen from Compound III and ceutically acceptable salts thereof is
administered twice daily. In some ments, at least one compound chosen from
nd IV and pharmaceutically acceptable salts thereof is administered once daily.
In some embodiments, at least one compound chosen from Compound IV and
pharmaceutically acceptable salts thereof is administered twice daily. In some
embodiments, a deuterated derivative of Compound II, III, and/or IV or a
pharmaceutically acceptable salt thereof is employed in any one of these embodiments.
In some embodiments, 10 mg to 1,500 mg of a compound disclosed herein, a
pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound
or salt are administered daily.
One of ordinary skill in the art would recognize that, when an amount of “a
compound or a pharmaceutically acceptable salt thereof’ is disclosed, the amount of the
pharmaceutically acceptable salt form of the compound is the amount equivalent to the
concentration of the free base of the compound. It is noted that the disclosed amounts of
the compounds or their pharmaceutically able salts thereof herein are based upon
their free base form. For example, “10 mg of at least one compound chosen from
compounds of Formula (I) and ceutically acceptable salts thereof’ includes 10
mg of a compound of Formula (I) and a concentration of a pharmaceutically acceptable
salt of compounds of Formula (I) equivalent to 10 mg of nds of Formula (I).
As stated above, disclosed herein are compounds of Formula (I):
0 0. X
(R2)P
/ N Y' N
R1 -r (R3)q
and pharmaceutically acceptable salts f,
wherein:
- one of Y1 and Y2 is N and the other is CH;
- X is chosen from 0, NH, and N(Ci-C4 alkyl) groups;
SUBSTITUTE SHEET (RULE 26)
- R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups,
wherein each Ring A is ndently chosen from C3-C10 cycloalkyl groups
optionally substituted with one or more substituents each independently chosen
from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens, and
wherein each R is independently chosen from H, OH, and C1-C2 alkyl groups
optionally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl , OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- k is 0 or 1;
- r is 0 or 1;
- mis 0,1, 2, or 3;
- n is 0 or 1;
- p is 0, 1, 2, 3, 4, or 5; and
- qis 0, 1, 2, 3, 4, 5, 6, 7, or 8.
Also disclosed herein are compounds of Formula (II):
0 Q XV//
H X(R2)p
R1 -r (R3)q
(r4),
and pharmaceutically acceptable salts thereof,
- X is chosen from O, NH, and N(Ci-C4 alkyl) groups;
- R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups,
wherein each Ring A is independently chosen from C3-C10 lkyl
groups optionally substituted with one or more substituents each independently
SUBSTITUTE SHEET (RULE 26)
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl , and halogens,
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups ally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- k is 0 or 1;
- r is 0 or 1;
- mis 0,1, 2, or 3;
- n is 0 or 1;
- p is 0, 1,2, 3, 4, or 5; and
- qis 0, 1,2, 3, 4, 5, 6, 7, or 8.
Encompassed within the scope of ae (I) and (II) are compounds
0 0
0 0
^ /NR'2 \^NRs
comprising an - or n group
(where R’ is H or C1-C4 alkyl), i.e., wherein X is chosen from NH and N(Ci-C4 alkyl)
groups. Non-limiting examples of such compounds include compounds having the
following structure:
mO \\ // N
rvs-.N W^o
O F
SUBSTITUTE SHEET (RULE 26)
and pharmaceutically able salts thereof, either as a isomeric mixture or
enantioenriched (e.g., >90% ee, >95% ee, or >98% ee) isomers.
Also disclosed herein are compounds of a (III):
o 0 0V/
H X(R2)p
N N N
(R3)q
(R4)r
(III)
and pharmaceutically acceptable salts thereof,
wherein:
- R1 is chosen from -(CR2)k(CR2)ra(CR)n(Ring A)n+i groups,
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally tuted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens,
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, ns, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- k is 0 or 1;
- ris 0 or 1;
- mis 0,1, 2, or 3;
- n is 0 or 1;
- p is 0, 1, 2, 3, 4, or 5; and
- qis 0, 1,2, 3, 4, 5, 6, 7, or 8.
SUBSTITUTE SHEET (RULE 26)
In some embodiments, in compounds of Formula (I), (II), (III), and
pharmaceutically acceptable salts f, if R2 is cyano, then R2 is meta or para relative
to the sulfur atom.
In some embodiments, in compounds of Formula (I), (II), (III), and
pharmaceutically able salts thereof:
- each Ring A is independently chosen from C3-C10 cycloalkyl groups optionally
tuted with one or more substituents each independently chosen from C1-C2 alkyl
groups, halogenated C1-C2 alkyl groups, and ns, and
- each R is independently chosen from H and OH;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups,
and halogens;
- R4 is F;
- k is 0;
- p is 0,1, or 2;
- q is 0,1,2, 3, or 4;
- r is 0; and
- m and n are not 0 at the same time.
In some embodiments, in compounds of Formula (I), (II), (III), and
pharmaceutically acceptable salts thereof:
- R1 is chosen from (CR2)m-R'ng A groups,
wherein Ring A is chosen from C3-C10 cycloalkyl groups optionally substituted
with one or more substituents each independently chosen from C1-C2 alkyl
groups, halogenated C1-C2 alkyl groups, and ns, and
- m is 1 or 2.
In some embodiments, in compounds of Formula (I), (II), (III), and
pharmaceutically acceptable salts thereof, each R3 is a methyl group and q is 3 or 4.
Also disclosed herein are compounds of Formula (IV):
° °v ,° ¥
r^X^N'" K X<R2)P
Ring A r N N N
SUBSTITUTE SHEET (RULE 26)
and pharmaceutically acceptable salts thereof,
wherein:
- Ring A is chosen from CN-Cio cycloalkyl groups optionally substituted with
one or more substituents each independently chosen from C1-C2 alkyl groups,
halogenated C1-C2 alkyl groups, and halogens; and
- each R2 is independently chosen from C1-C2 alkyl groups, OH, F, Cl, and Ci-
C2 alkoxy groups;
- m is 1 or 2; and
- p is 0, 1, or 2. In some ments, p is 0 or 1. In some embodiments, p is 0.
Also disclosed herein are compounds of Formula V:
0 0 Ov
H X(r2)p
J(t0 N\ XX
Ring A ' N N N
and pharmaceutically acceptable salts thereof,
wherein:
- Ring A is chosen from C3-C10 cycloalkyl groups optionally substituted with
one or more substituents each independently chosen from C1-C2 alkyl groups,
nated C1-C2 alkyl groups, and halogens; and
- each R2 is independently chosen from C1-C2 alkyl groups, OH, F, Cl, and Ci-
C2 alkoxy groups;
- m is 1 or 2; and
- p is 0, 1, or 2.
In some embodiments, in compounds of Formula (I), (II), (III), (IV), (V), and
ceutically acceptable salts f, each R2 is independently chosen from CH3,
OH, F, and OCH3. In some embodiments, p is 0 or 1. In some embodiments, p is 0.
In some embodiments, in compounds of Formula (I), (II), (III), (IV), (V), and
pharmaceutically acceptable salts thereof, Ring A is a cyclopropyl group substituted
SUBSTITUTE SHEET (RULE 26)
with a halogenated Ci alkyl group or a halogenated C2 alky] group. In some
embodiments, Ring A is a cyclopropyl group substituted with a CF3 group.
In some embodiments, in compounds of Formula (I), (II), (III), (IV), (V), and
pharmaceutically acceptable salts thereof, m is 1, Ring A is a cyclopropyl group
substituted with a CF3 group, p is 0 or 1, and R2, if t, is a methyl group, a hydroxy
group, or a methoxy group. In some embodiments, m is 2, Ring A is a cyclopropyl
group substituted with a CF3 group, and p is 0.
In some embodiments, in compounds of Formula (I), (II), (III), (IV), (V), and
pharmaceutically acceptable salts f, m is 2, Ring A is a C3 cycloalkyl group
substituted with a CF3 group, p is 0 or 1, and R2, if present, is a methyl group, a hydroxy
group, or a methoxy group. In some embodiments, m is 2, Ring A is a cyclopropyl
group substituted with a CF3 group, and p is 0.
In some ments, m is 2, Ring A is a cyclopropyl group substituted with
aCF3 group, and p is 0.
In some embodiments, in compounds of Formula (I), (II), (III), (IV), (V), and
pharmaceutically acceptable salts thereof, Ring A is chosen from C5 oalkyl groups
optionally substituted with one or more substituents each independently chosen from
C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens. In some
embodiments, Ring A is a C5 bicycloalkyl group optionally substituted with a halogen.
In some embodiments, in compounds of Formula (I), (II),(III), (IV), (V), and
pharmaceutically acceptable salts thereof, Ring A is chosen from C7 bicycloalkyl
groups and ycloalkyl groups optionally substituted with one or more substituents
each ndently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups,
and halogens. In some embodiments, Ring A is an unsubstituted C7tricycloalkyl group.
Also disclosed herein are compounds having a formula chosen from any one
of the formulae depicted in and pharmaceutically acceptable salts thereof.
Also sed herein are Compounds 1-5, 8, 10-16,18-30, 32, 33, 35-37, 39-
60, 63, and 64, and pharmaceutically acceptable salts thereof.
Also disclosed herein are Compounds 9, 31, 34, 38, 61, 62, and 65, and
pharmaceutically acceptable salts thereof.
Also sed herein are Compounds 6, 7, and 17, and pharmaceutically
acceptable salts thereof.
SUBSTITUTE SHEET (RULE 26)
Also disclosed herein are ated derivatives of any one of Compounds 1-
, 8,10-16,18-65, and pharmaceutically acceptable salts thereof.
Also disclosed herein are a compound having the following formula:
rf^rVS"Ph
O—P N N N-A(S)
and pharmaceutically acceptable salts thereof
Also sed herein are a compound having the following formula:
O o n 0H
(s)\^
0 N N
and pharmaceutically acceptable salts thereof.
Also disclosed herein are a compound having the following formula:
0 // N N N M OH
and pharmaceutically acceptable salts thereof.
Also disclosed herein are a nd having the following formula:
n-n^n^n H
,0 m.
SUBSTITUTE SHEET (RULE 26)
and pharmaceutically acceptable salts thereof.
Also disclosed herein are a compound having the following formula:
0 0 o F
QXr N N N"\S) ^
and pharmaceutically acceptable salts thereof.
Also disclosed herein are a compound having the following a:
.s\\//
N"N^N N k(S)
and pharmaceutically acceptable salts thereof.
Also disclosed herein are a compound having the following formula:
p // N N nA(S)
and pharmaceutically acceptable salts thereof.
In some embodiments, at least one novel nd (and/or at least one
pharmaceutically acceptable salt thereof and/or at least one ated derivative of such
compound or salt) can be administered in combination with at least one additional active
pharmaceutical ingredient. In some embodiments, at least one additional active
ceutical ingredient is chosen from:
(a) Compound II:
SUBSTITUTE SHEET (RULE 26)
FX J0 OH
F 0 ^ 0
F N / NH;
OH and pharmaceutically
acceptable salts f.
A chemical name for Compound II is (//)-!-(2.2-diriuorobenzo|d|| 1.3 |dio\olyl)-/V-
(l-(2,3-dihydroxypropyl)fluoro(l-hydroxymethylpropanyl)-lH-indol
yl)cyclopropanecarboxamide;
(b) Compound III:
H and pharmaceutically acceptable salts thereof
A chemical name for Compound III is ,V-(5-hydroxy-2.4-di-/m-biityl-phenyl)oxolH-quinolinecarboxamide
; and
(c) Compound IV:
0^,0 H
Ka ^ 0 H nV'N^X^
and pharmaceutically
acceptable salts f
A chemical name for Compound IV is l-(2,2-difluorobenzo[d][l,3]dioxol
yl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid.
Suitable pharmaceutically acceptable salts are, for example, those sed
in S. M. Berge, etal. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1
of that article provides the following pharmaceutically acceptable salts:
SUBSTITUTE SHEET (RULE 26)
Table 1:
Acetate Iodide Benzathine
Benzenesulfonate Isethionate Chloroprocaine
Benzoate Lactate Choline
Bicarbonate Lactobionate Diethanolamine
Bitartrate Malate Ethylenediamine
Bromide Maleate Meglumine
Calcium e Mandelate Procaine
Camsylate Mesylate Aluminum
Carbonate bromide Calcium
Chloride Methylnitrate Lithium
Citrate Methylsulfate Magnesium
Dihydrochloride Mucate Potassium
Edetate Napsylate Sodium
Edisylate Nitrate Zinc
Estolate Pamoate (Embonate)
Esylate Pantothenate
Fumarate Phosphate/diphosphate
Gluceptate lacturonate
Gluconate Salicylate
Glutamate te
Glycollylarsanilate Subacetate
Hexylresorcinate Succinate
Hydrabamine Sulfate
Hydrobromide e
Hydrochloride Tartrate
Hy droxy naphthoate te
Triethiodide
Non-limiting examples of pharmaceutically acceptable salts derived from
appropriate acids include: salts formed with inorganic acids, such as hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid, or oric acid; salts formed with
organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,
succinic acid or c acid; and salts formed by using other methods used in the art,
such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts
include adipate, te, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, e, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
ophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-
hydroxy-ethanesulfonate, ionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nate, nitrate, oleate, oxalate,
SUBSTITUTE SHEET (RULE 26)
palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,
pivalate, propionate, stearate, succinate, e, tartrate, thiocyanate, ptoluenesulfonate
, undecanoate, and valerate salts. ceutically acceptable salts
derived from appropriate bases e alkali metal, alkaline earth metal, ammonium,
and N+(Ci.4alkyl)4 salts. This disclosure also envisions the quatemization of any basic
nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting
es of alkali and alkaline earth metal salts include sodium, lithium, potassium,
calcium, and magnesium. Further non-limiting examples of pharmaceutically
acceptable salts include ammonium, quaternary7 ammonium, and amine s formed
using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate,
lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of
pharmaceutically acceptable salts include besylate and glucosamine salts.
In some embodiments, at least one compound chosen from the novel
nds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated
derivatives of the foregoing is administered in combination with at least one compound
chosen from Compound II, pharmaceutically acceptable salts thereof, and ated
derivatives of the foregoing. In some embodiments, at least one compound chosen from
the novel compounds disclosed herein, pharmaceutically acceptable salts f, and
deuterated tives of the ing is administered in combination with at least one
compound chosen from Compound III and pharmaceutically acceptable salts thereof. In
some embodiments, at least one compound chosen from the novel compounds disclosed
herein, pharmaceutically able salts thereof, and deuterated derivatives of the
foregoing is stered in combination with at least one compound chosen from
Compound IV and pharmaceutically acceptable salts thereof. In some embodiments, at
least one compound chosen from the novel compounds sed herein,
pharmaceutically acceptable salts, and deuterated tives of the foregoing thereof is
administered in combination with Compounds II or a pharmaceutically acceptable salt
or deuterated tive thereof and at least one compound chosen from Compound III,
pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the
ing. In some embodiments, at least one nd chosen from the novel
compounds disclosed herein, pharmaceutically acceptable salts, and deuterated
derivatives of any of the foregoing thereof is administered in combination with at least
one compound chosen from Compound III, pharmaceutically acceptable salts thereof,
SUBSTITUTE SHEET (RULE 26)
and deuterated tives of any of the foregoing and at least one compound chosen
from Compound IV, pharmaceutically acceptable salts thereof, and deuterated
derivatives of any of the foregoing.
Any of the novel compounds disclosed herein, such as for example,
compounds of Formula (I), (II), (III), (IV), (V), and their pharmaceutically acceptable
salts thereof, and ated derivatives of such compounds and salts can be comprised
in a single pharmaceutical composition or separate pharmaceutical compositions in
combination with other additional active pharmaceutical ingredient(s) (e g., Compound
II, III, or IV, or its ceutically acceptable salt thereof, or a ated tive of
such Compound or salt). Such pharmaceutical compositions can be administered once
daily or multiple times daily, such as twice daily. In some embodiments, the disclosure
features a pharmaceutical composition comprising at least one compound chosen from
any of the nds disclosed herein and pharmaceutically acceptable salts thereof,
and at least one pharmaceutically able carrier.
In some embodiments, the disclosure features a pharmaceutical composition
comprising at least one compound chosen from the novel compounds disclosed herein
and pharmaceutically acceptable salts thereof, at least one compound chosen from
Compound II and pharmaceutically acceptable salts thereof, and at least one
pharmaceutically acceptable carrier.
In some embodiments, the disclosure features a pharmaceutical ition
comprising at least one compound chosen from the novel compounds disclosed herein
and pharmaceutically acceptable salts thereof, at least one compound chosen from
Compound III and pharmaceutically acceptable salts thereof, and at least one
pharmaceutically acceptable carrier.
In some embodiments, the disclosure features a pharmaceutical composition
comprising at least one compound chosen from the novel compounds disclosed herein
and pharmaceutically able salts thereof, at least one compound chosen from
Compound II and pharmaceutically acceptable salts thereof, at least one compound
chosen from Compound III and pharmaceutically acceptable salts thereof, and at least
one ceutically acceptable carrier.
SUBSTITUTE SHEET (RULE 26)
In some embodiments, the sure es a pharmaceutical composition
comprising at least one compound chosen from the novel compounds disclosed herein
and pharmaceutically acceptable salts f, at least one compound chosen from
Compound III and pharmaceutically acceptable salts thereof, at least one compound
chosen from Compound IV and pharmaceutically acceptable salts thereof, and at least
one pharmaceutically acceptable carrier.
In some embodiments, pharmaceutical compositions disclosed herein
comprise at least one additional active pharmaceutical ingredient. In some
embodiments, the at least one additional active pharmaceutical ingredient is a CFTR
tor. In some embodiments, the at least one additional active pharmaceutical
ingredient is a CFTR corrector. In some embodiments, the at least one additional active
pharmaceutical ingredient is a CFTR iator. In some embodiments, the
pharmaceutical composition comprises (i) a compound of Formulae (I), (II), (III), (IV),
or (V), or a pharmaceutically acceptable salt thereof, or a deuterated tive of such
nd or salt; and (ii) at least two additional active pharmaceutical ingredients, one
of which is a CFTR corrector and one of which is a CFTR potentiator.
In some embodiments, at least one additional active pharmaceutical ingredient
is selected from mucolytic , bronchodialators, antibiotics, anti-infective agents,
and anti-inflammatory agents.
A pharmaceutical composition may further comprise at least one
pharmaceutically acceptable carrier. In some embodiments, the at least one
pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable
vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least
one pharmaceutically acceptable is chosen from ceutically acceptable fillers,
disintegrants, surfactants, binders, lubricants.
It will also be iated that a ceutical ition of this
sure, including a pharmaceutical composition comprising combinations described
previously , can be employed in combination therapies; that is, the compositions can be
administered concurrently with, prior to, or subsequent to, at least one additional active
pharmaceutical ingredient or medical procedures.
SUBSTITUTE SHEET (RULE 26)
Pharmaceutical compositions comprising these combinations are useful for
treating cystic fibrosis.
As described above, pharmaceutical compositions disclosed herein may
ally further comprise at least one pharmaceutically acceptable carrier. The at least
one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles.
The at least one pharmaceutically acceptable carrier, as used herein, includes any and all
solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active
agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid
binders, and lubricants, as suited to the particular dosage form desired. Remington: The
Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott
Williams & Wilkins, Philadelphia, wA Encyclopedia of Pharmaceutical Technology,
eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses
various earners used in formulating ceutical compositions and known ques
for the preparation f. Except insofar as any conventional carrier is incompatible
with the compounds of this disclosure, such as by ing any undesirable biological
effect or otherwise cting in a rious manner with any other component(s) of
the pharmaceutical composition, its use is plated to be within the scope of this
disclosure. Non-limiting es of le pharmaceutically acceptable carriers
include, but are not limited to, ion exchangers, alumina, um stearate, in,
serum proteins (such as human serum albumin), buffer substances (such as phosphates,
glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated
vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts),
dal silica, magnesium trisilicate, polyvinyl pyrrohdone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose,
glucose and sucrose), starches (such as com starch and potato starch), ose and its
derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and
suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, com oil and soybean oil), glycols (such as propylene glycol and polyethylene
glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffenng agents (such as
magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water,
isotonic saline, Ringer's solution, ethyl l, phosphate buffer solutions, non-toxic
SUBSTITUTE SHEET (RULE 26)
compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), ng
agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming
, preservatives, and antioxidants.
It will also be appreciated that a pharmaceutical composition of this
disclosure, including a pharmaceutical composition comprising any of the combinations
described previously, can be employed in combination therapies; that is, the
compositions can be administered concurrently with, prior to, or subsequent to, at least
one active pharmaceutical ingredients or medical procedures.
In some embodiments, the methods of the disclosure employ stering to
a patient in need thereof at least one compound chosen from any of the compounds
disclosed herein and ceutically acceptable salts thereof, and at least one
compound chosen from Compound II, Compound III, Compound IV, and
pharmaceutically acceptable salts of any of the foregoing.
Any le pharmaceutical compositions known in the art can be used for
the novel compounds sed herein, Compound II, Compound III, Compound IV,
and pharmaceutically acceptable salts thereof. Some exemplary ceutical
itions for Compound 1 and its pharmaceutically acceptable salts are described in
the Examples. Some exemplary pharmaceutical compositions for Compound II and its
pharmaceutically acceptable salts can be found in
2014/015841, all of which are incorporated herein by reference. Some exemplary
pharmaceutical compositions for Compound III and its ceutically acceptable
salts can be found in
2012/027731, and
Some exemplary pharmaceutical compositions for Compound IV and its
ceutically able salts can be found in
reference.
In some embodiments, a pharmaceutical composition comprising at least one
compound chosen from the novel compounds disclosed herein and pharmaceutically
acceptable salts thereof is administered with a pharmaceutical composition comprising
Compound II and Compound III. Pharmaceutical compositions comprising nd
II and Compound III are disclosed in PCT Publication No.
SUBSTITUTE SHEET (RULE 26)
incorporated herein by reference. An exemplary embodiment is shown in the following
Table:
Table 2. Exemplary Tablet Comprising 100 mg of Compound II and 150
mg of Compound III.
ient Amount per tablet (mg)
nd II SDD (spray
dried dispersion)
Intra-granular 125
(80 wt % Compound II, 20
wt % HPMC)
Compound III SDD
(80 wt % Compound III,
19.5 wt% HPMCAS-HG; 187.5
0.5 wt% sodium lauryl
sulfate)
Microcrystalline cellulose 131.4
Croscarmellose Sodium 29.6
Total 473.5
Extra-granular Microcrystalline cellulose 112.5
Magnesium Stearate 5.9
Total 118.4
Total uncoated Tablet 591.9
Film coat Opadry 11,1
Total coated Tablet 609.6
In some embodiments, a pharmaceutical composition comprising at least one
nd chosen from the novel compounds disclosed herein and ceutical salts
thereof is administered with a pharmaceutical composition comprising Compound III.
ceutical compositions comprising Compound III are disclosed in PCT
Publication No.
embodiment is shown in the following Table:
Table 3: Ingredients for Exemplary Tablet of Compound III.
Tablet Formulation Percent Dose Dose Batch
%Wt./Wt. (mg) (g)
SUBSTITUTE SHEET (RULE 26)
Compound III SDD
(80 wt % Compound III, 19.5 wt%
HPMCAS-HG; 0.5 wt% sodium lauryl
____________sulfate)____________ 34.09% 187.5 23.86
Microcrystalline cellulose 30.51% 167.8 21.36
Lactose 30.40% 167.2 21.28
Sodium croscarmellose 3.000% 16.50 2.100
SLS 0.500% 2.750 0.3500
Colloidal silicon dioxide 0.500% 2.750 0.3500
Magnesium te 1.000% 5.500 0,7000
Total 100% 550 70
Additional pharmaceutical compositions comprising Compound III are
disclosed in PCI Publication No.
Exemplary mini-tablets (~2 mm diameter, ~2 mm thickness, each mini-tablet weighing
about 6.9 mg) was formulated to have approximately 50 mg of Compound III per 26
mini-tablets and approximately 75 mg of Compound III per 39 mini-tablets using the
amounts of ingredients recited in Table 4, below.
Table 4: ients for mini-tablets for 50 mg and 75 mg potency
Tablet Formulation Percent Dose Dose (mg) Dose (mg) Batch
%Wt./Wt. 50 mg potency 75 mg potency (g)
nd III SDD 35 62.5 93.8 1753.4
(80 wt %
nd III, 19.5
wt% HPMCASHG
; 0.5 wt%
sodium lauryl
sulfate)_________
ol 13.5 24.1 36.2 675.2
Lactose 41 73.2 109.8 2050.2
Sucralose 2.0 3.6 5.4 100.06
Croscarmellose 6.0 10.7 16.1 300.1
sodium
Colloidal silicon 1.0 1.8 2.7 50.0
dioxide
Magnesium stearate 1.5 2.7 4.0 74.19
Total 100 178.6 268 5003.15
In some embodiments, the pharmaceutical compositions are a tablet. In some
embodiments, the tablets are suitable for oral administration.
These combinations are useful for treating cystic fibrosis.
SUBSTITUTE SHEET (RULE 26)
In some embodiments, sed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
stering an effective amount of at least one pharmaceutical composition of this
disclosure to the t, such as a human, n said patient has cystic fibrosis and is
chosen from patients with F508dellmm\mA function (MF) genotypes, patients with
F508del/F508del genotypes, patients with /oO-Vt/e//gating genotypes, and patients with
/o/Wc/e//residual function (RF) genotypes.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic on is any CF-causing mutation, and is ed to be and/or is
responsive to any combinations of (i) the novel compounds disclosed herein, such as
Compound 1, and (ii) Compound II, and/or Compound III and/or Compound IV
genotypes based on in vitro and/or clinical data.
] Patients with an F508del/mimma[ function genotype are defined as patients
that are heterozygous F508del-CFTR with a second CFTR allele containing a mutation
that is predicted to result in a CFTR n with minimal function and that is not
expected to respond to Compound II, Compound III, or the combination of nd
II and Compound III. These CFTR mutations were defined using 3 major sources:
• biological plausibility for the mutation to respond (i.e., mutation class)
• evidence of clinical severity on a population basis (per CFTR2 patient
registry; accessed on 15 February 2016)
o average sweat chloride >86 mmol/L, and
o prevalence of pancreatic insufficiency (PI) >50%
• in vitro testing
o mutations resulting in baseline chloride transport <10% of wild-type
CFTR were considered minimal function
o mutations resulting in chloride transport <10% of ype CFTR
following the addition of nd II and/or Compound III were
considered nonresponsive.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic is in a t comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the t, such as a human, wherein the patient possesses a CFTR genetic mutation
G551D. In some embodiments, the patient is homozygous forthe G551D genetic
SUBSTITUTE SHEET (RULE 26)
mutation. In some embodiments, the patient is heterozygous for the G551D genetic
on. In some embodiments, the patient is heterozygous for the G551D genetic
mutation, having the G551D mutation on one allele and any other CF-causing mutation
on the other allele. In some embodiments, the patient is heterozygous for the G55 ID
genetic mutation on one allele and the other CF-causing genetic mutation on the other
allele is any one of F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A,
621+1G->T, 2789+5G->A, 3849+10kbC->T, , G85E, 3120+1G->A, AI507,
1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T.
In some embodiments, the patient is heterozy gous for the G551D genetic mutation, and
the other CFTR genetic mutation is F508del. In some embodiments, the t is
heterozygous for the G551D genetic mutation, and the other CFTR genetic mutation is
R117H.
In some embodiments, disclosed herein is a method of treating, lessening the
ty of, or symptomatically ng cystic fibrosis in a t comprising
administering an effective amount of a pharmaceutical composition of this sure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
F508del. In some embodiments, the patient is homozygous for the F508del genetic
mutation. In some ments, the patient is heterozygous for the F508del genetic
mutation wherein the patient has the F508del c mutation on one allele and any
CF-causing genetic mutation on the other allele. In some embodiments, the patient is
heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing
mutation, ing, but not limited to G551D, G542X, N1303K, W1282X, R117H,
R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E,
3120+1G->A, AI507,1898+1G->A, lC, R347P, R560T, R334W, A455E,
2184delA, or 711+1G->T. In some embodiments, the patient is heterozygous for
F508del, and the other CFTR genetic on is G551D. In some embodiments, the
patient is heterozygous for F508del, and the other CFTR genetic mutation is R117H.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or matically treating cystic fibrosis in a patient sing
administering an effective amount of a pharmaceutical composition of this sure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G178R, G551S, G970R, , S1255P, G1349D, S549N, S549R,
SUBSTITUTE SHEET (RULE 26)
S125IN, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L,
L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N,
D1152H, 1717-1G->A, 621+1G->T, G->A, G->A, 711+1G->T,
2622+lG->A, 405+lG->A, 406-lG->A, 4005+lG->A, 1812-1G->A, 1525-1G->A,
->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+lG->T, 3850-lG->A,
G->A, 3849+1 OkbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-
>G, ->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A,
1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, T-
>C, 621+3A->G, 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, TT->A,
A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y,
D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L,
F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R,
G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G->A),
G91R, G970D, , H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R,
I1005R, I1234V, I1269N, I1366N, I175Y, I502T, I506S, I506T, I601F, I618T, I807M,
I980K, L102R, , L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P,
L453S, L571S, L967S, M1101R, M152V, MIT, M1V, M265R, M952I, M952T,
P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P,
Q98R, R1066C. R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G,
R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G,
S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L,
T1036N, T1053I, , T604I, V1153E, V1240G, V1293G, V201M, V232D,
V456A, V456F. V562I, W1098C, , W1282R, W361R, W57G, W57R,
Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.In
some embodiments, the patient has at least one combination mutation chosen from:
G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S125IN, E193K,
F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E,
D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G-+A,
621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+lG->A, 405+1G-+A,
406-lG->A, 4005+1G-+A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G-+A,
1341+1G->A, 3121-1G->A, 4374+lG->T, 3850-1G-+A, 2789+5G-+A, 3849+lOkbC-
>T, 6A->G, 711+5G->A, 3120G-+A, 1811+1.6kbA->G, 711+3A->G, 1898+3A-
SUBSTITUTE SHEET (RULE 26)
>G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T,
3850-3T->G, IYS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G
In some embodiments, the patient has at least one combination mutation
chosen from: l84, l9, 3195del6, l6, 3905InsT, 4209TGTT->A,
A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y,
D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L,
F191V, l, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R,
G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A),
G91R, G970D, H1054D, H1085P, , H1375P, H139R, H199R, H609R, H939R,
I1005R, I1234V, I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, I618T, I807M,
I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P,
L453S, L571S, L967S, M1101R, M152V, MIT, M1V, M265R, M952I, M952T,
P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P,
Q98R, R1066C. R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G,
R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G,
S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L,
T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D,
V456A, V456F, V562I, , W1098R, W1282R, W361R, W57G, W57R,
, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.
In some embodiments, the patient has at least one combination mutation
chosen from:
D443Y;G576A;R668C,
F508C;S1251N,
G576A; R668C,
G970R; M470V,
R74W;D1270N,
R74W;Y201M, and
R74W;V201M;D1270N.
In some ments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
SUBSTITUTE SHEET (RULE 26)
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, n the patient possesses a CFTR genetic mutation
selected from G178R, G551S, G970R, , S1255P, G1349D, S549N, S549R,
S1251N, E193K, F1052V and G1069R. In some embodiments, this disclosure provides
a method of treating CFTR comprising administering a compound of Formula (I), (II),
(III), (IV), (V), or a pharmaceutically acceptable salt thereof to a patient possessing a
human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P,
G1349D, S549N, S549R and S125 IN. In some embodiments, disclosed herein is a
method of treating, lessening the severity of, or symptomatically treating cystic fibrosis
in a patient comprising administering an effective amount of a ceutical
ition of this disclosure to the patient, such as a mammal, n the patient
possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R. In
some embodiments, the method produces an se in chloride transport relative to
baseline chloride transport of the t of the patient.
In some embodiments, sed herein is a method of treating, lessening the
severity of, or symptomatically ng cystic fibrosis in a patient comprising
administering an ive amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR c mutation
selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,
S1235R, S945L, R1070W, F1074L, D110E, D1270N andD1152H. In some
embodiments, the method produces an increase in chloride transport above the baseline
chloride transport of the patient.
] In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic on
selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,
2622+lG->A, ->A, 406-lG->A, 4005+lG->A, 1812-1G->A, 1525-1G->A,
712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+lG->T, 3850-lG->A,
2789+5G->A, 3849+1 OkbC->T, 6A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-
>G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C,
1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, +5G->A,
1898+1G->T, 4005+2T->C and 621+3A->G. In some embodiments, disclosed herein is
SUBSTITUTE SHEET (RULE 26)
a method of treating, lessening the severity of, or symptomatically treating cystic
fibrosis in a patient comprising stering an effective amount of a pharmaceutical
ition of this sure to the patient, such as a mammal, wherein the patient
possesses a CFTR c mutation selected from 1717-1G->A, 1811+1.6kbA->G,
2789+5G->A, 3272-26A->G and 3849+1 OkbC->T. In some embodiments, disclosed
herein is a method of treating, lessening the severity of, or symptomatically ng
cystic fibrosis in a patient comprising administering an effective amount of a
pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein
the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-
26A->G.
In some ments, disclosed herein is a method of treating, ing the
ty of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the t, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,
, E193K, F1052V, , R117C, D110H, R347H, R352Q, E56K, P67L,
L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N,
, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,
2622+lG->A, 405+lG->A, 406-lG->A, 4005+lG->A, 1812-1G->A, 1525-1G->A,
712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+lG->T, 3850-lG->A,
2789+5G->A, 3849+1 OkbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-
+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, A,
1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C
and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and
G551D.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,
S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selected from
F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of
treating, lessening the severity of, or symptomatically ng cystic fibrosis in a patient
SUBSTITUTE SHEET (RULE 26)
comprising administering an effective amount of a pharmaceutical composition of this
disclosure to the patient, such as a mammal, wherein the patient ses a CFTR
genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D,
S549N, S549R and S125 IN, and a human CFTR mutation selected from F508del,
R117H, and G551D. In some embodiments, disclosed herein is a method of ng,
lessening the severity of, or symptomatically treating cystic fibrosis in a patient
comprising administering an effective amount of a ceutical composition of this
disclosure to the patient, such as a mammal, wherein the t possesses a CFTR
genetic mutation selected from E193K, F1052V and G1069R, and ahuman CFTR
mutation selected from F508del, R117H, and G55 ID. In some embodiments, the
method produces an increase in chloride transport relative to baseline de transport
of the patient.
In some ments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composihon of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,
S1235R, S945L, R1070W, F1074L, D110E, D1270N and , and ahuman CFTR
mutation selected from F508del, R117H, and G55 ID. In some embodiments, the
method produces an increase in chloride transport which is above the baseline de
ort of the patient.
In some embodiments, sed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,
G->A, 405+lG->A, 406-lG->A, 4005+lG->A, 1812-1G->A, G->A,
712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+lG->T, 3850-lG->A,
2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+T6kbA-
>G,711+3A->G, A->G, G->A, 1342-2A->C, 405+3A->C, 1716G/A,
1811+1G->C, 1898+5G-+T, 3850-3T-+G, IVS14b+5G->A, 1898+1G->T, 4005+2T-+C
and 621+3A->G, and a human CFTR mutation selected from l, R117H, and
G551D. In some embodiments, disclosed herein is a method of treating, lessening the
SUBSTITUTE SHEET (RULE 26)
severity of, or symptomatically treating cystic is in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from 1717-1G->A, .6kbA->G, 2789+5G->A, 3272-26A->G and
3849+1 OkbC->T, and a human CFTR mutation selected from F508del, R117FI, and
G551D. In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this sure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from 2789+5G->A and 3272-26A->G, and a human CFTR mutation selected
08del, R117H.
In some ments, disclosed herein is a method of treating, lessening the
ty of, or matically treating cystic fibrosis in a t comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic on
selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,
S125IN, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L,
L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N,
D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,
2622+lG->A, 405+lG->A, 406-lG->A, 4005+lG->A, 1812-1G->A, 1525-1G->A,
712-1G->T, 1248+1G->A, G->A, 3121-1G->A, 4374+lG->T, 3850-lG->A,
2789+5G->A, 3849+1 OkbC->T, 3272-26A->G, ->A, 3120G->A, 1811+1.6kbA-
>G,711+3A->G, A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, A,
1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C
and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and
G551D.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the t possesses a CFTR c mutation
selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,
S1251N, E193K, F1052V and . In some embodiments, disclosed herein is a
method of treating, lessening the severity of, or matically treating cystic fibrosis
SUBSTITUTE SHEET (RULE 26)
in a patient comprising administering an effective amount of a pharmaceutical
composition of this disclosure to the patient, such as a mammal, wherein the patient
possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E,
S1255P, G1349D, S549N, S549R and SI25IN. In some embodiments, disclosed herein
is a method of ng, lessening the severity of, or symptomatically treating cystic
fibrosis in a patient comprising administering an effective amount of a pharmaceutical
composition of this disclosure to the patient, such as a mammal, wherein the patient
possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R. In
some embodiments, the method produces an increase in de transport relative to
baseline chloride transport of the patient.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or matically ng cystic fibrosis in a patient sing
administering an effective amount of a pharmaceutical composition of this sure to
the t, such as a mammal, wherein the patient possesses a CFTR genetic mutation
ed from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,
S1235R, S945L, R1070W, F1074L, D110E, D1270N andD1152H. In some
embodiments, the method produces an increase in chloride transport which is above the
baseline chloride transport of the t.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
stering an ive amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G->A, 621+1G->T, 3120+1G->A, G->A, 711+1G->T,
G->A, 405+lG->A, 406-lG->A, 4005+1G-+A, 1812-1G-+A, 1525-
1G->A, 712-1G->T, 1248+1 G->A, 1341+1G->A, 3121-1G-+A,
4374+1 G->T, 3850-1G-+A, 2789+5G-+A, 0kbC->T, 3272-26A->G, 711+5G-
>A, 3120G->A, 1811+1.6kbA->G, 711+3A-+G. 1898+3A->G, 1717-8G-+A.
1342-2A-+C, 405+3A-+C, 1716G/A, 1811+1G-+C, 1898+5G-+T, 3850-3T-+G,
+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G. In some embodiments,
disclosed herein is a method of treating, lessening the severity of, or symptomatically
ng cystic fibrosis in a patient comprising administering an effective amount of a
pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein
the patient possesses a CFTR genetic mutation selected from 1717-1G-+A,
SUBSTITUTE SHEET (RULE 26)
1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+1 OkbC->T. In
some embodiments, disclosed herein is a method of treating, lessening the severity of,
or symptomatically treating cystic is in a patient comprising administering an
effective amount of a pharmaceutical composition of this disclosure to the patient, such
as a mammal, wherein the patient possesses a CFTR genetic on selected from
2789+5G->A and 3272-26A->G.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,
S125IN, E193K, , G1069R, R117C, D110H, R347H, R352Q, E56K, P67L,
L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, ,
D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,
2622+lG->A, 405+lG->A, 406-lG->A, 4005+lG->A, G->A, G->A,
712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+lG->T, 3850-lG->A,
2789+5G->A, 3849+1 OkbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-
>G,711+3A->G, 1898+3A->G, G-+A, 1342-2A->C, 405+3A-+C, 1716G/A,
1811+1G->C, 1898+5G->T, 3850-3T-+G, +5G->A, 1898+1G->T, 4005+2T-+C
and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and
G551D, and one or more human CFTR ons selected from F508del, R117H, and
G551D.
In some ments, disclosed herein is a method of ng, ing the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from G178R, G551S, G970R, G1244E, S1255P, , S549N, S549R,
S1251N, E193K, F1052V and G1069R, and one or more human CFTR mutations
selected from l, R117H, and G55 ID. In some embodiments, disclosed herein is
a method of treating, lessening the severity of, or symptomatically treating cystic
fibrosis in a patient comprising stering an effective amount of a pharmaceutical
composition of this disclosure to the patient, such as a mammal, wherein the t
possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E,
SUBSTITUTE SHEET (RULE 26)
S1255P, G1349D, S549N, S549R and S125 IN, and one or more human CFTR
mutations selected from F508del, R117H, and G551D. In some embodiments,
disclosed herein is a method of ng, lessening the severity of, or matically
treating cystic fibrosis in a patient comprising administenng an effective amount of a
pharmaceutical ition of this disclosure to the patient, such as a mammal, n
the patient possesses a CFTR genetic mutation selected from E193K, F1052Y and
G1069R, and one or more human CFTR mutations selected from F508del, R117H, and
G551D. In some embodiments, the method produces an increase in chloride transport
relative to baseline chloride transport of the patient.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the t, such as a mammal, n the t possesses a CFTR genetic mutation
selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,
S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and one or more
human CFTR ons ed from F508del, R117H, and G551D. In some
embodiments, the method produces an se in chloride transport which is above the
baseline chloride transport of the patient.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a , n the patient possesses a CFTR genetic mutation
selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,
G->A, 405+lG->A, 406-lG->A, 4005+lG->A, 1812-1G->A, 1525-1G->A,
712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+lG->T, G->A,
2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-
>G,711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A,
G->C, 1898+5G-+T, 3850-3T-+G, IVS14b+5G->A, 1898+1G->T, 4005+2T-+C
and 621+3A->G, and one or more human CFTR mutations selected from F508del,
R117H, and G551D. In some embodiments, disclosed herein is a method of treating,
lessening the severity of, or symptomatically treating cystic fibrosis in a patient
comprising administering an effective amount of a pharmaceutical composition of this
disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR
SUBSTITUTE SHEET (RULE 26)
genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-
26A->G and 3849+10kbC->T, and one or more human CFTR mutations selected from
F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of
treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient
sing administering an effective amount of a pharmaceutical composition of this
disclosure to the patient, such as a , wherein the patient possesses a CFTR
genetic mutation ed from 2789+5G->A and 3272-26A->G, and one or more
human CFTR mutations selected from F508del, R117H, and G551D.
In some ments, the patient is heterozygous having one CF-causing
mutation on one allele and another CF-causing on on the other allele. In some
ments, the patient is heterozygous for F508del, and the other CFTR genetic
mutation is any CF-causing mutation, including, but not limited to F508del on one
CFTR allele and a CFTR mutation on the second CFTR allele that is associated with
minimal CFTR function, residual CFTR function, or a defect in CFTR channel gating
activity.
In some embodiments, the CF-causing mutation is selected from Table 5A.
In some embodiments, the t is heterozy gous having one CF-causing mutation on
one CFTR allele selected from the mutations listed in the table from and another
CF-causing mutation on the other CFTR allele is selected from the CFTR mutations
listed in Table 5A.
Table 5A.
Y122X
L218X
Q220X
C276X
Q290X
SUBSTITUTE SHEET (RULE 26)
G330X
W401X
Q414X
S434X
S466X
S489X
Q493X
W496X
Q525X
G542X
Q552X
R553X
E585X
G673X
R709X
K710X
L732X
R764X
R785X
R792X
E822X
W846X
R851X
Q890X
S912X
W1089X
Y1092X
El KMX
R1158X
R1162X
S1196X
W1204X
S1255X
W1282X
Q1313X
621+lG^T
711+lG^T
711+5G^A
712-lG^T
405+3A^C
406-1G^ A
SUBSTITUTE SHEET (RULE 26)
621+lG^T
1248+lG^A
1341+lG^A
1717-lG^A
1811+1.6kbA-»G
1811+lG^C
1812-lG^A
1898+lG^A
2622+IG^A
3120+lG^A
3120G^A
3850-lG^A
4005+1G^ A
4374+1 G^T
663delT
2183AA^G
3659delC
394delTT
3905insT
2184delA
1078delT
1154insTC
2183delAA^G
2143delT
1677delTA
3876delA
2307insA
4382delA
4016insT
2347delG
3007delG
574delA
2711delT
3791delC
le22-23
457TAT—>-G
2043delG
2869insG
3600+2insT
SUBSTITUTE SHEET (RULE 26)
3737delA
4040delA
541delC
T338I
R347P
L927P
S341P
L467P
07del
V520F
A559T
R560T
R560S
A561E
Y569D
L1065P
R1066C
R1066M
L1077P
H1085R
M1101K
N1303K
2789+5G^A
3849+lOkbC
3272-26A^G
D110E
D110H
R117C
L206W
R347H
R352Q
A455E
SUBSTITUTE SHEET (RULE 26)
D579G
E831X
S945L
S977F
F1052V
R1070W
F1074L
D1152H
D1270N
R117H
G178R
S549N
S549R
G551D
G551S
G1244E
S1251N
S1255P
G1349D
Table SB: CFTR Mutations
Criteria Mutation
Truncation S4X C276X G542X R792X El KMX
mutations G27X Q290X G550X E822X R1158X
• %PI >50% Q39X G330X Q552X W846X R1162X
and/or W57X W401X R553X Y849X S1196X
SwCT >86
E60X Q414X E585X R851X W1204X
mmol/L
R75X S434X G673X Q890X L1254X
• no fulllength
E92X S466X Q685X S912X S1255X
protein Q98X S489X R709X Y913X W1282X
Y122X Q493X K710X W1089X Q1313X
E193X W496X L732X Y1092X E1371X
L218X C524X R764X W1098X Q1382X
Q220X Q525X R785X R1102X Q1411X
Splice ons 185+1G 711+5G—>A. G^A 2622+1G- 3121-
• %PI >50% T A
and/or 296+1G- 712-lG^T 1717-lCr^A 2790- 3500-
SwCF >86 A 1G—>C 2A^G
mmol/L 405+1G- 1248+1G- 1811+1G—>C 3040G^C 3600+2insT
• no or little A A (G970R)
mature 405+3A- 1249- 1811+1.6kbA 3850-
mRNA C IG^A G IG^A
406- 1341+1G- 1812-lG^A 3120G^A 4005+1G-
IG^A A A
SUBSTITUTE SHEET (RULE 26)
Criteria Mutation
^ 1525- 1898+1G—>A G- 4374+1G-
T 2A^G A T
711+1G—> 1525- G^C 3121-
T 1G-^A 2A^G
Small (<3 182delT lA 1782delA 2732ms A 3876delA
nucleotide) 306insA 1138insG 1824delA sG 3878delG
insertion/deleti 365- 1154insTC 2043 delG 2896insAG 3905insT
on (ins/del) 366msT
frameshift
394delTT 1161delC 2143delT 2942insT 4016insT
mutations
A 1213delT 2183AA^Ga 2957delT 4021dupT
• %PI >50%
and/or 444delA 1259insA 2184delA 3007delG 4040delA
SwCr >86 457TAT^ sTA 2184ms A 3028delA 4279insA
mmol/L G
• garbled 541delC 1471 del A 2307insA 3171delC 4326delTC
and/or 574delA 1497delGG 2347delG 3659delC
truncated 663delT lG 2585delT 3737delA
protein 935delA 1609del CA 2594delGT 3791delC
1078delT 1677delTA 2711delT 3821delT
Non-small (>3 CFTRdele2,3 1461ins4 2991del32
nucleotide) CFTRdele22,23 1924del7 3667ins4
insertion/deleti 124del23bp 2055del9^A 4010del4
on (ins/del)
852del22 2105- 4209TGTT^AA
frameshift
2117del 13 ins AGAAA
mutations
991del5 272 Idelll
• %PI >50%
and/or
SwCF >86
mmol/L
• garbled
and/or
protein
SUBSTITUTE SHEET (RULE 26)
Criteria Mutation
Class IL III, IV A46Db V520F Y569Db N1303K
mutations not G85E A559Tb L1065P
responsive to R347P R560T R1066C
Compound III
R560S L1077Pb
alone or i in , ,
combination 15 07del A561E M1101K
Compound II
or Compound
• %PI>50%
and/or
SwCl >86
mmol/L
• Not
responsive
in vitro to
Compound
III alone or
combinatio
n with
Compound
II or
Compound
Note: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient
registry who are atic insufficient; SwCF: mean sweat chloride of F508del-CFTR
heterozy gous patients in the CFTR2 patient registry
a Also known as lAA^G.
b Unpublished data.
Table 5B above includes certain exemplary CFTR minimal function
mutations, which are able by an FDA-cleared genotyping assay, but does not
include an exhaustive list.
] In some embodiments, sed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a patient with F508del/MF
(F/MF) pes (heterozygous for F508del and an MF mutation not ed to
respond to CFTR modulators, such as Compound III); with F508del/F508del (F/F)
genotype (homozygous for F508del); and/or with F508delfgaXmg (F/G) genotypes
(heterozygous for F508del and a gating mutation known to be CFTR modulator-
SUBSTITUTE SHEET (RULE 26)
WO 64632
responsive (e.g., Compound Ill-responsive). In some embodiments, a patient with
UMY (F/MF) genotypes has a MF mutation that is not expected to respond to
Compound II, Compound III, and both of Compound II and Compound III. In some
embodiments, a patent with FSOSdellMF (F/MF) genotypes has any one of the MF
mutations in Table 5B.
In some ments, the patient is heterozygous for l, and the other
CFTR genetic mutation is any CF-causing mutation, including truncation mutations,
splice mutations, small (<3 nucleotide) insertion or deletion (ins/del) frameshift
mutations; non-small (>3 nucleotide) insertion or deletion el) frameshift
mutations; and Class II, III, IV mutations not responsive to Compound III alone or in
combination with Compound II or Compound IV.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is a truncation mutation. In some specific embodiments, the
truncation on is a truncation mutation listed in Table 5B.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is a splice on. In some specific embodiments, the splice
mutation is a splice mutation listed in Table 5B.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is a small (<3 nucleotide) insertion or deletion (ins/del)
frameshift mutation. In some specific ments, the small (<3 nucleotide) insertion
or deletion (ins/del) frameshift on is a small (<3 nucleotide) insertion or deletion
(ins/del) frameshift mutation listed in Table 5B.
] In some embodiments, the patient is heterozygous for F508del, and the other
CFTR c on is any CF-causing mutation expected to be and/or is responsive
to, based on in vitro and/or clinical data, any combination of (i) a novel compound
chosen from those disclosed herein (e.g., compounds of Formula (I), (II), (III), (IV), or
(V), and pharmaceutically acceptable salts f, and their deuterated derivatives), and
(ii) Compound II, and/or Compound III, and/or Compound IV.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is any CF-causing mutation expected to be and/or is sive,
based on in vitro and/or clinical data, to the triple combination of a novel compound
chosen from those disclosed herein (e.g., compounds of Formula (I), (II), (III), (IV), or
SUBSTITUTE SHEET (RULE 26)
(V), and pharmaceutically acceptable salts thereof, and their deuterated derivatives), and
Compound II, and Compound III.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic on is a non-small (>3 nucleotide) insertion or deletion el)
frameshift mutation. In some specific embodiments, the non-small (>3 nucleotide)
ion or deletion (ins/del) hift mutation is anon-small (>3 nucleotide)
insertion or deletion (ins/del) frameshift mutation listed in Table 5B.
In some embodiments, the t is heterozygous for F508del, and the other
CFTR genetic mutation is a Class II, III, IV mutations not responsive to Compound III
alone or in combination with Compound II or Compound IV. In some specific
ments, the Class II, III, IV mutations not sive to Compound III alone or in
ation with Compound II or Compound IV is a Class II, III, IV mutations not
responsive to Compound III alone or in combination with Compound II or Compound
IV listed in Table 5B.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is any mutation listed in Table 5B.
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is any mutation listed in Table 5A, 5B, and
In some embodiments, the patient is heterozygous for F508del, and the other
CFTR genetic mutation is any mutation listed in Table 5A. In some ments, the
patient is heterozygous for F508del, and the other CFTR genetic mutation is any
mutation listed in Table 5B. In some ments, the patient is heterozygous for
F508del, and the other CFTR genetic mutation is any mutation listed in
In some embodiments, the patient is homozygous for F508del.
In some embodiments, the patient is heterozygous having one CF-causing
mutation on one CFTR allele selected from the mutations listed in the table from
and another CF-causing mutation on the other CFTR allele is selected from the CFTR
ons listed in Table 5B.
ts with an /oWC/efgating mutation genotype are defined as patients
that are heterozygous F508del-CFTR with a second CFTR allele that contains a
mutation associated with a gating defect and clinically demonstrated to be responsive to
SUBSTITUTE SHEET (RULE 26)
Compound III. Examples of such mutations include: G178R, S549N, S549R, G551D,
G551S, G1244E, S1251N, S1255P, and G1349D.
Patients with an /oti/C/e/tiesidual function pe are defined as patients
that are heterozygous F508del-CFTR with a second CFTR allele that contains a
mutation that results in reduced protein ty or function at the cell e which
can produce partial CFTR activity. CFTR gene ons known to result in a residual
function phenotype include in some embodiments, a CFTR residual function mutation
selected from 2789+5G^ A, 3849+lOkbC^T, 3272-26A^ G, 711+3A^ G, E56K,
P67L, R74W, D110E, Dll OH, R117C, L206W, R347H, R352Q, A455E, D579G,
E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, and
K1060T. In some embodiments, the CFTR residual function on is selected from
R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C,
D614G, G1069R, R1162L, E56K, A1067T, E193K, or K1060T. In some embodiments,
the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C,
G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, or
A1067T.
In some embodiments, disclosed herein is a method of treating, lessening the
severity of, or symptomatically treating cystic fibrosis in a t comprising
administering an effective amount of a pharmaceutical composition of this disclosure to
the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation
selected from the mutations listed in
In some embodiments, the composition disclosed herein is useful for treating,
lessening the severity of, or symptomatically treating cystic is in patients who
exhibit residual CFTR activity in the apical ne of respiratory and nonrespiratory
epithelia. The presence of residual CFTR activity at the epithelial surface
can be readily ed using methods known in the art, e.g., standard
electrophysiological, biochemical, or histochemical techniques. Such methods fy
CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of
sweat or ry CF trations, or ex vivo biochemical or histochemical techniques
to monitor cell surface density. Using such methods, residual CFTR activity can be
readily detected for patients that are heterozygous or homozygous for a variety of
ent mutations, including patients heterozy gous for the most common on.
SUBSTITUTE SHEET (RULE 26)
F508del, as well as other mutations such as the G551D mutation, or the R117H
mutation. In some embodiments, itions disclosed herein are useful for treating,
lessening the severity of, or symptomatically treating cystic fibrosis in patients who
exhibit little to no residual CFTR activity. In some embodiments, compositions
disclosed herein are useful for treating, lessening the severity of, or symptomatically
treating cystic fibrosis in patients who t little to no residual CFTR activity in the
apical membrane of respiratory epithelia.
In some embodiments, the compositions disclosed herein are useful for
treating or ing the severity of cystic fibrosis in patients who exhibit residual
CFTR activity using pharmacological methods. Such methods increase the amount of
CFTR present at the cell surface, thereby inducing a to absent CFTR ty in a
patient or augmenting the existing level of residual CFTR activity in a patient.
In some embodiments, the compositions disclosed herein are useful for
treating or ing the severity of cystic fibrosis in patients with certain genotypes
exhibiting residual CFTR activity.
In some embodiments, itions disclosed herein are useful for treating,
lessening the severity of, or symptomatically treating cystic fibrosis in patients within
certain clinical phenotypes, e.g., a mild to te clinical phenotype that typically
correlates with the amount of residual CFTR ty in the apical membrane of
epithelia. Such phenotypes include patients exhibiting pancreatic sufficiency.
In some embodiments, the compositions disclosed herein are useful for
treating, lessening the severity of, or symptomatically treating ts diagnosed with
pancreatic sufficiency, idiopathic pancreatitis and ital bilateral absence of the vas
deferens, or mild lung disease wherein the patient exhibits residual CFTR activity.
In some embodiments, this sure relates to a method of augmenting or
inducing anion channel activity in vitro or in vivo, comprising contacting the channel
with a composition disclosed herein. In some embodiments, the anion channel is a
chloride channel or a bicarbonate channel. In some embodiments, the anion channel is a
de channel.
The exact amount of a pharmaceutical composition required will vary from
subject to subject, depending on the s, age, and general ion of the t,
SUBSTITUTE SHEET (RULE 26)
the severity of the disease, the particular agent, its mode of administration, and the like.
The compounds of this sure may be formulated in dosage unit form for ease of
stration and uniformity of dosage. The expression "dosage unit form" as used
herein refers to a physically discrete unit of agent appropriate for the patient to be
treated. It will be understood, however, that the total daily usage of the nds and
compositions of this disclosure will be decided by the attending physician within the
scope of sound medical judgment. The specific effective dose level for any particular
patient or organism will depend upon a variety of factors including the disorder being
treated and the severity of the disorder; the activity of the ic compound ed;
the specific composition employed; the age, body , general health, sex and diet of
the patient; the time of administration, route of stration, and rate of excretion of
the specific compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed, and like s well
known in the medical arts. The term “patient”, as used herein, means an animal, such as
a mammal, and even further such as a human.
In some embodiments, the disclosure also is directed to methods of treatment
using isotope-labelled compounds of the afore-mentioned compounds, which have the
same structures as disclosed herein except that one or more atoms therein have been
replaced by an atom or atoms having an atomic mass or mass number which differs
from the atomic mass or mass number of the atom which usually occurs naturally
(isotope ed). Examples of isotopes which are commercially available and suitable
for the disclosure include isotopes of en, carbon, nitrogen, oxygen, phosphorus,
fluorine and ne, for e 2H, 'H, 13C, 14C, 15N, 180,170,31P, 32P, 35S, 18F and
j6Cl, respectively.
The isotope-labelled compounds and salts can be used in a number of
beneficial ways. They can be suitable for medicaments and/or various types of assays,
such as substrate tissue distribution assays. For example, tritium (3H)- and/or carbon-14
(14C)-labelled compounds are particularly useful for various types of assays, such as
substrate tissue distribution , due to relatively simple preparation and excellent
detectability. For example, deuterium (2H)-labelled ones are therapeutically useful with
potential therapeutic advantages over the non-2H-labelled nds. In general,
deuterium ( H)-labelled compounds and salts can have higher metabolic stability as
ed to those that are not isotope-labelled owing to the kinetic isotope effect
SUBSTITUTE SHEET (RULE 26)
described below. Higher metabolic stability translates directly into an increased in vivo
half-life or lower dosages, which could be desired. The isotope-labelled compounds
and salts can usually be prepared by carrying out the procedures disclosed in the
synthesis s and the d description, in the example part and in the preparation
part in the present text, ing a non-isotope-labelled nt by a readily available
isotope-labelled reactant.
In some embodiments, the isotope-labelled compounds and salts are
deuterium (2H)-labelled ones. In some specific embodiments, the isotope-labelled
compounds and salts are deuterium (2H)-labelled, wherein one or more hydrogen atoms
therein have been replaced by deuterium. In chemical structures, ium is
represented as “2H” or "D."
The deuterium (2H)-labelled compounds and salts can manipulate the
oxidative metabolism of the compound by way of the primary kinetic isotope effect.
The primary kinetic isotope effect is a change of the rate for a chemical reaction that
s from exchange of isotopic nuclei, which in turn is caused by the change in
ground state energies necessary for covalent bond formation after this isotopic
exchange. Exchange of a r isotope usually results in a lowering of the ground
state energy for a al bond and thus causes a reduction in the rate-limiting bond
breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region
along the coordinate of a multi-product reaction, the product distribution ratios can be
d substantially. For explanation: if deuterium is bonded to a carbon atom at a nonexchangeable
position, rate differences of kM/ko = 2-7 are typical. For a further
discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and
Development, Ann. Rep. Med. Chem. 2011, 46, 403-417; and T.G. Gant “Using
deuterium in drug ery: leaving the label in the drug" J. Med. Chem. 2014, 57,
3595-3611, relevant portions of which are independently incorporated herein by
reference.
The concentration of the isotope(s) (e.g., deuterium) incorporated into the
isotope-labelled compounds and salt of the disclosure may be defined by the isotopic
enrichment . The term “isotopic enrichment factor” as used herein means the ratio
between the isotopic abundance and the natural abundance of a ied isotope. In
some embodiments, if a tuent in a compound of the disclosure is denoted
deuterium, such compound has an isotopic enrichment factor for each ated
SUBSTITUTE SHEET (RULE 26)
deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated
deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500
(82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least
6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium oration),
at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation).
When discovering and developing therapeutic agents, the person skilled in the
art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro
properties. It may be able to assume that many compounds with poor
cokinetic profiles are tible to oxidative metabolism.
One of ordinary skill in the art would understand that deuteration of one or
more metabohcally labile positions on a compound or active metabolite may lead to
improvement of one or more superior DMPK properties while maintaining biological
activity as compared to the corresponding hydrogen analogs. The superior DMPK
property or properties may have an impact on the exposure, half-life, clearance,
lism, and/or even food requirements for optimal absorption of the drug product.
Deuteration may also change the metabolism at other non-deuterated positions of the
deuterated compound.
In some embodiments, the disclosure es deuterated derivatives of the
novel compounds sed herein and of their pharmaceutically acceptable salts. Nonlimiting
examples of ated nds are disclosed in
In some embodiments, Compound IIF as used herein includes the deuterated nd
disclosed in U.S. Patent No. 8,865,902 (which is incorporated herein by reference), and
CTP-656.
In some embodiments, Compound IIP is:
.0 OH QP
// D
HN HN V \ fD
D D D
SUBSTITUTE SHEET (RULE 26)
Exemplary embodiments of the sure include: The novel compounds
disclosed herein (e.g., compounds of ae (I) - (V), pharmaceutically acceptable
salts thereof, and deuterated derivatives of any of the foregoing, including the
compounds in and those specifically ed herein) can be prepared by suitable
methods known in the art. For example, they can be prepared in accordance with
procedures described in WO2016/057572 and by the exemplary syntheses bed
below in the es. For example, deuterated derivatives of the novel compounds of
Formulae (I) - (V) and pharmaceutically acceptable salts thereof can be prepared in a
r manner as those for compounds of Formulae (I) - (V) and pharmaceutically
acceptable salts thereof by employing intermediates and/or reagents where one or more
hydrogen atoms are replaced with deuterium. For example, see T.G. Gant “Using
deuterium in drug discovery: leaving the label in the drug” J. Med. Chem. 2014, 57,
3595-3611, the relevant portions of which are incorporated herein by reference.
In some embodiments, compounds of Formulae (III), (IV) and (V) and
pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the
foregoing are prepared as depicted in Schemes 1-2, wherein the variables therein are
each and independently are as those for Formula (I), (II), (III), (IV), or (V) above, and
wherein each Ra is independently chosen from C1-C4 alkyl groups; and each Xa is
independently chosen from F or Cl. Suitable condition(s) known in the art can be
employed for each step depicted in the s. In some embodiments, each Xa for
Formulae B, C, D, F, B-l, C-l, D-l, and F-l in Schemes 2-4 is independently Cl. In
some embodiments, each Xa for Formulae D, L, 0, and P in Scheme 6 is ndently
In some embodiments, as shown in Scheme 1, the methods comprise reacting
a nd of a (F) or a salt thereof with a compound of Formula (G) or a salt
thereof to generate a compound of Formula (Ilia), a pharmaceutically acceptable salt
thereof, or a deuterated derivative of any of the ing.
SUBSTITUTE SHEET (RULE 26)
Scheme 1
HN"^R3)q
9 QD 9 o.p
yl ^ 97 Yi ^
1 n*mA (G) n.nA
rW/ n Yz Xa RXy Y
_// i' n
^Pr3),
(R4) r (F) (R4)r
(Ilia)
Any suitable conditions, such as those for a philic on of amine,
known in the art can be used. In some embodiments, the reaction depicted in Scheme 1
is performed in the presence of a base, such as a metal carbonate (e.g., Na2C03 or
k2co3).
In some embodiments, nds of Formula (Ilia), pharmaceutically
acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Y2 is
N and Y1 is CH in each of Formulae (F), (G) and (Ilia), are prepared by the methods in
Scheme 1.
In some embodiments, a salt of a compound of Formula (G) is ed In
some embodiments, an HC1 salt of a compound of Formula (G) is employed.
A compound of Formula (F) or a salt thereof and a compound of Formula (G)
or a salt thereof can be prepared by any suitable method known in the art, for e,
those in WO2016/57572 and those in the exemplary ses described below in the
Examples.
In some embodiments, as shown in Scheme 2, a compound of Formula (F), a
ceutically able salt thereof, or a deuterated derivative of any of the
foregoing is prepared by a method that comprises reacting a compound of Formula (D)
or a salt thereof with a compound of Formula (E) or a salt thereof. In some
embodiments, compounds of Formula (D), salts thereof, or deuterated tives of any
of the foregoing are prepared by a method that comprises reacting a compound of
Formula (A) or a salt thereof with a compound of Formula (B) or a salt thereof to
generate a compound of a (C) or a salt thereof; and hydrolyzing the -C(0)0Ra of
compound of Formula (C) to generate a compound of Formula (D) or a salt thereof.
Any suitable conditions known in the art can be used for steps (a), (b), and (c) of
Scheme 2 below, such as those for a coupling reaction between carboxylic acid and
SUBSTITUTE SHEET (RULE 26)
sulfonamide or those for an acylation of sulfonamide for step (a), those for ysis of
ester for step (b), and those for a nucleophilic reaction of amine for step (c).
In some embodiments, step (a) of Scheme 2 below is performed in the
ce of a base. In some specific embodiments, step (a) is performed in the presence
of a non-nucleophihc base. In some embodiments, in step (a), the reaction of a
compound of Formula (D) or a salt thereof with a compound of Formula (E) or a salt
f comprises reacting a compound of Formula (D) or a salt thereof with a coupling
reagent, such as carbonyl diimidazole (GDI), and subsequently with a nd of
Formula (E) or a salt thereof in the presence of a base, such as a non-nucleophilic base.
In some embodiments, a compound of a (D) or a salt thereof is reacted with GDI
prior to the reaction with a compound of Formula (E) or a salt thereof, and then
subsequently with a compound of Formula (E) or a salt thereof in the presence of a base,
such as DBU (l,8-Diazabicyclo(5.4.0)undecene).
In some embodiments, step (b) of Scheme 2 below is med in the
presence of a base. In some ments, step (b) is performed in the presence of an
aqueous base, such as aqueous hydroxide. In some embodiments, step (b) is med
in the presence of an aqueous metal hydroxide, such as aqueous NaOH.
In some embodiments, step (c) of Scheme 2 below is performed in the
presence of a base. In some embodiments, step (c) is performed in the presence of a
metal carbonate (e.g., Na2C03 or K2CO3).
SUBSTITUTE SHEET (RULE 26)
Scheme 2
IT 0
Y1^ 'ORa
RVN. Xa Y2xa -N'NA
Yi NH (B) z Xa
(A) 'r (C) (R4)r
SOpNHp
Y1^ V OH
N-N^ 2
N-NA r (E) R'-r Xa
(a) (R4)r
(R4) r (F) (D)
In some embodiments, disclosed herein is a method of preparing a compound
of the following formula:
PF3 P 0 o
N" 'Ph
b—f n N N-AlS)
or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing. The method comprises reacting a compound of Formula (F-l) or a salt
thereof with a nd of Formula (G-l) or a salt thereof, n Xa is F or Cl, as
shown in Scheme 3:
SUBSTITUTE SHEET (RULE 26)
Scheme 3
HNA(S)
pF3 0 0 0
0 o 0 XM:s:n,
AN:s'Th (G-1) N Ph
H b-A N ■na*®)
b->N Nx: xa
(F-1) Compound (1)
] Any suitable conditions, such as those for a nucleophilic reaction of amine,
known in the art can be used. In some ments, the reaction depicted in Scheme 3
is performed in the presence of a base, such as a metal carbonate (e.g., Na2C03 or
K2co3).
In some embodiments, a salt of nd of Formula (G-1) is employed. In
some embodiments, a HC1 salt of a compound of Formula (G-1) is employed.
] A compound of Formula (F-1) or a salt thereof and a nd of Formula
(G-1) or a salt thereof can be prepared by any suitable method known in the art, for
example, those in WO2016/57572 and those in the exemplary syntheses described
below in the Examples.
In some embodiments, as shown in Scheme 4, a compound of Formula (F-1)
or a salt thereof, or a deuterated derivative of any of the foregoing is prepared by a
method that comprises reacting a compound of Formula (D-l) or a salt thereof with a
compound of Formula (E-l) or a salt thereof. In some embodiments, nds of
Formula (D-l) or salts thereof, or their deuterated derivatives are prepared by a method
that comprises reacting a compound of Formula (A-l) or a salt thereof with a compound
of Formula (B-l) or a salt thereof to generate a compound of formula (C-1) or a salt
thereof; and hydrolyzing the -C(0)0Ra of compound of Formula (C-1) or salt thereof to
generate a nd of a (D-l) or a salt thereof. Any suitable conditions known
in the art can be used for steps (a-l), (b-l), and (c-1) of Scheme 4 below, such as those
for a coupling reaction between carboxylic acid and sulfonamide or those for an
ion of sulfonamide for step (a-l), those for hydrolysis of ester for step (b-l), and
those for a nucleophilic reaction of amine for step (c-1).
SUBSTITUTE SHEET (RULE 26)
In some embodiments, step (a-1) of Scheme 4 below is performed in the
presence of a base. In some embodiments, step (a-1) of Scheme 4 below is performed
in the presence of a non-nucleophilic base. In some embodiments, in step (a-1), the
reaction of a compound of Formula (D-l) or a salt thereof with a compound of Formula
(E-l) or a salt f comprises reacting a compound of Formula (D-l) or a salt thereof
with a coupling reagent, such as carbonyl diimidazole (GDI), and subsequently with a
compound of Formula (E-l) or a salt thereof in the presence of abase, such as anonnucleophilic
base. In some embodiments, (i) a compound of Formula (D-l) or a salt
thereof is reacted with GDI prior to the reaction with a nd of Formula (E-l) or a
salt thereof, and then subsequently (ii) the reaction product of step (i) is reacted with a
nd of Formula (E-l) or a salt thereof in the presence of a base, such as DBU
(l,8-Diazabicyclo(5.4.0)undecene).
In some ments, step (b-1) of Scheme 4 below is performed in the
presence of a base. In some ments, step (b-1) is performed in the presence of an
aqueous base, such as aqueous hydroxide. In some embodiments, step (b-1) is
performed in the presence of an aqueous metal hydroxide, such as aqueous NaOH.
In some embodiments, step (c-1) of Scheme 4 below is performed in the
presence of a base. In some ments, step (c-1) is med in the presence of a
metal carbonate (e.g., Na2CC>3 or K2CO3).
SUBSTITUTE SHEET (RULE 26)
Scheme 4
'ORa 0
F3C ■cf3
O^N. Xa N Xa ORa
NH (B-D N. ^5
n Xa
step (c-1)
(A-1) (C-1)
pF3 o cf3
PhSOoNHs
OH (E-1) v4
------------- ► \ N, - H
step(b-1) ^ Xa step (a-1) b-AN^N^2 Xa
(D-1) (F-1)
HN'AiS' pF3 0 0 0
XN:s:ph
\ J s'
N' 'N A(S
Compound (1)
In Scheme 4, Ra is chosen from C1-C4 alkyl groups; and each Xa is
independently chosen from F or Cl.
In some embodiments, s of preparing a compound of Formulae (I) and
(II), wherein X is NH or N(Ci-C4 alkyl) or a pharmaceutically able salt thereof, or
a deuterated derivative of any of the foregoing, comprise reacting a compound of
Formula (L) or a salt thereof with NR*3 where R* is H or C1-C4 alkyl, as depicted in
Schemes 5 and 6:
SUBSTITUTE SHEET (RULE 26)
Scheme 5
0 0
II 11 Y1 ^
yi^ rI^'N^Y^N-A ^
N-NA NR*3
R-tw Y
^R3),
VKyr (I: where X is NR*)
(r! (L)
Scheme 6
0 0 .s\V/
N'S N
H l>3)P
H t-(r2)p NR*3 Nv
■v rs
RXw N ^Ir3),
^R3),
(r4) (II: where X is NR*)
(L: where Y2 is CH)
Any le conditions known in the art can be used for the sulfoxamination
reaction, for example, for those for electrophilic additions by amines. In some
embodiments, the sulfoxamination reaction is performed in the presence of a
chlorinating or oxidizing agent, such as N-chlorosuccinimide (NCS).
In some ments, a compound of Formula (L) or a salt thereof is
ed by a method comprising oxidizing the sulfur unit of the H group
of a compound of Formula (M) or salt thereof as shown in Scheme 7 below:
SUBSTITUTE SHEET (RULE 26)
Scheme 7
0 0
yi^ 'OH yl ^ NH2 yi%
N'N^ N'N^'y2^xa
RXw i 'Xa
R'tV rV Y
(r4) (r4)lKjr (p) (r4), <°>
0 0
II II
yl^ K's1Qhr2)p Y1^
Y2' R,-tw Y
^R3). ^R3),
(R4)r
Any suitable conditions known in the art can be used for the oxidation
on. In some embodiments, the oxidation is performed in the presence of a
peroxycarboxylic acid, such as meta-Chloroperoxybenzoic acid (m-CPBA).
In some embodiments, a compound of Formula (M) or a salt thereof is
prepared by a method comprising reacting a compound of Formula (O) with a
compound of Formula (G) or a salt f. Any suitable conditions known in the art
can be used.
In some embodiments, a compound of Formula (0) or a salt thereof is
prepared by a method comprising reacting a nd of Formula (P) or salt thereof
;Hr2)
with a phenyl disulfide of a (Q): p. In some
embodiments, a compound of Formula (P) or a salt thereof is prepared by amidating the
-C(0)0H group of a compound of Formula (D) or salt thereof. Any le conditions
known in the art can be used.
SUBSTITUTE SHEET (RULE 26)
onal embodiments include:
1. A compound of Formula I:
0 O X
\(r2)„
R1 -r (R3),
(R4),
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing,
wherein:
- one of Y1 and Y2 is N and the other is CH;
- X is chosen from 0, NH, and N(Ci-C4 alkyl) groups;
- R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups,
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl , nated C1-C2 alkyl groups, and halogens,
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally tuted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- k is 0 or 1;
- ris 0 or 1;
- mis 0,1, 2, or 3;
SUBSTITUTE SHEET (RULE 26)
- n is 0 or 1;
- p is 0, 1, 2, 3, 4, or 5; and
- qis 0, 1, 2, 3, 4, 5, 6, 7, or 8.
2. A compound of a II:
0 a x¥
\<R2)p
/ N N N
R1 -r (R3)q
(r4),
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
- X is chosen from 0, NH, and N(Ci-C4 alkyl) groups;
- R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups,
wherein each Ring A is independently chosen from C3-C10 cycloalky]
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens,
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is ndently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- k is 0 or 1;
- ris 0 or 1;
- mis 0,1, 2, or 3;
- n is 0 or 1;
- p is 0, 1, 2, 3, 4, or 5; and
SUBSTITUTE SHEET (RULE 26)
- qis 0, 1,2, 3, 4, 5, 6, 7, or 8.
3. A nd of Formula III:
0 o. o
\(R2)p
N N N
* (R3)q
(R4)r
(HI),
a pharmaceutically acceptable salt thereof, or a ated derivative of any of the
foregoing, wherein:
- R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups,
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and ns,
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- k is 0 or 1;
- ris 0 or 1;
- mis 0,1, 2, or 3;
- n is 0 or 1;
- p is 0, 1, 2, 3, 4, or 5; and
- qis 0, 1, 2, 3, 4, 5, 6, 7, or 8.
SUBSTITUTE SHEET (RULE 26)
4. A compound according to any of embodiments 1-3, a pharmaceutically
acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein if R2
is cyano, then said R2 is meta or para relative to the sulfur atom.
. A compound according to any of embodiments 1-3, a ceutically
acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:
- each Ring A is independently chosen from C3-C10 lkyl groups optionally
substituted with one or more substituents each independently chosen from C1-C2 alkyl
groups, halogenated C1-C2 alkyl groups, and halogens, and
- each R is independently chosen from H and OH;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, and halogens;
- R4 is F;
- kis 0;
- p is 0, 1, or 2;
- qis 0, 1, 2, 3, or 4;
- r is 0; and
wherein m and n are not 0 at the same time.
6. A compound according to embodiment 5, a pharmaceutically acceptable salt
thereof, or a deuterated tive of any of the ing, wherein:
- R1 is chosen from (CR2)m-Ring A groups,
wherein Ring A is chosen from C3-C10 cycloalkyl groups
groups ally substituted with one or more substituents each ndently
chosen from C1-C2 alkyl groups, nated C1-C2 alkyl groups, and halogens,
- m is 1 or 2.
7. A compound according to embodiment 6, a pharmaceutically acceptable salt
thereof, or a deuterated derivative of any of the foregoing, wherein each R3 is a methyl
group and q is 3 or 4.
8. A compound according to embodiment 7 having Formula IV:
SUBSTITUTE SHEET (RULE 26)
l0 0 0 ¥
H X(R2)p
Ring AAx ' N N
(IV),
a pharmaceutically acceptable salt thereof, or a deuterated tive of any of the
foregoing,
wherein:
- Ring A is chosen from C3-C10 cycloalkyl groups optionally substituted with
one or more substituents each independently chosen from C1-C2 alkyl groups,
halogenated C1-C2 alkyl groups, and halogens; and
- each R2 is independently chosen from C1-C2 alkyl groups, OH, F, Cl, and Ci-
C2 alkoxy groups;
- m is 1 or 2; and
- p is 0, 1, or 2.
9. A compound according to embodiment 8, wherein p is 0 or 1.
. A compound according to embodiment 8, wherein p is 0.
11. A nd according to embodiment 8 having Formula V:
° °v PV
H r!,p
Jrk0 XX XX
' N N N fS)
Ring A
SUBSTITUTE SHEET (RULE 26)
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing,
- Ring A is chosen from C3-C10 lkyl groups optionally substituted with
one or more substituents each independently chosen from C1-C2 alkyl groups,
nated C1-C2 alkyl groups, and halogens; and
- each R2 is independently chosen from C1-C2 alkyl , OH, F, Cl, and Ci-
C2 alkoxy groups;
- m is 1 or 2; and
- p is 0, 1, or 2.
12. A compound according to any one of embodiments 1-11, a pharmaceutically
acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each
R2 is independently chosen from CH3, OH, F, and OCH3.
13. A compound according to embodiment 12, a ceutically acceptable salt
thereof, or a deuterated derivative of any of the foregoing, wherein p is 0 or 1.
14. A compound according to embodiment 13, a pharmaceutically acceptable salt
thereof, or a ated derivative of any of the foregoing, wherein p is 0.
. A compound according to embodiment 11, a pharmaceutically acceptable salt
f, or a deuterated derivative of any of the foregoing, wherein Ring A is a
cyclopropyl group substituted with a halogenated Ci alkyl group or a halogenated C2
alkyl group.
16. A compound ing to embodiment 15, a pharmaceutically acceptable salt
thereof, or a deuterated derivative of any of the foregoing, wherein Ring A is a
cyclopropyl group substituted with a CF3 group.
17. A compound according to embodiment 11, a pharmaceutically acceptable salt
f, or a deuterated derivative of any of the foregoing, wherein m is 1, Ring A is a
cyclopropyl group substituted with a CF3 group, p is 0 or 1, and R2, if present, is a
methyl group, a hydroxy group, or a methoxy group.
SUBSTITUTE SHEET (RULE 26)
18. A compound according to embodiment 11, a pharmaceutically acceptable salt
thereof, or a deuterated derivative of any of the foregoing, n m is 2, Ring A is a
C3 cycloalkyl group tuted with a CF3 group, p is 0 or 1, and R2, if present, is a
methyl group, a hydroxy group, or a methoxy group.
19. A compound according to embodiment 17 or 18, a pharmaceutically acceptable
salt thereof, or a deuterated derivative of any of the foregoing, wherein m is 2, Ring A
is a cyclopropyl group substituted with a CF3 group, and p is 0.
. A compound according to ment 11, a pharmaceutically acceptable salt
thereof, or a deuterated tive of any of the foregoing, wherein Ring A is chosen
from C5 bicycloalkyl groups optionally substituted with one or more substituents each
ndently chosen from Ci-C2 alkyl groups, halogenated Ci-C2 alkyl , and
halogens.
21. A compound according to embodiment 20, a pharmaceutically able salt
thereof, or a ated derivative of any of the foregoing, n Ring A is a C5
bicycloalkyl group optionally substituted with a halogen.
22. A compound according to embodiment 11, a pharmaceutically acceptable salt
thereof, or a deuterated derivative of any of the foregoing, wherein Ring A is chosen
from C? bicycloalkyl groups and Cytricycloalkyl groups optionally substituted with one
or more substituents each independently chosen from C1-C2 alkyl groups, halogenated
C1-C2 alkyl groups, and halogens.
23. A compound according to embodiment 22, a pharmaceutically acceptable salt
thereof, or a deuterated derivative of any of the foregoing, wherein Ring A is an
unsubstituted Cy tricycloalkyl group.
24. A compound having a formula chosen from any one of the formulae depicted in
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of
the foregoing.
. A compound ing to embodiment 1 having the following formula:
SUBSTITUTE SHEET (RULE 26)
OS N N N'A(S)
a pharmaceutically able salt thereof, or a deuterated derivative of any of the
foregoing.
26. A nd according to embodiment 1 having the following formula:
0 0 0 0H
oS V N N \(S)
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing.
27. A compound according to embodiment 1 having the following formula:
0 n'A(s)
a pharmaceutically acceptable salt thereof, or a ated derivative of any of the
foregoing.
28. A compound according to embodiment 1 having the following formula:
SUBSTITUTE SHEET (RULE 26)
HO KJ
,0 N
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing.
29. A compound according to embodiment 1 having the following formula:
0 Oo F
rfVWs
0^/' N N N
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
. A nd having the following formula:
r''V^N'®V^
N (S)
a pharmaceutically acceptable salt f, or a deuterated derivative of any of the
foregoing.
31. A compound having any one of the following formulae:
SUBSTITUTE SHEET (RULE 26)
|\L. ./x.
0 // N N N*A(S)
F or
P QO\'//
0~fJ NN. N'xfS)
a pharmaceutically acceptable salt thereof, or a ated derivative of any of the
foregoing.
32. A compound according to embodiment 1 having the following formula:
0 N cd3
F (S)
F 6D
or a pharmaceutically acceptable salt thereof.
33. A compound having the following formula:
/VVA°"fn ysv^
HO 0-// 'N-m- -M N N
R F DDD
or a pharmaceutically able salt thereof.
SUBSTITUTE SHEET (RULE 26)
34. A compound according to embodiment 1 having the following formula:
Q 0. 0
0 OH
or a pharmaceutically acceptable salt thereof.
. A pharmaceutical composition comprising at least one compound chosen from
compounds of any one of embodiments 1-34, a pharmaceutically able salt thereof,
or a ated derivative of any of the foregoing, and optionally one or more of:
(a) Compound II:
Fx0-^^ OH
F 0 F N / N
a pharmaceutically able salt thereof, or a deuterated derivative of any of the
foregoing;
(b) Compound III:
a pharmaceutically acceptable salt f, or a deuterated derivative of any of the
foregoing; and
(c) a pharmaceutically acceptable carrier.
SUBSTITUTE SHEET (RULE 26)
WO 64632
36. A method of treating cystic fibrosis comprising administering to a patient in
need thereof a pharmaceutical composition according to embodiment 35.
37. A method of preparing a compound of Formula :
...A H {R2)p
rW/ n Y
(R4)r
(III)
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing, comprising reacting a nd of Formula (F) or a salt thereof with a
nd of Formula (G) or a salt thereof to generate said compound of Formula (Ilia)
or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing:
P QO HN-0^R3)q o on
,sA'/ ^(O)
yi ^ yi ^
1 N-m^ nonG'/
^ V2 x" 2
rV n-A i'MJ Y
^R3),
(R4)r (F) (R4)r
(Ilia)
wherein in each of said ae:
- one of Y1 and Y2 is N and the other is CH;
- each R1 is independently chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i
groups.
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and ns,
wherein each R is independently chosen from H, OH, and Ci-C2 alkyl
groups optionally substituted with one or more halogens;
SUBSTITUTE SHEET (RULE 26)
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH ;
- each R4 is independently chosen from halogens;
- Xa is chosen from F or Cl;
- each k is independently 0 or 1;
- each r is independently 0 or 1;
- each m is independently 0, 1, 2, or 3;
- each n is independently 0 or 1;
- each p is independently 0,1, 2, 3, 4, or 5; and
- each q is independently 0, 1,2, 3, 4, 5, 6, 7, or 8.
38. The method of embodiment 37, wherein each Y2 is independently N; and each
Y1 is independently CH.
39. The method of embodiment 37 or 38, wherein said reacting a compound of
Formula (F) or a salt thereof with a compound of Formula (G) or a salt thereof is
performed in the presence of a base.
40. The method of any one of embodiments 37-39, wherein a salt of nd of
Formula (G) is employed.
41. The method of embodiment 40, wherein said salt of compound of Formula (G) is
a HC1 salt of a compound of Formula (G).
42. A method of ing a compound of Formula (F) or a salt thereof:
Q 0. o
yi^s N"
A c H 1r2)p
N y2
R1-^ ^
Mr (F)
SUBSTITUTE SHEET (RULE 26)
or a deuterated derivative of any of the foregoing, comprising reacting a compound of
Formula (D) or salt thereof with a compound of Formula (E) or a salt thereof to generate
a compound of Formula (F) or a salt thereof:
2 Q 0 0
o Y1^. 's'
In l>\
yi^ Rl-t^Y2" H
OH Xa
R1 /^'N^Y^X3 (E)
(R4)r (F)
wherein in each of said formulae:
- one of Y1 and Y2 is independently N and the other is independently CFI;
- each R1 is independently chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+1
groups,
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens,
n each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is ndently chosen from halogens;
- Xa is chosen from F or Cl;
- each k is independently 0 or 1;
- each r is independently 0 or 1;
- each m is independently 0, 1, 2, or 3;
SUBSTITUTE SHEET (RULE 26)
- each n is independently 0 or 1;
- each p is independently 0, 1.2, 3, 4, or 5; and
- each q is independently 0, 1.2, 3, 4, 5, 6, 7, or 8.
43. The method of embodiment 42, wherein each Y2 is ndently N; and each
Y1 is independently CH.
44. The method of embodiment 42 or 43, wherein said reacting a compound of
Formula (D) or a salt thereof with a compound of a (E) or salt thereof is
performed in the presence of a base.
45. The method of embodiment 42 or 43, wherein said reacting a compound of
Formula (D) or salt f with a compound of Formula (E) or salt thereof comprises
reacting a compound of Formula (D-l) with a coupling reagent and uently with a
compound of Formula (E-l) in the presence of a base.
46. A method of preparing a compound of the following formula:
CFs IX,
or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing, comprising reacting a compound of Formula (F-l) or a salt thereof, wherein
Xa is chosen from F or Cl, with a compound of Formula (G-l) or a salt thereof to
generate said compound or a ceutically acceptable salt thereof, or a deuterated
tive of any of the foregoing:
HN PF3
PF3 o 0 0
o o 0 XN:s',ph
AN:s:Ph (G-1)
b-oN N J H H
\ N«m°~O
n N Xa
(F-1) Compound (1)
SUBSTITUTE SHEET (RULE 26)
47. The method of embodiment 46, wherein said reacting a compound of Formula
(F-l) or a salt thereof with a nd of Formula (G-l) or a salt thereof is performed
in the presence of a base.
48. The method of embodiment 46 or 47, wherein a salt of compound of Formula
(G-l) is employed.
49. The method of embodiment 48, n said salt of compound of Formula (G-l)
is aHCl salt of a compound of Formula (G-l).
50. A method of preparing a compound of Formula (F-l) or a salt thereof:
~a H
Nk,,,
0 N' 'Xa
(F-1)
or a ated derivative of any of the foregoing, comprising reacting a compound of
a (D-l) and a compound of Formula (E-l) to generate a compound of Formula
(F-l) or a salt thereof:
PF3 0 PF3 o o 0
PhS02NH2
"A- XN:s:Ph
OH (E-1)
\ N.m N Xa \ n-m N Xa
(D-1) (F-1)
wherein each Xa is ndently chosen from F or Cl.
51. The method of ment 50, wherein said reacting a compound of Formula
(D-l) or a salt thereof with a compound of Formula (E-l) or a salt thereof is performed
in the ce of a base.
52. The method of embodiment 50, wherein said reacting a compound of Formula
(D-l) or a salt thereof with a compound of Formula (E-l) or a salt thereof comprises
reacting a compound of Formula (D-l) with a coupling reagent and subsequently with a
compound of Formula (E-l) in the presence of a base.
SUBSTITUTE SHEET (RULE 26)
53. A method of preparing a compound of Formula (D) or a salt thereof:
''s-'VY1^ OH
R1-// Xa
(R4)r
or a deuterated derivative of any of the ing, comprising:
(i) reacting a compound of Formula (A) or a salt thereof with a compound
of Formula (B) or a salt thereof to generate a compound of Formula (C) or a salt
thereof:
y2^ ORa
CI^Y1"" O
R' N xa
(B) Y1 'V' OR
riJHAY* xa
(R4)r
(C) ; and
(ii) hydrolyzing the -C(0)0Ra group of a compound of a (C) to
generate a compound of Formula (D) or a salt thereof, wherein in each said
formulae:
- one of Y1 and Y2 is ndently N and the other is independently CH;
- each R1 is ndently chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i
groups,
wherein each Ring A is independently chosen from C3-C10 cycloalky]
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and ns,
SUBSTITUTE SHEET (RULE 26)
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
groups, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
--each Ra is independently chosen from C1-C4 alkyl;
- each Xa is independently chosen from F or Cl;
- each k is independently 0 or 1;
- each r is independently 0 or 1;
- each m is independently 0,1, 2, or 3;
- each n is independently 0 or 1;
- each p is independently 0,1, 2, 3, 4, or 5; and
- each q is independently 0, 1,2, 3, 4, 5, 6, 7, or 8.
54. The method of embodiment 53, wherein each Y2 is independently N; and each
Y1 is independently CH.
55. The method of ment 53 or 54, wherein the ysis of the -C(0)ORa
group is performed in the presence of a base.
56. The method of any one of embodiments 53-55, wherein said reacting a
compound of Formula (A) or a salt thereof with a compound of Formula (B) or salt
thereof is performed in the presence of a base.
57. The method of any one of ments 53-56, wherein Ra is ethyl or l.
58. A method of preparing a compound of Formula (D-l) or a salt thereof:
SUBSTITUTE SHEET (RULE 26)
CF3 0
(D-1)
or a ated derivative of any of the foregoing, comprising:
(i) reacting a compound of a (A-l) or a salt thereof and a compound
of Formula (B-l) or a salt thereof to generate a compound of Formula (C-l) or a
salt thereof:
CFs ORa
CFs 0
X* N X*
°-v (B-1) "ORa
(A-1)
(C-1)
(ii) hydrolyzing the -C(0)0Ra group of a compound of Formula (C-l) or a
salt thereof to generate a compound of Formula (D-1) or a salt thereof,
wherein each Ra is independently chosen from C1-C4 alkyl; and each - Xa is
independently chosen from F or Cl.
59. The method of embodiment 58, wherein the hydrolysis of the -C(0)0Ra group
is performed in the presence of a base.
60. The method of 58 or 59, wherein said reacting a compound of Formula (A-l) or
a salt thereof and a nd of Formula (B-l) or a salt thereof is performed in the
presence of a base.
61. The method of any one of embodiments 58-60, wherein Ra is ethyl or l.
62. A method of preparing a compound of Formula (I) or a pharmaceutically
acceptable salt thereof, or a deuterated derivative of any of the foregoing, sing
reacting a compound of Formula (L) or a salt f with NR*3 :
SUBSTITUTE SHEET (RULE 26)
0 o v'
v2^ II 11
n Yf NR*3
Y R%v
RXy ^R3),
(R4)r
wherein in each of said formulae:
- X is NH orN(Ci-C4 alkyl);
- one of Y1 and Y2 is independently N and the other is independently CH;
- each R1 is independently chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i
groups,
wherein each Ring A is independently chosen from C3-C10 cycloalkyl
groups optionally substituted with one or more substituents each independently
chosen from C1-C2 alkyl , halogenated C1-C2 alkyl groups, and halogens,
wherein each R is independently chosen from H, OH, and C1-C2 alkyl
groups optionally substituted with one or more halogens;
- each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy
, halogens, and cyano;
- each R3 is independently chosen from C1-C2 alkyl groups optionally
substituted with one or more OH groups;
- each R4 is independently chosen from halogens;
- R* is H or C1-C4 alkyl.
- Xa is chosen from F or Cl;
- each k is independently 0 or 1;
- each r is independently 0 or 1;
- each m is independently 0, 1, 2, or 3;
- each n is independently 0 or 1;
SUBSTITUTE SHEET (RULE 26)
- each p is independently 0, l, 2, 3, 4, or 5; and
- each q is independently 0, 1.2, 3, 4, 5, 6, 7, or 8.
63. Use of at least one compound chosen from nds of any one of
embodiments 1-34, a pharmaceutically acceptable salt thereof, or a deuterated derivative
of any of the foregoing, and optionally one or more of:
(a) Compound II:
Fxl0 N
F 0 ^ 0
F N / N
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing; and
(b) Compound III:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the
foregoing;
for treating cystic fibrosis.
] Methods of Preparing Compounds
General Experimental Procedures
Reagents and starting materials were obtained by commercial sources unless
otherwise stated and were used without purification. Proton and carbon NMR a
were acquired on either of a Bruker n DRX 400 MHz FTNMR spectrometer
ing at a H and C resonant frequency of 400 and 100 MHz respectively, or on a
300 MHz NMR spectrometer. One dimensional proton and carbon spectra were
SUBSTITUTE SHEET (RULE 26)
acquired using a broadband observe (BBFO) probe with 20 Hz sample on at
0.1834 and 0.9083 Hz/Pt digital resolution respectively. All proton and carbon spectra
were acquired with temperature l at 30°C using standard, usly published
pulse sequences and routine processing parameters. Final purity of compounds was
determined by reversed phase UPLC using an Acquity UPLC BEH Cig column (50 x
2.1 mm, 1.7 pm particle) made by Waters (pn: 186002350), and a dual nt run
from 1-99% mobile phase B over 3.0 minutes. Mobile phase A = H2O (0.05 %
CF3CO2H). Mobile phase B = CFF,CN (0.035 % CF3CO2H). Flow rate = 1.2 mL/min,
injection volume = 1.5 pL, and column temperature = 60 °C. Final purity was
calculated by averaging the area under the curve (AUC) of two UY traces (220 nm, 254
nm). Low-resolution mass spectra were reported as [M+H]+ species obtained using a
single quadrupole mass spectrometer equipped with an electrospray ionization (ESI)
source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of
1000 (no units on resolution) across the ion range. Optical purity of methyl (2S)-
2,4-dimethylnitro-pentanoate was determined using chiral gas chromatography (GC)
analysis on an Agilent 7890A/MSD 5975C instrument, using a Restek Rt-(3DEXcst
(30m x 0.25mm x 0.25um_df) column, with a 2.0 mL/min flow rate (H2 r gas), at
an injection temperature of 220°C and an oven temperature of 120°C, 15 minutes.
Example 1: ation of a Spray Dried Dispersion (SDD) of
Compound 1
A spray dried dispersion of Compound 1 was prepared using Buchi Mini
Spray Dryer B290. HPMCAS-HG (6.0 grams) was dissolved in 200 mL of MeOH
(methanol)/DCM (dichloromethane) (1/1), and Compound 1 (6.0 grams) was added and
stirred for 30 minutes forming a clear on. The resulting on was spray dried
under the following conditions resulting in a 50% Compound 1/50% HPMCAS- HG
spray dried sion (Yield: 80%, Solid load: 6%).
Conditions
Inlet Temperature (°C) 77
Outlet Temperature (°C) 39
Nitrogen Pressure (PSI) 95
SUBSTITUTE SHEET (RULE 26)
WO 64632
Aspirator (%) 100
Pump (%) 30
Rotameter (mm) 60
Filter Pressure (mBar) -50
Condenser Temperature (°C) -10
Powder X-ray Diffraction
The powder x-ray diffraction measurements were performed using
PANalyticaTs X-pert Pro ctometer at room temperature with copper radiation
(1.54060 A). The incident beam optic was comprised of a variable ence slit to
ensure a constant illuminated length on the sample and on the diffracted beam side; a
fast linear solid state detector was used with an active length of 2.12 degrees 2 theta
measured in a scanning mode. The powder sample was packed on the ed area of a
zero background silicon holder and spinning was performed to achieve better statistics.
A symmetrical scan was measured from 4-40 degrees 2 theta with a step size of 0.017
degrees and a scan step time of 15.5s.
shows the XRPD spectrum of a SDD of 50% Compound 1 in
-HG, and shows that Compound 1 is amorphous in the SDD.
Modulated Differential Scanning Calorimetry (MDSC)
MDSC was used to determine the glass transition ature of the
amorphous material. MDSC was performed using TA Discovery DSC differential
scanning calorimeter (TA Instruments, New , DE). The instrument was calibrated
with indium. Samples of approximately 1-3 mg were weighed into hermetic pans that
were crimped using lids with one hole. The MDSC sample was scanned from -20°C to
210°C at a heating rate of 20C/min with +/- 1°C of modulation within 1 minute. Data
was collected and analyzed by TA Instruments Trios Software (TA Instruments, New
Castle, DE).
shows a MDSC spectrum of a SDD of 50% Compound 1 in
HPMCAS-HG, and shows that the SDD has an onset temperature of about 75.6°C, a
midpoint temperature of about 82.7°C, and an offset ature of about 89.7°C.
SUBSTITUTE SHEET (RULE 26)
WO 64632
Example 2: Synthesis of Compound II: (R)-l-(2,2-
Difluorobenzo[d][l,3]dioxolyl)-N-(l-(2,3-dihydroxypropyl)fluoro(lhydroxymethylpropanyl
)-lH-indolyl)cyclopropanecarboxamide
02N. '£3
F' N ■OCH2Ph
H d CsC03, DMF
o2n o2n
LiAIH/i. TK)F
F N + F N
•O -o
■□•V oV
02N OH H2N
H2, Pd-C ito:OH toOH SOCI7, DMF
-O XV 2) Et3N, CH2CI2
-O OH
Step 1: (R)-Benzyl 2-(l-((2,2-dimethyl-l,3-dioxolanyl)methyl)
nitro-lH-indolyl)methylpropanoate and ((S)-2,2-Dimethyl-l,3-
dioxolanyl)methyl 2-(l-(((R)-2,2-dimethyl-l,3-dioxolanyl)methyl)fluoro
nitro-lH-indolyl)methylpropanoate
Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl 2-(6-
fluoronitro-lH-indolyl)methylpropanoate (3.0 g, 8.4 mmol) and (S)-(2,2-
dimethyl-l,3-dioxolanyl)methyl 4-methylbenzenesulfonate (7.23 g, 25.3 mmol) in
DMF (N,N-dimethylformamide) (17 mL). The reaction was stirred at 80 °C for 46 hours
SUBSTITUTE SHEET (RULE 26)
under a nitrogen atmosphere. The e was then partitioned between ethyl acetate
and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl
acetate layers were washed with brine, dried over MgS04, filtered and concentrated.
The crude product, a viscous brown oil which contains both of the products shown
above, was taken directly to the next step without further purification. (R)-Benzyl 2-(l-
((2,2-dimethyl-l,3-dioxolanyl)methyl)fluoronitro-lH-indolyl)
methylpropanoate, ESI-MS m/z calc. 470.2, found 471.5 (M+l)+. Retention time 2.20
minutes. ((S)-2,2-Dimethyl-l,3-dioxolanyl)methyl 2-(l-(((R)-2,2-dimethyl-1,3-
dioxolanyl)methyl)fluoronitro-lH-indolyl)methylpropanoate, ESI-MS
m/z calc. 494.5, found 495.7 (M+l)+. Retention time 2.01 minutes.
Step 2: (l-((2,2-dimethyl-1,3-dioxolanyl)methyl)fluoro
nitro-lH-indolyl)methylpropan-l-ol
The crude reaction mixture obtained in step (A) was dissolved in THE
(tetrahydrofuran) (42 mL) and cooled in an ice-water bath. L1AIH4 (16.8 mL of 1 M
solution, 16.8 mmol) was added drop-wise. After the addition was te, the
mixture was stirred for an additional 5 minutes. The reaction was quenched by adding
water (1 mL), 15% NaOEl solution (1 mL) and then water (3 mL). The mixture was
filtered over Celite, and the solids were washed with THE and ethyl acetate. The filtrate
was concentrated and purified by column chromatography (30-60% ethyl acetatehexanes
) to obtain (l-((2,2-dimethyl-l,3-dioxolanyl)methyl)fluoronitrolH-indolyl
)methylpropan-l-ol as a brown oil (2.68g, 87 % over 2 steps). ESI-MS
m/'z calc. 366.4, found 367.3 (M+l)+. Retention time 1.68 s, 'll NMR (400
MHz, ?6) 5 8.34 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 13.4 Hz, 1H), 6.57 (s, 1H),
4.94 (t, J = 5.4 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.52 - 4.42(m, 2H), 4.16 - 4.14 (m, 1H),
3.76 - 3.74 (m, 1H), 3.63 - 3.53 (m, 2H), 1.42 (s, 3H), 1.38 - 1.36 (m, 6H) and 1.19 (s,
3H) ppm. (DMSO is dimethylsulfoxide).
] Step 3: (R)(5-amino-l-((2,2-dimethyl-l,3-dioxolanyl)methyl)
fluoro- lH-indolyl)methylpropan- l-ol
(R)(l-((2,2-dimethyl-l,3-dioxolanyl)methyl)fluoronitro-lH-indol-
2-yl)methylpropan-l-ol (2.5 g, 6.82 mmol) was ved in ethanol (70 mL) and the
reaction was flushed withN2. Then Pd-C (250 mg, 5% wt) was added. The reaction was
flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours only partial
SUBSTITUTE SHEET (RULE 26)
conversion to the t was observed by LCMS. The reaction was filtered through
Celite and concentrated. The residue was re-subjected to the conditions above. After 2
hours LCMS indicated complete conversion to product. The reaction mixture was
filtered through Celite. The filtrate was concentrated to yield the product (1.82 g, 79 %).
ESI-MS m/z calc. 336.2, found 337.5 (M+l)+. Retention time 0.86 minutes, 'tt NMR
(400 MHz, DMSO-<76) 5 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s,
1H), 4.79 - 4.76 (m, 1H), 4.46 (s, 2H), 4.37 - 4.31 (m, 06 (dd, J = 6.1, 8.3 Hz,
1H), 3.70 - 3.67 (m, 1H), 3.55 - 3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H)
Step 4: (R)-l-(2,2-difluorobenzo[d][l,3]dioxolyl)-N-(l-((2,2-dimethyl-
l,3-dioxolanyl)methyl)fluoro(l-hydroxymethylpropanyl)-lH-indol
yljcyclopi'opanecarboxainide
DMF (3 drops) was added to a stirring mixture of 1-(2,2-
difluorobenzo[d][l,3]dioxolyl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and
thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The
solution was concentrated under vacuum and then toluene (3 mL) was added and the
mixture was concentrated again. The toluene step was ed once more and the
residue was placed on high vacuum for 10 minutes. The acid de was then
dissolved in dichloromethane (10 mL) and added to a mixture of (5-amino-l-
((2,2-dimethyl-l,3-dioxolanyl)methyl)fluoro-lH-indolyl)methylpropan-l-ol
(1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL).
The reaction was stirred at room temperature for 1 hour. The reaction was washed with
IN HC1 on, ted NaHCCL solution and brine, dried over MgSCL and
concentrated to yield the product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7
(M+l)+. Retention time 2.05 minutes, 'll NMR (400 MHz, DMSO-t/6) 8 8.31 (s, 1H),
7.53 (s, 1H), 7,42 - 7.40 (m, 2H), 7,34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H),
4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51
(m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 -
1.12 (m, 2H) ppm
SUBSTITUTE SHEET (RULE 26)
Step 5: (2,2-difluorobenzo[d] [l,3]dioxolyl)-N-(l-(2,3-
dihydroxypropyl)fluoro(l-hydroxymethylpropanyl)-lH-indol
yl)cyclopropanecarboxamide
(2,2-difluorobenzo[d][l,3]dioxolyl)-N-(l-((2,2-dimethyl-l,3-
dioxolanyl)methyl)fluoro(l-hydroxymethylpropanyl)-lH-indol
yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL).
Water (5.2 mL) was added followed by p-Ts0H.H20 (p-toluenesulfonic acid hydrate)
(204 mg, 1.1 mmol). The reaction was heated at 80 °C for 45 s. The on was
concentrated and then partitioned between ethyl acetate and ted NaHCO, solution.
The ethyl acetate layer was dried over MgSC^ and concentrated. The residue was
purified by column chromatography (50-100 % ethyl acetate - hexanes) to yield the
product. (1.3 g, 47 %, ee >98% by SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+l)+.
Retention time 1.69 minutes. 'H NMR (400 MHz, DMSO-e/6) 8 8.31 (s, 1H), 7.53 (s,
1H), 7.42 - 7.38 (m, 2H), 7.33 - 7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J = 5.2 Hz, 1H),
4.90 (t, J = 5.5 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.40 (dd, J = 2.6, 15.1 Hz, 1H), 4.10
(dd, J = 8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65 - 3.54 (m, 2H), 3.48 - 3.33 (m, 2H), 1.48 -
1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.
Example 3: Synthesis of Compound HI: N-(2,4-di-/e/7-butyl
hydroxyphenyl)oxo-l,4-dihydroquinolinecarboxamide
Part A: Synthesis of 4-oxo-l,4-dihydroquinolinecarboxylic acid
Step 1: 2-Phenylaminomethylene-malonic acid diethyl ester
A mixture of aniline (25.6 g, 0.275 mol) and diethyl 2-
(ethoxymethylene)malonate (62.4 g, 0.288 mol) was heated at 140-150 °C for 2 h. The
mixture was cooled to room temperature and dried under reduced pressure to afford 2-
phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next
step without further purification, fa NMR (DMSO-c/r,) 5 11.00 (d, 1H), 8.54 (d, J=
SUBSTITUTE SHEET (RULE 26)
13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), .40 (m,
Step 2: 4-Hydroxyquinolinecarboxylic add ethyl ester
AIL three-necked flask fitted with a mechanical stirrer was charged with 2-
phenylarmnomethylene-malonic acid diethyl ester (26.3 g, 0.100 mol), osphoric
acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to 70 °C and
stirred for 4 h. The mixture was cooled to room temperature and filtered. The residue
was treated with aqueous Na2C03 solution, filtered, washed with water and dried. 4-
Hydroxyquinolinecarboxylic acid ethyl ester was obtained as a pale brown solid
(15.2 g, 70%). The crude product was used in next step without further purification.
Step 3: 4-Oxo-l,4-dihydroquinolinecarboxylic add
4-Hydroxyquinolinecarboxylic acid ethyl ester (15 g, 69 mmol) was
suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux.
After cooling, the mixture was filtered, and the filtrate was ied to pH 4 with 2N
HC1. The ing precipitate was collected via filtration, washed with water and dried
under vacuum to give 4-oxo-l,4-dihydroquinolinecarboxylic acid as a pale white
solid (10.5 g, 92 %). 'H NMR (DMSO-r/tf) 5 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H),
8.28 (d, ,/= 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
Part B: Synthesis of N-(2,4-di-fe/7-butylhydroxyphenyl)oxo-l,4-
dihydroquinolinecarboxamide
SUBSTITUTE SHEET (RULE 26)
CIC02Me
HN03, H2S04
NEt3, DMAP
’OH o 02N' o 0
ch2ci2 O^O
KOH, MeOH
o2n OH
hco2nh4
02N' 'OH Pd-C, EtOH
H2N' 'OH
Step 1: Carbonic acid -fe/7-butyl-phenyl ester methyl ester
Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution
of 2,4-di-fert-butyl-phenol (103.2 g, 500 mmol), EhN (139 mL, 1000 mmol) and
DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0
°C. The mixture was allowed to warm to room temperature while stirring overnight,
then filtered through silica gel (approx. 1L) using 10% ethyl acetate - hexanes (~ 4 L)
as the eluent. The combined tes were concentrated to yield carbonic acid 2,4-di-
fe/7-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.), 'h NMR (400 MHz,
DMSO-c/g) 5 7.35 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz,
1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).
] Step 2: Carbonic acid 2,4-di-to7-butylnitro-phenyl ester methyl ester
and Carbonic acid 2,4-di-fc/f-butyliiitro-phenyl ester methyl ester
] To a stirring mixture of carbonic acid 2.4-di-/e/V-butyl-phenyl ester methyl
ester (4.76 g, 180 mmol) in cone, sulfuric acid (2 mL), cooled in an ice-water bath, was
added a cooled mixture of sulfuric acid (2 mL) and nitric acid (2 mL). The addition was
done slowly so that the on ature did not exceed 50 °C. The reaction was
allowed to stir for 2 h while warming to room temperature. The reaction mixture was
then added to ice-water and extracted into diethyl ether. The ether layer was dried
SUBSTITUTE SHEET (RULE 26)
(MgS04), concentrated and purified by column chromatography (0 - 10% ethyl acetate
- hexanes) to yield a mixture of carbonic acid 2,4-di-rer/-butylnitro-phenyl ester
methyl ester and carbonic acid 2,4-di-fert-butylnitro-phenyl ester methyl ester as a
pale yellow solid (4.28 g), which was used directly in the next step.
Step 3: -/e/7-butylnitro-phenol and 2,4-Di-te/7-butylnitrophenol
The mixture of carbonic acid 2,4-di-/er/-butylnitro-phenyl ester methyl
ester and carbonic acid 2,4-di-/erf-butylmtro-phenyl ester methyl ester (4.2 g, 14.0
mmol) was dissolved in MeOH (65 mL) before KOH (2.0 g, 36 mmol) was added. The
mixture was stirred at room temperature for 2 h. The reaction mixture was then made
acidic (pH 2-3) by adding cone. HC1 and partitioned between water and diethyl ether.
The ether layer was dried (MgSCf). concentrated and purified by column
tography (0-5 % ethyl acetate - hexanes) to provide 2.4-di-fcr/-butvlnitrophenol
(1.31 g, 29% over 2 steps) and 2,4-di-/ert-butylnitro-phenol. 2.4-Di-/e/7-
butylnitro-phenol: 1HNMR(400 MHz, DMSO-c4) 5 10.14 (s, 1H, OH), 7.34 (s, 1H),
6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2.4-Di-/m-butylnitro-phenol: JH NMR (400
MHz, CDC13) 5 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 1.47 (s,
9H), 1.34 (s, 9H).
] Step 4: 5-Amino-2,4-di-to7-butyl-phenol
To a refluxing on of 2.4-di-/m-butylnitro-phenol (1.86 g, 7.40
mmol) and ammonium e (1.86 g) in ethanol (75 mL) was added Pd-5% wt. on
activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 h, cooled to
room temperature and filtered through Celite. The Celite was washed with ol and
the combined filtrates were concentrated to yield 5-amino-2,4-di-/ert-butyl-phenol as a
grey solid (1.66 g, quant). XH NMR (400 MHz, /6) 5 8.64 (s, 1H, OH), 6.84 (s,
1H), 6.08 (s, 1H), 4.39 (s, 2H, NH2), 1.27 (m, 18H); HPLC ret. time 2.72 mm, 10-99 %
CH3CN, 5 min run; ESI-MS 222.4 m/z [M+H]+.
Step 5: N-(5-hydroxy-2,4-di-terf-butyl-phenyl)oxo-lH-quinoline
carboxamide
SUBSTITUTE SHEET (RULE 26)
O OH O HN' OH
O o
N N
H H2N OH H
To a suspension of 4-oxo-l,4-dihydroquinolincarboxylic acid (35.5 g: 188
mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451
mmol) at ambient temperature. The mixture became homogeneous and was allowed to
stir for 10 min before 5-amino-2.4-di-/c/7-buty 1-phenol (50.0 g, 226 mmol) was added
in small portions. The mixture was allowed to stir overnight at ambient temperature.
The mixture became heterogeneous over the course of the reaction. After all of the acid
was consumed (LC-MS is, MH+ 190, 1.71 min), the solvent was removed in
vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry.
The mixture was stirred on a rotovap (bath temperature 65 °C) for 15 min without
placing the system under . The mixture was filtered and the captured solid was
washed with hexanes to e a white solid that was the EtOH crystalate. Et20
yl ether) was added to the solid obtained above until a slurry was formed. The
mixture was stirred on a rotovapor (bath temperature 25 °C) for 15 min without placing
the system under vacuum. The mixture was filtered and the solid captured. This
procedure was performed a total of five times. The solid obtained after the fifth
precipitation was placed under vacuum overnight to e N-(5-hydro\y-2.4-di-/mbutyl-phenyl
)oxo-lH-quinolinecarboxamide (38 g, 52%). HPLC ret. time 3.45
min, 10-99% CH3CN, 5 min run; 1HNMR(400 MHz, DMSO-c/6) 5 12.88 (s, 1H), 11.83
(s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H),
7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37
(s, 9H); ESI-MS m/z cak’d 392.21; found 393.3 [M+H]+.
Example 4: Synthesis of Compounds 1-65
Synthetic e 1: Synthesis of N-(benzenesulfonyl)[3-[2-[l-
(trifhioromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-ylJpyridinecarboxamide (Compound 1)
SUBSTITUTE SHEET (RULE 26)
Part A: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride
0 o
no2 PalataseLipase
THF, Base
no2 I
O i)
,SJ LiAIH4
Raney Ni, H? HN' HN^VS)
no2 * ii)
Step 1: Synthesis of methyl-2,4-dimethylnitro-pentanoate
0 O
0 0
ydrofuran (THF, 4.5 L) was added to a 20 L glass reactor and stirred
under N2 at room temperature. 2-Nitropropane (1.5 kg. 16.83 mol) and 1,8-
diazabicyclo[5.4.0]undecene (DBU) (1.282 kg, 8.42 mol) were then charged to the
reactor, and the jacket temperature was increased to 50 °C. Once the reactor contents
were close to 50 °C, methyl methacrylate (1.854 kg, 18.52 mol) was added slowly over
100 minutes. The reaction temperature was maintained at or close to 50 °C for 21 hours.
The reaction mixture was concentrated in vacuo then transferred back to the reactor and
diluted with methyl te/V-butyl ether (MTBE) (14 L). 2 M HCI (7.5 L) was added, and
this mixture was stirred for 5 minutes then allowed to . Two clear layers were
e - a lower yellow aqueous phase and an upper green organic phase. The aqueous
layer was removed, and the organic layer was stirred again with 2 M HCI (3 L). After
tion, the HCI washes were ined and stirred with MTBE (3 L) for 5
minutes. The aqueous layer was removed, and all of the organic layers were combined
in the reactor and stirred with water (3 L) for 5 minutes. After separation, the organic
layers were concentrated in vacuo to afford a cloudy green oil. This was dried with
MgSCE and filtered to afford methyi-2,4-dimethylmtro-pentanoate as a clear green
oil (3.16 kg, 99% yield). NMR (400 MHz, form-c/) 5 3.68 (s, 3H), 2.56 - 2.35
(m, 2H), 2.11-2.00 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.19 (d, 6.8 Hz, 3H).
SUBSTITUTE SHEET (RULE 26)
Step 2: sis of methyl (2S)-2,4-dimethylnitro-pentanoate
0 0
/ PalataseLipase^
NOo N02
A r was charged with purified water (2090 L; 10 vol) and then
potassium phosphate sic (27 kg, 198.4 moles; 13 g/L for water charge). The pH
of the reactor contents was adjusted to pH 6.5 (± 0.2) with 20% (w/v) potassium
carbonate solution. The reactor was charged with racemic methyl-2,4-dimethylnitropentanoate
(209 kg; 1104.6 , and Palatase 20000L lipase (13 L, 15.8 kg; 0.06
vol).
The reaction mixture was adjusted to 32 ± 2 °C and stirred for 15-21 hours,
and pH 6.5 was maintained using a pH stat with the automatic addition of 20%
potassium ate solution. When the racemic starting material was converted to
>98% ee of the S-enantiomer, as determined by chiral GC, external heating was
switched off. The reactor was then charged with MTBE (35 L; 5 vol), and the s
layer was extracted with MTBE (3 times, 400-1000L). The combined organic extracts
were washed with aqueous Na2C03 (4 times, 522 L, 18 % w/w 2.5 vol), water (523 L;
2.5 vol), and 10% aqueous NaCl (314 L, 1.5 vol). The organic layer was concentrated
in vacuo to afford methyl (25')-2.4-dimethylnitro-pentanoate as a mobile yellow oil
(>98% ee, 94.4 kg; 45 % yield).
Step 3: Synthesis of (3S)-3,5,5-trimethylpyrrolidinone
Raney-Ni O
H2 (5)
O' ■*>
] A 20 L reactor was purged with N2. The vessel was charged sequentially with
DI water-rinsed, damp Raney® Ni (2800 grade, 250 g), methyl (2S)-2,4-dimethyl
mtro-pentanoate , 9.2 mol), and ethanol (13.9 L, 8 vol). The reaction was stirred
at 900 rpm, and the reactor was flushed with H2 and maintained at ~2.5 bar. The
reaction mixture was then warmed to 60 °C for 5 hours. The reaction mixture was
cooled and filtered to remove Raney nickel, and the solid cake was rinsed with ethanol
SUBSTITUTE SHEET (RULE 26)
(3.5 L, 2 vol). The ethanolic solution of the product was ed with a second equal
sized batch and concentrated in vacuo to reduce to a m volume of ethanol (~1.5
volumes). Heptane (2.5 L) was added, and the suspension was concentrated again to
-1.5 volumes. This was repeated 3 times; the resulting sion was cooled to 0-5 °C,
fdtered under suction, and washed with heptane (2.5 L). The product was dried under
vacuum for 20 minutes then transferred to drying trays and dried in a vacuum oven at 40
°C overnight to afford (3S)-3,5,5-trimethylpyrrolidinone as a white crystalline solid
(2.042 kg, 16.1 mol, 87 %). 'H NMR (400 MHz, Chlorofomw/) 8 6.39 (s, 1H), 2.62
(ddq, J = 9.9, 8.6, 7.1 Hz, 1H), 2.17 (dd, J = 12.4, 8.6 Hz, 1H), 1.56 (dd, J = 12.5, 9.9
Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).
] Step 4: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride
(S) i) LiAlH4 HN
ii) HC1
A glass lined 120 L reactor was charged with lithium ium e
pellets (2.5 kg, 66 mol) and dry THF (60 L) and warmed to 30 °C. The resulting
suspension was charged with (S)-3,5,5-trimethylpyrrolidinone (7.0 kg, 54 mol) in
THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C.
After complete addition, the reaction temperature was increased to 60 - 63 °C and
maintained overnight. The reaction mixture was cooled to 22 °C, then cautiously
quenched with the addition of ethyl acetate (EtOAc) (1.0 L, 10 moles), followed by a
mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq), and then a mixture of water (1.75 kg)
with 50 % aqueous sodium hydroxide (750 g, 2 equiv water with 1.4 equiv sodium
hydroxide relative to aluminum), followed by 7.5 L water. After the addition was
complete, the reaction mixture was cooled to room temperature, and the solid was
removed by filtration and washed with THF (3 x 25 L). The filtrate and washings were
combined and treated with 5.0 L (58 moles) of aqueous 37% HC1 (1.05 equiv.) while
maintaining the temperature below 30°C. The ant solution was concentrated by
vacuum distillation to a slurry. Isopropanol (8 L) was added and the solution was
concentrated to near dryness by vacuum distillation. panol (4 L) was added, and
the t was slurried by warming to about 50 T. MTBE (6 L) was added, and the
SUBSTITUTE SHEET (RULE 26)
slurry was cooled to 2-5 °C. The product was collected by filtration and rinsed with 12
L MTBE and dried in a vacuum oven (55 oC/300 torr/N2 bleed) to afford (4S)-2,2,4-
trimethylpyrrolidine*HCl as a white, crystalline solid (6.21 kg, 75% yield). NMR
(400 MHz, DMSO-t/6) 6 9.34 (hr d, 2H), 3.33 (dd,J= 11.4, 8.4 Hz, 1H), 2.75 (dd,/ =
11.4, 8.6 Hz, 1H), 2.50-2.39 (m, 1H), 1.97 (dd,J= 12.7, 7.7 Hz, 1H), 1.42 (s,3H),
1.38 (dd, J= 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, .7=6.6 Hz, 3H).
Part B: sis of N-(benzenesulfonyl)[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
HO cf3
H O . o ,
0"CnAo^ DIAD TFA N.
f3c f3c
0 I 1) TFA
is k2co3
cr n ci DABCO P-{j 'N a 2) GDI, PhS02NH2,
f3c DBU
O^rjN-m^m N p-^ri^N
f3c k2co3
Synthesis of ng materials:
] Synthesis of ferf-Butyl 2,6-dichloropyridinecarboxylate
SUBSTITUTE SHEET (RULE 26)
O 1) (Boc)20
2) HCI
OH o
cr n ci cr n ci
A solution of 2,6-dichloropyridinecarboxylic acid (10 g, 52.08 mmol) in
THF (210 mL) was treated successively with di-fert-butyl dicarbonate (17 g, 77.89
mmol) and ethylamino)pyridine (3.2 g, 26.19 mmol) and stirred ght at
room temperature. At this point, HCI IN (400 mL) was added, and the mixture was
stirred vigorously for about 10 s. The product was ted with ethyl acetate
(2x300mL), and the combined organic layers were washed with water (300 mL) and
brme (150 mL) and dried over sodium sulfate and concentrated under reduced pressure
to give 12.94 g (96% yield) of utyl 2,6-dichloropyndinecarboxylate as a
colorless oil. ESI-MS m/z calc. 247.02, found 248.1 (M+l)+; Retention time: 2.27
s. 'H NMR (300 MHz, CDC13) ppm 1.60 (s, 9H), 7.30 (d, .7=7.9 Hz, 1H), 8.05
(d, 7=8.2 Hz, 1H).
Synthesis of tert-Butyl 3-o\o-2r3-dihydro-lH-pyrazole-l-carboxylate
1) H2N-NH2
2) (Boc)20 Va pH 0
A SOL reactor was started, and the jacket was set to 20 °C, with stirring at
150 rpm, reflux condenser (10 °C) and nitrogen purge. MeOH (2.860 L) and methyl
(E)methoxypropenoate (2.643 kg, 22.76 mol) were added, and the reactor was
capped. The reaction was heated to an internal temperature of 40 °C, and the system
was set to hold jacket temperature at 40 °C. Hydrazine hydrate (1300 g of 55 %w/w,
22.31 mol) was added portion wise via addition funnel over 30 min. The reaction was
heated to 60 °C for 1 h. The reaction mixture was cooled to 20 °C and triethyamine
(2.483 kg, 3.420 L, 24.54 mol) was added portion-wise, maintaining reaction
temperature <30 °C. A solution of Boc anhydride (di-tert-butyl dicarbonate) (4.967 kg,
.228 L, 22.76 mol) in MeOH (2.860 L) was added portion-wise maintaining
temperature <45 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction
SUBSTITUTE SHEET (RULE 26)
on was partially concentrated to remove MeOH, ing in a clear, light amber
oil. The resulting oil was transferred to the 50L reactor, stirred and water (7.150 L) and
heptane (7.150 L) were added. The additions caused a small amount of the product to
precipitate. The aqueous layer was drained into a clean container, and the interface and
heptane layer were filtered to separate the solid (product). The aqueous layer was
transferred back to the reactor, and the collected solid was placed back into the r
and mixed with the aqueous layer. A dropping funnel was added to the reactor and
loaded with acetic acid (1.474 kg, 1.396 L, 24.54 mol) and added dropwise. The jacket
was set to 0 °C to absorb the quench exotherm. After the addition was complete (pH=5),
the reaction e was stirred for 1 h. The solid was collected by filtration and washed
with water (7.150 L), and washed a second time with water (3.575 L). The crystalline
solid was transferred into a20L rotovap bulb, and heptane (7.150 L) was added. The
mixture was slurried at 45 °C for 30 mins, and 1-2 volumes of solvent were distilled off.
The slurry in the rotovap flask was filtered, and the solids were washed with heptane
(3.575 L). The solid was further dried in vacuo (50 °C, 15 mbar) to give /m-butyl 5-
oxo-lH-pyrazolecarboxylate (2921 g, 71%) as a coarse, lline solid. 1H N\1 R
(400 MHz, DMSO-d6) 5 10.95 (s, 1H), 7.98 (d, /= 2.9 Hz, 1H), 5.90 (d, J= 2.9 Hz,
1H), 1.54 (s, 9H).
Synthesis of 2-[l-(trifluoromethyl)cyclopropyl]ethanol
F F
F LAH HO F
F F
To a solution of lithium aluminum hydride (293 mg, 7.732 mmol) in THF
(10.00 mL) in an th, 2-[l-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948
mmol) in THF (3.0 mL) was added dropwise over a period of 30 minutes keeping the
reaction temperature below 20 0 C. The mixture was allowed to gradually warm to
t ature and was d for 18 h. The mixture was cooled with an ice-bath
and sequentially quenched with water (294 mg, 295 pL, 16.36 mmol), NaOH (297 pL
of 6 M, 1.784 mmol), and then water (884.0 pL, 49.07 mmol) to afford a granular solid
in the mixture. The solid was filtered off using celite, and the precipitate was washed
with ether. The filtrate was further dried with MgSCL and filtered and concentrated in
SUBSTITUTE SHEET (RULE 26)
vacuo to afford the product with al THE and ether. The mixture was taken directly
into the next step without further purification.
Step 1: fert-Butyl 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-
oxylate
0 HO cf3 0
0=CjnN. DIAD O'
/ert-Butyl 5-oxo-lH-pyrazolecarboxylate (1.043 g, 5.660 mmol), 2-[l-
(trifluoromethyl)cyclopropyl]ethanol (916 mg, 5.943 mmol), and triphenyl phosphine
(1.637 g, 6.243 mmol) were combined in THE (10.48 mL) and the reaction was cooled
in an ice-bath. Diisopropyl a/odi carboxyl ate (1.288 g, 1.254 mL, 6.368 mmol) was
added dropwise to the reaction mixture, and the reaction was allowed to w arm to room
temperature for 16 hours. The mixture was evaporated, and the ing material was
partitioned n ethyl acetate (30 mL) and IN sodium hydroxide (30 mL). The
organic layer was separated, washed with brine (30 mL), dried over sodium e, and
concentrated. The crude material was purified by silica gel chromatography eluting with
a gradient of ethyl acetate in hexanes (0- 30%) to give fert-butyl 3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate (1.03 g, 57%). ESI-MS
m/z calc. 320.13, found 321.1 (M+l)+; Retention time: 0.72 minutes.
Step 2: 3-[2-[l-(Trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole
0^rj oNk TFA N-MLJ
F3C F3C
/ert-Butyl[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-
carboxylate (1.03 g, 3.216 mmol) was dissolved in dichloromethane (10.30 mL) with
trifluoroacetic acid (2.478 mL, 32.16 mmol), and the reaction was stirred at room
temperature for 2 hours. The reaction was evaporated, and the ing oil was
partitioned between ethyl acetate (10 mL) and a saturated sodium onate solution.
SUBSTITUTE SHEET (RULE 26)
The organic layer was separated, washed with brine, dried over sodium sulfate, and
evaporated to give 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (612 mg,
86%). ESI-MS m/z calc. , found 221.0 (M+l)+; Retention time: 0.5 minutes. ^
NMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 7.50 (t,T = 2.1 Hz, 1H), 5.63 (t,J=2.3
Hz, 1H), 4.14 (t, J= 7.1 Hz, 2H), 2.01 (t, J= 7.1 Hz, 2H), 0.96 - 0.88 (m, 2H), 0.88 -
0.81 (m, 2H).
Step 3: ft?/'/-Butyl 2-chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]
ethoxy] py razol- 1-yl] py ridinecarboxylate
Kk 0 I
°N^n K2CO3
cr n ci NH >-
DABCO P-^J N Cl
/e/7-Butyl 2,6-dichloropyridinecarboxylate (687 mg, 2.770 mmol), 3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (610 mg, 2.770 mmol), and freshly
ground potassium carbonate (459 mg, 3.324 mmol) were combined in anhydrous
DMSO (13.75 mL). l,4-diazabicyclo[2.2.2]octane (DABCO (1,4-
diazabicyclo[2.2.2]octane), 62 mg, 0.5540 mmol) was added, and the mixture was
stirred at room temperature under nitrogen for 16 hours. The reaction mixture was
diluted with w ater (20 mL) and stirred for 15 minutes. The resulting solid was collected
and washed with water. The solid was dissolved in dichloromethane and dried over
magnesium e. The e was filtered and concentrated to give /e/7-butyl 2-
chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine
carboxylate (1.01 g, 84%). ESI-MS m/z calc. 431.12, found 432.1 (M+l) +; Retention
time: 0.88 minutes.
Step 4: 2-Chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-
l-yl]pyridinecarboxylic acid
Vc0 I O
L p^J n" c,
F3C f3c
SUBSTITUTE SHEET (RULE 26)
WO 64632
/e/7-Butyl 2-chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-
l-yl]pyridinecarboxylate (1.01 g, 2.339 mmol) and oroacetic acid (1.8 mL,
23.39 mmol) were combined in dichloromethane (10 mL) and heated at 40 °C for 3 h.
The on was concentrated. Hexanes were added, and the mixture was concentrated
again to give 2-chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
]pyridinecarboxylic acid (873 mg, 99%) ESI-MS m z calc. 375.06, found 376.1
(M+l)+; Retention time: 0.69 minutes.
Step 5: N-(Benzenesulfonyl)chloro[3-[2-[l-
uoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridinecarboxamide
S02NH2
Nv GDI
P-QN N Cl P-Q N Cl
F ► F
F- F
F F
A solution of 2-chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylic acid (0.15 g,
0.3992 mmol) and carbonyl diimidazole (77 mg, 0,4790 mmol) in THE (2.0 mL) was
stirred for one hour, and benzenesulfonamide (81 mg, 0.5190 mmol) and DBU (72 uL.
0.4790 mmol) were added. The reaction was stirred for 16 hours, acidified with 1 M
aqueous citric acid, and extracted with ethyl acetate. The combined extracts were dried
over sodium e and evaporated. The residue was purified by silica gel
chromatography eluting with a gradient of methanol in dichloromethane (0-5%) to give
N-(benzenesulfonyl)chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazoll-yl
]pyridinecarboxamide (160 mg, 78%). ESI-MS m/z calc. , found 515.1
(M+l)+; Retention time: 0.74 minutes.
Step 6: N-(Benzenesulfonyl)[3-[2-[l-(trifluoromethyl)cyclopropyl]
ethoxy] pyrazol-l-yl] [(4S)-2,2,4-trimethylpyrrolidin-I-yl] pyridine
carboxamide
SUBSTITUTE SHEET (RULE 26)
F3C- K2C03
P^JN-m^m N
A mixture of N-(benzenesulfonyl)chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl] ]pyrazol-l-yl]pyridinecarboxamide (160 mg,
0.3107 mmol), (4S)-2,2,4-trimethylpyrrolidine hloride salt (139 mg, 0.9321
mmol), and potassium carbonate (258 mg, 1.864 mmol) in DMSO (1.5 mL) was stirred
at 130 °C for 17 hours. The reaction mixture was acidified with 1 M s citric acid
and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate
and evaporated to yield a crude product that was purified by reverse-phase HPLC
utilizing a gradient of 10-99% itrile in 5 mM aqueous HC1 to yield N-
(benzenesulfonyl)[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (87 mg, 47%). ESI-MS
m/z calc. 591.21, found 592.3 (M+l)+; Retention time: 2.21 minutes, 'll NMR (400
MHz, DMSO-d6) 8 12.48 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.81 (d,
J= 8.2 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.70 - 7.62 (m, 2H), 6.92 (d, J= 8.2 Hz, 1H), 6.10
(d, .7=2.8 Hz, 1H), 4.31 (t, J= 7.0 Hz, 2H), 2.42 (t, /= 10.5 Hz, 1H), 2.28 (dd, J =
.2, 7.0 Hz, 1H), 2.17-2.01 (m, 3H), 1.82 (dd, J= 11.9, 5.5 Hz, 1H), 1.52 (d, 7=9.4
Hz, 6H), 1.36 (t, 7= 12.1 Hz, 1H), 1.01 - 0.92 (m, 2H), 0.92 - 0.85 (m, 2H), 0.65 (d, J =
6.3 Hz, 3H). pKa: 4.95±0.06.
Synthesis of sodium salt of N^benzenesulfonylJ-O-p-ll-tl-
oromethy^cyclopropyllethoxylpyrazol-l-yl]-!-!^)-!,!.^-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (sodium salt of Compound 1)
N-(benzenesulfonyl)[3-[2-[l-(tnfluoromethyl)cyclopropyl]ethoxy]pyrazol-
l-yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (1000 mg, 1.679
mmol) was dissolved in ethanol (19.87 ml) under warming, filtered clear through a
SUBSTITUTE SHEET (RULE 26)
e filter (0.2 |iin). washed with warm ethanol (10 ml) and the warm solution was
treated with 1M NaOH (1.679 ml, 1.679 mmol). The solution was evaporated at 30-35
°C, co-evaporated 3 times with ethanol (~20 ml), to give a solid, which was dried
ght under vacuum in a drying cabinet at 45 °C with a nitrogen bleed to give 951
mg of a cream colored solid. The solid was further dried under vacuum in a drying
cabinet at 45 °C with a nitrogen bleed over the weekend. 930 mg (89%) of the sodium
salt of N-(benzenesulfonyl)[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide was obtained as an
off-white amorphous solid. ^ NMR (400 MHz, 6) 5 8.15 (d, J= 2.7 Hz, 1H),
7.81 (dd, J= 6.7, 3.1 Hz, 2H), 7.61 (d, /= 7.9 Hz, 1H), 7.39 (dd, ,/ = 4.9, 2.0 Hz, 3H),
6.74 (d,J= 7.9 Hz, 1H), 6.01 (d, /= 2.6 Hz, 1H), 4.29 (X,J= 7.0 Hz, 2H), 2.93 - 2.78
(m, 2H), 2.07 (t, J= 7.1 Hz, 3H), 1.78 (dd, 7= 11.8, 5.6 Hz, 1H), 1.52 (d,/= 13.6 Hz,
6H), 1.33 (t, J= 12.0 Hz, 1H), 1.00 - 0.92 (m, 2H), 0.89 (q, J= 5.3, 4.6 Hz, 2H), 0.71 (d,
J= 6.3 Hz, 3H). EST-MS m/z calc. 591.2127, found 592.0 (M+l)+; Retention time: 3.28
minutes. XRPD (see .
ate synthesis of 2-Chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylic acid
] Step 1: ethyl 3-hydroxy-lH-pyrazolecarboxylate
o o O
NH2NH2*xH20 O OH
O' OEt EtOH
O N
k H
A mixture of EtOH (20.00 L, 10 vol) and diethyl 2-
(ethoxymethylene)propanedioate (2000 g, 9.249 mol, 1.0 equiv) was added under
nitrogen purge a to a 50 L r equipped with a reflux condenser (10 °C) and the
jacket set to 40 °C. The mixture was stirred, and then hydrazine hydrate (538.9 g of 55
%w/w, 523.7 mL of 55 %w/w, 9.249 mol, 1.00 equiv) was added in portions via an
addition funnel. Once the addition was complete, the reaction was heated to 75 °C for
22 h to afford a solution of ethyl 3-hydroxy-lH-pyrazolecarboxylate that was used
directly in the next step.
Step 2: l-(tert-butyl) 4-ethyl 3-hydroxy-lH-pyrazole-l,4-dicarboxylate
SUBSTITUTE SHEET (RULE 26)
0 0
0 OH Boc20, Eton 0 OH
( )n TEA
N N
H i
The solution of ethyl 3-hydroxy-lH-pyrazolecarboxylate was cooled from
75 °C to 40 °C, then triethylamine (TEA) (46.80 g. 64.46 mL, 462.5 mmol, 0.05 eq.)
was added. A solution of Boc ide (2.119 kg, 9.711 mol 1.05 equiv) in EtOH
(2.000 L, 1 equiv) was added to the reactor over 35 min. The mixture was d for 4
hours to complete the reaction; then water (10.00 L, 5.0 vol) was added over 15 mins.
The resulting mixture was cooled to 20 °C to complete crystallization of the product.
The crystals were allowed to age for 1 hour, then the mixture was filtered. The solid
was washed with a mixture of EtOH (4.000 L, 2.0 vol) and water (2.000 L, 10 vol) The
solid was then dried in vacuo to afford l-(tert-butyl)ethylhydroxy-lH-pyrazole-
carboxylate (1530 g, 65%) as colorless, fine needle, crystalline solid. 'HNMR
(400 MHz, DMSO-d6) 8 11.61 (s, 1H), 8.40 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.56 (s,
9H), 1.25 (t, J = 7.1Hz,3H).
Step 3: l-(tert-butyl) 4-ethyl 3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-l,4-dicarboxylate
.cf3 HO N.
S' DIAD, PPh3,
+ NBoc
toluene
Et02C NBoc
Et02C
A 5L reactor was started with the jacket set to 40 °C, stirring at 450 rpm,
reflux condenser at room temperature and nitrogen purge. The vessel was charged with
toluene (1.0L, 10.0 vol), 2-[l-(trifluoromethyl)cyclopropyl]ethanol (100.Og, 648.8
mmol, 1.0 equiv), and l-(tert-butyl) l oxy-lH-pyrazole-l,4-dicarboxylate
(166.3 g, 648.8 mmol), and the mixture was stirred. The reaction mixture was charged
with triphenyl phosphine (195.7 g, 746.1 mmol, 1.15 equiv), then the r was set to
maintain an internal temperature of 40 °C. Diisopropyl azoldicarboxylate (150.9 g,
746.1 mmol, 1.15 equiv) was added into an addition funnel and was added to the
SUBSTITUTE SHEET (RULE 26)
reaction while maintaining the reaction temperature between 40 and 50 °C (addition was
exothermic, exotherm addition controlled), and stirred for a total of 2.5 hours. Once the
reaction was deemed complete by HPLC, heptane was added (400 mL, 4 vol), the
solution was cooled to 20 °C over 60 minutes, and the bulk of tnphenylphosphine
oxide-DIAD complex (TPPO-DIAD) crystallized out. Once at room temp, the mixture
was filtered, and the solid was washed with heptane (400 mL, 4.0 vol) and pulled dry.
The filtrate was used in the next step as a solution in toluene-heptane without r
purification.
Step 4: ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-
4-carboxylate
cf3 cf3
O. O.
NBoc NH
Et02C' Et02C'
A 500mL reactor was started with the jacket set to 40 °C, stirring at 450 rpm,
reflux condenser at room temp, and nitrogen purge. The vessel was charged with a
e on consisting of imately 160 mmol, 65.0 g of l-(tert-butyl) 4-ethyl
3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-l,4-dicarboxylate in 3 vol of
toluene red by concentrating a 25% n of filtrate from previous reaction
down to 4 volumes in a rotovap). The reaction was set to maintain an internal
temperature at 40 °C and KOH (33.1 g, 1.5 eq. of aqueous 45 % KOH solution) w as
added in one portion, resulting in a mild exothermic addition, while CO2 was generated
upon removal of the ting group. The reaction proceeded for 1.5 hr, monitored by
HPLC, with the product partially crystallizing during the reaction. Heptane (160 mL,
2.5 vol) was added to the reaction mixture and the on was cooled to room
ature over 30 minutes. The resulting mixture was filtered, and the solid was
washed with heptane (80.00 mL, 1.25 vol), pulled dry, then dried in vacuo (55 °C,
vacuum). 52.3 g of ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole
carboxylate was obtained as a crude, colorless solid that was used without further
purification.
SUBSTITUTE SHEET (RULE 26)
] Step 5: 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole
carboxylic acid
CF3 cf3
KOH, MeOH
0\r^M o. .N
NH NH
Et02C' H02C'
A 500mL reactor was started with the jacket set to 40 °C, stirring at 450 rpm,
reflux condenser at room temp, and nitrogen purge. The vessel was charged with
methanol (150.0 mL, 3.0 vol), a solution of ethyl 3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazolecarboxylate (50.0 g, 171.1 mmol,
1.0 equiv), and the reaction was stirred to suspend the solids. The r was set to
maintain internal temperature at 40 °C. To the mixture was added KOH (96 g of
aqueous 45 % KOH, 1.71 mol, 10.0 equiv) in ns maintaining the internal
temperature <50 °C. Once addition was complete, the reaction was set to maintain
temperature at 50 °C, and the reaction proceeded for 23 hours, monitored by HPLC.
Once complete the reaction was cooled to 10 °C then partially trated on a rotary
evaporator to remove most of the MeOH. The resulting solution was diluted with water
(250 mL, 5.0 vol) and 2-Me-THF (150 mL, 3.0 vol), and transferred to the r,
stirred at room temp, then stopped, and layers were allowed to separate. The layers
were tested, with remaining TPPO-DIAD complex in the organic layer and product in
the aqueous layer. The aqueous layer was washed again with 2-Me-THF (100 mL, 2.0
vol), the layers separated, and the aqueous layer returned to the reactor vessel. The
stirrer was started and set to 450 rpm, and the reactor jacket was set to 0 °C. The pH
was adjusted to pH acidic by addition of 6M aqueous HC1 (427mL, 15 equiv) portion
wise, maintaining the internal temperature between 10 and 30 °C. The product began to
crystallize close to pH neutral and was anied with strong off-gassing, and so the
acid was added slowly, and then further added to reach pH 1 once the off-gassing had
ended. To the ing sion was added 2-Me-THF (400 mL, 8.0 vol), and the
product was allowed to dissolve into the organic layer. Stirring was stopped, the layers
were separated, and the aqueous layer was ed to the reactor, stirred and reextracted
with 2-Me-THF (100 mL, 2.0 vol). The c layers were combined in the
SUBSTITUTE SHEET (RULE 26)
reactor and stirred at room temperature, washed with brine (lOOmL, 2 vols), dried over
Na2S04: filtered through celite, and the solid was washed with 2-Me-THF (50 mL, 1.0
vol). The filtrate was transferred to a clean rotovap flask, stirred, warmed to 50 °C and
e (200 mL, 4.0 vol) added, and then partially concentrated with the addition of
heptane (300 mL, 6.0 vol) and then seeded with 50mg of 3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazolecarboxylic acid), and the product
crystallized during solvent removal. The lation was stopped when the bulk of the
2-Me-THF had distilled off. The bath heater was turned off, the vacuum removed, and
the mixture was allowed to stir and cool to room temperature. The mixture was filtered
(slow speed) and the solid wras washed with heptane (100 mL, 2.0 vol), and the solid
was collected and dried in vacuo (50 °C, p). 22.47 g of l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazolecarboxylic acid was obtained as an
off-white solid. ^ NMR (400 MHz, DMSCM) 5 12.45 (s, 2H), 8.01 (s, 1H), 4.26 (t, J
= 7.0 Hz, 2H), 2.05 (t, J= 7.0 Hz, 2H), 0.92 (m, 4H).
Step 6: l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole
cf3 cf3
O. O.
NH NH
H02C'
A mixture of toluene (490.0 mL), l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazolecarboxylic acid (70.0 g, 264.9
mmol), and DMSO (70.00 mL) w?as placed in a reactor and heated to 100 0C with
stirring. DBU (approximately 20.16 g, 19.80 mL, 132.4 mmol) was added to the reactor
over 15 min. The mixture was stirred for 20 h to complete the reaction and then cooled
to 20 °C. The mixture was washed with water (350.0 mL), then 0.5N aq HC1 (280.0
mL), then water (2 x 140.0 mL), and lastly with bnne (210.0 mL). The organic layer
was dried with Na2SC>4, and then activated charcoal (5 g, Darco 100 mesh) was added to
the stirred slurty. The dried mixture was filtered through , and the solid was
washed with toluene (140.0 mL) and then pulled dry. The filtrate was concentrated in a
rotovap (50 °C, vac) to afford 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-
SUBSTITUTE SHEET (RULE 26)
pyrazole (30.89 g, 53%) as an amber oil. ^ NMR (400 MHz, DMSO-dg) 5 11.87 (s,
1H), 7.50 (d, J= 2.4 Hz, 1H), 5.63 (d, 7= 2.4 Hz, 1H), 4.23 - 4.06 (m, 2H), 2.01 (t, J=
7.1Hz, 2H), 1.00-0.77 (m, 4H).
] Step 7: ethyl 2-chloro [3- [2- [ 1-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylate
cf3 PF3
0 0
OEt 'OEt
cr n ci N. xj-
°V^N O-fJ N Cl
T-— \
NH cat DABCO,
K2CO3, DMF
A mixture of DMF (180.0 mL), ethyl 2,6-dichloropyridinecarboxylate
(approximately 29.97 g, 136.2 mmol), l-(trifluoromethyl)cyclopropyl]ethoxy]-
azole (30.0 g, 136.2 mmol), and K2CO3, (325 mesh, approximately 24.48 g,
177.1 mmol) was added to a stirred reactor at 20 °C. DABCO (approximately 2.292 g,
.43 mmol) was then added to the reactor, and the mixture was stirred at 20 °C for 1
hour, and then the ature was increased to 30 °C, and the mixture stirred for 24
hours to complete the reaction. The mixture was cooled to 20 °C; then water (360 mL)
was added slowly. The mixture was then drained from the reactor and the solid was
isolated by filtration. The solid was then washed with water (2 x 150 mL), and then the
solid was dried under vacuum at 55 °C to afford ethyl 2-chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylate (51.37 g,
93%) as a fine, beige colored solid. XH NMR (400 MHz, DMSO-c/g) 8 8-44 (d, J=2.9
Hz, 1H), 8.41 (d,7= 8.5 Hz, 1H), 7.75 (d, 7= 8.5 Hz, 1H), 6.21 (d, 7= 2.9 Hz, 1H),
4.34 (m, 4H), 2.09 (t, 7= 7.1 Hz, 2H), 1.34 (t, 7= 7.1 Hz, 3H), 1.00 - 0.84 (m, 4H).
Step 8: 2-Chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-
l-yl]pyridinecarboxylic acid
PF3 0 ,cf3 0
OEt OH
b-JHl N- -Cl aq NaOH b-01 N- -Cl
SUBSTITUTE SHEET (RULE 26)
A solution of ethyl ro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylate (50.0 g, 123.8
mmol) in THF (300.0 mL) was prepared in a reactor at 20 °C. EtOH (150.0 mL) was
added, followed by aqueous NaOH (approximately 59.44 g of 10 %w/w, 148.6 mmol).
The mixture was stirred for 1 hour to complete the reaction; then aq IN HC1 (750.0 mL)
was slowly added. The resulting suspension was stirred for 30 mm at 10 °C, and then
the solid was isolated by tion. The solid was washed with water (150 mL then 2 x
100 mL) and then pulled dry by vacuum. The solid was then further dried under vacuum
with g to afford 2-chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazoll-yl
]pyridinecarboxylic acid (42.29 g, 91%). 'ff NMR (400 MHz, DMSO-t/,,) 5 13.63
(s, 1H), 8.48 - 8.35 (m, 2H), 7.73 (d, J= 8.4 Hz, 1H), 6.20 (d, J= 2.9 Hz, 1H), 4.35 (t, J
= 7.1 Hz, 2H), 2.09 (t, J= 7.1 Hz, 2H), 1.01 - 0.82 (m, 4H).
Synthetic Example 2: Synthesis of Compound 2, (R)-N-(Phenylsulfonyl)-
6-(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)(2,2,4-
trimethylpyrrolidin-l-yl)nicotinamide
Q o.o
's' K2CO3
H ►
'm N Cl HCI
R F • ml
P 0.0
N''s'b'
0^N'N^N^N
R F y W S^V(R).mi
(Phenylsulfonyl)(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-
pyrazol-l-yl)(2,2,4-trimethylpyrrolidin-l-yl)nicotinamide was synthesized in a
manner analogous to Compound 1 using N-(benzenesulfonyl)chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (1.5 g, 2.91
mmol), potassium carbonate (2.0 g, 14.56 mmol), (4R)-2,2,4-trimethylpyrrolidine
(hydrochloride salt) (1.0 g, 6.7 mmol) inNMP (jV-Methylpyrrolidone) (7.5 mL) and
1,2-diethoxy ethane (1.5 mL) affording N-(benzenesulfonyl)[3-[2-[l-
SUBSTITUTE SHEET (RULE 26)
WO 64632
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4R)-2,2,4-trimethylpyrrolidiii-lyl
]pyridinecarboxamide (1.38 g, 79%). ESI-MS m/z calc. 591.2127, found 592.0
(M+l) +; Retention time: 2.3 minutes. ^NMR (400 MHz, DMSO-d6) 5 12.51 (s, 1H),
8.19 (d, J = 2.8 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.76 - 7.69 (m,
1H), 7.66 (dd, J = 8.3, 6.7 Hz, 2H), 6.91 (d, J = 8.2Hz, 1H), 6.11 (d, J = 2.8Hz, 1H),
4.31 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 10.5 Hz, 1H), 2.27 (t, J = 8.7 Hz, 1H), 2.07 (t, J =
7.1 Hz, 3H), 1.82 (dd, J = 11.9, 5.5 Hz, 1H), 1.52 (d, J = 9.4 Hz, 6H), 1.36 (t, J = 12.1
Hz, 1H), 0.99 - 0.92 (m, 2H), 0.88 (tt, J = 3.9, 1.6 Hz, 2H), 0.64 (d, J = 6.3 Hz, 3H).
Synthetic Example 3: Synthesis of Compound 3, (S)-N-((4-Hydroxy
methoxyphenyl)sulfonyl)(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-
pyrazol-l-yl)(2,2,4-trimethylpyrrolidin-l-yl)nicotinamide
Step A: 2-Chloro-N-((4-hydroxymethoxyphenyl)sulfonyl)(3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)- IH-pyrazol- icotinamide
o=s=oI ^
o OH P 0 0's'
I OH .0.
GDI In
q-Q n' 'Cl✓5 P-^jN N^CI OH
R F DBU R F
A solution of 2-chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylic acid (0.843 g,
2.24 mmol) and carbonyl diimidazole (434 mg, 2.68 mmol) in THE (2.5 mL) was d
for 2.5 hours, and 4-hydroxymethoxybenzenesulfonamide (0.500 g, 2.46 mmol) and
DBU (0.5 mL, 3.35 mmol) were added. The reaction was stirred for 21 hours, diluted
with ethyl acetate (5 mL) ied with 1 N aqueous hydrochloric acid (10 mL), and
extracted with ethyl acetate. The combined extracts were washed with brine, dried over
sodium sulfate and evaporated. The residue was purified by silica gel chromatography
SUBSTITUTE SHEET (RULE 26)
eluting with a gradient of ethyl e in hexanes (50-100%) to give 2-chloro-N-((4-
hydroxymethoxyphenyl)sulfonyl)(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-
lH-pyrazol-l-yl)nicotinamide (906 mg, 72%). ESI-MS m/z calc. 560.07, found 515.1
(M+l) +; Retention time: 0.74 minutes.
Step B: (S)-N-((4-Hydroxymethoxyphenyl)sulfonyl)(3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)(2,2,4-
trimethylpyrrolidin-l-yl)nicotinamide
9 QwP
N''s5' Ox K2CO3 fr K ■ox
N- >5 H ->
N Cl 'OH sLfe 'OH
HCI F F /—/
A mixture of 2-chloro-N-((4-hydroxymethoxyphenyl)sulfonyl)(3-(2-
(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)nicotinamide (906 mg, 1.62
mmol), (4S)-2,2,4-trimethylpyrrolidine hydrochloride salt (545 mg, 3.64 mmol), and
potassium carbonate (1.29 g, 9.33 mmol) in DMSO (5.5 mL) was stirred at 120 0C for
24 hours. The on mixture was d with 15 mL of water and 5 mL of ethyl
acetate. The reaction mixture was then acidified with 6 N s hydrochloric acid the
layers were separated. The aqueous layer was extracted with 10 mL of ethyl acetate.
The combined extracts were washed with brine, dned over sodium sulfate and
evaporated to yield a crude product that was purified by silica gel chromatography
utilizing a gradient of ethyl acetate in hexanes to yield (S)-N-((4-hydroxy
methoxyphenyl)sulfonyl)(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazoll-yl
)(2,2,4-trimethylpyrrolidin-l-yl)nicotinamide (470 mg, 45%) ESI-MS m/z calc.
637.2, found 638.2 ; Retention time: 10.07 minutes.
SUBSTITUTE SHEET (RULE 26)
Synthetic Example 4: Synthesis of Compound 4, N-(o-Tolylsulfonyl)
[3- [2- [ l-(trifluoromethyl)cyclopropyl]ethoxy] pyrazol- 2- [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(o-tolylsulfonyl)[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
o=s=o
OH ,SA'/ I GDI N
D-An N- 'ClX H
R F P-An N' 'Clyi
DBU Fv F
To 2-chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (196 mg, 0.5217 mmol) in THF (1.739 mL) was added
l,r-carbonyldiimidazole ximately 106.6 mg, 0.6573 mmol) and reaction was
stirred for one hour. 2-Methylbenzenesulfonamide (approximately 89.32 mg, 0.5217
mmol) was added, followed by l,8-diazabicyclo(5.4.0)undecene (DBU)
ximately 262.2 mg, 257.6 |iL. 1.722 mmol) and reaction was stirred for 3 hours.
The reaction was diluted with ethyl acetate and 1 M s citric acid and the layers
were separated. The organic layers were dried and concentrated and resulting solid 2-
chloro-N-(o-tolylsulfonyl)[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
]pyridinecarboxamide (approximately 252 mg) was used for next step without
characterization.
SUBSTITUTE SHEET (RULE 26)
Step B: N-(o-Tolylsulfonyl)[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
o owo
O'/ K2C03
% N'S
P'0N ^ ^ H1 N Cl ►
h F HN R F
F F
To 2-chloro-N-(o-tolylsulfonyl)[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxainide
(approximately 252 mg) and potassium carbonate (392 mg, 2.84 mmol) in 0.4 mL of
DMSO was added (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (212 mg, 1.42
mmol) and reaction was d at 130 °C for 16 hours. The reaction was cooled, diluted
with ethyl acetate and 1 M s citric acid and the layers were separated. The
organics were dried, concentrated and the ing e was purified with silica gel
(24 g) eluting with 0-14% methanol in dichloromethane to give N-(o-tolylsulfonyl)
[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (60.6 mg, 19%) 'h NMR (400 MHz,
DMSO-d6) 5 12.63 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.04 (dd, J = 7.9,1.4 Hz, 1H), 7.81
(d, J = 8.2 Hz, 1H), 7.58 (td, J = 7.5, 1.5 Hz, 1H), 7.50 - 7.40 (m, 2H), 6.93 (d, J = 8.3
Hz, 1H), 6.10 (d, J = 2.7 Hz, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.39 (d, J = 8.8
Hz, 2H), 2.16 (ddt, J = 11.8, 9.0, 4.5 Hz, 1H), 2.08 (t, J = 7.0 Hz, 2H), 1.82 (dd, J =
11.9,5.6Hz, 1H), 1.52 (s, 6H), 1.35 (t, J= 12.1 Hz, 1H), 1.00-0.93 (m, 2H), 0.92-
0.84 (m, 2H), 0.69 (d, J = 6.2 Hz, 3H). ESI-MS m/z calc. 605.23, found 606.4 (M+l)+;
Retention time: 1.92 minutes
SUBSTITUTE SHEET (RULE 26)
Synthetic Example 5: sis of Compound 5, N-(3-
Fluorophenyl)sulfonyl [3- [2- [l-(trifluoromethyl)cyclopropyl] ethoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(3-fhiorophenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
o=s=o
OH ,S\\Jt F
GDI N
O-AjN N- 'ClX H
R F p-An n' 'Cl
DBU R F
To ro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (0.200 g, 0.532 mmol) in THF (1.7 mL) was added 1,1-
carbonyldiimidazole (108.8 mg, 0.6707 mmol) and reaction was stirred for 1 hour. 3-
Fluorobenzenesulfonamide (93.25 mg, 0.5323 mmol) was added, followed by 1,8-
diazabicyclo(5.4.0)undecene (DBU) (267.5 mg, 262.8 pL, 1.757 mmol) and reaction
was stirred for 2 hours. The reaction was diluted with ethyl acetate and 1 M aqueous
citric acid and layers were separated. The organics were dried and concentrated and
resulting solid 2-chloro-N-(3-fluorophenyl)sulfonyl[3-[2-[l-
uoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
(approximately 259 mg) was used in the next step without characterization.
Step B: N-(3-Fluorophenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]p yrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
AqsP F AqsP F
(Ay'n'sVV'F K2CO3
n'n^n^ciH ^ ■*« (Tr N YY
Fv F Afe KTo-U >Ms)
SUBSTITUTE SHEET (RULE 26)
] To 2-chloro-N-(3-fluorophenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
(approximately 259 mg, 0.486 mmol) and potassium carbonate (389.6 mg, 2.819 mmol)
in 0.4 mL of DMSO was added (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt)
(211.0 mg, 1.41 mmol) and the reaction was stirred at 130 °C for 16 hours. The reaction
was cooled, diluted with ethyl acetate and 1 M aqueous citric acid and the layers were
separated. The organics were dried, concentrated and ing the residue was purified
on silica gel (24 g) eluting with 0-14% methanol in dichloromethane to give N-(3-
phenyl)sulfonyl[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (50.0 mg, 15%) 'll NMR
(400 MHz, Methanol-d4) 5 8.23 (d, J = 2.7 Hz, 1H), 7.96 - 7.89 (m, 1H), 7.87 - 7.77 (m,
2H), 7.65 (td, J = 8.1, 5.3 Hz, 1H), 7.46 (tdd, J = 8.5,2.5, 1.0 Hz, 1H), 7.02 (d, J = 8.3
Hz, 1H), 5.95 (d, J = 2.8 Hz, 1H), 4.37 (t, J = 7.0 Hz, 2H), 3.34 (s, 1H), 2.68 (t, J = 10.3
Hz, 1H), 2.56 - 2.48 (m, 1H), 2.28 - 2.16 (m, 1H), 2.10 (t, J = 7.0 Hz, 2H), 1.89 (dd, J =
11.9, 5.7 Hz, 1H), 1.59 (d, J = 9.7 Hz, 6H), 1.48 (t, J = 12.1 Hz, 1H), 1.02 - 0.96 (m,
2H), 0.86 - 0.77 (m, 5H). ESI-MS m/z calc. 609.2, found 610.3 (M+l)+; Retention time:
0.81 minutes
Synthetic Example 6: Synthesis of Compound 4S)-3,3-Dideuterio-
2,2-dimethyl(trideuteriomethyl)pyrrolidin-l-yl]-N-(4-hydroxyphenyl)sulfonyl
[3- [2- [ l-(trifluoromethyl)cyclopropyl] ethoxy] pyrazol- l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
o=s=oI ^
o OH 0 0.0
‘OH \W/
GDI %■
P-^Q1 N 'ClNU I H
O-An n' Cl 'OH
F. F DBU Fv F
SUBSTITUTE SHEET (RULE 26)
2-Chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (0.100 g, 0.266 mmol) and GDI (approximately 51.38 mg,
0.3169 mmol) were combined in THF (600.0 pL) and stirred at room temperature for 2
hours. 4-Hydroxybenzenesulfonamide (approximately 50.69 mg, 0.2927 mmol) was
added followed by DBU ximately 54.41 mg, 53.45 pL, 0.3574 mmol) and the
reaction was stirred for an additional 16 hours at room ature. The reaction
mixture was diluted with 10 mL of 1 M aqueous citric acid, and extracted with three 10
mL portions of ethyl acetate. The combined organics were washed with brine, dried
over sodium sulfate, and concentrated to give a white solid 2-chloro-N-(4-
hy droxypheny l)sulfonyl [3-[2- [ 1 -(trifluoromethy l)cy pyl] ethoxy ] pyrazol-1 -
idinecarboxamide (128 mg, 91%) which was used in the next step without
further purification. ESTMS m/z calc. 530.1, found 531.0 (M+l)+; Retention time: 0.69
minutes.
Step B: 2-[(4S)-3,3-Dideuterio-2,2-dimethyl
(trideuteriomethyl)pyrrolidin- l-yl]-N-(4-hydroxyphenyl)sulfonyl [3- [2-[ 1-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
9 q„p
K2CO3
p^N N^CI ‘OH P-^S1 N' ‘OH
R F HN (S)PD V □DO
T'd ^ F □ D
2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (1.0 g, 1.9
mmol), (S)-2.2-dimethyl(methyl-cA)pyrrolidme-3.3-c/2 hydrochloride salt (0.892 g,
.66 mmol) and potassium carbonate (1.55 g, 11.2 mmol) were combined in DMSO (6
mL) and heated to 130 °C for and 16 hours. The reaction was cooled to room
temperature, and diluted with water (10 mL). After stirring for 15 minutes ethyl acetate
(50 mL) was added to the mixture. The mixture was acidified with 1M aqueous citric
acid (pH~3-4) (30 mL) and the layers were separated. The cs were combined,
washed with brine, dried over sodium sulfate and concentrated. The crude material
obtained was ed by column chromatography (24 g of silica gel) utilizing a gradient
SUBSTITUTE SHEET (RULE 26)
of 0-30% ethyl acetate in heptane. Individual fractions were analyzed by HPLC and the
fractions that met the required purity specifications were combined, evaporated and
triturated in a e of 9:1 ethyl acetate/MTBE. The organics were evaporated down
to 10% and the solid obtained was filtered and dried ght under high vacuum to
afford )-3,3-dideuterio-2,2-dimethyl(trideuteriomethyl)pyrroli dinyl]-N-(4-
hy droxypheny l)sulfonyl [3-[2- [ 1 -(trifluoromethy l)cy clopropyl] ethoxy ] pyrazol-1 -
yl]pyridinecarboxamide (0.38 g, 32%) ESI-MS m/z calc. 612.2, found 613.7
(M+l)+; ion time: 1.40 minutes.
Synthetic Example 7: Synthesis of Compound 7,
N-(Benzenesulfonyl)[(4S)-3,3-dideuterio-2,2-dimethyl
(trideuteriomethyl)pyrrolidin-l-yl][3-[2-hydroxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
AqsP k2co3 AQsP
■>> ft
HO jX? o HO
R F PYJ /S(ddd
HCI D
A reaction vessel was charged with N-(benzenesulfonyl)chloro[3-[2-
hydroxy[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine
carboxamide (0.500 g, 0.942 mmol), (4S)-3,3-dideuterio-2,2-dimethyl
(trideuteriomethyl)pyrrolidine (Hydrochloride salt) (320 mg, 2.07 mmol), NMP (3.000
mL) and 1,2-di ethoxy ethane (500.0 pL) under an atmosphere of nitrogen. Potassium
carbonate (650.8 mg, 4.709 mmol) was added and the reaction mixture was heated to
130 °C. The reaction mixture was stirred ght. The reaction mixture was cooled
and diluted with water (2.000 mL) and adjusted pH to <3 with aqueous HCI (1.3 mL of
6 M, 7.800 mmol), which was added dropwise. The pH was adjusted further with
hydrogen chloride (146.0 pL of 6 M, 0.8760 mmol). The aqueous layer was extracted
with ethyl acetate (4 mL) twice and the combined organic layers were washed with
water twice, brine, and dried over sodium sulfate. The organic layer was then
concentrated to a residue which was purified on silica gel utilizing a gradient of 0-60%
ethyl acetate in s. This material was then triturated in a e of heptanes and
MTBE to yield N-(benzenesulfonyl)[(4S)-3,3-dideuterio-2,2-dimethyl
SUBSTITUTE SHEET (RULE 26)
(trideuteriomethyl)pyrrolidin-l-yl][3-[2-hydroxy[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl]pyridinecarboxamide (266 mg,
46%) ESI-MS m/z calc. 612.2, found 613.1 (M+l)+; Retention time: 1.67 minutes.!H
NMR (400 MHz, DMSO-d6) 5 12.51 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.05 - 7.94 (m,
2H), 7.81 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.65 (t, J = 7.6 Hz, 2H), 6.90 (d,
J = 8.2 Hz, 1H), 6.12 (d, J = 2.8 Hz, 1H), 5.57 (dd, J = 5.5, 2.7 Hz, 1H), 4.42 - 4.28 (m,
1H), 4.23 - 4.09 (m, 1H), 3.89 (d, J = 4.9 Hz, 1H), 2.39 (d, J = 10.5 Hz, 1H), 2.37 - 2.22
(m, 1H), 2.06 (dd, J = 10.6, 7.0 Hz, 1H), 1.52 (d, J = 9.7 Hz, 6H), 1.04 - 0.83 (m, 4H).
Synthesis of (4S)-3,3-Dideuterio-2,2-dimethyl
(trideuteriomethyl)pyrrolidine Hydrochloride
0 to? se
D2C. enzyme
'OCD3 'OCD3
CD3 DBU N02 CD3
h2 LiAIH4 HN-AIS)
HN CD3
Raney-Ni CD3
OCD3 HCI D ° ■ HCI
N02 CD3 D D
Step A: Methyl-*/; 4-mcthyl(mcthyl-*/j)nitropcntanoate-3,3-f/2
OCD3 OCD3
cd3 DBU N02 CD3
A 500-mL, three-neck round bottom flask equipped with a magnetic stir bar,
a nitrogen line and a J-Kem couple with heating mantle was charged with 2-
nitropropane (34.3 g, 385 mmol), thyl rylate (50.0 g, 460 mmol), and was
stirred at ambient temperature when l,8-diazabicyclo[5.4.0]undecene (DBU, 1.47 g,
9.62 mmol) was added in one portion. The reaction solution exothermed from 20 to ~40
°C and was allowed to stir without heating or cooling for 16 h. The reaction was only
partially completed (HPLC) so the solution was warmed at 80 °C for 4 h. The reaction
mixture is d with MTBE (170 mL), washed with 1 M HCI (15 mL), dned over
SUBSTITUTE SHEET (RULE 26)
magnesium sulfate, filtered and trated (29” Hg at 60 °C) to remove solvent and
any residual starting materials to afford product as light yellow oil (75 g, 99%). It was
used to the next step without further purification by lation.
Step B: -rfs fV)methyl(methyl-r/i)nitropentanoate-3,3-r/2
D O Palatase D O
D D
enzyme
OCD3 ocd3
NO2 cd3 NO2 cd3
A 5-L, three-neck round bottom flask equipped an overhead mechanical
stirrer, a nitrogen line and a J-Kem thermocouple with heating mantle was d with
methyl-1/3 yl(methyl-t/3)nitropentanoate-3,3-1/2 (75 g, 380 mmol) and 2000
mL of pH 7.5 Na-phosphate buffer @ 0.8 M. To this was added lipase from
Rhizomucor miehei (sigma L4277, palatase from Novozymes) (0.5 vol) and stirred at 30
°C for 25 h. Chiral HPLC (ADH 4.6 x250 mm, 5gm, 1.0 mL/min, 98%Heptane /2%
IP A) shows .2 ratio of enantiomers. The reaction mixture was extracted twice
with MTBE (1 L each time). The organic included any emulsion formed during the
extractions. The combined organics were washed two times with an aqueous solution of
sodium bicarbonate (5 vol), brine (5 vol), dried over sodium sulfate and concentrated
under vacuum to afford the desired product methyl-^ (,5')methyl(methyl-t/3)
mtropentanoate-3,3-1/2 as pale yellow oil (32.5 g, 43% yield).
Step C: 6V)-5,5-Dimethyl(methyl-i/3)pyrrolidinone-4,4-i/2
D _ O H2
D HN \(S)
Raney-Ni CD3
(S) OCD3 ------------------►
NO2 cd3 D D
] A high-pressure vessel (Parr shaker bottle, 500 mL) was purged with and
maintained under N2. The vessel was charged sequentially with deionized water rinsed
(3 times) damp Raney®2800 Ni (6.1 g), methyl-tf (5')methYl(niethyl-<A)
entanoate-3,3-1/2 (32.5 g, 165 mmol), and ethanol (290 mL). The vessel was
sealed and evacuated/backfilled with N2 (3 times). With no stirring, the vessel was then
SUBSTITUTE SHEET (RULE 26)
evacuated and backfilled with H2 (30 psi). The Parr bottle was shaken while heating the
ts to 60 °C, and the H2 pressure was maintained at 30 psi for 8 hours. The vessel
was evacuated/backfilled with N2 (3 times) and the contents were d by vacuum
filtration (Celite pad; N2 blanket). The flask/filter-pad was washed with ethanol (3 x 50
mL). After the final w ash, the solvent-wet filter-cake was transferred to another receiver
and covered with water for al. Note: At no time should the catalyst be fully dried
(keep damp throughout the filtration process). The filtrate and washes were combined
and concentrated (40 °C/40 torr) to afford (A)-5.5-dimethyl(methyl-r/3)pyrrolidin
one-4,4-<f2 as white solid (20 g, 92%).
Step D: (4S)-3,3-Dideuterio-2,2-dimethyl
(trideuteriomethyl)pyrrolidine Hydrochloride
HN 8,(5)
HN'\(S) UAIH4 CD3
HCI D
D D “ -HCI
A 1-L, three-neck round bottom flask equipped an overhead mechanical
stirrer, a nitrogen line and a J-Kem thermocouple was charged with lithium aluminum
hydride s (7.6 g, 202 mmol) in THF (80 mL, 4 vol) warmed from 20 - 36 °C (heat
of mixing). A solution of (iS)-5,5-dimethyl(methyl-<i3)pyrrolidinone-4,4-(i2 (20. g,
150 mmol) in THF (120 mL, 6 vol) was added to the suspension over 30 minutes while
allowing the reaction temperature to rise to ~60 °C. The on temperature was
increased to near reflux (~68 °C) and maintained there for 16 h. The reaction mixture
was cooled to below 40 °C and diluted with 200 mL (10 vol) of MTBE. The mixture
was quenched slowly with ise addition of a saturated s solution of sodium
sulfate (1 vol) over 2 h. Note: Vigorous degassing (H2) was observed, the mixture
becomes thick then thins, and the dark gray mixture turns white. After the addition was
completed, the on mixture was cooled to room temperature. The solid was
d by filtration (Celite pad) and washed with ethyl acetate (4 vol). With external
cooling and a N2 blanket, the filtrate and washings were combined and treated with
drop-wise addition of anhydrous 4 M HCI in dioxane (38 mL, 152 mmol) while
maintaining the temperature below 20 °C. After the addition was completed (20
minutes), the resultant suspension was concentrated under vacuum at 45 °C. The
SUBSTITUTE SHEET (RULE 26)
suspension was lled with heptanes (4 vol) twice during tration. The
suspension was cooled to below 30 °C when the solid was collected by filtration under a
N2 blanket. The solid was dried under N2 suction and further dried under high vacuum
at 45 °C to afford (4S)-3,3-dideuterio-2,2-dimethyl(tndeuteriomethyl)pyrrolidine
hydrochloride (17.5 g, 75%). The product is quite hygroscopic so it was manipulated
under nitrogen.
Synthetic Example 8: Synthesis of nd 8,6-[3-
(Dispiro[2.0.24.l3]heptanylmethoxy)pyrazol-l-yl]-N-(o-tolylsulfonyl)[(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
P O. .0
N'S k2co3
o~fJNk N Cl HCI
P 0. 0
0~fj N N
2-Chloro[3-(dispiro[2.0.24.l3]heptanylmethoxy)pyrazol-l-yl]-N-(o-
tolylsulfonyl)pyridinecarboxamide (0.170 g, 0.341 mmol) and (4S)-2,2,4-
trimethylpyrrolidine (Hydrochloride salt) (0.116 g, 1.02 mmol) were combined and
dissolved in DMSO (2 mL). Finely ground potassium carbonate (95 mg, 0.68 mmol)
was added. The reaction mixture was sealed and heated overnight to 130 °C. After
cooling to room temperature, the on mixture was diluted with ethyl acetate (50
mL) and washed with aqueous citric acid (1 M, 2* 50 mL) and brine (lx 50 mL). The
organic layer was dried over sodium sulfate, filtered and trated under reduced
pressure. The product was isolated by silica gel column chromatography eluting with a
SUBSTITUTE SHEET (RULE 26)
0-20% gradient of methanol in dichloromethane on a 12 gram silica gel column to
afford 6-[3-(dispiro[2.0.24.l3]heptanylmethoxy)pyrazol-l-yl]-N-(o-tolylsulfonyl)
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (0.030 g. 15%). ESI-MS
m/z calc. 575.26, found 576.36 (M+l)+; Retention time: 2.46 minutes.
Synthetic Example 9: Synthesis of nd 9, N-(Benzenesulfonyl)
[4-(hydroxymethyl)-2,2-dimethyl-pyrrolidin-l-yl][3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
O O H
H H
N :0 N N
O ‘O —-
'OH O' OH
HO HO o.X./
4 4 9
,S N'S
F F H
°'SiX OH
Step A: 2-Hydroxymethylmethylnitro-pentanoic acid methyl ester
O 0
■0"N^0 "OH
l,8-Diazabicyclo[5.4.0]undecene (3.6 mL, 24 mmol) was added to 2-
mtropropane (26.5 mL, 292 mmol). This mixture was heated to 65 °C and the heat was
turned off and methyl 2-(hydroxymethyl)acrylate (25 mL, 243 mmol) was added
se. The heat was then turned back on at 80 °C. After heating for Ih the heat was
turned off and the on was stirred at room temperature overnight before heating at
80 °C for another 2h. The reaction was diluted with ethyl acetate (250 mL) and washed
with 1M hydrogen chloride (2 x 125 mL), aqueous bicarbonate (125 mL) and brine (125
mL). The reaction product mixture was chromatographed on a 330g column of silica gel
in 0-60% hexanes:ether eluting at 55-60% to give oxymethylmethylnitro-
SUBSTITUTE SHEET (RULE 26)
pentanoic acid methyl ester (29.68g, 60%) as alight green oil. ESI-MS m/z calc.
, found 206.1 (M+l)+. Retention time: 1.67 minutes. 'H NMR (250 MHz, CDC13)
ppm 1.50 - 1.59 (m, 6 H) 1.85 - 1.98 (m, 1 H) 2.10 - 2.23 (m, 1 H) 2.36 - 2.50 (m, 1 H)
2.60 (d, J=5.71 Hz, 1 H) 3.66 - 3.77 (s, 3 H)
Step B: 3-Hydroxymethyl-5,5-dimethyl-pyrrolidinone
O H
N .0
-0'n:0
Hydroxymethylmethylnitro-pentanoic acid methyl ester (4.45g, 21.7
mmol) was added to absolute ethanol (60 mL) followed by Raney Nickel (1.7g, -15%
wt). The on was heated at 60 °C under 2 bar of H2 overnight. More Raney Nickel
(1,0g, -50% wt) was added and the reaction heated at 60 °C under 5 bar H2 for 3.5 h. At
this point, more 2-hydroxymethylmethylnitro-pentanoic acid methyl ester (3.95g,
19.3 mmol) was added and the reaction heated for 72 h refilling H2 to maintain 5 bar.
The reaction was filtered through celite and washed with methanol. The crude reaction
was chromatographed on silica gel and eluted with 0-10% dichloromethanemethanol at
%, resulting 3-hydroxymethyl-5,5-dimethyl-pyrrolidinone (3.69g, 63%) as a white
solid. ‘H NMR (250 MHz, CDC13) 5 ppm 1.31 (d, J=9 01 Hz, 6 H) 1.72 (dd, JM2.52,
.33 Hz, 1 H) 2.04 (dd, 1=12.58, 8.84 Hz, 1 H) 2.73 - 2.91 (m, 1 H) 3.31 (d, J=4.72 Hz,
1 H) 3.64 - 3.95 (m, 2 H) 5.93 (br. s., 1 H)
Step C: (5,5-Dimethyl-pyrrolidinyl)-methanol
N H
O N
HO HO
Lithium aluminum hydride , 103.00 mmol) was suspended in
tetrahydrofuran (60 mL). Hydroxymethyl-5,5-dimethyl-pyrrohdmone , 25.77
SUBSTITUTE SHEET (RULE 26)
mmol) in tetrahydrofuran (30 mL) was then added dropwise and the reaction was heated
at 65°C for 40h. The reaction was diluted with 2-methyl-tetrahydrofuran (125 mL) and
then cooled in an ice bath before saturated aqueous Rochelle Salt (200 mL) was added
dropwise. The organic layer was extracted with 2-methyl-tetrahydrofuran (2 x 200 mL)
and dried over sodium sulfate to give crude imethyl-pyrrolidinyl)-methanol
, 104%). NMR (250 MHz, CDC13 5 ppm 1.06 - 1.24 (m, 6 H) 1.29 (dd,
J=12.58, 7.20 Hz, 2 H) 1.43 (s, 1 H) 1.68 - 1.89 (bs, 1 H) 2.31 - 2.52 (m, 1 H) 2.83 (dd,
J=11.10, 5.49 Hz, 1 H) 3.05 - 3.26 (m, 1 H) 3.48 - 3.71 (m, 1 H)
Step D: 4-(tert-Butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-
pyrrolidine
H H
N N
HO O
To (5,5-dimethyl-pyrrolidiny])-methanol (3.08g, 23.8 mmol), tert-
butyldimethylsilyl chloride (4.3Ig, 28.6 mmol) in acetonitrile (24 mL) was added 1,8-
Diazabicyclo[5.4.0]undecene (5.3 mL, 35.7 mmol) The reaction was stirred for 3.5
h. The reaction was diluted with chloroform (250 mL) and washed with water (125 mL)
and brine (125 mL) then dried over sodium sulfate. The crude was chromatographed on
silica gel and eluted with dichloromethane/methanol, g at 15-35% ol to
give 4-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-pyrrolidine , 67%) as
ayellow oil after two columns. ESI-MS m/z calc. 243.47, found 244.2 (M+l)+Retention
time: 2.52 minutes. LH NMR (250 MHz, CDC13) 5 ppm -0.05 - 0.11 (m, 6 H) 0.89 (s, 9
H) 1.19 (d, M8.02 Hz, 6 H) 1.25 - 1.32 (m, 1 H) 1.74 (dd, M2.63, 8.79 Hz, 1 H) 1.92
(br. s., 1 H) 2.32-2.50 (m, 1 H) 2.81 (dd, J=11.54, 6.37 Hz, 1 H) 3.11 (dd, J=11.48,
7.97 Hz, 1 H) 3.45 - 3.61 (m, 2 H)
Step E: N-(Benzenesulfonyl)[4-(hydroxymethyl)-2,2-(limethyl-
pyrrolidin- l-yl] [3- [2-[ l-(trifluoromethyl)cyclopropyl] ethoxy] l
yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
E tf 0^° NH
F' N'S
F H
Cl xx 1 \P
F. %p
F ^-0 "N
°'SiX
N-(benzenesulfonyl)chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridinecarboxainide (25 mg,
0.04855 mmol), tert-butyl-[(5,5-dimethylpyrrolidinyl)methoxy]-dimethyl-silane
(approximately 35.45 mg, 0.1456 mmol), and K2CO3 (approximately 33.56 mg, 0.2428
mmol) were combined in DMSO (0.5 mL) and heated at 130 °C for 16 h. The reaction
was partitioned between a 1M citric acid solution and ethyl acetate and the organics
were separated. The organics were washed with brine, dried over sodium sulfate and
evaporated. The crude matenal was purified by silica gel chromatography g with
0-10% methanol in dichloromethane to give N-(benzenesulfonyl)[4-[[tertbutyl
(dimethyl)silyl]oxymethyl]-2,2-dimethyl-pyrrolidin-l-yl][3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (15 mg,
43%) ESI-MS m/z calc. 721.2941, found 722.4 (M+l)+; Retention time: 0.97 minutes.
Step F: N-(Benzenesulfonyl)[4-(hydroxymethyl)-2,2-dimethyl-
pyrrolidin- l-yl] [3- [2-[ l-(trifluoromethyl)cyclopropyl] ethoxy] l
yl]pyridinecarboxamide
°'Si OH
] zenesulfonyl)[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-
dimethyl-pyrrolidin-1 -yl] [3-[2-[ 1 luoromethyl)cy clopropy 1] ethoxy |pyra/ol-1 -
yl]pyridinecarboxamide (15 mg, 43%) was dissolved in THE (1 mL) and cooled in an
SUBSTITUTE SHEET (RULE 26)
ice bath. Tetra-n-butylammonium fluoride in THF (300 |iL of 1 M, 0.3000 mmol) was
added and the reaction was allowed to warm to room temperature. The reaction mixture
was d for 1 h and then partitioned between ethyl acetate and 1M citric acid
solution. The organics were washed with brine, dried over sodium sulfate and
evaporated. The crude matenal was purified by silica gel chromatography eluting with
0-10% methanol in dichloromethane to give zenesulfonyl)[4-
(hydroxymethyl)-2,2-dimethyl-pyrrolidm-l-yl][3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (8.5 mg,
29%) ESI-MS m/z calc. 607.20764, found 608.4 ; ion time: 1.9 minutes.
Synthetic Example 10: Synthesis of nd 10, N-(Benzenesulfonyl)-
6-[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
(l-Trifluoromethyl-cyclobutyl)-methanol
PH LAH PH
F3p O F3C
] 1-Trifluoromethyl-cyclobutanecarboxylic acid (5.0 g, 30. mmol) was
dissolved in diethyl ether (60 mL) and cooled to 0 °C. Lithium aluminum hydride (38.66
mL, 1M in diethyl ether) was added se and the solution was allowed to warm to
room temperature overnight. The reaction solution was cooled to 0 °C with stirring, and
sodium sulfate decahydrate was added, which resulted in gradual evolution of gas.
Portionwise addition was continued until no more bubbling was observed at room
temperature. The reaction solution was then filtered over a bed of Celite, washing with
diethyl ether. The filtrate was concentrated under reduced pressure to give 5.44 g of a
mixture containing the d product and some diethyl ether e (36% by NMR
integration). This afforded 1-trifluoromethyl-cyclobutyl-methanol (3.46 g, 78%) as a
colorless oil. 'H NMR (250MHz, CDC13) 5 (ppm): 3.82 (s, 2H), 2.39-2.14 (m, 2H),
2.10-1.85 (m,4H).
3-(l-Trifluoromethyl-cyclobutylmethoxy)-pyrazole-l-carboxylic acid
tert-butyl ester
SUBSTITUTE SHEET (RULE 26)
Nk^Boc
o Boc
OH 0-//- N
F3C DIAD, Ph3P f3c
1-Trifluoromethyl-cyclobutyl-methanol (1.50 g, 9.73 mmol) and 3-oxo-2,3-
dihydro-pyrazolecarboxylic acid tert-butyl ester (1.63 g, 8.85 mmol) were dissolved
in anhydrous tetrahydrofuran (32 mL). The solution was degassed by sonication and
flushed with nitrogen gas. nylphosphine (2.55 g, 9.73 mmol) was added, and
diisopropyl azodicarboxylate (1.92 mL, 9.73 mmol) was then added dropwise. Upon
tion of addition, the on was heated to 50 °C for 16 hours. After cooling to
room temperature, the reaction was diluted with ethyl acetate (100 mL) and washed
with 1M sodium hydroxide solution (2 x 100 mL), then brine (125 mL). The organics
were dried over sodium sulfate, filtered, and concentrated under d pressure. The
crude yellow oil was purified by flash chromatography using a 0-10% ethyl acetate in
hexanes gradient method to afford rifluoromethyl-cyclobutylmethoxy)-pyrazole-lcarboxylic
acid tert-butyl ester (2.48 g, 87%) as an off-white solid. ESI-MS m/z calc.
320.31, found 321.1 (M+l)+. Retention time: 3.74 minutes
3-(l-Trifluoromethyl-cyclobutylmethoxy)-lH-pyrazole hydrochloride
N-'m'Boc N"NH
o-//- N HCI, dioxane
f3c f3c
3-(l-Trifluoromethyl-cyclobutylmethoxy)-pyrazole-l-carboxylic acid tert-
butyl ester (2.48 g, 7.74 mmol) was dissolved in 4M hydrogen chloride in dioxane (77
mL). The solution was stirred overnight at room temperature, followed by removal of
the volatiles under reduced re to afford the hloride salt of 3-(ltrifluoromethyl-cyclobutylmethoxy
)-lH-pyrazole (1.95 g, 98%) as a white powder. ESI-
MS m/z calc. 220.20, found 221.2 (M+l)+. Retention time: 2.67 minutes.
SUBSTITUTE SHEET (RULE 26)
tyl 2-chloro(3-((l-(trifluoromethyl)cyclobutyl)methoxy)-lH-
pyrazol-l-yl)nicotinate
.HCI 'OfBu
P-Afn cr N ci
N. s,
0_N N Cl
DABCO, K2CO3
F3C f3c
3-(l-Trifluoromethyl-cyclobutylmethoxy)-lH-pyrazole hydrochloride salt
(1.95 g, 7.61 mmol) and 2,6-dichloro-nicotinic acid tert-butyl ester (1.89 g, 7.62 mmol)
were dissolved in dimethylformamide (15 mL), and potassium carbonate (4.21 g, 30.5
mmol) was added followed by l,4-diazabicyclo[2.2.2]octane (0.43 g, 3.8 mmol). The
reaction was stirred at room temperature ght, then water (150 mL) was added and
the aqueous layer was extracted with 4:1 ethyl acetate:hexanes (100 mL). The organic
phase was washed with brine (70 mL), dried over sodium sulfate, and trated
under d pressure. The crude oil was purified by silica gel chromatography using a
0-10% ethyl acetate in hexanes nt method to afford 2-chloro[3-(ltrifluoromethyl-cyclobutylmethoxy
)-pyrazole-l-yl]-nicotinic acid tert-butyl ester (1.94
g, 66%) as a white solid. ESI-MS m/z calc. 431.85, found 432.2 (M+l)+. ion
time: 4.61 minutes.
2-Chloro[3-(l-trifluoromethyl-cyclobutylmethoxy)-pyrazole-l-yl]-
nicotinic acid
0 0
OfBu TFA OH
Ck/'N^N' 'Cl 0--^ N N Cl
f3c F3C
2-Chloro[3-(l-trifluoromethyl-cyclobutylmethoxy)-pyrazole-l-yl]-
nicotinic acid tert-butyl ester (1.9 g, 4.40 mmol) was dissolved in dichloromethane (20
mL) and trifluoroacetic acid (5.0 mL) was added. The reaction solution was stirred at
room temperature overnight, after which the volatiles were removed under reduced
pressure to afford 2-chloro[3-(l-tnfluoromethyl-cyclobutylmethoxy)-pyrazole-l-yl]-
SUBSTITUTE SHEET (RULE 26)
WO 64632
nicotinic acid (1.61 g, 97%) as a white solid. ESI-MS m/z calc. 375.74, found 376.2
(M+l)+. Retention time: 3.57 minutes.
Synthesis ofN-(Benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyri(lmecarboxamide
GDI, DBU 9 q
'OH M'S,N
■N"N H 0
0~^ N Cl h2n|-0 'Cl
f3c f3c
] To a stirred solution of 2-chloro[3-[[l-(trifluoromethyl)cyclobutyl]meth-
oxy]pyrazol-l-yl]pyridinecarboxylic acid (0.150 g, 0.399 mmol) in anhydrous
ydrofuran (3.0 mL) was added GDI (78 mg, 0.4810 mmol) in one portion. The
solution was stirred at ambient temperature for 2 h. Then solid benzenesulfonamide (76
mg, 0.48 mmol) was added in one portion, followed by DBU (183 mg, 1.20 mmol) and
the tea-colored solution was stirred at ambient temperature for an additional 2 h. To the
reaction mixture was slowly added citric acid (2.5 mL of 1.0 M, 2.500 mmol), followed
by brine (5 mL). After stirring for 10 min, the neous material was extracted with
ethyl acetate (3 x 25 mL). The combined organic extracts were washed with brine (10
mL), dried over anhydrous sodium sulfate, ed and concentrated under reduced
pressure. After drying under vacuum for 1 h, N-(benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridmecarboxamide (181 mg,
88%) was obtained as white solid. It contained some starting acid impurity, and used in
the subsequent step without further purification. ESI-MS m/z calc. 514.0689, found
515.1 (M+l) + ; Retention time: 1.98 minutes
sis ofN-(Benzenesulfonyl)[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
o o .HCI
Yb'S; 9 q
HN'Ais) M-S
OS'N'n^n' 'ci 0^,N'N^N✓s N s
K2C03
F3c f3c
A mixture of zenesulfonyl)chloro[3-[[l-(trifluoromethyl)cyclobutyl]-
methoxy]pyrazol-l-yl]pyridinecarboxamlde (0.160 g, 0.311 mmol), (4S)-2,2,4-
hylpyrrolidine (Hydrochloride salt) (139 mg, 0.932 mmol) and potassium
carbonate (215 mg, 1.554 mmol) was stirred in in anhydrous yl ide (2.7
mL) under an atmosphere of nitrogen at 130 °C for 18 h. The reaction was allowed to
cool to ambient temperature and diluted with water (15 mL) and extracted with ethyl
acetate (3 x 25 mL). The combined organics successively were washed with aqueous 1
M citric acid (310 pL of 1.0 M, 0.3107 mmol), and brine, dried over anhydrous sodium
sulfate, filtered and evaporated to give yellow crude material. It was purified from
CombiFlashRf system using 40 g gold silica gel column and during with 0-5 %
methanol in methylene chloride (over 45 min). The product came out at 25 min (2.6 %
methanol). The desired fractions were combined and concentrated under reduced
pressure. Upon further drying overnight under high vacuum, N-(benzenesulfonyl)[3-
[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (HCI salt, 40 mg, 20%) was obtained.
ESI-MS m/z calc. 591.2127, found 592.3 (M+l)+; Retention time: 2.25 minutes. 'H
NMR (400 MHz, DMSO-d6) 5 12.49 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.00 (dd, J = 8.2,
2.1 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.72 (tt, J = 8.2, 2.0 Hz, 1H), 7.65 (dt, J = 8.2, 2.0
Hz, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 4.48 (s, 2H), 2.42 (t, J = 10.5
Hz, 1H), 2.36 - 2.22 (m, 3H), 2.11 (td, J = 12.1, 5.7 Hz, 4H), 1.95 (qd, J = 9.7, 4.3 Hz,
1H), 1.83 (dd, J = 12.0, 5.6 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.37 (t, J = 12.2 Hz, 1H),
0.65 (d, J = 6.3 Hz, 3H).
Synthetic e 11: Synthesis of Compound 11, N-(4-Cyano
-phenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(4-cyanomethyl-phenyl)sulfonyl[3-[[l-
uoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
0. ,0
0 *Cl
XT'A°-<p ‘OH
N'CI GDI <u>-u N-N^N^CI ” )Cl.CN
F3C f3c
A solution of 2-chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (186.4
mg, 0.5 mmol) and l,r-carbonyldiimidazole (97.29 mg, 0.60 mmol) in THF (2.5 mL)
was d for 30 minutes, and 4-cyanomethyl-benzenesulfonamide (127.5 mg, 0.65
mmol) and azabicyclo(5.4.0)undecene (DBU) (89.7 pL, 0.60 mmol)were
added. After 16 hours the reaction was diluted with 1 M aqueous citric acid and
extracted with ethyl e. The combined extracts were dried over sodium sulfate and
evaporated. The residue was ed by silica gel chromatography with 0-5% ol
in dichloromethane to give 2-chloro-N-(4-cyanomethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (270 mg,
100%) ESI-MS m/z calc. 539.06, found 540.1 (M+l)+; Retention time: 0.73 minutes.
Step B: N-(4-Cyanomethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 Qo O Oo
11 vi'r
N'S K2CO3 N'S
H N- H
N- X
N Cl ON (s' V7 n~// "N N N c
-4^(s) N
f3c HN f3c
A mixture of 2-chloro-N-(4-cyanomethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (270 mg,
0.50 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (168.1 mg, 1.123
mmol), and potassium carbonate (310.4 mg, 2.246 mmol) in DMSO (1.87 mL)was
stirred at 130 °C for 15 hours. The reactions were acidified with 1 M aqueous citric acid
and extracted with ethyl acetate. The combined extracts were washed with brine, dried
over sodium sulfate, and evaporated. The residue was purified by silica gel
SUBSTITUTE SHEET (RULE 26)
chromatography with 0-5% methanol in dichloromethane to give impure product. The
impure product was re-purified using a reverse phase HPLC-MS method using a Luna
C18 (2) column (75 x 30 mm, 5 pm particle size) sold by Phenomenex (pn: 00C
UO-AX), and a dual gradient run from 1-99% mobile phase B over 15.0 minutes.
Mobile phase A = LLO (5 mM HC1). Mobile phase B = CLLCN. Flow rate = 50
mL/min, and column temperature = 25 °C to provide N-(4-cyanomethylphenyl
)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (150 mg, 48%) ESI-MS m/z
calc. 616.21, found 617.3 (M+l)+; Retention time: 2.06 minutes. 'HNMR (400 MHz,
DMSO-cfe) 5 12.96 (s, 1H), 8.23 - 8.18 (m, 2H), 8.03 (d, J= 1.6 Hz, 1H), 7.97 (dd, J =
8.0, 1.8 Hz, 1H), 7.88 (d, J= 8.3 Hz, 1H), 6.95 (d, J= 8.3 Hz, 1H), 6.16 (d, T = 2.7 Hz,
1H), 4.43 - 4.32 (m, 2H), 2.67 (s, 3H), 2.27 (d, J= 3.5 Hz, 1H), 2.25 (s, 1H), 2.17 (dd, J
= 11.3, 5.7 Hz, 1H), 1.83 (dd, J= 11.9, 5.3 Hz, 1H), 1.52 (d, J=4.4Hz, 6H), 1.36 (s,
1H), 1.09 (dt, J= 5.5, 1.6 Hz, 4H), 0.70 (d, J= 6.0 Hz, 3H).
] Synthetic e 12: Synthesis of Compound 12, N-(2-Methoxy
methyl-phenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: ro-N-(2-methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O. ,0
0 Xk
i V X0
<Lp-iJ N ClN- GDI
DBU <LP^2 N I
f3c f3c
A on of 2-chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (186.4
mg, 0 5 mmol) and l,r-carbonyldiimidazole (97.29 mg, 0 60 mmol) in THF (2.5 mL)
was stirred for 30 minutes, and 2-methoxymethyl-benzenesulfonamide (130.8 mg,
0.65 mmol) and l,8-diazabicyclo(5.4.0)undecene (DBU) (89.7 pL, 0.60 mmol) were
added. After 16 hours the reaction was diluted with 1 M aqueous citric acid and
extracted with ethyl acetate. The ed extracts were dried over sodium sulfate and
SUBSTITUTE SHEET (RULE 26)
evaporated. The residue was purified by silica gel tography with 0-5% methanol
in dichloromethane to give 2-chloro-N-(2-methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (210 mg,
77%) ESI-MS m/z calc. 544.1, found 545.1 (M+l)': Retention time: 0.73 minutes as a
colorless solid.
Step B: N-(2-Methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 op 9 0 OO O
K;CO,
N-S N-S'
N Cl (Si
3c /
F3C HN
A mixture of ro-N-(2-methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (210 mg,
0.3854 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (168.1 mg, 1.123
mmol), and potassium carbonate (310.4 mg, 2.246 mmol) in DMSO (1.87 mL) was
stirred at 130 °C for 15 hours. The reaction was acidified with 1 M s citric acid
and extracted with ethyl acetate. The ed extracts were washed with brine, dried
over sodium sulfate, and evaporated. The residue was purified by silica gel
chromatography with 0-5% methanol in dichloromethane to give impure product. The
impure product was ified using a reverse phase HPLC-MS method using a Luna
C18 (2) column (75 x 30 mm, 5 pm particle size) sold by Phenomenex (pn: 00C
U0-AX), and a dual gradient run from 1-99% mobile phase B over 15.0 minutes.
Mobile phase A = H20 (5 mM HCI). Mobile phase B = CH3CN. Flow rate = 50
mL/min, and column temperature = 25 °C to provide N-(2-methoxymethylphenyl
)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (95 mg, 39.25%) ESI-MS m/z
calc. 621.2, found 622.3 (M+l)+; Retention time: 2.19 minutes. 'H NMR (400 MHz,
DMSO-rfe) 8 12.39 (s, 1H), 8.20 (d,T= 2.8 Hz, 1H), 7.78 (t, J= 8.5 Hz, 2H), 7.10 (d, J
= 1.4 Hz, 1H), 6.94 (dd, J= 10.1, 8.1 Hz, 2H), 6.15 (d, J= 2.7 Hz, 1H), 4.43 - 4.30 (m,
SUBSTITUTE SHEET (RULE 26)
2H), 3.89 (s, 3H), 2.49 - 2.38 (m, 2H), 2.37 (s, 3H), 2.21 (dd, J= 11.2, 6.1 Hz, 1H),
1.85 (dd, J= 11.9, 5.5 Hz, 1H), 1.53 (d, J= 11.0 Hz, 6H), 1.37 (s, 1H), 1.12-1.04 (m,
4H), 0.78 (d, ,7=6.2 Hz, 3H).
Synthetic e 13: Synthesis of Compound 13: N-(2,4-
oxyphenyl)sulfonyl [3- [ [ fluoromethyl)cyclopropyl] methoxy] pyrazoll-yl
4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(2,4-dimethoxyphenyl)sulfonyl|3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
i 9 o.
'OH N'3'
<LP<2 N'CI GDI <LP-iJ NN- Cl 0 0
DBU I
f3c f3c
A solution of 2-chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (186.4
mg, 0.5 mmol) and l,r-carbonyldiimidazole (97.29 mg, 0.60 mmol) in THE (2.5 mL)
was stirred for 30 minutes, and 2,4-dimethoxybenzenesulfonamide (141.2 mg, 0.65
mmol) and azabicyclo(5.4.0)undecene (DBU) (89.7 pL, 0.60 mmol) were
added. After 16 hours the reaction was diluted with 1 M aqueous citric acid and
extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and
evaporated. The residue was purified by silica gel chromatography with 0-5% methanol
in dichloromethane to give 2-chloro-N-(2,4-dimethoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (210 mg,
75%) ESI-MS m/z calc. 560.1, found 561.1 (M+l)+; Retention time: 0.71 minutes as a
colorless solid.
Step B: N-(2,4-Dimethoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
0 oo Ovy.
0 9,0 0 k2co3
N'S I 'SS
^°~Cjn Cl N
0 (s I
f3c HN f3c
A e of 2-chloro-N-(2,4-dimethoxyphenyl)sulfonyl[3-[[l-
(trifluoromethy l)cy clo-propyl] methoxyjpyrazol-1 -y 1] pyridine-3 -carboxamide (210 mg,
0.3744 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (168.1 mg, 1.123
mmol), and potassium carbonate (310.4 mg, 2.246 mmol) in DMSO (1.87 mL) was
stirred at 130 °C for 15 hours. The reactions were acidified with 1 M aqueous citric acid
and extracted with ethyl acetate. The combined ts were washed with brine, dried
over sodium sulfate, and evaporated. The e was purified by silica gel
chromatography with 0-5% methanol in dichloromethane to give impure t. The
impure product was re-purified using a reverse phase HPLC-MS method using a Luna
C18 (2) column (75 x 30 mm, 5 pm particle size) sold by Phenomenex (pn: 00C
U0-AX), and a dual gradient run from 1-99% mobile phase B over 15.0 minutes.
Mobile phase A = H2O (5 mM HCI). Mobile phase B = CH3CN. Flow rate = 50
mL/min, and column ature = 25 °C to provide N-(2,4-dimethoxyphenyl)sulfonyl-
6-[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (110 mg, 46%) ESI-MS m/z calc.
637.2, found 638.3 (M+l)+; Retention time: 2.14 minutes. 1HNMR(400 MHz, DMSO-
4)5 12.34 (s, 1H), 8.20 (d, J= 2.8 Hz, 1H), 7.82 (d,J= 8.8 Hz, 1H), 7.77 (d,J= 8.3
Hz, 1H), 6.92 (d,/= 8.2 Hz, 1H), 6.74 (d, J= 2.3 Hz, 1H), 6.70 (dd, J= 8.8, 2.3 Hz,
1H), 6.15 (d, J= 2.7 Hz, 1H), 4.43 - 4.31 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.54 (s,
1H), 2.42 (dd, J= 10.5, 7.0 Hz, 1H), 2.21 (dd, /= 11.6, 5.9 Hz, 1H), 1.85 (dd, J= 11.9,
.5 Hz, 1H), 1.55 (s, 3H), 1.52 (s, 3H), 1.38 (s, 1H), 1.09 (dt, J = 5.9, 1.6 Hz, 4H), 0.80
(d, J= 6.3 Hz, 3H).
Synthetic Example 14: Synthesis of Compound 14: N-
(Benzenesulfonyl)[3-[[l-(trifhioromethyl)cyclopropyl]methoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin- 1-yl] pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
WO 64632
■N'N^cr^
°=U diad' pph^ O—f' HCI
F F F-
+ K2CO3, DABCO N'M^jD^'n^CI HCI
F- O-&
F F cr n ci
N'M^N^CIj(X CDI, DBU
o-^ + h2n
F- ■o
rs^AqsP 'O HN^!i ov-xtol9sP + K2CO3
F F F-
Step A: tert-Butyl (trifluoromethyl)cyclopropyl]methoxy]pyrazole-
1-carboxylate
DIAD, PPh3
+ N..°=u O-A
F F F
A 5000 mL 3 neck round bottom flask as fitted with a mechanical stirrer, a
heating mantle, a J-Kem temperature probe/controller, an on funnel, a water
cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a
nitrogen atmosphere with tert-bulyl 5-oxo-lH-pyrazolecarboxylate (70 g, 0.3800
mol) and tetrahydrofuran (840 mL, 12 mL/g) which provided a clear pale yellow
solution. Stirring was commenced and the pot temperature was recorded at 19 °C. The
vessel was then charged with [l-(trifluoromethyl)cyclopropyl]methanol (58.56 g,
0.4180 mol) added neat in one portion followed by triphenylphosphine (109.6 g, 0.4180
mol) added as a solid in one portion. The resulting clear pale yellow solution was then
treated with ropyl azodicarboxylate (clear reddish-orange liquid) (82.3 mL,
0.4180 mol) added neat dropwise over 1 hour which resulted in a gradual exotherm to
40 °C and a clear light amber solution. The reaction mixture was then heated to a pot
SUBSTITUTE SHEET (RULE 26)
temperature of 50 °C and the condition was maintained for 2 hours when analysis by
LC/MS indicated te consumption of the starting material. The clear amber
reaction mixture was concentrated under reduced pressure and the resulting clear dark
amber oil was suspended in toluene (560 mL) and stirred at room temperature for 1 hour
during which time a solid (triphenylphosphine oxide MW = 278.28) precipitated. The
thick slurry was filtered through a glass frit Buchner funnel and the filter cake was
displacement washed with toluene (150 mL) and then pulled for 30 minutes. The clear
amber te was concentrated under reduced pressure to provide a clear amber oil. The
material was ed by silica gel column flash chromatography (solid load on Celite
1.5 kg RediSep column) eluting with a gradient of 100% hexane to 20% EtOAc in
hexane collecting 450 mL fractions. The product elutes around 5% EtOAc in hexane.
The desired fractions were combined and concentrated under reduced re to
provide a clear pale yellow oil as the desired product utyl 3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazole-l-carboxylate (81 g, 0.264 mol, 70%).
^ NMR (400 MHz, DMSO-d6) 5 8.10 (d, J = 2.9 Hz, 1H), 6.14 (d, J = 3.0 Hz, 1H),
4.31 (s, 2H), 1.55 (s,9H), 1.07 (dp, J = 4.9, 4H). ESI-MS m/z calc. 306.11914,
found 259.0 (M-48)+; Retention time: 1.76 minutes
Step B: 3-[[l-(Trifluoromethyl)cyclopropyl]methoxy]-lH-pyrazole
,N'lAo''^ o-//N~nh
A 5000 mL 3 neck round bottom flask was fitted with a mechanical stirrer, a
g mantle, a J-Kem temperature probe, a water cooled reflux condenser, an
addition funnel and a en inlet/outlet. The vessel was charged under a nitrogen
atmosphere with tert-butyl (trifluoromethyl)cyclopropyl]methoxy]pyrazole-lcarboxylate
(80 g, 0.2612 mol), dichloromethane (320 mL, 4 mL/g) and methyl l
(320 mL, 4 mL/g) which provided a clear pale yellow solution. Stirring was commenced
and the pot temperature was recorded at 19 °C. The addition funnel was charged with 4
MHC1 in 1,4-dioxane (195.9 mL, 0.7836 mol) which was subsequently added dropwise
over 1 hour which resulted in a gradual exotherm to 30 °C. The resulting clear pale
yellow solution was heated to a pot temperature of 45 °C and the condition was
SUBSTITUTE SHEET (RULE 26)
maintained for 1 hour when analysis by LC/MS indicated reaction completion. The
reaction mixture was allowed to cool to room temperature and then trated under
reduced pressure. The remaining residue was dissolved in tert-butyl methyl ether (640
mL) and then transferred to a separatory funnel and partitioned with 2 M sodium
hydroxide solution (391.8 mL, 0.7836 mol). The organic layer was removed and the
residual aqueous was extracted with tert-buty l methyl ether (2 x 200 mL). The
combined c was washed with saturated sodium chloride solution (500 mL), dried
over sodium sulfate (300 g) and then filtered through a glass frit Buchner funnel. The
clear pale yellow filtrate was concentrated under reduced pressure to provide a clear
light yellow oil which solidified upon standing to provide a white solid (49.5 g, 0.240
mol, 92%) as the d product 3-[[l-(trifluoromethyl)cyclopropyl]methoxy]-lH-
pyrazole. 1HNMR(400 MHz,DMSO-d6)8 11.90 (s, 1H), 7.51 (d,J = 2.4Hz, 1H),
.67 (d, J = 2.4 Hz, 1H), 4.19 (s, 2H), 1.09 - 0.97 (m, 4H). ESI-MS m/z calc. 206.0667,
found 207.0 (M+l)+; Retention time: 1.07 minutes.
] Step C: utyl 2-chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy
] py razol- 1-yl] pyridinecarb oxylate
U ♦ F N'NH
CW' KyCOs, DABCQ
O-f/ N Cl
cr n 'ciX F F F'
A 5000 mL 3 neck round bottom flask was fitted with a ical stirrer, a
cooling bath used as ary containment, a J-Kem temperature probe, a water cooled
reflux condenser, an addition funnel and a nitrogen inlet/outlet. The vessel was charged
under a nitrogen atmosphere with 3-[[l-(trifluoromethyl)cyclopropyl]methoxy]-lH-
pyrazole (45 g, 0.2183 mol) and N,N-dimethylformamide (540 ml, 12 mL/g) which
provided a clear pale yellow solution. Stirring was commenced and the pot temperature
was recorded at 17 °C. The vessel was then charged with tert-butyl 2,6-
dichloropyridinecarboxylate (54 16 g, 0.2183 mol) added as a solid in one portion.
The resulting clear pale yellow solution was then treated with potassium ate
(39.22 g, 0.2838 mol) added as a solid in one portion followed by 1,4-
diazabicyclo[2.2.2]octane (3.67 g, 4 mol) added as a solid in one portion. The
SUBSTITUTE SHEET (RULE 26)
resulting pale yellow suspension was allowed to stir at room temperature for 24 hours.
The reaction mixture was cooled to 10 °C with a cmshed ice/water cooling bath. The
addition funnel was charged with water (540 mL) added dropwise over 45 s
which resulted in a thick suspension and an exotherm to 15 °C. The resulting suspension
was continued to stir at 15 °C for 30 minutes and then filtered through a glass frit
Buchner funnel. The filter cake was cement washed with water (2 x 500 ml) and
then pulled in the Buchner for 2 hours. The material was then allowed to air dry
overnight to provide (73 g, 0.175 mol, 80%) of a white granular solid as tert-butyl 2-
[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine
carboxylate. ESI-MS m/z calc. 361.0441, found 361.9 (M+l)+; Retention time: 2.27
minutes.
Step D: 2-Chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid
O Jk 0
if 'o
0 N'N' '[s|' 'ClX N-mAA H fY 0
O-// N N Cl
F F
F F F F
A 1000 mL 3 neck round bottom flask as fitted with a mechanical stirrer, a
heating mantle, a J-Kem temperature probe/controller, an addition funnel, a water
cooled reflux condenser and a en mlet/outlet. The vessel was charged under a
nitrogen atmosphere with tert-butyl 2-chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylate (70 g,
0.1675 mol) and anol (350 mL) which provided an off-white suspension. Stirring
was commenced and the pot ature was recorded at 19 °C. The addition funnel
was charged with aqueous 6 M HCI (139.6 mL, 0.8375 mol) which was added se
over 10 s which resulted in an exotherm to 30 °C. The resulting suspension was
then heated to reflux (pot temperature ~82 °C) Upon heating the suspension turns to a
clear pale yellow solution (pot temperature ~75 °C at this point). After stirring at reflux
for ~30 minutes a solid began to precipitate. The suspension was continued to stir at
reflux for an additional 30 minutes at which point water (210 mL) was added se
SUBSTITUTE SHEET (RULE 26)
over 15 minutes. The heat was then removed and the suspension was continued to stir
and allowed to slowly cool to room temperature. The material was collected by vacuum
filtration in a glass frit Buchner funnel and the filter cake was cement washed with
1:1 water/2-propanol (100 mL) followed by water (2 x 100 mL) and then pulled in the
Buchner for 30 minutes. The material was further dried in a vacuum oven at 45 °C for
24 hours to provide 2-chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxylic acid (56 g, 0.155 mol. 92%) as a white solid. 'H NMR (400
MHz, DMSCM;) 8 13.64 (s, 1H), 8.44 (d, /= 2.9 Hz, 1H), 8.41 (d, /= 8.4 Hz, 1H),
7.74 (d, J= 8.4 Hz, 1H), 6.24 (d, .7=2.9 Hz, 1H),4.41 (s, 2H), 1.16-1.07 (m, 4H).
ESTMS m/z calc. 41, found 361.9 (M+l)+; ion time: 3.23 minutes
Step E: N-(Benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O 1%P
‘OH QwP iT^rnY"!
GDI, DBU
0~//N'N'A'N<!^CI + H2N :s:X) N.
F- F-
F F F F
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0.4144 mmol) was dissolved in THF (2.000
mL). GDI (approximately 80.64 mg, 0.4973 mmol) was added. The reaction mixture
was stirred at room temperature for 1.5 hours. Benzenesulfonamide (approximately
84.68 mg, 0.5387 mmol) was added ed by DBU ximately 126.2 mg, 124.0
pL, 0.8288 mmol). The reaction mixture was allowed to stir at room temperature for
another 1.5 hours. The reaction mixture was concentrated to half volume, diluted with
dichloromethane and directly injected onto a 12 gram silica gel column and subjected to
a 0-10% methanol in dichloromethane gradient; product eluted at 10%. Fractions
ning the d product were combined and concentrated. N-(benzenesulfonyl)-
2-chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine
carboxarmde (168 mg, 81%) was ed as a clear colorless oil. ESI-MS m/z calc.
500.05328, found 501.0 (M+l)+; Retention time: 1.92 minutes (3 minute run).
SUBSTITUTE SHEET (RULE 26)
Step F: N-(Benzenesulfonyl)[3-[[l-(trifluoromethyl)cyclopropyl
] methoxy] pyrazol- 1-yl] [(4S)-2,2,4-trimethylpy rrolidin- 1-yl] pyridine
amide
0 o.XqsP HN^S], V?
k?co3 o-v^'n^n^nXs
F- F
F F F F
N-(Benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (168 mg,
0.3354 mmol) and (4S)-2,2,4-trimethylpyrrolidme chloride salt) (approximately
150.6 mg, 1.006 mmol) were combined and dissolved in DMSO (0.5 mL). Finely
ground potassium ate (approximately 278.1 mg, 2.012 mmol) was added, and the
reaction mixture was allowed to stir at 130 °C overnight. The reaction mixture was
diluted with EtOAc (50 mL) and washed with s 1 M citric acid (2x 50 mL) and
brme (1 x 50 mL). The organic layer was dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was punfied by silica gel
column chromatography: 24 gram silica gel column, 0-5% MeOH/DCM gradient;
product eluted at 2.5%. Pure fractions were combined and trated under reduced
pressure, and azeotroped with MeOH, to provideN-(benzenesulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide (74.9 mg, 39%). 'h NMR (400 MHz, DMSO-d6) 5 12.51
(s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.05 - 7.95 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.78 -
7.70 (m, 1H), 7.66 (dd, J = 8 3, 6 7 Hz, 2H), 6 92 (d, J = 8.3 Hz, 1H), 6.15 (d, J = 2.7
Hz, 1H), 4.43 - 4.30 (m, 2H), 2.40 (t, J = 10.5 Hz, 1H), 2.26 (t, J = 8.6 Hz, 1H), 2.09 (dt,
J = 12.3, 6.4 Hz, 1H), 1.82 (dd, J = 12.0, 5.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.36 (t,
J = 12.1 Hz, 1H), 1.15 -1.04 (m, 4H), 0.64 (d, J = 6.2 Hz, 3H). ESI-MS m/z calc.
577.1971, found 578.3 (M+l)+; Retention time: 2.16 minutes (3 minute run).
SUBSTITUTE SHEET (RULE 26)
] Synthetic Example 15: Synthesis of Compound 15: N-(o-Tolylsulfonyl)-
6- [3- [(2,2,3,3-tetramethylcyclopropyl)methoxy] pyrazol- l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
0 I 0
OH N-nh Ph^P, DIAD NaOH
I '0'^'
CI^N^CI
K2C03, DBU ^'N^N^CI NaOH rf™
N-n'^n^ci + ¥ CPI, DBU
p-CS h2n
o 0 0 |
KyCO-j
P~iJ " Cl p~Q NhJOXCIJjT
Step A: utyl 3-[(2,2,3,3-teti amethylcyclopropyl)methoxy|pyrazole-
1-carboxylate
OH n.naJ<
+HO-^j Ph^P, DIAD nj
To a degassed solution of PhT (approximately 51.28 g, 195.5 mmol) in
toluene (360.0 mL) under nitrogen gas at 0 °C was added DIAD
(diisopropylazodicarboxylate) (approximately 39.53 g, 37.86 mL, 195.5 mmol)
dropwise. The mixture was stirred at 0 °C for 30 min affording a white slurry. To the
mixture was added a solution of (2,2,3,3-tetramethylcyclopropyl)methanol
(approximately 29.84 g of 70 %w/w, 162.9 mmol) and tert-butyl 3-hydroxypyrazole-lcarboxylate
(30 g, 162.9 mmol) in toluene (600.0 mL) dropwise at ~5 °C over 2 hours.
The e was allowed to warm to ambient ature and stirred for 18 hours. The
mixture was heated to 75 °C for a total of 6 hours and then allowed to cool to t
temperature. The slurry was diluted with heptane (900.0 mL) and stirred at ambient
temperature for 3 hours. The slurry was filtered over celite and the precipitate washed
3X with 100 mL of heptane. The filtrate was concentrated in vacuo affording a thick
yellow oil. The crude t chromatographed on a 750 gram silica gel column loading
SUBSTITUTE SHEET (RULE 26)
WO 64632
with dichloromethane and eluting with a 0-20% hexanes gradient. Collected
fractions containing product were concentrated in vacuo affording an off-white solid,
tert-butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-l-carboxylate (30.1 g,
63%) was obtained. lH NMR (400 MHz, form-d) 5 7.82 (d, J = 3.0 Hz, 1H), 5.88
(d, J = 2.9 Hz, 1H), 4.30 (d, J = 7.7 Hz, 2H), 1.61 (s, 9H), 1.12 (s,6H), 1.04 (s, 6H),
0.70 (t, J = 7.8 Hz, 1H). ESI-MS m/z calc. 294.19434, found 295.0 (M+l)+; Retention
time: 2.19 minutes
Step B: 3-[(2,2,3,3-Tetramethylcyclopropyl)methoxy]-l H-pyrazole
p-O NaOH p-£t
To a solution of tert-butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-lcarboxylate
(127 g, 431.4 mmol) in THE (317.5 mL) and ethyl alcohol (635.0 mL) was
slowly added sodium hydroxide (approximately 431.4 mL of 2 M, 862.8 mmol) and
stirred at room temperature overnight. Most of the solvent was removed under reduced
pressure. The aqueous residue was d with water (400 mL) and extracted with
methyl t-butyl ether (762.0 mL). The organic phase was washed twice with brine (2 x
300 mL) and the s phases were back extracted once with methyl t-butyl ether
(250 mL). The combined organic phases were dried, filtered and evaporated to give 3-
[(2,2,3,3-tetramethylcyclopropyl)methoxy]-lH-pyrazole (75 g, 89%) as a viscous oil. 'H
NMR (400 MHz, DMSO-d6) 5 11.78 (s, 1H), 7.48 (t, J = 2.1 Hz, 1H), 5.65 (s, 1H), 4.05
(d, J = 7.7 Hz, 2H), 1.08 (s, 6H), 1.00 (s, 6H), 0.67 (t, J = 7.7 Hz, 1H). ESI-MS m/z
calc. 194.1419, found 195.0 (M+l)+; Retention time: 1.43 minutes.
Step C: Ethyl 2-chloro [3- [(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxylate
■ NH K2C03, DBU
+ % p-cyN. N Cl
cr n ci
SUBSTITUTE SHEET (RULE 26)
To the ethyl 2,6-dichloropyridinecarboxylate (16.8 g, 76.35 mmol) and 3-
[(2,2,3,3-tetramethylcyclopropyl)methoxy]-lH-pyrazole (approximately 14.83 g, 76.35
mmol) in DMF (201.6 mL) was added potassium carbonate (approximately 13.72 g,
99.26 mmol) followed by DABCO ximately 1.284 g. 11.45 mmol). The slurry
was stirred at ambient temperature for 16 hours. The cream fine suspension was slowly
diluted with water (201.6 mL), and the resulting thick slurry was d at ambient
temperature for 30 minutes with an overhead stirrer. The precipitate was collected
using an medium frit and washed 3 times with 25 mL of water. The solid was air dried
for 30 s, and then dried in vacuo using an EtOAc azeotrope. Ethyl 2-chloro[3-
[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxylate (28.8 g,
100%) was obtained as an off-white solid. ESI-MS m/z calc. 377.1506, found 378.37
(M+l)+; Retention time: 2.47 minutes, 'h NMR (400 MHz, DMSO-d6) 5 8.43 (dd, J =
2.9, 0.9 Hz, 1H), 8.39 (dd, J = 8.5, 0.9 Hz, 1H), 7.76 (dd, J = 8.5, 0.9 Hz, 1H), 6.24 (dd,
J = 2.9, 0.9 Hz, 1H), 4.34 (td, J = 7.5, 6.6 Hz, 2H), 4.28 (d, J = 7.8 Hz, 2H), 1.34 (td, J =
7.1, 0.9 Hz, 3H), 1.11 (s, 6H), 1.05 (s, 6H), 0.75 (t, J = 7.8 Hz, 1H).
Step D: 2-Chloro[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-
l-yl]pyridinecarboxylic acid
O O
N- N- ✓2 H
P-QI N XI N Cl
Ethyl 2-chloro[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine
ylate (146 g, 386.4 mmol) in THE (730.0 mL) and EtOH (292.0 mL) was treated
with NaOH ximately 772.8 mL of 1 M, 772.8 mmol) and the solution was stirred
at room temperature for 5 hours. Most of the solvent was removed under reduced
pressure, and the solution was acidified by addition of citric acid (approximately 148.5
g, 89.19 mL, 772.8 mmol) under ice cooling. The formed thick suspension (pH 2-3) was
stirred in the ice bath for 1 hour, filtered, washed with plenty of water and dried in a
drying cabinet under vacuum at 45 °C with a nitrogen bleed for two days to give 2-
[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine
carboxylic acid (128.2 g, 90%) as an off white solid. ESI-MS m/z calc. 349.11932,
SUBSTITUTE SHEET (RULE 26)
found 350.0 (M+l)+; Retention time: 2.11 minutes, 'll NMR (400 MHz, DMSO-d6) 5
13.64 (s, 1H), 8.69 - 8.22 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 2.9 Hz, 1H),
4.28 (d, J = 7.8 Hz, 2H), 1.08 (d, J = 24.9 Hz, 12H), 0.75 (t, J = 7.8 Hz, 1H).
Step E: 2-Chloro-N-(o-tolylsulfonyl)[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide
0 9 9P
"OH Qwp n:s
is CPI, DBU H
p^N N ■Cl + H2N P^N N XIN-
2-Chloro[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg 0.429 mmol) and was dissolved/suspended in
THF (2 mL), and carbonyl diimidazole (64.2 mg, 0.396 mmol) was added. The
suspension was allowed to stir at room temperature for 1.5 hours. 2-
benzenesulfonamide (73.4 mg, 0.429 mmol) was then added followed by DBU
(59.2 pL, 0.396 mmol). The resulting on was then stirred for another 1.5 hours.
Volatiles were evaporated. The remaining residue was taken up in dichloromethane (2
mL) and washed with aqueous 1 M citric acid (1x2 mL). The organic layer was
injected onto a silica gel column for chromatography: 12 gram silica gel column, 0-10%
MeOH/DCM nt. 2-chloro-N-(o-tolylsulfonyl)[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (115 mg, 53%)
was obtained. ESI-MS m/z calc. 502.14417, found 503.0 (M+l)+; Retention time: 2.25
minutes.
] Step F: N-(o-Tolylsulfonyl)[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrroli(lin-lyl
]pyridinecarboxamide
^1 HN'NS, K2CO3 vVvP
P-^jN Cl
p N
SUBSTITUTE SHEET (RULE 26)
2-Chloro-N-methylsulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (115 mg, 0.229
mmol) and (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (106 mg, 0.935 mmol)
were combined and dissolved in DMSO (1 mL). Finely ground potassium ate
(258 mg, 1.87 mmol) was added. The reaction mixture was sealed and heated overnight
at 130 °C. After g to room temperature, the reaction mixture was diluted with
EtOAc (50 mL) and washed with aqueous citric acid (1 M, 2x 50 mL) and brine (1 x 50
mL). The organic layer was dried over sodium sulfate, filtered and concentrated under
reduced pressure. The product was isolated by silica gel column chromatography
eluting with a 0-5% MeOH/DCM gradient on a 12 gram silica gel column. N-(o-
Tolylsulfonyl)[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (57.2 mg, 42%) was obtained.
ESI-MS m/z calc. 579.2879, found 580.3 (M+l)+; Retention time: 2.52 minutes, fa
NMR (400 MHz, DMSO-d6) 5 12.62 (s, 1H), 8.18 (d, J = 2.8 Hz, 1H), 8.04 (dd, J = 8.0,
1.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.59 (td, J = 7.5, 1.5 Hz, 1H), 7.50 - 7.40 (m, 2H),
6.93 (d, J = 8.2 Hz, 1H), 6.13 (d, J = 2.7 Hz, 1H), 4.24 (d, J = 7.8 Hz, 2H), 2.63 (s, 3H),
2.38 (d, J = 8.8 Hz, 2H), 2.16 (d, J = 10.3 Hz, 1H), 1.82 (dd, J = 11.9, 5.5 Hz, 1H), 1.52
(d, J = 1.6 Hz, 6H), 1.35 (t, J = 12.1 Hz, 1H), 1.10 (s, 6H), 1.04 (d, J= 1.1 Hz, 6H), 0.77
- 0.67 (m, 4H).
Synthetic e 16: Synthesis of Compound 16: N-(3-
Fluorophenyl)sulfonyl[3-[(2,2,3>3-tetramethylcyclopropyl)methoxy]pyrazol-lyl
4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(3-fluorophenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide
0 o o 0
‘OH u F GDI, DBU + h2n .voy©'
p-XS N Cl
2-Chloro[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0.429 mmol) was dissolved/suspended in THF
(2 mL), and yl diimidazole (64.2 mg, 0.396 mmol) was added. The suspension
SUBSTITUTE SHEET (RULE 26)
was allowed to stir at room ature for 1.5 hours. 3-fluorobenzenesulfonamide
(75.1 mg, 0.429 mmol) was then added followed by DBU (59.2 pL, 0.396 mmol). The
resulting solution was then stirred for another 1.5 hours. Volatiles were evaporated.
The remaining residue was taken up in dichloromethane (2 mL) and washed with
s 1 M citric acid (1x2 mL). The organic layer was injected onto a silica gel
column to be purified by chromatography: 12 gram silica gel column, 0-10%
MeOH/DCM gradient. 2-chloro-N-(3-fluorophenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (150 mg, 70%)
was ed. ESI-MS m/z calc. 506.11908, found 507.0 (M+l)+; Retention time: 2.24
minutes
Step B: N-(3-fluorophenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridmecarboxamide
9 oo o o 0
% Yxy. &
K?CO,
N' ■XCCp-'
2-Chloro-N-(3-fluorophenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (158 mg, 0.312
mmol), and ,2,4-trimethylpyrrolidine (Hydrochloride salt) (105.9 mg, 0.935
mmol) were ed and dissolved in DMSO (1 mL). Finely ground potassium
carbonate (258 mg, 1.87 mmol) was added. The reaction mixture was sealed and heated
overnight at 130 °C. After cooling to room temperature, the reaction mixture was
diluted with EtOAc (50 mL) and washed with aqueous citric acid (1 M, 2x 50 mL) and
brme (1 x 50 mL). The organic layer was dried over sodium sulfate, filtered and
concentrated under reduced re. The product was isolated by column
chromatography eluting with a 0-5% MeOH/DCM gradient on a 12 gram silica gel
column. N-(3-fluorophenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide (28.4 mg, 16%) was obtained. ESI-MS m/z calc. 583.2629,
found 584.6 (M+l)+; ion time: 2.46 minutes, 'H NMR (400 MHz, DMSO-d6) 8
12.61 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.79 - 7.71 (m, 2H), 7.63
SUBSTITUTE SHEET (RULE 26)
(tdd, J = 8.6, 2.6, 1.1 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.13 (d, J = 2.8 Hz, 1H), 4.24 (d,
J = 7.7 Hz, 2H), 2.44 (t, J = 10.4 Hz, 1H), 2.36 - 2.26 (m, 1H), 2.13 (td, J = 11.8, 6.0 Hz,
1H), 1.84 (dd, J= 11.8, 5.5 Hz, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.39 (t, J= 12.1 Hz, 1H),
1.10 (s, 6H), 1.04 (s, 6H), 0.74 (d, J = 7.7 Hz, 1H), 0.70 (t, J = 6.6 Hz, 3H).
Synthetic Example 17: Synthesis of Compound 17: N-(Benzenesulfonyl)-
2- [(4S)-3,3-dideuterio-2,2-dimethyl(trideuteriomethyl)pyrrolidin-l-yl] [3- [2-
[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
VX AqsP o' "O. wCDs k2co3 p-^-N N
F D D F
F- F
F F D D
N-(Benzenesulfonyl)chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazoll-yl
]pyridinecarboxamide (2 g, 3.884 mmol) was dissolved inNMP (10.00 mL) and
1,2-diethoxy ethane (2.000 mL). Potassium carbonate (approximately 2.684 g, 19.42
mmol) and (4S)-3,3-dideuterio-2,2-dimethyl(trideuteriomethyl)pyrrolidine
(Hydrochloride salt) ximately 1.502 g, 9.710 mmol) were added, and the resulting
slurry heated was to 130 °C and stirred overnight. The reaction mixture was cooled and
poured into rapidly stirred ice (60.00 mL) and acetic acid (approximately 3.499 g, 3.313
mL, 58.26 mmol). After stirring for 20 minutes to form a fairly uniform flowing solid,
the solids were ed off and washed with water. The cake was dissolved in
dichloromethane, and the resulting aqueous forced out was ted. The
romethane layer was washed with water twice and brine and dried over sodium
sulfate and concentrated. Ethanol (20 mL) was added, and the solution was
concentrated to a few milliliters. Water was very slowly added dropwise. The
suspension that formed was warmed to a thin suspension and allowed to cool over 30
minutes. Crystalline solids were filtered and washed with small amount of ethanol to
give N-(benzenesulfonyl)[(4S)-3,3-dideuteno-2,2-dimethyl
(trideuteriomethyl)pyrrolidin-l-yl][3-[2-[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl]pyridinecarboxamide (600 mg,
26%).. ESI-MS m/z calc. 596.24, found 597.0 ; Retention time: 2.29 minutes.
SUBSTITUTE SHEET (RULE 26)
Synthetic Example 18: Synthesis of Compound 18: N-
(Benzenesulfonyl)[3-[(cis)(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin- 1-yl] pyridinecarboxamide
n H °VN Ph3Rl DIAD 1) tBuOK.THF r
w °^N. CF3CH2NH2HCI/NaN02/H2Q
Br^0H
NBoc °^N.r [[.NBoc
nb°c 2) Boc20 Rh2(esp)2
N'NBoc N'NBoc N'NBoc N'NBoc
f3c'-A,‘o^ + FsC^-'O^ and f3c'-A"o^
+ F3C 'fp
FjC^-'O^N'NBoc A N'NH
A it /> ci N'N^N^CI
C.0-U TFA
DABCO, K2C03
TFA FjC''1 + ch2ci2
N'NBoc CHjCU i'o
N'NH DMF
f3cAA
f3c 0-u jfi 0N'N^n^CI
0 X ?s"°
f3c-<J 'OH F3C'"<J
5_^Sj^n ;|
^ 0 + h2n TO cdi.dbu + hn^A k2co3
f3c-<| OH A 'i"'0
°~ij.N-nAicI
F'CA[°~v TO
^■QCwX %° F3C'"<]
c.°-tJrJOTO *"0 AF
] Step A: te/7-Butyl romoethoxy)-li/-pyrazole-l-carboxylate
D ^ Ph3P, DIAD
/A/OH UVN^
Br r
+ NBoc Otj
] To the solution of 2-bromoethanol (1.69 g, 13.53 mmol), toV-butyl -2,3-
dihydrooxopyrazole-l-carboxylate (2.08 g, 11.28 mmol) and triphenylphosphine
SUBSTITUTE SHEET (RULE 26)
(3.55 g, 13.53 mmol) in anhydrous tetrahydrofuran (45 mL) at 0 C diisopropyl
azodicarboxylate (2.74 g, 13.53 mmol) was added dropwise. After the addition was
te, the reaction solution was stirred at 0 °C for 1 hour, then warmed up to room
temperature and stirred for additional 2 hours. Ether (400 mL) was added. The organic
solution was washed with saturated sodium ate aqueous solution (80 mL), brine
(50 mL), then dried over magnesium sulfate, filtered and concentrated under reduced
pressure. The residue obtained was purified by silica gel chromatography using
hexanes- ethyl acetate gradient method (0 to 15% ethyl acetate) to afford tert-butyl 3-(2-
bromoethoxy^liZ-pyrazole-l-carboxylate (2.56 g, 78%) as white solid, 'll NMR
(250MHz, CDCh) 6 (ppm): 7.85 (d, J= 3.0 Hz, 1H), 5.92 (d, 3.0 Hz, 1H), 4.63 (t,J
= 6.0 Hz, 2H), 3.68 (t, J= 6.0 Hz, 2H), 1.64 (s, 9H). ESI-MS m/z calc. 292.0 found
292.9 /M+1)1, Retention time: 4.91 minutes.
Step B: fert-Butyl 3-(vinyloxy)-l//-pyiazole-l-cai boxylate
1) tBuOK.THF r
O N,
O. N
v, 2) Boc20 NBoc
To the solution of tert-butyl 3-(2-bromoethoxy)-lH-pyrazole-l-carboxylate
(2.52 g, 8.66 mmol) in anhydrous tetrahydrofuran (90 mL) was added potassium tertbutoxide
(1.46 g, 13.0 mmol). The resulting solution was stirred for 2 hours, then ditert-butyl
dicarbonate (5.67 g, 26.0 mmol) and stirred for another 1 hour. Diethyl ether
(400 mL) was added. c layers were washed with water (50 mL), brine (2 x
50mL), dried over dried over ium sulfate, filtered and concentrated under
reduced pressure. The residue obtained was purified by silica gel chromatography using
hexanes-ethyl acetate gradient method (0 to 10% ethyl acetate) to afford tert-butyl 3-
(Yinylo\y)-l//-pyrazole-l-carbo\ylate (1.10 g, 60%) as colorless oil. 'h NMR
(250MHz, CDC13) S (ppm): 7.89 (d, J= 3.0 Hz, 1H), 7.24 (dd, J= 6, 13.5 Hz, 1H), 5.95
(d, .7=3.0 Hz, 1H), 4.88 (dd, J= 1.8,13.5 Hz, 1H), 4.50 (dd,/= 1.8, 6.0 Hz, 1H), 1.62
(s, 9H). ESI-MS m/z calc. 210.1 found 211.0 (M+l)+ Retention time: 4.74 s.
Step C: tert-Butyl 3-(2-(trifluoromethyl)cyclopropoxy)-l//-pyrazole-l-
ylate
SUBSTITUTE SHEET (RULE 26)
N'NBoc A N'NBoc
CF3CH2NH2HCI/NaN02/H20 F3C' F3C
0n^N.
T NBoc N-NBoc and
Rh2(esp)2 f3c^A'"o^ AA N'NBoc a}
f3c"' "0'^/
utyl 3-(vinyloxy)-l//-pyrazole-l-carboxylate (1.10 g, 5.23 mmol) in
pear-shape flask (100 mL) was added water (20 mL) and bubbled with argon for 5
minutes, then sodium acetate (85.8 mg, 1.05 mmol) was added followed by 2,2,2-
oroethylamine hydrochloride (3.57 g, 26.17 mmol) and concentrated sulfunc acid
(51.3 mg, 0.523 mmol). The solution was bubbled with argon for another 5 minutes
before bis[rhodium(a,a,a',a'-tetramethyl-l,3-benzenedipropionic acid)] (397 mg, 0.523
mmol) was added. The reaction solution was kept under argon with balloon while
s solution of sodium nitrite (2.17 g, 31.4 mmol) in water (12.8 mL) was added by
syringe pump within 10 hours. After the addition was complete, the resulting solution
was stirred for an additional 6 hours. Diethyl ether (300 mL) was added and the organic
layer was separated. Then organic layer was washed with brine (30 mL), dried over
magnesium sulfate, ed and concentrated under reduced re. The residue
obtained was purified by silica gel chromatography using hexanes - dichloromethane
gradient method (0 to 100% dichloromethane). The residue obtained was subjected to
silica gel chromatography again (hexanes and ethyl acetate, 0 to 10% ethyl acetate
gradient) to afford tert-butyl 3-(L2-trans(trifluoromethyl)cyclopropoxy)-li/-
pyrazole-l-carboxylate and utyl 3-(l,2-cis(trifluoromethyl)cyclopropoxy)
le-1 -carboxylate, /ert-buty 1 3-(1,2-trans(trifluoromethyl)cyclopropoxy)-\H-
pyrazole-l-carboxylate: (366 mg, 24%); a white solid, 'fl NMR (250MHz, CDCfl) d
(ppm): 7.84 (d, J = 2.8 Hz, 1H), 5.91 (d, 2.8 Hz, 1H), 4.49 (m, 1H), 1.75 (m, 1H),
1.62 (s, 9H), 1.56-1.25 (m, 2H). ESI-MS m/z calc. 292.1 found 293.1
(M+l)+.Retentiontime: 5,22 minutes. /677-butyl 3-(l.2-cis
(trifluoromethyl)cyclopropoxy)pyrazole-l-carboxylate: (314mg, 21%); a white
solid. ‘H NMR (250MHz, CDCfl) d (ppm): 7.90 (d, ./ = 2.8 Hz, 1H), 5.92 (d, ./ = 2.8
Hz, 1H), 4.49 (m, 1H), 1.94 (m, 1H), 1.62 (s, 9H), 1.30 (m, 2H). ESI-MS m/z calc.
292.1 found 293.1 (M+l)+ Retention time: 5 48 minutes.
Step D: 3-(L2-cis(Trifluoroinethyl)cyclopiopoxy)-l//-pyrazole
SUBSTITUTE SHEET (RULE 26)
N'NBoc A N'T
f3c TFA f3c
A N'T
N-NBoc
f3co‘
f3co-
] Trifluoroacetic acid (2.76 g, 24.3 mmol) was added to the solution of tertbutyl
3-(l,2-cis(trifluoromethyl)cyclopropoxy)-li7-pyrazole-l-carboxylate (708 mg,
2.43 mmol) in anhydrous dichloromethane (24 mL). The resulting solution was stirred
at room temperature for 16 hours. 1,2-Dichloroethane (10 mL) was added to the reaction
solution. All the solvents were removed under reduced re. The residue obtained
was disolved in ethyl ether (150 mL), washed with satuated sodium bicarbonate
aqueous on (30 mL). The organic solution was dried over magnesium sulfate,
ed and concentrated under the reduced pressure to afford crude 3-(l,2-cis
(trifluoromethyl)cyclopropoxy)-li7-pyrazole (461 mg, 99%) as yellow-brown oil. The
crude product was used directly in next step without any further purification. ESI-MS
m/z calc. 192.1 found 193.0 (M+l)+. Retention time: 3.26 minutes.
Step E: tert-Butyl 6-(3-(l,2-cis(trifluoromethyl)cyclopropoxy)-Lf7-
pyrazol-l-yl)chloropyridinecarboxylate
A N'NvH f3c 0
Cl -V DABCO, K2C03
+ .0 O
A N'NH Cl o f3c-<J '0
^^^Hni^n^ci
To the solution of crude -cis(trifluoromethyl)cyclopropoxy)-li7-
pyrazole (461 mg, 2.43 mmol) in dimethylformarmde (8 mL) was added ferf-butyl 2,6-
dichloropyridinecarboxylate (659 mg, 2.67 mmol), potassium carbonate (669 mg,
4.85 mmol) and 1,4-diazabicyclo [2.2.2]octane (55 mg, 0.49 mmol). The on was
stirred at room temperature for 48 hours. The reaction solution was diluted with ether
(200 mL), washed with water (4 x 20mL) and brine (20 mL). The organic layer was
SUBSTITUTE SHEET (RULE 26)
dried over magnesium sulfate, filtered and concentrated under reduced pressure. The
residue obtained was purified by silica gel tography using hexanes -
dichloromethane gradient method (0 to 100% dichloromethane) to afford tert-butyl 6-
2-cis(trifluoromethyl)cyclopropoxy)-l#-pyrazol-l-yl)chloropyridine
carboxylate (731mg, 68%) as a white solid, ’tt NMR (250MHz, CDCh) S (ppm): 8.39
(d, J= 2.8 Hz, 1H), 8.22 (d, J= 8.5Hz, 1H), 7.74 (d, J= 8.5Hz, 1H), 6.01 (d, /= 2.8 Hz,
1H), 4.33 (m, 1H), 1.93(m, 1H), 1.62(s, 9H), 1.45-1.26(m, 2H). ESI-MS m/z calc.
403.1 found 404.1 . Retention time: 7.29 minutes.
Step F: 6-(3-(l,2-cis(Trifluoromethyl)cyclopropoxy)-li7-pyrazol-l-yl)-
2-chloropyridinecarboxylic acid
O O
0 FX OH
°-u °-u
O O
0 f3c-<| OH
F3C-0
] Trifluoroacetic acid (2.03 g, 17.8 mmol) was added to the solution of tert-
butyl 6-(3-(l,2-cis(trifluoromethyl)cydopropoxy)-l#-pyrazol-l-yl)
chloropyridinecarboxylate (718 mg, 1.78 mmol) in anhydrous dichloromethane (18
mL). The resulting solution w as stirred at room temperature for 16 hours. 1,2-
Dichloroethane (10 mL) was added to the reaction solution. All the solvents were
removed under the reduced pressure. The crude solid obtained w as added 10% ethyl
ether in hexanes (25 mL) and sonicated for 30 s, filtered, washed with 10% ethyl
ether in hexanes (10 ml), hexances (10 mL) and dried under high vacumn to afford 6-
(3-(l,2-cis(trifluoromethyl)cyclopropoxy)-li7-pyrazol-l-yl)chloropyridine
carboxylic acid (517mg, 84%) as a white solid, 'h NMR (500MHz, DMSO) <5 (ppm):
13.6 (bs, 1H), 8.47 (d, J= 3.0 Hz, 1H), 8.42 (d, J= 8.8 Hz, 1H), 111 (d, J= 8.8 Hz,
1H), 6.27 (d, J= 3.0 Hz, 1H), 4.46 (m, 1H), 2.40 (m, 1H), 1.47 (m, 1H), 1.32 (m, 1H).
ESI-MS m/z calc. 347.0 found 347.9 (M+l)+. Retention time: 5.20 minutes.
SUBSTITUTE SHEET (RULE 26)
Step G: N-(Benzenesulfonyl)chloro[3-[(cis)
(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]pyridinecarboxamide
9 qwp
‘OH p-Q* N Cl
F> p-GN N Cl 9 Q.P
Fv""<I QwP F
F jr^OCPI, DBU TO
P<J N
p-Q N Cl pW
pW F
6-(3-(l,2-Cis(trifluoromethyl)cyclopropoxy)-li/-pyrazol-l-yl)
chloropyridinecarboxylic acid (125 mg, 0.360 mmol) was dissolved in THF (1 mL).
l,r-Carbonyldiimidazole (75.6 mg, 0.431 mmol) was added. The reaction mixture was
allowed to stir at room temperature for 1 hour, benzenesulfonamide (67.8 mg, 0.431
mmol) was added followed by DBU (64.5 pL, 0.431 mmol). The final reaction mixture
was allowed to stir overnight at room temperature. Volatiles were removed by
evaporation. It was taken up in EtOAc (50 mL) and washed with aqueous 1 M citric
acid on (2x 50 mL) and brine (lx 50 mL). The organic layer was dried over
sodium sulfate, ed and concentrated under reduced pressure. N-(benzenesulfonyl)-
2-chloro[3-[(cis)(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]pyndine
carboxarmde (201 mg) was ed. ESI-MS m/z calc. 486.03763, found 486.9
(M+l)+; Retention time: 0.67 minutes (1 minute run).
Step H; N-(Benzenesulfonyl)[3-[(cis)
uoromethyl)cyclopropoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxainide
SUBSTITUTE SHEET (RULE 26)
WO 64632
CC'tJA^9 .nj
p-0 N F
HN"^ XXp9 Qp K?COs
^ 0 o 0
f4""<]
F ..^'O
P-U FW
pW F
N-(benzenesulfonyl)chloro[3-[(cis)
(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]pyridinecarboxamide (175 mg, 0.3595
mmol) was dissolved in DMSO (1 mL). (4S)-2,2,4-tnmethylpyrrolidine (Hydrochlonde
salt) (161 mg, 1.08 mmol) was added followed by potassium carbonate (298 mg, 2.16
mmol). The reaction mixture was d to stir at 130 °C overnight. After cooling to
room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed
with s citric acid (1 M, 2x 50 mL) and brine (lx 50 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated under reduced re. The
product was isolated by silica gel column chromatography on a 12 gram silica gel
column eluting with a 0-10% EtOAc/hexane gradient. N-(benzenesulfonyl)[3-[(cis)-
2-(trifluoromethyl)cyclopropoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide (114.3 mg, 56%) was obtained. ESI-MS m/z calc. 563.1814,
found 564.5 (M+l)+; Retention time: 2.08 minutes
tic Example 19: Synthesis of Compound 19: N-
(Benzenesulfonyl)[3-[(trans)(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin- 1-yl] pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
F3C'"^Sy^N-NBoc A N'N\H F3C'"<3 fl°
F3C"' c,
TFA DABCO, K2C03 0-<^N N , U'bo
CH2CI2 DMF CH2CI2
N-NBoc Cl 0
FaC^-tA^ FsC^-'O^A N-NH F3c-<q
.N'N^N^-CIjTi 0
ȣ&A9sP F3C'"<^ jCtOH
°-u^ ^naci 'O
0 H!N9s°/\' x> CPI, DBU hn'AS. k2co3
F3CK]
J2&PAPsP A9sP
>rv-XJ Anj IT h
Step A: 3-(l,2-trans(Trifluoromethyl)cyclopropoxy)-l//-pyrazole
N-NBoc ^\A N'xqjCj>
f3c TFA f3c
^•.,a n-NBoc0aa ^•VA N'TqA/
f3c f3c
Trifluoroacetic acid (3.15 g, 27.64 mmol) was added to the solution of lerl-
butyl -trans(trifluoromethyl)cyclopropoxy)-li7-pyrazole-l-carboxylate (807
mg, 2.76 mmol) in anhydrous dichloromethane (28 mL). The resulting solution was
stirred at room temperature for 16 hours. 1,2-Dichloroethane (15 mL) was added to the
reaction solution. All the solvents were removed under the reduced pressure. The
residue obtained was disolved in ethyl ether (200 mL), washed with satuated sodium
onate aqueous solution (30 mL). The organic on was dried over magnesium
e, filtered and concentrated under reduced pressure to afford crude 3-(l,2-trans
SUBSTITUTE SHEET (RULE 26)
(trifluoromethyl)cyclopropoxy)-l#-pyrazole (525mg, 99%) as yellow-brown oil. The
crude product was used directly in next step without any further purification. ESI-MS
mfz calc. 192.1 found 193.0 /M+l ) . Retention time: 2.97 minutes.
Step B: tert-Butyl 6-(3-(l,2-trans(trifluoromethyl)cyclopropoxy)-l//-
l-l-yl)chloropyridinecarboxylate
F3C''A>o^A N'NxH FoC" ?0
Cl -V °-u
I DABCO, K2CO3
+ .0
DMF 0
A N^H Cl 0
f3c-<| ‘0
b-AN^N^CI
To the solution of crude 3-(l,2-trans(trifluoromethyl)cyclopropoxy)
pyrazole (525 mg, 2.76 mmoL) in ylformamide (9.2 mL) was added fert-butyl
2,6-dichloropyridinecarboxylate (751 mg, 3.04 mmol), potassium carbonate (763 mg,
.53 mmol) and 1,4-diazabicyclo [2.2.2]octane (62 mg, 0.55 mmol). The reaction was
stirred at room temperature for 48 hours. The reaction solution was diluted with ether
(250 mL), washed with water (4 x 20 mL) and brine (20 mL). The organic layer was
dried over magnesium sulfate, filtered and concentrated under reduced pressure. The
residue obtained was purified by silica gel chromatography using s -
dichloromethane gradient method (0 to 100% dichloromethane) to afford tert-butyl 6-(3-
rans(trifluoromethyl)cyclopropoxy)-li7-pyrazol-l-yl)chloropyridine
ylate (314 mg, 21%) as a colorless oil. ESI-MS mfz calc. 403.1 found 404.1
(M+l)+. Retention time: 6.92 minutes, 'll NMR (250MHz, CDCf ) 5 (ppm): 8.38 (d, J
= 3.0 Hz, 1H), 8.20 (d, T= 8.5 Hz, 1H), 7.73 (d, J= 8.5 Hz, 1H), 6.03 (d, 7 = 3.0 Hz,
1H), 4.39 (m, 1H), 1.77 (m, 1H), 1.62 (s, 9H), 1.44 (m, 1H), 1.31 (m, 1H).
Step C: 6-(3-(l,2-Trans(trilluoromethyl)cyclopropoxy)-l/f-pyrazol-l-
yl)chloropyridinecarb oxylic acid
SUBSTITUTE SHEET (RULE 26)
1 F3C"' <1 , OH
F3C1" 0
b~fjNv N Cl
f3c-<1 'OH
F5C^0 '0
b-0NL N Cl N Cl
Trifluoroacetic acid (2.39 g, 21.0 mmol) was added to the solution of tert-
butyl l,2-trans(trifluoromethyl)cyclopropoxy)-li/-pyrazol-l-yl)
chloropyridinecarboxylate (847 mg, 2.10 mmol) in anhydrous dichloromethane (21
mL). The resulting solution was stirred at room temperature for 20 hours. 1,2-
Dichloroethane (15 mL) was added to the reaction mixture. All the solvents were
removed under reduced pressure. Crude solid obtained was added 10% ethyl ether in
hexanes (30 mL) and sonicated for 30 minutes, filtered, washed with 10% ethyl ether in
hexanes (10 mL), hexances (10 mL) and dried under high vacumn to afford 6-(3-(l,2-
trans(trifluoromethyl)cyclopropoxy)-li:/-pyrazol-l-yl)chloropyridinecarboxylic
acid (600 mg, 82%) as a white solid. ESI-MS m/z calc. 347.0 found 347.9 (M+l)+.
Retention time: 4.91 minutes, 'll NMR z, DMSO) S (ppm): 8.46 (d, J= 2.8 Hz,
1H), 8.41 (d, J= 8.3 Hz, 1H), 7.74 (d, J= 8.3 Hz, 1H), 6.30 (d, 7 = 2.8 Hz, 1H), 4.46
(m, 1H), 2.15 (m, 1H), 1.40 (m, 1H), 1.34 (m, 1H).
Step D: zenesulfonyl)chloro[3-[(trans)
(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]pyridinecarboxainide
O F
‘OH F V <Lo
N'N iT'CI X H // ^
N' 'Cl
CPI, DBU
0 F F
‘OH 9 %D
P-^N N^CI <[ N
4'"<f b^QN N 'Cl
6-(3-(l,2-trans(Trifluoromethyl)cyclopropoxy)-l/f-pyrazol-l-yl)
pyridinecarboxylic acid (125 mg, 0.360 mmol) was dissolved in THF (1 mL).
SUBSTITUTE SHEET (RULE 26)
l,r-Carbonyldiimidazole (75.6 mg, 0.431 mmol) was added. The on e was
allowed to stir at room temperature for 1 hour. Benzenesulfonamide (67.8 mg, 0.431
mmol) was added followed by DBU (64.5 pL, 0.431 mmol). The final on mixture
was allowed to stir overnight at room temperature. Volatiles were removed by
evaporation. It was taken up in EtOAc (50 mL) and washed with s 1 M citric
acid solution (2x 50 mL) and brine (lx 50 mL). The c layer was dried over
sodium sulfate, filtered and concentrated under reduced pressure. N-(benzenesulfonyl)-
2-chloro[3-[(trans)(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]pyridine
amide (199 mg) was obtained. ESI-MS m/z calc. 486.0, found 486.9 (M+l)+;
Retention time: 0.65 minutes (1 minute run)
Step E: N-(Benzenesulfonyl)[3-[(trans)
(trifluoromethyl)cyclopropoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide
9 q„p
AQsP^ 's
E F ,,H 'O R F N'b
F F H
,,O^N N' "Jl
HN-^S, K,CCK
o o 0 9 Qwp
R F ^*0 R F
F^V F-V vao
N-(Benzenesulfonyl)chloro [3 - [(trans)
(trifluoromethyl)cyclopropoxy]pyrazol-l-yl]pyridinecarboxamide (175 mg, 0.3595
mmol) was dissolved in DMSO (1 mL). (4S)-2,2,4-Trimethylpyrrolidme
(Hydrochloride salt) (161 mg, 1.08 mmol) was added followed by potassium carbonate
(298 mg, 2.16 mmol). The reaction mixture was allowed to stir at 130 °C overnight.
After cooling to room temperature, the reaction mixture was diluted with EtOAc (50
mL) and washed with aqueous citric acid (1 M, 2x 50 mL) and brine (lx 50 mL). The
organic layer was dried over sodium sulfate, filtered and concentrated under reduced
pressure. The product was ed by silica gel column chromatography on a 12 gram
silica gel column eluting with a 0-10% EtOAc/hexane gradient. N-(benzenesulfonyl)
[3-[(trans)(trifluoromethyl)cyclopropoxy]pyrazol-l-yl][(4S)-2,2,4-
SUBSTITUTE SHEET (RULE 26)
trimethylpyrrolidin-l-yl]pyridinecarboxamide (115.7 mg, 57%) was obtained. ESI-
MS tn/z calc. 563.1814, found 564.5 (M+l)+; Retention time: 2.01 minutes
Synthetic Example 20: Synthesis of Compound 20: N-(2-
Hydroxyphenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(2-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
°vw,0;s
0 9 o,,o ?H
'OH N'S •%
<^{2 N Cl GDI <,0^J N C,
F3C f3c
A solution of 2-chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (181
mg, 0.5 mmol) and yldiirmdazole (approximately 97.3 mg, 0.60 mmol) in DMF
(2.5 mL) was stirred for 30 minutes. A solution of 2-hydroxybenzenesulfonamide
(approximately 113 mg, 0.65 mmol) and sodium hexamethyldisilazide (approximately
600 pL of 1 M, 0.60 mmol) in DMF (2.5 mL) was stirred for 30 minutes. The two
solutions were combined and stirred for 15 h at room temperature. The reaction mixture
was ied with lOmL 1 M aqueous citric acid, and extracted with 10 mL ethyl
e. The combined extracts were dried over sodium sulfate and concentrated under
reduced pressure. The crude material was purified by silica gel tography eluting
with a 0-5% gradient of methanol in dichloromethane to give 2-chloro-N-(2-
hy droxypheny onyl [3-[ [ 1 -(trifluoromethyl)cy clopropy 1] methoxy] py razol-1 -
yl]pyridinecarboxamide (82 mg, 32%) ESI-MS mlz calc. 516.0, found 517.2 (M+l)
+; ion time: 0.67 minutes.
Step B: N-(2-Hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrroli(lin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
0 00 OH
0 qp OH K2C03
N'S N
" Cl (S
f3c HN
2-Chloro-N-(2-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (82 mg,
0.16 mmol), (4S)-2,2,4-tnmethylpyrrolidine (Hydrochloride salt) (approximately 71 mg,
0.48 mmol), and potassium carbonate (approximately 132 mg, 0.95 mmol) were
combined in DMSO (793 pL) and heated at 130 °C for 15 h. The reaction was filtered
and purified using a e phase S method using a Luna C18 (2) column (75
x 30 mm, 5 pm particle size) sold by Phenomenex (pn: 00CU0-AX), and a dual
gradient run from 30-99% mobile phase B over 15.0 minutes [mobile phase A = H20 (5
mM HCI); mobile phase B = acetonitrile; flow rate = 50 mL/min, and column
ature = 25 °C] to give N-(2-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-tnmethylpyrrolidin-
I -yl |py ridinecarbo\amide (44 mg, 46%) ESI-MS m/z calc. 593.2, found 594.3
(M+l) +; Retention time: 2.07 s.
Synthetic Example 21: Synthesis of Compound 21: N-(3-
Hydroxyphenyl)sulfonyl[3-[[l-(trifluoromethyl)cydopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(3-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cydopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
Qs ,p:s
OH 9 o. ,o
%• OH N'b'
N. GDI N A H I
<LP-ij N Cl N Cl
DBU OH
F3C f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (181 mg, 0.50 mmol) and carbonyl diimidazole
(approximately 97 mg, 0.60 mmol) in DMF (2.5 mL) was d for 30 minutes. 3-
SUBSTITUTE SHEET (RULE 26)
WO 64632
hydroxybenzenesulfonamide (approximately 113 mg, 0.65 mmol) andNaH
(approximately 24.0 mg of 60 %w/w, 0.60 mmol) in DMF (2.5 mL) was stirred for 30
minutes. The two solutions were combined and stirred for 4 h at room temperature. The
reaction mixture was acidified with lOmL 1 M aqueous citric acid, and extracted with
mL ethyl acetate. The combined extracts were dried over sodium sulfate and
concentrated under d pressure. The crude material was purified by silica gel
chromatography eluting with a 0-8% gradient of methanol in dichloromethane to give 2-
chloro-N-(3-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (250 mg,
97%) E SI-MS m/z calc. 516.0482, found 517.2 (M+l) +; ion time: 0,67 minutes.
] Step B: N-(3-Hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 9P 0 00*!'/
N'S K2CO3 N'S
'jLP-iJ N OH OH
f3c (S f3c
2-Chloro-N-(3-hydroxyphenyl)sulfonyl[3-[[l-
(tnfluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyndinecarboxamide (290 mg,
0.56 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (approximately 252
mg, 1.68 mmol), and potassium carbonate (approximately 465 mg, 3.37 mmol) in
DMSO (2.80 mL) was heated at 130 °C for 15 h. The reaction was filtered and purified
using a reverse phase HPLC-MS method using a Luna Cl 8 (2) column (75 x 30 mm, 5
pm particle size) sold by Phenomenex (pn: 00CU0-AX), and a dual gradient run
from 30-99% mobile phase B over 15.0 minutes [mobile phase A = HiO (5 mM HC1);
mobile phase B = acetonitrile; flow rate = 50 mL/min, and column temperature = 25 °C]
to give ydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide (37 mg, 11%) ESI-MS m/z calc. 593. 2, found 594.3
(M+l) +; Retention time: 1.98 minutes.
SUBSTITUTE SHEET (RULE 26)
Synthetic Example 22: Synthesis of Compound 22: N-(4-
Hydroxyphenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
'OH II 0^°:s
'OH N'
Ss GDI <a^0-O H Cl S?
F3C f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (181 mg, 0.50 mmol) and carbonyl diimidazole
(approximately 97 mg, 0.60 mmol) in DMF (2.5 mL) was stirred for 30 minutes. 4-
hydroxybenzenesulfonamide (approximately 113 mg, 0.65 mmol) andNaH
(approximately 24.0 mg of 60 %w/w, 0.60 mmol) in DMF (2.5 mL) was stirred for 30
minutes. The two ons were combined and stirred for 4 h at room temperature. The
reaction mixture was acidified with lOmL 1 M aqueous citric acid, and extracted with
mL ethyl acetate. The combined extracts were dried over sodium sulfate and
concentrated under reduced pressure. The crude material was purified by silica gel
chromatography eluting with a 0-8% gradient of methanol in dichloromethane to give 2-
-N-(4-hydroxyphenyl)sulfonyl[3-[[l-
uoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (210 mg,
81%) ESI-MS m/z calc. 516.0, found 517.2 (M+l) +; Retention time: 0.64 s.
Step B: N-(4-Hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]inethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 9P 0 00
S' K2C03 N'S
H N-^
N Cl ‘OH WMJ N ‘OH
f3c F3C
SUBSTITUTE SHEET (RULE 26)
2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (220 mg,
0.42 mmol), ,2,4-tnmethylpyrrolidine (Hydrochloride salt) (approximately 191
mg, 1.28 mmol), and potassium carbonate (approximately 353 mg, 2.56 mmol) in
DMSO (2.13 mL) was heated at 130 °C for 15 h. The reaction was filtered and ed
using a e phase HPLC-MS method using a Luna Cl 8 (2) column (75 x 30 mm, 5
pm particle size) sold by Phenomenex (pn: 00CU0-AX), and a dual gradient run
from 30-99% mobile phase B over 15.0 minutes [mobile phase A = HiO (5 mM HC1);
mobile phase B = acetonitrile; flow rate = 50 mL/min, and column temperature = 25 °C]
to give N-(4-hydroxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazo l-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide (48 mg, 19%) ESI-MS m/z calc. 593.2, found 594.3
(M+l) +; Retention time: 1.98 minutes.
Synthetic Example 23: Synthesis of Compound 23: N-(o-Tolylsulfonyl)-
6- [3- [ [ l-(trifluoromethyl)cyclopropyl] methoxy] pyrazol- l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: ro-N-(o-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
SO2NH2
0 0 o, 0
N'S ■A-
vs-O'w 'Cl^5 GDI
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (200 mg, 0.5529 mmol) and CDI ximately 107.6
mg, 0.6635 mmol) were combined in THE (960 uL) and stirred at room ature for
2 hours. 2-methylbenzenesulfonamide (approximately 123.1 mg, 0.7188 mmol) was
added followed by DBU (approximately 101.0 mg, 99.21 pL. 0.6635 mmol) and the
reaction was stirred for an additional 16 h at room temperature. AIM citric acid
solution (1 mL) was added and the reaction was stirred for 20 min. The resulting solid
was collected by vacuum filtration (washing with water) and dried under vacuum to
SUBSTITUTE SHEET (RULE 26)
give a white powder, which was used in the next step without further purification. 2-
chloro-N-(o-tolylsulfonyl)[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (280 mg, 98%) ESI-MS m/z calc. 514.1, found 515.1
(M+l)+; Retention time: 0.73 minutes. lH NMR (400 MHz, DMSO) 5 d 13.56 - 12.55
(s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.71
(d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 6.23 (d, J = 2.9 Hz,
1H), 4.39 (s, 2H), 2.64 (s, 3H), 1.12-1.06 (m, 4H).
Step B: N-(o-Tolylsulfonyl) [3- [ [l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 q n 9 Q, .0
:s: HN HCI
%■ N's'
H (S)
K2CO3
f3c f3c
2-Chloro-N-(o-tolylsulfonyl)[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (114.7 mg, 0.2227 mmol), (4S)-2,2,4-trimethylpyrrolidine
(hydrochloride salt) (100 mg, 0.6682) and, K2CO3 (184.6 mg, 1.336 mmol) were
combined in DMSO (0.5 mL) in a screwcap tube and heated to 130 °C for 16 hours.
After cooling to room temperature, the reaction mixture was diluted with 20 mL of ethyl
acetate, and 10 mL water and transferred to a separatory funnel. AN aqueous 15 mL 1
M citric acid was added, and the organic layer was separated. The aqueous layer was
extracted two onal times with 15 mL ethyl acetate, and the combined organics
were washed with bnne, dried over sodium sulfate and concentrated. The resulting
crude material was purified by flash chromatography on silica gel, eluting with a 0-10%
methanol in dichloromethane gradient to give olylsulfonyl)[3-[[l-
uoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrohdinl-yl
inecarboxamide (101 mg, 77%). ESI-MS m/z calc. 591.21, found 592.3
(M+l)+; Retention time: 2.22 minutes, 'h NMR (400 MHz, DMSO) 5 12.74 (s, 1H),
8.38 (t, J = 1.7 Hz, 1H), 8.33 - 8.22 (m, 2H), 8.21 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 7.9
Hz, 1H), 7.89 - 7.85 (m, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.41 -
4.31 (m, 2H), 3.36 - 3.29 (m, 3H), 2.40 (t, J = 10.4 Hz, 1H), 2.27 (t, J = 8.6 Hz, 1H),
SUBSTITUTE SHEET (RULE 26)
WO 64632
2.11 (tt,J = 12.1, 6.3 Hz, 1H), .81 (m, 1H), 1.53 (d, J = 9.8Hz, 6H), 1.39(1, J =
12.1 Hz, 1H), 1.09 (dt, J = 6.7, 2.2 Hz, 4H), 0.68 (d, J = 6.2 Hz, 3H).
Synthetic Example 24: Synthesis of Compound 24: N-(p-Tolylsulfonyl)-
6- [3- [ [ l-(trifluoromethyl)cyclopropyl] methoxy] pyrazol-l-yl] [(4S)-2,2,4-
trimethylpyrroMin-l-ylJpyridinecarboxamide
Step A: 2-Chloro-N-(p-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
SO2NH2
o IhrCfrA V 'OH GDI XX
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (200 mg, 0.5529 mmol) and CDI (approximately 107.6
mg, 0.6635 mmol) were combined in THE (1.200 mL) and stirred at room temperature
for 2 hours. 4-methylbenzenesulfonamide (approximately 123.1 mg, 0.7188 mmol) was
added followed by DBU ximately 101.0 mg, 99.21 pL, 0.6635 mmol) and the
reaction was stirred for an additional 16 h at room temperature. The reaction mixture
was diluted with 1M aqueous citric acid and water, then extracted 3x 20 mL ethyl
acetate. The combined organics were w ashed with 10 mL 1M citric acid, followed by
brine, dried over sodium sulfate and concentrated, then purified by silica gel
chromatography, eluting with 0-10% methanol/dichloromethane to give 2-chloro-N-(ptolylsulfonyl
)[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine
carboxamide (262 mg, 92%) ESI-MS m/z calc. 514.0689, found 515.1 ;
ion time: 0.74 minutes.
Step B: N-(p-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]inethoxy]pyrazol-l-yl][(4S)-2,2,4-
hylpyrrolidin-l-yl]pyridinecarboxamide
9 V 9 Qp
N'b' HN HCI N's
yj-O N ‘Cl
f3c k2co3 3C '
SUBSTITUTE SHEET (RULE 26)
2-chloro-N-(p-Tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (114.7 mg,
0.2227), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (100 mg, 0.6682) and,
K2CO3 (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 mL) in a screwcap tube
and heated to 130 °C for 16 hours. After cooling to room ature, the reaction
mixture was diluted with 20 mL of ethyl acetate, and 10 mL water and erred to a
separatory funnel. An aqueous 15 mL 1 M citric acid was added, and the organic layer
was ted. The aqueous layer was extracted two additional times with 15 mL ethyl
acetate, and the ed organics were washed with brine, dried over sodium sulfate
and concentrated. The resulting crude al was purified by flash chromatography
on silica gel, eluting with a 0-10% methanol in dichloromethane gradient to give N-(p-
tolylsulfonyl)[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (65 mg, 49%). ESI-MS m/z
calc. 591.21, found 592.3 (M+l)+; Retention time: 2.25 minutes, 'h NMR (400 MHz,
DMSO) 5 12.74 (s, 1H), 8.38 (t, J = 1.7 Hz, 1H), 8.33 - 8.22 (m, 2H), 8.21 (d, J = 2.8
Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.89 - 7.85 (m, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.15 (d,
J = 2.7 Hz, 1H), 4.41 - 4.31 (m, 2H), 3.36 - 3.29 (m, 3H), 2.40 (t, J = 10.4 Hz, 1H),
2.27 (t, J = 8.6 Hz, 1H), 2.11 (tt, J = 12.1, 6.3 Hz, 1H), 1.88 - 1.81 (m, 1H), 1.53 (d, J =
9.8 Hz, 6H), 1.39 (t, J = 12.1 Hz, 1H), 1.09 (dt, J = 6.7, 2.2 Hz, 4H), 0.68 (d, J = 6.2 Hz,
Synthetic Example 25: Synthesis of Compound 25: N-(3-
Cyanophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(3-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
NCv^S02NH2U
O 9 °,,o
N''5' .CN
o^Hr-N-'c, N Cl
SUBSTITUTE SHEET (RULE 26)
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (200 mg, 0.5529 mmol) and CDI (approximately 107.6
mg, 0.6635 mmol) were combined in THF (1.200 mL) and d at room temperature
for 2 hours. 3-cyanobenzenesulfonamide (approximately 131.0 mg, 0.7188 mmol) was
added followed by DBU (approximately 101.0 mg, 99.21 pL. 0.6635 mmol) and the
reaction was d for an additional 16 h at room temperature. The reaction mixture
was diluted with 1M aqueous citric acid and water, and extracted 3x 20 mL ethyl
acetate. The combined organics were washed with 10 mL 1M citric acid, followed by
brine, then dried over sodium e and concentrated and used in the next step without
further purification. 2-chloro-N-(3-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (228 mg,
78%) ESI-MS m/z calc. 525.0485, found 526.0 (M+l)+; Retention time: 0.7 minutes.
Step B: N-(3-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
HCI ifVV’Y'YCN
F3c K2CO3
ro-N-(3-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (117.1 mg,
0.2227), (4S)-2,2,4-tnmethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and,
K2CO3 (184.6 mg, 1.336 mmol) were ed in DMSO (0.5 mL) in a screwcap tube
and heated to 130 °C for 16 hours. After cooling to room ature, the reaction
mixture was diluted with 20 mL ethyl acetate, and 10 mL water and transferred to a
separatory funnel. An aqueous 15 mL 1 M citric acid was added, and the organic layer
was separated. The aqueous layer was extracted two additional times with 15 mL ethyl
acetate, and the combined organics were washed with brine, dried over sodium sulfate
and trated. The resulting crude material was purified by flash tography
on silica gel, eluting with a 0-10% methanol in dichloromethane gradient to give N-(3-
cyanophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide, (73 mg, 54%) ESI-MS
m/z calc. 602.19, found 603.3 (M+l)+; Retention time: 2.04 minutes, 'll NMR (400
MHz, DMSO) 6 12.74 (s, 1H), 8.38 (t, J = 1.7 Hz, 1H), 8.30 (ddd, J = 8.1,1.9, 1.1 Hz,
SUBSTITUTE SHEET (RULE 26)
1H), 8.24 (dt, J = 7.8, 1.3 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.92 - 7.84 (m, 2H), 6.93 (d,
J = 8.3 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.42 - 4.31 (m, 2H), 2.40 (t, J = 10.4 Hz, 1H),
2.27 (t, J = 8.6 Hz, 1H), 2.11 (tt, J = 12.1, 6.3 Hz, 1H), 1.89 - 1.78 (m, 1H), 1.53 (d,J =
9.8 Hz, 6H), 1.39 (t, J = 12.1 Hz, 1H), 1.09 (dt, J = 6.7, 2.2 Hz, 4H), 0.68 (d, J = 6.2 Hz,
Synthetic Example 26: Synthesis of Compound 26: N-(2-
Cyanophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: ro-N-(2-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
S02NH2
o q q cn
GDI I
Vv°<JN N Cl
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyndinecarboxylic acid (200 mg, 0.5529 mmol) and CDI (approximately 107.6
mg, 0.6635 mmol) were combined in THE (1.200 mL) and stirred at room temperature
for 2 hours. 2-Cyanobenzenesulfonamide (approximately 131.0 mg, 0.7188 mmol) was
added followed by DBU (approximately 101.0 mg, 99.21 pL, 0.6635 mmol) and the
reaction was d for an additional 16 h at room ature. AIM citric acid
solution (1 mL) was added and the reaction was stirred for 20 minutes. The resulting
solid precipitate was collected by vacuum filtration (washing with water) to give a white
solid, which was dried on under vacuum and used in the next step without further
cation, 2-chloro-N-(2-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (279 mg,
96%) ESI-MS m/z calc. 525.0485, found 526.1 (M+l)+; Retention time: 0.69
minutes. 1H NMR (400 MHz, DMSO) 8 12.23 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.46 -
8.39 (m, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.21 - 8.13 (m, 1H), 7.96 - 7.90 (m, 2H), 7.82 (d,
J = 8.3 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H), 4.42 (s, 2H), 1.11 (dt, J = 7.6, 2.2 Hz, 4H).
SUBSTITUTE SHEET (RULE 26)
Step B: N-(2-Cyanophenyl)sulfonyl[3-[[l-
(trifliioromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
0 q ,o CN 0 q o cn
N:s' HN HCI s:
tS) N'
N Cl ys® N'^
f3c k2co3
2-Chloro-N-(2-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (117.1 mg,
0.2227), (4S)-2,2,4-tnmethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and,
K2CO3 (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 mL) in a screwcap tube
and heated to 130 °C for 16 hours. After g to room temperature, the reaction
mixture was diluted with 20 mL ethyl acetate, and 10 mL water and transferred to a
separatory funnel. An s 15 mL 1 M citric acid solution was added, and the
organic layer was separated. The aqueous layer was ted two additional times with
mL ethyl acetate, and the combined cs were washed with brine, dried over
sodium sulfate and concentrated. The ing crude material was purified by flash
chromatography on silica gel, eluting with a 0-10% methanol in dichloromethane
gradient to give. yanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide, (41 mg, 31%) ESI-MS m/z calc. 602.19, found 603.2
(M+l)+; Retention time: 2.12 minutes. 1HNMR (400 MHz, DMSO) 5 11.77 (s, 1H),
8.47 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.17-8.11 (m, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.94
- 7.87 (m, 2H), 6.97 (d, J = 8.3 Hz, 1H), 6.20 (d, J = 2.8 Hz, 1H), 4.44 - 4.32 (m, 2H),
3.07 - 2.91 (m, 2H), 2.32 (d, J = 19 0 Hz, 1H), 1.98 (q, J = 5.9, 5.5 Hz, 1H), 1.67 (s,
3H), 1.63 (s, 3H), 1.57 (t, J = 10.4 Hz, 1H), 1.13 - 1.06 (m, 4H), 1.02 (d, J = 6.3 Hz,
Synthetic Example 27: Synthesis of Compound 27: N-(4-
Cyanophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(4-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
jaSO2NH2 0
NC x v
'OH GDI
0 /,N'N"k|/kCI Y-P^N'N
iX-xxCN
f3c f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0 4147 mmol) and CDI (81 mg, 0.4995 mmol)
were combined in THF (900.0 pL) and stirred at room temperature for 2 hours. 4-
cyanobenzenesulfonamide (98 mg, 0.5379 mmol) was added followed by DBU (75 pL,
0.5015 mmol) and the reaction was stirred at room temperature for 2 hours. Additional
DBU (80 pL, 0.5350 mmol) was added, and the reaction was stirred for one additional
hour at room temperature. The reaction mixture was diluted with 20 mL of a 1M citric
acid solution and water and ted 3x 20 mL ethyl acetate. The combined organics
were washed with 10 mL 1M citric acid, followed by brine, then dried over sodium
sulfate and concentrated. The resulting material was further punfied by silica gel
chromatography g with a 0-10% gradient of methanol in dichloromethane, to give
a white solid; 2-chloro-N-(4-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyndinecarboxamide (192 mg,
88%) ESI-MS m/z calc. 525.0485, found 526.0 (M+l)+; Retention time: 0.71 s.
Step B: N-(4-Cyanophenyl)sulfonyl[3-[[l-
uoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
hylpyrrolidin-l-yl]pyridinecarboxamide
N CN
f3c K2CO3 f3c
] 2-Chloro-N-(4-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (117.1 mg,
0.2227), (4S)-2,2,4-tnmethylpyrrolidine (hydrochloride salt) (100 mg, ) and,
K2CO3 (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 mL) in a screwcap tube
and heated to 130 °C for 16 hours. After cooling to room temperature, the reaction
mixture was diluted with 20 mL ethyl acetate, and 10 mL water and transferred to a
separatory funnel. An aqueous 15 mL 1 M citric acid solution was added, and the
SUBSTITUTE SHEET (RULE 26)
WO 64632
organic layer was separated. The aqueous layer was ted two additional times with
mL ethyl acetate, and the ed organics were washed with brine, dried over
sodium sulfate and concentrated. The resulting crude material was purified by flash
chromatography on silica gel, eluting with a 0-10% methanol in dichloromethane
gradient to giveN-(4-cyanophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide, (62 mg, 46%) ESI-MS m/z calc. 602.19, found 603.3
(M+l)+; Retention time: 2.04 minutes. 'H NMR (400 MHz, DMSO) 5 12.77 (s, 1H),
8.20 (d, J = 2.8 Hz, 1H), 8.16 (s, 4H), 7.87 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H),
6.15 (d, J = 2.7 Hz, 1H), 4.50 - 4.17 (m, 2H), 2.33 (t, J = 10.3 Hz, 1H), 2.20 (dd, J =
.2, 6.9 Hz, 1H), 2.11 (tt, J= 11.9, 6.4 Hz, 1H), 1.83 (dd, J = 11.8, 5.4 Hz, 1H), 1.52
(d, J = 5.6 Hz, 6H), 1.37 (t,J = 12.1 Hz, 1H), 1.13-1.05 (m, 4H), 0.66 (d, J = 6.2Hz,
tic Example 28: Synthesis of Compound 28: N-(m-Tolylsulfonyl)-
6- [3- [ [ l-(trifluoromethyl)cydopropyl] methoxy] pyrazol-l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
] Step A: 2-Chloro-N-(m-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
SO2NH2
0 9 <U>xc
’OH GDI O rTNC|H
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (200 mg, 0.5529 mmol) and CDI (approximately 107 6
mg, 0.6635 mmol) were combined in THE (964.9 pL) and stirred at room temperature
for 2 hours. 3-methylbenzenesulfonamide (approximately 123.1 mg, 0.7188 mmol) was
added followed by DBU (approximately 101.0 mg, 99.21 pL, 0.6635 mmol) and the
reaction was stirred for an additional 16 h at room temperature. The reaction mixture
was diluted with a 1M aqueous citric acid solution and water, and extracted 3x 20 mL
ethyl acetate. The combined cs were washed with 10 mL 1M citric acid, followed
by brine, dried over sodium sulfate, concentrated, and finally purified by silica gel
chromatography eluting with 0-10% methanol/dichloromethane to give a white solid, 2-
SUBSTITUTE SHEET (RULE 26)
chloro-N-(m-tolylsulfonyl)[3-[[l-(trifluoromethyl)cyclopropyl]rnethoxy]pyrazol-lyl
]pyridinecarboxamide (178 mg, 63%) ESI-MS m/z calc. 514.0689, found 515.1
(M+l)+; Retention time: 0.74 minutes
Step B: N-(m-Tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 QwO 9 QwO:s:
N'S HN- HCI N'
-NJ-JviH (S)
N Cl "XP
f3c K2CO3 F3C '
2-Chloro-N-(m-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (114.7
mg, 0.2227 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg,
0,6682) and, K2CO3 (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 mL) in a
screwcap tube and heated to 130 °C for 16 hours. After cooling to room temperature,
the reaction mixture was diluted with 20 mL ethyl acetate, and 10 mL water and
transferred to a separator}7 funnel. An s 15 mL 1 M citric acid on was
added, and the organic layer was separated. The aqueous layer was extracted two
additional times with 15 mL ethyl acetate, and the combined organics were washed with
brme, dried over sodium sulfate and concentrated. The resulting crude material was
ed by flash chromatography on silica gel, eluting with a 0-10% methanol in
dichloromethane gradient to give N-(m-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide, (45 mg, 34%) ESI-MS m/z calc. 591.2, found 592.2
(M+l)+; Retention time: 2.24 minutes. 'H NMR (400 MHz, DMSO) 5 12.41 (s, 1H),
8.20 (d, J = 2.8 Hz, 1H), 7.79 (tt, J = 6.0, 2.5 Hz, 3H), 7.57 - 7.50 (m, 2H), 6.91 (d, J =
8.2 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.48 - 4.24 (m, 2H), 2.46 (s, 1H), 2.42 (s, 3H),
2.29 (t, J = 8.8 Hz, 1H), 2.11 (dt, J = 13.2, 6.5 Hz, 1H), 1.83 (dd, J = 11.8, 5.5 Hz, 1H),
1.53 (d, J = 12.0 Hz, 6H), 1.38 (t, J = 12.1 Hz, 1H), 1.09 (dd, J = 4.5, 3.2 Hz, 4H), 0.66
(d, J = 6.2 Hz, 3H).
SUBSTITUTE SHEET (RULE 26)
Synthetic Example 29: Synthesis of Compound 29: Synthesis ofN-
(Benzenesulfonyl)[3-[(l-methylcyclopropoxy)methyl]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: (l-Methyl-l-(propyn-l-yloxy)cyclopropane
^-OH + 0
1-Methylcyclopropan-l-ol (1.0 g, 13.9 mmol) was dissolved in Et20 (50 mL)
and cooled to 0°C. NaH (50% in oil, 0.67 g, 13.9 mmol) was added portion wise. The
mixture was stirred for 10 min at 0 °C before propargyl bromide (80% in e, 3.1 g,
.9 mmol) was added dropwise. The mixture was stirred for 1 hour at 0 °C. Since the
reaction did not proceed, DMF (20 mL) was added. The mixture was stirred for an
additional hour at 0° and quenched with sat. aq. NH4CI. The mixture was extracted with
Et20 (2x50 mL). The combined c layers were washed with water twice and brine,
dried over NajSCh and concentrated (at 40°C, 500 mbar) to afford crude (1-methyl-l-
(propyn-l-yloxy)cyclopropane which was used as such in the next step, 'id NMR
(CDCI3, 300 MHz): d 0.39 (m, 2H); 0.85 (m, 2H); 1.40 (s, 3H); 2.37 (s, 1H); 4.10 (s,
] Step B: 3-((l-methylcyclopropoxy)methyl)-lH-pyrazole
TMS n2
Crude (l-methyl-l-(propyn-l-yloxy)cyclopropane from several batches
(max 27.8 mmol, 3.0 g) was mixed with trimethylsilyl diazomethane (2.0 M in hexane,
mL, 20 mmol) and stirred in a sealed tube at 115 °C for 18 hours. The mixture was
cooled to 40 °C and ed with MeOH (20 mL) and concentrated. Column
chromatography a; heptanes/EtOAc 2:1) gave 3-((l-methylcyclopropoxy)methyl)-
IH-pyrazole as colorless oil (1.2 g, 28% over two steps). XHNMR (CDC13, 300 MHz):
d 0.44 (m, 2H); 0.85 (m, 2H); 1.44 (s, 3H); 4.60 (s, 2H); 6.23 (s, 1H); 7.51 (s, 1H). 13C-
NMR (75 MHz, CDC13): d 13.4, 20.3, 58.4, 61.9, 103.9,132.9 (one quatemaiy carbon
not shown).
] Step C: N-(Benzenesulfonyl)[3-[(l-
methylcyclopropoxy)methyl] pyrazol- l-yl] 2,2,4-trimethylpyrrolidin
yl]pyridmecarboxamide
SUBSTITUTE SHEET (RULE 26)
0 0 0
Sc(OTf)3 9 9wp
% N'S
NaH N'S
,N'NH + H
or n H
o N N'N^N^N^S)
(S) 0
N-(Benzenesulfonyl)chloro[(4S)-2,2,4-trimethylpyrrolidin-l-
yl]pyridinecarboxamide (83 mg, 0.2035 mmol), 3-[(l-methylcyclopropoxy)methyl]-
IH-pyrazole (62 mg, 0.4074 mmol), and scandium triflate (10 mg, 0.02032 mmol) were
combined in DMSO (1.660 mL). NaH (41 mg of 60 %w/w, 1.025 mmol) was added and
the reaction was stirred for 15 minutes before it was sealed and heated to 160 °C for 16
h. The reaction was cooled and partitioned between ethyl acetate and a 1 M citric acid
solution. The organics were separated, washed with brine, and dried over sodium
sulfate. The organics were then evaporated under reduced re, and the crude
material was purified by preparative HPLC (1-99 CH3CN in water with 5 mM HC1),
over 30 minutes. Fractions ning product were diluted with water and extracted
with ethyl acetate to give, upon concentration N-(benzenesulfonyl)[3-[(lmethylcyclopropoxy
)methyl]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide (10 mg, 9%) ESI-MS m/z calc. 523.22534, found 524.2
(M+l)+; Retention time: 2.04 s.
Synthetic Example 30: Synthesis of Compound 30: N-
(Benzenesulfonyl)[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin- 1-yl] pyridinecarboxamide
Step A: N-(Benzenesulfonyl)chloro[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide
.so2nh2 9 CLP
O N'S
OH H
GDI P^N 'Cl
O^N NT XI✓5
2-Chloro[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-
yl]pyridinecarboxylic 00 mg, 0.5717 mmol) and CDI (111 mg, 0.6846 mmol)
were ed in THF (1.2 mL) and stirred at room temperature for 2 hours.
Benzenesulfonamide (117 mg, 0.7443 mmol) was added followed by DBU (102 pL
SUBSTITUTE SHEET (RULE 26)
0.6821 mmol) and the reaction was stirred for an additional 6 h at room temperature.
The reaction mixture was diluted with a 1M citric acid on and water, and extracted
3 x 20 mL ethyl acetate. The combined organics were washed with brine, dried over
sodium e and concentrated, then purified by silica gel chromatography using a
gradient of 0-10% methanol in dichloromethane to give a white powder. N-
(Benzenesulfonyl)chloro [3 - [(2,2,3,3-tetramethy Icy pyl)methoxy] pyrazol-1 -
yl]pyridinecarboxamide (250 mg, 89%) ESI-MS m/z calc. 488.1285, found 489.2
; Retention time: 0.81 minutes.
Step B: N-(Benzenesulfonyl)[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrroli(lin-lyl
]pyridinecarboxainide
? CLP II CLP
N''3'- HM HCI N'S
H I H
p^N N^CI (S) p~0 n
K2CO3
N-(Benzenesulfonyl)chloro[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (115 mg, 0.2352
mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (approximately 105.9 mg,
0.7077 mmol), and potassium carbonate (approximately 195.6 mg, 1.415 mmol) were
combined in DMSO (575.0 pL) and heated at 130 °C for 16 h. The reaction was cooled
to room ature, diluted with 15 mL water, 15 mL 1M citric acid, and 30 mL ethyl
acetate. The aqueous and the organic layers were separated, and the aqueous layer was
extracted two additional times with 30 mL ethyl acetate, the organics were combined,
washed with brine, dried over sodium sulfate and trated. The resulting solid was
purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane,
and then additionally purified by silica chromatography using 0-100% ethyl e in
dichloromethane, to give N-(benzenesulfonyl)[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidm-lyl
]pyridinecarboxamide (43 mg, 32%) ESI-MS m/z calc. 565.2723, found 566.3
(M+l)+; Retention time: 2.43 minutes. 'H NMR (400 MHz, DMSO) 5 12.47 (s, 1H),
8.18 (d, J = 2.8 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.76 - 7.69 (m,
1H), 7.68 - 7.62 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.13 (d, J = 2.7 Hz, 1H), 4.24 (d, J =
SUBSTITUTE SHEET (RULE 26)
7.7 Hz, 2H), 2.42 (t, J = 10.5 Hz, 1H), 2.28 (dd, J = 10.2, 7.1 Hz, 1H), 2.17 - 2.03 (m,
1H), 1.82 (dd, J = 11.8, 5.5 Hz, 1H), 1.52 (d, J = 9.4 Hz, 6H), 1.36 (t, J = 12.1 Hz, 1H),
1.10 (s, 6H), 1.04 (s, 6H), 0.73 (t, J = 7.7 Hz, 1H), 0.65 (d, J = 6.2 Hz, 3H).
Synthetic e 31: Synthesis of Compound 31: N N-(4-
Hydroxyphenyl)sulfonyl[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
so2nh2
o 9 Qw,o
'OH iPd N*sT^s>l
GDI ,N'N^r\rx:iH
Cl p-O1
2-Chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (100 mg, 0.2661 mmol) and CDI (approximately 51.38
mg, 0.3169 mmol) were combined in THE (600.0 pL) and stirred at room temperature
for 2 hours. 4-Hydroxybenzenesulfonamide (approximately 50.69 mg, 0.2927 mmol)
was added followed by DBU (approximately 53.45 pL, 0.3574 mmol) and the reaction
was d for an additional 16 h at room temperature. The reaction mixture was
diluted with 10 mL 1M citric acid, and extracted 3 times with 10 mL of ethyl acetate.
The ed organics were washed with brine, dried over sodium sulfate, and
concentrated to give a white solid, which was used in the next step without r
purification. 2-chloro-N-(4-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (128 mg,
91%) ESI-MS m/z calc. 530.06384, found 531.0 (M+l)+; ion time: 0.69 minutes.
Step B: N-(4-Hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
HCI x V
ivCtVO.
'0hCj n OH
K2CO3
cf3 cf3
2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl]pyridinecarboxamide (134 mg,
0.2524 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (113 mg, 0.7550
mmol), and potassium carbonate (210 mg, 1.519 mmol) were combined in dimethyl
sulfoxide (670.0 pL) and heated at 130 °C for 16 h. The reaction was cooled to room
ature, and 1 mL of water was added. After 15 minutes stirring, the contents of
the vial were allowed to settle, the liquid portion was removed by pipet and the
remaining solids were dissolved with 20 mL ethyl acetate. The organics were washed
with 15 mL 1M citric acid. The aqueous and the organic layers were ted, and the
aqueous layer was extracted two additional times with 15 mL ethyl acetate. The
organics were combined, washed with brine, dried over sodium e and
concentrated. The resulting crude solid was purified by silica gel chromatography
eluting with 0-10% methanol in dichloromethane to give N-(4-hydroxyphenyl)sulfonyl-
6-[3-[2-[l-(tnfluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (43 mg, 28%) ESI-MS m/z calc.
607.20764, found 608.2 ; Retention time: 2.07 s, 'h NMR (400 MHz,
DMSO) 5 12.25 (s, 1H), 10.58 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.87 - 7.79 (m, 2H),
7.75 (d, J = 8.2 Hz, 1H), 6.97 - 6.91 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.10 (d, J = 2.7
Hz, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.44 (t, J = 10.4 Hz, 1H), 2.16 - 2.09 (m, 1H), 2.26 (t,
J = 8.8 Hz, 1H), 2.07 (t, J = 7.0 Hz, 2H), 1.82 (dd, J = 11.9, 5.5 Hz, 1H), 1.54 (s, 3H),
1.51 (s, 3H), 1.38 (t, J = 12.1 Hz, 1H), 1.00 - 0.93 (m, 2H), 0.91 - 0.86 (m, 2H), 0.69
(d, J = 6.2 Hz, 3H).
Synthetic Example 32: Synthesis of Compound 32: Ar-(Benzenesulfonyl)-
6- [5-fluoro [2- [ l-(trifluoromethyl)cyclopropyl] ethoxy] pyrazol- 1-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-ylJpyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
0 P,P NaH 9 QwP K2CO3 9 9wP
'OH + h2N :s N'S
GDI H
cr n ci CI^N^CI cr n N
Sc(OTf)3 9 PP
p^NH F3c —K
Step A: nzenesulfonyl)-2,6-dichloro-pyridinecarboxamide
0. o P 0. 0
\y/ NaH \V/
OH + H2N
GDI H
cr n ci cr n ci
A 5000 mL, 3 neck round bottom flask was fitted with a mechanical stirrer, a
cooling bath, a J-Kem temperature probe/controller, a water cooled reflux condenser, an
addition funnel and a nitrogen inlet/outlet. The vessel was charged under a nitrogen
atmosphere with 60 wt% sodium e in mineral oil (26.04 g, 0.6510 mol). The
vessel was then slowly charged with N,N-dimethylformamide (200 mL). Stirring was
commenced and the pot temperature was recorded at 19 °C. The addition funnel was
then charged with a solution of benzenesulfonamide (102.3 g, 0.6510 mol) in N,N-
dimethylformarmde (868 ml, ~8.5 mL/g, 0.75M), requmng some gentle g to get a
homogenous solution. The resulting clear pale yellow solution of benzenesulfonamide
was subsequently added dropwise over 1 hour to the round bottom flask which resulted
in some slight foaming and gas evolution. After the completed addition, the pot
temperature was recorded at 28 °C. The vessel was then fitted with a heating mantle and
the greyish mixture was warmed to 60 °C. Stirring of the mixture was continued at 60
°C for 1 hour at which point gas evolution appeared to have ceased. Stirring of the
e was ued while the mixture was allowed to cool to room temperature.
Meanwhile, a 1000 mL, 3 neck round bottom flask was fitted with a mechanical stirrer,
a heating mantle, a J-Kem ature probe/controller, a water cooled reflux condenser
and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with
SUBSTITUTE SHEET (RULE 26)
2,6-dichloropyridinecarboxylic acid (100 g, 0.5208 mol) andN,N-
dimethylformamide (500 mL: 5 ml/g) which provided a clear light yellow on.
Stirring was commenced and the pot ature was recorded at 17 °C. The vessel was
then charged with carbonyl diimidazole (84.45 g, 0.5208 mol) added as a solid in
portions over 10 minutes which resulted in slight foaming and gas evolution, no
exotherm was observed. Stirring of the resulting clear light amber solution was
continued at room ature for 1 hour. The flask which contained the previously
formed benzenesulfonamide sodium salt inN,N-dimethylformamide was treated
dropwise over 45 minutes with the clear amber solution chloropyridinyl)(lH-
imidazol-l-yl)methanone intermediate. After the completed addition, the vessel was
fitted with a heating mantle and the mixture was warmed to 60 C'C and the condition was
maintained for 1 hour when analysis by LC/MS indicated complete consumption of the
intermediate. The reaction was allowed to cool to room temperature and then poured
into ice cold 6M HC1 on (500 mL). The resulting mixture was further diluted with
water (500 mL) and then transferred to a separatory funnel and partitioned with ethyl
acetate (1000 mL). The organic layer was removed and the residual aqueous was
extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed
with ted sodium chloride on (3 x 500 mL), dried over sodium sulfate (300 g)
and then ed through a glass frit r funnel. The clear pale yellow solution was
trated under reduced pressure to a volume of about 200 mL. The clear residual
oil was diluted with methyl tert-butyl ether (1000 mL) and then concentrated again
under reduced pressure during which time a solid began to precipitate. The volume w as
reduced to about 200 mL. The resulting slurry was allowed to stand at room temperature
for 30 minutes and then filtered through a glass frit Buchner funnel. The filter cake was
displacement washed methyl tert-butyl ether (2 x 150 mL) and then pulled in the
Buchner funnel for 30 minutes. The al was further dried in a vacuum oven at
45°C for 2 hours to provide a white solid (101 g, 0.305 mol, 58% yield) as the desired
product, N-(benzenesulfonyl)-2,6-dichloro-pyridinecarboxamide. ESI-MS m/z calc.
329.96326, found 330.9 (M+l)+; Retention time: 1.22 minutes.
Step B: A-(benzenesulfonyl)chloro[(4A)-2,2,4-trimethylpyrrolidin-
1-yl] pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
Q o. o k2co3 Q o. o
\V/ \V/
N'S N'S
H H
cr n ci HN (S) cr N N (S)
A 5000 mL 3 neck RB flask was fitted with a mechanical stirrer, a heating
, a J-Kem temperature probe/controller, a water cooled reflux condenser and a
en inlet/outlet. The vessel was charged under a nitrogen atmosphere with N-
(benzenesulfonyl)-2,6-dichloro-pyridinecarboxamide (100 g, 0.3020 mol), (4S)-
2,2,4-trimethylpyrrolidine hydrochloride (54.24 g, 0.3624 mol) and dimethyl sulfoxide
(500 ml, 5 mL/g) which provided a clear pale yellow solution. Stirnng was commenced
and the pot temperature was recorded at 19 °C. The vessel was then charged with
ium carbonate powder (167 g, 1.208 mol, 325 mesh) added as a solid in portions
over 10 s which resulted in some minor gas evolution and foaming. The resulting
off-white suspension was stirred at room temperature for 10 minutes and then heated to
a pot ature of 115 °C and the condition was maintained for 24 hours. Analysis by
LC/MS indicated reaction completion and the amber suspension was allowed to cool to
room temperature. A 5000 mL 3 neck RB flask was fitted with a mechanical stirrer, a
cooling bath and a J-Kem temperature probe. The vessel was charged with 2M HCI
(1057 ml, 2.114 mol) and stirring was commenced at a us rate. The cooling bath
was charged with crushed ter and the pot temperature was lowered to 0°C. The
amber suspension reaction mixture was subsequently added slowly in portions over 30
minutes which resulted in the precipitation of a solid and an exotherm to 8 °C Note:
Mild foaming upon addition. After the completed addition the resulting suspension was
continued to stir at ~5 °C for 1 hour and then collected by vacuum filtration in a glass
frit Buchner funnel. The filter cake was displacement washed with water (4 x 500 mL)
and then pulled for 2 hours in the Buchner funnel to provide a white solid (150 g). A
5000 mL 3 neck RB flask was fitted with a mechanical stirrer, a g mantle, a JKem
temperature controller, a water cooled reflux condenser and a en
inlet/outlet. The vessel was charged under a nitrogen atmosphere with the isolated
product (150g) and 2-propanol (1050 ml, 7 ml/g) which provided a pale yellow
suspension. Stirring was commenced and the pot temperature was recorded at 19 °C.
The pot temperature was increased to reflux (~82 °C) and the condition was maintained
SUBSTITUTE SHEET (RULE 26)
for 10 minutes which resulted in a clear pale amber solution. Stirring of the solution was
continued and the solution was allowed to slowly cool to room temperature during
which time a solid began to form. ng of the suspension was continued and the
vessel was fitted with a cooling bath which was charged with crushed ice/water. The pot
temperature was d to 0 °C and stirring of the thick suspension continued at 0 °C
for 1 hour. The material was collected by vacuum filtration in a glass frit Buchner
funnel and the filter cake was displacement washed with ice cold 2-propanol (2 x 50
mL) and then pulled in the r for 30 minutes. The material was further dried in a
vacuum oven at 45 °C for 15 hours to e a white solid (100 g, 0.245 mol, 81%
yield) as the product, N-(benzenesulfonyl)chloro[(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide as 2-propanol solvate with 11 wt% anol. ESI-MS m/z
calc. 703, found 408.1 (M+l)+; Retention time: 1.9 minutes.
Step C: 5-Fluoro[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-
pyrazole
N-mu ^'NH
F3C f3c F
A solution of 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole
(0.68 g, 3.088 mmol) and l-(chloromethyl)fluoro-l,4-
diazoniabicyclo[2.2.2]octane;ditetrafluoroborate (1.3 g, 3.7 mmol) in acetonitrile (15
mL) was stirred at 50 °C for 17 hours. The reaction was diluted with water and
extracted with ethyl acetate. The combined extracts were washed with water, dried over
sodium sulfate, and evaporated. The residue was purified by silica gel column
chromatography eluting with a 0-30% ethyl acetate in hexanes gradient to give the still
impure t as a brown oil which was further punfied using a reverse phase HPLCMS
method using a Luna Cl 8 (2) column (75 x 30 mm, 5 pm particle size) sold by
Phenomenex (pn: 00CU0-AX), and a dual gradient run from 1-99% mobile phase
B over 15.0 minutes (Mobile phase A = LEO (5 mM HC1). Mobile phase B = CEECN.
Flow rate = 50 mL/min, and column temperature = 25°C) giving 5-fluoro[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (90 mg) as a tan oil. ESI-MS m/z
calc. 238.07292, found 239.1 (M+l)+; ion time: 0.56 minutes, 'hi NMR (400
SUBSTITUTE SHEET (RULE 26)
MHz, DMSO-d6) 5 7.70 (d, J = 4.5 Hz, 1H), 4.30 - 4.16 (m, 2H), 2.04 (t, J = 7.1 Hz,
2H), 0.97 - 0.91 (m, 2H), 0.88 - 0.81 (m, 2H).
] Step D: 7V-(benzenesulfonyl) [5-fluoro [2- [1-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidiii-l-yl]pyridinecarboxamide
XOCo o 0 AQsP
g- Sc(OTf)3 -C&Q
F3C- 0~<'
A mixture of 5-fluoro[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-
pyrazole (87 mg, 0.3653 mmol), A,-(benzenesulfonyl)chloro|(45')-2.2.4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (79 mg, 0.19 mmol), scandium triflate
(10 mg, 0.020 mmol) and sodium hydride (38 mg of 60 %w/w, 0.95 mmol) in DMSO
(0.92 mL) was stirred at 160 °C for 15 hours. The reaction was filtered and purified
using a e phase HPLC-MS method using a Luna Cl 8 (2) column (75 x 30 mm, 5
pm le size) sold by Phenomenex (pn: 00CU0-AX), and a dual gradient run
from 50-99% mobile phase B over 15.0 minutes (Mobile phase A = H20 (5 mM HC1).
Mobile phase B = CH3CN. Flow rate = 50 mL/min, and column temperature = 25 °C)
giving /V-(benzenesuironyl)|5-fluoro|2-| 1-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl] [(4S)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxamide (11 mg, 10%). ESI-MS m/z calc. 609.2033, found 610.3
(M+l)+; Retention time: 2.3 minutes. 'H NMR (400 MHz, DMSO-d6) 5 12.53 (s, 1H),
8.26 (d, J = 4.5 Hz, 1H), 8.00 (t, J = 1.3 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.82 (d, J =
8.3 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.66 (dd, J = 8.2, 6.7 Hz, 2H), 6.90 (d, J = 8.3 Hz,
1H), 4.41 (s, 2H), 2.38 (d, J= 10.5 Hz, 1H), 2.29 - 2.21 (m, 1H), 2.10 (q, J = 7.0 Hz,
3H), 1.82 (dd, J= 12.0, 5.5 Hz, 1H), 1.52 (s, 3H), 1.50 (s, 3H), 1.36 (s, 1H), 0.96 (dd, J
= 3.7, 2.4 Hz, 2H), 0.89 (dt, J = 3.7, 1.9 Hz, 2H), 0.64 (d, J = 6.3 Hz, 3H).
Synthetic Example 33: sis of Compound 33: N-(4-
Hydroxyphenyl)sulfonyl[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
Step A: 2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide
h2 0
OH HO
GDI OH
0^N N" Cl
2-Chloro[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0,4288 mmol) and CDI (83 mg, 0.5119 mmol)
were combined in THF (750 pL) and stirred at room temperature for 2 hours. 4-
Hydroxybenzenesulfonamide (86 mg, 0.4966 mmol) was added followed by DBU (90
|iL. 0.6018 mmol) and the reaction was stirred for an additional 16 h at room
temperature. The reaction mixture was diluted with 10 mL 1 M citric acid, and
extracted 3x 10 mL ethyl acetate. The combined organics were washed with water,
washed with brine, dried over sodium sulfate, and concentrated to give a white solid,
which w as used in the next step without further cation. ro-N-(4-
yphenyl)sulfonyl[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-lyl
]pyridinecarboxamide (235 mg, 94%) ESI-MS m/z calc. 504.1234, found 505.2
(M+l)+; Retention time: 0.75 minutes.
Step 2: N-(4-Hydroxyphenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxainide
-■CClP.A°"s9
O-^N^N^CI ----------------- OH
K2CO3
2-Chloro-N-(4-hydroxyphenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (235 mg, 0.4654
mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (approximately 209.2 mg.
1.398
SUBSTITUTE SHEET (RULE 26)
mmol), and potassium carbonate (approximately 387.4 mg, 2.803 mmol) were
combined in DMSO (775.7 pL) and heated at 130 °C for 16 h. The reaction was cooled
to room temperature, and 1 mL of water was added. After 15 s stirring, the
contents of the vial were allowed to settle, the liquid portion was removed by pipet and
the remaining solids were dissolved with 20 mL ethyl acetate, then washed with 15 mL
1M citric acid. The s and the organic layers were separated, and the aqueous
layer was extracted two additional times with 15 mL ethyl acetate. The organics were
combined, washed with brine, dried over sodium sulfate and trated. The
resulting solid was ed by silica gel chromatography eluting with 0-10% methanol
in dichloromethane to give N-(4-hydroxyphenyl)sulfonyl[3-[(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide (30 mg, 11%) ESI-MS m/z calc. 581.2672, found 582.3
(M+l)+; Retention time: 2.26 minutes, 'll NMR (400 MHz, DMSO) 5 12.24 (s, 1H),
.58 (s, 1H), 8.18 (d, J = 2.7 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.74 (d, J = 8.2 Hz, 1H),
6.97 - 6.92 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 4.23 (d, J = 7.7
Hz, 2H), 2.43 (t, J = 10.4 Hz, 1H), 2.26 (t, J = 9.0 Hz, 1H), 2.10 (dt, J = 13.1, 6.8 Hz,
1H), 1.82 (dd, 3=11.9,5.4 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.37 (t, J = 12.1 Hz, 1H),
1.10 (s, 6H), 1.04 (s, 6H), 0.73 (t, J = 7.7 Hz, 1H), 0.69 (d, J = 6.2 Hz, 3H).
Synthetic Example 34: Synthesis of Compound 34: N-(2-
hydroxyphenyl)sulfonyl[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(2-hydroxyphenyl)sulfonyl[3-[2-[l-
uoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
.S02NH2
0 o, 0 on
N-'S'
OH GDI I
p^N n" Cl p-0
DBU AT'
cf3 cf3
2-Chloro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (100 mg, 0.2661 mmol) and CDI (51 mg, 0.3145 mmol)
were combined in THF (600.0 pL) and stirred at room temperature for 2 hours. 2-
hydroxybenzenesulfonamide (51 mg, 0.2945 mmol) was added followed by DBU (55
SUBSTITUTE SHEET (RULE 26)
|iL. 0.3678 mmol) and the reaction was stirred for an additional 16 h at room
temperature. The reaction mixture was diluted with 10 mL 1 M citric acid, and
extracted 3x 10 mL ethyl acetate. The combined organics were washed with water,
brme, dried over sodium sulfate, and concentrated to give a white solid, which was used
in the next step without further purification. 2-chloro-N-(2-hydroxyphenyl)sulfonyl
[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (132
mg, 93%) ESI-MS m/z calc. 530.06384, found 531.1 (M+l)+; Retention time: 0.7
minutes.
Step B: N-(2-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
IX OH HN HCI XOH
9-<J N Cl p-O N H
N^(s)
AC7 k2co3 aT
cf3 cf3
2-Chloro-N-(2-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 ridinecarboxamide (132 mg,
0.2486 mmol), ,2,4-trimethylpyrrolidine (hydrochloride salt) (190 mg, 1.270
mmol), and ium carbonate (345 mg, 2.496 mmol) were combined in DMSO
(660.0 pL) and heated at 130 °C for 16 h. The reaction was cooled to room temperature,
and 1 mL of water was added. After 15 minutes stirring, the contents of the vial were
allowed to settle, the liquid portion was removed by pipet and the remaining solids were
ved with 20 mL ethyl acetate, then washed with 15 mL 1M citric acid. The
aqueous and the organic layers were separated, and the aqueous layer was extracted two
additional times with 15 mL ethyl acetate. The organics were ed, washed with
brme, dried over sodium e and concentrated. The resulting solid was further
purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane
to give N-(2-hydroxyphenyl)sulfonyl[3-[2-[l-
uoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl] [(4S)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxamide (51 mg, 31%) ESI-MS m/z calc. 607.20764, found 608.3
SUBSTITUTE SHEET (RULE 26)
(M+l)+; Retention time: 2.14 minutes 'H\MR (40() MHz. DMSO) 5 12.41 (s, 1H),
.89 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.79 (dd, J = 8.1, 2.1 Hz, 2H), 7.56 - 7.43 (m,
1H), 7.07 - 6.95 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.11 (d, J = 2.7 Hz, 1H), 4.31 (t, J =
7.1 Hz, 2H), 2.64 (d, J = 8.1 Hz, 1H), 2.58 (d, J = 10.6 Hz, 1H), 2.19 (d, J= 11.0 Hz,
1H), 2.08 (t, J = 7.0 Hz, 2H), 1.85 (dd, J = 11.9, 5.6 Hz, 1H), 1.54 (d, J = 8.1 Hz, 6H),
1.39 (t, J = 12.1 Hz, 1H), 1.00 - 0.92 (m, 2H), 0.90 (d, J = 10.8 Hz, 2H), 0.82 (d, J = 6.3
Hz, 3H).
Synthetic e 35: Synthesis of Compound 35: N-(3-
Hydroxyphenyl)sulfonyl[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(3-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
HOXXso2nh2
o x %p OH
GDI N-m
p~U " 01 p^J
ro[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (100 mg, 0.2661 mmol) and CDI (51 mg, 0.3145 mmol)
were combined in THF (600.0 pL) and stirred at room temperature for 2 hours. 3-
Hydroxybenzenesulfonamide (51 mg, 0.2945 mmol) was added followed by DBU (55
|iL. 0.3678 mmol) and the reaction was stirred for an additional 16 h at room
temperature. The reaction mixture was diluted with 10 mL 1 M citric acid, and
extracted 3 x 10 mL ethyl acetate. The combined organics were washed with water,
brine, dried over sodium sulfate, and trated to give a white solid, which was used
in the next step without further purification. 2-chloro-N-(3-hydroxyphenyl)sulfonyl
[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (135
mg, 96%) ESI-MS m/z calc. 530.06384, found 531.2 (M+l)+; Retention time: 0.69
minutes.
SUBSTITUTE SHEET (RULE 26)
Step B: N-(3-Hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
nvo"0 0 o ■■-CCaV r* aPOH
K2CO3
cf3 cf3
2-Chloro-N-(3-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide (135 mg,
0.2543 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (193 mg, 1.290
mmol), and potassium carbonate (352 mg, 2.547 mmol) were combined in DMSO
(508.6 pL) and heated at 130 °C for 16 h. The reaction was cooled to room temperature,
and 1 mL of water was added. After 15 minutes stirring, the ts of the vial were
allowed to settle and the liquid portion was removed by pipet and discarded. The
remaining solids were ved in 20 mL ethyl acetate then washed with 15 mL 1M
citric acid. The aqueous and the organic layers were separated, and the aqueous layer
was extracted two additional times with 15 mL ethyl acetate. The organics were
combined, washed with brine, dried over sodium sulfate and trated. The
resulting solid was purified by silica gel chromatography eluting with 0-10% methanol
in dichloromethane to give N-(3-hydroxyphenyl)sulfonyl[3-[2-[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl] [(4S)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxamide (40 mg, 26%) ESI-MS m/z calc. 764, found 608.3
(M+l)+; Retention time: 2.05 minutes. 'H NMR (400 MHz, DMSO) 5 12.44 (s, 1H),
.19 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H),
7.40 - 7.37 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.11 (d, J = 2.7
Hz, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.47 (d, J = 10.0 Hz, 1H), 2.33 (s, 2H), 2.08 (m, J =
8.1, 7.0 Hz, 2H), 1.84 (dd, J = 11.8, 5.5 Hz, 1H), 1.54 (s, 3H), 1.52 (s, 3H), , J =
12.1 Hz, 1H), 0.96 (td, J = 5.0, 3.3 Hz, 2H), 0.90 (d, J = 11.1 Hz, 2H), 0.70 (d, J = 6.2
Hz, 3H).
Synthetic Example 36: Synthesis of nd 36: N-
(Benzenesulfonyl) [3- [dideuterio-(2,2,3,3-
SUBSTITUTE SHEET (RULE 26)
WO 64632 2017/054611
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxainide
Step A: Dideuterio-(2,2,3,3-tetramethylcyclopropyl)methanol
LiAI(2H)4
■OH -OH
O 2H2H
2,2.3,3-Tetramethylcyclopropanecarboxylic acid (1.077 g, 7.574 mmol) was
dissolved in anhydrous diethyl ether in a nitrogen purged 100 mL round bottom flask.
The reaction mixture was cooled to 0 °C. Solid tetradeuterioalumanuide (lithium salt)
(420 mg, 10.01 mmol) was added in 3 portions. The reaction mixture was allowed to
gradually reach room ature and stirred for a total of 16 hours. The reaction
mixture was then again cooled to 0 °C. HC1 (aq, 0.2 N, 5 mL) was added dropwise,
followed by 20 mL water. The aqueous phase was extracted with diethyl ether (2 x 30
mL). The combined organic phases were washed with aqueous NaHCCf. followed by
brme, then dried over sodium sulfate, filtered and evaporated to give dideuterio-
(2,2,3,3-tetramethylcyclopropyl)methanol (920 mg, 93%). 'll NMR (400 MHz,
DMSO) 5 4.11 (s, 1H), 1.04 (s, 6H), 0.93 (s, 6H), 0.37 (s, 1H).
Step B: tert-Butyl euterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazole-l-carboxylate
n-n^o-^
HO. sJM. D DIAD
.OH + N
2H2H PPh3 2-h
] DIAD (1.4 mL, 7.111 mmol) was added dropwise to a solution of triphenyl
phosphine (1.815 g, 6.920 mmol) in 40 mL anhydrous toluene, at 0 °C. After 30
minutes at 0 0C, a solution of tert-butyl 3-hydroxypyrazole-l-carboxylate (1.155 g,
6.271 mmol) and dideuterio-(2,2,3,3-tetramethylcyclopropyl)methanol (980 mg, 7.525
mmol) in 30 mL toluene was slowly added by syringe. The reaction was warmed to
room temperature for 45 minutes, and then was heated to 55 °C for 18 h. The mixture
was evaporated and the resulting material was partitioned between ethyl acetate (30 mL)
and IN sodium hydroxide (30 mL). The organics were separated, washed with brine (30
mL), dried over sodium sulfate and evaporated. The crude material was purified by
silica gel chromatography eluting with 0-30% ethyl acetate in hexanes to give an oil that
ally solidified to a slightly yellow solid: utyl 3-[dideuterio-(2,2,3,3-
SUBSTITUTE SHEET (RULE 26)
tetramethylcyclopropyl)methoxy]pyrazole-l-carboxylate (820 mg, 44%) ESI-MS m/z
calc. 296.2069, found 297.2 (M+l)1: Retention time: 0.79 minutes.
Step C: 3-[Dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]-lH-
nun^0J< N32CO3 f-oN-NH
h2o *hh
'i 2h H
To utyl 3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazole-l-carboxylate (800 mg, 2.699 mmol) in 1,2-
dimethoxyethane (10 mL) was added sodium carbonate (460 mg, 4.340 mmol) in water
(3 mL), and the reaction mixture was heated to 90 °C for 16 hours in a screwcap vial.
The reaction mixture was cooled to room ature and diluted with water (50 mL)
and ethyl acetate (50 mL). The organics were separated, and the aqueous layer was
ted 2 x 25 mL ethyl acetate. The combined organics were washed with bnne, and
dried over sodium sulfate, then concentrated to give a colorless oil. euterio-
(2,2,3,3-tetramethylcyclopropyl)methoxy]-lH-pyrazole (492 mg, 93%) ESI-MS m/z
calc. 196.15446, found 197.1 (M+l)1; ion time: 0.57 minutes, 1HNMR(400
MHz, DMSO) 6 11.78 (s, 1H), 7.48 (t, J = 2.1 Hz, 1H), 5.65 (t, J = 2.3 Hz, 1H), 1.08 (s,
6H), 1.00 (s, 6H),0.66 (s, 1H).
Step D: Ethyl 2-chloro[3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxylate
,N'NH DABCO
'0'"v N Cl
2h2h cr n ci K2C03 2h2h
A round bottom flask was d under nitrogen with3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]-lH-pyrazole (485 mg, 2.471 mmol), ethyl 2,6-
dichloropyridinecarboxylate (545 mg, 2.477 mmol), K2CO3 (513 mg, 3.712 mmol)
(freshly ground in a mortar) and anhydrous DMF (4.128 mL). DABCO (50 mg, 0.4457
mmol) was added and the mixture was stirred at room temperature under nitrogen for 16
hours. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL)
and the two phases were separated. The aqueous phase was further extracted with ethyl
acetate (2 x 30 mL), and the combined extracts were washed with brine and dried over
SUBSTITUTE SHEET (RULE 26)
sodium sulfate, after which the solvent was removed under reduced pressure. The
material was subjected to flash tography on silica gel using a gradient of 0-20%
ethyl acetate in hexanes. The pure fractions were combined and the solvents removed
under reduced pressure to provide a white solid; ethyl 2-chloro[3-[dideuterio-
(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxylate (505 mg,
54%) ESI-MS m/z calc. 379.16318, found 380.1 (M+l)+; Retention time: 0.9 s
lH NMR (400 MHz, DMSO) 5 8.42 (d, J = 2.9 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.76
(d, J = 8.4 Hz, 1H), 6.24 (d, J = 2.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1
Hz, 3H), 1.11 (s, 6H), 1.04 (s, 6H), 0.74 (s, 1H).
Step E: 2-Chloro[3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxylic acid
O O
P^N N^CI o~Q N Cl
A solution of sodium hydroxide (275 mg, 6.875 mmol) in water (2.500 mL)
was added to a solution of ethyl 2-chloro[3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxylate (500 mg, 1.316
mmol) in isopropanol (2.500 mL) and stirred at 90 °C for 45 minutes. The reaction was
cooled to room temperature then diluted with 50 mL ethyl acetate, 20 mL 1M citric
acid, and 10 mL water. The organics were ted, and the aqueous portion was
extracted 2x 25 mL ethyl acetate. The combined organics were washed with brine,
dried over sodium sulfate and concentrated. The ing solid was triturated in 40 mL
water, briefly sonicated, and collected by tion then dried to give a white solid, 2-
chloro[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine-
3-carboxylic acid (404 mg, 87%) ESI-MS m/z calc. 351.13187, found 352.1 (M+l)+;
Retention time: 0.77 minutes. ^NMR (400 MHz, DMSO) 5 8.41 (d, J = 2.9 Hz, 1H),
SUBSTITUTE SHEET (RULE 26)
8.38 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 2.8 Hz, 1H), 1.11 (s, 6H),
1.04 (s, 6H), 0.74 (s, 1H).
Step F: N-(Benzenesulfonyl)chloro[3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide
SO2NH2
o O' X°"sP
‘OH ^C|H ^
f-u N Cl GDI p-^N «
DBU =HH
2-Chloro[3-[dideuteno-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-
l-yl]pyridinecarboxylic acid (100 mg, 0.2842 mmol) and CDI (55 mg, 0.3392 mmol)
were combined in THF (600.0 pL) and stirred at room temperature for 2 hours,
benzenesulfonamide (49 mg, 0.3117 mmol) was added followed by DBU (57 pL,
0.3812 mmol) and the reaction was stirred for an additional 16 h at room temperature.
The reaction mixture was diluted with 10 mL 1 M citric acid, and extracted 3x 10 mL
ethyl acetate. The combined organics were washed with water, brine, dned over sodium
sulfate, and concentrated to give approximately 135 mg of a white solid, which was
used in the next step without further purification. N-(benzenesulfonyl)chloro[3-
teno-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine
armde ESTMS m/z calc. 490.14105, found 491.2 (M+l)+; Retention time: 0.81
minutes.
Step G: zenesulfonyl)[3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxainide
HCI x0*p
•O-Cj n
K2C03 2h
2h 2h
zenesulfonyl)chloro[3-[dideuterio-(2,2,3,3-
tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (135 mg, 0.2749
mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (128 mg, 0.8553 mmol),
and potassium carbonate (237 mg, 1.715 mmol) were combined in DMSO (458.2 pL)
and heated at 130 °C for 16 h. The reaction was cooled to room temperature, and 1 mL
SUBSTITUTE SHEET (RULE 26)
of water was added. After 15 minutes stirring, the contents of the vial were allowed to
settle, the liquid portion was removed by pipet and the remaining solids were dissolved
with 20 mL ethyl acetate then washed with 15 mL 1M citric acid. The s and the
organic layers were separated, and the aqueous layer was extracted two additional times
with 15 mL ethyl acetate. The organics were combined, washed with brine, dried over
sodium sulfate and concentrated. The resulting solid was further purified by silica gel
chromatography eluting with 0-10% methanol in dichloromethane to giveN-
(benzenesulfonyl)[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (112 mg, 72%) ESI-
MS m/z calc. 567.28485, found 568.3 (M+l)+; Retention time: 2.42 minutes. 'H NMR
(400 MHz, DMSO) 8 12.51 (s, 1H), 8.18 (d, J = 2.8 Hz, 1H), 7.99 (dt, J = 7.1, 1.4 Hz,
2H), 7.80 (d, J = 8.3 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.70 - 7.62 (m, 2H), 6.92 (d, J = 8.3
Hz, 1H), 6.13 (d, J = 2.7 Hz, 1H), 2.40 (t, J = 10.4 Hz, 1H), 2.26 (t, J = 8.7 Hz, 1H),
2.09 (dq, J = 11.7, 6.0 Hz, 1H), 1.82 (dd, J = 11.8, 5.4 Hz, 1H), 1.52 (d, J = 9.5 Hz, 6H),
1.36 (t, J = 12.2 Hz, 1H), 1.10 (s, 6H), 1.04 (s, 6H), 0.72 (s, 1H), 0.64 (d, J = 6.2 Hz,
] tic Example 37: Synthesis of Compound 37: N-
(Benzenesulfonyl)[3-[[l-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-lyl
4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: t-butoxymethyl)-lH-pyrazole
TMS^Nj rU, NH 0
tert-Butylpropargyl alcohol (2.5 g, 22.2 mmol) was mixed with trimethylsilyl
diazomethane (2.0 M in , 11.1 mL, 22.2 mmol) and stirred in a sealed tube at 115
°C for 18 hours. The mixture was cooled to 40 °C and quenched with methanol (5 mL)
and concentrated. Column chromatography (silica; heptanes/EtOAc2:l to 1:1) afforded
3-(tert-butoxymethyl)-lH-pyrazole as colorless oil (1.5 g, 44%). JH NMR (CDC13, 300
MHz): 8 1.26 (s, 9H); 4.53 (s, 2H); 6.22 (s, 1H); 7.48 (s, 1H). R (75 MHz,
CDC13): 8 27.3, 57.2, 73.9,103.5,134.0 (one quaternary carbon not shown).
Step B: tert-Butyl 6-[3-(tert-butoxymethyl)pyrazol-l-yl]chloro-
pyridinecarboxylate
SUBSTITUTE SHEET (RULE 26)
DABCO *N'N
;,N'NH
o cr n ci k2co3
A 100 mL round bottom flask was charged under nitrogen with 3-(tert-
butoxymethyl)-lH-pyrazole (1.241 g, 8.047 mmol), tert-butyl 2,6-dichloropyridine
carboxylate (2.0 g, 8.061 mmol), K2CO3 (1.448 g, 10.48 mmol) (freshly ground in a
mortar) and anhydrous DMF (12.41 mL). DABCO (163 mg, 1.453 mmol) was added
and the mixture was d at room temperature under nitrogen for 16 hours. The
reaction e was diluted with ethyl acetate (50 mL) and water and brine (50 mL)
and the two phases were separated. The aqueous phase was further extracted with ethyl
acetate (2 x 30 mL). The combined extracts were washed with brine, dried over sodium
sulfate and the t removed under reduced pressure. The material was subjected to
flash chromatography on silica gel using a nt of ethyl acetate (0 to 10%) in
s. The pure fractions were combined and the solvents removed under reduced
pressure to provide tert-butyl 6-[3-(tert-butoxymethyl)pyrazol-l-yl]chloro-pyndine-
3-carboxylate (1.956 g, 66%) as a colorless oil, which solidified to a white solid
overnight on high vac. ESI-MS m/z calc. 365.1506, found 366.2 (M+l)+; Retention
time: 0.82 minutes
Step C: 2-Chloro[3-(hydroxymethyl)pyrazol-l-yl]pyridine
carboxylic acid
O k O
O HCI %■ OH
°V//N'N' 'N' 'Cl HO *N'N' '1ST 'Cl✓5
tert-Butyl 6-[3-(tert-butoxymethyl)pyrazol-l-yl]chloro-pyridine
carboxylate (538 mg, 1.471 mmol) was dissolved in HCI in dioxane (8.0 mL of 4 M,
32.00 mmol) and heated at 60 °C for 2 hours. The reaction e was then cooled to
room temperature and concentrated to dryness, giving a white powder. 2-chloro[3-
(hydroxymethyl)pyrazol-l-yl]pyridinecarboxylic acid (370 mg, 99%) ESI-MS m/z
calc. 253.02542, found 254.1 (M+l)+; Retention time: 0.33 minutes
SUBSTITUTE SHEET (RULE 26)
Step D: 2-Chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-yl]pyridinecarboxylic
A(CF3
o sA //
OH °0
HO A rr°V//N'N^N^CI0OH
'/N'N' 'N' 'ClxS
KO*Bu
[ 1 -(Tnfluoromethyl)cyclopropy 1] methyl 4-methyIbenzenesulfonate (1.3 g,
4.417 mmol), and 2-chloro[3-(hydroxymethyl)pyrazol-l-yl]pyridmecarboxylic
acid (370 mg, 1.459 mmol), were combined in ous DMSO (9.250 mb), tertbutoxypotassium
(660 mg, 5.882 mmol)was added and the reaction mixture was stirred
at room temperature. After 30 minutes the reaction mixture was poured into 1 M citric
acid (15 mL) and extracted 3 x 15 mL ethyl acetate. The combined organics were
washed with brine, dried over sodium e and concentrated. The resulting material
was purified by chromatography on silica gel using a 0-10% methanol in
dichloromethane nt. The fractions containing product were collected and
trated to give a white solid. 2-Chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-yl]pyridmecarboxylic acid
(292 mg, 53%) ESI-MS m/z calc. 375.05975, found 376.1 (M+l)+; Retention time:
0.62 minutes.
Step E: N-(Benzenesulfonyl)chloro[3-[[l-
uoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-yl]pyriclinecarboxamide
SO2NH2
A rrM3 N-mM OH GDI
c DBU
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-
yl]pyridinecarboxylic acid (60 mg, 0.1597 mmol) and GDI (31 mg, 0.1912 mmol)
were combined in THF (360.0 pL) and stirred at room temperature for 2 hours.
Benzenesulfonamide (28 mg, 0.1781 mmol) was added followed by DBU (35 pL.
0.2340 mmol) and the reaction was stirred for an onal 16 h at room temperature.
SUBSTITUTE SHEET (RULE 26)
The reaction e was diluted with 10 mL 1 M citric acid, and extracted 3 x 10 mL
ethyl acetate. The combined organics were washed with water, brine, dried over sodium
sulfate, and concentrated to give a white solid, which was used in the next step without
further cation. N-(benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-yl]pyridmecarboxamide
(approximately 78 mg) ESI-MS m/z calc. 514.0689, found 515.1 (M+l)+; Retention
time: 0.69 minutes.
Step G: N-(Benzenesulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxymethyl] pyrazol- l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Yo J?!L %nXcVoC, ^o o O HN^vjjp1 r|I 9 qw0
\ N.kMi
k2co3
N-(Benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-yl]pyridmecarboxamide (78
mg, 0.1515 mmol), (4S)-2,2,4-trimethylpyrrohdine (Hydrochlonde salt) (115 mg,
0.7684 mmol), and Potassium carbonate (210 mg, 1.519 mmol) were combined in
DMSO (390.0 pL) and heated at 130 °C for 16 h. The reaction was cooled to room
temperature, and 1 mL of water was added. After 15 minutes stirring, the contents of
the vial were allowed to settle, the liquid portion was removed by pipet and the
remaining solids were ved with 20 mL ethyl acetate, then washed with 15 mL 1M
citric acid. The aqueous and the organic layers were separated, and the aqueous layer
was extracted two additional times with 15 mL ethyl acetate. The cs were
combined, washed with brine, dried over sodium sulfate and concentrated. The
ing solid was further ed by silica gel tography eluting with 0-10%
methanol in dichloromethane to give N-(benzenesulfonyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (46 mg, 51%) ESI-MS m/z calc.
591.2127, found 592.3 (M+l)+; Retention time: 2.11 minutes. H NMR (400 MHz,
DMSO) 5 12.56 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.04 - 7.97 (m, 2H), 7,89 - 7.79 (m,
1H), 7.73 (t, J = 7.1 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 6.56 (d, J =
2.6 Hz, 1H), 4.55 (s, 2H), 3.59 (s, 2H), 2 42 (t, J = 10.4 Hz, 1H), 2.29 (d, J = 9.6 Hz,
SUBSTITUTE SHEET (RULE 26)
WO 64632 2017/054611
1H), 2.18 - 2.04 (m, 1H), 1.83 (dd, J = 11.7, 5.5 Hz, 1H), 1.54 (d, J = 9.4 Hz, 6H), 1.37
(t, J = 12.1 Hz, 1H), 1.03 - 0.94 (m, 2H), 0.91 - 0.80 (m, 2H), 0.65 (d, J = 6.2 Hz, 3H).
Synthetic Example 38: Synthesis of Compound 38: N-(Benzenesulfonyl)-
6- [3- [2-hydroxy [l-(trifluoromethyl)cyclopropyl]ethoxy] pyrazol- 1-yl] [(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Steps A-B: l-[l-(Trifluoromethyl)cyclopropyl]propen-l-ol
1.)PCC OH
F3C ^\P°H f3c
2.) vinylmagnesium bromide
ifluoromethyl)cyclopropyl]methanol (1 g, 7.138 mmol) was stirred in
dry dichloromethane (30 mL) and cooled to 0 °C in an ice bath. Chloro-hydroxy-
dioxo-chromium;pyridine (2.77 g, 12.85 mmol) was added in one portion, and the ice
bath was removed and the reaction was stirred for 24 hours at room ature. The
reaction mixture was poured into 100 mL diethyl ether and filtered through a pad of
silica with a layer of celite on top, eluting with diethyl ether. The resulting filtrate was
dried over sodium sulfate, then filtered through cotton and used in the next step without
concentration due to the volatility of the aldehyde. The crude filtrate was cooled to 0 °C,
and bromo(vinyl)magnesium (14.5 mL of 1 M, 14.50 mmol) (in THF) was slowly
added. The reaction mixture was allowed to slowly warm to near room temperature
over 2 hours. The reaction e was then cooled to 0 °C, quenched with 1M HC1,
and diluted with water. The layers were separated, and the aqueous was extracted 4
additional times with diethyl ether. The combined cs were washed with brine,
dried over sodium sulfate and partially trated. The resulting crude material was
used in the next step without further purification. 1-[1-
(trifluoromethyl)cyclopropyl]propen-l-ol (approximately 1.25g crude, with
substantial THF remaining) Crude XH NMR (400 MHz, DMSO) 8 5.95 - 5.84 (m, 1H),
.36 (d, J = 5.2 Hz, 1H), 5.32 (ddd, J = 17.1, 2.1, 1.4 Hz, 1H), 5.18 (ddd, J = 10.4, 2.0,
1.3 Hz, 1H), 4.17 (tt, J = 6.4, 1.4 Hz, 1H), 0.95 - 0.87 (m, 4H).
Step C: tert-Butyl-dimethyl-[l-[l-
(trifluoromethyl)cyclopropyl]allyloxy]silane
OH TBS-CI, imidazole
f3c OTBS
SUBSTITUTE SHEET (RULE 26)
l-[l-(Trifluoromethyl)cyclopropyl]propen-l-ol (270 mg, 1.625 mmol)
and imidazole (220 mg, 3.232 mmol) were dissolved in DMF (2 mL) and cooled to 0 °C
in an ice bath. TBS-C1 (tert-butyldimethylsilyl chloride) (370 mg, 2.455 mmol) was
then added in a single n, and after 15 s the ice bath was removed and the
reaction mixture was allowed to stir 16 hours at room temperature. Saturated aqueous
ammonium chloride (1 mL) was then added, and the on mixture was stirred for 20
minutes. The reaction mixture was then diluted with 30 mL diethyl ether and 20 mL of
water. The organics were separated, and the aqueous layer was extracted 2x15 mL
diethyl ether. The combined cs were washed with water, then brine and dried
over sodium sulfate, and trated under vacuum. The crude material was then
passed through a silica plug, eluting with hexanes, and concentrated to an oil containing
substantial overlapping silyl impurities, but used in the next step without further
purification, tert-butyl-dimethyl-[l-[l-(trifluoromethyl)cyclopropyl]allyloxy]silane
(approximately 317 mg, crude).
] Steps D-F: tert-butyl 3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate
1. ) 0s04, Nal04,
tidine N'N^O^
OTBS 2. ) NaBH4 TBSO
3.) DIAD, PPh3
tert-Butyl-dimethyl-[l-[l-(trifluoromethyl)cyclopropyl]allyloxy]silane (220
mg, 0.7846 mmol) (crude) was combined in dioxane (6 mL)and water (2 mL) with 2,6-
dimethylpyndine (185 |iL. 1.597 mmol) and sodium periodate (675 mg, 3.156 mmol).
Tetraoxoosmium (420 pL, 0.3139 mmol) was then added and the reaction mixture was
stirred for 20 hours at room temperature. The reaction was then d with 30 mL
dichloromethane and 30 mL water. The organics were separated, and the aqueous layer
was extracted 2 x 25 mL dichloromethane. The combined organics were dried over
sodium sulfate, and concentrated to about 8 mL and used in the next step, without
isolation.
The crude mixture from the previous step was diluted with methanol (10
mL), and cooled to 0 °C. Sodium borohydride (90 mg, 2.379 mmol) was added and the
SUBSTITUTE SHEET (RULE 26)
on mixture stirred for 1 hour. The reaction e was then quenched with acetic
acid and trated. The resulting material was partitioned between ethyl acetate and
aqueous sodium bicarbonate and the layers were separated. The aqueous portion was
extracted 2x ethyl acetate, and the combined organics were washed with brine, dried
over sodium sulfate and concentrated. The resulting crude alcohol was used in the next
step without purification. The crude t was ed with triphenylphosphine
(300 mg, 1.144 mmol) and tert-butyl 3-hydroxypyrazole-l-carboxylate (145 mg, 0.7872
mmol) dissolved in THF (15 mL). The reaction mixture was cooled to 0 °C and DIAD
(230 pL, 1.187 mmol) was slowly added. The ice bath was removed, and the reaction
was stirred at room temperature for an hour then heated to 55 °C for an additional 16
hours. The reaction mixture was partially concentrated, dissolved in 100 mL ethyl
acetate, washed with 25 mL IN NaOH, brine, dried over sodium sulfate and
concentrated. The resulting material was purified by chromatography on silica gel
eluting with 0-50% ethyl acetate in hexanes to give, with an overlapping UV active
impurity utyl 3- [2- [tert-buty l(dimethy l] oxy[ 1 -
(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate (63 mg, 18%) ESI-MS m/z
calc. 450.21616, found 451.3 (M+l)+; Retention time: 0.95 minutes
Step G: 3-(2-((tert-butyldimethylsilyl)oxy)(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyr azole
TFA TBSO 0-/'NH
tert-Butyl 3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate (63 mg, 0.1398 mmol)
(with a major impurity present) w as dissolved in dichloromethane (1.312 mL) with TFA
(trifluroracetic acid) (approximately 194.3 mg, 131.3 pL, 1.704 mmol) and the reaction
was stirred at room temperature for 30 minutes. s (1 mL) were added, and
reaction was evaporated and the resulting oil was partitioned between ethyl acetate (10
mL) and a saturated sodium bicarbonate on. The organics were separated, washed
with brine, dried over sodium sulfate and evaporated to give a colorless oil, 3-(2-((tertbutyldimethylsilyl
2-(l-(tnfluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole (37
SUBSTITUTE SHEET (RULE 26)
mg, 76%) ESI-MS m/z calc. 350.16373, found 351.2 (M+l)+; Retention time: 0.81
minutes.
Step H: tert-Butyl 6-[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]chloro-pyridinecarboxylate
DABCO
TBSO ,0-y/N'NH TBSO 0_//N'NAN'>kCI
K2CO3
cr N Cl
cf3 cf3
A round bottom flask was charged under nitrogen with tert-butyl-dimethyl-
[2-(lH-pyrazolyloxy)-l -[1 -(trifluoromethyl)cyclopropyl] ethoxy] silane (37 mg,
0.1056 mmol), tert-butyl 2,6-dichloropyridinecarboxylate (26 mg, 0.1048 mmol),
K2CO3 (25 mg, 0.1809 mmol) (freshly ground in a mortar) and anhydrous DMF (250
pL). DABCO (2 mg, 0.01783 mmol) was added and the mixture was stirred at room
temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl
acetate (15 mL) and water (15 mL) and the two phases were separated. The s
phase was further extracted with ethyl e (2x15 mL). The combined extracts were
washed with brine and dried over sodium sulfate and the solvent removed under reduced
pressure. The material was subjected to flash chromatography on silica gel using a
nt of ethyl e (0 to 20%) in hexanes. The pure fractions were ed and
the ts removed under reduced pressure to provide a colorless oil, tert-buty l 6-[3-
[2-[tert-butyl(dimethyl)silyl]oxy[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-lyl
]chloro-pyridinecarboxylate (20 mg, 34%). ESI-MS m/z calc. 561.20374,
found 562.4 (M+l)+; Retention time: 0.84 minutes, 'H NMR (400 MHz, DMSO) 8 8.44
(d, J = 2.9 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 6.17 (d, J = 2.9
Hz, 1H), 4.44 (dd, J = 10.7, 2.9 Hz, 1H), 0.13 - 0.03 (m, 6H), 4.32 - 4.25 (m, 1H), 3.89
(s, 1H), 1.56 (s, 9H), 0.98 (d, J = 35.8 Hz, 4H), 0.86 (s, 9H)
Step I: 2-[tert-Butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]chloro-pyridinecarboxylic
TBSO CW/N'N N Dl TBSO <W/N'N N' 'Cl
cf3 CF3
SUBSTITUTE SHEET (RULE 26)
WO 64632
tert-Butyl 6-[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cy pyl]ethoxy]pyrazol-1 -yl] chloro-pyridinecarboxylate (20
mg, 0.03558 mmol) and TFA (50 pL, 0.6490 mmol) were combined in dichloromethane
(0.75 mL) and heated at 45 °C for 3 h. The reaction was evaporated. Hexanes were
added and the mixture evaporated again to give a white solid 6-[3-[2-[tertbutyl
(dimethyl)sily 1] oxy[ 1-(trifluoromethy l)cy clopropyl] ethoxy ] pyrazoly 1]
chloro-pyridinecarboxylic acid (18 mg, 100%) ESI-MS m/z calc. 505.14114, found
506.3 (M+l)+; Retention time: 0.59 minutes.
Step J: N-(Benzenesulfonyl)[3-[2-[tert-butyl(dimethyl)silyl]oxy|l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]chloro-pyridine
carboxamide
fX* oso2nh2 0 QwP
N'N^N^C|H ^
TBSO N'N^n^ci c:
DBU cf3
6-[3-[2-[tert-Butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]chloro-pyndinecarboxylic acid
(19 mg, 0.03755 mmol) and GDI (8 mg, 0.04934 mmol) were combined in THE (200
pL) and stirred at room temperature for 2 hours, benzenesulfonarmde (7 mg, 3
mmol) was added followed by DBU (10 pL, 0.06687 mmol) and the reaction was stirred
for an additional 2 h at room temperature. The reaction mixture was then d with
mL 1 M citric acid, and extracted 3 x 10 mL ethyl acetate. The combined cs
were washed with water, brine, dried over sodium sulfate, and concentrated to give a
white solid, which was used in the next step without further cation N-
(benzenesulfonyl)[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]chloro-pyndinecarboxamide
(approximately 22 mg) ESI-MS m/z calc. 644.1503, found 645.3 (M+l)+; Retention
time: 0.8 minutes.
Step O: zenesulfonyl)[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
HCI £ <y>
TBSO // 'N N TBSO
K2CO3
cf3 CF3
zenesulfonyl)[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethy l)cy clopropy 1] ethoxy]pyrazol-1 -yl] chloro-pyndine-3 -carboxamide
(22 mg, 0.03410 mmol), ,2,4-trimethylpyrrolidine (Hydrochloride salt)
(approximately 40.83 mg, 0.2728 mmol), and potassium carbonate (approximately
75.40 mg, 0.5456 mmol) were combined in DMSO (180 pL) and heated at 130 °C for
24 hours. The reaction was cooled to room temperature and diluted with 15 mL 1M
citric acid and 20 mL ethyl acetate. The aqueous and the organic layers were separated,
and the aqueous layer was extracted two additional times with 15 mL ethyl acetate. The
organics were combined, washed with brine, dried over sodium sulfate and
concentrated. The resulting solid was purified by silica gel chromatography eluting
with 0-10% methanol in dichloromethane to give the TBS protected material as a white
solid, N-(benzenesulfonyl)[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-lyl
]pyridinecarboxamide (8 mg, 32%) ESTMS m/z calc. 721.2941, found 722.4
(M+l)+; ion time: 0.88 minutes
Step P: N-(Benzenesulfonyl)[3-[2-hydroxy[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
hylpyrrolidin-l-yl]pyridinecarboxamide
0 0 0 IqsP
TBSO HO ^-C&P
cf3 CF3
zenesulfonyl)[3-[2-[tert-butyl(dimethyl)silyl]oxy[l-
(trifluoromethyl)cy clopropy l]ethoxy]pyrazol-1 -yl] [(4S)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxamide (8mg, 0.0341 mmol) was then dissolved in THF (0.4 mL),
cooled to 0 °C, and tetrabutylammomum fluoride (1M in THF, imately 0.17mL,
0.1705 mmol) was added by syringe. After 5 minutes the reaction was allowed to warm
to room temperature. After 20 minutes at room temperature the reaction mixture was
poured into 10 mL 1M citric acid, and extracted 3 x lOmL ethyl e. The combined
SUBSTITUTE SHEET (RULE 26)
organics were washed with brine, dned over sodium sulfate, and concentrated. The
resulting crude material was then ed twice by silica gel chromatography eluting
with a 0-10% methanol in dichloromethane to give zenesulfonyl)[3-[2-
hydroxy[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (3 mg, 14%) ESI-MS m/z calc.
607.20764, found 608.3 (M+l)+; Retention time: 1.99 s, 'h NMR (400 MHz,
DMSO) 5 12.51 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 7.5 Hz, 2H), 7.79 (d, J =
8.2 Hz, 1H), 7.70 (d, J = 9.6 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 8.2 Hz, 1H),
6.11 (d, J = 2.8 Hz, 1H), 5.57 (dd, J = 5.5, 2.6 Hz, 1H), 4.40 - 4.32 (m, 1H), 2.46 - 2.39
(m, 1H), 4.20 - 4.12 (m, 1H), 3.89 (s, 1H), 2.28 (s, 1H), 2.09 (s, 1H), 1.82 (dd, J = 12.1,
.5 Hz, 1H), 1.52 (d, J = 9.7 Hz, 6H), 1.43 - 1.36 (m, 1H), 1.03 - 0.89 (m,4H), 0.65 (d, J
= 6.2 Hz, 3H).
Synthetic Example 39: Synthesis of Compound 39: N-(benzenesulfonyl)-
6- [3- [(lR,2S,4S)-norbomanyl] oxypyrazol-l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: tert-Butyl 3-(((lR,2S,4S)-bicyclo[2.2.1]heptanyl)oxy)-lH-
pyrazole-l-carboxylate
HO. H n-n-V^
^N. O DIAD
N °~V
O PPh3
tert-Butyl 3-hydroxypyrazole-l-carboxylate (1.632 g, 8.860 mmol), (+)-endo-
2-norbomeol (1 g, 8.915 mmol), and nyl phosphine (2.57 g, 9.798 mmol) were
combined in THE (21.98 mL) and the on was cooled in an ice bath. To the mixture
was added DIAD (2 mL, 10.16 mmol) dropwise and the reaction was allowed to warm
to room temperature and stir for 16 h. The mixture was evaporated and the resulting
material was partitioned between ethyl acetate (30 mL) and IN sodium hydroxide (30
mL). The organics were ted, washed with brine (30 mL), dried over sodium
sulfate and evaporated. The crude material was purified by silica gel chromatography
SUBSTITUTE SHEET (RULE 26)
eluting with 0-30% ethyl acetate in hexanes to give tert-butyl 3-(((lR,2S,4S)-
bicyclo[2.2.1]heptanyl)oxy)-lH-pyrazole-l-carboxylate (2.08 g, 84%) ESI-MS m/z
calc. 306, found 279.3 ; Retention time: 0.72 minutes. ^ NMR (400
MHz, DMSO) 6 8.05 (d, J = 3.0 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 4.47 (d, J = 6.8 Hz,
1H), 2.43 - 2.36 (m, 1H), 2.32 - 2.22 (m, 1H), 1.75 (td, J = 6.7, 2.4 Hz, 1H), 1.54 (s,
9H), 1.53 - 1.49 (m, 2H), 1.42 (ddt, J= 14.8, 7.8, 4.4 Hz, 2H), 1.18 - 1.07 (m, 3H).
Step B: 3-[(lR,2S,4S)-norbomanyl]oxy-lH-pyrazole
H N-kAo-^
TEA ,N'NH
H H
tert-Butyl 3-[(lR,2S,4S)-norbomanyl]oxypyrazole-l-carboxylate (2.08 g,
7.473 mmol) was dissolved in CH2CI2 (20.80 mL) with trifluoroacetic acid (5.8 mL,
75.28 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was
evaporated under reduced re and the resulting oil was partitioned between ethyl
acetate (50 mL) and a saturated sodium bicarbonate on (30 mL). The organics
were separated, washed with brine, dried over sodium sulfate and concentrated under
vacuum to give an oil, 3-[(lR,2S,4S)-norbomanyl]oxy-lH-pyrazole (1.29 g, 97%)
ESI-MS m/z calc. 178.11061, found 179.2 (M+l)+; Retention time: 0.45 minutes.
Step C: tert-Butyl 2-chloro[3-[(lR,2S,4S)-norbomanyl]oxypyrazol-
1-yl] pyridinecarboxylate
DABCO
H H N A A
i0 A'Nn 4 N Cl
cr n ci
K2CO3 0
H H
A 100 mL round bottom flask was charged under nitrogen with tert-butyl 2,6-
dichloropyridinecarboxylate (1.796 g, 7.239 mmol), ,2S,4S)-norboman
yl]oxy-lH-pyrazole (1.29 g, 7.238 mmol), and K2CO3 (1.310 g, 9.479 mmol) (freshly
ground in a mortar) and anhydrous DMF (12 mL). DABCO (146 mg, 1.302 mmol) was
added and the mixture was stirred at room ature under nitrogen for 8 hours. The
reaction mixture was diluted with ethyl acetate (50 mL), water and brine (50 mL) and
the two phases were separated. The aqueous phase was further ted with ethyl
SUBSTITUTE SHEET (RULE 26)
acetate (2 x 50 mL). The combined extracts were dried over sodium sulfate and the
solvent removed under reduced pressure. The material was subjected to flash
chromatography on silica gel using a gradient of ethyl acetate (0 to 20%) in hexanes.
The pure fractions were combined and the solvents removed under reduced pressure to
provide tert-butyl 2-chloro[3-[(lR,2S,4S)-norbomanyl]oxypyrazol-l-yl]pyridine-
3-carboxylate (1.814 g, 64%) ESI-MS m/z calc. 06, found 390.3 (M+l)+;
Retention time: 0.92 minutes lH NMR (400 MHz, DMSO) 8 8.40 (d, J = 2.9 Hz, 1H),
8.32 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 6.18 (d, J = 2.9 Hz, 1H), 4.53 (d, J =
6.6 Hz, 1H), 1.88 - 1.78 (m, 1H), 2.45 (d, J = 4.6 Hz, 1H), 2.29 (t, J = 4.3 Hz, 1H), 1.56
(s, 9H), 1.55 - 1.39 (m, 4H), 1.22 - 1.08 (m, 3H).
Step D: ro[3-[(lR,2S,4S)-norbomanyl]oxypyrazol-lyl
inecarboxylic acid
O 0
y N-MA A H Kl
j. q__// IN N U ^ (W'T 'N' 'Cl
H H
tert-Butyl 2-chloro[3-[(lR,2S,4S)-norbomanyl]oxypyrazol-lyl
]pyridinecarboxylate (1.814 g, 4.653 mmol) and TFA (5 mL, 64.90 mmol) were
ed in dichloromethane (18.14 mL) and heated at 40 °C for 2 h. The reaction was
evaporated. Hexanes were added and the mixture evaporated again to give a white solid,
which was used in the next step without r purification. ro[3-[(lR,2S,4S)-
norbomanyl]oxypyrazol-l-yl]pyndinecarboxylic acid (1.47 g, 79%) ESI-MS m/z
calc. 333.088, found 334.2 (M+l)+; Retention time: 0.71 minutes.
Step E: N-(Benzenesulfonyl)chloro[3-[(lR,2S,4S)-norbornan
yl]oxypyrazol-l-yl]pyridinecarboxainide
so2nh2
0 9 QP
'OH %■
H GDI
AnAn l/l H
7 N^rAciH
H H
2-Chloro[3-[(lR,2S,4S)-norbomanyl]oxypyrazol-l-yl]pyridine
carboxylic acid (100 mg)) and GDI (52 mg, 0.323 mmol) were combined in THF and
SUBSTITUTE SHEET (RULE 26)
stirred for 2 hours at room temperature. Benzene sulfonamide (52 mg, 0.331 mmol) and
DBU (0.048 mL, 0.323 mmol) were then added and the reaction was stirred an
additional 2 hours at room temperature. The reaction mixture was then poured into 20
mL 1 M citric acid and extracted 3x 20 mL ethyl acetate. The combined organics were
washed with water, then brine, dried over sodium sulfate, and concentrated to give
approximately 122 mg N-(benzenesulfonyl)chloro[3-[(lR,2S,4S)-norboman
yl]oxypyrazol-l-yl]pyridinecarboxamide which was used in the next step without
further purification. ESI-MS m/z calc. 490.12, found 491.3 (M+l)+; Retention time:
0.75 s.
Step F: N-(Benzenesulfonyl)[3-[(lR,2S,4S)-norboman
yl]oxypyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
flifc -,lC£po oo HN HCI
k2co3 trv
] zenesulfonyl)chloro[3-[(lR,2S,4S)-norbomanyl]oxypyrazol-
l-yl]pyridinecarboxamide (120 mg, 0.2537 mmol), (4S)-2,2,4-trimethylpyrrolidine
(hydrochlonde salt) (113.9 mg, 0.7611 mmol), and potassium carbonate (210.3 mg,
1.522 mmol) were combined in 0.423 mL DMSO in a screwcap vial and heated to 130
°C for 16 hours. The reaction mixture was then cooled to room temperature, and 3 mL
of water was added, resulting in the formation of a precipitate. After 30 minutes, the
liquid portion was removed by syringe and discarded, and the remaining solids were
dissolved in 15 mL ethyl e. The organics were washed with 15 mL 1M citric acid,
and the aqueous layer was extracted an additional time with 15 mL ethyl acetate. The
combined organics were washed with brine, dried over sodium sulfate and concentrated.
The crude material was ed by column chromatography on silica gel using a
gradient of 0-10% methanol in dichloromethane. The pure fractions were combined and
concentrated to give N-(benzenesulfonyl)[3-[(lR,2S,4S)-norbomanyl]oxypyrazoll-yl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (59 mg, 40%).
ESI-MS m/z calc. 549.24, found 550.4 ; Retention time: 2.37 minutes 'fl NMR
(400 MHz, DMSO) 5 12.50 (s, 1H), 8.17 (d, J = 2.8 Hz, 1H), 8.02 - 7.97 (m, 2H), 7.80
(d, J = 8.2 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.70 - 7.63 (m, 2H), 6.90 (d, J = 8.2 Hz, 1H),
SUBSTITUTE SHEET (RULE 26)
6.08 (d, J = 2.7 Hz, 1H), 4.49 (d, J = 6.7 Hz, 1H), 2.46 - 2.37 (m, 2H), 2.27 (q, J = 10.0,
7.6 Hz, 2H), 2.09 (dq, J = 11.6, 5.9, 5.4 Hz, 1H), 1.86 - 1.77 (m, 1H), 1.56 (d, J = 6.9
Hz, 1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.46 (dd, J = 13.8, 6.6 Hz, 3H), 1.36 (t, J = 12.1 Hz,
1H), 1.25 - 1.06 (m, 4H), 0.64 (d, J = 6.3 Hz, 3H).
Synthetic Example 40: Synthesis of Compound 40: N-(Benzenesulfonyl)-
6- [3- [ [(lR,4R)-norbomanyl] methoxyjpyrazol- l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: tert-butyl 3-[[(lS,4R)-norbornanyl]methoxy]pyrazole-l-
carboxylate
HOx^N OPm N-N
OH + DIAD
^ o PPh3
tert-Butyl 3-hydroxypyrazole-l-carboxylate (1.327 g, 7.204 mmol),[(lS,4R)-
norbomanyl]methanol (1 g, 7.924 mmol) (mixture of endo and exo), and triphenyl
phosphine (2.09 g, 7.968 mmol) were combined in THF (17.87 mL) and the on
was cooled in an ice bath. To the mixture was added DIAD (1.627 mL, 8.263 mmol)
dropwise and the reaction was allowed to warm to room temperature and d for 72
h. The mixture was evaporated and the resulting al was partitioned between ethyl
acetate (50 mL) and IN sodium hydroxide (50 mL). The organics were separated,
washed with brine, dried over sodium sulfate and evaporated. The crude material was
purified by silica gel chromatography eluting with 0-30% ethyl e in hexanes to
give tert-butyl 3-[[(lS,4R)-norbomanyl]methoxy]pyrazole-l-carboxylate (1.698 g,
81%) ESI-MS m/z calc. 292.17868, found 293.3 (M+l)+; Retention time: 0.77 s.
(2 diastereomers - mix of endo and exo substituted norbomane) 'H NMR (400 MHz,
DMSO) 5 8.06 (d, J = 2.9 Hz, 1H), 6.10 (dd, J = 2.9, TO Hz, 1H), 4.23 - 3.81 (m, 2H),
2.29-2.15 (m, 2H), 1.69 (dq, J= 12.1, 4.2 Hz, 1H), 1.54 (d, J = 1.4 Hz, 9H), 1.51 -1.03
(m, 7H), 0.75 (dd, J = 5.0, 2.4 Hz, 1H).
Step B: 3-[[(lS,4R)-norbornanyl]methoxy]-lH-pyrazole
SUBSTITUTE SHEET (RULE 26)
hay~ H TFA H
N-N N-NH
H H
tert-Butyl 3-[[(lS,4R)-norbomanyl]methoxy]pyrazole-l-carboxylate
(1.698 g, 5.808 mmol) was dissolved in CH2CI2 (16.98 mL) with trifluoroacetic acid
(approximately 6.622 g, 4.474 mL, 58.08 mmol) and the reaction was stirred at room
temperature for 2 h. The reaction was evaporated and the resulting oil was partitioned
between ethyl e (50 mL) and a saturated sodium bicarbonate solution (30 mL).
The organics were separated, washed with bnne, dried over sodium sulfate and
concentrated under vacuum to give an oil, 3-[[(lS,4R)-norbomanyl]methoxy]-lH-
pyrazole (1.11 g, 99%) ESI-MS m/z calc. 192.12627, found 193.2 (M+l)+; Retention
time: 0.52 minutes.
Step C: tert-Butyl 2-chloro[3-[[(lS,4R)-norbornan
yl]methoxy]pyrazol-l-yl]pyridinecarboxylate
dho DABCO
cr n ci
H' K2CO3
A round bottom flask was charged under nitrogen with 3-[[(l S,4R)-
norbomanyl]methoxy]-lH-pyrazole (1.11 g, 5.774 mmol) (mix of two
diastereomers), tert-butyl 2,6-dichloropyndmecarboxylate (1.433 g, 5.776 mmol),
K2CO3 (1.05 g, 7.597 mmol) (freshly ground in a mortar) and anhydrous DMF (10 mL).
DABCO (117 mg, 1.043 mmol) was added and the mixture was stirred at room
temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl
acetate (50 mL) and water (50 mL) and the two phases were separated. The aqueous
phase was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were
washed with brine, dried over sodium e and the solvent removed under reduced
pressure. The material was subjected to flash chromatography on silica gel using a
gradient of ethyl e (0 to 20% ) in hexanes. The pure fractions were combined and
the solvents d under d pressure to provide tert-butyl 2-chloro[3-
[[(lS,4R)-norbomanyl]methoxy]pyrazol-l-yl]pyridinecarboxylate (1.88 g, 81%)
ESI-MS m/z calc. 403.16626, found 404.3 ; ion time: 0.94 minutes
SUBSTITUTE SHEET (RULE 26)
Step D: 2-Chloro[3-[[(lS,4R)-norbornanyl]methoxy]pyrazol-l-
idinecarboxylic acid
TFA *H
.H P-J*'*}
] tert-Butyl 2-chloro[3-[[(lS,4R)-norbomanyl]methoxy]pyrazol-l-
idinecarboxylate (1.88 g, 4.655 mmol) and TFA (5 mL. 64.90 mmol) were
combined in dichloromethane (18.80 mL) and heated at 40 °C for 2 h. The reaction was
ated. Hexanes were added and the mixture evaporated again to give a white solid
2-chloro[3-[[(lS.4R)-norbomanyl]methoxy]pyrazol-l-yl]pyridinecarboxylic
acid (1.58 g, 98%) ESI-MS m/z calc. 347.10367, found 348.2 (M+l)+; Retention time:
0.75 minutes.
Step E: N-(Benzenesulfonyl)chloro[3-[[(lR,4R)-norbornan
yl] methoxy] py razol- 1-yl] pyridinecarb oxamidea
so2nh2
OH vH xy-o9 q, P
ci n
H' DBU H'
2-Chloro[3-[[(lS,4R)-norbomanyl]methoxy]pyrazol-l-yl]pyndine
carboxylic acid (100 mg, 0.2875 mmol) and GDI (60.59 mg, 0.3737 mmol) were stirred
in THF (0.5 mL) at room temperature for 2 hours. Benzenesulfonamide (50 mg, 0.3181
mmol) was then added, followed by DBU (0.05588 mL, 0.3737) and the reaction was
stirred an additional 4 hours at room temperature. The reaction mixture was then
diluted with 25 mL ethyl acetate and poured 25 mL citric acid. The aqueous layer was
extracted with an additional 25 mL ethyl acetate, and the combined organics were
washed with water then brine, dried over sodium sulfate, and concentrated to give N-
(benzenesulfonyl)chloro[3-[[(lR,4R)-norbomanyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (approximately 135 mg), which was used in the next step
without r purification. ESI-MS m/z calc. 486.11, found 487.2 (M+l)+; ion
time: 0.84 minutes.
SUBSTITUTE SHEET (RULE 26)
] Step F: N-(benzenesulfonyl)[3-[[(lR,4R)-norbornan
yl] y] pyrazol- 1-yl] [(4S)-2,2,4-trimethylpy rrolidin- 1-yl] pyridine
carboxamide
HN HCI
ivC#A °'s° (S) ?\0,P
.H o
k2co3
] zenesulfonyl)chloro[3-[[(lR,4R)-norboman
hoxy]pyrazol-l-yl]pyridinecarboxamide, (135 mg. 0.2772 mmol), (4S)-2,2,4-
trimethylpyrrolidine (Hydrochloride salt) (124.5 mg, 0.8316 mmol), and potassium
carbonate (229.8 mg, 1.663 mmol) were combined in DMSO in a screwcap vial and
heated to 130 °C for 16 hours. The reaction mixture was then cooled to room
temperature, and 3 mL of water was added, resulting in the formation of a precipitate.
After 30 minutes, the liquid portion was removed by syringe and discarded, and the
remaining solids were dissolved in 15 mL ethyl acetate. The organics were washed with
mL 1M citric acid, and the s layer was extracted an additional time with 15
mL ethyl acetate. The combined organics were washed with brine, dried over sodium
sulfate and concentrated. The crude material was purified by column chromatography
on silica gel using a gradient of 0-10% methanol in dichloromethane. The pure
fractions were combined and concentrated to give N-(benzenesulfonyl)[3-[[(lR,4R)-
anyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-
3-carboxamide, (mixture of endo and exo norbomane) ESI-MS m/z calc. 563.26, found
564.4 (M+l)+; Retention time: 2.45 minutes, 'h NMR (400 MHz, DMSO) 5 12.50 (s,
1H), 8.18 (dd, J = 2.8, 1.0 Hz, 1H), 7.99 (dd, J = 7.2, 1.7 Hz, 2H), 7.80 (dd, J = 8.3, 1.1
Hz, 1H), 7.79 - 7.70 (m, 1H), 7.66 (dd, J = 8.3, 6.7 Hz, 2H), 6.92 (dd, J = 8.3, 5.8 Hz,
1H), 6.12 (t, J = 2.9 Hz, 1H), 4.23 - 3.90 (m, 2H), 2.40 (t, J = 10.5 Hz, 1H), 2.35 - 2.16
(m, 4H), 2.09 (tt, J = 12.3, 6.2 Hz, 1H), 1.82 (dd, J = 11.9, 5.5 Hz, 1H), 1.73 (s, 1H),
1.52 (d, J = 9.7 Hz, 7H), 1.50 - 1.45 (m, 1H), 1.42 - 1.27 (m, 4H), 1.21 - 1.08 (m, 2H),
0.75 (ddd, J = 12.5, 5.0, 2.2 Hz, 1H), 0.64 (d, J = 6.2 Hz, 3H).
Synthetic Example 41: Synthesis of Compound 41: N-
(Benzenesulfonyl)[3-(2,2-dicyclopropylethoxy) pyrazolyl][(4A)-2,2, 4-
trimethylpyrrolidin-l-yl] pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
WO 64632
•OH 0 I fT 0
'N~NH ci^n^ci
n-naJ< TFA
0=U DIAD, PPh3 P'C!
K2CO3, DABCO
O' TFA
p^N' N XI PXJN N" Cl cqi, DBU
svC CIH.HN'^IS *aP
fT H 0
P~(j N' Cl p-^JNANiSA§i
K2CO3, DMSO
Step A: te/7-Butyl 3-(2,2-dicyclopropylethoxy) pyrazole-l-carboxylate
OH M-nV^0 I N-nX,^ 0-tJ
DIAD, PPh3
A solution of 2,2-dicyclopropylethanol (500 mg, 3.962 mmol), tert-butyl 3-
hydroxypyrazole-l-carboxylate (730 mg, 3.963 mmol), and triphenylphosphane (1.1 g,
4.194 mmol) in dry THF (20.0 mL) was cooled in an ice bath, and DIAD (800.0 pL,
4.063 mmol) was slowly added under N2 atmosphere. The reaction was allowed to
slowly warm to room temperature and was stirred for 16 h. The reaction e was
diluted with ethyl acetate, washed with ted aqueous sodium bicarbonate, brine,
dried over sodium sulfate, and concentrated. The residue was purified by silica gel
chromatography with 100% hexanes to 50% ethyl acetate in hexanes to afford tert-butyl
3-(2, 2-dicyclopropylethoxy)pyrazole-l-carboxylate (783 mg, 68%) as colorless oil.
ESI-MS m/z calc. 292.17868, found 293.3 (M+l)+; Retention time: 1.98 minutes. ^
NMR (400 MHz, Chloroform-d) 5 7.62 (d, J = 3.0 Hz, 1H), 5.67 (s, 1H), 4.13 (d, J = 5.3
Hz, 2H), 1.44 (s, 9H), 0.58 (qt, J = 8.2, 5.0 Hz, 2H), 0.36 (tt, J = 8.9, 5.6 Hz, 1H), 0.32 -
0.12 (m, 4H) 0.10 - 0.08 (m, 4H).
Step B: 3-(2,2-Dicyclopropylethoxy)-lH-pyrazole:
SUBSTITUTE SHEET (RULE 26)
TFA P^H
A solution of tert-butyl 3-(2, 2-dicyclopropylethoxy) pyrazole-l-carboxylate
(750 mg, 2.565 mmol) and trifluoroacetic acid (1.0 mL, 12.98 mmol) in
dichloromethane (4 mL) was stirred for 2.5 hours. The volatiles were removed under
reduced pressure and the residue was basified with saturated aqueous sodium
bicarbonate and extracted with ethyl acetate. The combined extracts were dried over
sodium sulfate and ated to give 3-(2.2-dicyclopropyletho\y)-1 /ole as
colorless oil which was used as it is without further purification for next reaction. ESIMS
m/z calc. 192.12627, found 193.3 (M+l)+; Retention time: 1.32 minutes.
Step C: fert-Butyl 2-chloro[3-(2,2-dicyclopropylethoxy) pyrazol-l-yl]
pyridinecarboxylate
V<9 | k2co3, dabco + A- —
^ Cl N^CI '°~U
A mixture of 3-(2,2-dicyclopropylethoxy)-lH-pyrazole (493.0 mg, 2.564
mmol), fe/7-butyl 2,6-dichloropyridinecarboxylate (682.0 mg, 2.749 mmol),
potassium carbonate (430.0 mg, 3.111 mmol), and azabicyclo[2.2.2]octane (60
mg, 0.5349 mmol) in DMSO (20.0 mL) was stirred at room temperature for 15 hours.
The reaction was diluted with water and extracted with ethyl acetate. The combined
extracts were washed with brine and dried over sodium e and ated. The
residue was purified by silica gel column chromatography with 100% hexanes to 20%
ethyl acetate in hexanes to afford utyl 2-chloro[3-(2,2-
dicyclopropylethoxy)pyrazol-l-yl]pyridinecarboxylate (680 mg, 66%) as colorless
oil. ESI-MS m/z calc. 403.16626, found 404.4 (M+l)+; ion time: 2.49 minutes.
lH NMR (400 MHz, Chloroform-d) 5 8.35 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H),
7.70 (d, J = 8.5 Hz, 1H), 5.98 (d, J = 2.9 Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 1.61 (s, 9H),
0.92 - 0.75 (m, 2H), 0.70 - 0.56 (m, 1H), 0.54 - 0.36 (m, 4H), 0.32 - 0.13 (m, 4H).
] Step D: 2-Chloro[3-(2,2-dicyclopropylethoxy) pyrazol-l-yl] pyridine-
3-carboxylic acid
SUBSTITUTE SHEET (RULE 26)
0 0
TFA OH
,0'^NANA'CI
A solution of fer/-butyl2-chloro[3-(2,2-dicyclopropylethoxy)pyrazol-l-
yl]pyridinecarboxylate (675 mg, 1.671 mmol) in trifluoroacetic acid (15 mL, 19 47
mmol) and dichloromethane (4.5 mL) was stirred for 4 hours at room ature. The
solvent was evaporated, and twice the residue was taken up in THF and concentrated
under vacuum to afford 2-chloro[3-(2, 2-dicyclopropylethoxy) pyrazol-l-yl]
pyridinecarboxylic acid (580 mg, 100%). ESI-MS m/z calc. 347.10367, found 348.3
(M+l) +; ion time: 1.95 minutes.
Step E: N-(Benzenesulfonyl)chloro[3-(2,2-dicyclopropylethoxy)
pyrazol-l-yl] pyridinecarboxamide
o 40 9 q
OH NH2 %- is
N “o H
N. U
P-^QN N Cl
GDI, DBU O^N N 'Cl
A solution of ro[3-(2, 2-dicyclopropylethoxy) pyrazol-l-yl]
pyridinecarboxylic acid (100 mg, 0.2875 mmol) and carbonyl diimidazole (60.0 mg,
0.3700 mmol) in THF (2.0 mL) was stirred for 45 minutes. Then, benzenesulfonamide
(50 mg, 0.3181 mmol) and DBU (60 pL, 0.4012 mmol) were added and the reaction
mixture was stirred for additional 2 hours at room temperature. The reaction mixture
was quenched with saturated ammonium chloride solution and extracted with ethyl
acetate. The combined c extracts were washed with brine, dried over sodium
sulfate and evaporated to afford N-(benzenesulfonyl)chloro[3-(2,2-
dicyclopropylethoxy)pyrazol-l-yl]pyridinecarboxamide which was used as it is for
next reaction. ESI-MS m/z calc. 486.11285, found 487.4 ; Retention time: 0.79
minutes.
Step F: N-(Benzenesulfonyl)[3-(2,2-<Hcyclopropylethoxy) pyrazol
yl][(4A)-2,2,4-trimethylpyrrolidin-l-yl] pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
9 Q HN-^S; 9 Q
M-S .'s
N 'N 'X H M 'X H
N- ° °
P-^N N XI K2CO3, DMSO
A mixture of N-(benzenesulfonyl)chloro[3-(2, 2-dicyclopropylethoxy)
pyrazol-l-yl] pyridinecarboxamide (140.0 mg, 0.2875 mmol), (45)-2, 2, 4-
trimethylpyrrolidine (Hydrochloride salt) (145.0 mg, 0.9689 mmol), and potassium
carbonate (240.0 mg, 1.737 mmol) in DMSO (2 mL) was stirred at 130 °C for 15 hours.
The reaction mixture was filtered through Whatman filter disc (puradisc 25 IF) and
filtrate was ed by a reverse phase HPLC-MS method using a dual gradient run
from 50-99% mobile phase B over 15.0 minutes (Mobile phase A = H2O (5 mM HCI)
and Mobile phase B = CH3CN) to affordN-(benzenesulfonyl)[3-(2,2-
dicyclopropylethoxy)pyrazol-l-yl][(4<S)-2,2,4-tnmethylpyrrolidin-l-yl]pyridine
carboxarmde (75.9 mg, 45%) as off white solid. ESI-MS m/z calc. 563.25665, found
564.5 (M+l) +; Retention time: 2.3 minutes. *H NMR (400 MHz, Chloroform-d) 8 8.35
(d, J = 8.6 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.66 - 7.47 (m, 5H),
.96 (d, J = 2.8 Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 3.48 (dd, J = 10.4, 8.4 Hz, 1H), 3.08
(dd, J = 10.4, 7.6 Hz, 1H), 2.61 (dt, J = 15.3, 7.8 Hz, 1H), 2.14 (dd, J = 12.4, 7.9 Hz,
1H), 1.73 (dd, J = 12.4, 9.5 Hz, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H),
0.81 (qt, J = 8.3, 5.0 Hz, 2H), 0.61 (tt, J = 8.8, 5.6 Hz, 1H), 0.55 - 0.38 (m, 4H), 0.23 (p,
J = 4.8 Hz, 4H).
Synthetic Example 42: Synthesis of Compound 42: N-
nesulfonyl)[3-(3, 3-dicyclopropylpropoxy) pyrazol-l-yl][(4A)-2, 2, 4-
hylpyrrolidin-l-yl] pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
n-nh [\ T
N-N CI^N^CI
'OH TFA
0=U DIAD, PPh3 K2CO3, DABCO
'OH ,'sX)
TFA H2N '0
PXjN^N""CI N c
GDI, DBU
VP CIH.HN'^S;
^0Xj NCi p^N N
k2co3, dmso
] 3,3-dicyclopropylpropan-l-ol
0 UAIH4
'OH OH
To a on of 3, 3-dicyclopropylpropanoic acid (200 mg, 1.297 mmol) in
dry THF (2.000 mL) was added lithium aluminum hydride (845.0 liL of 2 M, 1.690
mmol) in an ice/water bath under N2 atmosphere slowly drop wise. The mixture was
d to gradually warm to room temperature and stirred for 16 hours. The flask was
again cooled in an ice-bath and sequentially quenched with water (70.0 pL. 3.886
mmol) (slowly), followed by NaOH (70.0 liL of 6 M, 0.4200 mmol), then water (200
|iL. 11.10 mmol) affording a white granular solid in the mixture. To this mixture
anhydrous MgSCh was added and stirred for 10 minutes. The resultant white
heterogeneous mixture was filtered through celite and the precipitate was washed with
ether. The filtrate was concentrated to afford 3, 3-dicyclopropylpropan-l-ol (140 mg,
77%). ESI-MS nvz calc. 140.12012, found 141.2 ; ion time: 0.5 minutes.
Step A: fert-butyl 3-(3,3-dicyclopropylpropoxy) pyrazole-l-carboxylate
Wc 'OH
O-u DIAD, PPh3
SUBSTITUTE SHEET (RULE 26)
A solution of 3, 3-dicyclopropylpropan-l-ol (140.0 mg, 0.9984 mmol), tyl
3-hydroxypyrazole-l-carboxylate (185.0 mg, 1.004 mmol), and
triphenylphosphane (278 mg, 1.060 mmol) in dry THF (7.0 mL) was cooled in an ice
bath, and DIAD (200.0 pL, 1.016 mmol) was slowly added under aN2 atmosphere. The
reaction was allowed to slowly warm to room temperature and was stirred for 16 hours.
The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous
sodium bicarbonate on, bnne, dried over sodium sulfate, and evaporated under
. The residue was purified by silica gel chromatography using 100% hexanes to
50% ethyl acetate in hexanes to afford /m-butvl 3-(3,3-dicyclopropylpropoxy)pyrazole-
1-carboxylate (255 mg, 83%) as colorless oil. ESI-MS m/z calc. 306.19434, found 307.4
(M+l) +; Retention time: 0.81 minutes.
Step B: 3-(3,3-dicyclopropylpropoxy)-lH-pyrazole
<Vnn TEA OX/NH
A solution of /erf-butyl 3-(3, 3-dicyclopropylpropoxy) le-l-
carboxylate (255 mg, 0.8322 mmol) and trifluoroacetic acid (325.0 pL, 4.218 mmol) in
dichloromethane (1 mL) was d for 2.5 hours. The volatiles were removed under
vacuum to afford 3-(3, 3-dicyclopropylpropoxy)-lH-pyrazole (Trifluoroacetate salt) as
colorless oil which was used as it is t further purification for next reaction. ESIMS
m/z calc. 206.1419, found 207.2 (M+l)+; Retention time: 0.59 minutes.
Step C: fert-Butyl 2-chloro[3-(3, 3-dicyclopropylpropoxy) pyrazol
yl] ecarboxylate
•O^N. K2CO3, DABCO
XX'0' U™ N "Cl
Cr N'ul
A mixture of fer/-butyl 2,6-dichloropyridinecarboxylate (220.0 mg, 0.8867
mmol), 3-(3,3-dicyclopropylpropoxy)-lH-pyrazole (266.0 mg, 0.8305 mmol),
potassium carbonate (230 mg, 1.664 mmol) and l,4-diazabicyclo[2.2.2]octane (20 mg,
0.1783 mmol) in DMSO (10 mL) was stirred at room temperature for 15 hours. The
reaction was diluted with water and extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried over sodium sulfate and evaporated. The residue
SUBSTITUTE SHEET (RULE 26)
was purified by silica gel column chromatography using 100% hexanes to 20% ethyl
acetate in hexanes to afford rm-butyl 2-chloro[3-(3,3-dicyclopropylpropoxy)pyrazoll-yl
]pyridinecarboxylate (245 mg, 71%) as colorless oil. ESI-MS m/z calc.
417.18192, found 418.4 (M+l)+; Retention time: 1.28 minutes.
Step D: 2-Chloro[3-(3,3-dicyclopropylpropoxy) pyrazol-l-yl]
pyridinecarboxylic acid
O 0
•0^w 01 -°^y 'n''c,
A solution of fert-butyl 2-chloro[3-(3, 3-dicyclopropylpropoxy) pyrazol
yl]pyndinecarboxylate (245.0 mg, 0.5862 mmol) in tnfluoroacetic acid (500.0 pL,
6.490 mmol) and dichloromethane (1.5 mL) was stirred for 4 hours at room
temperature. The solvent was ated, and twice the e was taken up in THF
and concentrated under vacuum to afford 2-chloro[3-(3,3-
dicyclopropylpropoxy)pyrazol-l-yl]pyndinecarboxylic acid (204 mg, 96%) as white
solid which was used as it is for the next reaction. ESI-MS m/z calc. 361.11932, found
362.3 (M+l) +; ion time: 0.8 minutes. ’El NMR (400 MHz, ol-d4) 5 8.47 -
8.32 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 6.03 (d, J = 2.9 Hz, 1H), 4.45 (t, J = 6.7 Hz, 2H),
1.98 (q, J = 7.0 Hz, 2H), 0.75 - 0.64 (m, 2H), 0.50 - 0.39 (m, 4H), 0.35 - 0.26 (m, 1H),
0.26 - 0.19 (m, 2H), 0.15 - 0.06 (m, 2H).
Step E: N-(Benzenesulfonyl)chloro[3-(3,3-dicyclopropylpropoxy)
pyrazol- 1-yl] pyridinecarboxamide
0 q. ? vO
'OH :s . ,,'s;
h2N'6 NIV V\H
N. °
n Cl N Cl
GDI, DBU
] A solution of 2-chloro[3-(3, 3-dicyclopropylpropoxy) pyrazol
yl]pyridinecarboxylic acid (50.0 mg, 0.1382 mmol) and carbonyl diimidazole (30.0
SUBSTITUTE SHEET (RULE 26)
mg, 0.1850 mmol) in THF (2.0 mL) was stirred for 45 minutes. Then,
benzenesulfonamide (25.0 mg. 0.1590 mmol) and DBU (30 nL. 0.2006 mmol) were
added. The reaction mixture was stirred for additional 2 hours at room temperature. The
reaction mixture was ed with saturated ammonium chloride solution and
extracted with ethyl acetate. The combined organic extracts were washed with brine,
dried over sodium sulfate and evaporated to afford zenesulfonyl)chloro[3-
(3,3-dicyclopropylpropoxy)pyrazol-l-yl]pyridinecarboxarmde (84 mg, 121%) a s
light brown viscous oil which was used (considering 100% conversion) as it is for next
on. ESI-MS m/z calc. 500.1285, found 501.4 (M+l) +; Retention time: 0.83
minutes,
] Step F: N-(Benzenesulfonyl)[3-(3, 3-dicyclopropylpropoxy) pyrazol
yl][(45)-2,2,4-trimethylpyrrolidin-l-yl] pyridmecarboxamide
*0 HCI
HN'NS, lQS-0
o-ry N ClII n 6 I I H,s°
k2co3i dmso P-GN N
A mixture ofN-(benzenesulfonyl)chloro[3-(3,3-
opropylpropoxy)pyrazol-l-yl]pyridinecarboxamide (68.0 mg, 0.1357 mmol),
(4,S')-2.2.4-tn methyl idine (Hydrochloride salt) (70.0 mg, 0.4677 mmol), and
potassium carbonate (115.0 mg, 0.8321 mmol) in DMSO (1 mL) was stirred at 130 °C
for 15 hours. The reaction mixture was filtered through Whatman filter disc (puradisc
TF) and filtrate was purified by a reverse phase HPLC-MS method using dual
gradient run from 50-99% mobile phase B over 15.0 minutes (Mobile phase A=H20 (5
mM HCI) and Mobile phase B=CH3CN to afford zenesulfonyl)[3-(3,3-
dicyclopropylpropoxy)pyrazol-l-yl][(45)-2,2,4-tnmethylpyrrolidin-l-yl]pyndine
carboxarmde (23.1 mg, 29%). ESI-MS m/z calc. 577.2723, found 578.5 (M+l) +;
Retention time: 1.0 minutes, 'h NMR (400 MHz, Chloroform-d) 6 8.36 (d, J = 8.6 Hz,
1H), 8.21 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.64 -
7.57 (m, 2H), 7.57 - 7.51 (m, 2H), 5.94 (d, J = 2.8 Hz, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.49
(dd, J = 10.3, 8.5 Hz, 1H), 3.09 (dd, J = 10.4, 7.6 Hz, 1H), 2.70 - 2.56 (m, 1H), 2.14 (dd,
J = 12.4, 7.9 Hz, 1H), 1.97 (q, J = 6.8 Hz, 2H), 1.73 (dd, J = 12.4, 9.4 Hz, 1H), 1.36 (s,
SUBSTITUTE SHEET (RULE 26)
3H), 1.28 (s, 3H), 1.21 (d, J = 6.7 Hz, 3H), 0.73 - 0.59 (m, 2H), 0.50 - 0.37 (m, 4H),
0.37 - 0.29 (m, 1H), 0.24 - 0.15 (m, 2H), 0.12 - 0.07 (m, 2H).
Synthetic Example 43: Synthesis of Compound 43: hlorophenyl)
yl[3-[2-[l-(trifluoromethyl) cyclopropyl] ethoxy] pyrazol-l-yl][(45)-2, 2,
4-trimethylpyrrolidin- 1-yl] pyridinecarboxamide
Step A: 2-Chloro-N-(2-chlorophenyl) sulfonyl[3-[2-[l-
(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxamide
0 vO 9 o, p 91
‘OH Cl o H
p^jN N^'CI N-
F GDI, DBU F
F- F-
F F
Step 1: 2-Chlorobenzenesulfonyl chloride (50 pL, 0.3667 mmol) was
dissolved in ammonia in methanol (150 pL of 7 M, 1.050 mmol) and d at room
temperature for 30 minutes. The mixture was evaporated to dryness and re-evaporated
from dichloromethane. The solids were dissolved in THF (1 mL) and DBU (60 pi..
0.4012 mmol) was added. The mixture was stirred at 70 °C for 30 minutes to liberate
any remaining ammonia from the reaction.
Step 2: 2-Chloro[3-[2-[l-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-l-
yl]pyridinecarboxylic acid (100 mg, 0.2661 mmol) and yl diimidazole (53 mg,
0.3269 mmol) were combined in THF (1.000 mL) and stirred for 2 hours. At this point,
this mixture was added to the sulfonamide mixture (from step-1) and the reaction was
stirred for overnight at room temperature. The reaction was diluted with ethyl acetate
and washed with a 1 M citric acid solution, followed by brine. The organics were
separated, dried over magnesium sulfate, and evaporated to afford 2-chloro-N-(2-
chlorophenyl) sulfonyl[3-[2-[l-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-lyl
]pyridinecarboxamide along with starting material and primary amide. The mixture
was used as it is for the next on. ESI-MS mlz calc. 548.02997, found 549.28
(M+l) +; ion time: 0.76 minutes.
Step B: hlorophenyl) sulfonyl[3-[2-[l-(trifluoromethyl)
cyclopropyl] ethoxy] pyrazol-l-yl][(4A)-2,2,4-trimethylpyrrolidinyl]
pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
HCI 9 ,o 91
,^NXN^CI w jy jl h i
H' K2C03l dmso
A mixture of 2-chloro-N-(2-chlorophenyl) sulfonyl[3-[2-[l-
(trifluoromethyl) cyclopropyl] ethoxy] pyrazol-l-yl]pyridinecarboxamide (50.0 mg,
0.09102 mmol) (mixture as it from Step A ), (45')-2.2.4-trmiethylpyrrolidine
(Hydrochloride salt) (50.0 mg, 0.3341 mmol), and potassium carbonate (80.0 mg,
0.5788 mmol) in DMSO (2.0 mL) was stirred at 130 °C for 15 hours. The reaction
mixture was filtered through Whatman filter disc (puradisc 25 TF) and filtrate was
purified by a e phase S method using a dual gradient run from 50-99%
mobile phase B over 15.0 minutes (Mobile phase A=H20 (5 mM HCI) and Mobile
phase B=CH3CN) to afford N-(2-chlorophenyl) yl[3-[2-[l-(trifluoromethyl)
cyclopropyl] ethoxy[pyra/ol-l-yl |(4,S)-2.2.4-trirnethylpyrrolidin-l-yl | pyridine
carboxamide (18.7 mg, 31%). ESI-MS m/z calc. 625.17377, found 626.5 (M+l) +;
ion time: 2.35 minutes, 'll NMR (400 MHz, Chloroform-d) 5 8.43 - 8.36 (m, 1H),
8.32 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.53 - 7.44
(m, 3H), 5.94 (d, J = 2.7 Hz, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.51 (t, J = 9.5 Hz, 1H), 3.13
(dd, J = 10.6, 8.1 Hz, 1H), 2.73 - 2.55 (m, 1H), 2.16 (dd, J = 12.4, 7.7 Hz, 1H), 2.09 (t, J
= 7.1 Hz, 2H), 1.77 (dd, J = 12 5, 9 6 Hz, 1H), 1 47 (s, 3H), 1.41 (s, 3H), 1.20 (d, J = 6.6
Hz, 3H), 1.09 - 0.97 (m, 2H), 0.81 - 0.64 (m, 2H).
Synthetic Example 44: Synthesis of Compound 44: ation of (S)-
N-(phenylsulfonyl)(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-lyl
)(2,2,4-trimethylpyrrolidin-l-yl)nicotinamide
Step A: Methyl 6-(3-(2-(l-(trifhioromethyl)cyclopropyl)ethoxy)-lH-
pyrazol-i-yl)chloropyridinecarboxylate
N-m Cl
Fsf Cl Cl
•CL,N
F NH
SUBSTITUTE SHEET (RULE 26)
WO 64632 2017/054611
To the solution of 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole
(720 mg, 3.27 mmol) and methyl chloropyridinecarboxylate (742 mg, 3.60
mmol) in N,N-dimethylformamide (11 mL) were added potassium carbonate (9.36 g,
9.82 mmol) and 1,4-diazabicyclo [2.2.2]octane (110 mg, 0.98 mmol). The resulting
solution was heated at 80 °C for 16 hours. The reaction on was cooled to room
temperature and diluted with diethyl ether (400 mL). Then water (50 mL) was added,
and the organic layers were separated. The organic layers were washed with IN s
hydrogen chloride solution (15 mL), brine (3x15 mL), dried over magnesium sulfate,
filtered and concentrated. The residue was purified by silica gel column
chromatography using 0 - 20% hexanes - ethyl acetate to afford methyl 6-(3-(2-(l-
(trifluoromethyl)cy clopropyl)ethoxy)- IH-pyrazol-1 -yl)chloropyridinecarboxylate
(631 mg, 49%) as a white solid. ^NMR (250MHz, CDC13) 5 (ppm): 8.84 (s, 1H), 8.36
(d, J = 2.8Hz, 1H), 7.85 (s, 1H), 5.96 (d, J = 2.8Hz, 1H), 4.42 (t, J = 7.0Hz, 2H), 3.96 (s,
3H), 2.11 (t, J = 7.0Hz, 2H), 1.05 (m, 2H), 0.76 (m, 2H). ESI-MS m/z calc. 389.1 found
390.0 (Ml). Retention time: 7.08 minutes.
Step B: 6-(3-(2-(l-(Trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-
yl)chloropyridinecarb oxylic acid
rr0O NT OH
,N'N 01
p^Jn-n 01
Methyl 6-(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)
chloropyndinecarboxylate(553 mg, 1.42 mmol) was dissolved in a mixture of
tetrahydrofuran (3.5 mL) and methanol (3.5 mL), then 2N aqueous sodium hydroxide
solution (1.4 mL, 2.84 mmol) was added. The resulting solution was d at room
temperature for 3 hours. All solvents were removed under the reduced pressure. The
residue was acidified with IN aqueous hydrogen chloride solution until pH value
reached 2 and it was then extracted with ethyl e (3 x 80 mL). The organic layer
was washed with brine (2 x 20 mL), dried over magnesium sulfate, filtered and
SUBSTITUTE SHEET (RULE 26)
concentrated to afford 2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-lyl
)chloropyridinecarboxylic acid (534 mg, 97%) as a white solid, 'ft NMR
(250MHz, DMSO) 5 (ppm): 8.85 (s, 1H), 8.51 (d, J = 3.0Hz, 1H), 7.76 (s, 1H), 6.21 (d,
J = 3.0Hz, 1H), 4.36 (t, J = 7.0Hz, 2H), 2.11 (t, J = 7.0Hz, 2H), 0.95(m, 2H), 0.90 (m,
2H). ESI-MS m/z calc. 375.1 found 376.0 (M+l)+ Retention time: 5.80 minutes.
Step C: 4-Chloro-N-(phenylsulfonyl)(3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)nicotinamide
-s;jD rf°H Qs^
1X1 H2N Q n-n Cl
6-(3-(2-(l-(Trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)
chloropyridinecarboxylic acid (528 mg, 1.40mmol) and l,r-carbonyldiimidazole
(341 mg, 2.11 mmol) in tetrahydrofuran (9 mL) was stirred for 2 hours at room
temperature, then benzenesulfonamide (220 mg, 1.40 mmol) and 1,8-
diazabicyclo[5.4.0]undecene (641 mg, 4.21 mmol) were added. The reaction solution
was stirred for additional 16 hours and diluted with ethyl acetate (200 mL). The on
was washed with saturated aqueous tartaric acid solution (25 mL), water (40 mL), brine
(40 mL), then dried over magnesium sulfate, filtered and concentrated. The residue was
purified by silica gel chromatography using ethyl acetate to afford 4-chloro-N-
(phenylsulfonyl)(3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-lyl
)nicotinamide (411 mg, 57%) as a white solid, 'h NMR z, DMSO) 5 (ppm):
8.56 (s, 1H), 8.47 (d, J = 2.5Hz, 1H), 7.94 (d, J = 6.8Hz, 2H), 7.67 (s, 1H), 7.59 (m,
3H), 6.16 (d, J = 2.5Hz, 1H), 4 34 (t, J = 7.0Hz, 2H), 2.09 (t, J = 7.0Hz, 2H), 0.94 (m,
2H), 0.89 (m, 2H). ESI-MS m/z calc. 514.1 found 515.0 (Ml). Retention time: 6.31
minutes.
Step D: (Phenylsulfonyl)(3-(2-(l-
uoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)(2,2,4-
trimethylpyrrolidin-l-yl)nicotinaiiiide
SUBSTITUTE SHEET (RULE 26)
kO 0 0
9 o. D
n b H n '6
H H U
H HN
N'N’ 'Cl IS)
To the on of 4-chloro-N-(phenylsulfonyl)(3-(2-(l-
(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)nicotinamide (54.6 mg, 0.11
mmol) in dimethyl sulfoxide (0.5 mL) were added (S)-2,2,4-tnmethylpyrrolidine
hydrochloride (96 mg, 0 64 mmol) and cesium fluoride (97 mg, 0.64 mmol). The
resulting solution was heated at 120 °C for 48 hours. The mixture was purified by
reverse phase HPLC using 5-100% water-acetomtnle (containing 0.1% tnfluoroacetic
acid). Pure ons were ed and lyophilized to afford the product as
trifluoroacetic acid salt, which was re-dissolved in 50% water-acetonitrile (0.1%
hydrogen chloride) and lyophilized again to afford (S)-N-(phenylsulfonyl)(3-(2-(l-
uoromethyl)cyclopropyl)ethoxy)-lH-pyrazol-l-yl)(2,2,4-trimethylpyrrolidin-lyl
)nicotinamide hydrogen chloride salt (27.8 mg, 42%). 'h NMR (250MHz, DMSO) 5
(ppm): 12.65 (s, 1H), 8.40 (s, 1H), 8.08 (d, J = 1.3Hz, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.70
(m, 3H), 7.24 (s, 1H), 6.05 (dd, J = 1.3, 2.5Hz, 1H), 4.34 (d, J = 7.0Hz, 2H), 2.50 (m,
3H), 2.09 (t, J = 7.0Hz, 2H), 2.10 (m, 1H), 1.91 (m, 1H), 1.53 (s, 6H), 0.87 (m, 2H),
0.84 (m, 2H), 0.64 (d, J = 6.0Hz, 3H). ESI-MS m/z calc. 591.2 found 592.6 (Ml).
Retention time: 2.88 s.
Synthetic Example 45: Synthesis of Compound 45,46, 47: N-
(amino(oxo)(phenyl)-A,6-sulfaneylidene)(3-((l-
(trifluoromethyl)cyclopropyl)methoxy)-lH-pyrazol-l-yl)((S)-2,2,4-
trimethylpyrrolidin-l-yl)nicotinamide isomer 1 and isomer 2
Step A: tert-Butyl 2,6-difluoropyridinecarboxylate
I O O |
o 0 k
DMAP, 2-methyl-THF
'% OH 'o
F N F F N F
SUBSTITUTE SHEET (RULE 26)
WO 64632
2,6-Difluoropyndinecarboxylic acid (1.0 g, 6.3 mmol) was dissolved in
anhydrous 2-methyl tetrahydrofuran (12 mL). Di-rm-butyl dicarbonate (1.5 g, 6.9
mmol) was added in one n followed by 4-(dimethylamino)pyridine (462 mg, 3.78
mmol). The mixture became a slurry, with large amount of gas evolution. The
heterogeneous mixture was stirred at room temperature over d and then diluted
with methyl utvl ether (30 mL). The organic layer was washed successively with 1
M aqueous HC1 (10 mL), 5% w/v saturated aqueous sodium bicarbonate solution (10
mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel chromatography, eluting with 0-30%
ethyl e in es, to provide /m-butyl 2,6-difluoropyridinecarboxylate (360
mg, 26% yield) as a light yellow oil. 1HNMR(300 MHz, CDCl3)ppm 1.60 (s, 9 H),
6.88 (ddd, J= 8.4, 3.0, 0.5 Hz, 1 H), 8.40- 8.47 (m, 1 H). 19F NMR (282 MHz, CDC13)
ppm -61.5 - -61.4 (m, IF), -60.3 (t, J= 8.6 Hz, 1 F).
Step B: tot-Butyl 2-fluoro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylate
CW/N'NH
F F ^ "O
P N N F
K2CO3, DMSO
F N F F
/e/7-Butyl 2,6-difluoropyridinecarboxylate (1.8 g, 8.4 mmol), 3-[[l-
(tnfluoromethvl)cvclopropvl xv |-1 //-pvrazole (1.8 g, 8.7 mmol) and freshly
ground potassium carbonate (1.7 g, 12 mmol) were added to anhydrous
dimethylsulfoxide (20 mL). The mixture was stirred at 20 °C under nitrogen for 16
hours and then diluted with ethyl acetate (100 mL). The organic layer was washed with
water (3 x 30 mL), dned over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The residue was ed by silica gel chromatography, eluting with 0-
% ethyl acetate in heptanes, to afford fert-butyl 2-fluoro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylate (1.9 g, 57%
yield) as a white solid. 'H NMR (300 MHz, CDCI3) ppm 0.92 - 0.99 (m, 2 H), 1.13-
1.18 (m, 2 H), 1.60 (s, 9 H), 4.40 (s, 2 H), 6.00 (d, J= 2.8 Hz, 1 H), 7.61 (d, J= 8.4 Hz,
SUBSTITUTE SHEET (RULE 26)
1 H), 8.30 (d, J= 2.8 Hz, 1 H), 8.37 (t, /= 8.4 Hz, 1 H). 19F NMR (282 MHz, CDCI3)
ppm -69.7 (s, 3 F), -62.2 (d, 9.2 Hz, 1 F). LCMS: [M+H]+ = 402.1.
Step C: 2-Fluoro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-
l-yl]pyridinecarboxylic acid
O k 0
o OH
0-^ n^n^f DCM qV'N^N^F
F F-
F F F F
Trifluoroacetic acid (4 mL) was added to a solution of fert-butyl 2-fluoro
[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylate (1.9
g, 4.7 mmol) in dichloromethane (16 mL). The mixture was stirred at 40 °C for 4 hours,
after which TLC showed full conversion. The mixture was concentrated under reduced
re and the e was triturated with heptanes, filtered and dried under high
vacuum to provide 2-fluoro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxylic acid (1.6 g, 98% yield) as a white solid. 'H NMR (300 MHz,
DMSO-ie) ppm 1.06- 1.11 (m,4H), 4.39 (s,2H), 6.24 (d,/=2.8Hz, 1 H), 7.66 (dd,J
= 8.3, 1.0 Hz, 1 H), 8.43 (d,J= 8.3 Hz, 1 H), 8.47 (dd,J= 9.6, 8.4 Hz, 1 H). 19FNMR
(282 MHz, DMSO-<4) ppm -67.9 (s, 3 F), -63.2 (d, J= 7.9 Hz, 1 F). LCMS: [M+H]+ =
346.1.
Step D: 2-Fluoro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-
1-yl] pyridinecarboxamide
O O
•%- 'OH
1) oxalyl chloride NH2
OV N N F ^FM yk.
2) NH3
F F
F F F F
To a suspension of 2-fluoro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (1.6 g,
4.6 mmol) in dichloromethane (20 mL) was added one drop of At ,V-di methyl formamide
ed by the dropwise addition of oxalyl chlonde (0.52 mL, 6.0 mmol). The reaction
SUBSTITUTE SHEET (RULE 26)
was stirred at room temperature for two hours until bubbling had stopped. The solvent
was removed under reduced pressure. The resulting white solid was dissolved in
anhydrous tetrahydrofuran (10 mL) and added to a mixture of 28% ammonium
hydroxide (10 mL) and tetrahydrofuran (5 mL) cooled with an ice-water bath. The
reaction was stirred at room temperature for 1 hour and then diluted with ethyl acetate
(100 mL), washed with water (20 mL), dried over anhydrous sodium sulfate, filtered
and concentrated under d pressure to afford 2-fluoro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (1.55 g,
98% yield) as a white solid. ^ NMR (300 MHz, CDC13) ppml.06-1.11 (m,4H),4.38
(s, 2 H), 6.21 (d, J= 2.7 Hz, 1 H), 7.61 (dd, J= 8.2, 1.5 Hz, 1 H), 7.76 (d, J= 8.2 Hz, 2
H), 8.33 (dd, T= 9.4, 8.4 Hz, 1 H), 8.4 (d, J= 2.7 Hz, 1 H). 19F NMR (282 MHz,
CDCL,) .9 (s, 3 F), -66.3 (d, 8.9 Hz, 1 F). LCMS: [M+H]+ = 345.1.
StepE: 2-Fluoro-iY-phenylsulfanyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O Ph'S'S'Ph O
NH2 N'S
N A A H
<1^-0 N F MeCN, Pyridine N F
F3C f3c
Bromine (0.14 mL, 2.7 mmol) was slowly added to a suspension of diphenyl
disulfide (596 mg, 2.73 mmol) in anhydrous acetonitrile (4 mL) at 0 °C. The reaction
was stirred at room temperature for 2 minutes to afford a solution. This solution was
added to a on of 2-fluoro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazoll-yl
inecarboxamide (940 mg, 2.73 mmol) in anhydrous acetonitrile (4 mL) and
pyridine (4 mL) at 0 °C. The resulting dark mixture was stirred at room temperature
ght, then concentrated under reduced pressure and porated with toluene (10
mL). The residual brown solid was purified by silica gel chromatography, eluting with
0-30% ethyl acetate in heptanes, to give ro-/V-phenylsulfanyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (380 mg,
31%yield) as a white solid. ^ NMR (300 MHz, CDCf) ppm0.93 - 1.00 , 1.14
- 1.19 (m, 2 H), 4.41 (s, 2 H), 6.03 (d, /= 3.0 Hz, 1 H), 7.20 - 7.26 (m, 1 H), 7.30 - 7.42
(m, 4 H), 7.73 (dd, J= 8.4, 1.8 Hz, 1 H), 7.84 (d, J= 15 Hz, 1 H), 8.28 (d, J= 3.0 Hz, 1
H), 8.63 (t, 9.0 Hz, 1 H). LCMS: [M+H]+ = 453.0.
SUBSTITUTE SHEET (RULE 26)
WO 64632
Step F: rac-A,-(benzenesulfinyl)fluoio[3-[| l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
0 0 0
ll ii
N'S m-CPBA N'S
N A A H
N F □CM <Lp-tJn A -A H N F
F3c f3c
flieta-Chloroperoxybenzoic acid (469 mg of 77%, 2.1 mmol) was added to a
solution of 2-fluoro-iV-phenylsulfanyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (860 mg,
1.90 mmol) in dichloromethane (30 mL) at 0 °C and the reaction was stirred at the same
temperature for 1 hour. The reaction mixture was diluted with dichloromethane (70
mL), washed successively with 10% w/v sodium thiosulfate, 5% w/v sodium
bicarbonate, dried over anhydrous sodium sulfate, filtered and trated under
reduced pressure. The residue was purified by silica gel tography, eluting with 0-
40% ethyl acetate in heptanes, to afford racemic /V-(ben/enesulfinyl)fluoro|3-|| I -
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (700 mg,
78% yield) as a white solid. ^ NMR (300 MHz, CDC13) ppm0.92- 1.00 (m,2H), 1.13
-1.20 (m, 2 H), 4.38 (d, J= 12.1, 1 H), 4.43 (d, J= 12.1, 1 H), 6.03 (d, J= 3.0 Hz, 1 H),
7.56 - 7.65 (m, 3 H), 7.70 - 7.78 (m, 1 H), 7.80 - 7.88 (m, 2 H), 8.24 (d, J= 3.0 Hz, 1
H), 8.40 (d, J= 12 Hz, 1 H), 9.61 (t, 8.5 Hz, 1 H). 19F NMR (282 MHz, CDC13) ppm
-69.7 (s, 3 F), -63.2 (t, J= 10.5 Hz, 1 F). LCMS: [M+H]+ = 469.0.
Step G: .V-(Benzenesulfinyl)[3-[[l-
|ti’ifluoromcthyl)cyclopi’opyl|mcthoxy|pyiazol-l-yl|[(4lS)-2,2,4-
hylpyrrolidin-l-yl]pyridinecarboxamide
MCI ,—\(S)
O 0
Y'OII II
NaH, DMF
F3C f3c
2,2,4-Trimethylpyrrohdine hydrochloride (400 mg, 2.67 mmol) was
dissolved in anhydrous /V.A'-dimethylformamide (10 mL), the mixture was cooled with
SUBSTITUTE SHEET (RULE 26)
WO 64632
ice-water and sodium hydride (287 mg of 60% dispersion in mineral oil, 7.2 mmol) was
added. The reaction was stirred at room temperature for 10 minutes and cooled back to
0 °C. A solution of racemic ZV-(benzenesulfinyl)fluoro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (960 mg,
2.05 mmol) in AOV-dimethylformamide (10 mL) was added. After stirring at room
temperature for 10 s the reaction e was stirred at 50 °C for 3 hours (LCMS
showed 60% sion; there was a lot of unconsumed sodium hydride). Anhydrous
tetrahydrofuran (0.5 mL) was added and the reaction was stirred at room temperature
ght. The mixture was quenched with water (10 mL) at 0 °C then extracted with
ethyl acetate (80 mL). The organic layer was washed with water (3 x 20 mL), brine (10
mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The e was purified by silica gel chromatography, eluting with 0-50%
ethyl acetate in heptanes. The fractions containing product and starting material were
combined and concentrated under reduced pressure. The e was d in a mixture
of heptanes (10 mL) and dichloromethane (10 mL) for 30 minutes and then filtered. The
filtrate was concentrated under reduced pressure to afford Ar-(benzenesulfinyl)[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide (500 mg, 88% purity by LCMS, 38% yield) as ayellow
solid that was used in the following step without further purification. LCMS: [M+H]+ =
562.2.
Step H: Synthesis of A-(phenylsulfonimidoyl)[3-[[l-
!trifluoromethyl)cyclopi’opyl]methoxy]pyrazol-l-yl][(4A)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
O 0 9 o4jnh
NCS, IMH3 in dioxane N'S- %
MeCN H XX »
f3c f3c
Ammonia (7.8 mL of a 0.5 M solution in dioxane, 3.9 mmol) was added to a
solution of A-(benzenesu]finyl)[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazoll-yl
][(45)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (500 mg, 88%
, 0.78 mmol) in anhydrous acetonitrile (20 mL) at 0 °C. A-Chlorosuccinimide
(120 mg, 0.90 mmol) was added in one portion (the mixture turned orange) and the
reaction was stirred at 0 °C for one hour. Additional Ar-chlorosuccinimide (12 mg, 0.090
SUBSTITUTE SHEET (RULE 26)
mmol) was added and the reaction was stirred at the same temperature for 30 minutes
and then quenched with 10% w/v aqueous sodium thiosulfate solution and extracted
with ethyl acetate (50 mL). The organic layer was washed sively with 5% w/v
aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The residue was purified by silica gel
chromatography, eluting with 5-45% ethyl acetate in heptanes, to afford a white solid
(300 mg) which was triturated with acetonitrile (3 mL) to provide a diastereomeric
mixture ofN-(amino(oxo)(phenyl)-X6-sulfaneylidene)(3-((l-
(trifluoromethyl)cyclopropyl)methoxy)-lH-pyrazol-l-yl)((S)-2,2,4-
trimethylpyrrolidin-l-yl)nicotinamide (Compound 45) (180 mg, 97% purity by LCMS,
38%yield) as a white solid. ^ NMR (300 MHz, CDC13) ppm0.89 - 1.06 (m, 5 H), 1.08
-1.18 (m, 2 H), 1.59 - 1.72 (m, 7 H), 1.81 - 1.95 (m, 1 H), 2.07 - 2.40 (m, 1 H), 2.59 -
2.71 (m, 0.4 H), 2.82 - 2.96 (m, 0.6 H), 3.18 (t, J= 10.6 Hz, 0.4 H), 3.29 (t, J= 10.7 Hz,
0.6 H), 4.32 - 4.43 (m, 2 H), 5.90 (d, /= 2.6 Hz, 1 H), 6.25 (br. s., 2 H), 6.90 - 6.97 (m,
1 H), 7.48 - 7.57 (m, 2 H), 7.58 - 7.66 (m, 1 H), 7.97 - 8.09 (m, 2.6 H), 8.16 (d, /= 8.2
Hz, 0.4 H), 8.20 - 8.23 (m, 1 H). 19F NMR (282 MHz, CDC13) ppm -69.7 (s, 3 F).
LCMS: = 577.2.
The isomers were separated by chiral supercritical fluid chromatography
utilizing a Phenomenex Lux-1 (250 x 21.2 mm), 5pm column and g with 20 %
MeOH, 80 % C02 with a flow rate of 70 ute.
] Diastereoisomer 1 (Compound 46): >98 % de ESI-MS mJz calc. 576.2131,
found 577.4 (M+l) + ; Retention time: 1.82 minutes; 'll NMR (400 MHz, DMSO-d6) 5
8.19 (d, J = 2.7 Hz, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 3H), 7.75 (s, 2H), 7.68 - 7.49 (m,
3H), 6.85 (d, J = 8.1 Hz, 1H), 6.12 (d, J = 2.7 Hz, 1H), 4.35 (s, 2H), 3.08 (t, J = 10.6 Hz,
1H), 2.76 (dd, J = 10.6, 7.1 Hz, 1H), 2.21 (dq, J = 12 1, 6 2 Hz, 1H), 1 97 - 1.79 (m,
1H), 1.55 (d, J = 1.7 Hz, 6H), 1.44 (t, J = 12.0 Hz, 1H), 1.09 (dd, J = 4.5, 3.1 Hz, 4H),
0.92 (d, J = 6.2 Hz, 3H).
Diastereoisomer 2 (Compound 47): >98% de. ESI-MS m!z calc. 576.2131,
found 577.3 (M+l) + ; Retention time: 1.81 minutes; 1HNMR (400 MHz, DMSO-d6) 5
8.19 (d, J = 2.7 Hz, 1H), 7.99 - 7.88 (m, 3H), 7.79 (s, 2H), 7.69 - 7.55 (m, 3H), 6.87 (d,
J = 8.1 Hz, 1H), 6.11 (d, J = 2.7 Hz, 1H), 4.44 - 4.28 (m, 2H), 2.63 (t, J = 10.8 Hz, 1H),
SUBSTITUTE SHEET (RULE 26)
WO 64632
2.21 - 2.03 (m, 1H), 1.80 (dd, J = 11.8, 5.4 Hz, 1H), 1.52 (d, J = 1.7 Hz, 6H), 1.33 (t, J =
12.2 Hz, 2H), 1.09 (dt, J = 5.6, 2.1 Hz, 4H), 0.71 (d, J = 6.2 Hz, 3H).
Synthetic Example 46: Synthesis of Compound 48:
N-(Benzenesulfonyl)[3-(cyclopropoxy)pyrazol-l-yl][(4S)-2,2,4-
hylpyrrolidin-l-ylJpyridinecarboxamide
Step A: fert-Butyl 3-cyclopropoxy-LH-pyrazole-l-carboxylate
n H °VN- □BAD, toluene Y
XjNBoc °n^N.
110°C T NBoc
] To a solution of cyclopropanol (30.8 mg, 0.531 mmol), fert-butyl 2,3-
dihydrooxopyrazole-l-carboxylate (97.7 mg, 0.531 mmol) and triphenylphosphine
(139.3 mg, 0.531 mmol) in anhydrous toluene (2 mL) was added di-/e/7-butyl
azodicarboxylate (122.2 mg, 0.531 mmol). The solution was purged with argon for 1
minute, and stirred at ambient temperature for 30 minutes. Then the reaction solution
was heated at 110 °C for additional 5 hours before it cooled to ambient temperature. The
soluhon was diluted with ether (50 mL), washed with NaOH aqueous solution, brine,
dried over sodium e, filtered and concentrated under the reduced pressure. Residue
obtained was purified by silica gel chromatography (hexane and ethyl acetate, 0 to 10%
ethyl acetate gradient) to afford fert-butyl opropoxy-li7-pyrazole-l-carboxylate
(52mg, 46%) as a white solid. ESI-MS m/z calc. 224.116, found 225.0 (M+l)+;
Retention time: 4.38 minutes, 'h NMR (250 MHz, CDCT) 6 (ppm) 7.86 (d, J = 2.8Hz,
1H), 5.93 (d, J = 2.8Hz, 1H), .15 (m, 1H), 1.61 (s, 9H), 0.85-0.72 (m, 4H).
Step B: 3-Cyclopropoxy-l//-pyrazole
Y TFA Y
0>*N ------- - °n^N.
T NBoc CH2CI2
To a solution of utyl 3-cyclopropoxypyrazole-l-carboxylate (131
mg, 0.584 mmol) in dichloromethane (6 mL) was added TFA (667 mg, 0.38 mL, 5.84
mmol). The resulting solution was stirred at ambient temperature for 3 hours. All
solvents were removed under the reduced pressure. The residue ed was dissolved
in ether (100 mL), washed with saturated sodium bicarbonate aqueous solution, dried
over magnesium sulfate, filtered and concentrated under the reduced pressure to afford
SUBSTITUTE SHEET (RULE 26)
3-cyclopropoxy-lff-pyrazole as a pale yellow oil. Crude product obtained was directly
used in next step.
Step 3: fetf-Butyl 2-chloro(3-cyclopropoxy-l//-pyrazole-l-yl)pyridirie-
3-carboxylate
Y Cl N Cl 7
DABCO, K2C03 o.
LNH DMF N=< 0
Crude 3-cyclopropoxy-lif-pyrazole (73mg, 0.584 mmol), tert-butyl 2,6-
dichloro pyridinecarboxylate (159 mg, 0.643 mmol), K2CO3 (162mg, 1.17 mmol)
and DABCO (13 mg, 0.117 mmol) were dissolved in anhydrous DMF (1.5 mL). The
reaction solution was stirred at ambient temperature for 16 hours. The on solution
was diluted with ether (100 mL), washed with water (3 x 25 mL) and brine (25 mL).
Organic layers were separated, dried over magnesium sulfate, filtered and concentrated
under the reduced pressure. Residue ed was purified by silica gel chromatography
(hexane and dichloromethane, 0 to 100% dichloromethane gradient) to afford /erf-butyl
2-chloro(3-cyclopropoxy-li/-pyrazole-l-yl)pyridinecarboxylate (153 mg, 78%) as
a sticky oil. ESI-MS m/z calc. 335.104, found 336.1 (M+l)+; Retention time: 6.84
minutes.
Step D: 2-Chloro(3-cyclopropoxy-l//-pyrazole-l-yl)pyridine
carboxylic acid
Y Y
VN- /TA Pf N-f VA TFA 0.
ch2ci2 rV/vf
N=< 0 N=< OH
Cl Cl
To a solution of /e/V-butyl ro('3-cyclopropox\ -1 a/ole-1 -
yl)pyridinecarboxylate (153 mg, 0.456 mmol) in dichloromethane (2.2 mL) was
added TFA (519 mg, 0.35 mL, 4.56 mmol). The resulting solution was stirred at
t temperature for 48 hours. Then 1,2-dichloroethane (2 mL) was added, and all
solvents were removed under the d pressure. White solid obtained was suspended
in the mixture of hexane and ether (10 mL, hexane/ether, 19/1), sonicated, filtered.
SUBSTITUTE SHEET (RULE 26)
washed with hexane (10 mL) and dried to afford 2-chloro(3-cyclopropo\y-l//-
pyrazole-l-yl)pyndinecarboxylic acid (122 mg, 97%) as a white solid. ESI-MS m/z
calc. 279.041, found 279.9 (M+l)+; Retention time: 4.43 minutes. ]H NMR (500 MHz,
DMSO-d6) 5 (ppm) 13.6 (s, 1H), 8.43 (d, J = 3.0Hz, 1H), 8.39 (d, J = 8.5Hz, 1H), 7.72
(d, J = 8.5Hz, 1H), 6.28 (d,J = 3.0Hz, 1H), 4.16-4.13 (m, 1H), 0.79-0.71 (m, 4H).
Step E: N-(Benzenesulfonyl)chloro[3-(cyclopropoxy)pyrazol-l-
yl]pyridinecarboxainide
O q, 9 q,
<{ N H2N'Sb 'S;
N XI b-0 N Cl
ro[3-(cyclopropoxy)pyrazol-l-yl]pyridinecarboxylic acid (30
mg, 0.1073 mmol) in DMF (600.0 |iL). HATU (l-[bis(dimethylamino)methylene]-lH-
1.2.3- lo[4,5-b]pyridinium 3-oxide uorophosphate) (85 mg, 0.2235 mmol),
and DIEA (diisopropylethylamine) (38 uL. 0.2182 mmol) were combined and stirred at
room temperature for 16 h. The reaction mixture was filtered and purified on reverse
phase HPLC utilizing a gradient of 25-75% acetonitrile in water containing 5mM HC1
to giveN-(benzenesulfonyl)chloro[3-(cyclopropoxy)pyrazol-l-yl]pyridine
carboxarmde !H NMR (400 MHz, DMSO-d6) 5 12.97 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H),
8.12 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 9.4 Hz, 2H), 7.77 (s, 1H), 7.69 (d, J = 6.0 Hz, 3H),
6.31 - 6.26 (m, 1H), 4.16 (s, 1H), 0.76 (s, 4H). ESI-MS m/z calc. 418.05026, found
419.0 (M+l)+; Retention time: 1.63 minutes (3 min run).
Step F: N-(Benzenesulfonyl)[3-(cyclopropoxy)pyrazol-l-yl][(4S)-
2.2.4- trimethylpyrrolidin-l-yl]pyridinecarboxamide
1 N . rS'
<1 N N '}
b^QN N XI H O
°<j N JiX
A mixture of N-(benzenesulfonyl)chloro[3-(cyclopropoxy)pyrazol-l-
yl]pyndinecarboxamide, (4S)-2,2,4-tnmethylpyrrolidme (Hydrochloride salt)
(approximately 24.01 mg, 0.1604 mmol), CsF ximately 36.00 mg, 0.2370 mmol).
SUBSTITUTE SHEET (RULE 26)
K2CO3 (approximately 72.01 mg, 0.5210 mmol) in DMSO (0.5 mL) was stirred at 140
°C for 16 h. The reaction was ed and purified on ed on reverse phase HPLC
utilizing a gradient of 25-75% acetonitrile in water containing 5mM HC1 to give N-
(benzenesulfonyl)[3-(cyclopropoxy)pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
inecarboxamide (5.6 mg, 11% over 2 steps) ESI-MS m/z calc. 495.19403,
found 496.0 (M+l)+; Retention time: 1.98 minutes] (3 min run)
Synthetic Example 47: Synthesis of Compound 49: 7V-(3-
methoxyphenyl)sulfonyl [3- [ [l-(trifluoromethyl)cyclopropyl] methoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: (l-(Trifluoromethyl)cyclopropyl)methanol
OH orOH
l-(Trifluoromethyl)cyclopropane-l-carboxylic acid (858 mg, 5.57 mmol,
1.00 eq.) was dissolved in diethyl ether (15 mL). The reaction mixture was cooled to 0
°C. Lithium aluminum hydride (274 mg, 7.24 mmol, 1.30 eq.) was added portionwise.
The reaction mixture was stirred ght and allowed to reach room temperature. The
reaction mixture was cooled to 0 °C. HC1 (aq., 1 N, 25 mL) was added dropwise. The
aqueous phase was extracted with diethyl ether (2 x 25 mL). The combined organic
phases were washed with brine (25 mL), dried over sodium sulfate, filtered and
evaporated in vacuo (Tbath < 30 °C) to give (l-(trifluoromethyl)cyclopropyl)methanol
(547 mg, 3.90 mmol, 70% yield) as a colorless oil. ^ NMR (CDC13): d 3.73 (s, 2H),
1.58 (br, 1H), 1.07-1.01 (m, 2H), 0.82-0.75 (m, 2H).
Step B: l-(3-hydroxypyrazol-l-yl)ethanone
HO-^JN'NH n-iA
ho—<rJi
A 100 mL round bottom flask equipped with a stir bar and a condenser was
charged with lH-pyrazolol (4.97 g, 59.11 mmol) and ne (25 mL, 309.1 mmol).
The e was d at 95 °C. A solution of acetic anhydride (5.6 mL, 59.35 mmol)
in pyridine (10 mL, 123.6 mmol) was added dropwise over a period of 3 minutes. The
mixture was then stirred at 95 °C for an onal three hours. The solvents were
SUBSTITUTE SHEET (RULE 26)
removed under reduced pressure. The solid residue was triturated in 40 mL of diethyl
ether, filtered, washed with diethyl ether and dried to give l-(3-hydroxypyrazol-l-
yl)ethanone (6.96 g, 93%). ^ NMR (400 MHz, DMSO-d6) 5 10.96 (s, 1H), 8.13 (d, J
= 3.0 Hz, 1H), 6.01 (d, J = 3.0 Hz, 1H), 2.48 (s, 3H).
Step C: (l-(trifluoromethyl)cyclopropyl)methoxy)-lH-pyrazol-l-
yl)ethan-l-one
o O
nn'J' N'lA
f-vOH + HO-^J
] 1 -(3-Hydrox} -1 //-pyrazol-1 -\ l)ethan-1 -one (443 mg, 3.51 mmol, 1.00 eq.)
was ved in THF (8 mL). (l-(Trifluoromethyl)cyclopropyl)methanol (547 mg, 3.90
mmol, 1.11 eq.) and triphenyl phosphine (1.10 g, 4.21 mmol, 1.20 eq.) were added. The
reaction mixture was cooled to 0 °C. Diisopropyl azodicarboxylate (829 mL, 851 mg,
4.21 mmol, 1.20 eq.) was added se (maintaining temperature < 5 °C). The
reaction mixture was stirred at room ature over the weekend. Evaporation of the
volatiles in vacuo gave a slightly yellow oil (2.88 g). The crude material was purified by
silica gel chromatography eluting with 0-25% ethyl acetate in heptanes to give l-(3-((litnnuoromethyl
)cyclopropYl)metho\y)-l//-pyrazol-1 -yl)ethanone (701 mg, 2.82
mmol, 80% yield) as a white solid. ^ NMR (CDC13): 5 8.06 (d, 1H), 5.99 (d, 1H), 4.36
(d, 2H), 2.57 (s, 3H), 1.18-1.12 (m, 2H), 0.98-0.90 (m, 2H). 19F NMR (CDC13): 5 -
69.77.
Step D: 3-((l-(Trifluoromethyl)cyclopropyl)methoxy)-l//-pyrazole
<^°~vN'lA <^°~v•N'NH
f3c F3c
l-(3-((l-(Trifluoromethyl)cyclopropyl)methoxy)-l//-pyrazol-l-yl)ethan-l-
one (695 mg, 2.80 mmol, 1.00 eq.) was dissolved in MeOH (30 mL). NaOH (aq., 30%,
421 mL, 560 mg, 4.20 mmol, 1.50 eq.) was added. The reaction mixture was stirred at
room temperature overnight. Evaporation of the volatiles in vacuo gave a white solid
(940 mg). The residue was partitioned between ethyl acetate (25 mL) and water (25
mL). The s phase was extracted with ethyl e (2 x 25 mL). The combined
SUBSTITUTE SHEET (RULE 26)
organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered and
evaporated in vacuo to give 3-((l-(trifluoromethyl)cyclopropyl)methoxy)-lif-pyrazole
(548 mg, 2.66 mmol, 95% yield) as a slightly yellow oil. JH NMR (CDC13): 5 9.10 (hr,
1H), 7.36 (d, 1H), 5.77 (d, 1H), 4.29 (s, 2H), 1.14-1.08 (m, 2H), 0.96-0.89 (m, 2H). 19F
NMR (CDC13): 5 .
Step E: fert-Butyl 2-chloro[3-[[l-
uoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylate
<U°-C!N-NH
cr n ci
f3c f3o
/erz-Butyl 2,6-dichloropyridinecarboxylate (approximately 451.3 mg,
1.819 mmol), 3-| 11 -(tri niioromethyljcyclopropyl [melhoxy|-1 //-pyra/ole (375 mg, 1.819
mmol), and potassium carbonate ximately 301.7 mg, 2.183 mmol) (freshly
ground) were combined in anhydrous DMSO (9.026 mL). l,4-diazabicyclo[2.2.2]octane
(approximately 40.81 mg, 0.3638 mmol) was added and the mixture was stirred at room
temperature under nitrogen for 16 hours. The on mixture was diluted with ethyl
acetate (10 mL) and water (2x5 mL) and the two phases were separated. The organics
were washed with brine, dried over sodium sulfate and evaporated. The crude material
was purified by silica gel chromatography eluting with 0-30% ethyl e in hexanes
to give tert-butyl 2-chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylate (620 mg, 82%) ESI-MS in z calc. 417.1067, found 418.1
(M+l) +; Retention time: 0.85 s.
Step F: 2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-
l-yl]pyridinecarboxylic acid
<LP-G N' Cl NN
f3c F3C
/e/7-But}'I 2-chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-
l-yl]pyndinecarboxylate (620 mg, 1.484 mmol) and TFA (approximately 1.692 g.
SUBSTITUTE SHEET (RULE 26)
1.143 mL, 14.84 mmol) were combined in DCM (5 mL) and heated at 40 °C f or 16 h.
The reaction was evaporated to a white solid. Hexanes was added and the mixture was
evaporated again to give 2-chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (500
mg, 93%) ESI-MS m/z calc. 361.0441, found 362.1 (M+l)+; Retention time: 0.66
minutes.
Step G: 2-Chloro-N-(3-methoxyphenyl)sulfonyl[3-[|l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
n^n^ciH ^
N- N-
F3C f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
idinecarboxylic acid (200 mg, 0.55 mmol) and carbonyldiimidazole (110 mg,
0.66 mmol) were ed in THF (2 mL) and stirred at room ature for 2 hours.
3-methoxybenzenesulfonamide (104 mg, 0.55 mmol) was added, followed by DBU
(0.25 mL, 1.66 mmol) and the reaction mixture was stirred for 2 h at room temperature.
The reaction mixture was diluted with 10 mL ethyl acetate, and washed with 10 mL 1M
aqueous citric acid. The aqueous layer was extracted with ethyl e (2x10 mL), and
the combined organics were washed with brine, dried over sodium sulfate, and
concentrated under reduced re. The crude material was purified by silica gel
chromatography eluting with a 0-10% gradient of methanol in dichloromethane to give
2-chloro-N-(3-methoxyphenyl)sulfonyl[3-[[l-
uoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (217 mg,
74%) ESI-MS m/z calc. 530.06384, found 531.1 (M+l)+; Retention time: 0.72 minutes.
Step H: ;V-(3-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
wV- A 9 9,P l
f3c f3c
SUBSTITUTE SHEET (RULE 26)
2-Chloro-N-(3-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (120 mg,
0.23 mmol), (4S')-2.2.4-trimethylpyrrolidine (hydrochloride salt) (107 mg, 0.71 mmol),
and potassium carbonate (173 mg, 1.25 mmol) were combined in DMSO (600 pL) and
heated at 130 °C for 16 h. The reaction was partitioned between ethyl acetate and water.
The organics were separated, washed with a 1M citric acid solution, brine, dried over
sodium sulfate and evaporated. The crude material was ed by silica gel
chromatography eluting with 0-10% methanol in dichloromethane to give ,Y-(3-
methoxyphenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]-
2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (92 mg, 67%) ESI-MS
m/'z calc. 764, found 608.3 (M+l)+; Retention time: 2.17 minutes. 'H NMR (400
MHz, 6) 5 12.43 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H),
7.61 - 7.53 (m, 2H), 7.48 - 7.45 (m, 1H), 7.32 - 7.27 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H),
6.15 (d, J = 2.8 Hz, 1H), 4.42 - 4.31 (m, 2H), 3.84 (s, 3H), 2.45 (d, J = 10.5 Hz, 1H),
2.35 -2.28 (m, 1H), 2.20-2.03 (m, 1H), 1.84 (dd, J = 11.9, 5.6 Hz, 1H), 1.53 (d,J =
.9 Hz, 6H), 1.38 (t, J= 12.1 Hz, 1H), 1.12 -1.05 (m, 4H), 0.67 (d, J = 6.2Hz, 3H).
Synthetic Example 48: Synthesis of Compound 50: 7V-(2-
phenyl)sulfonyl [3-[ [ l-(trifhioromethyl)cyclopropyl] methoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-iV-(2-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
o 9 a ,o f
'OH N'S'
14 H
<U0-iJ N Cl <LP-iJ N ClN-
f3c f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
idinecarboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (97 mg, 0.6
mmol) were combined in THF (2.5 mL) and stirred at room temperature for 30 minutes.
robenzenesulfonamide (114 mg, 0.65 mmol) was added, followed by DBU (0.09
mL, 0.6 mmol) and the reaction mixture was stirred for 3 h at room temperature. The
reaction mixture was diluted with 10 mL ethyl acetate, and washed with 10 mL 1M
aqueous citric acid. The organics were dried over sodium sulfate, and concentrated
SUBSTITUTE SHEET (RULE 26)
under d pressure. The crude material was purified by silica gel chromatography
eluting with a 0-8% gradient of methanol in dichloromethane to give 2-chloro-N-(2-
fluorophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (180 mg, 69%) ESI-MS m/z calc. 518.0439, found 519.1
(M+l)+; Retention time: 0.70 minutes.
Step B: fluoiophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
O oo Fw O Oo F
n ci HCly "ft*
f3c f3c
2-Chloro-N-(2-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (78 mg,
0.15 mmol), (4,S')-2.2.4-tri methyl idine (hydrochloride salt) (67 mg, 0.45 mmol),
and potassium carbonate (124 mg, 0.9 mmol) were combined in DMSO (600 pL) and
heated at 130 °C for 16 h. The reaction mixture was ed and punfied by LC/MS
ing a gradient of 30-99% acetonitrile in 5 mM aq HC1 to give N-(2-
fluorophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (28 mg, 31%) ESI-MS m/z
calc. 595.1876, found 596.3 (M+l)+; Retention time: 2.08 minutes.
Synthetic Example 49: Synthesis of Compound 51: N-(3-
Fluorophenyl)sulfonyl [3- [ [ l-(trifluoromethyl)cydopropyl]methoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-.Y-(3-fluorophenyl)sulfonyl[3-[[ l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O 9 o, ,oW
" ci <}J^JN- "
f3c f3c
SUBSTITUTE SHEET (RULE 26)
2-chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (97 mg, 0.6
mmol) were ed in THF (2.5 mL) and stirred at room temperature for 30 minutes.
3-fluorobenzenesulfonamide (114 mg, 0.65 mmol) was added, followed by DBU (0.09
mL, 0.6 mmol) and the reaction mixture was stirred for 3 h at room ature. The
reaction mixture was diluted with 10 mL ethyl e, and washed with 10 mL 1M
aqueous citric acid. The organics were dried over sodium sulfate, and concentrated
under reduced pressure. The crude material was purified by silica gel chromatography
eluting with a 0-8% gradient of methanol in dichloromethane to give 2-chloro-N-(3-
fluorophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (190 mg, 73%) ESI-MS m/z calc. 518.0439, found 519.1
(M+l)+; Retention time: 0.72 minutes.
Step B: N-(3-Fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
hylpyrrolidin-l-yl]pyridinecarboxamide
9 ist 0 9P
.N jTXh TJ+ 4N~N/%'XI ^ HCl7\
f3c f3c
ro-N-(3-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (78 mg,
0.15 mmol), (45')-2.2.4-tri methyl pyrrolidine (hydrochloride salt) (67 mg, 0.45 mmol),
and potassium carbonate (124 mg, 0.9 mmol) were combined in DMSO (600 pL) and
heated at 130 °C for 16 h. The reaction mixture was filtered and punfied by LC-MS to
give A-(3-nuorophenyl)sul fonyl| 3-||l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidml-yl
]pyridinecarboxamide (47 mg, 52%) ESI-MS m/z calc. 595.1876, found 596.3
(M+l)+; Retention time: 2.14 minutes.lH NMR (400 MHz, DMSO-d6) 8 8.21 (d, J =
2.8 Hz, 1H), 7.90 - 7.82 (m, 2H), 7.80 - 7.69 (m, 2H), 7.68 - 7.59 (m, 1H), 6.93 (d, J =
8.2 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H), 4.43 - 4.27 (m, 2H), 2.44 (t, J = 10.4 Hz, 1H),
2.30 (dd, J = 10.2, 7.0 Hz, 1H), 2.23 - 2.08 (m, 1H), 1.84 (dd, J = 11.9, 5.5 Hz, 1H),
SUBSTITUTE SHEET (RULE 26)
1.53 (d, J = 9.7 Hz, 6H), 1.39 (t, J = 12.2 Hz, 1H), 1.17 -1.02 (m, 4H), 0.69 (d, J = 6.3
Hz, 3H).
] Synthetic Example 50: sis of Compound 52: N-(4-
phenyl)sulfonyl [3-[ [ l-(trifhioromethyl)cyclopropyl] methoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-Ar-(4-fluorophenyl)sulfonyl[3-[[ l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
XxaV 'OH
Cl N-N^N^CI " XX
F3C f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (97 mg, 0.6
mmol) were combined in THF (2.5 mL) and stirred at room temperature for 30 minutes.
4-fluorobenzenesulfonamide (114 mg, 0.65 mmol) was added, followed by DBU (0.09
mL, 0.6 mmol) and the reaction mixture was stirred for 3 h at room temperature. The
reaction e was diluted with 10 mL ethyl acetate, and washed with 10 mL 1M
aqueous citric acid. The organics were dried over sodium sulfate, and trated
under reduced pressure. The crude al was purified by silica gel chromatography
eluting with a 0-8% gradient of methanol in dichloromethane to give 2-chloro-N-(4-
fluorophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (160 mg, 62%) ESI-MS m/z calc. 518.0439, found 519.1
(M+l)+; Retention time: 0.72 minutes.
Step B: N-(4-Fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]inethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxaniide
n m xx+11 SP (§/
ys-v [\U1.1..J-l /e>
■n'nan'x'ci hcVn
f3c f3c
SUBSTITUTE SHEET (RULE 26)
ro-N-(4-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (78 mg,
0.15 mmol). (4S')-2.2.4-trimethylpyrrolidine (hydrochloride salt) (67 mg, 0.45 mmol),
and potassium carbonate (124 mg, 0.9 mmol) were combined in DMSO (600 pL) and
heated at 130 °C for 16 h. The reaction e was filtered and punfied by LC/MS
utilizing a gradient of 30-99% acetonitrile in 5 mM aq HC1 to give /V-(4-
fluorophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (34 mg, 38%) ESI-MS m/z
calc. 595.1876, found 596.3 (M+l)+; Retention time: 2.16 minutes. 1H NMR (400
MHz, DMSO-d6) 6 8.20 (d, J = 2.8 Hz, 1H), 8.12 - 8.02 (m, 2H), 7.82 (d, J = 8.3 Hz,
1H), 7.59 - 7.45 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.43 - 4.30
(m, 2H), 2.37 (t, J= 10.4 Hz, 1H), 2.22 (dd, J = 10.1, 7.0 Hz, 1H), 2.18 - 2.05 (m, 1H),
1.83 (dd, J = 11.9, 5.5 Hz, 1H), 1.52 (d, J = 8.8 Hz, 6H), 1.37 (t, J= 12.1 Hz, 1H), 1.15 -
1.00 (m, 4H), 0.67 (d, J = 6.3 Hz, 3H).
tic Example 51: Synthesis of Compound 53: 7V-(2-
methoxyphenyl)sulfonyl [3- [ [l-(trifluoromethyl)cyclopropyl] methoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-chloro-N-(2-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O 9 o. .o 9
"OH 4. N'S' ■4
14 14 H
<^J " Cl N Cl
f3c f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (200 mg, 0.55 mmol) and carbonyldiimidazole (110 mg,
0.66 mmol) were combined in THE (2 mL) and stirred at room temperature for 2 hours.
2-methoxybenzenesulfonamide (104 mg, 0.55 mmol) was added, followed by DBU
(0.25 mL, 1.66 mmol) and the on mixture was stirred for 2 h at room temperature.
The reaction mixture was diluted with 10 mL ethyl acetate, and washed with 10 mL 1M
aqueous citric acid. The s layer was ted with ethyl acetate (2x10 mL), and
the combined organics were washed with brine, dried over sodium sulfate, and
SUBSTITUTE SHEET (RULE 26)
concentrated under d pressure. The crude material was used without further
purification. 2-Chloro-N-(2-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (286 mg,
97%) ESTMS m/z calc. 530.06384, found 531.1 (M+l)+; Retention time: 0.70 minutes.
Step B: \-(2-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 9P ? O 00 o
IN'S w*
Cl HCI/
f3c f3c
2-Chloro-N-(2-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (120 mg,
0.23 mmol), (4^)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (107 mg, 0.71 mmol),
and ium carbonate (173 mg, 1.25 mmol) were combined in DMSO (600 pL) and
heated at 130 °C for 16 h. The reaction was partitioned between ethyl acetate and water.
The organics were separated, washed with a 1M citric acid solution, brine, dried over
sodium sulfate and evaporated. The crude material was purified by silica gel
chromatography g with 0-10% methanol in dichloromethane to give N-(2-
yphenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]-
)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (82 mg, 60%) ESI-MS
m/z calc. 607.20764, found 608.3 (M+l)+; Retention time: 2.15 minutes.
Synthetic Example 52: Synthesis of Compound 54: 7V-(4-
methoxyphenyl)sulfonyl [3- [ ifluoromethyl)cyclopropyl] methoxy] pyrazol
yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-A'-(4-methoxyphenyl)sulfonyl[3-|[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O 9 o, ,o
N- N- ciHU <lp~On n u°u N
f3c f3c
SUBSTITUTE SHEET (RULE 26)
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (300 mg, 0.83 mmol) and carbonyldiimidazole (162 mg,
1.0 mmol) were combined in THF (4 mL) and stirred at room temperature for 30
minutes. 4-Methoxybenzenesulfonamide (203 mg, 1.08 mmol) was added, followed by
DBU (0.15 mL, 1.0 mmol) and the reaction mixture was stirred for 2 h at room
temperature. The reaction mixture was diluted with 10 mL ethyl e, and washed
with 10 mL 1M aqueous citric acid. The organics were dried over sodium sulfate and
trated under reduced pressure. The crude material was purified by silica gel
chromatography eluting with 0-8% methanol in romethane to give 2-chloro-AL(4-
methoxyphenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (430 mg, 97%) ESI-MS m/z calc. 530.06384, found 531.1
(M+l)+; Retention time: 0.71 minutes.
Step B: /V-(4-Methoxyphenyl)sulfonyl[3-[[ l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 (s/ 0 QP
N jfX" + HnQ irV^Vi
)LP-0,N'NXNA'CI HCl/x
I I
f3c F3c
2-Chloro-N-(4-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (210 mg,
0.39 mmol), 2.2.4-tri methyl pyrrol i di nc (hydrochlonde salt) (180 mg, 1.2 mmol),
and potassium carbonate (330 mg, 2.39 mmol) were combined in DMSO (2 mL) and
heated at 130 °C for 15 h. The reaction was partitioned n ethyl acetate and water.
The organics were separated, washed with a 1M citric acid solution, brine, dried over
sodium e and evaporated. The crude al was purified by silica gel
chromatography eluting with 0-5% methanol in dichloromethane. The material was
further ed by LC/MS utilizing a gradient of 30-99% acetonitrile in 5 mM aq HC1
to yield /V-(4-methoxyphenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyndinecarboxamide (25 mg, 10%) ESI-MS m/z calc. 607.20764, found 608.3
(M+l)+; Retention time: 2.16 minutes. 1H NMR (400 MHz, DMSO-d6) 6 8.19 (d, J =
2.8 Hz, 1H), 7.99 - 7.87 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.26 - 7.10 (m, 2H), 6.91 (d, J
SUBSTITUTE SHEET (RULE 26)
= 8.2 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 4.44 - 4.28 (m, 2H), 3.84 (s, 3H), 2.40 (t, J =
.5 Hz, 1H), 2.29-2.21 (m, 1H), 2.16 - 2.00 (m, 1H), 1.82 (dd. J = 11.9, 5.6 Hz, 1H),
1.52 (d, J = 10.7 Hz, 6H), 1.37 (t, J= 12.1 Hz, 1H), 1.16 -1.02 (m, 4H), 0.64 (d, J = 6.3
Hz, 3H).
Synthetic Example 53: Synthesis of Compound 55: N-(Benzenesulfonyl)-
6- [3- [ [ l-(difluoromethyl)cyclopropyl] methoxy]pyrazol-l-yl] [(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: /er/-Butyl 3-((l-(difluoromethyl)cyclopropyl)methoxy)-li/-pyrazole-
1-carboxylate
HF2C~£ ^CnbocrOHo t! DIAD, Ph3P, THF
0°C to it, then 50°C °Xj Boc
] To the solution of (l-(difluoromethyl)cyclopropyl)methanol (867 mg, 7.11
mmol), fe/7-butyl 2,3-dihydrooxopyrazole-l-carboxylate (1.19 g, 6.46 mmol), and
triphenylphosphine (1.86g, 7.11 mmol) in
tetrahydrofuran (22 mL) at 0 °C was added diisopropyl azodicarboxylate (1.44 g, 7.11
mmol) se. After the addition was complete, the reaction was allowed to warm to
room temperature, then heated at 50 °C for 1 hour. The reaction solution was cooled to
room temperature and ethyl acetate (300 mL) was added. The solution was then washed
with aqueous sodium hydroxide (20 mL, 1M), water, brine and dried over magnesium
sulfate, filtered and concentrated. The residue obtained was purified by silica gel
chromatography (hexane and dichloromethane, 0 to 100% dichloromethane nt) to
afford fert-butyl (difluoromethyl)cyclopropyl) y)-1//-pyra/ole-1 -
carboxylate as a white solid (1.50 g, 80% yield). ESI-MS m/z calc. 288.1, found 289.2
(M+l)+. Retention time: 3.08 minutes, 'h NMR z, CDCh) d(ppm): 7.84(d, J=
3.0Hz, 1H), 5.97(t, J= 57.8Hz, 1H), 5.89(d, /= 3.0 Hz, 1H), 4.32(s, 2H), 1.61(s, 9H),
0.97(m, 2H), 0.75(m, 2H).
SUBSTITUTE SHEET (RULE 26)
Step B: 3-((l-(Difluoromethyl)cyclopropyl)methoxy)-lF-pyrazole
CF2H cf2h
HCI in dioxane
°xy VS, M
Boc o^Qih
Cold hydrogen e solution (30 mL, 4.0M in 1,4-dioxane) was added to
/e/7-butyl 3-((l-(difluoromethyl)cyclopropyl)methoxy)-li7-pyrazole-l-carboxylate (1.69
g, 5.88 mmol) in a round-bottom flask, and the reaction solution was warmed to room
temperature and stirred for 3 hours. After removal of all the solvents under reduced
pressure, the residue so obtained was partitioned n water (50 mL) and diethyl
ether (80 mL). The organic layer was separated and the s layer extracted with
diethyl ether (2 x 80 mL). The combined organic layers were washed with brine (2 x 30
mL), dried over sodium sulfate, filtered and trated under reduced pressure. The
residue so obtained was ed by silica gel chromatography (hexanes and ethyl
acetate, 0 to 40% ethyl acetate gradient) to afford 3-((l-
(difluoromethyl)cyclopropyl)methoxy)-li/-pyrazole as a white solid (997 mg, 90%
yield). ESI-MS »i/z calc. 188.1, found 189.1 (M+l)+. Retention time: 1.94 minutes.
^ NMR (250MHz, DMSO) <5(ppm): 11.87(s, 1H), 7.51(m, 1H), 5.98(t. ./ = 57.0Hz.
1H), 5.66(m, 1H), 4.10(s, 2H), 0.80(m, 4H).
Step C: tert-butyl 2-chloro [3- [ [1-
(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylate
0^//N'NH + o-//N'NA'isrXi
cr n ci
f- F
F F
] tert-Butyl 2,6-dichloropyridinecarboxylate (approximately 659.2 mg,
2.657 mmol), 3-[[l-(difluoromethyl)cyclopropyl]methoxy]-lH-pyrazole (500 mg, 2.657
mmol), and potassium carbonate (approximately 440.6 mg, 3.188 mmol) (freshly
) were combined in anhydrous DMSO (13.18 mL). l,4-diazabicyclo[2.2.2]octane
(approximately 59.61 mg, 0.5314 mmol) was added and the mixture was stirred at room
temperature under nitrogen for 16 hours. The reaction mixture was diluted with water
SUBSTITUTE SHEET (RULE 26)
(20 mL) and stirred for 15 min. The resulting solid was collected and washed with
water. The solid was ved in dichloromethane and the small amount of aqueous
layer removed. The cs were dried over sodium sulfate and evaporated to give tertbutyl
2-chloro[3-[[l-(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine
carboxylate (842 mg, 79%). ESI-MS m/z calc. 399.11612, found 400.1 (M+l)+;
Retention time: 0.82 s.
Step D: 2-chloro[3-[[l-(difluoromethyl)cyclopropyl]methoxy]pyrazol-
yridinecarboxylic acid
N O^'N^N rDI
0-('• N N Cl
F F
F F
tert-Butyl 2-chloro[3-[[ 1 -(difluoromethyl)cyclopropyl]methoxy]pyrazol-1 -
yl]pyridinecarboxylate (842 mg, 2.106 mmol) and TFA (approximately 2.401 g,
1.622 mL, 21.06 mmol) were dissolved in dichloromethane (8.420 mL) and heated at 40
0C for 3 h. The reaction was evaporated and the ing solid was triturated with
hexanes and re-evaporated to give 2-chloro[3-[[l-
(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxylic acid (710 mg,
98%). ESI-MS m/z calc. 343.05353, found 344.1 (M+l)+ ; Retention time: 0.62
minutes. 1H NMR (400 MHz, DMSO-d6) 5 13.59 (s, 1H), 8.43 (d, J = 2.9 Hz, 1H), 8.39
(d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 2.9 Hz, 1H), 5.98 (t, J = 56.4
Hz, 1H), 4.32 (s, 2H), 0.93 - 0.84 (m, 4H).
Step E: N-(Benzenesulfonyl)chloro[3-[[l-
(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O Sv
O^'N^N^CI
F- F
F F
2-Chloro[3-[[l-(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (200 mg, 0.5819 mmol) and carbonyl diimidazole
SUBSTITUTE SHEET (RULE 26)
WO 64632
(approximately 113.2 mg, 0.6983 mmol) were combined in THF (2.5 mL) and stirred
for 2 h. At this point, benzenesulfonamide (approximately 91.47 mg, 0.5819 mmol) was
added followed by DBU (approximately 265.8 mg, 261.1 |iL. 1.746 mmol) and the
reaction was stirred for an additional 2 h at room temperature. A 1M citric acid solution
(5 mL) was added and the reaction was stirred for 20 min. The solution was extracted
with ethyl acetate. The organics were washed with brine, dried over sodium e and
evaporated. The crude matenal was d by silica gel chromatography eluting with
0-10% methanol in dichloromethane to give N-(benzenesulfonyl)chloro[3-[[l-
(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (153.6 mg,
55%) ESI-MS m/z calc. 482.0627, found 483.1 (M+l)+; Retention time: 0.68 minutes.
Step F: N-(benzenesulfonyl)[3-[[l-
(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
V-O oo 9 (sjf
0-/N XX"0 +l~N'A'N''XI ^ HCI/%
F F
N-(Benzenesulfonyl)chloro[3-[[l-
(difluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (116 mg,
0.24 mmol), (45)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (71 mg, 0.63 mmol),
and potassium carbonate (145 mg, 1.05 mmol) were combined in DMSO (600 pL) and
heated at 130 °C for 16 h. The reaction was partitioned between ethyl acetate and water.
The organics were separated, washed with a 1M citric acid solution, brine, dried over
sodium e and evaporated. The crude al was purified by silica gel
chromatography eluting with 0-10% methanol in dichloromethane to giveN-
nesulfony l)[3- [ [1 -(difluoromethy l)cy clopropy 1] methoxy ] py razol-1 -y 1]
[(4S)-2,2,4-trimethylpyrrolidm-l-yl]pyridinecarboxamide (87 mg, 65%) ESI-MS m/z
calc. 559.2065, found 560.3 ; Retention time: 2.06 minutes. 1H NMR (400
MHz, DMSO-d6) 8 12.47 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.00 (t, J = 1.3 Hz, 1H), 7.98
(d, J = 1.6 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.65 (tt, J = 6.8, 1.6
Hz, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.13 (d, J = 2.8 Hz, 2H), 4.32 - 4.23 (m, 2H), 2.47 -
2.37 (m, 1H), 2.28 (dd, J = 10.3, 7.0 Hz, 1H), 2.09 (dq, J 11.9, 6.2 Hz, 1H), 1.82 (dd, J
SUBSTITUTE SHEET (RULE 26)
= 11.9, 5.6 Hz, 1H), 1.52 (d, J = 9.5 Hz, 6H), 1.36 (t, J = 12.1 Hz, 1H), 0.87 (dt, J = 5.1,
2.0 Hz, 4H), 0.65 (d, J = 6.2 Hz, 3H).
Synthetic Example 54: Synthesis of Compound 56: N-(Benzenesulfonyl)-
2-(2,2,4,4-tetramethylpyrrolidin- l-yl) [3- [ [1-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
Step A: ,4-Trimethylpentanyl)picolinamide
o 0
h2n■KM ‘OH NH
HATU, DIEA, DMF
At 5 °C, to picolinic acid (20.5 g, 167 mmol) in DMF (200 mL) was added
HATU (65 g, 171 mmol, -1.0 eq), followed by 2,4,4-trimethylpentanamine (27.0
mL, ~1.0 eq), and then DIEA (65 mL, ~2.5 eq). The reaction was stirred at RT for 1.0
h. The reaction mixture was poured to ice-water (350 mL) and extracted with EtOAc
(2x600 mL). The combined extract was washed with water (2x300 mL) and brine (150
mL), dried over , and concentrated to give crude product, which was purified by
plug filtration through a pad of silica gel, eluted with 25% EtOAc in hexanes, giving a
lightyellow oil. N-(2,4,4-tnmethylpentanyl)picolinamide (36 g, 92%).: MS [M+l]:
Step B: Pyridinyl(2,2,4,4-tetramethylpyrrolidin-l-yl)methanone
O O
Phl(OAc)2, Pd(OAc)2
'NH vs*
PhMe, 80 °C 1 d
N-(2,4,4-trimethylpentanyl)picolinamide (36.0 g, 153 mmol), Pd(OAc)2
(1.72 g, 5%), PhI(OAc)2 (99.2 g, 308 mmol) were mixed in toluene (600 mL) and
heated at 80 °C overnight (~18 h). The reaction was concentrated to remove most of the
e and the residue loaded to a silica gel column, eluted with 50% EtOAc in
hexanes, resulting in a lightyellow solid. pyndinyl(2,2,4,4-tetramethylpyrrolidin-lyl
none (32 g, 90%).; MS [M+l]: 233. 1HNMR (250 MHz, CDC13) 8.56 (d, J =
4.8 Hz, 1H), 7.76 (td, J = 7.7, 1.7 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.35 - 7.25 (m, 1H),
3.36 (s, 2H), 1.79 (s, 2H), 1.67 (s, 6H), 1.08 (s, 6H)
Step C: 2,2,4,4-Tetramethylpyrrolidine (HC1 salt)
SUBSTITUTE SHEET (RULE 26)
V\| NaOH HN'
150 °C .HCI
Pyridinyl(2,2,4,4-tetramethylpyrrolidin-l-yl)methanone (6 g, 25.9 mmol)
was dissolved in a mixture of NaOH (9.0 g, 225 mmol) in water (6 mL) and EtOH (18
mL) in a small pressure reactor (~45 mL) and heated at 140 °C for 48 h. The reaction
was completed. The mixture was dissolved with 80 mL of water and extracted with
Et20 (3x200 mL). The extract was washed with water (2x100 mL) and dried over
Mg2S04. After filtenng, HCI gas was bubbled through the filtrate for 5 min. An oil
formed on the bottom of the flask. The top ether layer was ed carefully, the
remaining oil was washed with ether (2x30 mL) and the washing was decanted. The
final oil was evaporated to give a white olid, which was dned in a vacuum oven
at 50°C for 1 day, to give an off-white solid. 2,2,4,4-tetramethylpyrrolidine (HCI salt)
(4.0 g, 95%). MS [M+l]: 128. 1HNMR (250 MHz, DMSO-d6) 9.39 (s, 2H), 3.01 (t, J =
.5 Hz, 2H), 1.69 (s, 2H), 1.40 (s, 6H), 1.16 (s, 6H).
Step D: zenesulfonyl)(2,2,4,4-tetramethylpyiroli(lin-l-yl)[3-
[ [ l-(trifluoromethyl)cyclop ropyl] y] py razol- 1-yl] pyridinecarboxamide
9 V 0 00
N JTI h' 10 + HnO
N'M^N^CI ^ HCI/x
OS' OS'■XOvP
F- FF
N-(Benzenesulfonyl)chloro[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (100 mg,
0.2 mmol), 2,2,4,4-tetramethylpyrrolidine (hydrochloride salt) (98 mg, 0.6 mmol), and
potassium carbonate (138 mg, 1.0 mmol) were combined in DMSO (500 pL) and
heated at 130 °C for 16 h. The reaction was diluted with water (3mL) and stirred for 20
min. A solid formed and the aqueous liquid was ed. The solid was dissolved in
ethyl acetate and washed with a 1M citric acid solution, then brine. The organics were
dried over sodium sulfate and evaporated. The crude material was purified by silica gel
chromatography eluting with 0-10% ol in dichloromethane to giveN-
(benzenesulfonyl)(2,2,4,4-tetramethylpyrrolidin-l-yl)[3-[[l-
SUBSTITUTE SHEET (RULE 26)
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (57 mg,
48%) ESI-MS m/z calc. 591.2127, found 592.2 (M+l)+; Retention time: 2.20 minutes.
1H NMR (400 MHz, 6) 5 12.52 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.04 - 7.97
(m, 2H), 7.82 - 7.72 (m, 2H), 7.72 - 7.63 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.14 (d, J =
2.8 Hz, 1H), 4.36 (s, 2H), 2.38 (s, 2H), 1.72 (s, 2H), 1.58 (s, 6H), 1.14 - 1.04 (m, 4H),
0.81 (s, 6H).
Synthetic Example 55: Synthesis of Compound 57: ethoxy
methyl-phenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-lyl
][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(4-methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
ii o, p
OH N:'S
N- H
N Cl N Cl O''
f3c f3c
2-Chloro[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0.4023 mmol) and carbonyl diimidazole (82 mg,
0.5057 mmol) were combined in THF (1.299 mL) and stirred for 2 h. At this point, 4-
methoxymethyl-benzenesulfonamide (85 mg, 0.4224 mmol) was added followed by
DBU (200 pL, 1.337 mmol) and the reaction was stirred for an additional 2 h at room
temperature. The reaction was diluted with ethyl acetate and washed with a 1M citric
acid solution, ed by brine. The organics were ted, dried over sodium
sulfate, and evaporated to give 2-chloro-N-(4-methoxymethyl-phenyl)sulfonyl[3-
[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (205
mg, 94%) ESI-MS m/z calc. 544.0795, found 545.0 (M+l) +; Retention time: 0.73
minutes.
Step B: N-(4-Methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
SUBSTITUTE SHEET (RULE 26)
l9i 0 ooV-
+ HN-
5Zv0~O N Cl O HCI 0
I y-p-<J jy1 I
ro-N-(4-methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (100 mg,
0.18 mmol), (4»S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (90 mg, 0.6 mmol),
and potassium ate (138 mg, 1.0 mmol) were combined in DMSO (500 pL) and
heated at 130 °C for 16 h. The reaction was diluted with water (3mL) and stirred for 20
min. A solid formed and the aqueous liquid was decanted. The solid was dissolved in
ethyl acetate and washed with a 1M citric acid solution, then brine. The organics were
dried over sodium sulfate and evaporated. The crude material was purified by silica gel
chromatography eluting with 0-10% methanol in dichloromethane to give N-(4-
methoxymethyl-phenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidinl-yl
]pyridinecarboxamide (75 mg, 67%) ESI-MS m/z calc. 327, found 622.3
(M+l)+; Retention time: 2.23 minutes.lHNMR(400 MHz, DMSO-d6) 5 12.46 (s, 1H),
8.20 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.01 - 6.94
(m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.14 (d, 1 = 2.1 Hz, 1H), 4.41 - 4.32 (m, 2H), 3.82 (s,
3H), 2.59 (s, 3H), 2.41 - 2.29 (m, 2H), 2.22 - 2.10 (m, 1H), 1.82 (dd, J = 11.9, 5.6 Hz,
1H), 1.52 (s, 6H), 1.36 (t, J = 12.1 Hz, 1H), 1.12 - 1.06 (m, 4H), 0.70 (d, J = 6.2 Hz,
Synthetic Example 56: Synthesis of Compound 58: N-(o-Tolylsulfonyl)-
6-[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: 2-Chloro-N-(o-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O 9 o, ,o
'OH N'S'
N^CI H
O^'N^N^CI
F3c f3c
SUBSTITUTE SHEET (RULE 26)
WO 64632
ro[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0.3992 mmol) and carbonyl diimidazole
(approximately 81.69 mg, 0.5038 mmol) were combined in THF (1.339 mL) and stirred
for 2 h. At this point, 2-methylbenzenesulfonamide (approximately 71.77 mg, 0.4192
mmol) was added, followed by DBU (approximately 202.6 mg, 199.0 pL, 1.331 mmol)
and the reaction was stirred for an additional 2 h at room temperature. The reaction was
diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine.
The organics were separated, dried over sodium e, and evaporated to give 2-
chloro-N-(o-tolylsulfonyl)[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-lyl
]pyridinecarboxamide (208 mg, 99%) ESI-MS m/z calc. 528.0846, found 529.0
(M+l) +; Retention time: 0.77 minutes
Step B: N-(o-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
0 00 O oo
(s! %
N-mA.A„.h + HN- AN, H
n ci HCly N
f3c f3c
2-Chloro-N-(o-tolylsulfonyl)[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridmecarboxamide (100 mg,
0.19 mmol), (45')-2.2.4-tri methyl pyrrolidine (hydrochloride salt) (90 mg, 0.6 mmol),
and potassium carbonate (138 mg, 1.0 mmol) were combined in DMSO (500 pL) and
heated at 130 °C for 16 h. The reaction was diluted with water (3mL) and stirred for 20
min. A solid formed and the aqueous liquid was decanted. The solid was dissolved in
ethyl acetate and washed with a 1M citric acid solution, then brine. The organics were
dried over sodium sulfate and evaporated. The crude material was purified by silica gel
chromatography eluting with 0-10% methanol in dichloromethane to give N-(otolylsulfonyl
-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (69 mg, 60%) ESI-MS m/z calc.
605.22833, found 606.5 (M+l)+; Retention time: 2.33 minutes. 1H NMR (400 MHz,
DMSO-d6) 5 12.63 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.82 (d, J
= 8.2 Hz, 1H), 7.59 (td, J = 7.5, 1.5 Hz, 1H), 7.49 - 7.40 (m, 2H), 6.96 (d, J = 8.3 Hz,
SUBSTITUTE SHEET (RULE 26)
1H), 6.18 (d, J = 2.7 Hz, 1H), 4.48 (s, 2H), 2.63 (s, 3H), 2.39 (d, J = 8.8 Hz, 2H), 2.35 -
2.23 (m, 2H), 2.21 - 2.04 (m, 4H), 2.02 -1.91 (m, 1H), 1.83 (dd, J= 11.9, 5.6 Hz, 1H),
1.53 (s, 6H), 1.35 (t, J = 12.1 Hz, 1H), 0.69 (d, J = 6.2 Hz, 3H).
tic Example 57: Synthesis of Compound 59: N-(3-
Fluorophenyl)sulfonyl [3- [ [ l-(trifluoromethyl)cyclobutyl]methoxy] pyrazol- 1-yl]-
2- [(4S)-2,2,4-trimethylpyrrolidin- 1-yl] pyridinecarboxamide
Step A: 2-Chloro-N-(3-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridinecarboxamide
O II O, ,p
0^-n'nxn^ci N^N^CI ^
F3c f3c
2-Chloro[3-[[l-(tri£luoromethyl)cyclobutyl]methoxy]pyrazol-l-
yl]pyridinecarboxylic acid (150 mg, 0.3992 mmol) and yl diimidazole
(approximately 81.69 mg, 0.5038 mmol) were combined in THF (1.339 mL) and stirred
for 2 h. At this point, 3-fluorobenzenesulfonamide (approximately 69.93 mg, 0.3992
mmol) was added followed by DBU (approximately 202.6 mg, 199.0 pL, 1.331 mmol)
and the reaction was d for an additional 2h at room temperature. The reaction was
diluted with ethyl acetate and washed with a 1M citric acid solution, followed by brine.
The organics were separated, dried over sodium sulfate, and evaporated to give 2-
chloro-N-(3-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridmecarboxamide (210 mg,
99%) ESI-MS m/z calc. 95, found 533.0 (M+l)+; Retention time: 0.77 minutes.
Step B: N-(3-Fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 9,9 (S)/ 0 9,p
„ jfxVlY4 hiQ
a,°-csN'N^N^CI Hci/\
f3c f3c
SUBSTITUTE SHEET (RULE 26)
] ro-N-(3-fluorophenyl)sulfonyl[3-[[l-
(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridinecarboxamide (100 mg,
0.19 mmol), (4S')-2.2.4-trimethylpyrrolidine (hydrochloride salt) (90 mg, 0.6 mmol),
and potassium carbonate (138 mg, 1.0 mmol) were ed in DMSO (500 pL) and
heated at 130 °C for 16 h. The reaction was diluted with water (3mL) and stirred for 20
min. A solid formed and the aqueous liquid was decanted. The solid was dissolved in
ethyl acetate and washed with a 1M citric acid solution, then brine. The organics were
dried over sodium sulfate and evaporated. The crude material was purified by silica gel
chromatography eluting with 0-10% methanol in dichloromethane to give N-(3-
fluorophenyl)sulfonyl[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide (73 mg, 63%) ESI-MS m/z
calc. 609.2033, found 610.2 ; Retention time: 2.27 minutes. 1H NMR (400
MHz, DMSO-d6) 5 12.63 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H),
7.84 (d, J = 2.0 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.66 - 7.59 (m, 1H), 6.96 (d, J = 8.2 Hz,
1H), 6.18 (d, J = 2.7 Hz, 1H), 4.48 (s, 2H), 2.43 (d, J = 10.4 Hz, 1H), 2.35 - 2.25 (m,
3H), 2.19 - 2.05 (m, 4H), 1.96 (td, J = 10.0, 5.3 Hz, 1H), 1.84 (dd, J = 11.8, 5.6 Hz, 1H),
1.55 (s, 3H), 1.52 (s, 3H), 1.40 (t, J= 12.2 Hz, 1H), 0.69 (d, J = 6.2 Hz, 3H).
tic Example 58: Synthesis of Compound 60: N-(Benzenesulfonyl)-
6-[3-(spiro[2.2]pentanylmethoxy)pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-
1-yl] pyridinecarboxamide
Step A: spiro[2.2]Pentyl-methanol
‘OH ‘OH
To a suspension of lithium aluminum e (888 mg, 23.4 mmol) in
tetrahydrofuran (30 mL) was added spiro[2.2]pentane-l-carboxylic acid (1.75g, 15.6
mmol) in tetrahydrofuran (5 mL) dropwise over 5 minutes. The reaction was heated to
50 °C for 16 hours. The reaction was diluted with diethyl ether (20 mL) and quenched
with solid sodium sulfate decahydrate. The mixture was diluted with diethyl ether (100
mL), filtered through celite pad and concentrated to give spiro [2.2] pentyl-methanol
(793 mg, 52%) as an oil. ESI-MS m/z calc. 98.15 found 98.8 (M+l)+ . Retention time:
SUBSTITUTE SHEET (RULE 26)
2.54 minutes. 1H NMR (250 MHz, CDC13) ppm 0.58 - 0.89 (m, 4 H) 0.91 -1.09 (m, 1
H) 1.20 - 1.37 (m, 1 H) 1.43 (m, 1 H) 3.60 (dd, J = 11.98, 6.37 Hz, 2 H)
] Step B: 3-(spiro[2.2]Pent-l-ylmethoxy)-pyrazole-l-carboxylic acid tertbutyl
ester
N'NA0^0 I 0 I
'OH XLP-XJ
To a on of crude spiro[2.2]pent-l-yl-methanol (966 mg, 9.8 mmol) in
tetrahydrofuran (40 mL) was added triphenyl phosphine (2.58 g, 9.8 mmol), 3-hydroxypyrazolecarboxylic
acid utyl ester (1.64 g, 8.9 mmol). The reaction mixture was
cooled in an ice bath followed by the addition of diisopropyl azodicarboxylate (1.9 mL,
9.8 mmol). The ice bath was removed and the reaction was stirred for 2 hours. The
solvent was removed in vacuum and the crude mixture was purified by silica gel column
chromatography using 10-20% hexanes-diethyl ether to give 3-(spiro[2.2]pent-lylmethoxy
)-pyrazole-l-carboxylic acid tert-butyl ester (1.20 g, 44%) as a clear oil. ESI-
MS m/z calc. 264.33 found 265.1 (M+l)+ . Retention time: 3.36 minutes
Step C: 3-(spiro[2.2]Pent-l-ylmethoxy)-lH-pyrazole
To 3-(spiro[2.2]pent-l-ylmethoxy)-pyrazole-l-carboxylic acid tert-butyl ester
(1.2 g, 4.54 mmol) was added dichloromethane (30 mL) and trifluoroacetic acid (3.4
mL, 45 mmol). The on mixture was stirred for 2 hours at room temperature and
trated to dryness in vacuum. The residue was azeotroped twice with 1,2-
dichloroethane (15 mL) to give cmde 3-(spiro[2.2]pent-l-ylmethoxy)-lH-pyrazole (1.87
g, 51%) as ayellow oil. ESI-MS m/z calc. 164.09 found 164.6 (M+l)+ . Retention time:
2.11 minutes
Step D: 2-Chloro[3-(spiro[2.2]pentylmethoxy) l-l-yl]-
nicotinic acid methyl ester
SUBSTITUTE SHEET (RULE 26)
0 'o
CXLv0'UNH + O'' N^CI
cr n 'ci>£
To crude ro[2.2]pent-l-ylmethoxy)-lH-pyrazole (1.87 g, assumed 4.54
mmol) was added methyl 2,6-dichloromcotinate (935 mg, 4.54 mmol), 1,4-
diazabicyclo[2.2 2]octane (102 mg, 0 91 mmol), ylformamide (8 mL) and
potassium carbonate (1.9 g, 13.6 mmol). The reaction was stirred for 48 hours at room
temperature, diluted with diethyl ether (75 mL) and washed with water ning a
small amount of brine (3 x 50 mL) and brine (50 mL). This organic layer was dried over
sodium sulfate and concentrated in vacuum. The crude reaction mixture was purified by
silica gel column chromatography using 0-15% s:diethyl ether to afford 2-chloro-
6-[3-(spiro[2.2]pent-l-ylmethoxy) pyrazol-l-yl]-nicotinic acid methyl ester (1.02 g,
67%) as an off-white solid. ESI-MS m/z calc. 333.09 found 333.9 (M+l)+ . Retention
time: 3.85 minutes.
Step E: ro[3-(spiro[2.2]pent-l-ylmethoxy)-pyrazol-l-yl]-
nicotinic acid
O O
O 'OH
N- NU ^5
\X\__p-<J N Clyi XLP-Cj
To 2-Chloro[3-(spiro[2.2]pent-l-ylmethoxy) l-l-yl]-nicotinic acid
methyl ester (990 mg, 2.97 mmol) was added water (6 mL), methanol (6 mL) and
tetrahydrofuran (6 mL) followed by lithium hydroxide (285 mg, 11.88 mmol). The
reaction was stirred for 1 hour and 1M hydrochloric acid (12 mL) was added. Formed
white solid was filtered off, washed with water and hexanes to give 2-chloro[3-
(spiro[2.2]pent-l-ylmethoxy)-pyrazol-l-yl]-nicotinic acid (927 mg, 98%) as a white
solid. ESI-MS m/z calc. 319.07 found 320.0 (M+l)+ . Retention time: 3.25 minutes 1H
NMR (250 MHz, CDC13) ppm: 0.76 - 0.88 (m, 5 H), 1.11-1.13 (m, 1 H), 1.60-1.75
(m, 1H), 4.22 (dd, J=7.0, 3.3, Hz, 2H) 6.00 (d, J=2 5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H),
8.38 (d, J=2.5 Hz, 1H), 8.43 (d, J=8.5 Hz, 1H).
Step F: N-(benzenesulfonyl)chloro[3-(spiro[2.2]pentan
ylmethoxy)pyrazol-l-yl]pyridinecarboxainide
SUBSTITUTE SHEET (RULE 26)
0 QvP
\XLP~iJ N ClN- N'CI
ro[3-(spiro[2.2]pentanylmethoxy)pyrazol-l-yl]pyridine
carboxylic acid (50 mg, 0.16 mmol) and carbonyl diimidazole (38 mg, 0.23 mmol) were
combined in THF (1.5 mL) and stirred for 2 h. At this point, benzenesulfonamide (25
mg, 0.16 mmol) was added followed by DBU (70 |iL. 0.47 mmol) and the on was
stirred for an additional 2 h at room temperature. The reaction was d with ethyl
acetate and washed with a 1M citric acid solution, ed by brine. The organics were
separated, dried over sodium sulfate, and evaporated to give N-(benzenesulfonyl)
[3-(spiro[2.2]pentanylmethoxy)pyrazol-l-yl]pyridinecarboxamide (72
mg, 98%) ESI-MS m/z calc. 458.08154, found 459.2 (M+l)+; Retention time: 0.75
minutes.
Step G: N-(benzenesulfonyl)[3-(spiro[2.2]pentanylmethoxy)pyrazol-
l-yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 %9 (s/ O 00
XX H TQ + HnQ
0-^N'NAN^CI ^ HciS
N-(benzenesulfonyl)chloro[3-(spiro[2.2]pentanylmethoxy)pyrazol-l-
yl]pyndinecarboxamide (72 mg, 0.16 mmol), (4<S,)-2,2,4-trimethylpyrrohdme
(hydrochlonde salt) (63 mg, 0.42 mmol), and potassium carbonate (97 mg, 0.7 mmol)
were combined in DMSO (1 mL) and heated at 130 °C for 16 h. The reaction was
diluted with water (3mL) and stirred for 20 min. A solid formed and the aqueous liquid
was decanted. The solid was dissolved in ethyl acetate and washed with a 1M citric acid
solution, then brine. The organics were dried over sodium sulfate and ated. The
crude material was purified by silica gel chromatography eluting with 0-10% methanol
in dichloromethane to give N-(benzenesulfonyl)[3-(spiro[2.2]pentan
ylmethoxy)pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
(38 mg, 45%) ESI-MS m/z calc. 535.22534, found 536.1 (M+l)+; Retention time: 2.22
minutes.
SUBSTITUTE SHEET (RULE 26)
Synthetic Example 59: sis of Compound 61: (5S)
(benzenesulfonyl)-3,3,5-trimethyl(3-{2-[l-
(trifluoromethyl)cyclopropyl]ethoxy}- IH-pyrazol- l-yl)-2,7,13-
tricyclo[7.4.0.02,6]trideca-l(9),10,12-trienone
9 9PYn O oo
N- p^QN NN- nA(S)^
F^ F Fn F
F F
N-(Benzenesulfonyl)[3-[2-[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl] [(4S)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxamide (52 mg, 0.08789 mmol), NaOAc (14 mg, 0.1707 mmol),
water (16 pL, 0.89 mmol), and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (5 mg, 0.004 mmol) were
combined in DMA (dimethylacetamide) (0.9 pL) and the reaction mixture was placed
next to a 23 W CFL light source for 1.5 h. The reaction was injected directly onto a
silica gel column without any workup. The crude mixture was purified by silica gel
chromatography eluting with 0-100% ethyl acetate in hexanes to give (5S)
(benzenesulfonyl)-3,3,5-trimethyl(3-{2-[l-(trifluoromethyl)cyclopropyl]ethoxy}-
lH-pyrazol-l-yl)-2,7,13-triazatricyclo[7.4.0.02,6]trideca-l(9),10,12-trienone (10 mg,
19%) ESI-MS m/z calc. 71, found 590.3 (M+l)+; Retention time: 2.51 minutes.
^ NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 7.7 Hz, 2H),
7.81 (d, J = 8.2 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.66 (t, J = 7.6 Hz, 2H), 6.97 (d, J =
8.2 Hz, 1H), 6.07 (d, J = 2.7 Hz, 1H), 6.02 (d, J = 3.9 Hz, 1H), 4.36 (t, J = 7.0 Hz, 2H),
3.04 (dt J = 12.2, 5.7 Hz, 1H), 2.17 (dd, J = 13.4, 7.3 Hz, 1H), 2.11 (m, 2H), 1.86 (d, J
= 13.2 Hz, 1H), 1.71 (s, 3H), 1.61 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H), 0.97 (m, 2H), 0.88
(m, 2H)
Synthetic Example 60: Synthesis of Compound 62: (5S)-3,3,5-trimethyl-
12-(3-{2-[l-(trifluoromethyl)cyclopropyl]ethoxy}-lH-pyrazol-l-yl)oxa-2,13-
diazatricyclo[7.4.0.02,6]trideca-l(13),9,ll-trienone
Step A: 2-[l-(Trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]
[(4S)-2,2,4-trimethylpyrrolidin- 1-yl] pyridinecarboxylic acid
SUBSTITUTE SHEET (RULE 26)
0 0
'OH ‘OH
,O^N N' Cl N- y-i
Fv F Fv F p-tj Njy
F F
To a mixture of 2-chloro[3-[2-[l-
(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridinecarboxylic acid (1 g, 2.661
mmol) and (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (620 mg, 4.143 mmol)
in N-methylpyrrolidinone (5 mL) and 1,2-diethoxy ethane (1 mL) was added potassium
carbonate (1.8 g, 13.02 mmol). The slurry was heated at 125 °C for 68 h. LC/MS
showed 40% conversion. More (4S)-2,2,4-trimethylpyrrolidine (400 mg) was added and
the on was continued for 18 h at 135 °C. Cooled reaction suspension to ambient
temperature and added slowly to a rapidly stirred solution of HC1 (2 mL of 6 M, 12.00
mmol) in ice (foams!) affording a brown slurry. The slurry was extracted with ethyl
e. The organic was washed with water, brine, dried over sodium sulfate and
concentrated. The crude material was chromatographed on silica using a gradient of
hexane/ethyl acetate. Product came out -30% ethyl acetate. 6-[3-[2-[l-
(trifluoromethyl)cy clopropyl]ethoxy]pyrazol-1 -yl] [(4S)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxylic acid (667.8 mg, 55%). ESI-MS m/z calc. 352, found
453.0 (M+l) +; Retention time: 1.87 minutes. 1H NMR (400 MHz, DMSO-d6) 5 12.68
(s, 1H), 8.24 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 32.9, 7.9 Hz, 1H), 6.29 -
6.01 (m, 1H), 4.31 (s, 2H), 3.54 (s, 1H), 2.89 (s, 1H), 2.33 (s, 1H), 2.08 (s, 2H), 1.95 (s,
1H), 1.74 - 1.46 (m, 7H), 1.12 - 1.01 (m, 3H), 0.92 (d, J = 29.3 Hz, 4H).
Step B: (5S)-3,3^-Trimethyl(3-{2-[l-
(trifluoromethyl)cyclopropyl]ethoxy}-lH-pyrazol-l-yl)oxa-2,13-
diazatricyclo[7.4.0.02,6]trideca-l(13),9,ll-trienone
O O
•OH 'Y o
p^N ; p-uN. nT'nAis)
F F F. F
F F
6-[3-[2-[l-(Trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxylic acid (50 mg, 0.1105 mmol), water (20
SUBSTITUTE SHEET (RULE 26)
HL, 1.110 mmol),NaOAc (18 mg, 0.22 mmol), and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (4
mg, 0.003565 mmol) were dissolved in DMA (0.9 mL) and the reaction mixture was
placed next to a 23 W CFL light source for 1.5 h. The reaction was injected directly
onto a silica gel column without any workup. The crude mixture was purified by silica
gel tography g with 0-100% ethyl acetate in hexanes to give (5S)-3,3,5-
trimethyl- 12-(3 - {2- [1 -(trifluoromethy l)cy clopropy 1] ethoxy} -1 H-pyrazol-1 -yl)oxa-
2,13-diazatricyclo[7.4.0.02,6]trideca-l(13),9,ll-trienone (30.8 mg, 62%) ESI-MS
m/z calc. 450.18787, found 451.3 (M+l)+; Retention time: 2.35 minutes.
Synthetic Example 61: Synthesis of Compound 63: N-(Benzenesulfonyl)-
6- [3- [(3-fluoro- l-bicyclo[l. 1.1] pentanyl)methoxy] pyrazol- l-yl|[(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: tert-Butyl 3-[(3-fluoro
bicyclo [ 1.1.1] yl)methoxy] py razole- oxylate
^3% N- F
OH + HO— OW
A on of (3-fluoro-l-bicyclo[l.l.l]pentanyl)methanol (0.27 g, 2.3
mmol), tert-butyl 3-hydroxypyrazole-l-carboxylate (0.46 g, 2.5 mmol), and triphenyl
phosphine (0.67 g, 2.6 mmol) in THF (12 mL) was cooled in an ice bath, and isopropyl
N-isopropoxycarbonylimmocarbamate (0.50 mL, 2.6 mmol) was slowly added. The
reaction was allowed to slowly warm to room temperature and was stirred for three
days. It was diluted with ethyl acetate, washed with saturated s sodium
bicarbonate, dried over sodium sulfate, and evaporated under vacuum. The residue was
ed by silica gel tography with 0-40% ethyl acetate in hexanes to give tertbutyl
3-[(3-fluoro-l-bicyclo[l.l.l]pentanyl)methoxy]pyrazole-l-carboxylate (0.43 g,
66%) ESI-MS m/i calc. 282.13797, found 283.3 (M+l)1. Retention time: 0.65 minutes.
Step B: 3-[(3-Fluoro-l-bicyclo|l.l.l]pentanyl)methoxy]-lH-pyrazole
F- N.
F >N'NH
OW O W
A solution of utyl 3-[(3-fluoro-l-
bicyclo[l.l.l]pentanyl)methoxy]pyrazole-l-carboxylate(0.43 g, 1.523 mmol) and
SUBSTITUTE SHEET (RULE 26)
trifluoroacetic acid (587 (xL, 7.62 mmol) in dichloromethane (4 mL) was stirred for 5
hours. The volatiles were removed under vacuum, and the residue was basified with
saturated aqueous sodium bicarbonate and ted with ethyl e. The combined
extracts were dried over sodium sulfate and evaporated to give 3-[(3-fluoro-l-
bicyclo[l.l.l]pentanyl)methoxy]-lH-pyrazole (0.28 g, 100%) ESI-MS m/z calc.
182.08554, found 183.1 (M+l)+ ; Retention time: 0.39 minutes.
Step C: tert-Butyl 2-chloro[3-[(3-fluoro-l-
o[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyridinecarboxylate
-N- F NH +
oW F An N Cl
Cl N Cl oW
A mixture of 3-[(3-fluoro-l-bicyclo[l.l.l]pentanyl)methoxy]-lH-pyrazole
(0.28 g, 1.5 mmol), tert-butyl chloropyridinecarboxylate (0.38 g, 1.5 mmol),
potassium carbonate (0.26 g, 1.9 mmol), and l,4-diazabicyclo[2.2.2]octane (34 mg, 0.30
mmol) in DMSO (7.5 mL) was d at room temperature for 16 h. The reaction was
diluted with water and extracted with ethyl acetate. The combined extracts were washed
with brine and water, dried over sodium sulfate, and evaporated. The residue was
ed by silica gel chromatography with 0-5% methanol in dichloromethane to give
tert-butyl 2-chloro[3-[(3-fluoro-l-bicyclo[l.l.l]pentanyl)methoxy]pyrazol-lyl
]pyridinecarboxylate (0.50 g, 85%) ESI-MS m/z calc. 393.12555, found 394.2
(M+l) +; Retention time: 0.86 minutes.
Step D: 2-Chloro[3-[(3-fluoro-l-
bicyclo[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyri(linecarboxylic acid
v<0 I o
F- An N Cl✓5 F An N Cl
OW 0 W
A solution of tert-butyl 2-chloro[3-[(3-fluoro-l-
o[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyridinecarboxylate (0.50 g, 1.270
mmol) and trifluoroacetic acid (978 pL, 12.7 mmol) in dichloromethane (6 mL) was
stirred for 15 hours. The solvent was evaporated, and the residue was taken up in
SUBSTITUTE SHEET (RULE 26)
acetonitrile. The solvent was evaporated to give 2-chloro[3-[(3-fluoro-l-
bicyclo[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyridinecarboxylicacid (0.43 g, 100%)
ESI-MS m/z calc. 296, found 338.1 (M+l)+ ; Retention time: 0.63 minutes 1H
NMR (400 MHz, Chloroform-d) 5 8.43 (d, J = 8.5 Hz, 1H), 8.39 (d, J = 2.9 Hz, 1H),
7.73 (d, J = 8.5 Hz, 1H), 6.00 (d, J = 2.8 Hz, 1H), 4.51 (s, 2H), 2.13 (d, J = 2.6 Hz, 6H).
Step E: N-(benzenesulfonyl)chloro[3-[(3-fluoro-l-
bicyclo[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyridinecarboxamide
O 9 Q„P
N''S'
H %
F- N Cl F- ,n'n N XI
OW oW
2-Chloro[3-[(3-fluoro-l-bicyclo[l.l.l]pentanyl)methoxy]pyrazol-l-
idinecarboxylic acid (100 mg, 0.3 mmol) and carbonyl diimidazole (58 mg,
0.36 mmol) were combined in THF (1.5 mL) and stirred for 2 h. At this point,
benzenesulfonamide (61 mg, 0.39 mmol) was added followed by DBU (54 |iL 0.36
mmol) and the on was stirred for an additional 16 h at room temperature. The
reaction was dduted with ethyl acetate and washed with a 1M citric acid solution,
ed by brine. The organics were separated, dried over sodium sulfate, and
evaporated to give N-(benzenesulfonyl)chloro[3-[(3-fluoro-lbicyclo
[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (190 mg, 135%)
ESI-MS m/z calc. 476.07214, found 477.2 (M+l)+; Retention time: 0.69 minutes.
Step F: N-(Benzenesulfonyl)[3-[(3-fluoro-l-
bicyclo|l.l.l]pentanyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-trimethylpyrrolidin-l-
yl] pyridinecarb oxamide
N /X H T) + HnQ
F- n-n^n^ci W hciA
N-(Benzenesulfonyl)chloro[3-[(3-fluoro-l-
bicyclo[l.l.l]pentanyl)methoxy]pyrazol-l-yl]pyridinecarboxamide (140 mg, 0.29
mmol), (45)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (131 mg, 0.88 mmol), and
potassium carbonate (243 mg, 1.76 mmol) were combined in DMSO (1.5 mL) and
SUBSTITUTE SHEET (RULE 26)
heated at 130 °C for 16 h. The reaction mixture was filtered and punfied by LC/MS
utilizing a gradient of 30-99% acetonitrile in 5 mM aq HC1 to give N-(benzenesulfonyl)-
6-[3-[(3-fluoro-l-bicyclo[l.l.l]pentanyl)methoxy]pyrazol-l-yl][(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide (89 mg, 54%) ESI-MS m/z calc.
553.2159, found 554.4 (M+l)+; Retention time: 2.16 minutes. 1HNMR (400 MHz,
DMSO-d6) 5 8.19 (d, J = 2.8 Hz, 1H), 8.05 - 7.95 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H),
7.77 - 7.70 (m, 1H), 7.70 - 7.61 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.14 (d, J = 2.8 Hz,
1H), 4.47 (s, 2H), 2.45 - 2.36 (m, 1H), 2.31 - 2.22 (m, 1H), 2.15 - 2.08 (m, 7H), 1.82
(dd, J = 11.9, 5.5 Hz, 1H), 1.52 (d, J = 9.2 Hz, 6H), 1.36 (t, J = 12.1 Hz, 1H), 0.64 (d, J
= 6.2 Hz, 3H)
] Synthetic Example 62: Synthesis of Compound 64: N-
(Benzenesulfonyl)[3-(dispiro[2.0.2.1]heptanylmethoxy)pyrazol-l-yl][(4S)-
2,2,4-trimethylpyrrolidin-l-yl]pyridinecarboxamide
Step A: totf-Butyl 3-(dispiro[2.0.2.1]heptanyl methoxy)-l//-pyrazole-l-
carboxylate
NUrBoc
OH p-V
A solution of dispiro[2.0.2.1]heptanyl methanol (1.36 g, 11.0 mmol) (Meijere, et al.,
Eur. J. Org. Chem. 2002,485-492), fert-butyl 3-hydroxypyrazole-l-carboxylate (2.3 g,
12 mmol), and triphenyl phosphine (3.2 g, 12 mmol) in THE (28 mL) was cooled in an
ice bath, and diisopropyl azodicarboxylate (DIAD) (2.4 mL, 12 mmol) was slowly
added. The cooling bath was removed, and the reaction was stirred for 15 hours. The
on was diluted with ethyl acetate, washed with ted aqueous sodium
onate, dried over sodium sulfate, and evaporated under vacuum. The residue was
ed by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to
give /m-bulyl 3-(dispiro[2.0.2.1]heptanyl methoxy)-1 a/ole- 1-carboxylate
(1.57 g, 49% yield) as a colorless oil. ESI-MS m/z calc. 290.16306, found 291.3
(M+l)+; Retention time: 0.76 minutes.
] Step B: 3-(Dispiro[2.0.2.1 |heptanylmethoxy)-l//-pyrazole
SUBSTITUTE SHEET (RULE 26)
WO 64632
N.m.Boc
,0-^N - 'NH
A solution of /cvv-butyl piro[2.0.2.1]heptanyl melhoxx )-1//-
pyrazole-l-carboxylate (1.57 g, 5.41 mmol) and trifluoroacetic acid (2.2 mL, 29 mmol)
in dichloromethane (20 mL) was d for three hours. The volatiles were removed
under vacuum, and the residue was basified with saturated aqueous sodium bicarbonate
and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate
and evaporated to give 3-(dispiro[2.0.2.1]heptanylmethoxy)pyrazole (0.94 g,
91%yield) as pale yellow oil. ESI-MS m/z calc. 190.11061, found 191.1 (M+l)+;
Retention time: 0.52 minutes
Step C: Ethyl 2-chloro(3-(dispiro[2.0.2.1]heptanylmethoxy)-l//-
pyrazol-l-yl)nicotinate
- NH P_An N' -Cl✓i
A mixture of 3-(dispiro[2.0.2.l]heptanylmethoxy)pyrazole (0.94 g,
4.9 mmol), ethyl chloropyridinecarboxylate (1.15 g, 5.23 mmol), potassium
carbonate (0.83 g, 6.0 mmol), and azabicyclo[2.2.2]octane (0.12 g, 1.1 mmol) in
DMSO (16 mL) was stirred for 24 hours. The reaction was diluted with water and
extracted with ethyl acetate. The combined ts were washed with brine and water,
dried over sodium sulfate, and evaporated under vacuum. The residue was purified by
silica gel column chromatography eluting with 0-20% ethyl acetate in hexanes to give
ethyl 2-chloro(3-(dispiro[2.0.2.1]heptanylmethoxy)-li7-pyrazol-l-yl)nicotinate
(1.39 g, 75% yield) as a colorless solid. ESI-MS m/z calc. 373.11932, found 374.2
; Retention time: 0.87 minutes. 'H NMR (400 MHz, Chloroform-d) 5 8.36 (d, J
= 2.8 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 5.96 (d, J = 2.9 Hz,
1H), 4.41 (q, J = 7.1 Hz, 2H), 4.30 (d, J = 7.0 Hz, 2H), 1.94 (t, J = 7.0 Hz, 1H), 1.42 (t, J
= 7.1 Hz, 3H), 1.02-0.89 (m, 4H), 0.75-0.65 (m, 2H), 0.65-0.53 (m, 2H)
Step D: 2-Chloro[3-(dispiro[2.0.2.1]heptanylmethoxy)pyrazol-l-
yl]pyridinecarboxylic acid
SUBSTITUTE SHEET (RULE 26)
0 0
O^QN N-'CIxi P-A N''GIxl
A solution of ethyl ro(3-(dispiro[2.0.2.1]heptanylmethoxy)-li/-
pyrazol-l-yl)nicotinate (1.39 g, 3.72 mmol) and sodium hydroxide (7.5 mL of 1 M
solution, 7.5 mmol) in THF (6 mL) and ethanol (3 mL) was stirred for 90 s. The
volatiles were removed under vacuum, and water was added. The reaction was cooled in
an ice bath, and hydrochloric acid (7.5 mL of 1 M solution, 7.5 mmol) was slowlyadded.
The reaction was diluted with water and extracted with ethyl acetate. The
combined extracts were washed with brine, dried over sodium sulfate, and evaporated to
give 2-chloro[3-(dispiro[2.0.2. l]heptanylmethoxy)pyrazol-l-yl]pyridine
carboxylic acid (1.16 g, 82% yield) as a colorless solid. ESI-MS m/z calc. 345.088,
found 346.1 (M+l)+; Retention time: 0.73 minutes. 'H NMR (400 MHz, DMSO-d6) 8
8.41 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.19 (d, J =
2.8 Hz, 1H), 4.27 (d, J = 7.0 Hz, 2H), 1.93 (t, J = 7.0 Hz, 1H), 0.97 - 0 79 (m, 4H), 0 76
- 0.66 (m, 2H), 0.65 - 0.56 (m, 2H)
Step E: A/-(Benzenesulfonyl)chloro[3-(dispiro[2.0.2.l]heptan
ylmethoxy)pyrazol-l-yl]pyridinecarboxamide
O 9 QwP
N:s''
p^N N^CIH
] A solution of 2-chloro[3-(dispiro[2.0.2.1]heptanylmethoxy)pyrazol-l-
yl]pyridinecarboxylic acid (0.10 g, 0.29 mmol) and carbonyl diimidazole (0.06 g, 0.4
mmol) in THF (1.4 mL) was stirred for 45 minutes, and esulfonamide (55 mg,
0.35 mmol) and l,8-diazabicyclo(5.4.0)undecene (DBU) (130 pL, 0.87 mmol) were
added. After 15 hours the reaction was diluted with 1 M aqueous citric acid and
ted with ethyl acetate. The combined extracts were washed with brine, dried over
sodium sulfate, and evaporated to give crude A-(benzenesulfonyl)chloro[3-
(dispiro [2.0.2.1 ]heptan-7 -y xy)pyrazol-1 -y 1] pyridine-3 -carboxamide (0.16 g)
which was used in the next step as-is. ESI-MS m/z calc. 484.0972, found 485.2 ;
Retention time: 0.81 minutes.
SUBSTITUTE SHEET (RULE 26)
] Step F: 7V-(Benzenesulfonyl)[3-(dispiro[2.0.2.1]heptan
ylmethoxy)pyrazol-l-yl][(4V)-2,2,4-trimethylpyrrolidin-l-yl]pyridine
carboxamide
9 qpVo o o 0
•N'N-CC%P
A mixture of jV-(benzenesulfonyl)chloro[3-(dispiro[2.0.2.1]heptan
ylmethoxy)pyrazol-l-yl]pyridinecarboxamide (0.14 g, 0.29 mmol), (4S)-2,2,4-
trimethylpyrrolidine hydrochloride (0.14 g, 0.94 mmol), and potassium carbonate (0.24
g, 1.7 mmol) inNMP (1.3 mL) was stirred at 130 °C for 15 hours. The reaction was
filtered and purified using a reverse phase HPLC-MS method using a dual gradient run
from 30-99% acetonitrile in 5 mM aqueous HC1. .V-iBenzenesulfonvl )|3-
(dispiro[2.0.2.1 ]heptan-7 -ylmethoxy)pyrazol-l -yl] [(45)-2,2,4-trimethylpyrrolidin-1 -
yl]pyridinecarboxamide (65 mg, 40% yield) was ed. ESI-MS m/z calc.
561.24097, found 562.3 (M+l)+; Retention time: 2.35 minutes.
Synthetic Example 63: Synthesis of Compound 65: zenesulfonyl)-
6-(3-hydroxypyrazol-l-yl)[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine
carboxamide
Step A: fezt-Butyl 3-((l-ethylcyclopropyl)methoxy)-lf7-pyrazole-l-
carboxylate
^ X)°v-N DIAD, Ph3R, THF
0°C to rt, then 50°C T NBoc
To the solution of (l-ethylcyclopropyl)methanol (1.68 g, 16.73 mmol), tertbutyl
2,3-dihydrooxopyrazole-l-carboxylate (2.80 g, 15.21 mmol) and
triphenylphosphine (4 39 g, 16.73 mmol) in tetrahydrofuran (40 mL) at 0 °C was added
diisopropyl arboxylate (3.38 g, 16.73 mmol) se. The reaction was warmed
up to room temperature, then heated at 50 °C for 21 hours. The reaction solution was
cooled to room temperature and ethyl e (500 mL) was added. The organic layer
was washed with 0.3M aqueous sodium hydroxide solution (100 mL), brine (2 x 50 mL)
and dried over magnesium sulfate, filtered and concentrated. The residue was purified
SUBSTITUTE SHEET (RULE 26)
by silica gel chromatography using 0 to 80% hexanes/dichloromethane gradient method
to afford re/Y-butyl 3-(( I -ethylcyclopropyl)methoxy)-1 //-pyrazole-1 -carboxylate (1.73
g, 43%) as a yellow oil. ESI-MS m/z calc. 266.2, found 267.3 (M+l)+. ion time:
3.47 s. 1HNMR (250MHz: CDCh) 8 (ppm): 7.82 (d, J= 2.5Hz, 1H), 5.88 (d, / =
2.5Hz, 1H), 4.09 (s, 2H), 1.60 (s, 9H), 1.48 (q, J= 7.5Hz, 2H), 0.94 (t, J= 7.5Hz, 3H),
0.49 (m, 2H), 0.42 (m, 2H).
Step B: 3-((l-Ethylcyclopropyl)methoxy)-l//-pyrazole
HCI in e
0V^N. tVN.X/NH
T NBoc
A solution of 4M hydrogen chloride in 1,4-dioxane (65 mL) was added to
/e/V-butyl 3-(( l-cthylcyclopropyi)mctho\))-1//-pyrazole-1 -carboxylate (1.73 g, 6.49
mmol) and the reaction solution was stirred at room temperature for 16 hours and
concentrated to dryness to obtain crude 3-((l-ethylcyclopropyl)methoxy)-l//-pyrazole
as an oil which was used ly in next step. ESI-MS m/z calc. 166.1, found 167.3
(1VM) . Retention time: 0.60 minutes.
Step C: Methyl 2-chloro(3-((l-ethylcyclopropyl)methoxy)-lH-pyrazol-
l-yl)nicotinate
/ K2C03/DABCO
Ox^N.
WNH x: f O'
cr n ci DMF .Cl
3-((l-Ethylcyclopropyl)methoxy)-lH-pyrazole (6.49 mmol) and methyl 2,6-
dichloronicotinate (1.81 g, 8 mmol) were added into dimethylformamide (20 mL).
Potassium carbonate (2.8 g, 20 mmol) and l,4-diazabicyclo[2.2.2]octane (0.167 g, 1.5
mmol) were added into reaction e which was allowed to stir at room temperture
for 16 hours. The reaction mixture was diluted with water (60 mL) and ted with
diethyl ether (3 x 60 mL). Combined organic layer was dried over sodium e and
evaporated under reduced pressure. The residue was subjected to flash chromatography
on silica gel using 0 to 100% hexanes/dichloromethane gradient method to give methyl
2-chloro(3-((l-ethylcyclopropyl)methoxy)-lH-pyrazol-l-yl)nicotinate (1.7 g, 77%)
as a white solid. ESI-MS m/z calc. 335.10, found 336.5 (M+l)+. Retention time: 4.29
minutes, fa NMR (250 MHz, DMSO) S (ppm): 8.43 (d, J = 2.8Hz, 1H), 8.41 (d, / =
SUBSTITUTE SHEET (RULE 26)
8.4Hz, 1 H), 7.74 (d, J = 8.4Hz, 1 H), 6.23 (d, 2.8Hz, 1 H), 4.08 (s, 2H), 3.88 (s,
3H), 1.44 (q, J= 7.4Hz, 2H), 0.93 (t. ./= 7.4Hz, 3H): 0.53 (m, 2H), 0.42 (m: 2H).
Step D: 2-Chloro(3-((l-ethylcyclopropyl)methoxy)-lH-pyrazol-l-
yl)nicotinic acid
0 NaOH 0
f '0- // OH
-c, THF/MeOH
Methyl 2-chloro(3-((l-ethylcyclopropyl)methoxy)-lH-pyrazol-l-
yl)nicotinate (1.7 g, 50 mmol) was added in a ice-cooled round bottom flask with
tetrahydrofuran (5 mL) and methanol (5 mL). Sodium hydroxide (0.4 g, 10 mmol) in
water (5 mL) was added slowly and reaction solution was stirred at room temperature
for 5 hours. The resulting reaction mixture was concentrated under d pressure to
remove tetrahydrofuran and acidified by IN aqueous hydrogen chloride solution to pH
= 1 in ice bath. Formed white solid was filtered off to give 2-chloro(3-((lethylcyclopropyl
)methoxy)-lH-pyrazol-l-yl)-nicotinic acid (1.54 g, . ESI-MS
m/z calc. 321.09, found 322.2 . Retention time: 3.59 minutes. 'H NMR (250
MHz, DMSO) S (ppm): 8.43 (d, J= 2.8Hz, 1H), 8.42 (d, J= 8.4Hz, 1 H), 7.72 (d, J=
8.4Hz, 1 H), 6.24 (d, J= 2.8Hz, 1 H), 4.09 (s, 2H), 1.45 (q, J= 7.4Hz, 2H), 0.92 (t, J
7.4Hz, 3H), 0.54 (m, 2H), 0.44 (m, 2H).
Step E: N-(Benzenesulfonyl)chloro[3-[(l-
ethylcyclopropyl)methoxy] l-l-yl] pyriilinecarboxamide
O Q o..o
OH In '
N‘N N-m H
.0^ N Cl✓5 0—& N N Cl
2-Chloro[3-[(l-ethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine
carboxylic acid (157 mg, 0.4879 mmol) and carbonyl diimidazole (100 mg, 0.6167
mmol) were combined in THE (2 mL) and d for 2 h. At this point,
benzenesulfonamide (77 mg, 0.4899 mmol) was added followed by DBU (243 pL.
1.625 mmol) and the reaction was stirred an additional 30 min at room temperature. The
reaction was diluted with ethyl e and washed with a 1M citric acid solution,
followed by brine. The organics were separated, dried over sodium sulfate, and
SUBSTITUTE SHEET (RULE 26)
evaporated to give crude N-(benzenesulfonyl)chloro[3-[(lethylcyclopropyl
)methoxy]pyrazol-l-yl]pyridinecarboxamide (224 mg, 100%) ESI-
MS mxz calc. 460.0972, found 461.1 (M+l) +; Retention time: 0.75 minutes.
Step F: N-(Benzenesulfonyl)chloro(3-hydroxypyrazol-l-yl)pyridine-
oxamide
Q 0 0
\'0 Q oo
N-S \V/
H H
o-^n'n N Cl ho-^n N Cl
zenesulfonyl)chloro[3-[(l-ethylcyclopropyl)methoxy]pyrazol-l-
yl]pyridinecarboxamide (224 mg, 100%) was dissolved in dichloromethane (2 mL)
with TFA (1 mL, 12.98 mmol) and the reaction was stirred for 4 h. The reaction was
evaporated to dryness to give N-(benzenesulfonyl)chloro(3-hydroxypyrazol-lyl
)pyridinecarboxamide (136 mg, 74%) ESI-MS m/z calc. 378.01895, found 379.1
(M+l) +; Retention time: 0.54 minutes.
Step G: N-(benzenesulfonyl)(3-hydroxypyrazol-l-yl)[(4S)-2,2,4-
trimethylpyrrolidin-l-yl]pyridinecarboxamide
9 9P .(s)
+ HN N-
ho^n^n^ci joifio
N-(benzenesulfonyl)chloro(3-hydroxypyrazol-l-yl)pyridine
carboxarmde (100 mg, 0.26 mmol), ('4T)-2.2.4-tri methyl pyrrolidine (hydrochloride salt)
(110 mg, 0.76 mmol), and potassium carbonate (180 mg, 1.3 mmol) were combined in
DMSO (0.5 mL) and heated at 130 °C for 16 h. The reaction was diluted with water
(3mL) and stirred for 20 min. A solid formed and the aqueous liquid was decanted. The
solid was ved in ethyl acetate and washed with a 1M citric acid solution, then
brme. The organics were dried over sodium sulfate and ated. The crude material
was purified by silica gel chromatography eluting with 0-10% methanol in
romethane to give N-(benzenesulfonyl)(3-hydroxypyrazol-l-yl)[(4S)-2,2,4-
SUBSTITUTE SHEET (RULE 26)
trimethylpyrrolidin-l-yl]pyridinecarboxamide (4.6 mg, 4%) ESI-MS m/z calc.
272, found 456.3 (M+l)+; Retention time: 1.50 minutes.
Examples: ASSAYS & DATA
5A. Assays for Detecting and Measuring F508del-CFTR modulator
Properties of Compounds
Membrane potential optical methods for assaying properties of F508del-CFTR
The assay utilizes fluorescent voltage sensing dyes to measure changes in
membrane potential using a scent plate reader (e.g., FLIPR III, Molecular
Devices, Inc.) as a readout for increase in functional F508del in NIH 3T3 cells. The
driving force for the se is the creation of a chlonde ion gradient in conjunction
with channel activation and concurrent with compound ent by a single liquid
addition step after the cells have usly been loaded with a voltage sensing dye.
5A-A1. Identification of F508del-CFTR modulators
To identify modulators of F508del, a fluorescence based HTS assay format was
developed. This HTS assay utilizes fluorescent voltage sensing dyes to measure
changes in membrane potential on the FLIPR III as a measurement for increase in
gating (conductance) of F508del NIH 3T3 cells. The driving force for the se is
the creation of a chloride ion gradient in conjunction with channel activation and
rent with compound treatment by a single liquid on step after the cells have
previously been loaded with a voltage sensing dye. Data for nds 1-65 that
were obtained using the assay described here are summarized in Table 6 below. For
example, using this method, Compound 1 had an EC50 of less than 3 pM and a %
Efficacy of > 100% relative to Compound II.
Solutions
Bath on#!: (inmM)NaCl 160, KC14.5, CaCl22, MgCl21,HEPES 10,
pH 7.4 with NaOH, Glucose 10.
Chloride-free bath solution: Chloride salts in Bath Solution #1 (above) are
substituted with gluconate salts.
SUBSTITUTE SHEET (RULE 26)
Cell Culture
NIH3T3 mouse fibroblasts stably expressing F508del are used for optical
measurements of membrane ial. The cells are maintained at 37 °C in 5% CCh and
90 % humidity in Dulbecco’s ed Eagle’s medium supplemented with 2 mM
glutamine, 10 % fetal bovine serum, 1 XNEAA, [3-ME, 1 X pen/strep, and 25 mM
HEPES in 175 cm2 culture flasks. For all optical , the cells were seeded at 12,000
cells/well in 384-well matrigel-coated plates and cultured for 18-24 hrs at 37 °C for the
potentiator assay. For the correction assays, the cells are cultured at 37 °C with and
without compounds for 18 - 24 hours.
Electrophysiological Assays for assaying F508del modulation properties of
compounds.
Ussing Chamber Assay
Ussing chamber experiments were performed on polarized airway epithelial
cells expressing F508del to further characterize the F508del modulators fied in the
optical assays. Non-CF and CF airway epitheha were isolated from bronchial ,
cultured as previously described (Gahetta, L.J.V., Lantero, S., Gazzolo, A., Sacco, O.,
Romano, L., Rossi, G.A., & Zegarra-Moran, O. /« Vitro Cell. Dev. Biol. 34, 478-
481), and plated onto Costar® Snapwell™ filters that were precoated with NIH3T3-
conditioned media. After four days the apical media was removed and the cells were
grown at an air liquid interface for >14 days prior to use. This resulted in a monolayer
of fully differentiated columnar cells that were ciliated, features that are characteristic of
airway epithelia. Non-CF HBE were ed from non-smokers that did not have any
known lung disease. E were isolated from patients homozygous for F508del or
compound heterozygous for F508del with an different e causing on on the
other .
HBE grown on Costar® Snapwell™ cell culture inserts were mounted in an
Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the transepithelial
ance and short-circuit current in the presence of a basolateral to apical CF gradient
(Isc) were measured using a e-clamp system (Department of Bioengineering,
University of Iowa, IA). Briefly, HBE were examined under voltage-clamp recording
conditions (Vhoid = 0 mV) at 37 °C. The basolateral solution contained (in mM) 145
SUBSTITUTE SHEET (RULE 26)
NaCl, 0.83 K2HPO4, 3.3 KH2PO4,12 MgCl2,1.2 CaCl2,10 Glucose, 10 HEPES (pH
adjusted to 7.35 with NaOH) and the apical solution contained (in mM) 145
NaGluconate, 1.2 MgCl2,1.2 CaCE, 10 glucose, 10 HEPES (pH adjusted to 7.35 with
NaOH).
SA-A2. fication of F508del-CFTR modulators
Typical protocol utilized a teral to apical membrane Cl' concentration
nt. To set up this gradient, normal ringers was used on the basolateral membrane,
whereas apical NaCl was replaced by equimolar sodium gluconate ted to pH 7.4
with NaOH) to give a large CE concentration gradient across the epithelium.
Modulators were added either to the basolateral side 18-24 prior to assay or to the
apical side during the assay. lin (10 pM) was added to the apical side during the
assay to stimulate CFTR-mediated Cl' transport.
Patch-clanw Recordings
Total Cl" current in F508del-NIH3T3 cells was monitored using the
perforated-patch recording configuration as previously described (Rae, J., Cooper, K.,
Gates, P., & Watsky. M. (1991) J. Neurosci. s 37, . Yoltage-clamp
recordings were performed at 22 °C using an Axopatch 200B patch-clamp amplifier
(Axon Instruments Inc., Foster City, CA). The e solution contained (in mM) 150
A-methy 1-D-glucamine (NMDG)-Cl, 2 MgCl2, 2 CaCl2, 10 EGTA, 10 HEPES, and 240
pg/mL amphotericm-B (pH adjusted to 7.35 with HC1). The extracellular medium
contained (in mM) 150 NMDG-C1, 2 MgCf, 2 CaCE, 10 HEPES (pH adjusted to 7.35
with HC1). Pulse generation, data acquisition, and analysis were performed using a PC
equipped with a Digidata 1320 A D ace in conjunction with Clampex 8 (Axon
Instruments Inc.). To activate F508del, 10 pM forskolin and 20 pM genistein were
added to the bath and the current-voltage relation was monitored every 30 sec.
5A-A3. Identification of -CFTR modulators
The ability of F508del-CFTR modulators to increase the macroscopic F508del CF
current (Esnsdci) in NIH3T3 cells stably expressing F508del was also investigated using
perforated-patch-recording ques. Modulators identified from the optical assays
SUBSTITUTE SHEET (RULE 26)
evoked a dose-dependent increase in IAfsos with similar potency and efficacy ed
in the l assays.
Cell e
NIH3T3 mouse fibroblasts stably expressing F508del are used for whole-cell
ings. The cells are maintained at 37 °C in 5% CO2 and 90 % ty in
Dulbecco’s modified Eagle’s medium supplemented with 2 mM glutamine, 10 % fetal
bovine serum, 1 X NEAA, [1-ME. 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture
flasks. For whole-cell recordings, 2,500 - 5,000 cells were seeded on -lysinecoated
glass coverslips and cultured for 18 - 24 hrs in the presence or absence of
tors 37 °C.
Single-channel recordings
Gating activity of F508del-CFTR expressed in NIH3T3 cells following
modulator treatment was observed using excised inside-out membrane patch recordings
as previously described (Dalemans, W., Barbry , P., Champigny, G., Jallat, S., Dott, K.,
Dreyer, D., Crystal, R.G., Pavirani, A., Lecocq, J-P., Lazdunski, M. (1991) Nature 354,
526 - 528) using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc ).
The pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5 CaCl2, 2 MgCl2, and
HEPES (pH adjusted to 7 35 with Tris base). The bath contained (in mM): 150
NMDG-C1, 2 MgCl2, 5 EGTA, 10 TES, and 14 Tris base (pH adjusted to 7.35 with
HC1). After excision, both wt- and l were activated by adding 1 mM Mg-ATP,
75 nM of the catalytic subunit of ependent protein kinase (PKA; Promega
Corp. Madison, WI), and 10 mMNaF to inhibit protein phosphatases, which prevented
current rundown. The pipette potential was maintained at 80 mV. Channel activity
was analyzed from membrane patches containing < 2 active channels. The maximum
number of simultaneous openings determined the number of active channels during the
course of an experiment. To determine the single-channel current amplitude, the data
ed from 120 sec of F508del activity was filtered “off-line” at 100 Hz and then
used to construct mt amplitude histograms that were fitted with multigaussian
functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total
microscopic current and open probability (P0) were ined from 120 sec of channel
activity. The P0 was determined using the Bio-Patch software or from the relationship
SUBSTITUTE SHEET (RULE 26)
P0 = I/i(N), where I = mean current, i = single-channel current amplitude, and N =
number of active channels in patch.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing F508del are used for excised-
membrane patch-clamp recordings. The cells are maintained at 37 °C in 5% CO2 and 90
% humidity in Dulbecco’s modified Eagle’s medium supplemented with 2 mM
ine, 10 % fetal bovine serum, 1 XNEAA, [3-ME, 1 X pen/strep, and 25 mM
HEPES in 175 cm2 culture flasks. For single channel recordings, 2,500 - 5,000 cells
were seeded on poly-L-lysine-coated glass lips and cultured for 18 - 24 hrs in the
ce or absence of modulators at 37 °C.
5B. Chromatographic determination of Human Serum Albumin (HSA)
Assay
Chromatographic determination of Human Serum Albumin (HSA) values
was performed on aUPLC-MS system using a Pak® HSA column (p/n:
58469AST) from Sigma Aldrich. Mobile phase A consisted of 50 mM ammonium
acetate buffer in water adjusted to pH=7.4, and mobile phase B was 2-propanol. The
column compartment was kept at constant temperature of 30°C. ination of
retention time on the HSA column was performed by injecting 3 mL of 0.5 mM of
compound (in DMSO) using a linear gradient from 0% - 30% B in 2.5 minutes,
followed by a hold at 30 %B for 2 minutes, and the final equilibration step from 30% -
0% B in 1.5 minutes, for a total run time of 6 minutes. Flow rate was kept constant
throughout the gradient and set to 1.8 mL/min. Compound retention time on the HSA
column was converted to %HS A values according to a previously published protocol
(Valko, et. al, 2003) correlating column retention times to standard plasma protein
binding (PPB) values obtained from is experiments. HSA data for certain
compounds are summarized below in Table 8 below.
Valko, K., Nunhuck, S., Bevan, C., Abraham, M. H., Reynolds, D. P. Fast
Gradient HPLC Method to Determine Compounds Binding to Human Semm Albumin.
onships with Octanol Water and Immobilized Artificial Membrane Lipophilicity.
./. m. Sci. 2, 2236-2248.
] 5C. Experimental Protocol for Rat IV and PO PK studies
SUBSTITUTE SHEET (RULE 26)
The tested compound was administered to male Sprague-Dawley rats as a
single nominal intravenous dose of 3.0 mg/kg as a solution in 10% NMP, 10% solutol,
% EtOH, 35% PEG400 and 30% D5W. The tested nd was also administered
to male Sprague-Dawley rats at single nominal oral dose of 3 mg/kg as a solution in
% NMP, 30% PEG400, 10% TPGS, 5% PVP-K30 at 5 mL/kg dose volume. es
of plasma and dose preparations were performed using LC/MS/MS.
Plasma concentration-time profiles of the tested compound in Sprague-
Dawley rats at scheduled (nominal) sampling times were analyzed by
noncompartmental pharmacokinetic methods using PK function within Watson LIMS
re, Version 7.4.2 (Thermo Scientific Inc, m, MA). AUC values were
calculated using the linear trapezoidal rule.
5D. Experimental Protocol for PXR assay
The propensity for PXR mediated CYP3A4 induction is assessed using the
DPX-2 cell line in vitro. This cell line, which has been licensed from Puracyp Inc. was
derived from HepG2 cells and has been stably transfected with genes ng human
PXR as well as a modified luciferase reporter linked to the CYP3A4 promoter region
and related distal and al enhancers.
The assay is run in 384 well format and each test article is administered in 11
doses ranging from 0.1 to 60 gM. On day 1, DPX-2 cells which have previously been
expanded in-house and cryopreserved are thawed and seeded in tissue culture plates.
The following day, media is changed and cells are cultured in media containing test
e, vehicle control or the positive control compound, the clinically ted
CYP3A4 inducer rifampicin. Cells are cultured in the presence of test article for 48
hours and then cell viability is assessed using fluorescence based assay (Cell Titer-
Fluor, Promega) with an EnVision Plate Reader (PerkinElmer). Subsequently, CYP3A4
transactivation, which is proportional to luciferase activity, is measured by g
luminescense using the Promega One-Glo reagent system using the same plate reader.
Data processing within the Genedata software package allows reporting of
max fold induction ed to vehicle control, an EC5o value for CYP3 A4 rs
and an 11 point-dose response curve. Wells with cell viability less than 70% are not
used for the analysis and plates where the rifampicin positive control se falls
outside of the expected range, either in y or max fold induction, are not reported.
SUBSTITUTE SHEET (RULE 26)
] 5E. CFTR Data of Compounds 1-65
] The compounds of formula (I) are useful as modulators of CFTR activity.
The Table 6 below illustrates the EC50 of the compounds of Table 6 using procedures
described above (assay described above in Example 5A-A1). In Table 6 below, the
following meanings apply. EC50: “+++” means < 0.1 uM; “++” means between 0.1
uM and 1 uM; “+” means greater than 1 uM.
Table 6. CFTR Activity
Comp. No. CFTRdF508 EC50 ]uM)
1 +++
2 ++
3 +++
4 +++
+++
6 NAa
7 NAa
8 +++
9 ++
+++
11 ++
12 +++
13 ++
14 +++
+++
16 +++
17 +++
18 ++
19 ++
++
21 +++
22 ++
23 +++
24 +++
+++
26 +
27 ++
28 +++
29 ++
+++
31 +++
SUBSTITUTE SHEET (RULE 26)
Comp. No. CFTRdF508 EC50 (uM)
32 +++
33 +++
34 +++
+++
36 +++
37 +++
38 ++
39 +++
40 +++
41 +++
42 +++
43 +++
44 ++
45 ++
46 ++
47 +++
48 +
49 +++
50 +++
51 +++
52 ++
53 +++
54 +++
55 +++
56 ++
57 +++
58 +++
59 +++
60 ++
61 NAa
62 +
63 ++
64 +++
65 +
a.: notmeasurec
] 5F. Metabolites
It has been determined that Compound 1 is metabolized both in vitro and in
vivo, mostly by oxidative metabolism. nd 1 and the metabolites shown in the
following table were prepared and tested.
Table?. Data for Metabolites
Metabolite CFTRdF508 Dculernled nnnlo« of
EC50 (llM) metabolite
SUBSTITUTE SHEET (RULE 26)
Mef.nholifo CFTRdF508 Deulci'nlcd nl
EC50 (uM) metabolite
Compound 1 (Parent 0.03 Compound 17
Compound)
V-Y;Xub._J XiH
(jP+h”
Compound 38 0.24 Compound 7
9 o. o A
N'-3'
v 9 9
•hrHO o fjyy. a.
n,° ‘V M
Compound 62 >30
Compound 31
vW°° o
N-\ ^ OH
Compound 34
L H I
•k' °iJJJ.. Vn^Vl
5G. lfoxamides. Compounds comprising an acylsulfoxamide moiety
(i.e., sulfonimidoylamide moiety - wherein X in Formulae I or II is chosen from
SUBSTITUTE SHEET (RULE 26)
substituted or unsubstitued amines) were determined to result in decreased human
serum albumin binding and enhanced free fraction as compared to compounds
comprising an acylsulfonamide group (i.e., wherein X in Formulae I or II is chosen
from 0). The HAS data were measured as described above in Example 5B. Decreased
human serum albumin g may result in a higher amount of free (unbound) drug
which can affect biological activity.
Tables. HSAData
Ae\lsiiironamide MSA Siilfbviiiiine HSA
ng binding
99.1% VY 98.1%
Compound 15 '~N
_>.jCcCq0 o 0 0 /Ss,
fyk'-aH.ll r o'-y)
0 F'A
ereomeric mixture:
Compound 45))_______
97.9%
o y /•=»,
fVs--N 'o"Yl
W o F-/
(diastereoisomer 1:
Compound 46)
XX 98.4%
o A*.
A'S':N
W o Ft(
(diastereoisomer 2:
nd 47)
Table 8 below summarizes CFTR activity (CFTR dF508 EC50), PXR Max
induction. Rat IV clearance, Rat PO AUC, and Rat PO data for certain nds
described above.
Table 9. Comparative Data
SUBSTITUTE SHEET (RULE 26)
Cnmp nds Cl IK P\K Max Kill i\ Knt po Rat
(Hind dl'508 I ml n d ion Cl. \l ( po
No. l'. ('50 I'1.) of (mL IMS?- %F
(ii\li riliimpicinl min.' hi ml. in
ku) 3 mu
dose1
Comp. 0.06 2 17.8 1.2a 28%
A 0 o 0 NHi
Comp. 0.12 9 29.2
B 0 00
Comp. 0.26 3
C 0 00 0
I I II
H /)
Comp. 0.4 20
D 0q p w.
!l V^'A1
Comp. 0.21 10
E Jo.,o
oJ-MV/)
SUBSTITUTE SHEET (RULE 26)
Cnmp Compounds Cl IK P\K Max Kill i\ Knt po Rat
(Hind dl'508 I ml n d ion Cl. \l ( po
No. l'. ('50 I'1.) of (mL IMS?- %F
(ii\li picinl min.' hi ml. in
ku) 3 mu
dose1
Comp. o 0.02 19
49 vO
FX/'°
Comp. 0.02 4
4 0 0.
(Y'wr
IX/■—-/ '^4
f A-1
Comp. 0.02 0
0 00
vi o7'N « N' /?
Comp. 0.02 2 24.8 0.25 12%
16 0 00
Yf “TV
Comp. 0.03 3 1.6 21 63%
1 0 00
F LX
FI rv
F I H ks
Comp. 0.03 32
50 0 00
SUBSTITUTE SHEET (RULE 26)
WO 64632
Cnmp Compounds Cl IK P\K Max Kill i\ Knt po Rat
(Hind dl'508 I ml n d ion Cl. \l ( po
No. l'. ('50 I'1.) of (mL IMS?- %F
(ii\li riliimpicinl min.' hi ml. in
ku) 3 mu
dose1
Comp. 0.03 22 2.7 12.5 69%
F c®
Comp. 0.03 17
Comp. 0.03 7
31 o 0.0
F •aOXO.
Comp. o 0 0 0.04 19 2.0 14.7 58%
v-erft-jctfo
Comp. n 0.04 39 2.3 13.7 98%
(rtCQ,o a 53
/yVV'eu
yn —j'-j
Comp. 0.04 6 11.2 2.2 41%
?0. .0
Comp. 0.04 4
32 H1J:s y
Fktfp
SUBSTITUTE SHEET (RULE 26)
WO 64632
Cnmp Compounds Cl IK P\K Max Kill i\ Knt po Rat
(Hind dl'508 I ml n d ion Cl. \l ( po
No. l'. ('50 I'1.) of (mL IMS?- %F
(ii\li riliimpicinl min.' hi ml. in
ku) 3 mu
dose1
Comp. 0.05 17 5.2 10.5 100
51 -krtvo ooi! •«" %
Comp. 0.05 22
55 ? 'i.JJ
tfc&rI li H °
Comp. 0.05 0 9.6 2.7 50%
A.liWF
0-// H
/"J W
Comp. 0.05 4
58 ? o. .0
Comp. 0.05 4 3.4 9b 79%
nY //
Comp. 0.05 12
43 w0 o 0 Cl
)Hr H
Comp. vs 0.05 3 5.4 4.4b 51%
42 0 00
^Arr^
SUBSTITUTE SHEET (RULE 26)
Cnmp Compounds Cl IK P\K Max Kill i\ Knt po Rat
(Hind dl'508 I ml n d ion Cl. \l ( po
No. l'. ('50 I'1.) of (mL IMS?- %F
(ii\li riliimpicinl min.' hi ml. in
ku) 3 mu
dose1
Comp. 0.07 6 1.9 6.4 41%
41 ooo
Comp. 0.07 9 2.6 20 98%
24 »°-P
Comp. 0.07 8
37 ?0..0
F o^W
Comp. 0.07 13
39 ?0.,0
Comp. 0.09 0 6.1 2.3 26%
9o..o
. o. n is ^:s:
Comp. 0.08 2
/y %
0. />
1 'O’
F [-1
SUBSTITUTE SHEET (RULE 26)
Cnmp Compounds Cl IK P\K Max Kill i\ Knt po Rat
(Hind dl'508 I ml n d ion Cl. \l ( po
No. l'. ('50 I'1.) of (mL IMS?- %F
(ii\li riliimpicinl min.' hi ml. in
ku) 3 mu
dose1
i 0.11 2
Comp. ?0 0
Comp. 0.08 0
33 JLs:»°- 0
Comp. 0.08 2
40 °0..°
r JL:s:
Comp. 0.27 8 3.6 20.3 100
27 %
Comp. ft 0.62 18 5.0 8.5 81%
44 vM V
^■N ft
Comp. 0.12 4 6.7 3.6 31%
22 000
a: 10 mg/kg for Compound A, and for the other compounds at 3 mg/kg.
Example 6: Chloride Transport ments
SUBSTITUTE SHEET (RULE 26)
In one Ussing Chamber experiment with F508del/F508del-HBE cells.
nd 1 enhanced chloride transport. The effect of Compound 1 on chloride
transport was additive to the effect of Compound IF In addition, F508del-CFTR
delivered to the cell surface by either Compound 1 alone or in combination with
Compound II was potentiated by Compound III. The triple combination of Compound 1
/ Compound II / Compound III provided a superior (approximately 3-fold) increase in
chloride transport compared to the 3 dual ns under most conditions tested.
Example 7: F508del-CFTR Processing and Trafficking In Vitro
Experiments
In vitro, Compound 1 improved the processing and trafficking of
F508del-CFTR, thereby increasing the quantity of functional F508del-CFTR protein at
the cell surface. The CFTR protein delivered to the cell surface by Compound 1 alone or
in combination with Compound II (Compound 1 / Compound II) was iated by
Compound III. In human bronchial epithelial (HBE) cells studied in vitro, the triple
combination of Compound 1, nd II, and Compound III (Compound 1 /
Compound II / Compound III) increased CFTR de transport more than any of the
dual combinations und 1 / nd II, Compound 1 / Compound III, and
Compound II / Compound III) or individual components (Compound 1, Compound II,
and nd III) under most conditions studied.
Processing and cking of F508del-CFTR was directly monitored by the
appearance of a 170 to 180 kDa band Such monitoring established that Compound 1 is a
CFTR corrector, as it facilitates the processing and trafficking of F508del-CFTR to
increase the amount of onal F508del-CFTR at the cell surface.
Incubation of F508del/F508del-HBE cells for 16 to 24 hours with 1 pIYI
Compound 1 alone or in combination with 3 pM Compound II resulted in an increase in
-state levels, reaching 6.5-fold and 18.7-fold of ted levels, respectively.
Other Embodiments
The foregoing discussion discloses and describes merely exemplary
embodiments of this disclosure. One skilled in the art will readily recognize from such
discussion and from the accompanying drawings and claims, that s changes,
modifications and variations can be made therein without departing from the spirit and
SUBSTITUTE SHEET (RULE 26)
scope of this disclosure as defined in the following claims.
SUBSTITUTE SHEET (RULE 26)
Claims (11)
1. A compound of Formula I: 0 o x vi^V^N^ H X(R2)p / N Y N R1 -r (R3), (R4), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - one of Y1 and Y2 is N and the other is CH; - X is chosen from 0, NH, and N(Ci-C4 alkyl) groups; - R1 is chosen from k(CR2)m(CR)n(Ring A)n+i groups, wherein each Ring A is independently chosen from C3-C10 lkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens, wherein each R is ndently chosen from H, OH, and C1-C2 alkyl groups optionally substituted with one or more halogens; - each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups, ns, and cyano; - each R3 is independently chosen from C1-C2 alkyl groups optionally substituted with one or more OH groups; - each R4 is independently chosen from halogens; - k is 0 or 1; - ris 0 or 1; - mis 0,1, 2, or 3; - n is 0 or 1; - p is 0, 1, 2, 3, 4, or 5; and - qis 0, 1, 2, 3, 4, 5, 6, 7, or 8. SUBSTITUTE SHEET (RULE 26)
2. A compound of Formula II: 0 O X H X(R2)p '/' N N N (R3)q (II), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - X is chosen from 0, NH, and N(Ci-C4 alkyl) groups; - R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups, wherein each Ring A is ndently chosen from C3-C10 cycloalky] groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl , and halogens, wherein each R is independently chosen from H, OH, and C1-C2 alkyl groups optionally tuted with one or more halogens; - each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups, halogens, and cyano; - each R3 is independently chosen from C1-C2 alkyl groups optionally substituted with one or more OH groups; - each R4 is independently chosen from halogens; - k is 0 or 1; - ris 0 or 1; - mis 0,1, 2, or 3; - n is 0 or 1; - p is 0, 1, 2, 3, 4, or 5; and - qis 0, 1, 2, 3, 4, 5, 6, 7, or 8. SUBSTITUTE SHEET (RULE 26)
3. A compound of Formula III: 0 o. o V(r2)p / N N N / \R3)q (R4)r (ni), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the ing, wherein: - R1 is chosen from -(CR2)k(CR2)m(CR)n(Ring A)n+i groups, wherein each Ring A is independently chosen from C3-C10 cycloalky l groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl , halogenated C1-C2 alkyl groups, and halogens, wherein each R is independently chosen from H, OH, and C1-C2 alkyl groups optionally substituted with one or more halogens; - each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups, halogens, and cyano; - each R is independently chosen from C1-C2 alkyl groups ally substituted with one or more OH groups; - each R4 is independently chosen from halogens; - k is 0 or 1; - ris 0 or 1; - mis 0,1, 2, or 3; - n is 0 or 1; - p is 0, 1, 2, 3, 4, or 5; and - qis 0, 1, 2, 3, 4, 5, 6, 7, or 8. SUBSTITUTE SHEET (RULE 26)
4. A compound according to any of claims 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the ing, wherein if R2 is cyano, then said R2 is meta or para relative to the sulfur atom.
5. A compound according to any of claims 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - each Ring A is independently chosen from C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens, and - each R is independently chosen from H and OH; - each R2 is independently chosen from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups, and halogens; - R4 is F; - kis 0; - p is 0, 1, or 2; - qis 0, 1, 2, 3, or 4; - r is 0; and n m and n are not 0 at the same time.
6. A compound according to claim 5, a pharmaceutically acceptable salt thereof, or a ated tive of any of the foregoing, wherein: - R1 is chosen from 2)m-Ring A groups, wherein Ring A is chosen from C3-C10 cycloalkyl groups groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens, - m is 1 or 2.
7. A compound ing to claim 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R3 is a methyl group and q is 3 or 4. SUBSTITUTE SHEET (RULE 26)
8. A compound according to claim 7 having Formula FV: 0 °n P ¥ H X(R2)p Ring AJrk ' N N N (IV), a pharmaceutically able salt thereof, or a deuterated derivative of any of the - Ring A is chosen from C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from Ci-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; and - each R2 is independently chosen from C1-C2 alkyl groups, OH, F, Cl, and Ci- C2 alkoxy groups; - m is 1 or 2; and - p is 0, 1, or 2.
9. A compound according to claim 8, wherein p is 0 or 1.
10. A compound according to claim 8, wherein p is 0.
11. A compound according to claim 8 having Formula V: O O. pY ' N N l
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/402,838 | 2016-09-30 | ||
| US62/410,353 | 2016-10-19 | ||
| US62/415,409 | 2016-10-31 | ||
| US62/419,935 | 2016-11-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ792410A true NZ792410A (en) | 2022-09-30 |
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